Hla Complex And Mechanisms Of Susceptibility To Or Protection From

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Amino acid polymorphism at position 57 the HLA-DQP-chain could influence the interaction between the class II molecule on the antigen-presenting cell, the peptide antigen, and the TCR of the helper T-cell. Consequently, this influences the control of the specificity of the immune response to foreign and/or self antigens (see Fig. 6) (22).

However, other residues in the DQP-chain as well as the DQa-chain (124-126) also appear to be involved in the susceptibility to T1DM. As discussed earlier, genetic susceptibility to autoimmune diabetes is strongly conferred by DQ DQA1*0501-dQb1*0201 and DQA1*0301-DQB1*0302 haplotypes. This concept is strengthened by recently published results obtained in vivo providing experimental evidence for the contribution of HLA-DQ molecules to autoimmune-related diabetes development. Using a unique "humanized" animal model of diabetes, the replacement of human HLA-DQ6 for human HLA-DQ8 molecules completely prevented the disease (127).

The importance of class II molecules in playing a role in the pathogenesis of T1DM is also indicated by studies in a transgenic NOD mouse model, in which the expression of an I-A (the equivalent to the human class II DQB1 locus) P-chain transgene carrying Asp 57 instead of Ser 57 protects these mice from developing diabetes (128,129). Moreover, expression of Pro56 instead of the normal His56 in the I-A a-chain has the same effect (130). Finally, expression of certain I-E (the equivalent of the human HLA-DR locus) transgenes appears to confer resistance to the disease (130,131). Of note, the treatment of NOD mice with a monoclonal antibody reacting with the murine class II molecule, also prevents the progression to overt diabetes (132). These findings obtained in an animal model of T1DM certainly support the role of both HLA-DQ and HLA-DR in human T1DM.

The mechanisms by which the class II genes can influence susceptibility to, or protection from, T1DM are still the subject of discussion. Brown et al. (133,134) have characterized the structure of the crystallized HLA class II molecule. One hypothesis is that effective antigen-binding depends on the conformation of the antigen-binding site on the DQ dimer. The two critical residues, DQa 52 and DQP 57 are located at opposite ends of the a-helices that form the antigen-binding site of the DQ molecule (see Fig. 3). It has been postulated that a substitution of an amino acid residue at these positions of the DQ molecule leads to conformational changes of the antigen-binding site and, consequently, to a modification of the affinity of the class II molecule for the "diabetogenic" peptide(s) (22). In support for this hypothesis, it is known that in the DR molecule Asp-57 is involved in hydrogen- and salt-bonding with the antigenic peptide and the Arg-76 position of the a-chain, respectively (130,131). Theoretically, modifications in the DRa Arg-76 residue would also alter the antigen-binding site. This is physiologically difficult to observe since the DRa-chain is not polymorphic.

It is noteworthy that studies of the regulatory regions of the genes encoding DQa-and DQP-chains have shown that the level of transcription of these genes may also influence antigen binding. An increased level of production of a certain class II a-chain may increase the availability for dimerization in trans with the P-chain of the other haplotype (135,136). Although the actual ratio of cis-encoded vs trans-encoded DQ heterodimers at the cell surface remains to be determined experimentally, it is possible that moderate differences in chain production translate into large functional differences with respect to antigen presentation and T-cell activation (22). Studies by Demotz et al. (137) suggest that relatively few class II heterodimers need to be present at the surface of an antigen-presenting cell to efficiently crosslink the TCR and initiate a T-cell response. On this basis, it is easily understandable why the study of IDDM1 must acknowledge the role of the T-cell and, more specifically, the role of particular TCRs in mediating disease.

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