Viral induction of autoimmunity: mechanisms and examples in hepatology.

Autoimmunity may be observed in chronic viral hepatitis, in particular hepatitis C and D. The hepatitis C virus (HCV) displays numerous interactions with the immune system. Hepatitis C virus induces a number of diseases of presumed autoimmune background, like mixed cryoglobulinaemia, glomerulonephritis, panarthritis, arthritis, thyroiditis and skin lesions. On the other hand a number of autoantibodies are observed during the course of hepatitis C. Of particular interest are liver/kidney microsomal antibodies (LKM). Their occurrence in viral hepatitis may indicate an increased risk for treatment with interferons. LKM antibodies in chronic hepatitis C recognize several autoepitopes differing from those in autoimmune hepatitis. Hepatitis C-associated LKM antibodies are more heterogeneous. They recognize either conformational or several distinct linear autoepitopes on cytochrome P450 2D6; they may also react with other microsomal proteins. Apart from their molecular weight at 59 and 70 kDa these microsomal antigens are not yet identified. Another model of virus-induced autoimmunity in man is chronic hepatitis D which always requires co-infection with hepatitis B. Hepatitis D is known to be associated with a number of autoantibodies, amongst them LKM-3. LKM-3 antibodies have recently been shown to react with proteins of the UDP glucuronosyltransferase family (UGT). The main antigen is an autoepitope expressed on exon 2-5 of family 1 UGTs. Some hepatitis D sera recognize a minor second epitope on family 2 UGTs. It is interesting that hepatitis C patients recognize proteins of the cytochrome P450 family while hepatitis D sera react with UGTs. There seems to be little overlap between autoimmunity seen in hepatitis C and D as far as autoepitopes are concerned. LKM-3 antibodies against UGT 1 are also seen in a minority of patients with autoimmune hepatitis type 2. However, the autoimmune response against UGTs seen in autoimmune hepatitis differs from that observed in viral hepatitis. Autoantibodies in autoimmune liver disease are usually more homogenous and are directed against precise linear epitopes. Autoepitopes in autoimmune hepatitis usually represent conserved regions of these proteins, the antibody usually is inhibitory and antibody titres are very high. In contrast, autoantibodies in viral hepatitis are more heterogenous, recognize several linear and conformational epitopes; antibody titres are much lower. However, the major LKM autoantigen in chronic hepatitis C also is P450 2D6. Autoimmune hepatitis and autoimmunity in viral hepatitis must be distinguished clinically by all means due to the need for specific therapeutic interventions. These liver diseases may serve as models to study virus induced autoimmunity and autoimmune disease in man.