IL28B CC genotípus: védő tényező és az interferonválasz prediktora krónikus hepatitis C-vírus-infekcióban | IL28B CC genotype: a protective factor and predictor of the response to interferon treatment in chronic hepatitis C virus infection

Bevezetes: Kronikus hepatitis C-virus-fertőzesben a citokineket kodolo genvariansok szerepenek kutatasa az erdeklődes előterebe kerult. Celkitűzes: A szerzők kronikus hepatitis C-virus-fertőzottekben vizsgaltak az IL28B-polimorfizmusok előfordulasat es az egyes variansok hatasat az interferonalapu antiviralis kezeles kimenetelere. Meghataroztak az osszefuggest az IL28B genotipusok es a betegek periferias vereben az aktivalt monocytak es lymphocytak Th1/Th2 citokin termelese kozott. Modszer: A genetikai tanulmanyba 748 kronikus hepatitis C-virus-fertőzott egyent vontak be. Kozuluk 420 beteget kezeltek pegilalt interferon alfa 2a/2b injekcioval es per os ribavirinnel 24–72 heten at. A kezeles utani kovetesi időszak tartama 24 het volt. A peginterferonnal es ribavirinnel kezelt betegek kozul 195 (46,4%) ert el tartos virologiai valaszt, vagyis 24 hettel a kezeles befejezese utan hepatitis C-virus-RNS-negativitast. Kontrollkent 105 egeszseges egyen szolgalt, normalis majprobakkal es negativ hepatitis B- es C-virus, valamint human immundeficientiavirus-szerologiaval. Genotipizaltak meg 475 egeszseges roma egyent (230 ferfi, 245 nő, atlageletkor 47±8 ev). Az IL28B rs12979860 polimorfizmust Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA) segitsegevel hataroztak meg. A Th1/Th2 citokinszint-vizsgalatokhoz 40 hepatitis C-virus-fertőzott beteg TLR-4 ligand lipopoliszacharidaval aktivalt periferias ver monocytainak, valamint PMA+Ionomycin stimulalt lymphocytainak tumornekrozis-faktor-α-, interleukin-2-, interferon-γ-, interleukin-2- es interleukin-4-termeleset mertek a sejtek feluluszojaban FACS-CBA, Becton–Dickinson-teszttel. Eredmenyek: Az IL28B rs12979860 CC genotipus hepatitis C-virus-fertőzott betegekben kisebb gyakorisaggal fordult elő, mint a kontrollban (26,1% vs. 51,4%, OR 0,333, p<0,001), mig a T-allel a betegekben volt gyakoribb (73,9% vs. 48,6%, OR 3,003, p<0,001). Az IL28B CC genotipusu peginterferonnal es ribavirinnel kezelt betegekben a tartos virologiai valasz aranya 58,6%, a CT genotipusuakban 40,8% (OR 2,057, p = 0,002), mig a T-allelt hordozokban 41,8% volt (OR 1,976, p = 0,002). Az aktivalt monocytak tumornekrozis-faktor-α-termelese magasabb volt IL28B CC genotipusu betegekben, mint a nem CC genotipusuak eseteben (p<0,01). Hasonlokeppen, az aktivalt lymphocytak tumornekrozis-faktor-α-, interleukin-2- es interferon-γ-termelese is szignifikansan magasabb volt IL28B CC-hordozo egyenekben (p<0,01). Kovetkeztetesek: Az IL28B CC protektiv hatasu kronikus hepatitis C-virus-fertőzessel szemben, es pozitiv prediktora a tartos virologiai valasznak az interferonalapu antiviralis terapia soran. Hepatitis C-virus-fertőzott betegekben IL28B CC genotipus eseten fokozott Th1 citokin termelese indukalhato a periferias ver monocytaiban es lymphocytaiban, ami szerepet jatszhat a virus gyors immunologiai kontrolljaban es a tartos virologiai valasz letrejotteben. Orv. Hetil., 2013, 154, 1261–1268. | Introduction: In chronic hepatitis C-virus infection the possible role of gene variants encoding cytokines has become the focus of interest. Aim: The aim of the study was to investigate the effect of IL28B polymorphisms on the outcome of chronic hepatitis C-virus genotype 1 infection in the Hungarian population. In addition, the association between IL28B genotypes and the Th1/Th2 cytokine production of activated peripheral blood monocytes and lymphocytes was evaluated. Method: Total of 748 chronic hepatitis C-virus genotype 1 positive patients (365 males and 383 females, aged between 18 and 82 years; mean age, 54±10 years) were enrolled, of which 420 patients were treated with pegylated interferon plus ribavirin for 24–72 weeks. Of the 420 patients, 195 patients (46.4%) achieved sustained virological response. The IL28B rs12979860 polymorphism was determined using Custom Taqman SNP Genotyping Assays (Applied Biosystems, Life Technologies, Foster, CA, USA). For cytokine studies, tumour necrosis factor-α, interleukin-2, interferon-γ, interleukin-2 and interleukin-4 production by LPS-stimulated monocytes and PMA-ionomycine activated lymphocytes were measured from the supernatant of the cells obtained from 40 hepatitis C-virus infected patients, using FACS-CBA Becton Dickinson test. The cytokine levels were compared in patients with different (CC, CT, TT) IL28B genotypes. Results: The IL28B rs12979860 CC genotype occurred in lower frequency in hepatitis C-virus infected patients than in healthy controls (26.1% vs 51.4%, OR 0.333, p<0.001). Patients carried the T allele with higher frequency than controls (73.9%, vs 48.6%, OR 3.003, p<0.001). Pegylated interferon plus ribavirin treated patients with the IL28B CC genotype achieved higher sustained virological response rate than those with the CT genotype (58.6% vs 40.8%, OR 2.057, p = 0.002), and those who carried the T allele (41.8%, OR1.976, p = 0.002). LPS-induced TLR-4 activation of monocytes resulted in higher tumour necrosis factor-α production in patients with the IL28B CC genotype compared to non-CC individuals (p<0.01). Similarly, increased tumour necrosis factor-α, interleukin-2 and interferon-γ production by lymphocytes was found in the IL28B CC carriers (p<0.01) Conclusions: The IL28B CC genotype exerts protective effect against chronic hepatitis C-virus infection and may be a pretreatment predictor of sustained virological response during interferon-based antiviral therapy. The IL28B CC polymorphism is associated with increased Th1 cytokine production of activated peripheral blood monocytes and lymphocytes, which may play a role in interferon-induced rapid immune control and sustained virological response of pegylated interferon plus ribavirin treated patients. Orv. Hetil., 2013, 154, 1261–1268.