Insulin dependent diabetes mellitus (type 1): current concepts on HLA contribution to a etiopathogenesis of the disease
Henryk W. Witas, Marcin Różalski, Wojciech Mlynarski, Jerzy Bodalski
Med Sci Monit 1996; 2(6): RA864-872
Available online: 1996-11-01
Insulin-dependent (type 1) diabetes mellitus (IDDM) is an autoimmune disease and is suggested to be induced both by environmental as well as genetic factors. Although the role of the genetic component in the IDDM a etiopathogenesis is not dominant, as it was shown in monozygotic twins studies, it still remains significant. A Linkage analysis showed the HLA region located on the short arm of chromosome 6 to be in the strongest association with IDDM. Several alleles of genes within the HLA region have been proposed as candidate susceptibility factors, however, a hypothesis assuming an association of IDDM with two genes of DQ region (DQA1 and DQB1) belonging to class II HLA genes seems to be widely accepted now. Both genes are highly polymorphic and their alleles have been shown to segregate into three groups: conferring susceptibility, resistance and a neutral one, with respect to IDDM. Studies carried out in different ethnic groups revealed that allelic combinations are involved in protection. Allelic variants of both genes concerned as independent genetic factors also seem to be important, however, DQB1 alleles are thought to be more significant than DQA1. At the protein level, an association between the absence of DQβAsp57, and presence of DQαArg52, and IDDM has been widely reported, however, with an exception of the Japanese population. Two attractive hypotheses presenting current views on a possible explanation of the association between DQ molecules and IDDM are discussed. According to the first hypothesis 'diabetogenic peptide(s)' (unknown so far) are able to bind tighter to the resistance DQ molecules than to that conferring susceptibility to IDDM, which results in elimination of autoreactive T-cell clones in the thymus during ontogenesis of the immune system. Out of the thymus resistance the DQ molecules would overcome an action of the susceptible ones and would prevent autoimmune reactions. The second hypothesis assumes that the molecular mimicry hypothesis could be relevant with respect to IDDM. According to this hypothesis HLA-derived peptides are prominent in selecting the repertoire of CD4&plus;, T-cells and, consequently in defining susceptibility to IDDM. The latter hypothesis seems to be supported by primary structure similarities observed between the susceptibility DQβ chains and GAD-65, JunB and ICA-512.
Keywords: iinsulin dependent diabetes mellitus (IDDM), Genetics, HLA