Identification of a beta-cell-specific HLA class I restricted epitope in type 1 diabetes.
Type 1 diabetes is an autoimmune disease in which pancreatic beta-cells are destroyed by cytotoxic T-cells that recognize peptide epitopes presented by HLA class I molecules. The identification of human beta-cell epitopes may significantly improve the prospects for immunodiagnosis and immunotherapy in type 1 diabetes. Using algorithms to predict nonameric beta-cell peptides that would bind to the common HLA allele, HLA-A*0201, we identified a potential epitope from the leader sequence of islet amyloid polypeptide (human islet amyloid polypeptide [IAPP] precursor protein [preproIAPP] 5-13: KLQVFLIVL). Peripheral blood mononuclear cells (PBMCs) were isolated from 18 HLA-A*0201 patients with type 1 diabetes (9 with recent-onset [<180 days; range, 1-120 days] and 9 with long-standing diabetes [>180 days; range, 183-3,273 days]) and 9 healthy, nondiabetic control subjects. PBMCs were screened for peptide recognition using interferon-gamma enzyme-linked immunospot (ELISpot) assays. Of the nine patients with recent-onset type 1 diabetes, six had ELISpot responses to preproIAPP 5-13 that were >3 SDs above the mean of the nondiabetic control subjects (P = 0.002). In contrast, no patients with type 1 diabetes for >180 days had a response above this threshold. In summary, preproIAPP 5-13 is a novel HLA class I epitope recognized by a significant proportion of cytotoxic T-cells from HLA-A*0201 patients with recent-onset type 1 diabetes and may prove to be a useful tool for the prediction and/or prevention of this disease.
Department of Pathology & Laboratory Medicine, B.C. Research Institute for Children's and Women's Health, Vancouver, British Columbia, Canada.
Constadina
C
Panagiotopoulos
Huilian
H
Qin
Rusung
R
Tan
C Bruce
CB
Verchere
D000595:Amino Acid Sequence; D000818:Animals; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D000939:Epitopes / Q000737:chemistry; D015234:HLA-A Antigens / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000032:analysis*; D006801:Humans; D007515:Islets of Langerhans / Q000276:immunology*; D051379:Mice; D016688:Mice, Inbred NOD; D010446:Peptide Fragments / Q000737:chemistry
D000939:Epitopes; D015234:HLA-A Antigens; D015395:Histocompatibility Antigens Class I; D010446:Peptide Fragments