„tuberkulozis sensitiur da rezistentul formebTan sisxlis jgufuri ...

1

baTumis SoTa rusTavelis saxelmwifo universiteti

ganaTlebis da mecnierebaTa fakulteti

biologiis departamenti

sofiko cqvitiniZe

„tuberkulozis sensitiur da rezistentul formebTan

sisxlis jgufuri antigenebis (ABO; Rh-Hr; MN; Kell)

asocirebis da daavadebulTa humoruli imunuri statusis

Seswavla saqarTveloSi mcxovreb eTnikur populaciebSi“

biologiis doqtoris akademiuri xarisxis mosapoveblad

warmodgenili disertacia

specialobiT - adamianis populaciebis genetika

xelmZRvanelebi: prof. r. xuxunaiSvili

prof. k. vaWaraZe

baTumi

2013

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S i n a a r s i

Sesavali ----------------------------------------------------------------------------------------------------- 4

terminTa ganmarteba------------------------------------------------------------------------------------ 10

Tavi I. literaturuli mimoxilva ------------------------------------------------------------- 12

I.1. tuberkulozis epidemiologia, misi kontrolisa da prevenciis

Tanamedrove strategiebi ---------------------------------------------------------------------------- 12

I.2. tuberkulozis epidemiologia saqarTveloSi ------------------------------ 17

I.3. tuberkulozis gamomwvevi - Mycobacterium tuberculosis ------------------------- 21

I.3.1. mikobaqteriis rezistentobis ganmapirobebeli faqtorebi------------ 24

I.4. rezistentuli tuberkulozis globaluri epidemiologia da

etiologia ---------------------------------------------------------------------------------------------------------- 26

1.5. multifaqtoruli daavadebebi da populaciebis genetikuri

polimorfizmi ---------------------------------------------------------------------------- 28

I.5.1 eriTrocituri jgufuri antigenebi da maTi asociaciuri kavSirebi

sxvadasxva tipis paTologiebTan ---------------------------------------------------------- 32

I.6. organizmis imunuri dacvis meqanizmebi mikobaqteriis mimarT

ganviTarebul imunur pasuxSi -------------------------------------------------------------- 44

I.7. tuberkulozi da M. tuberculosis mimarT organizmis mgrZnobelobaSi

monawile genebi ------------------------------------------------------------------------------- 53

Tavi II. kvlevis masala da meTodebi--------------------------------------------- 62

II.1. kvlevis masala ------------------------------------------------------------------ 62

II.2. kvlevis meTodebi --------------------------------------------------------------- 63

II.2.1. imunoserologiuri meTodebi --------------------------------------------- 63

II.2.2. biostatistikuri analizis meTodebi ----------------------------------- 64

II.2.3. kvlevis molekulur-bioqimiuri meTodebi-------------------------------- 66

II.2.4. imunologiuri analizis meTodebi ----------------------------------------- 43

Tavi III. Kkvlevis Sedegebi ------------------------------------------------------------------------ 77

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III.1. filtvis tuberkulozis sensitiuri da wamalrezistentuli

formebs asocireba АВ0, Rh-Hr, Kell, MN sistemis eriTrocitur jgufur

antigenebTan qarTul populaciaSi ------------------------------------------------------------ 77

III.1.1. sensitiuri da wamalrezistentuli tuberkulozis asocireba

eriTrocituri jgufuri sistemebis (ABO, Rh, MN) alelebTan saqarTveloSi

mcxovreb azerbaijanul populaciaSi-------------------------------------------------------------- 98

III.1.2. eriTrocituri ABO (r,p,q), Rh-Hr (RhD+,RhD-) da MN (p,q) jgufuri

sistemis alelTa gavrcelebis SedarebiTi analizi tuberkuloziT

daavadebul qarTul da azerbaijanul populaciebSi --------------------------- 105

III. 2. IgM, IgG da IgA done filtvis tuberkuloziT daavadebul

populaciaSi ----------------------------------------------------------------------------------------------------- 109

III.3. SLC11A1 genis D543N lokusis polimorfizmis Seswavla filtvis

tuberkulozis wamalrezistentuli da sensitiuri formebiT daavadebul

pacientebSi -------------------------------------------------------------------------------------------------------- 121

daskvnebi ---------------------------------------------------------------------------------------------------- 129

gamoyenebuli literatura ----------------------------------------------------------------------- 131

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Sesavali

tuberkulozi Mycobacterium tuberculosis-is paTogenuri agentiT gamowveuli

infeqciuri daavadebaa, romelic uZvelesi droidan moyolebuli dRemde

sazogadoebis janmrTelobis seriozul problemas warmoadgens. M.

tuberculosis infeqciuri agenti msoflioSi yovelwliurad 2-3 mln adamianis

sikvdilis mizezi xdeba, xolo msoflio mosaxleobis 1/3 inficirebulia

aRniSnuli paTogeniT da daavadebis klinikuri ganviTarebis mudmivi

safrTxis winaSe dgas. tuberkulozi gansakuTrebiT mwvave problemas

warmoadgens ganviTarebad qveynebSi. daavadebis SemTxvevebis 95%

aRmosavleT aziis, afrikis, laTinuri amerikis da aRmosavleT evropis

qveynebze modis, maT Soris sakmaod mniSvnelovani sixSiriT _ postsabWoTa

sivrceze, sadac mosaxleobis 55% infeqciuri agentis matarebelia. bolo

wlebSi daavadebis SemTxvevaTa matebis tendencia gamovlinda iseT

ganviTarebul qveynebSi, rogoricaa aSS, dasavleT evropisa da skandinaviis

qveynebi.

tuberkulozis problema mwvaved dgas saqarTveloSic. janmrTelobis

msoflio organizaciis monacemebiT, saqarTvelo 27-e adgilzea im

qveynebs Soris, sadac daavadebis maRali prevalentoba fiqsirdeba. Tumca,

ukanaskneli 10 wlis monacemebiT, tuberkulozis aRniSnuli maCvenebeli

met-naklebad stabiluria antituberkulozuri programebis moqmedebis

Sedegad. magram, sagangaSo mdgomareobas qmnis wamlis mimarT rezistentuli

tuberkulozis SemTxvevebis zrda. situacias kidev ufro amZimebs pirveladi

rezistentobis axal SemTxvevaTa maRali maCvenebeli.

tuberkulozi multifaqtorul daavadebaTa (mfd) ricxvs miekuTvneba. M.

Tuberculosis CxiriT inficirebis SemTxvevaSi daavadebis klinikur

ganviTarebaze mravali faqtori moqmedebs, romelTagan aRsaniSnavia:

ekonomikuri mdgomareoba (cxovrebis done), individis mgrZnobeloba

infeqciisadmi, asaki, kvebis racioni, koinfeqciebis arseboba, emociuri da

fizikuri stresi, samedicino momsaxurebis done da xelmisawvdomoba,

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higienuri pirobebi, SesaZloa, individis sqesic da aS. Tumca, xSiria

SemTxvevebi, roca adamianebi inficirdebian, magram ar avaddebian zemoT

CamoTvlili faqtorebis arsebobis SemTxvevaSic ki. am mosazrebas isic

adasturebs, rom daavadeba klinikuri saxiT tuberkulozis CxiriT

inficirebulTa 10%-Si viTardeba, xolo 90% infeqciis matareblad rCeba

mTeli sicocxlis manZilze. bolo periodis mecnieruli kvlevebis Tanaxmad

(Ryu et al., 2000; Remus et al., 2004; Deglado et al., 2002; Li et at al., 2006; Takahashia et al.,

2008; Tamaria et al., 2010; Tyagi et al., 2010), tuberkulozis klinikur ganviTarebaSi

garemo faqtorebTan erTad arsebiT rols asrulebs individis genetikuri

konstitucia, romelic gansazRvravs daavadebisadmi sensibilobas an misdami

organizmis mdgradobas.

yovel cocxal organizms gaaCnia Tavisi individualuri genotipi,

romelic konkretulad misTvis damaxasiaTebel genTa nakrebs Seicavs.

genomSi arsebuli calkeuli geni an genTa jgufi pasuxismgebelia

organizmis gansazRvrul niSan-Tvisebaze. maT Soris aris genebi, romlebic

daavadebaTa mimarT organizmis sensibilobas an mdgradobas gansazRvravs.

aRniSnul genebSi momxdari, Tundac, erTnukleotidiani cvlileba

genetikur polimorfizms ganapirobebs da paTogenuri agentebis mimarT

organizmis gansxvavebuli mgrZnobelobis safuZvels warmoadgens. amasTan,

multifaqtoruli daavadebebis didi nawili eTnospecifikuri

winaswarganpirobebulobiT xasiaTdeba. Cveulebriv, adamianTa eTnikuri

jgufebi genTa SemadgenlobiT Wrelia, rac daavadebebis gamovlenis

sixSiriT da maTi ganmapirobebeli faqtorebis variabelobiT gamoixateba.

fiqsirdeba daavadebaTa sensibilizaciis gansxvavebuli maCveneblebi,

Tundac, erTi da igive teritoriaze mcxovreb eTnikur populaciebSi.

swored amitom, populaciur doneze, xSirad, daavadebaTa mimarT

gansxvavebuli midrekileba ikveTeba. aris populaciebi, romlebic advilad

eqvemdebarebian romelime konkretul daavadebas, maSin, roca sxvebi am

daavadebis mimarT bunebrivi mdgradobiT gamorCevian.

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adamianTa eTnoteritoriuli jgufebis formireba Sesabamis saarsebo

garemo piobebTan urTierTobaSi xangrZlivi evoluciuri procesis Sedegia

da maTi genofondis Tanamedrove struqtura istoriuli ganviTarebis

sxvadasxva etapze Camoyalibda. am procesebis safuZvelze eTnikur

populaciebSi, erTi mxriv, adgili aqvs mfd-is genuri lokusebis

cvalebadobis farTo diapazonis Camoyalibebas, meore mxriv ki, im

haplotipebis struqturul unikalobas, sadac esa Tu is konkretuli genia

lokalizebuli. aqedan gamomdinare, gansxvavebul eTnosebSi mfd-is genebi

imyofeba gansxvavebul alelur mdgomareobasa da garemocvaSi, rac

gavlenas axdens konkretuli genis fenotipur gamovlenaze da xSir

SemTxvevaSi gansazRvravs daavadebis mimarT winaswarganpirobebulobas.

kvlevebiT gamovlenili iqna, rom eTnosebis garkveuli nawili metad

sensibiluria tuberkuloziT daavadebis mimarT, maSin, roca sxvebs

Camoyalibebuli aqvT e.w. „populaciuri imuniteti“, rasac im alelebis

evoluciuri gacxrilvis procesiT xsnian, romlebTanac mkacradaa

asocirebuli Sesabamisi daavadebebi.

daavadebebis winaswarganpirobebulobaSi CarTuli genebis kvleva

warmoebs, rogorc uSualod genis struqturis SeswavliT, aseve mis mier

myarad determinirebuli fenotipuri niSnebiT. eriTrocituri jgufuri

antigenebi aseT fenotipur niSans warmoadgens. aRniSnuli antigenebiT

determinirebuli gansxvavebuli fenotipuri jgufebi da, Sesabamisad, maTi

imunogenetikuri lokusebi gansxvavebulad arian midrekilni ama Tu im

daavadebis ganviTarebisken, rogorc individis, ise eTnikuri jgufebis

doneze. eriTrocituri jgufuri sistemebis antigenebisa Tu haplotipebis

kvlevisas xSirad vlindeba maTi korelacia sxvadasxva infeqciur Tu

arainfeqciur daavadebasTan.

infeqciuri daavadebis mimdinareobisas aqtiuradaa CarTuli organizmis

imunuri sistema. tuberkulozis sxvadasxva klinikuri formis dros,

namkurnalev Tu pirvelad pacientebSi, samkurnalwamlo preparatebis

mimarT sensitiur da rezistentul formebSi organizmis imunuri sistema

gansxvavebulad reagirebs ujreduli an humoruli imunuri meqanizmebiT.

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Sesabamisad, organizmis imunuri statusi gansxvavebulia. informacia

organizmis imunuri statusis Sesaxeb genetikur faqtorebTan erTad srul

suraTs iZleva daavadebis riskis Sefasebisa da drouli prevenciuli

RonisZiebebis gatarebisTvis.

infeqciuri daavadebis ganviTarebaze pasuxismgebeli genebis umetesi

nawili CarTulia organizmis imunuri dacvis meqanizmebSi. dReisaTvis

Seswavlilia tuberkulozisadmi winaswarganpirobebulobis mravali geni

(SLC11A1, TLR, HLA, TNF-α, VDR, IL10, TGFβ, TGFβ da a.S.) da maTi polimorfuli

variaciebis asociaciuri kavSirebi tuberkulozis mimarT mosalodnelobasa

da daavadebisadmi mdgradobasTan. dawyebulia rezistentuli tuberkulozis

genetikuri aspeqtebis kvleva. arsebul monacemebze dayrdnobiT, ikveTeba

adamianis organizmis genetikuri struqturis mniSvneloba wamlis mimarT

rezistentuli tuberkulozisadmi organizmis midrekilebasa Tu

mdgradobasTan mimarTebaSi.

Temis aqtualoba. tuberkulozis gavrcelebis maRali maCvenebeli

saqarTveloSi daavadebis kontrolis da prevenciis efeqturi RonisZiebebis

gatarebis aucileblobas ganapirobebs. es SesaZlebelia, miRweul iqnes,

erTi mxriv, daavadebis klinikuri marTvis meTodebis srulyofiT, meore

mxriv, profilaqtikuri RonisZiebebis SemuSavebiT. daavadebisadmi

midrekili „maRali riskis“ jgufebis gamoyofa SemdgomSi maT mimarT

prevenciuli zomebis SemuSavebis safuZvels warmoadgens.

Tanamedrove genetikisa da genomikis ganviTarebasTan erTad gaizarda

paTogenuri procesebis marTvis SesaZlebloba. eriTrocituri jgufuri

antigenebis, rogorc genetikurad myari niSnis Seswavla, tuberkuloziT

daavadebulebSi jansaR donorebTan mimarTebaSi, SesaZlebels xdis,

gamoiyos daavadebisadmi midrekili risk-jgufebi da maT mimarT

ganxorcieldes profilaqtikuri RonisZiebebi. tuberkulozTan

asocirebuli genebis (maT Soris eTnospecifikuri) da maTi polimorfuli

variaciebis gamovlena, agreTve, recipientis imunuri reaqciis Seswavla

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tuberkulozis diagnostikis axali meTodebis Ziebis da vaqcinaciis axali

midgomebis SemuSavebis saSualebas iZleva.

aRniSnul monacemebze dayrdnobiT, SesaZlebelia eTnikuri jgufis Tu

organizmis daaavadebis mimarT sensibilobis an mdgradobis winaswari

prognozireba, rac, saboloo jamSi, daavadebis ukeT kontrolis

ganxorcielebis saSualebas iZleva.

saqarTveloSi mcxovrebi eTnikuri populaciebi am mimarTebiT dRemde

ar iyo Seswavlili.

kvlevis mizani. zemoT aRniSnulidan gamomdinare, kvlevis mizans

warmoadgenda:

filtvis tuberkuloziT daavadebul pacientebSi genetikurad

determinirebuli faqtorebis _ eriTrocituri jgufuri antigenebis

gavrcelebis Taviseburebebis Seswavla da maTTan daavadebis SesaZlo

asociaciuri kavSirebis gamovlena;

eriTrocituri jufuri antigenebis mixedviT tuberkulozisadmi

mgrZnobiare fenotipebisa da alelebis gamoyofa da daavadebisadmi

midrekili maRali risk-jgufebis gamovlena saqarTveloSi mcxovreb

eTnikur (qarTuli, azerbaijanuli) populaciebSi;

organizmSi tuberkulozis infeqciuri agentisadmi ganviTarebuli

humoruli imunuri pasuxis Seswavla antituberkulinuri specifikuri Tu

saerTo antisxeulebis donis gamovlenis safuZvelze daavadebis sxvadasxva

klinikuri formis dros;

SLC11A1 genis D543N lokusis polimorfizmis Seswavla filtvis

tuberkulozis sensitiuri da rezistentuli formiT daavadebul qarTul

populaciaSi.

kvlevis amocanebi:

eriTrocituri jgufuri sistemebis (ABO, Rh, Kell, MN) antigenebis,

fenotipebis, maTi ganmsazRvreli alelebis da haplotipebis gavrcelebis

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Taviseburebebis Seswavla filtvis tuberkulozis sensitiur da wamlis

mimarT rezistentul formebSi;

eriTrocituri jgufuri sistemebis korelaciuri kavSiris

gamovlena filtvis tuberkulozTan da daavadebis mimarT maRali risk-

jgufebis gamoyofa daavadebul qarTul da azerbaijanul populaciaSi;

antituberkulinuri imunoglobulinebis jamuri da

imunoglobulinebis (IgA+G+M) saerTo donis SeswavliT daavadebulTa

humoruli imunuri statusis Sefaseba pirvelad da namkurnalev pacientebSi,

filtvis tuberkulozis sensitiuri, rezistentuli da gansxvavebuli

simZimis klinikuri (infiltraciuli, kerovani, fibro-kavernozuli)

formebis dros;

infeqciuri daavadebis mimarT organizmis bunebriv rezisten-

tobasTan asocirebuli makrofaguli NRAMP1 cilis makodirebeli SLC11A1

genis D543N lokusis polimorfizmis Seswavla filtvis tuberkulozis

sensitiur da rezistentul formebSi.

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terminTa ganmarteba

mfd – multifaqtoruli daavadebebi

ftb – filtvis tuberkulozi

BCG- (Bacilli Camlet_Guerine) kamlet-guerinis vaqcina

CFU – (Colony Forming Unit) – kolonia-warmomqmneli erTeuli

DOTS – (Directly observed treatment, short course) meTvalyureobis qveS

E - eTanbutoli

GWAS - Genome-wide Association Study- genomis masStabis asosiaciuri kvleva

HLA- (Human Leukocyte Antigen) adamianis leikocituri antigeni

IL- (Interleukin) interleikini

IFN γ – (Interferon γ) interferoni-gama

INH/H - izoniazidi

Ig- (Immunoglobulin) - imunoglobulini

LAM – (LipoArabinoManan) - lipoarabinomanani

MDR TB -(multidrug-resistant Tuberculosis) –multirezistentuli tuberkulozi

MHC- (Major Histocompatibility Complex)- histoSeTavsebulobis mTavari

kompleqsi

PAMP – (Pathogen Assocciated Molecular patterns) -paTogenTan asocirebul

molkulebi

PAS – (Para-Aminosalicylate Sodium) –para-aminosalicilatis marili

PZA - pirazinamidi

R – rifampicini

S - streptomicini

SLC11A1- SoLute Carrier family 11 member 1 gene – bunebriv rezistentobasTan

asocirebuli makrofaguli cila-1-is makodirebeli geni

SNP- single nucleotide polimorfism – erTnukleotidiani polimorfizmi

TGFβ -(Transforming Growth Factor β) -matransformirebeli zrdis faqtori β

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TLR- (Toll Like Receptor) – tolis msgavsi receptori

TNF-α - Tumor Necrosis Factor α – simsivnis nekrozis faqtori-α

VDR – Vitamin D Receptor – vitamin D-s receptori

USAID - United States Agency for International Development – aSS-s serTaSoriso

ganviTarebis saagento

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Tavi I

literaturuli mimoxilva

I .1. tuberkulozis epidemiologia, misi kontrolisa da prevenciis

Tanamedrove strategiebi

tuberkulozi antikuri xanidan momdinare daavadebaa, romelic am

droidanve iyo sazogadoebis janmrTelobis seriozuli problema.

Mycobacterium tuberculosis-is gvari 150 000 wlis win warmoiSva (Daniel., 2006). Zv.w.aR.-

iT daTariRebuli egviptisa da andebis mumiebSi, egvipturi da kolumbiuri

xelovnebis nimuSebSi napovnia ConCxis tipuri tuberkulozuri

deformaciebi (Nerlich et al., 1997; Donoghue et al., 2004; Palomino et al., 2007).

Mycobacterium bovis-iT gamowveuli tuberkulozuri anomaliebi Cv.w.aR-mde 8000

wliT daTariRebul Crdilo evropisa da aziis namarxebSic aris napovni (Cosivi

et al., 1995; Behera., 2010).

„fTizis“ (filtvebis anTeba) pirvelad daaxloebiT Zv.w.aR-iT 60 wels

berZnul literaturaSi hipokrates mier iqna moxseniebuli, rogorc im

droisTvis yvelaze gavrcelebuli momakvdinebeli daavadeba. me-17

saukunidan tuberkulozi evropaSi „TeTri Wiri“-s saxeliT TiTqmis ori

saukune mZvinvarebda. am periodidan daiwyo daavadebis paTanatomiuri

Seswavla. tuberkuloziT gamowveuli sikvdilianobis maCvenebelma Zalian

maRal niSnuls 1650 wels miaRwia. populaciebis maRali simWidrove, cudi

sanitaruli mdgomareoba, romelic im drois evropisa da Crdilo

amerikisTvis tipur suraTs warmoadgenda, paTogenis gavrcelebisTvis

srulyofil garemos qmnida (Palomino et. Al., 2007).

simptomebis mravalferovnebis gamo tuberkulozuri daavadebis

identifikacia me-19 saukunis pirvel naxevarSi Zalian rTuli iyo. Semdgomma

mecnierulma aRmoCenebma daavadebis ara Tu identifikacia, aramed misi

prevalentobis maCveneblis Semcireba, garkveulwilad kontroli da

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prevenciuli RonisZiebebis gatarebac ki gaxada SesaZlebeli. 1882 wels

robert koxis mier identificirebuli iqna infeqciuri agenti, xolo 1921 wels

kamletisa da guerinis mier gamoyofili iqna tuberkulozis baqteriis

specifikuri, dabalvirulenturi Stami, romelic safuZvlad daedo BCG

vaqcinis Seqmnas da miuxedavad misi arasakmarisi efeqturobisa, igi dResac

erTaderTi tubsawinaaRmdego vaqcinaa. ukanasknel wlebSi aqtiurad

mimdinareobs muSaoba axali vaqcinis dizainze (Montanes et al., 2011).

1895 wels rentgenis sxivebis aRmoCenam SesaZlebeli gaxada swori

diagnostireba. 1944 wlidan daiwyo tubsawinaaRmdego qimioTerapiis era,

romelic ukavSirdeba vaqsmanis da satzis mier antibiotik streptomicinis

mignebas streptomicinis Semdeg medicina mivida izoniazidamde.

tubsawinaaRmdego preparatebiT mkurnalobam garkveulwilad Seamcira

tuberkuloziT avadobisa da sikvdilianobis maCvenebeli. im periodisTvis

mTel rig qveynebSi realurad arsebobda tuberkulozis kontrolis

SesaZlebloba, magram me-20 saukunis 80-iani wlebidan msoflioSi kvlav

aRiniSna tuberkulozis SemTxvevaTa mateba da daavadebis globaluri

Semoteva. tubsawinaaRmdego wamlebis mimarT mikobaqteriis rezistentuli

Stamebis warmoSobam da gavrcelebam arsebuli problema kidev ufro

gaaRrmava (Palomino et al., 2007).

sadReisod, tuberkulozi, ara marto samedicino, aramed sxva dargebis

(genetikuri, imunogenetikuri, imunologiuri) kvlevebis fokusSi moeqca.

Tanamedrove mecnieruli kvlevebiT xdeba daavadebis winaswar-

ganpirobebulobis Seswavla molekuluri donidan eTnikur-populaciur

donemde. mecnierebi cdiloben, miagnon daavadebis prevenciis da kontrolis

ukeTes meqanizmebs, axali qimioTerapiuli medikamentebisa da srulyofili

vaqcinis Seqmnis gzebs (Schulger & Rom, 1998; Casanova & Abel, 2002). aRniSnuli

Zalzed mniSvnelovania janmrTelobis usafrTxoebis organizebis,

profilaqtikis, diagnostirebis, mkurnalobis da daavadebasTan brZolis

programebis SesamuSaveblad.

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yovelwliurad tuberkulozis CxiriT msoflios mosaxleobis 1/3

inficirdeba, xolo 2 mln. adamiani daavadebis mZime formiT iRupeba.

janmrTelobis msoflio organizaciis masalebiT, tuberkulozi gavrcelebis

mixedviT meSvide adgilzea, mis mier gamowveuli sikvdilianobis maCvenebliT

ki _ mexuTeze (WHO, 2012). daavadebaTa kontrolis programebis,

antituberkulozuri medikamentebis, prevenciuli RonisZiebebis miuxedavad,

tuberkulozis epidemiologiuri prognozi sakmaod SemaSfoTebelia.

magaliTad, afrikis zogierT qveyanaSi tuberkuloziT daavadebulTa

ricxvma 50%-s gadaaWarba. mecnierebis prognoziT, Tu daavadebis

sawinaaRmdegod intensiuri RonisZiebebi ar iqna gatarebuli, arsebuli

mdgomareoba 2020 wlisTvisac SenarCundeba (Dye et al., 1999, Smith & Frieden, 2004;

Dye et al., 2005). ufro metic, momdevno 20 wlis ganmavlobaSi tuberkuloziT

miliardi adamiani daavaddeba, xolo letalobis maCvenebeli 25 mln-mde

gaizrdeba. arsebuli mdgomareobiT, tuberkuloziT daavadebulTa 75%

ekonomikurad produqtiuli (15-54 wlis) asakobrivi jgufia, romelSic

sikvdilianobis maCvenebeli msoflio masStabiT 95%-s aRwevs, maqsimaluri

sixSiriT Sua saharis afrikaSi da samxreT-aRmosavleT aziaSi fiqsirdeba

(WHO, 2011; Tiemersma at al., 2011.).

tuberkulozis marTvis saqmeSi mniSvnelovan rols asrulebs diagnosti-

rebis meTodebis SerCeva. ganviTarebul qveynebSi am mizniT baqteriuli

kulturis meTodi (oqros standarti) da efeqturi sadiagnostiko

molekuluri testebi gamoiyeneba. CamorCenil da ganviTarebad qveynebSi

tuberkulozis gakontrolebis SesaZleblobas aferxebs diagnostirebis

moZvelebuli meTodebi, romelebic ver iZleva daavadebis zusti

identificirebis saSualebas. Sesabamisad, mkurnaloba araefeqturia, rac

sikvdilianobis maCveneblis zrdazec aisaxeba (Tiemersma at al., 2011). araswori

diagnostika da mkurnaloba mikobaqteriis rezistentuli Stamebis

gavrcelebis erT-erT mizezad iTvleba.

15

WHO-is mier xorcieldeba tuberkulozis epidemiologiis Seswavlis,

misi mimdinareobis Sefasebis, prevenciuli RonisZiebebis dagegmvisa da

ganxorcielebis globaluri kontroli. 2006 wlidan tuberkulozis

Sefasebis sami mTavari maCvenebeli gamoyeneba: axali SemTxveva

(mikobaqteriiT inficirebis axali SemTxvevebi), prevalentoba

(tuberkuloziT daavadebulTa ricxobrivi maCvenebeli konkretuli

periodisaTvis) da letaloba (tuberkuloziT gamowveuli sikvdilianoba

drois gansazRvrul periodSi, ZiriTadad, erTi wlis farglebSi). aRniSnul

maCveneblebze dayrdnobiT, axali ,,epidemiis’’ warmoSobis saSiSroebis gamo

tuberkulozi gamocxadda ,,globalur safrTxed’’, ris gamoc WHO

axorcielebs mizanmimarTul programebs „Stop TB Partnership - WHO Global Task

Force on TB Impact Measurement“-is farglebSi, raTa Semcirebuli iqnes zemoT

aRniSnuli maCveneblebi 2015 wlisTvis. programaSi CarTulni arian wamyvani

teqnikuri da finansuri partniorebi da tuberkulozis maRali maCveneblebis

mqone qveynebi (Palomino et al., 2007). tuberkulozis regionul doneze marTvis

saqmeSi aqtiurad gamoiyeneba 1994 wlidan WHO-s mier rekomendebuli pirdapiri

meTvalyureobiT mkurnalobis - DOTS strategia.

WHO-s mxardaWeriT ganxorcielebuli tuberkulozis kontrolis

Tanamedrove programebis Sedegebis mixedviT, 2006 wlidan rig qveynebSi

aRiniSna tuberkulozis axal SemTxvevaTa absoluturi ricxvis, xolo 2002

wlidan - misi sixSiris (yovel 100,000 individze) 1.3%-iT kleba. gamonakliss

warmoadgens afrikis regioni. partniorobis mizani faqtiurad miRweulia

amerikis da wynari okeanis dasavleT regionSi. daavadeba radikalurad

Semcirda CineTis regionSi (China Tuberculosis Control Collaboration, 1996).

aRsaniSnavia, rom 1990 wlis Semdeg letalobis maCvenebelic (aiv-dadebiTi

SemTxvevebis letaluri maCveneblis gamoricxviT) 1/3-T Semcirda da Tu

aRniSnuli tempi SenarCunebuli iqneba, „Stop TB Partnership’s“ mizani 2015 wlisTvis

50%-iT miRweulad CaiTvleba (WHO/HTM/TB/2010; WHO,2011). amavdroulad, WHO-

is monacemebiT jer kidev arsebobs qyveynebi, sadac axal SemTxvevaTa raodenoba

16

tuberkulozis prevalentobis 80% -s aRwevs. tuberkulozis axal SemTxvevaTa

raodenoba WHO-is 2010 wlis monacemebiT naCvenebia rukaze (sur.1).

tuberkulozis axal SemTxvevaTa, prevalentobis da letalobis

maCveneblebze gansakuTrebul gavlenas axdens: siRaribis zrda, demogra-

fiuli Zvrebi, paraleluri infeqciebi (pandemuri aiv) (Chretien et al, 1990;

Chintu et al, 2005) da aS. sagangebo mdgomareobas qmnis, aseve, mikobaqteriis

rezistentuli Stamebi (Haas et al., 1994; Fatkenheuer et al., 1999 Ballif et al., 2012).

daavadebis kontrolis organizaciebis Zalisxmevis, antituberkulo-

zuri programebis ganxorcielebis, mkurnalobis kombinirebuli meTodebis

gamoyenebis da maRalefeqturi medikamentebis xelmisawvdomobis miuxedavad,

tuberkulozi jer isev rCeba globalur safrTxed.

sur 1. tuberkulozis axal SemTxvevaTa gavrcelebis ruka msoflios masStabiT (WHO.2010). ferebiT naCvenebia tb-is axal SemTxvevaTa raodenoba yovel 100 000 mosaxleze

tuberkulozis epidemiologiur mdgomareobas gansakuTrebiT amwvavebs

ukanasknel aTwleulSi gazrdili multirezistentuli tuberkulozis

(MDR-TB) SemTxvevebi. 1994 wlidan rig qveynebSi tuberkulozuri pacientebis

17

5%-dan 19%-mde avaddeba axladSeZenili multirezistentuli mikobaqteriiT.

prevalentoba yovelwliurad 1.5 mln-s (60%) aRwevs (Zignol M, 2011).

I.2. tuberkulozis epidemiologia

saqarTveloSi

tuberkulozi saqarTveloSi, iseve, rogorc mTel msoflioSi,

sazogadoebis janmrTelobis sakmaod seriozuli da sayuradRebo problemaa.

sxva postsabWouri qveynebis msgavsad, saqarTvelo tuberkulozis pre-

valentobis maRali maCvenebliT gamoirCeva.

tuberkulozis pirveli kvali saqarTveloSi Cv.w.aR-is VI-VII saukuneebis

namarxebSia aRmoCenili. Zvel qarTul samedicino ZeglebSi tuberkulozi anu

„Wleqi" pirvelad X saukuneSi, kananelis "usworo karabadinSi", mogvianebiT ki

sxva Zvel qarTul samedicino xelnawerebSic gvxvdeba. aRniSnulma senma

saukuneebis ganmavlobaSi uamravi adamianis sicocxle imsxverpla.

tuberkulozTan brZolis pirveli mcdeloba qveyanaSi 1918-1921 ww.-Si

daiwyo, Seiqmna samedicino samecniero da kvleviTi centrebi. 1970-1990 ww.

tuberkulozis sawinaaRmdego RonisZiebebis gatarebis Sedegad, saqarTve-

los respublikaSi tuberkuloziT avadoba 56%-dan 28,3%-mde Semcirda,

xolo letaloba _ 10,9% dan 4,91%-mde.

