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Recognition of HLA Class I–Restricted ß-Cell Epitopes in Type 1 Diabetes

¹ Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia and British Columbia Children’s Hospital, Vancouver, Canada
² Benaroya Research Institute at Virginia Mason, Seattle, Washington
³ Barbara Davis Center for Childhood Diabetes, University of Colorado Health Sciences Center, Denver, Colorado
⁴ Department of Pediatrics, Child and Family Research Institute, University of British Columbia and British Columbia Children’s Hospital, Vancouver, Canada

Address correspondence and reprint requests to Dr. Rusung Tan, Department of Pathology and Laboratory Medicine, Child and Family Research Institute, University of British Columbia and British Columbia Children’s Hospital, 4480 Oak St., Vancouver, British Columbia V6H 3V4, Canada. E-mail: roo{at}interchange.ubc.ca

Abbreviations: BIMAS, BioInformatics and Molecular Analysis Section; CMV, cytomegalovirus; CTL, cytotoxic T-lymphocyte; EBV, Epstein-Barr virus; ELISpot, enzyme-linked immunospot; FITC, fluorescein isothiocyanate; HCV, hepatitis C virus; IA-2, insulinoma-associated antigen 2; IAPP, islet amyloid polypeptide; IFN-, -interferon; IGRP, islet-specific glucose-6-phosphatase catalytic subunit–related protein; MHC, major histocompatibility complex; PBMC, peripheral blood mononuclear cell

Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic ß-cells by cytotoxic T-lymphocytes (CTLs). In humans, few ß-cell epitopes have been reported, thereby limiting the study of ß-cell–specific CTLs in type 1 diabetes. To identify additional epitopes, HLA class I peptide affinity algorithms were used to identify a panel of peptides derived from the ß-cell proteins islet amyloid polypeptide (IAPP), islet-specific glucose-6-phosphatase catalytic subunit–related protein (IGRP), insulin, insulinoma-associated antigen 2 (IA-2), and phogrin that were predicted to bind HLA-A*0201. Peripheral blood mononuclear cells from 24 HLA-A*0201 recent-onset type 1 diabetic patients and 11 nondiabetic control subjects were evaluated for -interferon secretion in response to peptide stimulation in enzyme-linked immunospot assays. We identified peptides IAPP9-17, IGRP215-223, IGRP152-160, islet IA-2(172-180), and IA-2(482-490) as novel HLA-A*0201–restricted T-cell epitopes in type 1 diabetic patients. Interestingly, we observed a strong inverse correlation between the binding affinity of ß-cell peptides to HLA-A*0201 and CTL responses against those peptides in recent-onset type 1 diabetic patients. In addition, we found that self-reactive CTLs with specificity for an insulin peptide are frequently present in healthy individuals. These data suggest that many ß-cell epitopes are recognized by CTLs in recent-onset type 1 diabetic patients. These epitopes may be important in the pathogenesis of type 1 diabetes.

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