HLA and Insulin-Dependent Diabetes. A protective perspective

Abstract

This article presents a model for the HLA effect in insulin-dependent diabetes mellitus (IDDM) that is almost the mirror image of a model suggested by Nepom. In the Nepom model, the products of certain HLA alleles are associated with IDDM because they bind and present a specific peptide or peptides so as to induce an immune response to pancreatic beta-cells; certain other alleles can protect against IDDM if they compete strongly for binding of the diabetogenic peptide. My model focuses instead on the failure of the immune system to maintain tolerance to pancreatic beta-cells. I suggest that the HLA alleles negatively associated with IDDM (e.g., DR2 and DQw1) produce products with high affinity for certain beta-cell peptide or peptides needed to establish and maintain tolerance to beta-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 peptides or that bind the peptide or peptides in the wrong orientation or configuration for establishing tolerance. I also discuss 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.

Human Type 1 Diabetes Is Associated with T Cell Autoimmunity to Zinc Transporter 8

“…At present the mechanism responsible for this genetic protection from T1D remains a matter of debate, but has variously been proposed to be due to a failure of the protective molecules to productively present key diabetogenic peptides (23) or an enhanced ability to bind key tolerogenic peptides (24). Consequently, we were also concerned by the fact that 13/41 controls but 0/35 patients expressed 1 or more of the molecules encoded by these “protective” alleles.…”

HLA DR/DQ alleles and risk of type I diabetes in childhood: a population–based case–control study

“…The major gene situated in this region is represented by the HLA-DR and DQ alleles. Susceptibility to type 1 diabetes seems to be linked to at least three class II genes: DQA1, DQB1 and DRB1 [6]. A significant contribution to type 1 diabetes genetic susceptibility appears to be encoded by the HLA DQB1 locus and in particular by DQB1*0302 and DQB1*0201, found on the DR4 and DR3 haplotypes, respectively [7,8].…”

Autoantibodies and High-Risk HLA Susceptibility Markers in First-Degree Relatives of Brazilian Patients with Type 1 Diabetes Mellitus: A Progression to Disease Based Study

“…Recent genome-wide association studies have indicated that >40 loci are associated with T1DM [6]. Among these, polymorphisms of human leukocyte antigen (HLA) class II genes of major histocompability complex (MHC), account for approximately 40-50% of the familial aggregation of T1DM [7,8]. Specifically, the haplotypes with the highest risk for T1DM are DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and DRB1*04:01/05/-DQA1*0301-DQB1*0302/04 (DR4).…”