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Evidence for Molecular Mimicry between Human T Cell Epitopes in Rotavirus and Pancreatic Islet Autoantigens


Honeyman, MC; Stone, NL; Falk, BA; Nepom, G; Harrison, LC
2010-02-15
JOURNAL OF IMMUNOLOGY
Journal Article
184
4
2204-2210
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 I diabetes and were also T cell epitopes in humans at risk for type I 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. The Journal of Immunology, 2010, 184: 2204-2210.
AMER ASSOC IMMUNOLOGISTS
GLUTAMIC-ACID DECARBOXYLASE; DIABETES-MELLITUS; CROSS-REACTIVITY; TRANSGENIC MICE; TYPE-1; RESPONSES; COXSACKIEVIRUS; PEPTIDES; PROTEIN; AUTOIMMUNITY
10.4049/jimmunol.0900709
Refer to copyright notice on published article.

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Creation Date 2010-02-15 12:00:00