1991-1994 ww.-Si saqarTveloSi mimdinare socialur-politikurma

movlenebma, jandacvis sistemis moSlam, samoqalaqo omma, afxazeTisa da

samxreT oseTis konfliqtebma, mosaxleobis mZime socialurma da ekonomi-

kurma pirobebma, aseve, msoflio masStabiT tuberkulozis epidemiologiuri

situaciis damZimebam gamoiwvia avadobis zrda da epidemiologiuri

mdgomareobis gauareseba. am periodSi tuberkulozTan brZolis Ronis-

Ziebebi praqtikulad ar xorcieldeboda, inerciiT grZeldeboda daavade-

http://www.ncbi.nlm.nih.gov/pubmed?term=%22Zignol%20M%22%5BAuthor%5D

18

bulTa usistemo diagnostika da mkurnaloba. yovelive amis Sedegad gaizar-

da daavadebiT gamowveuli sikvdilianobis da axal SemTxvevaTa sixSire.

USAID-is monacemebiT, tuberkulozis axal SemTxvevaTa da prevalen-

tobis maCveneblis sagrZnobi mateba saqarTveloSi 2001 - 2005 wlebSi

dafiqsirda. gansakuTrebiT maRali sixSiriT gamoirCeoda Sida qarTlis,

qvemo qarTlis, kaxeTis, aWaris, imereTis da samegrelos regionebi.

magaliTad, 2001 wels samegreloSi registrirebuli iyo 670 pacienti,

xolo 2005 wels maTi ricxvi 865-mde gaizarda. imereTSi 2001 wels

dafiqsirda 630, xolo 2005 wels _ 876 SemTxveva. aWaris regionSi xuTi

wlis ganmavlobaSi daavadebuli pacientebis raodenobam 496-dan 897-mde

moimata. aRniSnul periodSi gaizarda axali SemTxvevebis maCvenebelic.

magaliTad, aWaraSi 2001 wels tuberkulozis 364 axali SemTxveva

dafiqsirda, 2005 wels ki _ 614. 2005 wels saqarTvelos tuberkulozis

epidemiologiuri mdgomareoba TiTqmis utoldeboda maRali maCveneblis

mqone centraluri aziis regions (USAID, 2007).

2005 wlidan saqarTveloSi tuberkulozi SedarebiT ufro kotrolireba-

di gaxda, rasac xeli Seuwyo USAID-is da WHO-is mier ganxorcielebulma

programebma (mag., DOTS), romelTa strategiulma muSaobam met-naklebad

gaaumjobesa tuberkulozTan brZolis RonisZiebebi (Gegia M. et al. 2011).

sadReisod, daavadeba met-naklebad eqvemdebareba kontrols da tuberkulozis

prevalentobis maCvenebelic SedarebiT dastabilurebulia. aRniSnuli

mdgomareoba ar vrceldeba sapyrobileebze, sadac SeiniSneba daavadebis

sagangaSo zrda (Gegia M. et al. 2011).

saqarTvelos tuberkulozisa da filtvis daavadebaTa erovnuli

centridan mopovebul masalebze dayrdnobiT, tuberkulozis prevalentobisa

da axal SemTxvevaTa maCvenebeli populaciis ricxovnobasTan SefardebiT

2005-2010 wlebSi naCvenebia diagramebze (diagr. 1-2):

19

diagr. 1. saqarTvelos mosaxleobis ricxovnobis dinamika 1996-2010 wlebSi

diagr. 2. saqarTveloSi tuberkulozis prevalentobis da axal SemTxvevaTa maCvenebeli 1996-2010 wlebSi

mocemul statistikur monacemebze dayrdnobiT, SeiZleba iTqvas, rom

tuberkulozis prevalentoba saqarTveloSi maqsimaluri sixSiriT 2002-2005

ww. gamovlinda, xolo axal SemTxvevaTa mateba aRiniSna 2009-2010 wlebSi.

janmrTelobis globaluri marTvis organizaciis (Global Health Policy,

2011) monacemebiT, saqarTveloSi 2011 wlisaTvis dafiqsirda tuberkulozis

5400 axali SemTxveva, xolo daavadebis prevalentoba 6900-s Seadgenda, rom-

lis maCvenebeli yovel 100 000 mosaxleze, 159-is tolia. tuberkuloziT

5154497

4369500

43980004410900

4452800

3800000

4000000

4200000

4400000

4600000

4800000

5000000

5200000

5400000პოპულაც. რიცხ.

5887

3789 3117 3032

2826

3175 3230

9213

5019 5060

4546

4592 4526

0

2000

4000

6000

8000

10000

12000

14000

16000

პრევალენტობა ახალი შემთხვ.

20

gamowveuli sikvdilianobis maCvenebeli yovel 100 000 mosaxleze 160-s

Seadgens.

evropuli regionis masStabiT, saqarTvelo mexuTe qveyanaa

tuberkulozis prevalentobis maRali maCvenebliT da 27-ze maRali pre-

valentobis qveynebs Soris (Gegia et al., 2011). tuberkulozis kontrolis

gaZlierebis mizniT, 2012 wlis saxelmwifo programaSi, daavadebulTa mkur-

nalobis garda, gaTvaliswinebulia latenturi tuberkulozis mqone maRali

riskis jgufebis epidemiologiuri kvleva da mkurnaloba. saqarTveloSi

tuberkulozis diagnostika da mkurnaloba dReisaTvis ufaso da

xelmisawvdomia.

2012 wels daigegma tuberkulozis epidemiologiuri kvlevebis

gafarToveba, laboratoriuli diagnostikis xarisxis gaumjobeseba

da daavadebis droul gamovlenasa da mkurnalobis efeqturobaze mimarTuli

sxva RonisZiebebi, romelSic CarTulia tuberkulozisa da filtvis

daavadebaTa erovnuli centri da regionuli marTvis dawesebulebebi. Agarda

amisa, WHO rekomendaciiT, saqarTveloSi 1995 wlidan moqmedebs tuberkuloz-

Tan brZolis erovnuli programa, romlic efuZneba DOTS strategiebs.

ganxorcielebuli RonisZiebebis miuxedavad, daavadebis riskiT

saqarTvelo kvlav seriozuli safrTxis winaSe mdgom ganviTarebad qveynebs

Soris moiazreba. amis erT-erTi mTavari mizezi wamalrezistentuli formis

tuberkulozis sagrZnoblad gazrdili maCvenebelia, romelsac sxvadasxva

tipis medikamentisadmi gamZle mikobaqteriebi iwvevs. magaliTad, 2005 wels

94 axali SemTxvevidan (100 000 mosaxleze) multirezistentuli tuberkulo-

zis 6,8% pirveladi rezistentobis, xolo 27,4% warsulSi namkurnalevi

SemTxvevebi Seadgenda (Mdivani et al, 2009; Gegia et al, 2011).

gansakuTrebul safrTxes sazogadoebaSi mikobaqteriis rezistentuli

Stamebis gavrceleba qmnis. aseTi StamiT inficirebis SemTxvevaSi pacienti

pirdapir rezistentuli tuberkuloziT xdeba avad. rogorc me-3

diagramidan Cans, saqarTvelos tuberkulozisa da filtvis daavadebaTa

21

erovnuli centris monacemebiT, 2009-2010 ww.-Si mkveTrad moimata pirveladi

rezistentobis axal SemTxvevaTa raodenobam.

diagr. 3. saqarTveloSi rezistentuli tuberkulozis axal da namkurnalev SemTxvevaTa

maCvenebeli 2006-2010 wlebSi (saqarTvelos tuberkulozisa da filtvis daavadebaTa

erovnuli centri)

mdgomareobas amZimebs is faqti, rom pirveladi rezistentobis dros

mikobaqteriebis Stamebi gansxvavebul mdgradobas avlenen sxvadasxva

antituberkulozuri medikamentis mimarT, rac kidev ufro arTulebs

samkurnalo preparatebis efeqturobas rezistentuli tuberkulozis

srulyofili mkurnalobisTvis.

I .3. tuberkulozis gamomwvevi -Mycobacterium tuberculosis

M. tuberculosis da masTan monaTesave koloniebi warmoiSva ramdenime aTeuli

aTasi wlis win aRmosavleT afrikaSi da SemdgomSi evoluciurad gamoeyo Tavis

winapar saxeobas da Camoyalibda, rogorc M. tuberculosis kolonia. M. tuberculosis -

is winaprebi 3 mln wlisaa (Gutierrez et al., 2005).

0 20 40 60 80 100 120 140

2006

2007

2008

2009

2010

43,3

21,9

54,4

87,8

88,6

28,8

12,4

31,4

33,8

33,3

ახალი შემთხ. % ნამკურნ. %

22

mikobaqteriebis umravlesoba aratuberkulozuri anu atipuri,

arapaTogenuri mikobaqteriebia. maTi ramdenime saxeoba adamianisa da

cxovelebis ujredSida paTogenia (M. tuberculosis, M. canettii M. africanum, da M. bovis,

M. Microti). M. tuberkulosis, M. africanum da M. bovis mikobaqteriebi cnobilia,

rogorc ,,tuberkulozis kompleqsi’’, romlis TiToeuli wevri paTogenuria

da iwvevs daavadebas. M.africanum-is Stami ZiriTadad dasavleT afrikaSi

gvxvdeba. M.bovis tuberkulozis ganviTarebas iwvevs Sinaur da gareul

msxvilfexa saqonelSi. iSviaTad, auduRari an arapasterizebuli rZis

miRebis Sedegad is SeiZleba adamiansac gadaeces. aRniSnuli saxeoba,

savaraudod, M. tuberculosis winaparia. varaudoben, rom am gziT pirvelad indo-

evropelebi dainficirdnen, aqedan daavadeba dasavleT evropasa da aziaSi

gadavida, xolo Cv.w.aR-mde 1000 wlisTvis mTels msoflioSi gavrcelda.

M. Tuberculosis 1,5–6mkm sigrZis da 0,2–0,5mkm sisqis moxrili formis

baqteriaa, romelic paTologiur masalaSi grovebs qmnis. igi daculia

unikaluri, lipidebiT mdidari ujreduli kedliT, romelSic uxvadaa

cximovani mJavebi da glikolipidebi, rac gamoSrobisa da qimiuri agentebis

moqmedebisgan icavs. msgavsi Sedgenlobis membrana bacilas saSualebas

aZlevs, antimikrobuli damcvelobiTi meqanizmebis moqmedebisagan Tavi

gadairCinos da recipient organizmSi gamravldes (Hingley-Wilson et al, 2003;

Zahrt,2003; Rom & Garay, 2003; Rom & Garay, 2004). M. tuberculosis gram-rezistentuli

aerobia da Zalian nela izrdeba (maTi ricxvis gaormagebas saSualod 20 sT

sWirdeba). filtvebis bneli, JangbadiT mdidari are da 37°C temperatura

bacilis gamravlebisaTvis idealuri garemoa. igi swrafad iSleba

ultraiisferi sxivebis zemoqmedebiT, magram mdgradia sxvadasxva fizikuri

da qimiuri agentebisadmi. baqteria 5–6 Tvis ganmavlobaSi inarCunebs sico-

cxlisunarianobas Txevad naxvelSi. aseve, ramdenime Tvis ganmavlobaSi

sicoclisunariani rCeba gamomSral mdgomareobaSi da inarCunebs

virulentobas. xelsayrel garemo pirobebSi moxvedrisas avlens paTogenur

aqtivobas.

23

M.tuberculosis, Cveulebriv, azianebs filtvebs (filtvis tuberkulozi) da

sxva organoebs (filtvgare tuberkulozi _ Tavis tvinis garsebi, Zvlebi,

saxsrebi, Tirkmlebi, Sardis buSti). daavadeba kontagiozuria.

M.tuberculosis-iT inficirebulTa 90% SemTxvevaSi baqteria rCeba latentur

fazaSi, mxolod 10%-Si aRiniSneba daavadebis klinikuri ganviTareba.

pirveladi inficirebis Sedegad yalibdeba nawilobrivi imuniteti, Tumca,

masiuri infeqciis an imunosupresiis arsebobis pirobebSi imuniteti ver

uzrunvelyofs daavadebis prevencias da igi gadadis aqtiur fazaSi. pirvelad

tuberkulozur keraSi arsebuli mikobaqteriebi iwyeben intensiur

gamravlebas, kera moculobaSi matulobs, SeiZleba SemdgomSi qsovili

dairRves da daSlili qsovilis adgilze Camoyalibdes Rru. pirveladi keridan

mikobaqteriebi sisxlis nakadis meSveobiT SeiZleba moxvdnen sxvadasxva

organoSi, sadac, aseve, viTardeba tuberkulozuri procesi (Kochar et.al., 2011).

daavadebis Ria formis (mgb+) dros avadmyofi xvelis, ceminebis an saubris

dros saSualod 10-15 adamians ainficirebs. janmrTeli adamianis imunuri

sistema, an xocavs tuberkulozis bacilebs, an "akonservebs" wlebis ganmavlo-

baSi (Kochar et.al. 2011).

tuberkulozis mimarT mRali riskis qveS arian daavadebulTa ojaxis

wevrebi, Raribi, usaxlkaro, saerTo sacxovreblebSi mcxovrebni, gansa-

kuTrebiT - patimrebi; paraleluri daavadebebis (simsivne, diabeti, Sidsi)

mqoneni, eqimebi da jandacvis sxva momsaxure personali; aseve, adamianebi,

romlebic infeqciuri daavadebebisadmi maRali mgrZnobelobis imunogeneti-

kur faqtorebs atareben.

daavadebis mkurnaloba sakmaod xangrZlivi da rTuli procesia. Tu

mkurnaloba uwyvetad da, amasTanave, erTdroulad ramdenime antituber-

kulozuri preparatiT mimdinareobs, SesaZlebelia pirveladi tuberkuloziT

daavadebuli TiTqmis yvela pacientis gamojanmrTeleba. Sewyvetili

mkurnaloba, xSirad, infeqciis recidiul formas iwvevs da

antituberkulozuri medikamentebis mimarT rezistentobis Camoyalibebas

24

ganapirobebs, rac arc Tu iSviaTad ukontrolo procesebSi gadadis da

letaluri SedegiT sruldeba.

1.3.1. mikobaqteriis rezistentobis ganmapirobebeli faqtorebi

antibiotikebiT tuberkulozis arasaTanado mkurnalobis an misi

Sewyvetisas mikobaqteriaSi momxdari genuri mutaciebi, xSirad, sxvadasxva

saxis medikamentisadmi rezistentobas iwvevs. konkretuli wamlis mimarT

rezistentobas metwilad baqteriaSi momxdari spontanuri mutaciebi

ganapirobebs, romelTa sixSire 10-6-dan 10-8-mde meryeobs romelime erTi

wamlis mimarT, xolo erTze meti wamlis mimarT rezistntobisas mutaciaTa

sixSire 1012-1016 mikrobul ujreds Seadgens (Palomino et al., 2007). Mutaciebi,

SesaZloa, gamowveuli iyos replikaciis dros momxdari genetikuri

struqturis iseTi cvlilebiT, romlis gavleniT baqteriam SeiZleba

dakargos adekvaturoba antituberkulozuri medikamentis mimarT.

mikobaqteriis populaciaSi mudmivad mimdinare transmisiebi rezistentobis

Camoyalibebis mniSvnelovani wyaro xdeba (Bartu et al., 2007).

rezistentobis gamomwvevi klasikuri meqanizmis mixedviT, mutacia xdeba

mikobaqteriis genis im nawilSi, romelic akodirebs wamlis samizne

ligandebs. mutacia axdens im fermentebis inhibirebas, romlebic

pasuxismgebelia wamlis samizne receptorebis Camoyalibebaze. faqtobrivad,

aRniSnuli mutaciebi amcirebs wamlis SesaZleblobas, ipovos da

daukavSirdes samizneebs mikobaqteriaSi.

sxva tipis mutaciebis dros ki, piriqiT, matulobs wamlis samizne

ligandebi. baqteriis zedapirze yalibdeba ufro meti ligandi, vidre es

wamliTaa SesaZlebeli. zogierTi medikamenti, magaliTad, izoniazidi (INH)

da pirazinamidi (PZA) baqteriis ujredSi Sedis, rogorc prowamali, romelsac

gaaqtiurebisTvis sWirdeba baqteriuli fermenti. aqedan gamomdinare, nebis-

25

mieri mutacia, romelic Trgunavs aRniSnuli fermentis sinTezs, TavisTavad

blokavs wamlis aqtivobas da saboloo jamSi yalibdeba rezistentoba.

mikobaqteriis rezistentobis mizezi SesaZloa iyos iseTi tipis

mutaciebic, romlebic amcireben wamlis akumulacias baqteriis SigniT. es

SesaZlebelia baqteriaSi wamlis ganvladobis SemcirebiT an baqteriidan misi

gamosvlis aCqarebiT. sabolood, rezistentoba SeiZleba preparatis qimiuri

modificirebiT da inaqtivirebiT ganviTardes (Bastian & Portales, 2000).

poli- da multirezistentobis gamomwvevi mutaciebi xdeba ara erT

romelime genur lokusSi, aramed _ ramdenimeSi erTad.

amJamad cnobilia rezistentobis ganmapirobebeli mutaciuri saitebi.

magaliTad, rpsL (STM-streptomicinis samizne) rpoB (RIF-rifampicinis samizne)

an 16S ribosomul rnm-Si (KAN kanamicinis, AMK amikacinis da 2-deoqsistrep-

tamin aminoglikozidebis samizne) momxdari mutaciebi asocirdeba

rezistentobis maRal donesTan, xolo gldB (STM-streptomicinis samizne) eis

(KAN kanamicinis samizne) da inhA (INH izoniazidis samizne) genebSi momxdari

mutaciebi asocirdeba rezistentobis SedarebiT dabal donesTan. zogjer,

erTi wamlis mimarT rezistentoba, SesaZloa, gamowveuli iyos mravali

genis erToblivi gardaqmnebiT an kidev piriqiT, SesaZloa, erTi da igive

genis sxvadasxva lokusSi momxdari mravlobiTi gardaqmnebiT (Bottger, 2011).

molekulur doneze mutaciebis dadgenas specialuri teqnikis

gamoyenebiT axdenen. es meTodebi sakmaod sensitiuri, specifikuri da swra-

fia da misi saSualebiT SesaZlebelia Canacvlebuli iqnes baqteriologiu-

ri testirebis meTodi. amavdroulad, testis saimedoobas mutaciis identifika-

ciis sizustec ganapirobebs (Lee et al., 2000; Goh et al., 2006; Bottger, 2011).

rezistentoba, SesaZloa, iyos bunebrivi anu pirveladi an SeZenili anu

meoradi, rac metwilad pacientis anamneziT dgindeba. SeZenil da bunebriv

rezistentobebs Soris Tanafardoba araTanabaria (Bastain & Portales, 2000).

rezistentobis ganviTarebis Tavidan acilebis saukeTeso gza kargad dagegmili

26

pirveli rigis mkurnalobaa. aseve, mniSvnelovania profilaqtikuri

RonisZiebebis gatareba tuberkulozisadmi maRali riskis jgufebSi.

I .4. rezistentuli tuberkulozis globaluri

epidemiologia da etiologia

antituberkulozuri medikamentebis mimarT rezistentoba dokumenturad

1940 wlidan dafiqsirda, xolo problemis monitoringi mxolod 1994

wlidan daiwyo, rodesac rezistentobis problemam globaluri saxe miiRo.

ukanaskneli aTwleulis ganmavlobaSi msoflioSi tuberkulozis epidemio-

logiuri situaciis gauareseba, garkveulwilad, wamalrezistentuli

formis gavrcelebas ukavSirdeba. daavadebam samxreT afrikaSi ifeTqa aiv-is

virusis fonze, ramac mniSvnelovnad gazarda sikvdilianobis maCvenebeli

(Zignol et al, 2011).

wamalrezistentuli tuberkulozis (DR-TB) gamomwvevia M. tuberculosis,

romelic mdgradia tubsawinaaRmdego medikamentebis mimarT. imisda mixedviT,

Tu romeli rigis da ra tipis wamlebis mimarTaa mikobaqteria rezistentuli,

gamoyofen tuberkulozis mono-, poli- da multirezistentul formebs.

tuberkulozis samkurnalod gamoiyeneba I rigis (eTanbutoli (EMB/E,

izoniazidi (INH/ H), pirazinamidi (PZA/Z)) da II rigis wamlebi (aminoglikozi-

debi: amikacini (AMK), kanamicini (KM); polipeptidebi: kapreomicini, viomicini,

enviomicini; fluoroqinolebi: ciprofloqsacini (CIP), levofloqsacini

(MXF); Tioamidebi: eTionamidi, proTionamidi).

roca mikobaqteria gamZlea ori an meti tubsawinaaRmdego medikamentis

mimarT, magram ara erTdroulad izoniazidis da rifampicinis mimarT,

polirezistentul tuberkulozad (PDR-TB) iwodeba. multirezistentuli

tuberkulozis (MDR-TB) _ daavadebis gamomwvevi mikobaqteria gamZlea, minimum,

izoniazidis da rifampicinis mimarT. Tu pacienti rezistentulia pirveli


27

rigis wamlebis mimarT, maT mkurnaloben meore rigis wamlebiT, romlebic

sakmaod ZviradRirebulia, axasiaTebs gacilebiT meti gverdiTi efeqti da

moiTxovs xangrZliv mkurnalobas. rezistentuli tuberkulozis umZimesi

formaa eqstensiuri tuberkulozi (XDR-TB), romlis gamomwvevi mikobaqteria

gamZlea izoniazidinis da rifampicinis, fluoroqinolebis jgufis

medikamentebis da, Tundac, erTi saineqcio medikamentebis (kanamicini, amikacini,

kapreomicini) mimarT (Floyd., 2003; Smith., 2003; WHO, 2005).

medikamentebisadmi rezistentoba SeiZleba bunebrivi an SeZenili iyos.

mutaciebi, romlebic iwvevs bunebriv rezistentobas, oTxive pirveli rigis

tubsawinaaRmdego medikamentis mimarT, gansazRvruli albaTobiT xdeba

aranamkurnalev adamianebSi H–10-6; S–10-6; E–10-6; R–10-8. xolo ori damoukidebeli

medikamentis mimarT rezistentobis ganviTarebis albaToba, magaliTad, H+R

SemTxvevaSi Seadgens 10-6 X 10-8=10-14. imis gamo, rom baqteriebis raodenoba,

mZime kavernozuli formis drosac ki iSviaTad aRwevs 10-14

multirezistentuli baqteriis spontanuri evolucia Zalian iSviaTia.

SeZenili (meoradi) rezistentoba viTardeba tuberkulozis mkurnalobisas,

roca mkurnalobis zemoqmedebiT xdeba baqteriebis mutanturi formebis

seleqcia (Long, 2000). rezistentobis xSiri mizezia mkurnalobaze pacientis

cudi damyoloba an arasrulfasovani reJimi (gaidlaini, 2007).

multirezistentoba seriozuli problemaa aRmosavleT evropis, aziisa da

afrikis qveynebisTvis. WHO-s monacemebiT, rezistentuli tuberkuloziT 2008

wels gardaicvala 150 000 adamiani. 2010 wlisTvis multirezistentuli

tuberkulozis 650 000 axali SemTxveva dafiqsirda (WHO 2011/2012).

varaudeben, rom multirezistentuli tuberkuloziT gamowveuli

letalobis maCvenebeli gacilebiT maRalia, vidre es oficialurad aris

cnobili. statistikuri monacemebis sizustes eWvqveS ayenebs is faqti, rom

tuberkulozuri pacientebis Zalian did nawils ara aqvs diagnozis sworad

28

dasmis SesaZlebloba Tanamedrove sadiagnostiko laboratoriebis ararse-

bobis an arasakmarisobis gamo (Bastain & Portales, 2000; Zignol et al, 2011).

rezistentuli tuberkulozis problema mwvaved dgas saqarTveloSic.

qveyanaSi multirezistentuli tuberkulozis maCvenebelma 1995-1996 wlebSi

axal SemTxvevaTa 23-25%-s miaRwia, xolo namkurnalev SemTxvevebSi _ 39%-s.

2003 wlis monacemebiT, axal SemTxvevaTa 15%-Si da namkurnalevi

SemTxvevebis 23%-Si dafiqsirda daavadebis multirezistentuli forma

(Zalesky et, al., 1999). 2005 wels yovel 100 000 mosaxleze dafiqsirda

tuberkulozis 94 SemTxveva, sadac axali SemTxvevebis 6.8% da warsulSi

namkurnalevi SemTxvevebis 27.4% multirezistentul tuberkulozze modioda

(gaidlaini, 2007). 2009 wels multirezistentuli formam tuberkulozis

prevalentobis saerTo maCveneblis 28,1% Seadgina, romlis 10,5% pirvelad

rezistentobaze modis, 53,1% ki _ namkurnalev SemTxvevebze (Mdivani et al.,2009).

rezistentuli Stamebis farTod gavrcelebis saSiSroeba msoflioSi

moiTxovs tuberkulozis damatebiTi kontrolis meqanizmebis amoqmedebas,

diagnostirebis axali meTodebis Seqmnas da danergvas, arsebuli

antituberkulozuri medikamentebis gaumjobesebas (Palomino et al., 2007).

1.5. multifaqtoruli daavadebebi da

populaciebis genetikuri polimorfizmi

evoluciuri ganviTarebis procesSi adamianTa populaciebi sxvadasxva

faqtoris zemoqmedebis qveS, garkveulwilad, „genetikurad erTmaneTs

emijnebodnen“ da iZendnen individualobas. amavdroulad, maT Soris mudmivad

mimdinareobda genebis gacvla, rac Tavis mxriv, saerTo genetikuri niSnebis

Camoyalibebas uwyobda xels. adamiani, rogorc biologiuri saxeoba, imdenad


29

axalgazrdaa, rom arc erT mis populacias ar gaaCnia drois iseTi maragi, rac

maT srul izolacias uzrunvelyofda (Степанов, 2010).

eTnikuri populaciebis genofondi masSi Semavali genebis doneze inaxavs

informacias yvela im mniSvnelovani procesis Sesaxeb, romlebic eTnosma

istoriuli ganviTarebis procesSi gadaitana (Cavalli-Sforza., 1998). populaciis

genofondSi genebis da maTi alelebis mravalferovneba populaciur

polimorfizms qmnis. polimorfuli variaciebis (geno- Tu fenotipuri)

wonasworoba, romelic Camoyalibda genTa nakadebisa da bunebrivi gadarCevis

moqmedebiT, individualobas sZens yovel populacias.

populaciaTa polimorfizmis individualoba xSirad daavadebaTa mimarT

gansxvavebul mgrZnobelobaSi vlindeba (Conrad et al., 2010). arsebobs

populaciebi, romlebic metad eqvemdebarebian romelime konkretul daavadebas,

maSin, roca sxvebi mis mimarT mdgradobiT gamoirCevian. es faqti gansakuTrebiT

kargad Cans multifaqtorul daavadebebTan mimarTebaSi (diasamiZe, 2008; Conrad

et al., 2010). daavadebaTa mimarT populaciebis gansxvavebuli mgrZnobeloba

zogjer populaciaTa lokaluri adaptaciebiTac aixsneba (Cheboksari et al., 2006).

cnobilia, rom xSirad daavadebisadmi mdgradoba Tu sensibiloba

damokidebulia genomSi ara erTi romelime konkretuli genis arsebobaze,

aramed - ramdenimeze erTad. daavadebaTa mravali faqtoriT ganpirobebulobis

gamo, maT mimarT memkvidruli midrekileba maRali variabelobiT xasiaTdeba

da igi pirdapir kavSirSia populaciuri polimorfizmis siZlieresTan

(Степанов, 2010). mfd-sadmi populaciaTa gansxvavebuli midrekileba naCvenebia

gul-sisxlZarRvTa daavadebebis (Voevoda et al., 2006; Wassel et al.,2009), diabetis

(Karter et al., 2002), zogierTi tipis simsivnis (Shibata et al., 1997), glaukomis (Tielsch et

al.,1991), nefropaTiebis (Tarver-Carr et al., 2002) da mravali sxva daavadebis

mimarT.

TiTqmis saukunea, rac aRiarebulia, rom tuberkulozis mimarT

mgrZnobeloba gansxvavebulia, rogorc rasebis, aseve populaciebis doneze

30

(Millar, 1908). mecnierebi miiCneven, rom populaciis mdgradoba tuberkulozis

mimarT ganisazRvreba populaciis „klinikuri“ istoriiT (Stead., 1992). zogadad,

msoflios Savkaniani populacia tuberkulozisadmi maRali mgrZnobelobiT

gamoirCeva, vidre evropelebi, rac SesaZloa, aixsnas imiT, rom evropis

regionisTvis tuberkulozi endemuria da bevrad didi xnis istoria aqvs,

rogorc gadamrCev evoluciur faqtors (Dubos & Dubos, 1952), xolo Savkanian

mosaxleobaSi daavadebis (gansakuTrebiT daavadebis mZime formebis) maRali

sixSire tuberkulozis mimarT aRniSnuli rasis maRal mgrZnobelobaze

miuTiTebs (Bellamy et al.,1998). samedicino sferos warmomadgenlebis azriT,

tuberkulozis mimarT rasobrivi gansxvavebebi garemo faqtorebiT

ganisazRvreba, magram mravali faqti adasturebs daavadebisadmi genetikur

winaswarganpirobebulobasac. stidisa da misi TanamSromlebis (Stead et al.,

1990) mier dafiqsirda, rom saerTo sacxovreblis 25000 tuberkulin-

uaryofiT mobinadres Soris Savkanianebi orjer meti sixSiriT

dainficirdnen tuberkuloziT, vidre TeTrkanianebi, romlebic igive

garemoSi cxovrobdnen. aRniSnuli faqti aSkarad metyvelebs, rom tuber-

kulozisadmi organizmis mgrZnobelobaze genetikur faqtorebs garkveuli

roli akisriaT.

daavadebaTa mimarT populaciebis gansxvavebuli mgrZnobeloba

(midrekileba Tu mdgradoba) garkveulwilad alelTa garemocvazec aris

damokidebuli. aqedan gamomdinare, daavadebebis mimarT populaciis memkvidrul

winaswarganpirobebulobas populaciis mTliani genetikuri struqtura

gansazRvravs (Cavalli-Sforza, 1998; Степанов, 2010).

eTno-genetikuri divergenciis da mravalferovnebis msgavseba- gansxvavebis

Seswavla eTnikur jgufebSi da populaciebSi 1950 wlidan daiwyo cilovani

markerebis gamoyenebiT (Cavalli-Sforza, 1971; Mourant et al., 1976). mogvianebiT am

mizniT genetikuri markerebis gamoyeneba daiwyes. dagrovili faqtobrivi

masalis safuZvelze eTnogenetika calke mimarTulebad Camoyalibda (Underhill et

al., 2000). ukanasknel wlebSi ki populaciebis variabelobis Seswavla da

31

daavadebebTan maTi asociaciuri kavSirebis gamovlena dnm-is erTnukleo-

tidiani cvlilebebis polimorfizmis (SNP) doneze xdeba. Tanamedrove teqnika,

aseve, saSualebas iZleva genomis seqvenirebis safuZvelze GWAS-meTodiT

Seswavlil iqnes mTeli populaciis genofondi (Novembre et al., 2008; Auton et al.,

2009).

adamianis populaciebs Soris genetikuri gansxvaveba genetikuri

variabelobis mxolod 10-15%-s Seadgens. misi Seswavla personalizebul

medicinaSi monogenuri daavadebebis diagnostirebis saukeTeso saSualebaa,

xolo mfd-sas saSualebas iZleva, gamovlenili iqnes daavadebisadmi

winaswarganpirobebulobis faqtorebi. ukanaskneli daavadebis winaswari

prognozirebis da efeqturi Terapiis saSualebas iZleva (Степанов, 2010).

udavoa, rom eTnikuri faqtori unda iqnes gaTvaliswinebuli samedicino

kvlevebSi, gansakuTrebiT ki personalizebul medicinaSi (Genet. Hum. Race, 2004).

mkvlevarebi, romlebic muSaoben personalur genomikaSi, seriozul

yuradRebas uTmoben populaciur aspeqtebs. monacemTa Segrovebis da

damuSavebisas monacemebis interpretacias individualur an populaciur

doneze axdenen (Khoury et al., 2009).

iseve, rogorc yovel populacias aqvs Tavisi genofondi, yovel

individs gaaCnia Tavisi individualuri genotipi. genomSi arsebuli

TiToeuli geni pasuxismgebelia organizmis gansazRvrul niSan–Tvisebaze,

maT Soris daavadebebis mimarT organizmis mgrZnobelobaze. geografiuli

regioni, eTnikuri jgufi da populacia mniSvnelovnad gansazRvravs

individis aRniSnul maxasiaTeblebs (Cavalli-Sforza, 1998). cnobilia, rom bevri

infeqciuri paTogenis gamovlenis xarisxze imunogenetikuri lokusebi axdens

gavlenas.

mikobaqteriis aqtivacias da tuberkulozis klinikur ganviTarebas iwvevs

organizmis imunuri sistemis daqveiTeba, romelic ganpirobebulia rogorc

garemo (Holmes et al.,1998; Davies,1999; Schwenk & Macallan. 2000), ise genetikuri

(genebi, alelebi, haplotipebi) faqtorebiT, rac tyupebis Seswavlis klasikuri

32

meTodebiT gamovlinda. jer kidev gasul saukuneSi Catarebuli kvlevebiT

monozigotur tyupebSi daavadebisadmi maRali konkordantoba dafiqsirda

dizigoturebTan SedarebiT, rac imaze miuTiTebs, rom eTnikuri jgufebis

SigniT (individebis doneze) genetikuri faqtorebi gavlenas axdens

tuberkulozisadmi winaswarganpirobebulobaze (Comstock, 1978).

daavadebaTa mimarT organizmis midrekileba an mdgradoba xSir

SemTxvevaSi fenotipur niSnebiTanaa dakavSirebuli. erT-erT aseT

fenotipur niSans warmoadgens eriTrocituri jgufuri antigenebi,

romlebic ganlagebulia eriTrocitebis membranaze da gansazRvraven

pirovnebis individualobas da xSirad daavadebebisadmi asociacias avlenen

(Tamaria et al, 2010).

