Immunogenetics and IDDM

Abstract

Comparison of genetic determinants associated with susceptibility to IDDM in different countries remains important for understanding disease epidemiology and aetiology. The strong association of the human leukocyte antigens (HLA) with IDDM continues to be demonstrated in different populations. Genetic heterogeneity of HLA is always encountered in different ethnic groups and in the patients with varying clinical manifestations. Detailed studies by molecular design help to unify the hypothesis that the structural and functional changes in HLA class 11 molecules leads to autoimmune processes. Our studies in the Chinese living in Taiwan reveal that certain HLA class II alleles confer predisposition to or protection from IDDM. Moreover, some of them contribute to the clinical heterogeneity among IDDM subjects, eg. the presence or absence of thyroid autoantibodies. Although the specific HLA alleles might not be the true pathogenic factor(s) for IDDM or thyroid autoimmunity, the inference from the structural biology of the HLA molecules suggests that the amino acid residue 57 of the HLA DQβ chain might play a role in antigen presentation and T cell recognition. This hypothesis is almost correct through tests so far inmost of the populations except in the Japanese. However, the single HLA-DQB-57 locus is not sufficient to explain the difference in the world-wide incidence of IDDM. In complementation with HLA-DQα chain, HLA-DQα, β heterodimers strongly influence the risk to IDDM in Chinese population as well as in other ethnic groups, suggesting the direct role of HLA-DQ genes in IDDM. There are many genes resided within the MHC region on the short arm of chromosome 6. The presence of the linkage disequilibrium between these loci render it difficult to establish the role of individual genes. We have characterized a diallelic polymorphism of heat shock protein 70 gene on the chromosome 6 (HSP70-2 and HLA loci contribute to IDDM independently although these loci are in linkage disequilibrium. In conclusion, molecular typing of HLA class II genes allows us to re-examine the role of HLA in IDDM. Other genetic and environmental factors also contribute to the pathogenesis of IDDM.