title: Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes.
abstract: Type 1 diabetes results from the autoimmune destruction of insulin-producing pancreatic beta-cells by cytotoxic T-lymphocytes (CTLs). In humans, few beta-cell epitopes have been reported, thereby limiting the study of beta-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 beta-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 gamma-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 beta-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 beta-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.
authors.affiliation: 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.
authors.forename: Qin
authors.initials: Q
authors.lastname: Ouyang
authors.forename: Nathan E
authors.initials: NE
authors.lastname: Standifer
authors.forename: Huilian
authors.initials: H
authors.lastname: Qin
authors.forename: Peter
authors.initials: P
authors.lastname: Gottlieb
authors.forename: C Bruce
authors.initials: CB
authors.lastname: Verchere
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.forename: Rusung
authors.initials: R
authors.lastname: Tan
authors.forename: Constadina
authors.initials: C
authors.lastname: Panagiotopoulos
mesh_terms: D000595:Amino Acid Sequence; D000915:Antibody Affinity; D001402:B-Lymphocytes / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D000939:Epitopes / Q000235:genetics / Q000276:immunology*; D015234:HLA-A Antigens / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050417:Insulin-Secreting Cells / Q000276:immunology*; D010446:Peptide Fragments / Q000737:chemistry; D012016:Reference Values
chemical_list: D000939:Epitopes; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments