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Class III Alleles at the Insulin VNTR Polymorphism Are Associated With Regulatory T-Cell Responses to Proinsulin Epitopes in HLA-DR4, DQ8 Individuals

¹ Department of Internal Medicine I, Division of Endocrinology, University of Ulm, Ulm, Germany
² Institute of Pathophysiology Karlsburg, University of Greifswald, Greifswald, Germany
³ Institute of Transfusion Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
⁴ Endocrine Genetics Laboratory, McGill University Health Center, Department of Pediatrics, Montreal, Canada

A variable number of tandem repeats (VNTR) polymorphism upstream of the insulin promoter is strongly associated with type 1 diabetes. The short class I alleles are predisposing and the long class III alleles are protective. As a possible mechanism for this effect, we previously reported a two- to threefold higher insulin transcription from class III than from class I chromosomes in thymus where insulin is expressed at low levels, presumably for the purpose of self-tolerance. In this article, we confirm this finding with independent methodology and report studies testing the hypothesis that class III alleles are associated with T-cell tolerance to (pro)insulin. Cytokine release in vitro after stimulation with 21 overlapping preproinsulin epitopes was assessed in blood mononuclear cells as well as naive and memory CD4⁺ T-cell subsets from 33 individuals with the high-risk DRB1*04, DQ8 haplotype (12 type 1 diabetic patients, 11 healthy control subjects, and 10 autoantibody-positive subjects). No significant differences between genotypes (24 I/I subjects versus 10 I/III or III/III subjects) were observed for -interferon, tumor necrosis factor-, or interleukin (IL)-4. By contrast, the I/III + III/III group showed a significant threefold higher IL-10 release in memory T-cells for whole proinsulin and the immunodominant region. Given that IL-10 is a marker of regulatory function, our data are consistent with the hypothesis that higher insulin levels in the thymus promote the formation of regulatory T-cells, a proposed explanation for the protective effect of the class III alleles.

Abbreviations: Ab⁺, autoantibody-positive; IFN, interferon; PBMC, peripheral blood mononuclear cell; SNP, single nucleotide polymorphism; Th, T-helper; TNF, tumor necrosis factor; VNTR, variable number of tandem repeats

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