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T-Cell Epitopes in Type 1 Diabetes Autoantigen Tyrosine Phosphatase IA-2: Potential for Mimicry with Rotavirus and Other Environmental Agents

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Abstract

The tyrosine phosphatase IA-2 is a molecular target of pancreatic islet autoimmunity in type 1 diabetes. T-cell epitope peptides in autoantigens have potential diagnostic and therapeutic applications, and they may hold clues to environmental agents with similar sequences that could trigger or exacerbate autoimmune disease. We identified 13 epitope peptides in IA-2 by measuring peripheral blood T-cell proliferation to 68 overlapping, synthetic peptides encompassing the intracytoplasmic domain of IA-2 in six at-risk type 1 diabetes relatives selected for HLA susceptibility haplotypes.

The dorninant epitope, VTVMLTPLVEDGVKQC (aa 805–820), which elicited the highest T-cell responses in all at-risk relatives, has 56% identity and 100% similarity over 9 amino acids (aa) with a sequence in VP7, a major immunogenic protein of human rotavirus. Both peptides bind to HLA-DR4(*0401) and are deduced to present identical aa to the T-cell receptor. The contiguous sequence of VP7 has 75% identity and 92% similarity over 12 aa with a known T-cell epitope in glutamic acid decarboxylase (GAD), another autoantigen in type 1 diabetes. This dominant IA-2 epitope peptide also has 75–45% identity and 88–64% similarity over 8–14 aa to sequences in Dengue, cytomegalovirus, measles, hepatitis C, and canine distemper viruses, and the bacterium Haemophilus influenzae. Three other IA-2 epitope peptides are 71–100% similar over 7–12 aa to herpes, rhino-, hanta- and flaviviruses. Two others are 80–82% similar over 10–11 aa to sequences in milk, wheat, and bean proteins. Further studies should now be carried out to directly test the hypothesis that T-cell activation by rotavirus and possibly other viruses, and dietary proteins, could trigger or exacerbate β-cell autoimmunity through molecular mimicry with IA-2 and (for rotavirus) GAD.

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Acknowledgments

We are grateful to the volunteers for their generous blood donations, and to Dr. Barbara Coul-son and Mr. Vladimir Brusic for helpful discussions. Dr. Brian Tait for tissue typing. Dr. Robert Schmidli and Dr. Peter Colman for autoantibody assays, and Mrs. Margaret Thompson for secretarial assistance. N.L.S. is supported by Vic Health, M.C.H. and L.C.H. by the National Health &Medical Research Council of Australia and The Angelo and Susan Alberti Program Project Grant from the Juvenile Diabetes Foundation International.

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  1. Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Royal Melbourne Hospital, Parkville, Victoria, 3050, Australia

    Margo C. Honeyman, Natalie L. Stone & Leonard C. Harrison

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  1. Margo C. Honeyman
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  2. Natalie L. Stone
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  3. Leonard C. Harrison
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Correspondence to Margo C. Honeyman.

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Communicated by L. C. Harrison.

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Honeyman, M.C., Stone, N.L. & Harrison, L.C. T-Cell Epitopes in Type 1 Diabetes Autoantigen Tyrosine Phosphatase IA-2: Potential for Mimicry with Rotavirus and Other Environmental Agents. Mol Med 4, 231–239 (1998). https://doi.org/10.1007/BF03401920

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