I.5.1 eriTrocituri jgufuri antigenebi da maTi

asociaciuri kavSirebi sxvadasxva tipis paTologiebTan da

tuberkulozTan

eriTrocituri jgufuri antigenebi da maT mier gansazRvruli sisxlis

jgufebi genetikurad myarad determinirebul fenotipur niSans warmoadgens

(Донсков, 2001). mravali mecnieruli kvleva adasturebs, rom arsebobs

korelaciuri kavSirebi sxvadasxva tipis infeqciur Tu arainfeqciur

daavadebasa da eriTrocitur jgufur antigenebs da, Sesabamisad, sisxlis

fenotipur jgufebs Soris. dRes ukve cnobilia, Tu romeli daavadebisken

arian midrekilni sisxlis pirveli jgufis adamianebi meoresTan SedarebiT

da a.S.

АВ0 sistemis antigenebi, maTi gavrceleba da asociacia daavadebebTan.

ABO sistema xasiaTdeba eriTrocitis zedapirze sami ZiriTadi antigenis - А, В,

H da plazmaSi - bunebrivi jgufspecifikuri glikoproteinuli anti -А da anti

- В antisxeulebis arsebobiT (Ogasawara et al., 1996). isini eriTrocitebis garda,

aRmoCenilia agreTve sekretebSi da adamianis qsovilTa umravlesobaSi

33

(Головачев, 1983). АВH antigenebi napovnia, aseve, sisxlSi leikocitebisa da

Trombocitebis membranis zedapirze (Доссе, 1959). АВ0 sistemis genuri lokusi

moTavsebulia me-9 qromosomaSi -9 q 34.1-q34.2. H genuri lokusi, romelic H

nivTierebis sinTezs akontrolebs, moTavsebulia 19 q13.3. igi АВ0-sgan

damoukidebel antigenur sistemas warmoadgens (Reguigne-Arnould et al., 1995;

Schenkel-Brunner, 2000).

sisxlis ABO sistemis fenotipuri jgufebis sixSire araTanabaria

msoflios populaciebSi, rac damokidebulia 0, А da В alelebis

ganawilebaze. eriTrocituri jgufuri antigenebis gavrcelebis variabe-

loba gamowveulia wlebis win populaciebis migraciebiTa da maTi SereviT.

aseve, populaciebis klinikuri istoriiT (gadatanili daavadebebi), re-

produqciuli TaviseburebiT da wes-CveulebiT, geografiuli arealiT,

genetikuri TaviseburebiT da a.S. mogvianebiT populaciebSi moxda maTi

dabalanseba da dafiqsireba, rogorc populaciisTvis damaxasiaTebeli

myari genetikuri niSani (Nasidze, 1995; Kucher at al., 2000; Михайлова c соавт., 2002;

Varsahr at al., 2003; Schmidt & Scheil, 2003).

msoflioSi yvelaze maRali sixSiriT (63%) O fenotipuri jgufia

gavrcelebuli. centralur da samxreT amerikis mkvidr populaciaSi misi

gavrceleba TiTqmis 100%-ia. aseve, maRalia misi sixSire avstraliel

aborigenebSi da dasavleT evropaSi. yvelaze dabali sixSiriT aRniSnuli

fenotipuri fgufi aRmosavleT evropasa da centralur aziaSia warmodgenili

(Garratty et al., 2004; Daniels et al, 2004; Dean 2005).

A aleli SedarebiT ufro farTodaa gavrcelebuli (21%) msoflios

mosaxleobaSi, vidre B. misi yvelaze maRali koncentracia montanas Savkanian

indielebSi (80%), avstraliel aborigenebSi (40-53%) da Crdilo skandinaviis

qveynebSi (laplandia, saamis qyveynebi) (50-90%) fiqsirdeba. aRniSnuli aleli

TiTqmis ar gvxvdeba centralur da samxreT amerikis indielebSi (Dean, 2005).

B(III) fenotipuri jgufi SedarebiT iSviaTi gavrcelebiT xasiaTdeba. B

alels msoflio mosaxleobis mxolod 16% atarebs. SedarebiT maRali

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Kucher+AN%22%5BAuthor%5D

34

sixSiriT fiqsirdeba igi centralur aziasa da afrikaSi. Zalian dabalia misi

gavrcelebis sixSire amerikisa da avstraliis aborigenul mosaxleobaSi

(Garratty et al., 2004; Dean, 2005).

AB iSviaTi fenotipuri jgufia. maqsimaluri sixSiriT (10%) igi CinelebSi

da koreelebSi gvxvdeba (Dean, 2005).

evropelebSi ABO sistemis fenotipuri jgufebi Semdegi TanafardobiT

nawildeba: O-44%; A1-33%, A2-10%; B-9%; A1B,-3%, A2B-1% (Dean, 2005).

saqarTveloSi ABO sistemis fenotipebis gavrcelebiT pirvel adgilzea

sisxlis O fenotipuri jgufi, meore adgils ikavebs A fenotipuri jgufi,

mesames B, xolo yvelaze dabali sixSiriT AB jgufi fiqsirdeba (Арчвадзе, 1978).

ukanaskneli monacemebiT, aWaris regionSi ABO sistemis fenotipuri jgufebis

gavrceleba Semdeg suraTs iZleva: O fenotipuri jgufi 47,6±3%; A _ 36±5,1%; B –

11,4±3,5%; AB _ 4,2±2% (Nagervadze et al., 2010). aRniSnuli sistemis alelebidan

yvelaze maRali (0,68) sixSiriT O alelia warmodgenili. rac Seexeba A alels,

misi sixSire 0,23-s, xolo B alelis - 0,09-s utoldeba (Nagervadze et al, 2010).

ramdenadac, yvela aloantigeni Sesabamisi genis serologiur produqts

warmoadgens da met-naklebad CarTulia organizmis imunur SesaZ-

leblobebSi, amdenad, sakmaod zustad SeiZleba korelaciuri kavSiris

Seswavla antigenur Semadgenlobasa da sxvadasxva saxis paTologias Soris.

dRes TiTqmis srulyofiladaa Seswavlili ABO sistemis sisxlis

jgufuri antigenebis klinikuri mniSvneloba da maTi roli transfuzi-

ologiaSi, magram aRniSnuli sistemis daavadebebTan asociaciuri kavSirebis

Seswavla, jer kidev, mecnieruli kvlevebis interesis sferod rCeba.

sisxlis jgufebsa da sxvadasxva saxis paTologiebs Soris

asociaciuri kavSirebis Sesaxeb literaturaSi monacemebi mravlad

moipoveba, romelic xSirad populaciebis Taviseburebebze aisaxeba.

infeqciuri daavadebebi yovelTvis mniSvnelovan rols TamaSobda

populaciebis genetikuri struqturis cvlilebaSi. cnobilia, rom popula-

ciebSi АВ0 sistemis antigenebis gavrcelebis sixSire pirdapir kavSirSia

35

aRniSnuli populaciis klinikur warsulTan, kerZod, iseT epidemiur,

infeqciur daavadebebTan, rogoricaa: Savi Wiri, qolera, yvavili, malaria.

im regionebSi, sadac gasul saukuneSi aRniSnuli epidemiebi mZvinvarebda,

gamoikveTa АВ0 sistemis р alelis sixSiris kleba, xolo q alelis sixSiris

zrda. swored, daavadebebis kerebTan alelTa sixSiris damokidebulebiT

aixsneba 0(I) da B(III) jgufis warmomadgenlebis simcire mongoloidur

populaciebSi, xolo A(II)-jgufis – evropoidul populaciebSi da a. S. (Salmon,

1979; Прокоп и Геллер., 1991).

gasuli saukunis 90-ian wlebSi ganxorcielebuli mecnieruli kvlevebiT

dadgenili iqna, rom mniSvnelovani asociaciebi arsebobs АВ0 fenotipur

jgufebsa da ama Tu im saxis paTologias Soris (Markovic et al., 1991; Nazaretian et

al., 1993; Albarus et al., 1997; Vojvodic, 2000). zogjer ABO sistemis fenotipebsa da

daavadebebs Soris imdenad myari korelacia ikveTeba, rom xSirad ama Tu im

fenotipuri jgufis matarebloba romelime konkretuli daavadebis mimarT

midrekilebas gansazRvravs.

ABO sistemis antigenebi korelaciaSia kuWis wylulovan da simsivnur

daavadebebTan (Dean, 2005). amas adasturebs gasuli saukunis mecnieruli

kvlevebic, romlis Tanaxmad, kuWisa da Tormetgoja nawlavis wylulovan da

simsivnur daavadebebTan sisxlis 0(I) jgufi asocirdeba (Туманова & Томилина,

1969; Косяков, 1974), xolo A(II) fenotipi xSirad prevalirebs kuWisa da sarZeve

jirkvlis kibos, miokardis infarqtis dros (Прокоп с соавт., 1991; Мороков с

соавт., 2002). A(II) jgufis matarebeli individebi xSirad eqvemdebarebian

virusul respiratorul da gulis iSemiur daavadebebs. aseve, maTSi ufro

xSiria magistraluri gzebis aTerosklerozi, vidre 0(I) da B(III) jgufis

matareblebSi (Nazaretian et al., 1993; Кузнецов с соавт., 2000).

gulis iSemiuri daavadebis ganviTarebis maRali sixSire A(II) jgufis

matareblebSi dakavSirebulia antihemofiluri globulinis aqtiur

sinTezTan. iTvleba, rom es ukanaskneli aRniSnuli paTologiis

ganviTarebaSi udides rols TamaSobs da ganapirobebs Trombozis mimarT

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Vojvodic+S%22%5BAuthor%5D

36

organizmis midrekilebas (Шабалин с соавт., 1988). dafiqsirebuli iqna agreTve,

rom A(II) sisxlis jgufis mqone bavSvebi xasiaTdebian pnevmoniis mwvave

mimdinareobiT (Моисеев, 1987). aseve, virusuli hepatitiT xSirad avaddebian A

jgufis sisxlis matareblebi (Kiango et al., 1982). A(II) jgufis adamianebSi

sustad producirdeba interferonebi. swored, amiT SeiZleba aixsnas am jgufis

matareblebis sakmaod maRali midrekileba infeqciuri daavadebebis mimarT

(Донсков, 1987).

sahas (Saha, 1985) monacemebiT, asociaciuri kavSiri iqna napovni ABO

sistemas da keTrs Soris. kerZod, aRniSnuli seniT avaddebian A da O jgufis

mqone individebi. A jgufis matareblebi rezistentulebi aRmoCndnen ciebis

mimarT (Gupta & Chowdhuri, 1980). amerikelebSi O jgufis maRal prevalentobas

sifilisis mimarT aRniSnuli jgufis matarebel individTa maRali mdgradobiT

xsnian (Morrison, 1966).

arsebobs monacemebi, romlebic A(II) da B(III) jgufis maRal sixSires

adastureben TromboflebitiT daavadebul qalebSi. magram aRniSnuli

jgufebis matareblebi gacilebiT rezistentulebi aRmoCndnen qoleris

mimarT, vidre O(I) jgufis sisxlis mqone individebi. dadgenili iqna

magistraluri sisxlZarRvebis aTerosklerozis uaryofiTi asociacia 0(I)

fenotipis matarebel mamakacebSi. 0(I) jgufis matarebloba, SesaZloa, CaiT-

valos “damcvelobiT” faqtorad, radganac maTSi Semcirebulia zogierTi

saxis sisxlZarRvis paTologiis ganviTarebis riski (Кузнецов с соавт., 2000).

zogadad, adamianebis umravlesoba, romelTa eriTrocitebis zedapirze

ar gvxvdeba ABO sisitemis antigenebi, daavadebaTa mimarT mdgradobiT

gamoirCevian. amis dasturad, SesaZloa, gamoyenebuli iqnes O(I) jgufis

gavrcelebis maRali sixSire msoflios mosaxleobaSi.

pensilvaniis universitetis mecnierebis mier Catarebuli kvlevebis

Tanaxmad, genebi, romlebic pasuxismgebelia O(I) jgufis Camoyalibebaze,

organizms icaven gulis Setevisgan. amave dros, sxva kvlevebma aCvena O(I) jgufis

pacientebSi maRalia sisxldenis riski da sisxlis gadasxmis aucilebloba,

http://www.ncbi.nlm.nih.gov/pubmed/?term=Gupta%20M%5Bauth%5D

http://www.ncbi.nlm.nih.gov/pubmed/?term=Chowdhuri%20AN%5Bauth%5D

37

gulze qirurgiuli Carevis Semdeg. harvardis universitetis mkvlevarebi

askvnian, rom sisxlis aRniSnuli jgufis matareblebi midrekilni arian

gulis daavadebebisken (Hope, 2012).

korelaciuri kavSiri iqna dadgenili sisxlis jgufebsa da mwvave

dizenterias Soris. maqsimaluri koeficientebi B(III) da 0(I) jgufis mqone

pacientebSi dafiqsirda, xolo minimaluri _ A(II) jgufis matarebel

pirebSi (Земсков, 1994). skleroziT daavadebulTa 22,22% aRmoCnda B(III)

jgufis fenotipis matareblebi, maSin, roca sakontrolo jgufSi misi

gavrcelebis sixSire 11.10%-is tolia (Markovic et al., 1991).

ABO sistemis sisxlis 0(I), A(II) da B(III) jgufis matareblebSi arsebobs

gansxvavebuli imunuri pasuxi. kerZod, sinTezirebuli jgufspecifikuri,

bunebrivi antisxeulebi IgG da IgM klasis imunoglobulinebia. amasTan,

cnobilia, rom А(II) da В(III) jgufis matareblebi upiratesad asinTezeben IgM

klasis antisxeulebs, maSin, roca 0(I) jgufis matareblebSi IgM-sTan erTad

damatebiT sinTezdeba maRalaviduri IgG (anti-A an anti-B). isini aqtiurebi

arian 37оС-ze da floben gamoxatul hemolizur Tvisebas. am mizezis gamo

АВ0 sistemis mixedviT gansxvavebuli fenotipebis matareblebi bunebaSi

farTod gavrcelebuli А- da В- substanciebis eliminaciis araerTgvarovan

unars floben (Issitt, 1985; Dean, 2005). gamovlenili iqna asociacia ABO sistemas

da simsivniT, sifilisiT, diabetiT, ciroziT, gripiT, pnevmoniiT, bronqitiT

da asTmiT gamowveul sikvilianobas Soris (Masse et all, 1979).

sasunTqi sistemis daavadebebidan cnobilia, rom bronquli asTmiT da

mwvave pnevmoniiT daavadebul pirebSi O(I) jgufis maRali sixSire vlindeba

(Джавишеишвили и Ксенофонтов, 1981).

ABO sistemis antigenebis korelacia filtvis tuberkulozTan. sxvadasxva

populaciaSi tuberkulozsa da ABO sistemis antigenebs Soris asociaciuri

kavSirebis gamosavlenad Catarebul kvlevebSi alternatiuli daskvnebi

fiqsirdeba. rigi mecnierebisa adasturebs, rom ar arsebobs mniSvnelovani

asociacia aRniSnuli sistemis antigenebs da filtvis tuberkulozs Soris

38

(Saha, 1965; Saha & Banerjee, 1968; Reddy & Usha, 1990; Seth & Chahal, 2003; Ukaejiofo &

Nubila, 2006.), maSin, roca, sxvebi aRniSnul faqts uaryofen (Kothare, 1959; Shenoy &

Daftary, 1962; Navani & Narang, 1962; Nath et al., 1963; Sidhu et al., 1974; Mourant et al., 1976;

Ramachandraiah et al., 1984; Bhasin, 1994).

rigi mecnierebis monacemebiT, tuberkuloziT daavadebul pacientebSi

maqsimaluri sixSiriT dafiqsirda 0 (I) da Semdgom B (III) fenotipuri jgufebi,

xolo minimaluri sixSiriT A(II) jgufi (Rao, 1994; Platonova, 1999). tiagisa da misi

TanamSromlebis mier tuberkuloziT daavadebul mgb+ pacientebSi, B (III)

fenotipuri jgufi maqsimaluri sixSiriT gamovlinda, xolo Semdgom adgilze

0 (I) fenotipuri jgufi _ donorul populaciasTan SedarebiT (Tyagi et al., 2010).

naumovisa da TanamSromlebis (Naumov et al.,1993) mier dadgenilia, rom

filtvis tuberkuloziT daavadebulebSi sakontrolo donorul jgufTan

SedarebiT, 0(I) jgufi maRali sixSiriT vlindeba. A(II) jgufis mqone pirebSi

ki daavadeba dabali sixSiriTaa warmodgenili da maT yvelaze naklebad

aReniSnebodaT postoperaciuli garTulebebi.

viskumis (Viskum, 1975) kvlevis Sedegad tuberkuloziT daavadebul

pacientebSi dafiqsirda O da AB jgufis gamovlenis maRali sixSire. amave

avtoris mier SeniSnuli iqna O jgufis matarebel daavadebulTa

sikvdilianobis maRali ricxvi, maSin, roca am mxriv dabali maCvenebelia

SeniSnui A jgufis matareblebSi.

ABO sistemis antigenebis asociaciuri kavSirebi Seswavlili iqna

daavadebis formebSic. MmkvlevarTa mier dafiqsirebulia tuberkulozis

msubuqi forma da mkurnalobis Sedegianoba 0 (I) da A (II) jgufis matareb-

lebisaTvis, maSin, roca B (III) jgufis matareblebSi mkurnalobis kursi

xSirad uSedegoa (Volkova et al., 1991; Platonova, 1999).

tuberkulozTan sisxlis jgufuri antigenebis da alelebis asociaciur

kavSirs adasturebs singapuris Cinur populaciaSi (Saha, 1965), iaponelebSi

(Hirano, 1972), eskimosebSi (Overfield & Klauber, 1980) Catarebuli kvlevebi,

romlebmac gamoavlina tuberkulozis mniSvnelovani asociacia B antigenTan

39

da, Sesabamisad, B da AB fenotipur jgufebTan. B antigenTan asociaciuri

kavSirebi gamovlinda indoelebSi, sadac, aseve, tuberkuloziT daavade-

bulebSi mniSvnelovani sixSiriT A(II) fenotipic dafiqsirda (Jain, 1970; Saha,

1985; Seth & Chahal, 2003; Saha & Banerjee, 2003). aseve, unda aRiniSnos, rom raos da

TanamSromlebis (Rao et al., 2012) monacemebiT, indoeTis teritoriaze mcxovreb

andras regionis tuberkuloziT daavadebul populaciaSi dafiqsirda sisxlis

B(III) da AB(IV) fenotipuri jgufebi, xolo Tamarias (Thamaria, 2010)

monacemebiT, indურ populaciaSi dafiqsirebuli iqna alternatiuli, daava-

debis 0(I) jgufTan asociaciuri kavSiri.

eTnikur jgufebSi eriTrocitur antigenebTan gansxvavebuli asociaciuri

kavSirebis gamovlena, SesaZloa, dakavSirebuli iyos eTnikur jgufebSi maTi

ganawilebis sxvadasxva sixSiresa da daavadebis multifaqtorul bunebaze.

Rh-Hr sisxlis jgufebis gavrceleba da misi asocireba daavadebebTan.

rezus sistema adamianis erT-erTi yvelaze polimorfuli da kompleqsuri

imunogenetikuri sistemaaDda moicavs 49 damoukidebel antigens. antigenebis

polimorfuloba serologiurad sisxlis mraval fenotipur jgufs iZleva.

klinikuri TvalsazrisiT yvelaze mniSvnelovania D, C, E, c, e antigenebi (Avent

& Reid., 2000).

Rh faqtori ganpirobebulia ori, erTmaneTTan Wdomili RHD da RHCE

genebiT, romlebic moTavsebulia 1 p36.1 – p34-3-Si. RHD lokusiT kontroldeba

D antigenis produqcia, RHCE lokusi ki ganapirobebs C an c da E an e

antigenebis sinTezs (Оловникова, 2001).

Rh sistemis antigenebi maRali imunogenuri TvisebebiT xasiaTdebian.

gansakuTrebuli imunogenuri aqtivobiT D antigeni gamoirCeva, romelic 30-ze

met epitops Seicavs da xSirad iwvevs alosensibilizacias D uaryofiT

pirebSi (Avent & Reid, 2000).

RHCE da RHD genebiT kodirebuli haplotipebidan (genuri kompleqsi)

yvelaze maRali sixSiriT 8 haplotipia warmodgenili: CDE (Rz), Cde (R1), cDE

(R2), cDe (Ro), cde (r), Cde (R’), cdE (R’’), CdE (Ry). gamoyofilia aRniSnuli sistemis

40

18 fenotipuri jgufi: CDE, CDEe, Cde, CcDE, CcDEe, CcDe, cDE, cDEe, cDe, CD(-)E,

CD(-)Ee, CD(-)e, CcD(-)E, CcD(-)Ee, CcD(-)e, cD(-)E, cD(-)Ee, cD(-)e. zemoT CamoTvlilTagan

Cde, cDE, cDe da cde sxvebTan SedarebiT ufro farTo gavrcelebiT xasiaTdeba.

maTi sixSire damokidebulia krosingoveris albaTobaზე (Syst. immunogen.

Polymorp., 2000).

msoflios mosaxleoba xasiaTdeba Rh-polimorfizmiT. D da d alelebis

sixSiriT evropeiduli da negroiduli rasebi mniSvnelovnad gansxvavdebian

mongoloidurisagan. mongoloiduri populaciisaTvis d aleli iSviaTobas

warmoadgens, zogierT maTganSi ki saerTod ar gvxvdeba, maSin, roca

aRmosavleT evropaSi misi sixSire 15-20%-ia, dasavleT evropaSi (magaliTad,

baskebSi) ki _ 40-50%-s aRwevs.

adgilobriv amerikelebSi, vidre maT msoflios sxva regionebis

mosaxleoba Seereoda, d alelis koncentracia praqtikulad ar fiqsirde-

boda, xolo D alelis koncentracia 99-100%-s Seadgenda, Sua saharis

afrikelebSi 97-99% Rh+-ia, xolo aRmosavleT aziaSi - 93-99%.

msoflios mosaxleobaSi rezusis sxva antigenebis gavrcelebis sixSire

Semdegnairia: C - 70%; E - 30%; e - 97% (Умнова c соавт., 1979).

rac Seexeba Rh-haplotipebis gavrcelebas CDe(R1), igi yvelaze farTod

gavrcelebuli haplotipia evropaSi, SedarebiT naklebad -afrikaSi (0,05-0,09).

cDE(R2) haplotipi mniSvnelovnad farTodaa dafiqsirebuli indielebSi

(0,50). cDe (R0) koncentracia msoflios sxva regionebTan SedarebiT maRalia

(0.90) afrikis kontinentze. Cde haplotipis maqsimaluri sixSire evropaSi

fiqsirdeba da sruliad ar gvxvdeba Soreul aRmosavleTSi. msoflios

yvela populaciisTvis iSviaTi CDE-haplotipi SedarebiT maRali koncentra-

ciiT gvxvdeba indur da avstraliur tomebSi, xolo aseve iSviaTi cdE haplotipi

SedarebiT xSirad - iaponur tomebSi.

Rh sistemis kvlevis TvalsazrisiT, saqarTveloSi monacemebi sakmaod

mwiria. cnobilia, rom dasavleT saqarTveloSi D(+) fenotipi gvxvdeba 95,9%-

is, xolo D(-)ki _ 4,1%-is sixSiriT. aRniSnul populaciur jgufSi D

41

alelis sixSire 0,796-is tolia, d alelisa ki _ 0,204 (Джавишеишвили и

Ксенофонтов, 1981). ukanaskneli monacemebiT, safuZvlianad iqna Seswavlili Rh

sistemis antigenebisa da haplotipebis gavrceleba aWaris regionSi, sadac D -

78,2%; e- 97.6%; c – 90.2%; C – 53.4%; E-21, 12% sixSiriT gvxvdeba. Sesabamisad,

aRniSnuli sistemis alelebi Semdegi sixSiriT aris warmodgenili: D – 0.54; d –

0.43; C-0.28; c-0.74; E- 0.11 da e – 0.87. aWaris regionisTvis farTo gavrcelebiT

dafiqsirda cde – 0.436 da Cde – 0,192 haplotipebi (Nagervadze, 2010).

daavadebebTan rezus sistemis asociaciis Sesaxeb zogierTi avtoris mier

naCvenebi iqna Rh(D) antigenis korelacia alcheimeriT daavadebul pacientebSi,

sadac pacientTa 95,55% rezus dadebiTi, 84,29% rezus uaryofiTi faqtoris

matarebeli aRmoCnda (Markovic et al., 1991). aseve, rezus dadebiTi, CcDe fenotipis

kavSiri gamovlenili iqna kuWis wylulTan (Пелешук c соавт., 1974). rezus

uaryofiT pacientebSi mcirea aortis anevrizmiT daavadebis albaToba. rezus-

uaryofiT adamianebSi gacilebiT ukeT funqcionirebs humoruli imuniteti,

xolo rezus-dadebiT pirebSi ki -ujreduli imuniteti (Norrgard et al., 1984

Донсков, 1987, 2001).

baqteriuli anatoqsinebiT gamowveuli imunuri pasuxis intensivoba

maRalia D da Е antigenebis matarebl pirebSi (Вереш с соавт., 1985). gulis

iSemiuri daavadeba maRali sixSiriT SeiniSneba CC genotipis mqone individebSi,

vidre Cc genotipis matareblebSi (Nazaretian et al., 1993).

tuberkulozTan rezus faqtorisa da misi antigenebis korelaciuri

kavSiris Sesaxeb Zalian mwiri masalebi moipoveba. mecnierTa nawili

tuberkulozTan Rh faqtoris pirdapir korelacias uaryofs. magaliTad, raos

(Rao et al., 2012) mier Catarebuli kvlevebis mixedviT A(II) sisxlis jgufis mqone

pacientebSi Rh+ faqtoris mniSvnelovnad maRali sixSire dafiqsirda sxva

kombinaciebTan SedarebiT. arsebobs monacemebi, rom ufro meti rezus-

uaryofiTi pacienti daiRupa tuberkuloziT, vidre rezus-dadebiTi (Viskum,

1975).

42

Kell sistemis sisxlis jgufebis gavrceleba da misi asocireba

daavadebebTan. Кеll sistemis genuri lokusi moTavsebulia meSvide

autosomur qromosomaSi _ 7q 32 – q 36. sistema kompleqsuria da moicavs 25

antigens (K, k; Kpa, Kpb; Jsa, Jsb…). yvelaze maRali imunogenurobiT К antigeni

gamoirCeva, romlis imunuri aqtivoba mcirediT Tu Camouvardeba rezus D

antigenis aqtivobas (Dean, 2005).

К antigenis gavrcelebis sixSire msoflio mosaxleobaSi sakmaod dabalia

(10%). homozigotur mdgomareobaSi ki igi mxolod 0.3%-ia (Рагимов и Дашкова,

2004). evropeidebs Soris Kell (K)-s Sexvedris albaToba 3-dan 12%-mdea.

evropeodebSi misi gavrcelebis sixSire 9%-ia (Dean, 2005), arabeTis mosax-

leobaSi -10%. espaneTis erT-erT lokalur populaciaSi maqsimaluri

sixSire - 31,71% dafiqsirda. negroidebSi da mongoloidebSi K antigeni

iSviaTad gvxvdeba, xolo Cinelebsa da iaponelebSi igi praqtikulad ar

aris gamovlenili (Mourant et al., 1978; Bowman et al., 1992). saqarTveloSi Kell

sistemis antigenebis gavrcelebis Sesaxeb informacia moipoveba mxolod aWaris

regionis masStabiT. К+ fenotipi aq 6%-ia, p(K) alelis koncentracia 0.04-is

tolia (Nagervadze, 2010).

paTologiebTan Кеll sistemis antigenebis kavSiri praqtikulad

Seuswavlelia. literaturuli wyaroebidan cnobilia Kell-dadebiTi sisxlis

jgufis maRali sixSire aortis anevrizmiT daavadebulebSi (Norrgard et al.,

1984). tuberkulozTan Kell sistemis antigenebis asociaciis Sesaxeb informacia

literaturul wyaroebSi TiTqmis ar moipoveba.

MN sisxlis jgufebis gavrceleba da misi asocireba daavadebebTan. MN-Ss

sistemis antigenebi kodirebulia GYPA da GYPB genebiT, romlebic

moTavsebulia me-4 qromosomaSi (4q28-q28) (McKusick, 1985; Dean, 2005). MN sistemis

43 antigenidan yvelaze mniSvnelovania M, N, S, antigenebi. maTgan SedarebiT

ukeT M da N antigenebia Seswavlili (Dean, 2005; Reid, 2009).

43

literaturuli monacemebiT, evropeodebSi M antigenis sixSire 78%-ia; N-

72%; S-55% xolo s-89% (Dean, 2005). murantis monacemebiT, saqarTveloSi,

kerZod, qalaq Tbilisis mcxovreblebSi M fenotipis gavrcelebis sixSire

Seadgens 39,6%-s, MN –is - 46,0; N fenotipisa ki _ 0,374%-s (Mourant et al., 1979).

nagervaZis monacemebiT, aWaris regionSi M fenotipi 50,2%; N - 29.8%; xolo MN

20,2% sixSiriT aris warmodgenili (Nagervadze, 2010).

rac Seexeba daavadebebTan MN sistemis korelacias, MN fenotipuri

jgufis maRali sixSire aRiniSneba Saqriani diabetiT daavadebulebSi

(Ксенофонтов, 1974). aseve, mwvave pnevmoniiT xSirad avaddebian MN fenotipis

matarebeli bavSvebi (Алтухов c соавт., 1981). aRniSnulia M fenotipis maRali

sixSire aTeroskleroziT daavadebulebSi, xolo N fenotipuri jgufi

sakontrolo jgufTan SedarebiT ufro xSirad gvxvdeba osteoqondroziT

daavadebul pirebSi (Колодченко., 1979).

cnobilia, rom MN sistemis makodirebel GYPB genSi (asinTezirebs

jgufobriobis ganmsazRvrel A da B glikofurinebs) momxdari konversia

gavlenas axdens malariisadmi mgrZnobelobaze (Ko., 2011).

MN-Ss sistemasa da gul-sisxlZarRvovan daavadebebs Soris garkveuli

asociaciuri kavSiri iqna napovni (Gleiberman et al., 1984). SeniSnulia agreTve M

jgufis matarebeli pirebis gansakuTrebuli midrekileba alkoholis mimarT

(Kojic et al., 1977). botinisa da misi TanamSromlebis mier dadgenili iqna MN

sistemis antigenebis dadebiTi korelaciuri kavSiri asTmasTan. kerZod,

donorebTan SedarebiT M fenotipis maRali sixSire - araalergiul asTmasTan,

xolo N antigenisa - alergiul asTmasTan. arsebobs varaudi, rom SesaZloa, MN

sistemis genetikuri variabeloba gavlenas axdendes baqteriul da virusul

konkurenciaze, sasunTqi sistemis lorwovani garsis dazianebis SemTxvevaSi

IgE-s hiperproduqciis ararsebobisas, rac gavlenas axdens asTmur reaqciebze

(Bottini et al., 2005).

informacia MN sistemisa da filtvis tuberkulozis korelaciuri

kavSirebis Sesaxeb literaturul wyaroebSi ver iqna moZiebuli.

