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Similar Peptides from Two β Cell Autoantigens, Proinsulin and Glutamic Acid Decarboxylase, Stimulate T Cells of Individuals at Risk for Insulin-Dependent Diabetes

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Abstract

Background

Insulin (1) and glutamic acid decarboxylase (GAD) (2) are both autoantigens in insulin-dependent diabetes mellitus (IDDM), but no molecular mechanism has been proposed for their association. We have identified a 13 amino acid peptide of proinsulin (amino acids 24–36) that bears marked similarity to a peptide of GAD65 (amino acids 506–518) (G. Rudy, unpublished). In order to test the hypothesis that this region of similarity is implicated in the pathogenesis of IDDM, we assayed T cell reactivity to these two peptides in subjects at risk for IDDM.

Materials and Methods

Subjects at risk for IDDM were islet cell antibody (ICA)-positive, first degree relatives of people with insulin-dependent diabetes. Peripheral blood mononuclear cells from 10 pairs of at-risk and HLA-DR matched control subjects were tested in an in vitro proliferation assay.

Results

Reactivity to both proinsulin and GAD peptides was significantly greater among at-risk subjects than controls (proinsulin; p < 0.008; GAD: p < 0.018). In contrast to reactivity to the GAD peptide, reactivity to the proinsulin peptide was almost entirely confined to the at-risk subjects.

Conclusions

This is the first demonstration of T cell reactivity to a proinsulin-specific peptide. In addition, it is the first example of reactivity to a minimal peptide region shared between two human autoimmune disease-associated self antigens. Mimicry between these similar peptides may provide a molecular basis for the conjoint autoantigenicity of proinsulin and GAD in IDDM.

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Acknowledgments

The authors express their appreciation to Margaret Thompson for secretarial assistance and thank the Victorian Health Promotion Foundation for their support. GR is a recipient of a National Health and Medical Research Council fellowship. MBF was a recipient of a Medical Research Council of Canada fellowship.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, Melbourne, Australia

    George Rudy, Natalie Stone, Leonard C. Harrison, Vladimir Brusic, Michelle B. French, Margo C. Honeyman & Andrew M. Lew

  2. The Royal Melbourne Hospital, Melbourne, Australia

    Peter G. Colman, Peter McNair & Brian Tait

  3. Burnet Clinical Research Unit, The Walter and Eliza Hall Institute of Medical Research, Post Office, Royal Melbourne Hospital, Victoria, 3050, Australia

    George Rudy

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Rudy, G., Stone, N., Harrison, L.C. et al. Similar Peptides from Two β Cell Autoantigens, Proinsulin and Glutamic Acid Decarboxylase, Stimulate T Cells of Individuals at Risk for Insulin-Dependent Diabetes. Mol Med 1, 625–633 (1995). https://doi.org/10.1007/BF03401603

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