Genetic factors affecting the occurrence, clinical phenotype, and outcome of autoimmune hepatitis.

摘要

Autoimmune hepatitis is a polygenic disorder of unknown cause in which the genetic risk factors that affect occurrence, clinical phenotype, severity, and outcome still are being clarified. The susceptibility alleles in white North American and northern European patients reside on the DRB1 gene, and they are DRB1*0301 and DRB1*0401. These alleles encode a 6 amino acid sequence at positions 67-72 in the DRbeta polypeptide chain of the class II molecules of the major histocompatibility complex. This sequence is associated with susceptibility, and lysine at position DRbeta71 is the key determinant. Molecular mimicry between foreign and self-antigens may explain the loss of self-tolerance and the occurrence of concurrent immune diseases in anatomically distant organs. Disease severity is associated with the number of alleles encoding lysine at DRbeta71 (gene dose) and the number of polymorphisms, including those of the tumor necrosis factor-alpha gene, cytotoxic T lymphocyte antigen-4 gene, and tumor necrosis factor-receptor superfamily gene, that can modify the immune response. Individuals in different geographic regions may have different susceptibility alleles that reflect indigenous triggering antigens, and these may provide clues to the etiologic agent. Knowledge of the genetic predispositions for autoimmune hepatitis may elucidate pathogenic mechanisms, identify etiologic agents, characterize susceptible populations, foresee outcomes, and target new therapies. These lessons may be applicable to autoimmune disease in general.