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=PubMed&cmd=Search&term=%22Gleiberman+L%22%5BAuthor%5D

http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pubmed&cmd=Search&term=%22Bottini+N%22%5BAuthor%5D

44

I.6. organizmis imunuri dacvis meqanizmebi

mikobaqteriis mimarT ganviTarebul imunur pasuxSi

tuberkulozis ganviTarebaSi fundamentur rols asrulebs M.

Tuberculosis-is mimarT organizmis imunuri pasuxi, rasac daavadebulebTan

SedarebiT inficirebulTa gacilebiT maRali ricxvi adasturebs. infeqciuri

agentis bedi organizmSi moxvedris Semdeg, organizmis sxva faqtorebTan

erTad, damokidebulia mis mimarT ganviTarebul araspecifikur Tu specifikur

imunur pasuxze. arasaTanado SemTxvevaSi inficirebul individSi daavadeba

klinikuri saxiT vlindeba. imunuri sistemis arsebiTi rolis damadasturebel

faqts warmoadgens isic, rom mniSvnelovnad izrdeba tuberkuloziT avadoba

adamianis imunodeficitis virusiT koinfeqciisas (Palomino et al., 2007).

aseve, kargad aris cnobili, rom BCG vaqcinaciac saTanadod ver

uzrunvelyofs tuberkulozis prevencias. aRniSnuli faqtebidan gamomdinare,

Seiqmna aSkara moTxovnileba axali antituberkulozuri Tu sxva saxis

qimioTerapiuli preparatebis da axali, maRalefeqturi vaqcinis Sesaqmnelad

(Palomino et al., 2007).

adreuli kvlevebis umravlesoba, ZiriTadad, xazs usvamda mikrobis

virulentobas da maspinZeli organizmis imunuri sistemisagan Tavdacvis

strategiebs. naklebi yuradReba eqceoda TviT makroorganizmis damcvelobiTi

sistemis arsebiT rols am procesSi (Shinnic et al, 1995; Soolingen, 2001; Smith, 2003).

bolo periodis kvlevebSi xazgasmulia, rom daavadebis klinikuri ganviTareba

Tanabrad ganisazRvreba, rogorc mikobaqteriis virulentobiT, ise maspinZeli

organizmis damcvelobiTi meqanizmebiT (Rajpal et al., 2011). kvlevebi mimdinareobs,

rogorc mikobaqteriis biologiuri Taviseburebebis gasarkvevad, ise adamianis

mier daavadebis winaaRmdeg ganviTarebuli imunuri pasuxis meqanizmebis

Sesaswavlad (Schluger, 2001; Casanova& Abel, 2002). mikobaqteriuli infeqciis

45

Sedegi ganisazRvreba imunuri sistemis, maspinZeli organizmis da mikobaqteriis

gadarCenis strategiebis erTobliobiT.

antituberkulozur dacvaSi TanabarmniSvnelovnadaa CarTuli, rogorc

Tandayolili, ise SeZenili imuniteti, romlebic komplementurad da

sinergiulad moqmedeben. am procesSi CarTuli imunuri meqanizmebis srul-

yofilad gageba samomavlod migviyvans, rogorc prevenciis, aseve Terapiis

axali midgomebis mignebamde (Flyn & Chan., 2001; Kaufmann., 2001; Raja., 2004).

Tandayolili imunuri pasuxi M. Tuberkulosois-is winaaRmdeg.

tuberkulozuri infeqciis adreul stadiaze Tandayolili imuniteti

asrulebs mniSvnelovan rols, magram igi, aseve, SeZenili imunitetis

iniciaciisa da moqmedebis gasaRebia (Crevel et al, 2002).

M. Tuberkulosois-iT inficirebis SemTxvevaSi pirveli xazis damcveli

ujredebi, romlebic inhalirebul paTogenze moqmedebs, alveoluri

makrofagebia, romlebic STanTqaven da moineleben bacilas. gadamuSavebuli

bacila Semdeg etapze waredgineba T ujredebs, rac iwvevs mikobaqteriis mimarT

ujreduli imunitetis stimulirebas. makrofagebis mier baqteriis gamocnobas

da Semdeg mis STanTqmas ganapirobebs mis zedapirze arsebuli zedapiruli

receptorebi –komplementis receptori (CR- C3), manozas receptori,

skavenjeruli receptori, Fc-γ, CD14 fagocituri ujredebi (Schlesinger et al, 1993;

Pugin et al, 1994 Schluger & Rom., 1998; Le Cabec et al, 2000; Kaufmann, 2001).

mikobaqteriis raodenobis Semcirebisa da misi gavrcelebisagan Tav-

dacvis mizniT makrofagebi ganicdian apoptozs, rac TavisTavad anadgurebs

ujredSida bacilebs. am procesis mTavari mastimulirebeli faqtori aris

simsivnis nekrozis faqtori (TNFα) (Balcewicz-Sablinska et al, 1998). TNFα-

transmembranuli cilaa, romelic Tandayolil imunitetSi gamoicnobs

paTogenTan asocirebul molekulebs (PAMP), romlebic Tandayolili imunite-

tis saukeTeso samizneebs warmoadgenen (Medzhitov et al., 2001; Akira et al., 2001).

46

Toll cilebi citokinebis, qemokinebis, histoSeTavsebulobis mTavari

komleqsis cilebis, azotis oqsidis sinTetazas da sxvaTa sinTezs aaqtiveben.

ufro metic, TLR akontrolebs SeZenil imunitetsac (Iwasaki & Medzhitov., 2004).

kerZod, maT mier ligandebis gamocnoba iwvevs interleikin-12-is sinTezs,

romelic ganapirobebs Th0-is Th1 helperebad diferencirebas. TLR-ebi

astimulireben antigen-warmdgeni dendrituli ujredebis momwifebas (Medzhitov,

2001; Akira et al, 2001).

cnobilia, rom tuberkulozis mimarT imunur pasuxSi mTavari roli

alveolur makrofagebs akisriaT.Mmagram aRsaniSnavia, rom mikobaqteriiT

inficirebidan ramdenime dRis Semdgeg infeqciis kerebSi Cndeba neitrofilebi

(Pedrosa et al., 2000; Fultonet al., 2002). isini xels uSlian bacilis gamravlebas.

aseve fiqroben, rom isini akontroleben infeqcias qemokinebis produqciiT,

granulomebis CamoyalibebiT da a.S. (Riedel et at., 1997; Urban et al., 2006).

tuberkulozur kerebSi napovnia dendrituli ujredebis didi

raodenoba. isini Seicnoben, iWeren, gadaamuSaveben antigens da waradgenen

histoSeTavsebulobis mTavari kompleqsis (MHC) molekulebTan erTad.

(Banchereau 1998, Gumperz 2001).

filtvebSi mikobaqteriuli infeqciidan 21 dRis Semdeg bunebrivi

qilerebis raodenoba matulobs. isini umniSvnelod zrdian citotoqsi-

kurobas CD8+T-ujredebis mier IFNγ produqciis optimizaciis gziT. amiT,

garkveulwilad, xels uwyoben mikobaqteriiT inficirebuli ujredebis daSlas

(Vankayalapati et al., 2004).

adapturi imunuri pasuxi M. Tuberkulosois-is winaaRmdeg. araspecifikuri

imunuri pasuxi gavlenas axdens specifikuri imunuri meqanizmebis moqmedebaze,

romelic axorcielebs efeqtorul funqciebs. orive meqanizmi urTierTdamo-

kidebulia.

specifikuri ujreduli da humoruli imunitetis Seswavla tuberkulo-

ziT daavadebulebSi, jer kidev, koxis dros daiwyo. T-limfocitebi da

gaaqtivebuli makrofaguli sistema aregulirebs tuberkulozis infeqciisadmi

47

organizmis mdgradobas. antituberkulinuri antisxeulebis roli jer kidev ar

aris srulyofilad garkveuli.

ujreduli imunuri pasuxi. mas Semdeg, rac tuberkulozis Cxiri

makrofagSi SeiWreba, misi antigeni CD4+T-limfocitebs waredgineba MHCII

klasis molekulebTan erTad. isini mniSvnelovan rols asruleben M.tuberculisis

winaaRmdeg damcvelobiTi pasuxis ganviTarebaSi. maT gareSe SeuZlebelia

organizmSi bacilis zrdis kontrolireba. aRniSnuli SemTxvevebi xdeba

imunodeficitebisas (Caruso et al., 1999). CD4+T-ujredebi TavianT funqcias

citokinebis produqciiT axorcieleben. isini aaqtiveben makrofagebs da xels

uwyoben bacilis destruqcias (Serbina et al., 2001). aseve, SesaZloa, isini

monawileobdnen inficirebuli makrofagebis apoptozSi da sabolood _

baqteriis sicocxlisunarianobis reduqciaSi CD95 ligandis meSveobiT (Oddo et

al., 1998). Sesabamisad, tuberkulozuri infeqciisas organizmSi izrdeba T-

ujredebis done, romlis Semcireba daavadebis gamwvavebas iwvevs.

gansakuTrebuli funqcia aqvs γδ T-ujredebs. isini monawileoben lizisur

procesebSi, asinTezeben citokinebs (IL17 da IFN-γ) da monawileoben

citotoqsikur aqtivobebSi.

humoruli imunuri pasuxi. imis gamo, rom mikobaqteria ujredSida

paTogenia, xSirad miiCneven, rom humoruli imunuri pasuxi am SemTxvevaSi

damcvelobiT rols ver asrulebs. Tumca, sawyisi infeqciis mimdinareobisas

antisxeulebi, rogorc damoukideblad, ise citokinebTan kavSirSi, SesaZloa,

uzrunvelyofdnen lorwovan garsebSi baqteriis SeWris prevencias. arsebobs

monacemebi, rom humoruli imunuri pasuxi mniSvnelovan rols asrulebs iseTi

infeqciebis mimarT, rogoricaa: qlamidiuri respiratoruli (Skeldin, 2006),

aqtinomicetebiT da, maT Soris, M. Tuberculosis-iT gamowveuli infeqciebis

(Salinas-Carmona et al., 2004, Williams et al., 2004, Reljic et al., 2006) dros.

M. tuberculosis-gan dacvis humoruli imunuri pasuxi srulyofilad ar aris

Seswavlili. mikobaqteriuli infeqciisas antisxeulebis damcvelobiTi

48

funqciis garda, specifikuri antituberkulozuri antisxeulebi, SesaZloa,

mniSvnelovnad Rirebuli iyos klinikur-serologiuri diagnozirebisas.

serologiuri meTodebi Tavisi simartiviT, xelmisawvdomobiT da dabali

fasiT mimzidveli sadiagnostiko saSualeba iyo me-20 saukuneSi. jer kidev 1898

wels arlongma aCvena, rom pacientebis sisxlis Srati awebebda tuberkulozis

bacilebs. me-20 saukunis 70-ian wlebSi mecnierebi Seecadnen, imunofermen-

tuli analizis meTodebis gamoyenebiT gamoevlinaT serodiagnostirebis-

Tvis optimaluri antigeni. im droisaTvis aqcenti keTdeboda kompleqsur

antigenebze, rogoricaa: mTliani baqteria, kulturis filtrati, baqteriuli

eqstraqtebi - tuberkulini da maTi sufTa narCenebi (PPD). SemdgomSi, analizi

tardeboda gasufTavebul antigenebze, romlebic moicavda cilebs, lipopoli-

saqaridebs da glikolipidebs (Ag85, 38-kDa cila, LAM an diaciltrehalozebi).

daavadebul da janmrTel populaciebSi 38-kDa, rMTB48, rCFP-10/ESAT-6–s da

HLA-s SeswavliT maT mimarT gamomuSavebuli antisxeulebis gacilebiT

maRali koncentraciebi gamovlinda tuberkuloziT daavadebul pacientebSi,

janmrTelebTan SedarebiT (Bothamley, 1995; Lyashchenko et al, 1998; Xueqiong et al,

2010). Tumca, aRsaniSnavia, rom maRali specifikuroba zusti diagnostikuri

TvalsazrisiT verc erTma maTganma ver aCvena (Singh et al., 2003; Raqib et al., 2003;

Lopez-Marin et al., 2003; Julián at al., 2004).

SratSi mocirkulire antisxeulebi (IgG, IgA, IgM) zrdian imunitetis

dones sxvadasxva meqanizmis (toqsinebis neitralizacia, ofsonizacia,

komplementis aqtivacia, citokinebis sekreciis stimulacia, antisxeul-

damokidebuli citotoqsikuroba, antigen-warmdgenis reaqciebis gazrda)

saSualebiT. mTeli rigi kvlevebi miuTiTebs, rom anti-mikrobuli antisxeulebi

mniSvnelovan rols asrulebs antituberkulozuri imunuri pasuxis

sxvadasxva etapze (Costello et al., 1992; Teitelbaum 1998; Hoft et al., 2002; Williams et al.,

2004). valieris mier naCvenebi iqna, rom specifikuri antisxeulebi zrdian BCG-s

internalizacias da ganadgurebas makrofagebisa da neitrofilebis mier.

49

ufro metic, antisxeulebiT SefuTul BCG bacilebs imunur pasuxSi

dendrituli ujredebi ukeT gadaamuSaveben da warudgenen CD4+ da CD8+ T-

ujredebs (De Valliére,2005).

antisxeulebis mier mikrobTa internalizacia da maTi pirdapiri

ganadgureba specifikuri mikrobuli samizneebis gamocnobis xarjze cnobili

ar aris. magram, eqsperimentSi BCG vaqcinaciiT gamowveuli humoruli imunuri

pasuxis Seswavlisas ikvlevdnen 17 saxis rekombinantul, mikobaqteriul

cilovan antigens (bunebriv Ag85 kompleqss, LAM da mikobaqteriis gamonawurs).

aRmoCnda, rom LAM-reaqtiuli Sratis mimarT imunur pasuxSi IgG-is done

mniSvnelovnad iyo gazrdili, rogorc vaqcinirebul individebSi, aseve

tuberkulozur pacientebSi. oraluri BCG vaqcinaciisas ki LAM-reaqtiuli

sekretoruli IgA donis mniSvnelovani zrda gamoikveTa (Brown et al., 2003).

aRniSnuli faqti miuTiTebs, rom Sratis imunoglobulinebi aqtiuradaa

CarTuli organizmis antimikobaqteriul dacvaSi da maTi donis gamovlena M.

Tuberculosis-iT inficirebis indikators warmoadgens.

IgA-s antimikobaqteriuli moqmedebis gasarkvevad Tagvebze Catarebul

eqsperimentSi gamovlinda, rom monoklonuri IgA-s intranazaluri (aerozoli)

inokulireba alfa kristalinis (stresuli faqtori) winaaRmdeg, daaxloebiT

9 dReSi 10-jer amcirebs mikobaqteriis kolonia-warmomqmnel erTeuls (CFU)

filtvebSi. rogorc monomeruli, ise polimeruli IgA-s Seyvanam Tanabrad

Seamcira kolonia-warmomqmneli erTeulebi, rac SesaZloa, gamowveuli iyos

imiT, rom inficirebuli filtvis makrofagebSi antisxeulebis samizneebs

warmoadgends Fcα receptorebi (Fc-αR) da ara polimeruli imunoglobu-

linuri receptori (poli-IgR). rogorc mosalodneli iyo, dacva ganxor-

cielda xanmokle periodis manZilze, rac SesaZloa, aixsnas imunoglobulinis

intranazaluri Seyvanis Semdeg misi swrafi degradaciiT (Williams et al., 2004;

Palomino et al., 2007).

50

mogvianebiT, tuberkuloziT daavadebul cxovelebSi jer gama

interferonebis inokulirebas axdendnen, xolo sami dRis Semdeg SehyavdaT

IgA-s drois gansxvavebuli intervaliT (2sT, 2 da 7 dRe). Sedegad CFU 10-is

nacvlad Semcirda 17-jer, iseve, rogorc, Semcirda granulomatozuri

infiltracia filtvSi (Reljic et al., 2006). amrigad, INF-γ da IgA, tuberkulozur

imunodeficitur pacientebSi SesaZlebelia gamoyenebuli iqnas, rogorc

profilaqtikuri an damatebiTi qimioTerapiuli samkurnalo saSualeba.

garda IgA-isa, IgG-c mniSvnelovan rols asrulebs tuberkulozuri

infeqciis marTvis procesSi. qvemo respiratoruli traqtis lorwovan garsebSi

IgA-Tan erTad aRmoCenili iqna IgG (Boyton & Openshaw., 2002).

jainisa da misi TanamSromlebis (Jain et al., 1984) mier filtvis

tuberkuloziT daavadebulebSi imunoglobulinebis donis Seswavlisas,

aseve gamovlenili iqna IgG-sa da IgA-s mniSvnelovnad maRali done donorebTan

SedarebiT. IgA mniSvnelovnad maRali sixSiriT qalebSi dafiqsirda, xolo IgG-

sa da IgM-s done sqesis mixedviT ar varirebda. daavadebis klinikuri

formebis SemTxvevaSi IgG-s maRali done gamovlenili iqna tuberkulozis

fibro-kavernozul formaSi. zogierTi avtoris mier dafiqsirebuli iqna, rom

IgM klasis imunoglobulinis mateba SeiniSneba daavadebis adreul stadiaze,

xolo daavadebis Semdeg stadiebze gazrdili IgG-is koncentracia, SesaZloa,

kavSirSi iyos baqteriebis aqtiuri ganadgurebis procesTan (Ferdous et al., 2008).

specifikuri da araspecifikuri imunuri markerebis garda, romelic

moicavs M. tuberculosis Sratis specifikur antisxeulebs, humorul imunur

pasuxSi CarTulia sxva iseTi nivTierebebic, romelTa arseboba organizmSi

daavadebis indikatorad SeiZleba miviCnioT, rogorc filtvis, ise filtvgare

tuberkulozis SemTxvevaSi. aRniSnul indikatorebs ekuTvnis T-limfocitebis

fermentuli adenozin-deaminazebi, makrofagebis aqtivaciis neopterinuli

produqtebi, mononukleuri ujredebis zedapiruli cila β2 mikroglobulini,

T- ujredebis xsnadi interleikin (IL)-2-is receptorebi, iseve, rogorc xsnadi

51

CD4 da CD8 receptorebi, makrofagebisa da T-ujredebis adheziis molekulebi

da mwvave fazis reaqtiuli cilebi (Hosp et al., 1997; Baumer et al., 1998).

antimikobaqteriul dacvaSi, aseve, CarTulia sxvadasxva saxis

mediatorebi: pre-inflamatoruli citokinebi - IFN-γ (Lalvani et al., 1998), romlis

producirebas da CD4 T- ujredebis diferencirebis stimulirebas IL-12 –

iwvevs (Cooper et al., 1997; Flynn & Chan, 2001). cnobilia, rom IFN-γ-s, IL-12-sa da

misi receptorebis makodirebel genebSi napovni mutaciebi asocirdeba mZime

mikobaqteriul infeqciasTan (Malik & Schurr, 2002). aseve, IL-1β citokini

aqtiuradaa CarTuli granulomebis formirebaSi tuberkulozuri infeqciisas

(van Crevel et al., 2002). xolo IL-18 astimulirebs sxva preinflamatoruli

citokinebis, qemokinebis da transkripciuli faqtorebis produqcias (Netea et al.,

2000). IL-18-iT blokirebul TagvebSi maRali mgrZnobeloba gamovlinda BCG-iT

da mikobaqteriiT inficirebisas (Sugavara et al., 2002).

anti-inflamatoruli citokinebidan aRsaniSnavia IL-10. igi sinTezirdeba

makrofagebis mier mikobaqteriis STanTqmis Semdeg, aseve sinTezirdeba T-

ujredebis mier (Shaw et al., 1998; Boussiotis et al., 2000). igi Trgunavs IFNγ-s, Il-12-s

da TNFα-s producirebas (Fulton et al.,1998). TagvebSi misi blokirebis

SemTxvevaSi mikobaqteriisadmi mdgradoba aRar vlindeboda (North et al., 1999),

Tumca, misi roli bolomde garkveuli ar aris.

TGFβ sinTezirdeba monocitebisa da dendrituli ujredebis mier, mas

Semdeg, rac mikobaqteriiT stimulireba moxdeba (Toossi et al., 1995). is Trgunavs

T-ujredebis proliferacias, IFNγ-s produqcias, makrofagebis mier antigenis

wardgenis reaqciebs, pro-inflamatoruli citokinebis produqcias da

ujredul aqtivacias. cnobilia, rom isini tuberkulozisas iwveven qsovilebis

dazianebas da fibrozs (Toossi & Ellner, 1998).

TagvebSi tuberkulozis gamwvavebisas aRiniSna IL-4 -is donis mateba

(Howard & Zwilling, 1998). cnobilia, rom ujreduli imuniteti IL-4 -is produqciis

52

Semdeg ar stimulirdeba (North et al., 1999), amitom misi roli klinikuri Sedegis

TvalsazrisiT mniSvnelovania.

tuberkulozis mimdinareobisas mniSvnelovania qemokinebi - IL-8,

monocitis qemoatraqtuli cila-1 (MCP-1) da RANTES (Zhang et al., 1995; Kurashima

et al., 1997; Sadek et al.,1998; Pedrosa et al., 2000). cnobilia, rom tuberkulozis

mkurnalobis Semdeg pacientebis SratSi IL-8 done aweulia (Murphy, 1997). MCP-1

sinTezirdeba makrofagebisa da monocitebis saSualebiT da misi done

tuberkulozur pacientebSi maRalia (Kurashima et al., 1997). RANTES - qemokini

tuberkulozur procesebSi pasuxismgebelia granulomebis warmoqmnaze

(Chensue et al.,1999).

filtvis tuberkulozis aqtivaciisas SratSi gazrdilia komplementis

cilebis C3 –sa da C4-s koncentraciebi (Bothamley, 1995). aseve, isini ganixileba,

rogorc daavadebis aqtivaciis markerebi (Bekker et al., 1998; Juffermans et al., 1998;

Verbon et al., 1999).

tuberkulozis dros ujreduli da humoruli imunuri pasuxis

meqanizmebis srulyofilad codna, SesaZloa, gamoyenebul iqnes

tuberkulozis axali srulyofili vaqcinis Sesaqmnelad, alternatiuli

imunoTerapiis, daavadebis garTulebis prevenciisa da misi marTvis saqmeSi.

53

I.7. tuberkulozi da M. tuberculosis-is mimarT

organizmis mgrZnobelobaSi monawile genebi

tuberkulozis gamomwvevi baqteriiT inficirebisas daavadebis klinikur

ganviTarebaze mepatrone organizmis genetikuri faqtorebis mniSvneloba eWvs

aRar iwvevs (Bellamyet al.,1998; Bellamy, 2005; Freidin et al., 2006; Hill, 2006; Ottenhoff, 2005;

Remus, 2003). ukanaskneli ori aTwleulis manZilze ganxorcielebuli

kvlevebiT dadasturebulia, rom tuberkulozis mimarT arsebobs organizmis

genetikuri winaswarganpirobebuloba (Stead et al.,1990; Shaw et al.,1997; Li et al.,

2006/2006; van der Eijk et al.,2007). Catarebuli kvlevebi ZiriTadad tuberkulozis

filtvis formas exeba, radgan tuberkulozuri daavadebebis 95% masze mo-

dis da filtvgareSe formebTan SedarebiT srulyofiladaa Seswavlili.

identificirebuli iqna filtvis tuberkulozis mimarT mgrZnobelobis

ara erTi geni da genTa aleli, romelTa, Tundac erTnukleotidiani cvlileba

ganapirobebs misi funqciis Secvlas da gavlenas axdens daavadebis mimarT

organizmis sensibilobasa Tu mdgradobaze. magram amavdroulad,

tuberkulozis mimarT mgrZnobiare kandidati genebis Sesaxeb miRebuli

monacemebis mixedviT zogadi daskvnebis gakeTebas arTulebs is garemoeba, rom

kvlevebi gansxvavebul populaciebSi gansxvavebul, zogjer sapirispiro

Sedegebs iZleva. Tu erTi romelime konkretuli geni an genis aleli asocirebu-

lia tuberkulozTan konkretul populaciaSi, aRniSnuli asociacia ar

fiqsirdeba sxva populaciaSi (Li et al., 2006). amis mizezi xSirad konkretuli

populaciisTvis damaxasiaTebeli balansuri polimorfizmis Sedegia, romelic

konkretul garemoSi evoluciurad TviT am populaciebTan erTad Camoyalibda.

gansxvavebuli alelebis Semcveloba populaciur doneze pirdapir

gansazRvravs tuberkulozis mimarT populaciis mgrZnobelobas an mdgradobas.

xSirad populaciebSi alelur da araalelur genebTan urTierTqmedebis

balansi gansazRvravs specialuri imunuri genebis eqspresirebis dones da

xasiaTsac, Sesabamisad Sedegebic gansxvavebulia.

54

tuberkulozTan asocirebuli genebis TiTqmis 90% organizmis imunuri

sistemis makontrolebeli genebia, romlebic infeqciuri agentebis mimarT

damcvelobiT imunur pasuxs aviTareben. mecnieruli kvlevebis mTavari

fokusic, swored, maTi genetikuri lokusebis Seswavlisa da daavadebasTan

asociaciis gamovlenis mimarTulebiT warimarTa. aRniSnuli genebis

gamovlena inficirebamde an inficirebis Semdeg daavadebis mimarT

prognozirebis da prevenciis sakmaod did perspeqtivas warmoadgens.

cnobilia, rom antituberkulozur imunur pasuxSi mTavari alveolebSi

ganviTarebuli fagocituri pasuxia, sadac arsebiT rols alveoluri

makrofagebi asruleben (van Crevel et al., 2002; Adams et al., 1997). am procesebSi

CarTulia, aseve, TLR, romelic ganapirobebs organizmis imunuri pasuxis

stimulirebas da mikobaqteriis ganadgurebas (Kaufmann, 2001). Sesabamisad,

gasul aTwleulSi kvlevebis ZiriTadi nawili am procesebSi CarTuli

makrofaguri cilebis da TLR makodirebeli genebis kvlevebs moicavs

(Medzhitov, 2001; Krutzik et al, 2001; Iwasaki & Medzitov, 2004).

TLR (TLR1, 2, 4 da 6) Seicnobs sxvadasxva paTogenTan asocirebul

molekulebs (adapturi MyD88 cila) da astimulirebs Tandayolili

imunitetis ganviTarebas, citokinebis producirebas da adapturi imunitetis

process (Cook et al, 2004). maT aqvT unari, imoqmedon tol-interleikin-1-is

receptoris adaptur cilasTan (TIRAP lokalizebulia citoplazmaSi TLR2 da

TLR4 cilebis saxiT,) da moaxdinon makrofagebisa da dendrituli ujredebis

aqtivacia (Heldwein 2002; Khor et al., 2007). aRniSnuli adapturi cilis makodire-

beli genis polimorfuli variaciebi gansazRvraven organizmis gansxvavebul

midrekilebas infeqciuri daavadebebis mimarT. magaliTad, vietnamis

populaciaSi am genis TIRAPC558T*T polimorfuli variacia asocirdeba

tuberkulozur meningitTan (Hawn et al., 2006), xolo kolumbiis populaciaSi

igive polimorfuli variacia (TIRAPC558T*T) filtvis tuberkulozis mimarT

organizmis mdgradobasTan asocirdeba (Castiblanco et al., 2008).

55

infeqciuri daavadebis mimarT mgrZnobelobis ganmsazRvreli genebis

didi nawili moTavsebulia adamianis histoSeTavsebadobis mTavar kompleqs-

Si (MHC) (Medzitov, 2001). pacientebi, romlebic atareben gansazRvruli tipis

adamianis leikocituri antigenebis (HLA) II klasis alelebs, aviTareben

gansxvavebul imunur pasuxs tuberkulozis mimarT da gansxvavebulad arian

midrekilni daavadebis ganviTarebisken. HLA-s da tuberkulozs Soris

asociaciuri kavSiris Sesaswavlad sxvadasxva populaciaSi Catarebuli

kvlevebis Sedegad gamovlenilia tuberkulozisadmi genis mgrZnobelobis 10

polimorfuli variacia. (Kim et al.,2005; Freidin et al., 2006; Palomino et al., 2007; Taype et

al., 2010;).

HLA-DRB1*1501 da -DQB1*0601 alelebi tuberkulozTan asocirdeba

indoeTis Crdilo da samxreTis eTnikur populaciebSi (Ravikumar et al., 1999),

xolo -DQB1*0503 aleli - vietnamis populaciaSi (Goldfeld et al., 1998). HLA-

DQB1*05 da -DQB1*02 alelebis asociaciuri kavSiri tuberkulozTan

dafiqsirda poloneTis populaciaSi (Dubaniewicz et al., 2003). meqsikaSi - HLA-

DQA1*0101, -DQB1*0501 (Escandon et al., 1999), xolo koreaSi HLA-DRB1*0803 da -

DQB1*0601 alelebi aRmoCnda CarTuli daavadebis progresirebaSi. kanadis

mosaxleobis kvlevisas gamovlinda tuberkulozis winaswarganpirobebulobis

HLA-B8 aleli, CrdiloeT amerikis zangebSi –HLA-B5, -B15 da DR-5 aleli,

egviptelebSi - HLA- A2 da –B5, berZnebSi - HLA–B27 aleli. kvlevaTa Sedegebi

metyvelebs, rom MHC genebis polimorfizmi msoflios mraval populaciaSi

asocirdeba tuberkulozisadmi populaciis mdgradobis gaZlierebasTan

(Kim et al., 2005).

TNFα-is makodirebeli genis, romelic mTavar rols TamaSobs

tuberkulozis dros granulomis warmoqmnaSi da makrofagebis aqtivaciaSi,

lokusi ganTavsebulia MHC klasis III regionSi. bekeris (Bekker et al., 2000)

monacemebiT, TNF-α asocirdeba eqstensiur tuberkulozTan. msgavsi asociacia

eqstensiuri tipis tuberkulozTan rusul populaciebSi TNF-308 polimor-

fizmTan gamovlinda (Bikmaeva et al., 2002), Tumca, peruSi tuberkulozTan

56

aRniSnuli lokusis asociaciuri kavSiri ar iqna napovni (Ben-Selma et al., 2010;

Fan et al., 2010). selvarajis (Selvaraj et al., 2001) mier indur populaciaSi miRebuli

monacemebiT, Tu genomSi HLA-A1, -B17, -B21 da -DR7 TNF-308*A erTad iqneba,

kompleqsi ganapirobebs tuberkulozis mimarT organizmis mdgradobas da

mikobateriis inhibirebas.

rigi mecnierebis azriT, tuberkulozis winaswarganpirobebulobas

gansazRvravs gama-interferonis (IFN-γ) makodirebeli lokusebi, romelTa

produqtebi CarTulia mikobaqteriis mimarT ganviTarebul ujredul imunur

pasuxSi (Flynn, 1993; Lalvani et al, 1998; Hill et al., 2006; Taype et al., 2006).

garda zemoT aRniSnuli genetikuri lokusebisa, mecnierTa yuradReba

miipyro interleikinebis makodirebeli genebis polimorfizmsa da

tuberkulozs Soris asociaciurma kavSirma. aRniSnuli lokusebi maRali

variabelobiT xasiaTeba da xSirad specifikuria sxvadasxva eTnikuri

populaciisTvis. cnobilia, rom IL-12BR1 geni akodirebs IL- 12 receptors. igi

marokos (Remus et al., 2004; cooper et al., 2007) da iaponiis (Akahoshi et al., 2003)

populaciaSi asocirdeba filtvis tuberkulozTan da aRniSnuli lokusis

matarebel pirebSi daavadebisadmi mgrZnobeloba gazrdilia, magram genis IL-

12RB1 variacia, romelic gamowveulia erTnukleotidiani cvlilebiT, iaponur

populaciaSi ar asocirdeba daavadebasTan (Lee et al., 2005).

gambiis mosaxleoba filtvis tuberkulozisagan garkveulwilad

„daculia“ heterozigoturi IL1RNVNTR*2 (IL-1receptoris antagonisturi geni)

genuri alelis matareblobiT. aRniSnul populaciaSi Seswavlili iqna

agreTve IL1B-511 aleli, magram mikobaqteriul infeqciasTan misi asociaciuri

kavSiri ver iqna gamovlenili (Bellamy et al., 1998). sxva avtorebis mier gambiaSi

Catarebulma kvlevebma gamoavlina heterozigoturi IL1B-511*C alelis

asociacia filtvis tuberkulozTan, maSin, roca IL1B-511*C-iT homozigotur

individebSi aranairi asociaciuri kavSiri ar gamovlinda am mimarTulebiT

(Awomoyi et al., 2005). rusul populaciaSi Catarebulma kvlevebma daadastura

57

IL1RNVNTR*2 alelis maRali mgrZnobeloba filtvis tuberkulozisadmi

(Freidin et al., 2006).

belamisa da TanamSromlebis (Bellamy et al., 1998) mier napovni iqna

korelacia IL10 polimorfizmsa da filtvis tuberkulozs Soris gambiaSi.

heterozigoturi IL10-1082 da IL10-1082*G alelebis matarebloba asocirdeba

filtvis tuberkulozis mosalodnelobasTan kambojasa da TurqeTSi

Catarebuli gamokvlevebiT (Delgado et al., 2002; Ates et al., 2007). IL10-592*A -

ganapirobebs antimikobaqteriul dacvas koreis mosaxleobaSi (Shin et al., 2005),

xolo IL10-1082*A ki tuberkulozis mosalodnelobas gansazRvravs kolumbiaSi

(Henao et al., 2006). morenosa da TanamSromlebis (Moreno et al.,2007) mier

Seswavlili iqna IL10 makodirebeli genis -1082, IL10-819 da IL10-592 alelebi,

Tumca, miRebuli Sedegebi sxvadasxva eTnikur populaciaSi sakmaod

gansxvavebuli aRmoCnda.

antituberkulozur imunitetSi mniSvnelovani roli akisria

transformaciuli zrdis faqtor 1-s TGF-b1 (Moore et al., 2001), romelic

aregulirebs ujreduli zrdisa da gare matriqsis warmoqmnis procesebs da

monawileobs imunoregulaciaSi tuberkulozis dros (Wenner and Yan, 2003).

aRniSnuli genis polimorfizmi Seswavlili iqna CineTis, hong-kongis,

kolumbiisa da TurqeTis populaciebSi (Niimi et al., 2002; Henao et al., 2006; Oral et al.,

2006; Mak et al., 2007), sadac tuberkulozsa da TGFβ1+869 alels Soris

asociaciuri kavSiri ver iqna napovni, maSin, roca aRniSnuli genis TGFβ1+869*T

aleli iranul populaciaSi gansazRvravs organizmis mdgradobas

mikobaqteriuli infeqciis mimarT (Amirzargar et al., 2006).

