THE MOLECULAR-GENETICS OF AUTOIMMUNE LIVER-DISEASE

The dual observations that human leukocyte antigens have an antigen-bi nding groove and that the polymorphism we study as human leukocyte ant igen types is largely related to amino acid substitutions in and aroun d that groove have provided a new focus for immunogenetic studies. In autoimmune liver disease, recent studies have described specific amino acid substitutions in the antigen-binding groove of human leukocyte a ntigen DR molecules that may determine both disease susceptibility, th rough their direct influence on antigen binding, and the severity of t he disease. In autoimmune hepatitis, lysine residues at DR beta positi on 71 in European subjects and arginine or histidine residues at DR be ta position 13 in Japanese subjects may be responsible for much human leukocyte antigen-encoded disease susceptibility. Similar claims have been made for leucine residues at DR beta 38 in primary sclerosing cho langitis and for leucine residues at DP beta 35 in Japanese patients w ith primary biliary cirrhosis. To date, our knowledge of genetic susce ptibility to autoimmune liver disease is incomplete. Other genes may c ontribute to susceptibility to autoimmune liver disease-for example th e contribution of TAP genes, upstream promoter sequences and class III genes on chromosome 6 and the T-cell receptor genes and complement ge nes elsewhere in the human genome is currently unclear. Additional inf ormation concerning the immunogenetic contribution to disease severity is needed to complete the picture.