Analiza polimorfizama gena značajnih za diferencijaciju T(H)17 i T regulatornih ćelija kod bolesnika sa antifosfolipidnim sindromom
Analysis of polymorphisms in genes important for differentiation of T(H)17 and T regulatory cells in patients with antiphospholipid syndrome
Author
Popović-Kuzmanović, Dragana V.Mentor
Novaković, Ivana
Committee members
Stojanović, LjudmilaLuković, Ljiljana
Marisavljević, Dragomir
Cvetković, Dragana

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Uvod: Antifosfolipidni sindrom (AFS) je autoimunska bolest koju karakteri#e pojava
arterijskih i venskih tromboza, gubitak ploda i prisustvo antifosfolipidnih antitela u
serumu. AFS, kao i mnoge druge autoimunske bolesti, ima multifaktorsku etiologiju
koja uklju!uje naslednu komponentu i delovanje faktora spolja#nje sredine. Jedan od
pokazatelja nasledne predispozicije kod multifaktorskih bolesti je udru"enost odre$enih
genskih polimorfizama sa pojavom oboljenja. Genski tj. DNK polimorfizmi
predstavljaju varijacije u naslednoj osnovi koje se sre%u u op#toj humanoj populaciji.
Naj!e#%i je polimorfizam pojedina!nih nuleotida (SNP) koji obuhvata oko 90% svih
DNK polimorfizama. Otkri%e Th17 i T regulatornih %elija (Treg), dve nove
subpopulacije CD4+ %elija, ukazalo je na mogu%nost u!e#%a ovih %elijskih linija u
patogenezu mnogih autoimunskih bolesti, uklju!uju%i i AFS. To je uslovilo i interes za
polimorfizme u genima povezanim sa funkcionisanjem ovih %elija.
Cilj: Cilj ovog istra"ivanja j...e bio da ispita povezanost AFS sa nivoima citokina IL-17,
IL-23, IL-6, TGF& i transkripcionih faktora ROR't i Foxp3 kao i mogu%nost
povezanosti nastanak AFS sa genotipovima na sedam polimorfnih mesta u genima za te
citokine i transkripcione faktore. Svi ovi citokini i transkripcioni faktori su uklju!eni u
neku of faza diferencijacije Th17 ili Treg %elija. Prema dostupnim podacima iz
literature, istra"ivanja povezanosti ovih citokina i njihovi genskih polimorfizama sa
antifosfolipidnim sindromom su retka, a takvi podaci ne postoje za srpsku populaciju.
Materijal i metode: Ispitivali smo koncentracije citokina IL-17, IL-23, TGF-& i IL-6 i
odabrane genske polimorfizme kao osetljive markere antifosfolipidnog sindroma.
Ispitivali smo grupu od pedeset bolesnika s primarnim AFS (PAFS), pedeset bolesnika
sa sekundarnim AFS (SAFS) i kontrolnu grupu od pedeset zdravih ispitanika. Serumske
koncentracije IL-17, IL-23 i TGF-& su merene komercijalnim ELISA kitovima, a IL-6
je meren elektro-hemi-luminescencijom. SNP: rs2275913, rs763780, rs11209026,
rs1800471, rs1800795, rs9826 i rs3761548 koji se nalaze u genima IL-17A, IL-17F, IL-
23, TGF&, IL-6, ROR't i FOXP3 (redom) su genotipizirani kori#%enjem komercijalnih
TaqMan eseja ili metodom alel specifi!nog PCR-a...
Introduction: Antiphospholipid syndrome (APS) is an autoimmune disease
characterized by the occurrence of arterial and venous thrombosis, fetal loss and the
presence of antiphospholipid antibodies in the serum. AFS, like other autoimmune
diseases, has multifactor etiology which includes hereditary component and the
influence of external factors. One of the indicators of hereditary predisposition for
multifactorial diseases is the association of certain genetic polymorphisms with the
emergence of diseases. Gene Polymorphisms are variations in inherited basis that
normally appear in human population. The most common individual nucleotide
polymorphism (SNP), which comprises about 90% of all DNA polymorphisms, is an
exchange of individual bases. Discovery of Th17 and regulatory T cells (Treg), two new
subsets of CD4+ cells, indicates the possibility of involvement of these cell lines in the
pathogenesis of many autoimmune diseases, including AFS. Subsequently,
polymorphisms in correspondin...g genes are of particular interest.
Aim: The aim of this study was to investigate the association of APS with the cytokine
IL-17, IL-23, IL-6, TGF& and the transcription factors ROR't and Foxp3 and
development of AFS possible link with the seven polymorphic genotypes of the genes
for these cytokines and transcription factors. All of these cytokines and transcription
factors involved in some stage of differentiation of Th17 and Treg cells. According to
available data in the literature, researches of these cytokines and their gene
polymorphisms in antiphospholipid syndrome are rare, and no such data exist for the
Serbian population.
Material and methods: We investigate the serum concentrations of cytokines IL-17,
IL-23, TGF-& and IL-6 and gene polymorphisms of those genes as susceptibility
markers for Antiphospholipid syndrome. We studied a group of fifty patients with
primary APS (PAPS), fifty with secondary APS (SAPS) and fifty healthy controls.
Serum concentrations of IL-17, IL-23 and TGF-& were measured by commercial ELISA
kits, and IL-6 was measured by electro-chemo-luminescence method. The SNPs:
rs2275913, rs763780, rs11209026, rs1800471, rs1800795, rs9826 and rs3761548
located in genes encoding IL-17A, IL-17F, IL-23, TGF&, IL-6, ROR't and Foxp3
(respectively) were genotyped using commercial pre-synthesized TaqMan allelic
discrimination assay or by allele-specific PCR...