Tvlian, rom vitamin D-s receptoris geni (VDR) raRac rols asrulebs

infeqciuri agentebis mimarT antituberkulozuri imunuri pasuxis aqtivaciaSi

(Prithvi R. et.al. 2011). sanam antituberkulozur mkurnalobaSi CaerTveboda

qimiuri preparatebi, sanatoriuli mkurnalobis ganuyofeli nawili D

vitaminiT mdidari racioni da mzis sxivebis abazanebi iyo (Evans, 1994). vitamin

D3 -is sinTezi damokidebulia kanze ultraiisferi sxivebis moqmedebaze,

58

romelSic mTavar rols pigmenti melanini asrulebs. mecnierTa varaudiT, igi

SesaZloa, garkveulwilad gansazRvravdes tuberkulozisadmi organizmis

mgrZnobelobas (Liu et al., 2006). pigmentirebul rasebSi, sadac daavadeba

gansakuTrebiT maRali prevalentobiT xasiaTdeba, SeiniSneba D vitaminis

ukmaroba, gansakuTrebiT ki - naklebadmziani klimatis pirobebSi (Wilkinson et al.,

2000). MogvianebiT gamovlenili iqna VDR-is polimorfuli variaciebi

(Uitterlinden., 2004) da dadgenil iqna aRniSnuli genis polimorfizmis

mgrZnobeloba osteoarTritis, diabetis, simsivnis da kardiovaskularuli

daavadebebis (Uitterlinden et al., 2004) da tuberkulozis mimarT (Bellamy et al., 1999).

gamovlenili iqna VDR-is FokI, TaqI, BsmI da ApaI polimorfuli alelebi

(Bornman et al., 2004). meta-analizis Sedegad gamovlinda, rom VDR-is

polimorfuli variaciebi sxvadasxva populaciaSi asocirdeba

tuberkulozisadmi mgrZnobelobasTan (Sharma et al., 2011). uilkinsonisa da

Tanaavtorebis azriT (Wilkinson et al., 2000), vitamin D-s receptori sxva genetikur

Tu garemo faqtorebTan erToblivad ganapirobebs tuberkulozisadmi

mdgradobas

radganac makrofagebi tuberkulozuri paTologiisas yvelaze metad

CarTuli ujredebia dacvis pirveli xazis SeqmnaSi, mecnierTa gansakuTrebuli

yuradReba SLC11A1 genma miiqcia.

bunebriv rezistentobasTan asocirebuli makrofaguri cilis

makodirebeli SLC11A1 genis roli tuberkulozuri infeqciis dros. geni

SLC11A11 Tavdapirvelad bcg genad iwodeboda (Skamene, 1994). igi tuberkulozis

mikobaqteriiT inficirebuli maspinZeli organizmis genetikur struqturaSi

daavadebis mimarT mgrZnobelobis Seswavlis mizniT aprobirebuli pirveli

geni iyo da napovni iqna anomalurad sensibiluri xazis BCG Salmonella da

Leishmania infeqciis mqone TagvebSi, sadac baqteriuli infeqciebisadmi

mdgradobas ganapirobebda.

SLC11A1 geni akodirebs makrofagebis membranaSi ganvlad transmembranul

cilas, romlis funqcias orvalentiani kaTionebis (Fe(2+) da Mn(2+), rogorc

59

pro- da eukariotuli katalazebisa da zeJangebis kofaqtorebi) membranuli

transporti da fagolizosomebSi ionuri statusis SenarCuneba warmoadgens,

rac Tavis mxriv, iwvevs makrofagebis aqtivacias (Nevo, 2006), maspinZlis

antimikrobuli radikalebis generalizebas da mikobaqteriis winaaRmdeg

damcavi fermentebis gamomuSavebas (Blackwell et al, 2000, 2003; Goswami et al, 2001).

tuberkulozTan SLC11A1 genis asociaciuri kavSiris Sesaxeb pirveli

eWvi mas Semdeg gaCnda, rac TagvebSi Catarebuli eqsperimentis Sedegebi

gamoaqveynes. rodesac Tagvebis erT-erT xazs gauTiSes aRniSnuli geni, isini

veluri xazebisagan gansxvavebiT iseTi rezistentulebi ar aRmoCndnen M.

tuberculosis mimarT (North et al., 1999). SLC11A1 genSi momxdari konkretuli saxis

mutacia mniSvnelovnad amcirebs fagosomebis momwifebas da asidifikacias.

amdenad, mutanturi Tagvebi ufro mgrZnobiareni aRmoCdnen tuberkulozis

mimarT (Vidal et al, 1996).

mas Semdeg, rac am genis analogi SLC11A1 geni adamianis genetikur

struqturaSic iqna napovni kanaduri ojaxis magaliTze (risk faqtori = ~ 10)

(Cellier et al., 1994) da gairkva misi polimorfizmis Zlieri asociaciuri kavSiri

tuberkulozisadmi mgrZnobelobaSi, interesi kvlav ganaxlda (Greenwood et al.,

2000).

gamovlenili iqna asociaciuri kavSiri tuberkulozis mosalodnelobasa

da SLC11A1 genetikur variaciebs Sorisac adamianTa populaciebSi (Cervino et al.,

2000; Takahashi et al., 2008). amJamad cnobilia SLC11A1 genis oTxi variacia (Bellamy

et al., 1998), romlebic yvelaze xSirad gvxvdeba tuberkulozuri infeqciebisadmi

winaswarganpirobebulobis Tu mdgradobis Seswavlis mizniT ganxorcielebul

kvlevebSi. SLC11A1 geni da misi polimorfuli variaciebi yvelaze metad

Seswavlili genetikuri faqtoria tuberkulozis SemTxvevaSi msoflios

sxvadasxva eTnikur populaciaSi (Bellamy et al., 1998; Ryu et al., 2000; Blackwell et al.,

2001; Zhang et al., 2005; Li et al., 2006; Liu et al., 2004; Abel & Casanova 2010)

bolo dros gamoqveynebuli meta-analizis SedegebiT, romelic

eyrdnoboda 17 sxvadasxva kvlevas (Li et al., 2006), naCvenebi iqna, rom SLC11A1 genis

60

4 sxvadasxva lokusSi arsebuli polimorfizmi (5’(GT)n, INT4, 3′UTR, D543N)

asocirdeba tuberkulozis mimarT organizmis mgrZnobelobasTan.

afrikis da aziis populaciebSi SLC11A1-s 3’UTR, D543N da 5’(GT)n

lokusebis polimorfizmi myarad asocirdeba filtvis tuberkulozTan.

individebi, romlebic atarebdnen aRniSnul lokusebSi, Tundac,

erTnukleotidian cvlilebas, tuberkulozis ganviTarebis 27%, 61% da 25%-iT

maRali riskis jgufebs miekuTvnebodnen aRniSnuli lokusebis Sesabamisad.

aziis polulaciebSi samive aleli ufro maRali sixSiris asociaciur kavSirSi

(39%, 59%, 65%) gamovlinda tuberkulozis mimarT, vidre sxva regionis

warmomadgenlebSi. genis zemoT CamoTvlili oTxi variaciidan mxolod 3’UTR-

is polimorfizmi araa dafiqsirebuli tuberkuloziT daavadebul afrikul

populaciaSi. rac Seexeba evropul regions, kvlevebis Sedegad Seswavlil

populaciebSi aRniSnuli oTxidan tuberkuloziT daavadebul populaciaSi

arc erTi lokusis polimorfizmi ar gamovlenila, Tumca, arsebobs varaudi

dabali sixSiriT (9.3%) misi arsebobis Sesaxeb (Li et al., 2006).

multirezistentuli tuberkulozis prevalentobis maCveneblis

zrdasTan erTad mecnierebi axali gamowvevis winaSe dadgnen (Espinal et al., 2003).

arsebuli monacemebi MDR-TB-is ganviTarebaze maspinZeli organizmis

genetikuri faqtorebis zegavlenis Sesaxeb Zalze mwiria, Tumca, msgavsi

zegavlenis arseboba sruliad SesaZlebelia. 2005 wels zangisa da misi

TanamSromlebis mier dafiqsirda, rom SLC11A1 genis polimorfizmi asocirdeba

tuberkulozis mZime formasTan (Zhang et al., 2005), xolo iaponiaSi Catarebuli

kvlevebiT am genis D543N da 30UTR lokusebSi momxdari cvlilebebi

asociaciur kavSirSia MDR-TB-Tan iaponur populaciaSi (Takahashi et al., 2008).

aRniSnulidan gamomdinare, SesaZloa, SLC11A1-s polimorfizmi gavlenas

axdendes multirezistentuli tuberkulozis SemTxvevebze.

dRes mecnierTa interesi mimarTulia tuberkulozisadmi organizmis

mdgradobis ganmapirobebeli genetikuri faqtorebisa da misi moqmedebis

61

meqanizmebis gamovlenisken. genetikuri mdgradobis faqtorebis garkvevam,

SesaZloa, axlo momavalSi migviyvanos populaciis doneze tuberkulozis

prevenciasTan bunebriv mdgradobaze pasuxismgebeli meqanizmebis

stimulirebiT.

62

Tavi II. kvlevis masala da meTodebi

II.1. kvlevis masala

kvleva Catarebuli iqna qarTuli da saqarTveloSi mcxovrebi

azerbaijanuli populaciebis tuberkuloziT daavadebul pacientebSi.

kvlevisas Seswavlili iqna filtvis tuberkulozis sxvadasxva formiT

daavadebuli 415 pacienti, romlebic Sedarebuli iqna janmrTel donorul

populaciasTan.

sakvlev masalas warmoadgenda pacientebis venuri (2ml) da

periferiuli (20mkl) sisxli. kvlevisTvis sxvadasxva etapze gamoyenebuli

iqna eriTrocituri masa, garecxili eriTrocitebi; eriTrocitebi

plazmaSi, sisxlis SratSi da fiziologiur xsnarSi; pacientis sisxlis

Srati da pacientis dnm.

sisxli Segrovili iqna randomulad orTave sqesis 17-65 wlis asakis

pacientebidan. pacientTa umravlesoba iyo kultura-dadebiTi.

kvleva ganxorcielda Semdegi mimarTulebebiT:

1. tuberkulozTan eriTrocituri jgufuri antigenebis korelaciuri

kavSiris gamosavlenad Seswavlili iqna:

- filtvis tuberkuloziT daavadebuli 203 qarTveli pacienti, (113

sxvadasxva tipis wamlis mimarT sensitiuri, xolo 90 tuberkulozis

wamlis mimarT rezistentuli formiT iyo daavadebuli). sakvlevi

jgufebis monacemebi Sedarebuli iqna donorul (janmrTel) populacias-

Tan (Nagervadze, 2010);

- 92 azerbaijaneli pacienti (53 f./tb. sensitiuri, 39 f./tb.

wamalrezistentuli formiT daavadebuli). sakvlevi masala Sedarebuli

iqna donorul (janmrTel) azerbaijanul populaciasTan (Геноф. геногеогр.

Народoнос.Т.I. 2000).

2. tuberkuloziT daavadebulTa imunuri statusis Sesaswavlad

gamokvleuli iqna 120 pacienti, romelTagan calke sakvlev jgufebad

63

gamoiyo: sensitiuri da rezistentuli tuberkulozis, daavadebis

sxvadasxva klinikuri (kerovani, infiltraciuli rRvevis fazaSi, fibro-

kavernozuli) formis mqone, aseve, pirveladi da namkurnalevi pacientebi

da Sedarebuli iqna janmrTel moxaliseebTan.

3. infeqciuri daavadebebis mgrZnobelobasTan asocirebuli SLC11A1

genis D543N lokusis polimorfizmis rezistentul tuberkulozTan asoci-

aciuri kavSiris gamosavlenad gamokvleuli iqna sul 120 pacienti (80 rezisten-

tuli da 40 sensitiuri filtvis tuberkuloziT daavadebuli pacienti).

kvlevebi ganxorcielda Semdegi laboratoriebis bazaze:

baTumis SoTa rusTavelis saxelmwifo universitetis biologiis

departamentTan arsebuli imunogenetikis saswavlo-kvleviTi laboratoria;

filtvis daavadebaTa da tuberkulozis erovnuli centris

bioqimiuri laboratoria;

aleqsandres teqnologiuri saganmanaTleblo institutis bazaze

arsebuli saswavlo-samecniero laboratoria (saberZneTi);

kompania “Bioprobe”-is samecniero-diagnostikuri laboratoria „bio-

probi“ (saberZneTi).

II.1. kvlevis meTodebi

II.1.1. imunoserologiuri meTodebi

kvlevisas viyenebdiT saerTaSorisod aRiarebul imunoserolo-giur

meTodebs (Parsons, 1985; Judd, 1994):

- АВО sistemis gansazRvris pirdapiri reaqcia monoklonuri

antisxeulebis (anti-A da anti-B) gamoyenebiT;

- rezus sistemis antigenebis gansazRvra

a) eqspres-meTodi universaluri reagentebis gamoyenebiT;

64

b) eqspres-meTodi planSetze sruli formis antisxeulebiT;

- MN da Kell sistemis antigenebis gansazRvra eqspres-meTodiT uni-

versaluri monoklonuri antisxeulebis gamoyenebiT (Voak, 1986, 1989).

muSaobisas viyenebdiT Semdegi specifikurobis mqone test-

sistemebs: anti -АВ, -В, -А, -D, -CD(G), -C, -c, -E, -Ce, -e, -K, -M, -N (Messeter et al.,

1984; Watkins et al., 1988; OОО «Гемостандарт», Москва), standartul 0(I), A(II), B(III),

AB (IV) Sratebs (gamoyenebuli reaqtivebis titri ar iyo 1:32-ze dabali)

(Voak, 1999). (sur.2-3).

sur. 2-3. sisxlis jgufebis tipireba monoklonuri antisxeulebis gamoyenebiT

II.1.2. biostatistikuri analizis meTodebi

АВ0 sistemis genebis alelebis gavrcelebis sixSires vTvlidiT

berSteinis (F.Bernstein) mier SemoTavazebuli formuliT, romelic

gamoiyeneba samaleliani genetikuri sistemis kvlevisas. I0, IА da IВ genebis

sixSire mocemul SemTxvevaSi aRniSnulia r, p da q asoebiT:

r = O

p = 1- OA

q = 1- OB

65

sadac 0, А da В – 0(I), A(II) da B(III) jgufis matarebel adamianTa

Tanafardobaa sakvlev obieqtTa saerTo raodenobasTan mimarTebaSi.

Rh sistemis genebisa da haplotipebis sixSire gamoTvlili iqna

Semdegi formulebis gamoyenebiT:

1. D = 1 - dd

2. C = 1 - cc

3. E = 1 - ee

4. c = 1 - CC

5. e = 1 - EE

6. d = 1 -√ D

sadac D, C, E, c, e genebis matarebel pirTa raodenobaa sakvlevi

masalis raodenobasTan TanafardobaSi; dd, cc, ee, CC da EE – Sesabamisi

fenotipebis sixSire. Rh haplotipebis sixSire gamoTvlil iqna mourantis

(A. E. Mourant) mier SemoTavazebuli formuliT:

1. cde = ccddee

2. Cde =cde

Ссddee

2

3. cdE = cde

ссddEe

2

4. cDe =cde

ccDee

2

5. cDE = 2cdEccDEE - сdE

6. CDe =2CdeCCDee - Сde

7. CDE=)(2 cdeCDe

CCDEe

sadac ccddee, Ccddee, ccddEe, ccDee, CCDee da ccDEE – Sesabamisi

fenotipebis sixSirea.

66

RhD da Kell sistemis alelebis koncentraciis gamosaTvlelad

gamoviyeneT Semdegi formulebi:

q = N

naa ,

p= 1-q

sadac aan aRniSnuli lokusebis mixedviT recesiuli homozigotebia

(dd da kk); N - gamokvleul pirTa saerTo raodenoba.

MN sistemis alelebis koncentraciis dasadgenad Cvens mier

gamoyenebul iqna Semdegi formulebi:

P= N

nn ABA2

1

,

q = N

nn ABB2

1

sadac An – M fenotipis matarebelTa raodenobaa,

ABn - MN

fenotipebisa, xolo Bn - N fenotipis matarebelTa raodenobaa.

cdomilebebi gamoTvlil iqna formuliT:

M = (100 ) /P P n (Урбах, 1975)

sadac Р – antigenebis sixSirea % -Si, n – sakvlevi obieqtebis

raodenoba.

II.1.3. kvlevis molekulur-bioloqimiuri meTodebi

SLC11A1 genis D543N lokusis polimorfizmis Seswavlisa da filtvis

tuberkulozis multirezistentul formebTan SesaZlo asociaciuri

kavSirebis gamovlenis mizniT gamoyenebuli iqna polimeruli jaWvuri (PCR) da

restriqciuli fragmentebis sigrZis polimorfizmis (RFLP) reaqciebi.

eqsperimenti moicavda Semdeg etapebs:

67

1. dnm-is eqstraqcia;

2. praimerebis dizaini;

3. polimeruli jaWvuri reaqcia (PCR);

4. restriqciuli fragmentebis sigrZis polimorfizmi (RFLP);

5. agarozas gel-eleqtroforezi.

II.1.3.1. dnm-is eqstraqcia

dnm-is eqstraqciisTvis SerCeuli iqna “invitrogenis” mier warmoebuli

„PureLink™ Genomic DNA Kits“ kiti sisxlis nimuSebisTvis, katalogis nomriT -

K1820-01, K1820-02, K1821-04.

dnm-is gamoyofas vaxdendiT pacientebidan aRebuli 200 mkl venuri

sisxlidan (sur. 4-5).

sasurveli raodenobis dnm-is misaRebad SevarCieT meTodika, romelic

moicavs Semdeg Tanmimdevrul procedurebs:

I. lizatas momzadeba, - ujredebis lizisi

- sterilur epindorfebSi vaTavsebdiT 200 mkl sisxls;

- vamatebdiT proteinkinaza K 20 mkl;

- vamatebdiT rnm-azas 20 mkl-s;

- narevs frTxilad vurevdiT da vaCerebdiT 2 wT inkubaciisTvis;

- vamatebdiT 200 mkl PureLink™ genomur lizisur/SemboWav bufers da

vurevdiT homogenuri masis miRebamde;

- vaCerebdiT 10 wuTis ganmavlobaSi 55°C-ze wylis abazanaSi;

- vamatebdiT 200 mkl 96-100% eTanols da vanjRrevdiT ~5 wm homogenuri

siTxis miRebamde.

Semdeg etapze gamoviyeneT:

lizata;

steriluri 1.5 ml-iani mikrocentrifugis sinjarebi;

mikrocentrifuga - 10 000 brunze maRali sixSiris;

68

steriluri wyali - pH 7.0-8.5 an damleqavi buferi;

PureLink™ genomuri gamrecxi buferi - 1 da 2;

PureLink™ genomuri gamomleqi buferi;

PureLink™ filtriani svetebi;

PureLink™ plastikuri sinjarebi filtriani svetebis mosaTavseblad;

II. dnm-is SeboWva - am etapze lizata muSavdeba specifikuri dnm-is

SemboWveli buferiT:

- dnm-is Semcveli lizata gadavitaneT filtrian svetSi (~640mkl);

- davamateT PureLink™ genomis lizisuri/SemboWveli buferi;

- davacentrifugeT 10 000 brunze 1wT-is ganmavlobaSi;

- gafiltruli siTxe gadavRvareT, filtriani sveti gadavitaneT axal

mikrocentrifugis sinjaraSi.

-

sur. 4-5 dnm-is eqstraqciis procesi.

III. dnm-is garexcva: dnm vrecxavdiT ori tipis (1 da 2) gamrecxi xsnariT.

isini uzrunvelyofen dnm-is Semcveli lizatidan ujredis komponentebis

narCenebis da rnm-is Camocilebas. sinjaris filtrian svetSi vasxamdiT 500 mkl

gamrecx bufers-1 da vacentrifugebdiT 10 000 brunze 1wT-is ganmavlobaSi,

oTaxis temperaturaze;

- gafiltrul siTxes vRvridiT, filtriani svetebi gadagvqonda axali

mikrofugis sinjaraSi;

69

- vamatebdiT 500 mkl gamrecx bufers-2, vacentrifugebdiT 3 wT-is

ganmavlobaSi, maqsimalur siCqareze oTaxis temperaturis pirobebSi.

IV. dnm-is gamoleqva - sinjaris filtris mier SeboWili dnm-is gamoleqva

movaxdineT specifikuri gamomleqi buferis saSualebiT. gamoviyeneT

gamoleqvis ori etapi: pirveli 100 mkl (dnm-is gamosavlianoba 80-85%), xolo

meore - 50 mkl moculobiT (gamosavlianoba 10-15%).

dnm-is raodenobis gansazRvra da misi ganzaveba. dnm-is eqstraqciis

Semdeg misi raodenobis gansazRvrisTvis gamoyenebuli iqna ultraTa-

namedrove, srulspeqtriani (220-750 nm) speqtrofotometri Nano-Drop ND-1000

(sur. 6-7).

sur. 6-7. dnm-is raodenobis gansazRvra

polimerazuli jaWvuri reaqciis gansaxorcieleblad SerCeuli iqna dnm-

is optimaluri koncentracia 10 ng/mk.l-ze, risTvisac TiToeuli saanalizo

nimuSi ganvazaveT tris acetatis edta-s (eTilendiamintetraacetatis mJava)

(TAE) gamoyenebiT. sasurvel koncentraciamde ganzavebisTvis gamoviyeneT

torsiuli kalkulatori, romelic damyarebulia moculobisa da

koncentraciis Semdeg principze:

C1V1 = C2V2 V2 = C1V1 / C2

sadac C1 da V1 aris saanalizo nimuSis/xnaris sawyisi koncentracia da

moculoba, xolo C2 da V2 saanalizo nimuSis saboloo moculoba da

koncentracia.

70

II.2.3.2. praimerebis dizaini

genTa eleqtronuli bazidan (NCBI) aviReT SLC11A1 genis (2q 36.1)

nukleotiduri Tanmimdevroba da davgegmeT D543N lokusis (me-15 egzoni)

SeswavlisTvis saWiro praimerebi standartuli wesebis Sesabamisad (Innis and

Gelfand, 1991):

Sinaarsiani praimeri: 5´GTGAGACGACAGACAAATGTAGT3´

uSinaarso praimeri: 5´GGTACCGTCCAGCTGAGA3´

II.2.3.3. polimeruli jaWvuri reaqcia

PCR optimizacia

dnm-is amplificirebisTvis gamoviyeneT polimeruli jaWvuri reaqcia

(PCR). sakvlevi nimuSebis dnm-is sasurveli raodenobis misaRebad movaxdineT

PCR reaqciis standartuli protokolis modificireba/ optimizacia.

optimizaciis pirvel etapze SevarCieT reaqciisTvis saWiro reagentebis

optimaluri koncentraciebi. reaqciis moculoba Seadgenda 20 mk.l-s TiToeuli

saanalizo nimuSisTvis.

reagentebi raodenoba (mkl)

buferi 2

nukleotidebis narevi 2

praimerebis narevi 0,8

ormagad distilirebuli H20 6,1

Taq polimeraza 0,1

MgCl2 6

dnm 3

20 mk.l

PCR-is optimizaciis Sedegad SevarCieT amplifikaciisTvis yvelaze

xelsayreli pirobebi dnm-is saWiro raodenobis misaRebad:

71

PCR reaqciis Semdeg amplificirebuli dnm-is nimuSebs vuSvebdiT agarozas

gelis eleqtroforezze da vamowmebdiT transiluminatorSi (sur.8).

sur. 8. PCR produqti gelze

II.2.3.4. restriqciuli fragmentebis sigrZis polimorfizmi (RFLP)

SLC11A1 genis D543N lokusis polimorfizmis gamosavlenad

amplificirebuli dnm-is nimuSebi restriqciuli fragmentebis sigrZis

polimorfizmis meTodis (RFLP) gamoyenebiT damuSavda NEB-is (new England

Biolabs) restriqciuli fermentiT - Hpy188I, romelic saZiebel regionSi axdens

AG da GG nukleotiduri wyvilebis Secnobas da maT Soris arsebuli

wyalbaduri da kovalenturi bmebis gaxleCas, ris Sedegadac miiReba dnm-is

fragmentebis sigrZis polimorfizmi (sur.9):

sur.9. Hpy 188I-is restriqciuli saiti

940C → 2 wT

denaturacia 940C → 20 wm

gamowva 560C → 30 wm 40 cikli

elongacia 720C → 20wT

720C → 2 wT

72

optimizaciis gziT SevarCieT fermentis aqtivaciisTvis saukeTeso

porobebi. RFLP reaqciis moculoba Seadgenda 50 mkl-s:

reagentebi moculoba (µl)

amplificirebuli dnm 10

restriqtaza - Hpy 188I 1

10xNEB buferi 1

ormagad distil. H2O 38

50 µl

reaqcia ganxorcielebuli iqna wylis abazanaSi 370C-ze erTi saaTis

ganmavlobaSi inkubirebiT. inkubaciis Semdeg fermentis deaqtivaciisTvis

sakvlev masalas vaCerebdiT 800C-ze 20 wuTis ganmavlobaSi. Semdgom etapze

saanalizo masalas vRebavdiT da vamowmebdiT gel-eleqtroforeziT.

II.2.3.5. agarozas gel-eleqtroforezi

eleqtroforezisTvis viyenebdiT Cveulebriv agarozas da maRali

mgrZnobelobis ultra - sufTa „agaroza 1000“-s. SerCeuli iqna gelis

optimaluri simkvrive, buferuli sistemebi, gelis saxeoba da sisqe.

eleqtroforezis buferad viyenebdiT tris-boratis edtas (TBE).

eleqtroforezisTvis viyenebdiT agarozas 2%-an gels; dnm-s

vizualizacisTvis agarozas gelze vamatebdiT fluorescenciul eTidiumis

bromidis 0.5 mkg/ml saRebavs gelis yovel 100 ml-Si winaswar SetaniT. gelze

vuSvebdiT amplificirebuli dnm-is 10 mkl 5 mkl saRebavTan erTad. dnm-is

sazomad viyenebdiT 100 n.f. standarts. eleqtroforezi grZeldeboda 1 sT-is

ganmavlobaSi 110v Zabvaze. eleqtroforezis dasrulebis Semdeg gels

73

vamowmebdiT ultraiisferi sxivebis qveS transiluminatorSi (Bio-Rad) (sur.

10-11).

sur. 10. gel-eleqtroforezi sur. 11. dnm-is vizualizacia agaroza . 1000-is gelze

II.2.4. imunologiuri analizis meTodebi

tuberkuloziT daavadebul pacientTa imunuri statusis dasadgenad

gamoyenebuli iqna imunoturbidometruli da imunofermentuli analizis

meTodebi, romelTa saSualebiT gamovlenili iqna antituberkulinuri jamuri

da imunoglobulinebis (IgA, IgM, IgG) saerTo done tuberkuloziT daavadebul

pacientTa sakvlev nimuSebSi.

II.2.4.1. imunoturbidometruli meTodi

TiToeuli pacientis sakvlev nimuSSi (sisxlis Srati) arsebuli

calkeuli imunoglobulinis - IgA, IgM, da IgG-s saerTo donis gamovlena moxda

imunoturbidometruli meTodiT bioqimiuri analizatoris - Humalyser 2000-is

gamoyenebiT.

calkeuli imunoglobulinisTvis (IgA, IgM, IgG) imunoturbidometrSi

movaxdineT dakalibreba standartuli kalibratorebis gamoyenebiT, romelTa

sakalibro mrudzec moxda sakvlevi pacientebis nimuSebis wakiTxva.

74

kalibraciisas gamoyenebuli iqna:

5 kalibratori+1 nulovani 10 mkl

buferi 500 mkl

anti IgA, IgM, IgG Srati 500 mkl

imunoturbidometruli analizisÈmeTodiÅmoicavda reagentebs Semdegi

TanafardobiT:

reagentebi moculoba mk.l

buferi 500

antiSrati 500

sakvlevi nimuSi 10

1010 mk.l

procedura:

8,5%–ian polieTilenglikolis (pH-7,2) Semcvel tris-buferSi vazavebdiT

standartul xsnarebs (kalibratorebi) da sakvlev nimuSebs. TiToeul

sinjaras vamatebdiT antiglobulinur xsnars, romelic Sedgeboda tris-

buferisa da cxvris antiSratisagan, TiToeuli imunoglobulinisaTvis (anti–

IgA, anti–IgG, anti–IgM) - cal-calke, vainkubirebdiT 370C-ze 10 wT-is ganmav-

lobaSi. kalibratorebi da nimuSSi arsebuli imunoglobulinebi iwvevdnen

aglutinacias anti–adamianis imunoglobulinTan reagentis antiSratSi.

aglutinaciis xarisxi sakvlevi pacientis nimuSi-imunoglobulinebis

koncentraciis proporciuli iyo da isazRvreboda turbidometrulad.

