Genetic susceptibility to type 1 autoimmune hepatitis in white northern Europeans is related to female sex, HLA alleles encoding the six amino acid sequence LLEQKR at positions 67-72 of the DRB1 polypeptide, and CTLA-4 gene polymorphism. The principal HLA alleles associated with type 1 autoimmune hepatitis in Britain and North America are DRB1* 0301 and DRB1* 0401. In this model of susceptibility, lysine at position 71 of the expressed DR molecule is the critical amino acid. In Japan, Argentina and Mexico, susceptibility is linked to DRB1* 0405 and DRB1* 0404. These two alleles encode arginine at position 71 rather than lysine, but they share the LLEQ-R with DRB1* 0401 and DRB1* 0301. Thus, K or R at position 71 in the context of LLEQ-R may be critical for susceptibility. This" shared motif" or" epitope" may optimize T-cell recognition of autoantigen, and other alleles that encode lysine at DRβ7 1 may also affect susceptibility and outcome, possibly by increasing the density of lysine or arginine 71 molecules on the surface of antigen-presenting cells. Since the DRB1* 0301 allele is part of the extended ancestral 8.1 haplotype, it carries with it additional risk factors for autoimmunity, including TNFA* 2 and C4A* Q0. Type 1 autoimmune hepatitis is a polygenic disorder and other yet undefined polymorphic genes may be non-specific immunoregulators. These additional MHC encoded genes and other non-MHC encoded genes may be important determinants of disease susceptibility and severity in type 1 autoimmune hepatitis.