Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens

J Immunol. 2010 Feb 15;184(4):2204-10. doi: 10.4049/jimmunol.0900709. Epub 2010 Jan 18.

Abstract

In type 1 diabetes, insulin-producing beta cells in the islets of the pancreas are destroyed by autoreactive T cells. Rotavirus (RV) has been implicated in the pathogenesis of type 1 diabetes. Peptides in VP7, a major immunogenic protein of RV, have high sequence similarity to T cell epitope peptides in the islet autoantigens tyrosine phosphatase-like insulinoma Ag 2 (IA2) and glutamic acid decarboxylase 65 (GAD65). We aimed to educe evidence for the hypothesis that molecular mimicry with RV promotes autoimmunity to islet autoantigens. Peptides in RV and their sequence-similar counterparts in IA2 and GAD65 were assayed for binding to HLA molecules associated with type 1 diabetes and for the ability to elicit T cell proliferative responses in HLA-typed individuals. T cells expanded or cloned to epitopes in IA2 or RV were then tested for cross-reactivity with these epitopes. Peptides in RV-VP7, similar to T cell epitopes in IA2 and GAD65, bound strongly to HLA-DRB1*04 molecules that confer susceptibility to type 1 diabetes and were also T cell epitopes in humans at risk for type 1 diabetes. The proliferative responses of T cells to the similar peptides in RV and islet autoantigens were significantly correlated. T cells expanded to the IA2 epitope could be restimulated to express IFN-gamma by the similar peptide in RV-VP7, and T cell clones generated to this RV-VP7 peptide cross-reacted with the IA2 epitope. Our findings are consistent with the hypothesis that molecular mimicry with RV could promote autoimmunity to islet Ags.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Amino Acid Sequence
  • Antigens, Viral / immunology*
  • Antigens, Viral / metabolism
  • Autoantigens / immunology*
  • Autoantigens / metabolism
  • Capsid Proteins / immunology*
  • Capsid Proteins / metabolism
  • Child
  • Child, Preschool
  • Clone Cells
  • Diabetes Mellitus, Type 1 / enzymology
  • Diabetes Mellitus, Type 1 / immunology
  • Diabetes Mellitus, Type 1 / metabolism
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Female
  • Genetic Predisposition to Disease
  • Glutamate Decarboxylase / immunology
  • Glutamate Decarboxylase / metabolism
  • HLA-DR Antigens / immunology
  • HLA-DR Antigens / metabolism
  • HLA-DRB1 Chains
  • Humans
  • Interferon-gamma / biosynthesis
  • Islets of Langerhans / enzymology
  • Islets of Langerhans / immunology*
  • Islets of Langerhans / virology
  • Male
  • Middle Aged
  • Molecular Mimicry / immunology*
  • Molecular Sequence Data
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / biosynthesis
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / immunology
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8 / metabolism
  • Rotavirus / immunology*

Substances

  • Antigens, Viral
  • Autoantigens
  • Capsid Proteins
  • Epitopes, T-Lymphocyte
  • HLA-DR Antigens
  • HLA-DRB1 Chains
  • VP7 protein, Rotavirus
  • Interferon-gamma
  • PTPRN protein, human
  • Receptor-Like Protein Tyrosine Phosphatases, Class 8
  • Glutamate Decarboxylase
  • glutamate decarboxylase 2