Immunogenetics of disease susceptibility: new perspectives in HLA.

Structural analysis of HLA class II molecular variation occurring within haplotypes implicated in specific HLA-associated diseases now provides more specific and sensitive mechanisms for investigation of genetic susceptibility to disease. Using the HLA-DR4 association with two distinct diseases, IDDM and JRA, as a model, we can conclude the following: There are at least seven distinct haplotypes which share the HLA DR4 specificity; these haplotypes include six alleles at the DR-beta genetic locus. These allelic differences are subtle, encompassing a very few clustered amino acid changes, but are sufficient to generate different patterns of T cell alloreactivity; there are at least three different alleles of DQ-beta genes associated with DR4+ haplotypes, with major structural differences recognized by biochemical analysis and by specific antibodies; different DR4-associated diseases are associated with different specific allelic variants of DR and DQ genes. DR4+ IDDM is most closely associated with the DQ 3.2 allele at DQ-beta; DR4+ JRA, on the other hand, appears to be highly associated with rare alleles at DR-beta, but not DQ. Notably, there are many alleles, and therefore DR4+ haplotypes, which are not implicated in 'HLA-DR4-associated' diseases.