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

  1. Ivana Durinovic-Belló1,
  2. Eva Jelinek1,
  3. Michael Schlosser2,
  4. Thomas Eiermann3,
  5. Bernhard O. Boehm1,
  6. Wolfram Karges1,
  7. Luc Marchand4 and
  8. Constantin Polychronakos4
  1. 1Department of Internal Medicine I, Division of Endocrinology, University of Ulm, Ulm, Germany
  2. 2Institute of Pathophysiology Karlsburg, University of Greifswald, Greifswald, Germany
  3. 3Institute of Transfusion Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany
  4. 4Endocrine Genetics Laboratory, McGill University Health Center, Department of Pediatrics, Montreal, Canada
  1. Address correspondence and reprint requests to Constantin Polychronakos, MD, McGill University Health Center (Children’s Hospital), 2300 Tupper St., Montréal, Québec, Canada H3H 1P3. E-mail: constantin.polychronakos{at}mcgill.ca

Abstract

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 γ-interferon, tumor necrosis factor-α, 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.

Footnotes

  • This article is based on a presentation at a symposium. The symposium and the publication of this article were made possible by an unrestricted educational grant from Servier.

    • Accepted June 2, 2005.
    • Received March 2, 2005.
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