Sedegebs viTvlidiT speqtrofotometrulad 340 nm talRis sigrZeze

HUMALYSER 2000-is aparatiT (sur. 12):

sur. 12. HUMALYSER 2000

75

II.2.4.2 imunofermentuli analizis meTodi

SratSi specifikuri antituberkulinuri jamuri antisxeulebis

(IgM+IgG+ IgA) gamosavlenad gamoyenebuli iqna arapirdapiri imunofermentuli

analizi (ELISA).

analizi tardeboda 96-fosoian brtyelZirian planSetze, romlis

fskerzec winaswar datanili iyo antituberkulinuri antisxeulebi.

reaqciisTvis gamoyenebuli iqna:

96-fosoiani planSeti, romelzec datanili iyo specifikuri

antituberkulinuri antigeni;

nimuSebis gasazavebeli siTxe PBS/BSA (karbonat-bikarbonatuli

xsnari) da buferuli, romelic Seicavs < 0.1 % NaN3;

ferment–koniugati HRP-moniSnuli anti–adamianis Txis IgG /-IgM /-IgA;

substrat - qromogeni (3, 3’, 5, 5’ tetrameTilbenzidini);

gamrecxi xsnari (10 x koncentrirebuli) PBS/Tween;

6 standartuli kalibratori;

mablokirebeli xsnari -M0.5 M gogirdmJava.

procedura:

1. mikroplanSetis pirvel fosos vtovebdiT cariels, xolo

meoredan meSvide fosoebSi vaTavsebdiT 50 mkl sakalibro xsnarebs,

koncentraciis zrdadobis mixedviT, xolo danarCen fosoebSi - winaswar

ganzavebul sakvlev nimuSebs (Sratebs) 50 mkl moculobiT. nimuSebs

vazavebdiT 1:101 karbonat-bikarbonatuli (kbb) buferiT, romelic

Seicavda 1%-ian kazeins. misi saSualebiT vaxdendiT fosoebis

blokirebas araspecifikuri dakavSirebebis Tavidan asacileblad;

76

2. planSets vafarebdiT specialur saizolacio polieTilenis

naWers da vainkubirebdiT oTaxis temperaturaze (250C-ze) erTi saaTis

ganmavlobaSi;

3. inkubaciis Semdeg Sratidan araspecifikurad dakavSirebuli

komponentebis mosacileblad mikroplanSets vrecxavdiT xuTjer

fosfaturi buferiT, romelic Seicavda 0.05% Tween-20 xsnars, risTvisac

TiToeul fosoSi vamatebdiT 400 mkl moculobis gamrecx xsnars;

4. garecxvis proceduris Semdeg planSetis TiToeul fosos

(pirvelis garda) vamatebdiT 100 mkl winaswar gansxavebul tute-

fosfatazaTi moniSnul anti–adamianis winaaRmdeg mimarTul

antisxeulebs anu koniugatis xsnars da vainkubirebdiT 30 wuTis

ganmavlobaSi oTaxis temperaturaze;

5. inkubirebis Semdeg kvlav vrecxavdiT gamrecxi xsnariT xuTjer;

6. SratSi antimikobaqteriuli antisxeulebis arsebobis

SemTxvevaSi, tute fosfatazaTi moniSnuli anti–adamianis antisxeulebi

ukavSrdebodnen planSetis fosoebs;

7. bolo etapze fermentuli reaqciisTvis TiToeul fosoSi

(kontrolis CaTvliT) vasxamdiT 100 mkl substrats, romelic Seicavda

MgCl2 da p-nitrofenilfosfatids karbonat-bikarbonatul buferSi.

sakvlevi antisxeulebis raodenoba dakavSirebuli koniugatis raodeno-

bis proporciuli iyo. is ganisazRvreboda fosfatazas fermentuli aqtivobiT,

rac substratTan urTierTqmedebisas mas yviTlad Rebavda. es registrirdeba

speqtrofotometrulad. optikuri simkvrive izomeboda speqtrofotometr

„Humareader Single”-ze (germania) 450 nm talRis sigrZeze. analizi tardeboda

“Вектор Бест”-is firmis komerciuli reaqtivebis nakrebiT. dublikatebisaTvis

vTvlidiT saSualo ariTmetikuls.

77

Tavi III. kvlevis Sedegebi

III.1. filtvis tuberkulozis sensitiuri da wamalrezistentuli formebis asocireba АВ0, Rh-

Hr, Kell, MN sistemis eriTrocitur jgufur antigenebTan

qarTul populaciaSi

100 welze meti gavida mas Semdeg, rac dadgenili iqna, rom gansxvavebul

rasebsa da eTnosebs tuberkulozis mimarT gansxvavebuli mgrZnobeloba

axasiaTebT da radgan mgZnobelobis gansxvavebul faqtorebs atareben

(Budd,1867). saqarTvelos teritoriaze mcxovrebi eTnikuri jgufebi am dromde

Seswavlili ar iyo. Cvens mier pirvelad iqna gamokvleuli imunogenetikuri

markerebis gavrcelebis Taviseburebani [eriTrocituri jgufuri sistemebis

(АВ0, Rh-Hr, Kell, MN) antigenebi, feno- da genotipuri jgufebi, alelebi da

haplotipebi] filtvis tuberkuloziT daavadebul qarTul populaciaSi.

kvlevis pirvel etapze SevecadeT, dagvedgina filtvis tuberkulozur

(yvela tipis tuberkulozi) daavadebasTan zemoxsenebuli imunogenetikuri

markerebis asociaciuri kavSirebi. filtvis tuberkuloziT daavadebuli yvela

pacientis monacemi damuSavebuli iqna statistikuri analizis meTodebiT

daavadebisadmi mgrZnobiare fenotipebis, alelebis Tu haplotipebis

gamosavlenad da Sedarebuli iqna janmrTel (donorul) populaciasTan.

miuxedavad imisa, rom tuberkuloziT daavadebul pacientebSi sisxlis

eriTrocituli jgufuri antigenebis gavrceleba sakmaod kargadaa

Seswavlili msoflios populaciebSi, informacia daavadebis sensitiuri da

rezistentuli formebis eriTrocitur jgufur antigenebTan asociacirebis

78

Sesaxeb samecniero literaturaSi TiTqmis ar moipoveba. Seuswavlelia

saqarTveloSi mcxovrebi sxvadasxva eTnikuri warmoSobis pacientebic. amitom,

kvlevis meore etapze pacientebi dayofili iqna or - wamlis mimarT sensitiur

da wamalrezistentul sakvlev jgufebad. Seswavlil iqna eriTrocituri

jgufuri antigenebis gavrcelebis Taviseburebebi TiToeul sakvlev jgufSi.

sisxlis ABO sistemis jgufuri antigenebis mixedviT daavadebuli

populaciis kvlevisas miRebuli Sedegebis statistikuri damuSavebis Sedegad

gamovlinda sisxlis O(I) (55.5%±3,4) fenotipuri jgufis maRali sixSire

tuberkuloziT daavadebul populaciaSi, sxva jgufebTan SedarebiT maRali

sixSiriT gvxvdeba B(III) (12%±2,2) fenotipuri jgufi. xolo donorebSi

maRali sixSiriT A(II) (36%±5.1) fenotipuri jgufi aris warmodgenili

(diagr.4). am mxriv aRniSnuli monacemi emTxveva rigi sxva avtorebis monacemebs

(Platonova, 1997; Nagervadze et al., 2006).

diagr. 4. ABO sistemis fenotipuri jgufebis gavrcelebis Taviseburebani filtvis tuberkuloziT daavadebul da janmrTel qarTul populaciaSi

daavadebis sensitiur formaSi dafiqsirda O(I) (57.5±4,6) da B(III) (13.4±1,0)

fenotipuri jgufebis sagrZnoblad maRali sixSire donorebTan (O(I)-47,6±5,3;

B(III)-11,4±3,3) SedarebiT. wamalrezistentuli tuberkulozis SemTxvevaSi

0

10

20

30

40

50

60

70

0(I) A(II) B(III) AB(IV)

ფ.ტბ.

დონორი

79

maRali sixSiriT mxolod O(I) fenotipuri jgufi (51,1±5,2) dafiqsirda, xolo

B(III) jgufis SemTxvevaSi ar gamovlinda korelacia (diagr.5).

aqedan gamomdinare, SeiZleba iTqvas, rom sensitiuri tuberkuloziT

daavadebuli O(I) da B(III) jgufis fenotipis, xolo wamalrezistentuli formis

SemTxvevaSi ki mxolod O(I) fenotipuri jgufis matarebeli individebi

warmoadgens daavadebis maRali riskis jgufebs.

diagr. 5. ABO sistemis fenotipuri jgufebis gavrcelebis Taviseburebani rezistentuli da sensitiuri tuberkuloziT daavadebul da janmrTel qarTul populaciaSi

zemoT aRniSnuli fenotipuri jgufebis sixSiris maRali maCvenebeli

(1.207-jer maRali sensitiur da 1.07-jer maRali wamalrezistentul formaSi)

tuberkuloziT daavadebul populaciaSi donorebTan SedarebiT,

SesaZlebelia, gamowveuli iyos qarTuli populaciisTvis damaxasiaTebeli

TaviseburebiT.

imunoserologiuri analiziT miRebuli Sedegebis statistikuri

kvlevis meTodebiT damuSavebis Sedegad gamoTvlili iqna ABO sistemis

fenotipTa makodirebeli r(O), p(A) da q(B) alelebis sixSire.

kvlevis Sedegad dafiqsirda r(O) alelis sarwmunod maRali (0,739)

koncentracia filtvis tuberkuloziT daavadebulebSi donorul

0

10

20

30

40

50

60

70

0(I) A(II) B(III) AB(IV)

სენსიტ.ტბ

რეზისტ.ტბ

დონორი

80

populaciasTan SedarebiT, sadac aRniSnuli alelis sixSire 0,69-is tolia da

igi 1,07-jer naklebia daavadebul populaciasTan SedarebiT. rac Seexeba p(A)

alels, igi TiTqmis Tanabari sixSiriTaa daavadebul da donorul

populaciaSi. q(B) alelis maRali (0,23) sixSire donorul populaciaSia

warmodgenili, xolo daavadebulSi ki 1.24-jer naklebia (0,18) (diagr. 6):

diagr. 6. ABO sistemis antigenebis makodirebeli alelebis gavrcelebis Taviseburebani filtvis tuberkuloziT daavadebul da janmrTel populaciaSi

msgavsi maCvenebeli dafiqsirda daavadebis orive formis dros.

rogorc sensitiur, ise wamalrezistentul pacientebSi maTi gavrcelebis

sixSire TiTqmis Tanabaria. sensitiuri tuberkulozis dros r alelis

koncentracia 1,11-jer (0.75), xolo wamalrezistentuli tuberkulozis dros

ki 1.05-jer maRali (0.71) aRmoCnda donorebTan SedarebiT, sadac aRniSnuli

alelis gavrcelebis maCvenebeli 0.67-is tolia (cxr.1).

miRebul monacemebze dayrdnobiT, damajereblad SeiZleba iTqvas, rom

filtvis tuberkulozi asociaciur kavSirSi imyofeba me-9 qromosomaSi (9q34.1-

34.2) arsebul genur lokusTan, romelic gansazRvravs sisxlis ABO sistemis

fenotipebs. kvlevis Sedegebidan gamomdinare, sensitiuri tuberkulozisadmi

maRali sensibilobis jgufs miekuTvneba ABO sistemis sisxlis O(I) an B(III)

0

0,2

0,4

0,6

0,8

r p q

0,739

0,085

0,185

0,67

0,09

0,23

ფ.ტბ. დონორი

81

fenotipuri jgufis da r alelis matarebeli individebi. xolo rezistentuli

tuberkulozis SemTxvevaSi ki sisxlis O(I) fenotipuri jgufis da r alelis

matareblebi.

genetikuri sakvlevi obieqtebi

markerebi alelebi sensitiuri wamal.rezist. donorebi

tb. tb.

ABO r 0.75 0.71 0.67

p 0.09 0.09 0.09

q 0.17 0.22 0.23

n= 90 n=113 n=485

cxrili 1. ABO sistemis fenotipebis makodirebel r, p, q alelTa sixSire filtvis sensitiuri da wamalrezistentuli tuberkuloziT daavadebul da janmrTel populacaSi.

ABO sistemis A(II) fenotipuri jgufi da q alelis matarebloba,

garkveulwilad, SeiZleba miviCnioT tuberkulozis mimarT mdgradobis

ganmapirobebel faqtorad.

saintereso Sedegebi iqna dafiqsirebuli rezus (Rh-Hr) sistemis

antigenebis kvlevisas. kvlevis Sedegebze dayrdnobiT gamovlenili iqna

tuberkulozis mimarT maRali mgrZnobelobis fenotipebi da maTi makodirebeli

haplotipebi.

rogorc me-7 diagramidan Cans, tuberkuloziT daavadebulebSi

donorebTan SedarebiT (78±3,5%) 1,06-jer maRali sixSiriT gamovlinda rezus-

dadebiTi fenotipi (83±2.6%).

82

diagr. 7. Rh fenotipebis gavrcelebis Tavisebureba filtvis tuberkuloziT daavadebul da janmrTel populaciaSi

msgavsi Sedegebi gamoikveTa rezistentuli da sensitiuri tuberkulozis

SemTxvevebSic (diagr.8):

diagr.8. Rh fenotipebis gavrcelebis Tavisebureba sensitiuri da rezistentuli tuberkuloziT daavadebul da janmrTel populaciaSi

Rh+ fenotipis SedarebiT maRali sixSire gansakuTrebiT senstitiuri

tuberkuloziT daavadebul sakvlev jgufSi gamoikveTa. aq misi sixSire 1.07-jer

maRali (84±3,4%) aRmoCnda, vidre donorebSi (78±3,5%).

0

10

20

30

40

50

60

70

80

90

Rh+ Rh-

ფ.ტბ.

დონორი

0

10

20

30

40

50

60

70

80

90

100

სენსიტიური რეზისტენტ. დონორი

Rh+

Rh-

83

Rh+ fenotipis maRali sixSire daavadebul populaciaSi saSualebas

gvaZlevs, rom filtvis tuberkulozisadmi mgrZnobiare fenotipad moviCnioT

rezus-dadebiTi faqtori.

rezus sistemis alelTa ( Rh-C, Rh-c, Rh-D, Rh-E, Rh-e) sixSiris Seswavlis

mizniT, Catarebuli eqsperimentis Sedegad gamovlenili iqna garkveuli

asociaciuri kavSirebi daavadebis, rogorc wamalrezistentul, ise

sensitiur formebTan mimarTebaSi (diagr. 9, cxr. 2).

diagr. 9. Rh sistemis alelebis (E,e,C,c,D) gavrceleba tuberkuloziT daavadebul da donor populaciaSi

rogorc me-9 diagramidan Cans, janmrTeli populaciisagan gansxvavebiT,

filtvis tuberkuloziT daavadebulebSi gamoikveTa sakmaod myari korelacia

RhD, RhC da RhE alelebTan.

yvelaze maRali sixSiriT pacientebSi Rh-E (0,21) aleli dafiqsirda.

kerZod, misi sixSire 1.90-jer maRali iyo, vidre donorebSi (0.11).

daavadebulebSi, aseve, maRali aRmoCnda Rh-C alelis gavrcelebis sixSirec,

romlis maCvenebeli 0,37-is tolia, maSin, roca donorebSi 0,28-s utoldeba.

rac Seexeba rezus sistemis yvelaze Zlieri imunogenurobis Rh-Dalels, igi

daavadebul populaciaSi 1.05-jer meti sixSiriT (0,57) dafiqsirda, maSin roca

0,57

0,37

0,83

0,21

0,79

0,54

0,28

0,74

0,11

0,87

D

C

c

E

e


84

donorebSi ki Rh-d aleli metadadaa gavrcelebuli. igi 1.72-jer maRali

sixSiriT gvxvdeba donorebSi (diagr.9).

rezus sistemis alelTa gavrcelebis sixSire Seswavlili iqna

daavadebis orive formaSic (cxr.2):

genetikuri sakvlevi populaciebi

markerebi alelebi sensitiuri rezistentuli donorebi

tb. tb.

Rh-Hr D 0,58 0.56 0.54

C 0,42 0.32 0.28

c 0,71 0.75 0.74

E 0,20 0.22 0.11

e 0,82 0.77 0.87

n= 90 n=113 n=485

cxr. 2. Rh sistemis alelebis gavrcelebis sixSire sensitiuri da rezistentuli tuberkuloziT daavadebul da donorul populaciaSi

kvlevis Sedegebis damuSavebisas rezus sistemis alelebTan

gansxvavebuli korelacia gamoikveTa sensitiuri da wamalrezistentuli

tuberkulozis dros. senstiuri tuberkulozisadmi SedarebiT ufro metad

mgrZnobiare Rh-D (0,58) da Rh-C (0,42) alelebi aRmoCnda, xolo rezistentuli

tuberkulozisadmi ki Rh- E (0,22) aleli, xolo rezus sistemis recesiuli

alelebis SemTxvevaSi aseT kavSiri ar vlindeba.

rezus sistemis Rh-c da Rh-e alelebs, isini maRali gavrcelebiT mxolod

donorebSi gamovlinda. aqedan gamomdinare, rezus sitemis dominanturi Rh-D,

Rh-C da Rh-E alelebi mkacrad korelirebs filtvis tuberkulozTan.

85

rezus sistemis antigenebis gavrcelebis Seswavlis mizniT,

Catarebuli kvlevis Sedegebis mixedviT, tuberkuloziT daavadebul

populaciaSi gamovlinda C (60,09±3,43%) da gansakuTrebiT E (36,94±3,3%)

antigenis sixSiris maRali maCveneblebi (diagr.10).

diagr. 10. Rh sistemis antigenebis gavrcelebis procentuli maCveneblebi tuberkuloziT daavadebul da donorul populaciaSi

kvlevis Sedegebi wamalrezistentuli da sensitiuri tuberkulozis

SemTxvevaSi naCvenebia me-11 diagramaze. unda aRiniSnos, rom E antigenis

procentuli maCvenebeli RhE alelis koncentraciis Sesabamisad, maRali

sixSiriT dafiqsirda wamalrezistentuli (38,8±5,1%) tuberkulozis

SemTxvevaSi, sensitiur (35,3±4,4%) da sakontrolo jgufTan (20±4,0%) SedarebiT.

C antigeni mniSvnelovnad maRali sixSiriT sensitiuri tuberkulozis

SemTxvevebSi gamovlinda. misi procentuli maCvenebeli 65,4±4,4%-s Seadgens,

maSin, roca wamalezistentuli tuberkuloziT daavadebulebSi 53,3±5,2%-s,

xolo donorebSi 51±4,9%-s.

0

20

40

60

80

100

120

D C c E e

ფ.ტბ. %

დონორი %

86

diagr.11. Rh sistemis antigenebis gavrcelebis sixSire sensitiuri da rezistentuli tuberkuloziT daavadebul da donorul populaciaSi

filtvis tuberkulozTan asociaciuri kavSiris gamovlenis da maRali

sensibilobis jgufebis gamoyofis mizniT, aseve, Seswavlili iqna rezus

sistemis haplotipebi. am mizniT gamokvleuli iqna Rh-Hr sistemis 7 haplotipuri

cde, Cde, cdE, cDe, cDE, CDe, CDE jgufi da miRebuli Sedegebi Sedarebuli iqna

donorul populaciasTan.

aRsaniSnavia, rom cde, cDe, CDe da cDe haplotipebi, sxva iSviaT

haplotipebTan SedarebiT, zogadad maRali gavrcelebiT xasiaTdeba janmrTel

qarTul populaciaSi. analogiuri Sedegebi miviReT daavadebulTa populaciis

analizis Sedegad. aqve unda aRiniSnos, rom daavadebul populaciaSi rezus

sistemis zogierTi iseTi haplotipis gavrceleba gamoikveTa, romlebic

janmrTelebSi TiTqmis ar fiqsirdeba (diagr.12).

0

20

40

60

80

100

120

D C c E e

სენსიტიური%

რეზისტენტ. %


87

diagr. 12. Rh-Hr sistemis haplotipebis gavrcelebis Taviseburebani tuberkuloziT daavadebulebsa da donorebSi

kvlevis Sedegebis mixedviT filtvis tuberkuloziT daavadebuli

pacientebis qarTul populaciaSi Rh-cdE haplotipi 0,063 sixSiriTaa

gavrcelebuli. maSin, roca es haplotipi donorebSi saerTod ar gvxvdeba da

misi gavrcelebis maCvenebeli 0-s utoldeba. Cde haplotipis sixSire

daavadebulebSi 2,0-jer maRali aRmoCnda, vidre donorebSi, xolo CDe

haplotipi daavadebul populaciaSi donorebTan SedarebiT 1.05-jer maRali

sixSiriT dafiqsirda. rogorc me-12 diagramidan Cans, daavadebis mimarT

SedarebiT mdgradi aRmoCnda cde, cDe, cDE haplotipebi, romelTa gavrceleba

donorul populaciaSi gacilebiT maRalia.

aqedan gamomdinare, SeiZleba iTqvas, rom Cde, cdE da CDe haplotipebis

matarebeli individebi tuberkulozis ganviTarebis maRal risk-jgufs

miekuTvneba, xolo daavadebisadmi mdgrad jgufad cde da cDE haplotipebis

matarebeli individebi SeiZleba CaiTvalos.

rezus sistemis haplotipebis SeswavliT daavadebis wamalrezistentul

da sensitiur formebSi gamoikveTa gansxvavebuli korelaciuri kavSirebi,

rogorc daavadebis formebsa da haplotipebs Soris, aseve donorul

populaciasTan mimarTebaSi (cxr.3):

0,39

0,012

0,0063

0,13

0,07

0,2

0,004

0,436

0,006

0

0,148

0,126

0,192

0,004

0% 20% 40% 60% 80% 100%

cde

Cde

cdE

cDe

cDE

CDe

CDE

ფ.ტბ.

დონორი

88

genetikuri sakvlevi populaciebi

markerebi haplotipebi sensit. wamal.rezist. donorebi

tb. tb.

Rh-Hr cde 0,37 0.421 0,436

Cde 0 0.01 0.006

cdE 0,01 0 0

cDe 0,11 0.14 0.148

cDE 0,01 0 0,126

CDe 0,28 0.22 0.192

CDE 0 0,01 0,004

cxr. 3. Rh-Hr sistemis haplotipebis gavrceleba tuberkulozis rezistentul da sensitiur

formebSi da donorebSi

Rh-Cde haplotipi dafiqsirda mxolod wamalrezistentuli tuberkulo-

zis SemTxvevaSi, maSin, roca misi koncentracia sensitiur tuberkulozSi 0-s

utoldeba, xolo donorebSi ki 1,66-jer dabalia. filtvis tuberkulozis

sensitiuri formiT daavadebul sakvlev populaciaSi 0,01 sixSiriT

dafiqsirda cdE haplotipuri jgufi. rezus sistemis es haplotipi praqtikulad

ar gamovlenila donorul populaciasa da daavadebis wamalrezistentuli

formis pacientebSi.

samive dominanturi alelis matarebeli RH-CDE haplotipi sensitiuri

tuberkulozis dros ar gamovlenila, xolo rezistentul tuberkulozSi 0.01

koncentraciiT dafiqsirda, maSin, roca donorebSi misi maCvenebeli mxolod

0.004-is tolia.

aRniSnuli faqtidan gamomdinare, SeiZleba vivaraudod, rom

tuberkulozis rezistentuli forma asociaciur kavSirSia Cde da CDE

haplotipebTan, xolo daavadebis sensitiuri forma ki - cdE da CDe

haplotipebTan. SesaZloa, aRniSnuli haplotipebis mqone individebi

89

inficirebis SemTxvevaSi gansxvavebulad daeqvemdebaron daavadebis sensitiur

an rezistentul formas.

vinaidan cDE, cDe da cde haplotipebi mniSvnelovnad dabali sixSriT

gamovlinda daavadebul populaciaSi, savaraudod, isini ganapirobeben

daavadebis mimarT organizmis mdgradobas da maTi matarebloba erTgvar

damcvelobiT faqtorad SeiZleba miviCnioT.

Rh sistemis genotipebis kvlevisas daavadebulebSi SedarebiT maRali

sixSiriT gamovlinda Cc (52,21±4,2%) da igi 1.12-jer aRemateboda donoruls.

mniSvnelovnad maRali iyo EE (4,4±1,4%) da Ee (32,51±3,2%) genotipebis sixSire. EE

genotipi 2-jer, xolo Ee 1.69-jer aRemateba daavadebul populaciaSi mis

gavrcelebas. ee genotipi ki 1.22-jer dabali sixSiriT aris warmodgenili

(63±%) daavadebulebSi donorebTan (77,4±4,4%) SedarebiT (diagr.13).

diagr. 13. Rh-Hr sistemis genotipebis gavrcelebis Tavisebureba tuberkuloziT daavadebul da donorul populaciebSi

rac Seexeba Rh-genotipebis gavrcelebas filtvis tuberkulozis

wamalrezistentul da sensitiur formebSi, naCvenebia me-14 diagramaze.

0

10

20

30

40

50

60

70

80

90

CC Cc cc EE Ee ee

ფ. ტბ.

დონორი

90

diagr. 14. Rh-Hr sistemis genotipebis gavrcelebis Tavisebureba tuberkulozis rezistentuli da sensitiuri tuberkuloziT daavadebul da donorul populaciebSi

Cc genotipi maRali sixSiriT gvxvdeba (56,63±4,6%) sensitiuri

tuberkulozis SemTxvevebSi, xolo rezistentuli tuberkulozis maCvenebeli

donoruls utoldeba (46.6±5,3%). EE genotipis procentuli maCvenebeli 2.52-

jer maRalia (5,55±2,4%) rezistentul tuberkulozSi, xolo daavadebis orive

formaSi TiTqmis Tanabrad maRalia Ee genotipis maCvenebeli. rac Seexeba CC

genotips, igi mxolod 1.1-jer maRalia daavadebis sensitiur formaSi

donorebTan SedarebiT (diagr. 14).

rezus genotipebidan tuberkulozisadmi mdgradobiT gamoirCeva ee

genotipi, rasac ver vityviT Cc, EE, Ee genotipebze. rezus sistemis es

genotipebi, piriqiT, filtvis tuberkulozur paTologiasTan korelaciiT

xasiaTdebian.

Rh sistemis fenotipebis kvlevisas filtvis tuberkuloziT daavadebul

populaciaSi 0,49%±0,69 sixSiriT dafiqsirda iSviaTi - ccddEe, CCDEe da ccddEE

fenotipi. amaTgan iSviaTi - CCDEe (1,11±1,1) da ccddEE (1,11±1.1) fenotipuri

jgufebi dafiqsirda rezistეntuli tuberkulozisas, xolo ccddEe (0,88±0,03) ki

0

10

20

30

40

50

60

70

80

90

CC Cc cc EE Ee ee

სენსიტ. ტბ.

რეზისტ. ტბ

დონორი

91

- sensitiuri tuberkulozisas. Rh sistemis es fenotipebi donorul

populaciaSi ar gamovlinda.

kvlevis Sedegebze dayrdnobiT, SeiZleba iTqvas, rom CcDEe (19,7±2,7)

fenotipi, romelic 2,46-jer maRali sixSiriT gamovlinda daavadebul

populaciaSi donorulTan (8±2,7) SedarebiT, myarad asocirdeba filtvis

tuberkulozTan (diagr.15).

diagr. 15. Rh-Hr sistemis genotipebis gavrcelebis Tavisebureba tuberkuloziT daavadebul da donorul populaciebSi

rezistentuli tuberkuloziT daavadebul populaciaSi gamovlinda

Ccddee (2,22±1,5), xolo sensitiuri tuberkuloziT daavadebul populaciaSi

mxolod ccDEE (2,65±1,4) fenotipi dafiqsirda (diagr. 16).

-5

0

5

10

15

20

25

30

35

40

45

CcDee ccddee ccDee ccDEe CCDee CcDEe Ccddee ccDEE ccddEe CCDEe ccddEE

ფ.ტბ. %

დონორი%

92

diagr. 16. Rh-Hr sistemis fenotipebis gavrcelebis Tavisebureba tuberkuloziT daavadebul da donorul populaciebSi

miRebuli Sedegebidan gamomdinare, SeiZleba davaskvnaT, rom sensitiuri

tuberkulozi korelirebs CcDEe fenotipTan. misi sixSire 23±3,9%-is tolia,

maSin, roca donorebSi TiTqmis samjer dabalia (8±2.7%). kvlevis SedegebiT,

wamalrezistentuli tuberkulozi korelirebs ccDEe fenotipTan, radgan misi

sixSire 15,55±3,8%-ia, maSin, roca igi sensitiuri formis tuberkuloziT

daavadebul pacientebSi (7,07±2,4) donorebze (10±3%) ufro dabalia.

kvleva Catarda MN jgufuri sistemis mixedviTac, sadac mniSvnelovani

asociaciuri kavSiri gamovlinda filtvis tuberkulozsa da MN sistemis

fenotipur jgufebs Soris.

daavadebul populaciaSi gamoikveTa M(M+N-) fenotipuri jgufis maRali

sixSire (62.5±3,3%), donorebSi ki misi maCvenebeli mniSvnelovnad dabalia

(50,2±5,3). donorul populaciaSi, piriqiT, 1.78-jer maRalia N(M-N+)

fenotipuri jgufis procentuli maCvenebeli (diagr.17).

-5

0

5

10

15

20

25

30

35

40

45

CcDee ccddee ccDee ccDEe CCDee CcDEe Ccddee ccDEE ccddEe CCDEe ccddEE

სენსიტიური%

რეზისტენტ. %


93

diagr. 17. MN sistemis fenotipebis gavrceleba tuberkuloziT daavadebul da janmrTel populaciaSi

rogorc me-18 diagramaze Cans, filtvis tuberkulozis, rogorÝ

wamalrezistentuli (58,8±5,1%), ise sensitiuri (65,4±3.7%) formisas pacientTa

didi umravlesoba M fenotipis matarebelia, sensitiur tuberkulozSi ki

aRniSnuli fenotipuri jgufi 1.11-jer ufro metad gamovlinda, vidre

wamalrezistentulis dros (diagr. 18).

diagr. 18. MN sistemis fenotipebis gavrceleba sensitiuri da rezistentuli tuberkuloziT daavadebul da janmrTel populaciaSi

0

10

20

30

40

50

60

70

80

M N MN

ფ.ტბ.

დონორი

0

10

20

30

40

50

60

70

80

M N MN

სენსიტ. ტბ

რეზისტ. ტბ

დონორი

94

aRsaniSnavia, rom N fenotipis dabali xvedriTi wili gansakuTrebiT

wamalrezistentuli tuberkulozisas dafiqsirda. igi, SesaZloa, aseve

miviCnioT tuberkulozisadmi mdgradobis faqtorad.

aRniSnuli jgufuri sistemis kvlevisas alelebis koncentraciaTa, aseve,

mniSvnelovani sxvaoba gamoikveTa. eqsperimentis Sedegebis Tanaxmad, p(M)

alelis koncentracia SedarebiT maRali (0,75) daavadebul populaciaSi

aRmoCnda, xolo donorebSi - 0,65 iyo. alternatiuli Sedegi dafiqsirda q(N)

alelis kvlevisas. igi mxolod 0,24 sixSiriT gamovlinda daavadebulebSi,

donorebSi ki - 0,35 sixSiriT (diagr.19):

diagr. 19. MN sistemis alelebis gavrceleba tuberkuloziT daavadebul da donorul populaciebSi.

p alelis Tanabrad maRali koncentracia gamovlinda filtvis

tuberkulozis, rogorc wamalrezistentuli, ise sensitiuri pacientebis

SemTxvevaSi da maTi gavrcelebis sixSire, Sesabamisad, 0,75 - 0,76-s Seadgenda,

rac 1,15-1,16-jer maRalia donorebTan SedarebiT. rac Seexeba donorebs, aq

mniSvnelovnad maRali sixSiriT gamovlinda q aleli (0,35) (diagr.20):

0%

50%

100%

p (M)

q (N)

0,75

0,24

0,65

0,35 დონორი

ფ. ტბ

95

diagr. 20. MN sistemis alelebis sixSire tuberkulozis rezistentul da sensitiur formebSi da donorebSi.

miRebuli Sedegebis analizis safuZvelze SeiZleba iTqvas, rom p aleli

da, Sesabamisad, M antigeni sensibiluria tuberkulozis mimarT da maTi

matarebeli individebi miekuTvnebian tuberkuloziT inficirebis maRali

riskis jgufebs, xolo q alelis da, Sesabamisad, N antigenis matarebloba

daavadebis mimarT erTgvar „damcvelobiT“ niSans warmoadgens.

sakvlevi populaciebi Seswavlili iqna Kell sistemis mixedviTac. Kell

fenotipuri jgufebis kvlevisas K+ fenotipuri jgufis gavrcelebis maRali

sixSire (7,3±1,8%) donorebTan (4,2±1,8%) SedarebiT dafiqsirda

wamalrezistentuli tuberkulozis SemTxvevaSi. aseve, donorebTan SedarebiT,

daavadebulebSi 4-jer ufro maRali aRmoCnda p(k) alelis koncentraciac. Kell

sistemis fenotipebis gavrcelebis sixSire da alelTa koncentraciebi

tuberkuloziT daavadebul da janmrTel populaciebSi warmodgenilia 21-e da

22-e diagramebze:

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

სენსიტ.

ტბ

რეზისტ.

ტბ

დონორი

0,23 0,25

0,35

0,76 0,75

0,65

q(N)

p (M)

96

diagr. 21. Kell sistemis fenotipebis gavrcelebis sixSire tuberkuloziT daavadebul da janmrTel populaciebSi.

diagr. 22. Kell sistemis p(K) da q(k) alelTa sixSire tuberkuloziT daavadebul da janmrTel populaciebSi.

