Perspectives in Diabetes

This article presents a model for the HLA effect in insulin-dependent dlabetes mellitus (IDDM) that is almost the mirror image of a model suggested by Nepom (1). In the Nepom model, the products of certain HLA alleles are associated wlth IDDM because . they bind and present a specific peptide or peptides so as to induce an immune response to pancreatic p-cells; certaln other alleles can protect agalnst IDDM If they compete strongly for binding of the dlabetogenic peptlde. My model focuses instead on the failure of the immune system to maintain tolerance to pancreatic p-cells. I suggest that the HLA alleles negatively associated with IDDM (e.g., DR2 and DQwl) produce products with high affinity for certain p-cell peptide or peptides needed to establish and malntain tolerance to p-cells, whereas the alleles that are common in IDDM (e.g., DR3, DR4, and DQw8) produce products that have low affinity for the tolerogenic peptide or peptldes or that bind the peptide or peptldes in the wrong orientation or configuration for establishing tolerance. I also dlscuss the multiplicity of HLA loci, alleles, and amino acids contributing to IDDM and the fact that the associations of specific loci, alleles, and even genotypes with IDDM depend not only on their intrinsic properties but also on various population parameters. Diabetes 41 :123-29, 1992. genes, IDDM susceptibility seems to be significantly affected by at least three HLA class II genes: DQA1, DQB1, and DRB1, and probably by the DPBl locus as well. In an earlier Perspective, Nepom (1) suggested a model wherein HLA class II alleles affect IDDM susceptibility as follows. 1) The array of class II dimers, encoded by any individual's HLA complex, vary in their affinities for a specific peptide that can induce autoimmunity to p-cells. 2) Only certain class II dimers, the products of "susceptibility genes," actually promote autoimmunity to p-cells after binding that peptide. 3) An individual is susceptible if the product of a susceptibility gene binds the peptide more strongly than the products of the nonsusceptibility genes present in that individual. An unstated assumption is that the concentration of the diabetogenic peptide is limiting. The mechanism whereby susceptibility and nonsusceptibility gene products differ was not specified. In this article, I argue for an alternative model in which immunological tolerance is the primary determinant of IDDM susceptibility. This is almost the mirror image of the Nepom model (1). In the model proposed herein, a specific peptide or peptides can potentially induce toler. . ance to p-cells, and p-cell tolerance actually occurs if the individual has one or more class II dimers that can bind