1. Recognition of HLA Class I–Restricted β-Cell Epitopes in Type 1 Diabetes
- Author
-
Rusung Tan, C. Bruce Verchere, Qin Ouyang, Huilian Qin, Constadina Panagiotopoulos, Peter A. Gottlieb, Nathan Standifer, and Gerald T. Nepom
- Subjects
Endocrinology, Diabetes and Metabolism ,medicine.medical_treatment ,Antibody Affinity ,Human leukocyte antigen ,CD8-Positive T-Lymphocytes ,Biology ,Epitope ,Epitopes ,Antigen ,Reference Values ,Insulin-Secreting Cells ,Internal Medicine ,medicine ,Humans ,Cytotoxic T cell ,Amino Acid Sequence ,Peptide sequence ,B-Lymphocytes ,Type 1 diabetes ,HLA-A Antigens ,Insulin ,Histocompatibility Antigens Class I ,medicine.disease ,Peptide Fragments ,CTL ,Diabetes Mellitus, Type 1 ,Immunology - 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.
- Published
- 2006