RESUMO
BACKGROUND: Hepatitis C virus (HCV) is able to bypass the immune system modulating innate and adaptive immune response and blocking T helper 1 (Th1) cell production. Because the human leukocyte antigen (HLA)-G molecule has immunomodulatory properties inhibiting the function and production of natural killer and cytotoxic lymphocyte T cells, as well as promoting shift from Th1 toward Th2 response, we hypothesized its involvement in susceptibility to HCV infection. MATERIALS AND METHODS: Considering that HLA-G mRNA expression has been reported to be under genetic control, an association study was conducted analyzing 800 base pairs upstream the ATG at the 5'upstream regulator region (URR) and 850 base pairs from ATG to exon 3 and the 3'untranslated region (UTR) of HLA-G gene in Italian HCV-positive patients and uninfected controls. RESULTS: Four 5'URR polymorphisms (-725C>G>T, -509C>G, -400G>A and -398G>A), 7 polymorphisms at coding region (+15G>A, +36G>A, +243G>A, insC506, 531G>C, delA615 and 685G>A), the +644G>T polymorphism, and 1 haplotype (TTGTTCCIGAC) showed different frequency distributions between HCV patients and uninfected controls. CONCLUSION: The results from our study suggest a possible involvement of HLA-G in the risk modulation toward HCV infection.
Assuntos
Predisposição Genética para Doença , Antígenos HLA-G/genética , Hepacivirus/imunologia , Hepatite C/genética , Polimorfismo de Nucleotídeo Único , Regiões 3' não Traduzidas , Regiões 5' não Traduzidas , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Éxons , Feminino , Expressão Gênica , Frequência do Gene , Estudos de Associação Genética , Antígenos HLA-G/imunologia , Haplótipos , Hepatite C/diagnóstico , Hepatite C/imunologia , Hepatite C/virologia , Humanos , Itália , Masculino , Pessoa de Meia-Idade , Risco , Células Th1/imunologia , Células Th1/virologiaRESUMO
Hepatitis C is disease that damages the liver, and it is caused by the hepatitis C virus (HCV). The pathology became chronic in about 80% of the cases due to virus persistence in the host organism. The standard of care consists of pegylated interferon plus ribavirin; however, the treatment response is very variable and different host/viral factors may concur in the disease outcome. The mannose-binding protein C (MBL) is a component of the innate immune system, able to recognize HCV and consecutively activating the immune response. MBL is encoded by MBL2 gene, and polymorphisms, two in the promoter region (H/L and X/Y) and three in exon 1 (at codon 52, 54 and 57), have been described as functionally influencing protein expression. In this work, 203 Italian HCV patients and 61 healthy controls were enrolled and genotyped for the five MBL2 polymorphisms mentioned above to investigate their role in HCV infection susceptibility, spontaneous viral clearance and treatment response. MBL2 polymorphisms were not associated with HCV infection susceptibility and with spontaneous viral clearance, while MBL2 O allele, O/O genotype, HYO haplotype and DP combined genotype (all correlated with low or deficient MBL expression) were associated with sustained virological response. Moreover, a meta-analysis to assess the role of MBL2 polymorphisms in HCV infection susceptibility was also performed: YA haplotype could be associated with protection towards HCV infection.
Assuntos
Hepacivirus/fisiologia , Hepatite C/genética , Imunoterapia/métodos , Lectina de Ligação a Manose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Éxons/genética , Feminino , Estudos de Associação Genética , Predisposição Genética para Doença , Genótipo , Hepatite C/imunologia , Hepatite C/terapia , Humanos , Imunidade Inata/genética , Interferon-alfa/uso terapêutico , Itália , Masculino , Pessoa de Meia-Idade , Polietilenoglicóis/uso terapêutico , Polimorfismo Genético , Regiões Promotoras Genéticas/genética , Proteínas Recombinantes/uso terapêutico , Resultado do Tratamento , Carga Viral/genéticaRESUMO
This study aims to comprehensively analyze human leucocyte antigen (HLA)-G polymorphisms association with susceptibility to systemic lupus erythematosus (SLE) development and clinical manifestations. The HLA-G 5' upstream regulatory region (URR), 3' untranslated region (UTR) and a cytosine deletion at exon 3 (ΔC, HLA-G*0105N allele) were analyzed in 114 SLE patients and 128 healthy controls from North East Brazil. The +3003T>C (rs1707) C allele and the HG010101c extended HLA-G allele were significantly more frequent in SLE patients than healthy controls (+3003C allele frequency: 12% in SLE patients vs 6% in controls; odds ratio (OR), 2.10, 95% confidence interval (CI), 1.06-4.28, P = 0.026; HG010101c frequency: 11.8% in SLE patients and 6.3% in controls; OR, 2.14, 95% CI, 1.01-4.51, P = 0.046) and were associated with susceptibility for disease development. Other polymorphisms were associated with different clinical manifestations. Although HLA-G role in SLE disease is far from being elucidated yet, our association study results along with a systematic review and meta-analysis suggest that HLA-G might be able to slightly modulate the complex SLE phenotype (pooled OR, 1.14, 95% CI, 1.02-1.27, P = 0.021).