Kell sistemis fenotipebi gaanalizebuli iqna tuberkulozis sensitiur da

rezistentul formebSi cal-calke. kvlevam aCvena, rom K+ fenotipi

donorebTan SedarebiT 1,2-jer maRali sixSiriT vlindeba sensitiuri da 2,14-

jer maRali sixSiriT - wamalrezistentuli tuberkuloziT daavadebul

populaciaSi (diagr.23):

0

20

40

60

80

100

120

K+ K-

ფ. ტბ

დონორი

p (K) q(k)

0,08

0,92

0,02

0,97ფ. ტბ დონორი

97

diagr. 23. Kell sistemis fenotipebis gavrcelebis sixSire wamalrezistentuli da sensitiuri tuberkuloziT daavadebul da janmrTel populaciebSi.

Kell sistemis alelebis gavrcelebis sixSiris kvlevis Segdegebis

analiziT miRebuli Sedegebi Semdeg suraTs iZleva: wamalrezistentuli

tuberkulozis SemTxvevaSi q alelis koncentracia 0,1-ia, xolo sensitiuri

tuberkulozisas - 0,05. donorul populaciaSi aRniSnuli aleli mxolod 0,02

sixSiriT aris warmodgenili (diagr. 24):

diagr. 24. Kell sistemis alelebis sixSire wamalrezistentuli da sensitiuri tuberkuloziT daavadebul da janmrTel populaciebSi

p (K)

q(k)0

0,2

0,4

0,6

0,8

1

სენსიტ. ტბ.რეზისტ.ტბ.

დონორი

p (K)

q(k)

98

Kell sistemis analiziT miRebuli Sedegebis miuxedavad, rTulia sarwmuno

daskvnis gakeTeba daavadebasTan misi asociaciuri kavSiris Sesaxeb, vinaidan

Kell dadebiTi fenotipi sxvadasxva eTnikur da maT Soris, qarTul

populaciaSi, Zalian dabali sixSiriTaa gavrcelebuli. miuxedavad amisa,

sakvlev daavadebul jgufSi es antigeni imdenad gansxvavebuli sixSiriT (5-jer

maRali) gvxvdeba, rom didi albaTobiT SeiZleba vivaraudoT filtvis

tubekulozis rezistentul formasTan Kell dadebiTi fenotipisa da p alelis

korelaciis arsebobis Sesaxeb.

III.1.1. sensitiuri da wamalrezistentuli tuberkulozis

asocireba eriTrocituri jgufuri sistemebis (ABO, Rh, MN)

alelebTan saqarTveloSi mcxovreb

azerbaijanul populaciaSi

infeqciuri daavadebebi yovelTvis mniSvnelovan rols TamaSobda

populaciebSi sasargeblo genTa dagrovebasa da genetikuri struqturis

gardaqmnaSi, Sesabamisad, maTi genofondis CamoyalibebaSi. evoluciurad

populaciebis genofondSi dagrovda genTa iseTi aleluri Tu araaleluri

balansi, romelic xelsayreli aRmoCnda im saarsebo garemoSi populaciis

TviTmyofadobisa da homeostazis SesanarCuneblad.

mfd-sadmi memkvidruli midrekileba, maRali variabelobiT xasiaTdeba

da igi pirdapir kavSirSia populaciuri polimorfizmis siZlieresTan.

radganac eTnikuri jgufebi genTa sxvadasxva alels atarebs, romlebic,

aseve, gansxvavebul alelur da araalelur garemocvaSi imyofeba,

gansxvavebulad zemoqmedebs sxvadasxva infeqciuri paTogenis gamovlenis

99

xarisxzec. es gansakuTrebiT exeba imunogenetikur lokusebs. amaze

miuTiTebs qronikuli daavadebebis gamovlenis gansxvavebuli sixSire

populaciebSi, maSinac ki, Tu isini migrirebis gamo msgavs garemoSi an

kidev, erTsa da imave teritoriaze cxovroben an ikaveben sxvadasxva

geografiul areals.

tuberkulozis mimarT msoflios sxvadasxva, maT Soris, erTsa da

imave teritoriaze mcxovreb populaciaSi eriTrocituri jgufuri

antigenebis mimarT vlindeba gansxvavebuli asociaciuri kavSirebi. iaponur

da eskimosur populaciaSi filtvis tuberkulozi asocirdeba B antigenTan,

Sesabamisad, B(III) da AB(IV) fenotipebTan (Saha 1985); indur populaciaSi B(III) da

A(II) feno-jgufTan (Seth et al, 2003); indoeTis teritoriaze mcxovreb andras

regionis populaciaSi B(III) da AB(IV) fenotipur jgufebTan da Rh-- faqtorTan

(Rao & Reddy et al, 2012) da aS.

daavadebebis mimarT populaciebis mgrZnoblobis da misi

ganmsazRvreli gansxvavebuli faqtorebis arsebobis gamo maTi gamovlenis

da Sedarebis mizniT, erT-erT sakvlev jgufad aRebuli iqna saqarTveloSi

mcxovrebi azerbaijanuli populacia. am eTnikuri jgufis warmomadgenlebi

filtvis tuberkuloziT daavadebuli saqarTvelos moqalaqeebis

mniSvnelovan nawils Seadgens.

tuberkulozisa da filtvis daavadebaTa erovnul centris

azerbaijaneli erovnebis pacientiebis kvlevis pirvel etapze eriTrocituri

jgufuri sistemis alelebis gavrcelebis sixSire Seswavlili iqna yvela tipis

tuberkuloziT daavadebul pacientSi. donorebis Sesaxeb monacemebi aRebuli

iqna literaturuli wyarodan.

kvlevis meore etapze sakvlev populaciaSi gamoyofili iqna

tuberkulozis wamalrezistentuli da sensitiuri formiT daavadebuli

pacientebis sakvlevi jgufebi.

filtvis tuberkuloziT daavadebul azerbaijanul populaciaSi

eriTrocituri jgufuri ABO sistemis alelTa kvlevisas janmrTelebTan

SedarebiT daavadebul populaciaSi q alelis mniSnelovnad maRali sixSire

100

dafiqsirda. kerZod, Cvens mier Catarebuli kvlevebiT, daavadebul

populaciaSi misi gavrcelebis sixSire 0.293-s Seadgenda, maSin, roca

literaturuli monacemebis mixedviT, donorul populaciaSi misi

gavrcelebis sixSire mxolod 0,125-ia. aRniSnuli miuTiTebs, rom ABO sistemis

q alelis gavrceleba daavadebul populaciaSi 2.3-jer aRemateba mis

gavrcelebas janmrTel populaciaSi.

SeviswavleT am sistemis r alelis gavrcelebis suraTic. aRmoCnda, rom

igi Tanabari sixSiriT aris warmodgenili orive sakvlev jgufSi, p aleli ki

2,51-jer maRali sixSiriT aris gavrcelebuli donorebSi (diagr.25).

daavadebis wamalrezistentul da sensitiur formebSi q aleli Tanabrad

maRali (0,31-0,29) maCvenebliT dafiqsirda. misi gavrcelebis sixSire

daavadebis formebis Sesabamisad, 2,48 - 2,32-jer maRalia, vidre janmrTel

populaciaSi (diagr.25):

doagr. 25. ABO sistemis r, p, q alelebis gavrceleba filtvis tuberkuloziT daavadebul da janmrTel azerbaijanul populaciaSi

gansakuTrebiT saintereso aRmoCnda P alelis analizis Sedegebi. misi

sixSire donorebSi 3,48 -jer maRali aRmoCnda wamalrezistentul da 1.99-jer

maRali - sensitiuri tuberkulozis SemTxvevebSi dafiqsirebul maCveneblebze

0

0,1

0,2

0,3

0,4

0,5

0,6

rp

q

0,577

0,111

0,293

0,596

0,279

0,125


101

(diagr.26). aRniSnuli aleli azerbaijanul populaciaSi SeiZleba ganvixiloT

daavadebis mimaT organizmis mdgradobis ganmapirobebel faqtorebs Soris.

diagr. 26. ABO sistemis r, p, q alelTa koncentracia filtvis sensitiuri da wamalrezistentuli tuberkuloziT daavadebul da janmrTel azerbaijanul populaciaSi

aqedan gamomdinare, SesaZlebelia, dabejiTebiT vTqvaT, rom q aleli

azerbaijanul populaciaSi asocirdeba filtvis tuberkulozis, rogorc

wamalrezistentul, aseve daavadebis sentitiur formasTan, p alelis

matarebloba ki gansazRvravs daavadebis mimarT organizmis mdgradobas da igi

SeiZleba miviCnioT erTgvar damcvel faqtorad.

Rh sistemis alelebis kvlevisas azerbaijanul populaciaSi dafiqsirda

Rh-”d“ alelis 1,23-jer maRali (0,37) sixSire filtvis tuberkuloziT

daavadebulebSi donorebTan (0,30) SedarebiT (diagr.27):

r p q

0,54

0,14

0,29

0,61

0,08

0,31

0,596

0,279

0,125

სენსიტიური რეზისტენტ. დონორი

102

diagr. 27. Rh sistemis alelebis gavrcelebis Tavisebureba filtvis tuberkuloziT daavadebul da janmrTel azerbaijanul populaciaSi

28-e diagramidan Cans, rom miRebuli Sedegebi analogiuria

tuberkulozis wamalrezistentul da sensitiur pacientebSi da misi

gavrcelebis sixSire Seadgens 0.63-s. daavadebis orive formisas RhD”-“

aleli 1.23-jer maRali sixSiriT dafiqsirda janmrTel populaciasTan

SedarebiT.

diagr. 28. Rh D alelis gavrcelebis Tavisebureba rezistentuli da sensitiuri tuberkuloziT daavadebul da janmrTel azerbaijanul populaciaSi

D

d

0,63

0,37

0,699

0,301


0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

სენსიტიურირეზისტენტ.

დონორი

0,63 0,630,699

0,370,37

0,301 D

d

103

aqedan gamomdinare, SeiZleba, rom tuberkulozisadmi mgrZnobelobis

faqtorad azerbaijanul populaciaSi rezus uaryofiToba miviCnioT.

MN sistemis alelTa kvlevisas gamoikveTa, rom tuberkulozi aRniSnul

populaciaSi korelirebs p (M) alelTan. misi koncentracia daavadebulebSi

0,701-is, donorebSi ki 0,61-is tolia (diagr.29):

diagr. 29. MN sistemis alelebis gavrceleba tuberkuloziT daavadebul da janmrTel

azerbaijanul populaciaSi

rac Seexeba MN sistemis q alels, igi donorul populaciaSi

warmodgenilia SedarebiT maRali sixSiriT (0,39) daavadebulebTan

SedarebiT (0,29) (diagr.29).

msgavsi suraTi gamoikveTa filtvis tuberkulozis orive formis

SemTxevaSi. P(M) alelis gavrcelebis sixSire Tanabrad maRali maCvenebliT

dafiqsirda (diagr.30):

q(N) p (M)

0,29

0,701

0,39

0,61


104

diagr. 30. MN sistemis alelebis gavrceleba senstiuri da wamalrezistentuli tuberkuloziT daavadebul da janmrTel azrbaijanel populaciaSi

daavadebis rogorc sensitiuri, ise wamalrezistentuli formis

SemTxvevaSi msgavsi Sedegi gamoikveTa. orive formis tuberkulozi

azerbaijanul populaciaSi Tanabari siZlieriT korelirebs p alelTan da

misi matarebeli individebi SeiZleba CaiTvalos tuberkuloziT inficirebis

risk-jgufebad. rac Seexeba q alels, didi albaTobiTaa SesaZlebeli, igi

ganxilul iqnes tuberkulozis mimarT organizmis mdgradobis erT-erT

faqtorad.

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

სენსიტ. ტბრეზისტ. ტბ

დონორი

0,310,27

0,39

0,68 0,72

0,61

q(N)

p (M)

105

III.1.2. eriTrocituri ABO (r,p,q), Rh-Hr (RhD+,RhD-) daMN (p,q)

jgufuri sistemis alelTa gavrcelebis SedarebiTi analizi tuberkuloziT

daavadebul qarTul da azerbaijanul populaciebSi

cnobilia, rom qarTuli da azerbaijanuli populaciebi, kavkasiis

mkvidri, SedarebiT msgavs geografiul sivrceSi mcxovrebi eTnikuri

jgufebia. wlebis manZilze gadamrCevi faqtorebis zemoqmedebis Sedegad,

isini konkretul saarsebo garemos Seegua maTi genetikuri struqturis

cvlilebis safuZvelze. ramdenadac kavkasiis regioni paTogenebis

gavrcelebisa Tu daavadebaTa gamomwvevi faqtorebis gamo sakmaod

gansxvavebulia, Sesabamisad, aq mcxovreb populaciebs sxvadasxva tipis

daavadebisadmi mgrZnobelobis Tu mdgradobis gansxvavebuli unari

CamouyalibdaT.

iseve, rogorc bevri sxva genetikuri niSani, eriTrocituri jgufuri

antigenebiT determinirebuli sisxlis fenotipuri jgufebis sixSirec

araTanabrad aris ganawilebuli azerbaijanul da qarTul populaciebSi.

Tumca, rogorc qarTul, aseve azerbaijanul populaciaSic dominirebs

sisxlis O(I) fenotipuri jgufi.

populaciur-genetikuri kvlevebisTvis alelebis Seswavla ufro

sarwmuno informacias iZleva, amitom kvlevas eriTrocituri ABO jgufuri

sistemis - (r (0), p (A) da q (B), rezus sistemis - RhD“+“ da RhD“-„ da MN sistemis -

p (M) da q (N) alelebis doneze vawarmoebdiT.

kvlevis Sedegad gamovlinda garkveuli Tavisebureba ABO da Rh-Hr

sistemis alelTa gavrcelebis mixedviT, qarTul da azerbaijanul rogorc

donorul, ise daavadebul populaciebSi.

aRmoCnda, rom qarTul da azerbaijanul populaciebSi ABO sistemis r, p

da q alelebis sixSires Soris Tanafardoba gansxvavebulia. qarTul

populaciaSi r alelis koncentracia 0,69-is tolia, azerbaijanulSi 0,596-s

Seadgens, anu qarTul populaciaSi misi gavrcelebis sixSire 1.15-jer maRalia,

106

vidre azerbaijanulSi. Tumca, r aleli orive populaciaSi gavrcelebis mxriv

pirvel adgils ikavebs, momdevno adgilze p aleli dgas, xolo yvelaze mcire

sixSiriT, rogorc qarTul, ise azerbaijanul populaciaSi q alelia warmod-

genili. maTi gavrcelebis ricxobriv maCveneblebs Semdegi saxe aqvs:

- P alelis koncentracia azerbaijanul populaciaSi 0,279-is, xolo

qarTulSi - 0,09-is tolia, anu azerbaijanul populaciaSi igi 3.1-jer

maRali koncentraciiTaa warmodgenili;

- q alelis sixSire azerbaijanul populaciaSi 0,125-s Seadgens, xolo

qarTul populaciaSi 0,23-s utoldeba, anu 1.92-jer maRali sixSiriT

gavrcelebuli qarTul populaciaSi.

filtvis tuberkulozTan ABO sistemis r, p da q alelebis korelaciis

Sesaswavlad Catarebuli kvlevebis safuZvelze gamovlinda, rom orive

eTnikuri jgufi gansxvavebulad avlens korelacias filtvis tuberkulozTan.

aRmoCnda, rom filtvis tuberkulozTan qarTul populaciaSi r aleli

korelirebs, sadac igi 1.08-jer maRali sixSiriTaa warmodgenili donorul

populaciasTan SedarebiT, maSin, roca r aleli azerbaijanul populaciaSi

donorebSia ufro maRali (0,596) koncentraciiT warmodgenili, vidre

daavadebul populaciaSi (0,557).

saintereso sxvaoba dafiqsirda, aseve, p da q alelebis kvlevisas.

filtvis tuberkuloziT daavadebul qarTul populaciaSi p aleli Tanabrad

aris ganawilebuli daavadebul da donorul populaciaSi, xolo daavadebul

azerbaijanul populaciaSi aRniSnuli alelis matarebloba aSkarad

ganapirobebs organizmis mdgradobas filtvis tuberkulozis mimarT. amaze

metyvelebs is faqti, rom p aleli daavadebulTan SedarebiT 2.5-jer maRali

koncentraciiTaa warmodgenili janmrTel azerbaijanul populaciaSi (0,279)

(cxr. 4).

tuberkulozTan q aleli qarTul populaciaSi aranair korelacias ar

avlens, azerbaijanul populaciaSi ki aSkarad korelirebs daavadebasTan. am

107

daskvnis safuZvels is faqti iZleva, rom daavadebul azerbaijanul

populaciaSi q aleli 2,34-jer maRali sixSiriTaa warmodgenili donorebTan

SedarebiT.

aqedan gamomdinare, SeiZleba davaskvnaT, rom filtvis tuberkulozi

qarTul populaciaSi asocirdeba ABO sistemis r alelTan, azerbaijanul

populaciaSi ki - q alelTan.

rezus sistemis Rh-D da Rh“d„ alelebis kvlevisas eTnikur jgufebSi

dafiqsirda alternatiuli Sedegebi. filtvis tuberkulozi qarTul

populaciaSi korelirebs Rh-D alelTan, xolo azerbaijanul populaciaSi -

Rh-“d„ alelTan.

Seswavlili iqna MN sistemis alelebis sixSire orive eTnikuri jgufis

filtvis tuberkuloziT daavadebul pacientebSi. kvlevis Sedegad aRmoCnda,

rom aRniSnuli sistemis alelebi orive eTnikur jgufSi msgavs korelacias

avlenen daavadebasTan. kerZod, p(M) alelis kvlevisas filtvis tuberkuloziT

daavadebul qarTul populaciaSi misi gavrcelebis sixSire 0,73-s Seadgens

anu 1.12-jer maRalia donorul populaciasTan mimarTebaSi. azerbaijanul

populaciaSi ki igive aleli 1.14 -jer maRali iyo daavadebul pacientebSi.

q(N) aleli orive sakvlevi populaciisTvis, savaraudod, tuberkulozi-

sadmi mdgradobis ganmapirobebel alels SeiZleba mivakuTvnoT. misi

koncentracia Tanabrad - 1.34-jer naklebia daavadebulebSi, rogorc qarTuli,

aseve azerbaijanuli populaciisTvis, xolo janmrTel populaciaSi

sarwmunod maRali koncentraciiT (0.29) - qarTul da 0.39 - azerbaijanul

populaciaSi.

108

genetikuri sakvlevi jgufebi

markerebi alelebi

f. tb f.tb. donori donori

qarT. pop. azer. pop. qarT. pop. azer.pop.

ABO r (0) 0.739 0.557 0.68 0.596

p (A) 0,85 0.111 0.09 0.279

q (B) 0,185 0.293 0.23 0.125

Rh-Hr RhD+ 0.57 0.63 0.54 0.699

RhD- 0.25 0.37 0.43 0.301

M N

M(P) 0.73 0.701 0.65 0.61

N(q) 0.26 0.29 0.35 0.39

n =203 n=92 n=485

cxr. 4. ABO, Rh da NM sistemis alelebis gavrcelebis Tavieburebani qarTul da azerbaijanul donorebSi da filtvis tuberkuloziT daavadebul populaciebSi.

filtvis tuberkulozTan ABO da Rh eriTrocituri jgufuri sistemebis

alelTa gansxvavebuli korelaciuri kavSiri da MN sistemis alelTa msgavsi

korelaciis gamovlena daavadebasTan qarTul da azerbaijanul

populaciaSi, SesaZlebelia, aixsnas populaciur doneze mudmivad moqmedi

elementaruli evoluciuri faqtorebis Sedegad (genebis dreifi, mutaciuri

procesi, genuri nakadebi, izolacia, bunebrivi gadarCeva da a.S.), ris

safuZvelzec zemoT ganxiluli antigenuri determinantebis mixedviT

Camoyalibda balansuri polimorfizmi. eriTrocituri jgufuri sistemebis

ganmapirobebel da mis garemocvaSi myof sxva imunogenetikur lokusebs Soris

damyarda garkveuli wonasworuli balansi, ramac ganapiroba ABO, Rh da MN

sistemis alelTa specifikuri asociaciuri kavSirebis Camoyalibeba filtvis

tuberkulozis mimarT qarTul da azerbaijanul populaciebSi.

109

III.2. IgM, IgG da IgA imunoglobulinebis done filtvis

tuberkuloziT daavadebulebSi

bolo aTwleulebSi imunologiuri kvlevis teqnikis daxvewam

ganapiroba mzardi interesi antituberkulinuri imunuri pasuxis ukeT

gasagebad da am mimarTulebiT mravali mecnieruli kvleva iqna Catarebuli

msoflios sxvadasxva populaciaSi.

Mycobacterium tuberculosis-iT organizmis inficirebis Semdeg mniSvnelovan

rols asrulebs ujreduli (specifikuri) imunuri pasuxi. ujredSida

paTogenis kontrols da mis ganadgurebas T-ujredebis efeqtoruli meqanizmebi

uzrunvelyofs (Bothamley et al., 1995). adre fiqrobdnen, rom humoruli imunuri

pasuxis damcvelobiTi roli minimaluri iyo tuberkulozuri infeqciisas.

magram mecnierTa interesis gaZlierebam da kvlevebis speqtris gafarToebam

aCvena, rom antigeniT gaaqtivebuli B- ujredebi da maT mier sinTezirebuli

antisxeulebi antituberkulozuri imunitetis mniSvnelovani Semadgeneli

nawilia. antigen-antisxeulis reaqciebi aCqarebs dendrituli ujredebis,

makrofagebis da antigen- specifikuri T-limfocitebis lokalur akumulacias

dazianebul kerebSi da zrdis mikobaqteriis mimarT ujredul imunur pasuxs

(Dannenberg, 2006; Palomino et al., 2007). IgA-s mniSvnelovani roli akisria

mikobaqteriisgan organizmis dacvaSi. igi lorwovani garsebis mTavari

imunoglobulinia (Julian et al.,2000; de Larrea et al.,2006). garda IgA-sa, IgG-c

mniSvnelovan rols asrulebs tuberkulozuri infeqciis marTvis procesSi.

mikobaqteriuli antigeniT aqtivirebuli T-ujredebi urTierTqmedeben

B-ujredebTan, romlebic, Tavis mxriv, jer IgM-s asinTezeben, xolo

mogvianebiT, infeqciuri procesidan aRdgenis periodSi xdeba IgG-s sinTezi,

romelic specifikurad anadgurebs SeWril mikroorganizms. igive

mikroorganizmis xelmeored SeiWrisas maspinZel organizmSi B ujredebi

http://www.google.ge/search?tbo=p&tbm=bks&q=inauthor:%22Arthur+M.+Dannenberg%22

110

dauyovnebliv warmoqmnian specifikur IgG antisxeulebs mikrobis

gasanadgureblad (Jain et al.,1984, Palomino et al.,2007).

sxvadasxva paTogenis mimarT organizmis mier producirebuli

antisxeulebi sakmaod Zlier markerebs warmoadgenen infeqciuri daavadebis

diagnostikis TvalsazrisiT da maTi gamovlena sakmaod iafi da martivia,

amitom serologiurma diagnostikam kargad moikida fexi (Silva et al., 2003).

mikobaqteriis winaaRmdeg ganviTarebuli humoruli imunuri pasuxi SeiZleba

gamoyenebul iqnes tuberkulozis adreuli serodiagnostikis saqmeSic

(Bothamley, 1995; Lenka, 2003; Demkow et al., 2005; Demkow et al., 2006; Senol, 2006; Liu et

al., 2007; Araujo et al., 2008; Bezerra et al., 2009). tuberkulozis SemTxvevaSi

serologiuri testebis specifikuroba mas Semdeg gaumjobesda, rac

gamovlenili iqna mikobaqteriuli kompleqsis maRal-specifikuri da

rekombinantuli antigenebi (Demkow et al., 2002).

mikobaqteriis mravalferovani antigenuri determinantebis

(polipeptidebi, romlebic Trgunaven makrofagebis funqcias da iwveven

ujredul imunur pasuxs: molekuluri masis cilovani antigenebi 71, 65, 38, 36,

23, 19, 16, 14 da 12kd, romelTagan 36kd da 16kd dominanturi antigenebia,

polisaqaridebi - II-arabinomanani (LAM), romelic Trgunavs T-ujredebis

proliferacias) winaaRmdeg organizmi gamoimuSavebs sxvadasxva klasis (IgA,

IgG, IgM) specifikur antisxeulebs, romelTa aRmoCena SeiZleba pacientis

SratSi imunofermentuli (ELISA) meTodiT (Tomoka et al., 1990; Demkow et al., 2002;

Beck et al., 2005).

antituberkulozuri humoruli imunuri pasuxisas, aqtiuri

tuberkulozis dros gamomuSavebuli antisxeulebi ZiriTadad IgM da IgG

klasisaa. aRniSnuli antisxeulebi avlenen maRal specifikurobas da

mgrZnobelobas mikobaqteriis antigenuri determinantebis mimarT (Julian et al.,

2004; Bam & Karn., 2009). mkvlevarTa meore jgufis mier Catarebul gamokvlevebSi

111

naCvenebia, rom mikobaqteriuli infeqciisas mniSvnelovania, aseve, IgA (Julian et

al., 2004).

naklebadaa Seswavlili imunuri sistemis mdgomareoba daavadebis

sxvadasxva klinikuri formis dros. cnobilia, rom daavadebis stadiebis

mixedviT imunoglobulinebis done cvalebadobs. daavadebis meore stadiaze

mniSvnelovnad izrdeba IgG, IgA da IgM done pirvel stadiasTan SedarebiT,

mesame stadiaze - IgG da IgA done. daavadebis klinikur formebSi cnobilia, rom

IgG-is done maRalia tuberkulozis eqsudaciuri da kavernozuli

dazianebebisas fibro-produqciul da fibrokavernozul formasTan SedarebiT

(Jain et al.,1984). Cvens mier Seswavlili iqna organizmis humoruli imunuri

pasuxi daavadebis kerovani, fibro-kavernozuli da rRvevis fazaSi myofi

infiltraciuli formis dros. amasTanave, radganac tuberkulozis mZime

klinikuri formebi xSir SemTxvevaSi asocirdeba baqteriis rezistentobis

CamoyalibebasTan, swored amitom, igive kvleva ganvaxorcieleT tuberkulozis

rezistentuli da wamlis mimarT sensitiur formebSi. amasTanave,

mikobaqteriuli infeqciisas antisxeulebis done daavadebis

wamalrezistentul formebSi TiTqmis Seuswavlelia.

gamokvleuli iqna sami klasis imunoglobulinebis - IgG, IgM da IgA done

filtvis tuberkulozis sensitiuri da rezistentuli formisas da aseve,

daavadebis kerovani, fibro–kavernozuli da rRvevis fazaSi myofi

infiltraciuli formebis dros. saerTo imunoglobulinebis donis

Seswavlis garda, kvlevas vatarebdiT specifikuri antituberkulinuri

imunoglobulinebis jamuri (Ig G+M+A) donis Seswavlis mizniTac.

gamokvleuli 30 pacientidan (asakobrivi jgufi 16–73 wlamde), 15

iyo filtvis tuberkulozis kerovani formis mqone, xolo 15 -

infiltraciuli tuberkuloziT rRvevis fazaSi. sakontrolo masalad

aRebuli iqna imave asakobrivi jgufis 30 janmrTeli moxalise. aseve,

gamokvleuli iqna antisxeulebis titri wamalrezistentuli da wamalTa

112

mimarT sensitiuri tuberkuloziT daavadebul pacientebSi (30– sensitiuri, 30–

wamalrezistentuli formiT). sensitiuri formis mqone 30 pacientidan xuTi,

xolo rezistentuli 30 pacientidan rva iyo mdedrobiTi sqesis.

Catarebuli eqsperimentis Sedegad gamovlinda, rom filtvis tuberku-

lozisas, Cveulebriv, IgG klasis specifikuri antisxeulebi Warbobs, IgM

antisxeulebi, ufro metad, daavadebis sawyis stadiaze Cndebian, xolo IgA

gvxvdeba ufro iSviaTad, amitom saWirod miviCnieT jamuri antisxeulebis

gansazRvra.

mikobaqteriis sawinaaRmdego specifikuri jamuri antisxeulebis

Seswavlisas fibro-kavernozuli, infiltraciuli rRvevis fazaSi myofi da

kerovani tuberkuloziT daavadebul pacientebSi jamuri antisxeulebis (IgG +

M + A) done mniSvnelovnad maRali aRmoCnda fibro-kavernozuli (saSualo

maCvenebelia 0,695±0.01) da rRvevis stadiaSi myofi infiltraciuli (saSualo

maCvenebeli - 0,687±0.01) tuberkulozis mqone pacientebSi, sakontrolo,

janmrTel populaciasTan SedarebiT. miRebuli monacemebis Tanaxmad

aRniSnuli maCveneblis saSualo sidide 0,257 iyo, sarwmunoobis maCvenebeli

Seadgenda P<0,05. jamuri imunoglobulinebi mniSvnelovnad maRali titriT

dafiqsirda kerovani formis tuberkuloziT daavadebul pacientebSi, sadac

igi Seadgenda 0,489±0.01, xolo P<0,001 (diagr. 31).

113

sakontrolo jgufi

kerovani infiltr.

rRv. faza fibr/kav.

0.257±0.03 0.489±0.01 0.687±0.01 0.695±0.01

diagr. 31. jamuri (IgG, IgA, IgM) antisxeulebis saSualo optikuri simkvrive tuberkulozis sxvadasxva stadiaze (1-sakontrolo jgufi, 2- kerovani, 3- infiltraciuli tb rRvevis fazaSi,

4-fibro-kavernozuli, opt. – 405 nm)

rogorc gamokvlevam gviCvena, tuberkulozuri daavadebis sxvadasxva

klinikuri formisas specifikuri imunoglobulinebis done gansxvavebulia.

zogierTi avtori amtkicebs, rom daavadebis garTulebuli mimdinareobisas,

romelsac Tan axlavs filtvis qsovilis destruqciuli cvlilebebi,

organizmis imunuri sistemis humoruli rgoli reagirebs IgE-is sinTezis

gaZlierebiT IgG-is sinTezis daTrgunvis fonze, xolo IgM da IgA-s

koncentracia praktikulad ar icvleba (Jain et al., 1984; Rohini et al., 2012). Tumca,

Cvens SemTxvevaSi daavadebis formis simZimesTan erTad specifikuri jamuri

antisxeulebis done matulobs. yvelaze maRali maCvenebeli dafiqsirda fibro–

kavernozuli tuberkulozis dros, Tumca, es maCvenebeli didad ar gansxvavdeba

infiltraciuli rRvevis fazaSi myofi pacientebis maCveneblisagan. rogorc

Cans, daavadebis fazis sirTulesTan erTad adgili aqvs imunostimulacias,

rac antisxeulebis sinTezis matebaSi gamoixateba. savaraudod, es maCvenebebli

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

46

0ნმ

საკონტ.ჯგ

კეროვ.ტბ.

ინფ. ტბ

რღვ.ფ.

ფიბრ/კავ.

114

SeiZleba dagvexmaros daavadebis fazebis diferencirebul diagnostikaSi,

rogorc damatebiTi informacia.

radgan daavadebis fazebTan mimarTebaSi adgili hqonda

imunoglobulinebis koncentraciis cvlilebebs, mizanSewonilad CavTvaleT,

Segveswavla, axdenda Tu ara gavlenas mkurnaloba antibaqteriul humorul

imunitetze. aRmoCnda, rom specifikur antisxeulTa titri xangrZlivad

namkurnalev pacientebSi pirvelad pacientebTan (axal dawyebuli mkurnalobiT

an aranamkurnalevi) SedarebiT ufro maRali iyo (diagr. 32), rac sruliad

adekvaturia, radgan xangrZlivi mkurnalobis qveS, umetesad,

wamalrezistentuli pacientebi imyofebebodnen, romlebSic baqteriis

koncentacia maRali unda iyos da imunuri sistema, Sesabamisad, antisxeulebis

matebiT pasuxobs.

savaraudod, antituberkulinuri jamuri antisxeulebis koncentraciis

Seswavla efeqturi iqneba mkurnalobis monitoringis TvalsazrisiTac.

diagr. 32. specifikuri jamuri ( IgG, IgA, IgM) antisxeulebis done donorebSi, namkurnalev da aranamkurnalev pacientebSi

literaturul monacemebSi aris informacia imis Sesaxeb, rom

tuberkuloziT avadobisas mniSvnelovnad matulobs specifikuri

antituberkulozuri IgG da mis gansazRvras aqvs didi mniSvneloba daavadebis

0

0,1

0,2

0,3

0,4

0,5

0,6

donori xanm. xang.

