Evidence for molecular mimicry between human T cell epitopes in rotavirus and pancreatic islet autoantigens.
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.
Honeyman
Margo C
MC
Autoimmunity and Transplantation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
Stone
Natalie L
NL
Falk
Ben A
BA
Nepom
Gerald
G
Harrison
Leonard C
LC
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D000956:Antigens, Viral / Q000276:immunology* / Q000378:metabolism; D001324:Autoantigens / Q000276:immunology* / Q000378:metabolism; D036022:Capsid Proteins / Q000276:immunology* / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D002999:Clone Cells; D003922:Diabetes Mellitus, Type 1 / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D018984:Epitopes, T-Lymphocyte / Q000276:immunology* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D005968:Glutamate Decarboxylase / Q000276:immunology / Q000378:metabolism; D006684:HLA-DR Antigens / Q000276:immunology / Q000378:metabolism; D059811:HLA-DRB1 Chains; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D007515:Islets of Langerhans / Q000201:enzymology / Q000276:immunology* / Q000821:virology; D008297:Male; D008875:Middle Aged; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8 / Q000096:biosynthesis / Q000276:immunology / Q000378:metabolism; D012401:Rotavirus / Q000276:immunology*
D000956:Antigens, Viral; D001324:Autoantigens; D036022:Capsid Proteins; D018984:Epitopes, T-Lymphocyte; D006684:HLA-DR Antigens; D059811:HLA-DRB1 Chains; C050779:VP7 protein, Rotavirus; D007371:Interferon-gamma; C516862:PTPRN protein, human; D054635:Receptor-Like Protein Tyrosine Phosphatases, Class 8; D005968:Glutamate Decarboxylase; C401141:glutamate decarboxylase 2