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Chronic hepatitis C virus (HCV) infection is associated with immunological abnormality, including circulating immune complexes, production of autoantibodies, and concurrent autoimmune disorders.1,2 Both viral and host factors may contribute to the development of autoantibodies and rheumatological manifestations. In this study we investigated the production of autoantibodies in patients with HCV in order to determine a possible link between the polymorphic HLA-DRB1 allele(s) and autoantibody production in chronic HCV infection.
We analysed HLA-DR polymorphisms in 288 HCV infected subjects in the Department of Internal Medicine, National Taiwan University Hospital. All patients were assayed for their serum autoantibodies with detection of antinuclear antibodies (ANA), rheumatoid factor (RF), antithyroid antibodies (antithyroglobulin (ATG) and antimicrosomal (AMG) antibodies), and antineutrophil cytoplasmic antibodies (ANCA). The HLA-DR polymorphisms were genotyped by polymerase chain reaction and sequence-specific oligonucleotide probe hybridisation as previously described.3 The allelic distribution of the DRB1 gene of the HCV infected subjects was compared with that of a control group of 238 unrelated healthy adults. The results showed that 125/288 (43.4%) subjects had at least one of the autoantibodies, with ANA being the most prevalent (23.2%). RF was also detectable in 52/288 (18.1%) subjects. The antithyroid (ATG: 4.9%, AMC: 8.3%) and antineutrophil (proteinase 3-ANCA: 4.9%, myeloperoxidase-ANCA: 5.2%) antibodies were less common.
The presence of autoantibodies did not correlate significantly with the presence of clinical rheumatological manifestations. In the HLA-DR study we found no significant difference in the DRB1 allelic distribution between the HCV infected subjects and the non-infected control group. The genotypic frequency of HLA-DR11 was significantly decreased in patients with chronic hepatitis C with ANA (odds ratio (OR) = 0.2, p⩽0.001) or ATG (OR = 0.2, p⩽0.0408) (table 1). The genotypic frequency of HLA-DRB11 was also significantly lower among subjects with at least one autoantibody than among those without any serum autoantibodies (OR = 0.5, p⩽0.0357). HLA-DR2 was more prevalent in HCV infected patients in whom RF was absent (OR = 0.4, p⩽0.0133). These results indicate that HLA-DR11 and HLA-DR2 are negatively associated with autoantibody production in Taiwanese patients with chronic hepatitis C.
In our study we found that serum autoantibodies were commonly found in patients with HCV infection. Forty three per cent of the subjects had at least one detectable autoantibody in their sera. ANA and RF were the predominant autoantibodies in HCV infected patients. Recent genetic studies have indicated that HLA class II genotypes strongly influence the outcome of HCV infection.4,5 HCV infection has been frequently detected in patients with immune complex mediated disease such as mixed cryoglobulinaemia, Sjögren’s syndrome, and glomerulonephritis.6,7 It has been reported that HLA-DR11 is significantly more common in patients with HCV associated type II cryoglobulinaemia (mixed cryoglobulinaemia (MC)); whereas, HLA-DR7 is less common in HCV infected patients with MC.8
It has also been reported that HLA-DR4 is positively associated with autoantibody production, whereas HLA-DR3 subjects are predisposed to cryoglobulinaemia.9 The differences in the immunological abnormalities and HLA-DR genotype may be related to the genetic background in different ethnic groups. In this report we clearly observed a protective effect conferred by HLA-DRB1*11 against autoantibody production in chronic hepatitis C. Our results also demonstrated that HLA-DR2 was more prevalent in HCV infected patients without RF. These findings support the hypothesis that specific HLA-DR alleles have an important role in the immunological abnormalities in chronic hepatitis C, and our results present clear evidence for a relationship between HCV infection and immunological abnormalities.
Investigation of the molecular mechanism of HLA-DR11 and HLA-DR2 involvement in protecting subjects from autoantibody production in chronic HCV infection awaits further investigation. In conclusion, our results suggest that the existence of HLA-DR linked protection genes (DR11 or DR2) prevents the production of serum autoantibodies in Taiwanese patients with chronic hepatitis C.
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