Recognition of HLA class I-restricted beta-cell epitopes in type 1 diabetes.
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.
Ouyang
Qin
Q
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.
Standifer
Nathan E
NE
Qin
Huilian
H
Gottlieb
Peter
P
Verchere
C Bruce
CB
Nepom
Gerald T
GT
Tan
Rusung
R
Panagiotopoulos
Constadina
C
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
D000939:Epitopes; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments