Determinants of genetic susceptibility in HLA-associated autoimmune disease.

The predominant genetic elements contributing to HLA-associated disease susceptibility have been localized within the HLA-D, or class II, region of the major histocompatibility complex for a large number of autoimmune diseases. Two likely candidate susceptibility genes in this region have been identified: the DQ beta 3.2 gene is the single allele most highly associated with type I diabetes (IDDM) and accounts for the HLA-DR4 association with that disease. DNA sequence analysis and mutagenesis studies implicate a small set of key residues within the DQ3.2 molecule as critical polymorphic residues likely contributing to disease-associated immune mechanisms. Different class II genes, Dw4 and Dw14, specific alleles at the DR beta locus, account for the HLA-DR4 association with rheumatoid arthritis (RA). A single cluster of polymorphic residues within the DR beta molecule may be sufficient to account for nearly all of the structural and genetic contributions of the HLA complex to the pathogenesis of RA.