Immunogenetics in liver disease

Recent advances in molecular biology, in particular X-ray crystallography of the purified antigens A2 and DR1 and development of PCR-based HLA genotyping techniques, has revolutionized our understanding of immunogenetics and cellular immunology. The application of molecular immunogenetics has refined our understanding of HLA-encoded susceptibility and resistance to both autoimmune and chronic viral liver disease. Recent studies of autoimmune hepatitis (AIH), primary sclerosing cholangitis (PSC) and primary biliary cirrhosis (PBC) have identified substitutions of specific amino acid residues in the HLA DR beta-polypeptide (AIH and PSC) and DP beta-polypeptide (PBC) which may determine susceptibility to and resistance from disease. Although these models of HLA-encoded susceptibility in PSC and PBC are currently controversial, the model for AIH, based on lysine residue at DR beta 71 has recently been confirmed in an independent series. Data on chronic viral liver disease are less abundant, but a number of interesting observations are beginning to emerge. In the Gambia, resistance to chronic hepatitis B infection has been associated with the HLA DRB1*1302 allele, and in studies of patients with chronic hepatitis C virus infection DQA1*03 and DQB1*05 have been identified as a possible protective factors. Clarifying these HLA associations is not simply an academic pursuit; in addition to providing useful clues to the pathogenesis of these diseases, HLA associations may be important indicators of prognosis. In AIH, patients with the DRB1*0301-DRB3*0101 haplotype appear to have more severe disease than those with DRB1*0401, while in PSC, DRB3*0101 is associated with early onset of disease and DRB1*0401 may be a marker of more rapid disease progression. To date, our knowledge of immunogenetic susceptibility in liver disease is incomplete and further work is needed.