%

115

prognozirebis TvalsazrisiT. IgG-Tan erTad IgM-s gansazRvris SemTxvevaSi

bevrad izrdeba specifikuroba mikobaqteriuli antigenebis mimarT da,

Sesabamisad, misi prognozuli mniSvneloba aRwevs 88,5%-s (Lenka, 2003; Bam &

Karn 2009). aRniSnulidan gamomdinare, jamuri antisxeulebis donis gansazRvra

ufro efeqturia am TvalsazrisiT, vidre TiToeulisa cal-calke.

specifikuri antituberkulinuri imunoglobulinebis jamuri

koncentracia, rogorc Cans, damokidebulia daavadebis formasa da fazaze,

lokalizaciaze da organizmSi daavadebis gavrcelebaze. xSirad, daavadebis

gamwvavebisas aRiniSneba antisxeulebis koncentraciis talRiseburi cvlileba

(Jain et al., 1984). saerTo jamSi, antisxeuluri pasuxis suraTi tuberkulozis

dros Zalian individualuri da rTulia. amitom saWirod CavTvaleT,

zogadad humoruli imunuri pasuxis dadgenis mizniT gamogvekvlia filtvis

tuberkuloziT daavadebulebSi saerTo imunoglobulinebis, kerZod, IgG,

IgM da IgA-s koncentraciac.

filtvis tuberkuloziT daavadebuli pacientebis sisxlis SratSi

imunoglobulinebis (IgA, IgG, IgM) saerTo donis gansazRvris mizniT

Catarebuli kvlevis Sedegad gamovlinda, rom samive imunoglobulinis - IgA, IgG

da IgM done filtvis tuberkuloziT daavadebul pacientebSi maRali

koncentraciiT dafiqsirda. gansakuTrebiT maRali iyo IgG-s (1757,432) done,

Semdeg - IgM (437,8162) da IgA-isa (363,1182), sakontrolo jgufTan (IgA - 235±233

mg/dl, IgG - 1150±636 mg/dl, IgM - 135±134 mg/dl.) mimarTebaSi (diagr. 33):

116

diagr. 33. imunoglobulinebis IgG, IgA da IgM saerTo done (mg/dl) filtvis tuberkuloziT daavadebul pacientebSi da sakontrolo jgufSi

filtvis tuberkulozis wamalrezistentul da sensitiur pacientebSi

imunoglobulinebis saerTo done Semdeg suraTs iZleoda: sensitiur formebSi

- IgA - 362,16±214,35 mg/dl, IgG -1878,96±1093,88 mg/dl, IgM - 426,84±845,63 mg/dl,

xolo wamalrezistentul formebSi - IgA - 381,49±225,71 mg/dl, IgG -

1696,91±1049,37 mg/dl, IgM - 467,70±948,56 mg/dl koncentraciiT dafiqsirda

(diagr.34):

diagr. 34. imunoglobulinebis IgG, IgA da IgM saerTo done (mg/dl) tuberkulozis wamal- sensitiur da wamal-rezistentul formebSi da sakontrolo jgufSi

363,1182

1757,432

437,8163

235

1150

135

0

200

400

600

800

1000

1200

1400

1600

1800

2000

IgA IgG IgM

ტბ.

კონტრ.

362

1878

426381

1696

467

0

200

400

600

800

1000

1200

1400

1600

1800

2000

IgA IgG IgM

საკონტრ.ჯგ.

სენსტ.

რეზისტ.

117

IgG da IgM-is done IgA-Tan SedarebiT, tuberkuloziT daavadebuli

pacientebis SratSi (P<0.001) sakontrolo jgufTan (P<0.05) SedarebiT maRali

koncentraciiT dafiqsirda. IgA umniSvnelod maRali koncentraciiT iyo

momatebuli filtvis tuberkulozis, rogorc wamalrezistentuli, ise sensi-

tiuri formiT daavadebulebSi (P<0.01) (diagr. 34).

IgG daavadebis sensitiur formaSi 1.107-jer maRali iyo, vidre

wamalrezistentul tuberkulozSi. IgM da IgA-s mixedviT mniSvnelovani

sxvaoba ar gamovlenila, orive klasis imunoglobulini sakontrolo jgufTan

SedarebiT, Tanabrad maRali koncentraciiT iyo warmodgenili, rogorc

sensitiur, ise wamalrezistentuli tuberkulozis mqone pacientebSi (diagr.

34).

imunoglobulinebis done filtvis tuberkuloziT daavadebul

pacientebSi Seswavlili iqna sqesis mixedviTac. sensitiuri tuberkuloziT

daavadebul mdedrobiTi sqesis individebSi Sratis imunoglobulinebis done

Semdeg suraTs iZleva: IgA - 396,18±160mg/dl, IgG - 1865,0±915mg/dl da IgM -

295,5±208mg/dl; mamrobiTi sqesis pacientebSi ki – IgA - 348±214mg/dl, IgG -

1875±1146 mg/dl, IgM - 436±883mg/dl. aRniSnuli monacemi samive

imunoglobulinis, gansakuTrebiT ki IgG-s SemTxvevaSi, maRali iyo

sakontrolo jgufTan SedarebiT, sadac imunoglobulinebis koncentracias

Semdegi saxe aqvs - IgA-s done 235±233mg/dl-ia (P<0.05), IgG - 1150±636mg.dl

(P<0.001) da IgM - 135±134mg/dl (P<0.05) (diagr. 35).

118

diagr. 35. imunoglobulinebis saerTo done (mg/dl) sensitiuri tuberkulozis mqone qalebsa da mamakacebSi sakontrolo jgufTan SedarebiT

daavadebis wamalrezistentul formebSic msgavsi monacemebi

dafiqsirda. filtvis tuberkuloziT daavadebul mdedrobiT da mamrobiT

pacientebSi imunoglobulinebis maCveneblebs Semdegi saxe aqvs - IgA qalebSi-

358±183mg/dl, mamakacebSi-386,68±235mg/dl; IgG - qalebSi-1686±1048mg/dl,

mamakacebSi 1624.95±1158 mg/dl; IgM -qalebSi - 308±166 mg/dl, mamakacebSi-

521.93±893 mg/dl. (diagr. 36).

diagr. 36. imunoglobulinebis saerTo done (mg/dl) mdedrobiTi da mamrobiTi sqesis wamalrezistentuli tuberkulozis mqone pacientebSi da sakontrolo jgufSi

235

1150

135

396

1865

296384

1875

436

0

200

400

600

800

1000

1200

1400

1600

1800

2000

IgA IgG IgM

საკონტრ.გჯუფი

ქალები

მამაკაცები

235

1150

135

358

1686

308368

1626

521

0

200

400

600

800

1000

1200

1400

1600

1800

IgA IgG IgM

საკონტრ.ჯგ.

ქალები

მამაკაცები

119

literaturuli monacemebiT, janmrTel populaciaSi IgM da IgG-s

koncerntraciebSi sqesis mixedviT arsebiTi gansxvaveba ar fiqsirdeba. Cvens

SemTxvevaSi tuberkulozis, rogorc sensitiuri ise wamalrezistentuli

formiT daavadebulebSi IgM-is done mamrobiTi sqesis pacientebSi

mniSvnelovnad maRali (sensitiuri tb - 436±883mg/dl wamalrezistentuli tb.-

521.93±893mg/dl) iyo, vidre mdedrobiTi sqesis pacientebis sisxlis SratSi

(sensitiuri tb. - 295,5±208mg/, wamalrezistentuli tb. - 521.93±893mg/dl) da

sakontrolo jgufSi (135mg/dl) (P<0.01) (diagr.36). aRniSnuli SesaZloa

gamowveuli iyos cxovrebis maTi wesidan gamomdinare. analogiuri Sedegebi

fiqsirdeba literaturul wyaroebSic (alarchon-Segovia & Fishbein, 1971; Maddison

et al., 1975)

rogorc kvlevis Sedegebma gviCvena, antisxeulebis maRali titrs

ganpirobebda IgG-s koncentraciis sagrZnobi mateba. aRniSnuli

imunoglobulinis done daavadebis, rogorc sensitiuri, ise

wamalrezistentuli formisas sagrZnoblad maRalia sakontrolo jgufTan

SedarebiT (P<0.001). es exeba, rogorc mdedrobiTi, ise mamrobiTi sqesis

pacientebs (diagr.37).

sensitiuri tuberkulozis SemTxvevaSi IgG-s koncentracia orTave sqesis

warmomadgenlebSi Tanabrad maRali maCvenebliT dafiqsirda (diagr.36), xolo

daavadebis rezistentul formaSi igi 1.05-jer maRali koncentraciiT -

qalebSi, vidre mamakacebSi (diagr.37).

120

diagr. 37. imunoglobulin IgG –s (mg/dl) done mdedrobiTi da mamrobiTi sqesis sensitiur da wamalrezistentul pacientebSi da sakontrolo jgufSi

Catarebuli kvlevebidan gamomdinare, filtvis tuberkuloziT

daavadebul pacientebSi specifikuri anti-tuberkulozuri antisxeulebis

gamovlena mniSvnelovania tuberkulozis sxvadasxva klinikur formaSi.

gansakuTrebiT mniSvnelovania rRvevis stadiaSi myofi infiltraciuli

tuberkulozisas da daavadebis fibrozul/kavernozuli formisas, radgan

aRniSnuli monacemi SeiZleba gamoyenebuli iqnes, rogorc damatebiTi

diagnostikuri meTodi. radgan, baqterioskopuli gamokvlevebi xSirad ar

iZleva zusti diagnozis dasmis saSualebas da bavSvebSi TiTqmis ar gamoiyeneba

masalis mopovebis sirTulis gamo, xolo kulturis meTodi xangrZliv dros

moiTxovs. sakmaod zusti imunofermentuli analizis (ELISA) meTodiT

pacientis SratSi arsebuli specifikuri antisxeulebis titris gansazRvra

daavadebis adreul stadiaze daavadebis adreuli diagnostirebis saSualebas

iZleva (Bam& Karn 2009).

imunoglobulinebis saerTo donis gansazRvris Sedegad Cvens mier

miRebuli Sedegebi emTxveva samecniero literaturaSi arsebul monacemebs,

romlis Tanaxmad specifikur IgG antisxeuls aqvs maRali specifikuroba da

mgrZnobeloba mikobaqteriuli antigenebis mimarT. Tu IgG-Tan erTad IgM-is

donis gansazRvra moxdeba, mniSvnelovnad izrdeba diagnostirebis

1865 1875

1150

1686 1626

0

200

400

600

800

1000

1200

1400

1600

1800

2000

კონტრ. ქალები მამაკაცები

სენს. ტბ.

რეზ.ტბ.

121

specifikurobis xarisxi, rasac tuberkulozis diagnostirebisTvis didi

mniSvneloba aqvs (Bam & Karn, 2009).

rac Seexeba humorul imunur pasuxs (imunoglobulinebis saerTo

koncentracia), filtvis tuberkulozis sensitiuri da rezistentuli

formebisas mniSvnelovan sxvaobas ar iZleva da organizmi daavadebis orive

formis dros aviTarebs msgavs imunur pasuxs, rac gamoixateba IgG-s donis

mniSvnelovan matebaSi.

Cvens mier miRebuli Sedegebi, am mxriv, emTxveva sxva avtorebis monacemebs

(Fabio et al., 1994; Lenka et al., 2003), romlebic aRniSnaven, rom tuberkulozuri

paTologiisas organizmSi mniSvnelovnad izrdeba IgG antisxeulebis done.

122

III.3. SLC11A1 genis D543N lokusis polimorfizmis

Seswavla filtvis tuberkulozis wamalrezistentuli da

sensitiuri formebiT daavadebul pacientebSi

tuberkulozis mimarT organizmis winaswarganpirobebulobaSi monawile

kandidat genebs (TLR (Medzhitov, 2001; Krutzik et al, 2001), MHC (HLA) (Palomino et.al

2007; Taype et.al. 2010), IFN-γ Hill 2006; Taype et al., 2006), TGF (Moore et al., 2001; Niimi et

al., 2002; Henao et al., 2006; Oral et al., 2006; Mak et al., 2007), VDR (Prithvi R. et.al. 2011)

Soris yvelaze metad bunebriv mdgradobasTan asocirebuli geni SLC11A1-ia

Seswavlili. mis mier kodirebuli makrofaguli cila 1 (NRAMP1) monawileobs

rkinis ionebis membranul cvlaSi, ris Sedegadac xdeba makrofagebis aqtivacia

da maspinZlis antimikrobuli radikalebis generalizeba, rasac mniSvnelovani

damcvelobiTi funqcia aqvs mikobaqteriis winaaRmdeg ganviTarebul imunur

pasuxSi (Blackwell et al, 2000, 2003; Goswami et al, 2001).

saqarTveloSi filtvis tuberkuloziT daavadebuli pacientebSi,

romlebic Cveni kvlevis obieqts warmoadgenda, daavadebis winaswar-

ganpirobebulobaSi Tu mis klinikur ganviTarebaSi monawile kandidati genebi

Seuswavlelia. qveyanaSi wamalrezistentuli tuberkulozis maRali

prevalentobis da mis zogierT eTnoteritoriul jgufSi [Sida qarTlis, qvemo

qarTlis, kaxeTis, aWaris, imereTis da samegrelos regionebi (USAID 2007)],

daavadebis maRali gavrcelebis gamo sakiTxi gansakuTrebiT aqtualuria.

Cvens mier Seswavlili iqna SLC11A1 genis D543N lokusi misi

polimorfuli variaciebis, filtvis tuberkulozis wamalrezistentul

formebTan SesaZlo asociaciuri kavSiris gamovlenis mizniT.

SLC11A1 moTavsebulia me-2 qromosomis grZeli mxris 36.1 lokusSi (2q36.1)

(sur. 13):

123

sur. 13. SLC11A1 genis lokusi me-2 qromosomaSi.

SLC11A1 genis oTx sxvadasxva lokuSi (sqema.1) gamovlenili - 5´(GT)n

(mikrosatelituri ubani G/T cvalebadi raodenobis ganmeorebadi

Tanmimdevrobebi (n) SLC11A1 5’-dan); INT4 (erTnukleotidiani cvlileba me-4

intronSi 4: 469+14G/C-Si); D543N (me-15 egzonis 543 kodonSi momxdari

cvlilebiT, romelic iwvevs asparaginis mJavis aspartamiT Secvlas); 3´ UTR (a

TGTG delecia, romelic xdeba me-15 egzonis ukanasknel 55-e nukleotidur

wyvilSi, 15:1729+55del4) - polimorfizmi msoflios sxvadasxva populaciaSi

araTanabrad aris gavrcelebuli da araTanabrad asocirdeba tuberkulozTan.

5´8----- -----//------- ----------- ------//------ -------- 3´

5´(GT)n INT4 D543N 3´UTR

sqema 1. SLC11A1polimorfuli lokusebi

magaliTad, aziuri qveynebis populaciebSi gamovlinda 5’(GT)n, 3′UTR,

D543N lokusebis polimorfizmis asociaciuri kavSiri tuberkulozTan, maSin,

roca evropul populaciaSi mocemuli oTxi lokusidan arc erTi maTganis

polimorfizmTan ar dafiqsirda tuberkulozis asociaciuri kavSiri.

ეგზ.15 ეგზ.5 ეგზ.2 ეგზ. 1

124

yvelaze dabali sixSiriT tuberkulozis dros meoTxe intronSi (INT4)

momxdari mutaciebi fiqsirdeba (Takahashi, 2008; Li 2006). zangisa da misi

TanamSromlebis (Zhang et al., 2005) mixedviT, INT4 da D543N-is polimorfizmi

asociaciur kavSirSia inficirebis Semdeg tuberkulozis mZime formis

progresirebasTan. SLC11A1-s zemoT aRniSnul alelTa polimorfizmis

asociaciuri kavSiri tuberkulozis mZime formasTan dadasturebuli iqna

tarakaSis da misi TanamSromlebis mier iaponur populaciaSi. amave avtorebis

mier Catarebuli kvlevis safuZvelze gamoiTqva varaudi, rom SLC11A1–s

polimorfizmi asociaciur kavSirSia tuberkulozis wamalrezistentul

formasTan (White et al., 1994; Liu et al., 1995; Takahashi et al., 2007).

Cvens mier kvleva Catarebuli iqna filtvis tuberkulozis

wamalrezistentuli formiT daavadebul pacientebSi. sakvlev jgufs

warmoadgenda 18-dan 67 wlamde asakis 80 pacienti - 21 qali da 59 mamakaci,

romlebic rezistentulni iyvnen, sul mcire, izoniazidisa da rifampicinis

mimarT, maTi 37.5% rezistentuli iyo eTanbutolis, izoniazidis,

pirazinamidis da rifampicinis mimarT, 15% - eTanbutolis, izoniazidisa da

rifampicinis mimarT, 38% - izoniazidis da rifampicinis mimarT, xolo 5%-

eTanbutolis mimarT. pacientTa 50%-ze mets mkurnalobdnen meore rigis

preparatebiT: fluoroqinolebiT (levofloqsacini, ciprofloqsacini da a. S.)

da TioamidebiT (ZiriTadad eTionamidi), aseve damatebiT – aminoglikozidebiT

(amikacini, kanamicini) da polipeptidebiT (ZiriTadad kapreomicini).

daavadebulTa 49% pirveladi wamalrezistentobiT, xolo 51% meoradi

rezistentobiT iyo avad. rezistentuli tuberkulozis mqone pacientTa

82.5%-s daudginda daavadebis Ria forma. pacientTa 50%-s - infiltraciuli,

23% - diseminirebuli, 18,75% - fibro-kavernozuli, 6.25% - kavernozuli da

5% - infiltraciul-diseminirebuli formiT iyo daavadebuli.

sakontrolo variantad aRebuli iqna wamlis mimarT sensitiuri

tuberkuloziT daavadebuli 18-dan 64 wlamde asakis 40 pacienti - 12 qali

da 28 mamakaci. sensitiuri tuberkulozis mqone 77.5% - baqteriagamoomyofi

125

iyo (mgb+). pacientTa 45-45% daavadebis diseminirebul da infiltraciul, xolo

danarCeni 10% kavernozul da fibrokavernozul formaze modioda.

SLC11A1-is polimorfuli variaciebis gamosavlenad eleqtronuli

bazidan aRebuli iqna genis saanalizo monakveTi (sqema. 2).

SLC11A1 genis D543N lokusi, sadac mutaciiT gamowveuli

erTnukleotidiani cvlileba iwvevs genis mier kodirebuli cilis

(moTavsebulia endosomebSi/ lizosomebSi) molekulaSi aspartamis mJavis

asparaginiT Canacvlebas. amis gamo irRveva rkinis ionebis cvla da aRniSnuli

cvlileba gavlenas axdens makrofagebis funqciur aqtivobaze.

saZiebeli ubnis amplifikaciisTvis SerCeuli iqna praimerebi da

gansazRvrul iqna restriqciuli fermentis (Hpy188I) samizne saitebi (sqema. 2):

SLC11A1-s sakvlevi regioni (PCR produqti)

praimeri 1 (Frw)

restriqciuli saiti

GAGCAAAACTCTATTTCGAAAAAAAAAAAAAAAGTTTATCTCTGCCTTTCCATCTC

CTGTATGCTCTTCCTACATAAGGTAGGAAGCCCATTGGCCAGACTGTCTAGTAAATGTA

GTCTGAGACGACAGACAAATGTAGTCTGAGACGACAGGCAAATAACCG

GCCCACCCTTAATGAAGGATCATCTCCTCCCCATAGGTGCCCCGCAC

CGTCCTCTGGCTGACCATCGAGCTAGCCATTGTGGGCTCCRACATGC

AGGAAGTCATCGGCACGGCCATTGCATTCAATCTGCTCTCAGCTGGAC

GGTACCACCCCAGTGTACCCCAACTCTTCAGGCCAGGCAGAGAACAGCTGCTGCTACT

TCCCCCCCTAACCAGTCCCTCCCAGAGTCTATTTTATCCTGCTGTCCCCTCTGAAGCAGG

GCTGCTGCCCTGTTTTCCAGAAATGTAAAGTGACTTGTCTAAAGTCACACAGATGTGAG

TCATGCAGGACTTTGGGAC

restriqciuli saiti praimeri 2 (Rev)

sqema. 2. SLC11A1 genis monakveTi, romelic moicavs saanalizo 543 kodons. PCR -produqti

moicavs 194 nukleotidur wyvils

126

SLC11A1 genis 543-e kodonSi polimorfizmi vlindeba azotovani fuZeebis

CanacvlebiT, romlebic SLC11A1-s D543N alelSi qmnian GG, AA, AG variaciebs.

sakvlevi dnm damuSavebuli iqna Hpy188I restriqtaziT.

Hpy188I- restriqtaziT damuSavebis Semdeg:

GG: 23 (kontroli) + 108 + 61

AA: 23 (kontroli) + 169

AG: 23 (kontroli) + 169 + 108 + 61

cxr.5. RFLP-is mosalodneli Sedegebi

restriqciuli endonukleazas moqmedebis sakontrolod SerCeul iqna

erTi restriqciuli saiti, romlis produqtic gelze dnm-is 23

nukleotiduri fuZis mqone fragmenti unda yofiliyo. SLC11A1 genis D543

lokusSi GG alelis arsebobis SemTxvevaSi gelze unda gamovleniliyo

sakontrolo variantis-23 + 108 da 61 nukleotiduri fuZis Semcveli

fragmentebi, GA alelis SemTxvevaSi - sakontrolo variantis-23 + 169, 108 da 61

nukleotiduri fuZis mqone frgmentebi, xolo AA alelis SemTxvevaSi - mxolod

sakontrolo variantis-23 + 169 n.f.-is mqone fragmentebi (cxr. 5).

rogorc SLC11A1 genis eleqtroforegramidan Cans (sur.14), rom

aRniSnuli geni 543 kodonSi iZleva 23, 61 da 108 nukleotiduri fuZis mqone dnm-

is fragmentebs, sadac pirveli sakontrolo variantia, xolo 61 da 108 nf-is

mqone fragmentebi - GG alelis damadasturebeli fragmentebi.

127

sur.14. D543N lokusi restriqciuli endonukleaziT damuSavebis Semdeg (isrebiT naCvenebia RFLP-

-is Sedegebi agarozas gelze. isris gaswvriv cifrebiT naCvenebia dnm fragmentis nukleotiduri fuZis raodenoba)

SLC11A1 genSi momxdari mutaciebi, romlebic genis polimorfizms

ganapirobeben, xels uSlian fagosomebis momwifebas da asociaciuri kavSiri

gaaCniaT tuberkulozis mimarT organizmis mgrZnobelobasTan (Greenwood 2000;

Bellamy et al., 1998; Cevino et al., 2000; Ryu et al., 2000; Gao et al.,2000), maSin, roca sxva

mkvlevarebi aseTi tipis kavSiris arsebobas ar adastureben (liaw et al., 2002;

Delgado et al., 2002; El Baghdadi et al., 2003; Soborg et al.,2002; Puzyrev et al., 2003).

kvlevis Sedegad miRebuli erTgvarovani eleqtroforezuli speqtri

miuTiTebs, rom SLC11A1 geni D543N lokusSi genetikuri polimorfizmiT ar

xasiaTdeba tuberkuloziT daavadebuli qarTuli populaciaSi. rogorc

multirezistentul, ise sensitiur pacientTa absoluturi ricxvi atarebs

mxolod D543 GG alels (sur.14).

literaturul monacemebze dayrdnobiT myarad SeiZleba iTqvas, rom

SLC11A1 genis sxvadasxva polimorfuli variaciis korelacia tuberkulozis

winaswarganpirobebulobasTan eTnikuri specifikurobiT xasiaTdeba.

daavadebis klinikur formebTan mimarTebaSi Catarebuli kvlevis Sedegad

gamovlinda, rom D543N A aleli da 3’UTR lokusis polimorfizmi kavSirSia

filtvSi Rru dazianebebis ganviTarebasTan da Sesabamisad, kavernozul

formasTan iaponur populaciaSi (Abe et al., 2003), xolo afrikul populaciaSi

23ნფ

108ნფ

61ნფ

128

gamovlinda 5’(GT)n, INT4 da D543N lokusebis polimorfizmis asociaciuri

kavSiri tuberkulozTan. veranairi asociaciuri kavSiri ver iqna napovni

SLC11A1 alelebis polimorfizmTan, rogorc filtvis, ise filtvgare

tuberkulozTan daniur populaciaSi (Soborg et al.,2002).

Cvens mier Catarebuli kvlevebidan gamomdinare, SeiZleba davaskvnaT,

rom SLC11A1 genis D543N lokusis polimorfizmi qarTul populaciaSi ar

asocirdeba filtvis tuberkulozis multirezistentul formasTan da ar

monawileobs daavadebisadmi organizmis winaswarganpirobebulobaSi. kvlevis

Sedegad miRebuli monacemebi emTxveva soborgis, delganos da sxvaTa (Soborg et

al.,2002; liaw et al., 2002; Delgado et al., 2002; El Baghdadi et al.,2003; Puzyrev 2003) mier

miRebul Sedegebs.

vfiqrobT, SLC11A1-s polimorfizmis sruli analizisTvis qarTul

populaciaSi aucilebelia aRniSnuli genis sxva lokusebis polimorfuli

variaciebis Ziebac, aseve, sxva kandidati genebis Zieba da analizi, vinaidan

cnobilia, rom arsebobs tuberkulozis winaswarganpirobebulobaze moqmedi

sxva genetikuri faqtorebi (Medzhitov, 2001; Krutzik et al, 2001; Moore et al., 2001; Hill

2006; Taype et al., 2006; Niimi et al., 2002; Henao et al., 2006; Oral et al., 2006; Mak et al., 2007;

Taype et.al., 2010; Prithvi et.al., 2011), romlebic, aseve, maRali eTnospecifikurobiT

xasiaTdebა.

129

daskvnebi

1. filtvis tuberkuloziT daavadebul sakvlev qarTul populaciaSi

dadgenil iqna daavadebis asociacia O(I) da B(III) fenotipur jgufebTan.

aRniSnuli jgufebis matarebeli individebi tuberkulozis mimarT

mgrZnobelobiT gamoirCevian da miekuTvnebian daavadebis ganviTarebis risk-

jgufebs. A(II) fenotipuri jgufis matarebeli individebi SedarebiT maRali

imunuri mdgradobiT xasiaTdebian filtvis tuberkulozis mimarT.

2. sensitiuri tuberkuloziT daavadebis maRali riskis jgufebs

warmoadgens O(I) da B(III) jgufis fenotipis matarebeli individebi, xolo

wamalrezistentuli formis SemTxvevaSi - mxolod O(I).

3. ABO sistemis q alelis matarebloba qarTul populaciaSi

korelaciaSia daavadebis mimarT organizmis mdgradobasTan. janmrTel

populaciaSi igi 1.27-jer maRali sixSiriTaa warmodgenili daavadebulTan

SedarebiT, xolo r alelis matarebloba SeiZleba CaiTvalos, rogorc

sensitiuri, ise wamalrezistentuli tuberkulozis mimarT mgrZnobelobis

indikatorad. azerbaijanel pacientebSi, piriqiT, q(B) aleli asocirdeba

daavadebis mgrZnobelobasTan, radgan igi donorulTan SedarebiT 2.3-jer

maRali sixSiriT tuberkulozur pacientebSi fiqsirdeba. p alelis 2,51-jer

maRali sixsSire donorebSi asocirdeba aRniSnuli alelis mdgradobasTan

filtvis tuberkulozis mimarT. ABO sistemis alelebis gansxvavebuli

asociacia daavadebasTan, SesaZloa, qarTuli da azerbaijanuli populaciebis

eTnospecifikurobiT iyos ganpirobebuli.

4. filtvis tuberkuloziT daavadebul qarTul populaciaSi Rh+

faqtori, azerbaijanul populaciaSi ki - Rh- faqtori dominirebs. rezus

sistemis madeterminirebeli RhD, RhC da RhE alelebi gansxvavebul

korelacias avlenen filtvis tuberkulozis sxvadasxva formasTan. RhC

130

aleli mgrZnobiarea sensitiuri, xolo RhE aleli - daavadebis

wamalrezistentuli formis mimarT. tuberkulozisadmi sensibilobiT

gamoirCeva individebi rezus sistemis Cde, cdE da CDe haplotipebiT, xolo

daavadebisadmi mdgrad haplotipebs warmoadgens cde, cDe da cDE haplotipebi.

5. kvlevis Sedegad dadgenil iqna, rom rezus sistemis CcDEe (19,7±2,7)

fenotipi, romelic daavadebul populaciaSi 2,46-jer maRali sixSiriT

fiqsirdeba donorulTan (8±2,7) SedarebiT, mniSvnelovan asociaciur kavSirs

avlens filtvis tuberkulozis orive formasTan.

6. tuberkulozTan myarad korelirebs MN sistemis q aleli da,

Sesabamisad, M antigeni. aqedan gamomdinare, maTi matarebeli individebi

miekuTvnebian tuberkulozis maRali sensibilobis jgufs, xolo p alelis da,

Sesabamisad, N antigenis matarebloba daavadebis mimarT erTgvar

„damcvelobiT“ niSans warmoadgens saqarTveloSi mcxovreb filtvis

tuberkuloziT daavadebul, rogorc qarTul, ise azerbaijanul populaciaSi.

7. Seswavlil pacientebSi daavadebis formis (kerovani, infiltraciuli

rRvevis fazaSi, fibro/kavernozuli) simZimesTan erTad specifikuri jamuri

antisxeulebis done matulobs. savaraudod, daavadebis fazis sirTulesTan

erTad adgili aqvs imunostimulacias, rac antisxeulebis sinTezis matebaSi

gamoixateba. es SeiZleba, gamoyenebul iqnes daavadebis fazebis

diferencirebul diagnostikaSi, rogorc damatebiTi informacia.

8. specifikur antisxeulTa titri xangrZlivad namkurnalev pacientebSi

(metwilad, wamalrezistentuli pacientebi, romlebSic baqteriis koncentacia,

savaraudod, maRalia) pirvelad pacientebTan (axal dawyebuli mkurnalobis an

aranamkurnalevi) SedarebiT maRalia, radgan imunuri sistema daavadebis

simZimes antisxeulebis matebiT pasuxobs. savaraudod, antituberkulinuri

jamuri antisxeulebis koncentraciis Seswavla efeqturi iqneba mkurnalobis

monitoringis TvalsazrisiTac.

131

9. antisxeulebis maRali titri gansakuTrebiT vlindeba IgG-s

koncentraciis matebaSi. aRniSnuli imunoglobulinis done daavadebis,

rogorc sensitiuri, ise rezistentuli formisas sagrZnoblad maRalia

sakontrolo jgufTan SedarebiT (P<0.001). es exeba, rogorc mdedrobiTi, ise

mamrobiTi sqesis pacientebs. aRniSnuli monacemi SesaZlebelia, gamoyenebul

iqnes, rogorc damatebiTi sadiagnostiko saSualeba.

10. filtvis tuberkuloziT daavadebul pacientebSi specifikuri

antituberkulinuri antisxeulebis gamovlena gansakuTrebiT mniSvnelovania

rRvevis stadiaSi myofi infiltraciuli tuberkulozisas da daavadebis

fibrozul-kavernozuli formis dros. pacientis SratSi arsebuli

specifikuri antisxeulebis titris gansazRvra daavadebis adreul stadiaze

diagnostirebis saSualebas iZleva da SeiZleba, gamoyenebuli iqnes, rogorc

damatebiTi diagnostikuri meTodi.

11. humoruli imunuri pasuxi (imunoglobulinebis saerTo done)

filtvis tuberkulozis sensitiur da wamalrezistentul formebs Soris

mniSvnelovan sxvaobas ar iZleva da organizmi daavadebis orive formis dros

aviTarebs msgavs imunur pasuxs, rac gamoixateba IgG-is donis mniSvnelovan

matebaSi.

12. SLC11A1 geni, romlis polimorfuli variaciebi zogierT eTnikur

populaciaSi asocirdeba filtvis tuberkulozTan da gansazRvravs

daavadebisadmi midrekilebas, filtvis tuberkuloziT daavadebul qarTul

populaciaSi polimorfulobas ar avlens. am mimarTebiT gamokvleuli

evropuli populaciebis msgavsad, SLC11A1 genis D543N-is lokusis

polimorfuloba ar asocirdeba rezistentul tuberkulozTan qarTul

populaciaSi da aziuri populaciebisgan gansxvavebiT, ar gansazRvravs

daavadebisadmi winaswarganpirobebulobas.

132

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