Diabetes, Vol 48, Issue 10 1937-1947, Copyright © 1999 by American Diabetes Association

ARTICLES

Identification of peptides from autoantigens GAD65 and IA-2 that bind to HLA class II molecules predisposing to or protecting from type 1 diabetes

E Harfouch-Hammoud, T Walk, H Otto, G Jung, JF Bach, PM van Endert and S Caillat-Zucman
Laboratory of Immunology and INSERM U25, Hopital Necker, Paris, France.

Type 1 diabetes is a T-cell-mediated disease in which presentation of autoantigens to CD4+ T-cells is thought to play a crucial role. Polymorphism of HLA class II genes accounts for 50% of the genetic risk of contracting type 1 diabetes. HLA-DQ and -DR molecules predisposing to or protecting from type 1 diabetes have been identified, but the molecular basis controlling these associations is as yet undefined. Apart from distinct thymic selection of autoreactive T-cells by susceptible and protective HLA molecules, exclusive presentation of autoantigenic peptides by type 1 diabetes-predisposing HLA molecules or, alternatively, induction of regulatory T-cells by protective alleles are potential mechanisms for modification of type 1 diabetes risk by HLA polymorphism. As a first step in exploring the role of HLA molecules in autoantigen-specific cellular responses in type 1 diabetes, we have screened peptides covering the sequence of two major autoantigens targeted by humoral and cellular immune responses, GAD65 and islet associated-2 (IA-2), for binding to class II molecules. We developed a sensitive novel competition binding assay allowing us to measure peptide binding on intact cells to 10 HLA-DR and 4 HLA-DQ molecules. For all tested alleles, multiple peptides binding with high affinity were identified. We report clustering of binding peptides in the COOH-terminal regions of GAD65 and IA-2, as well as highly promiscuous binding patterns of some peptides. Our results demonstrate that most peptides derived from the GAD and IA-2 autoantigens can bind to both type 1 diabetes-predisposing and type 1 diabetes-protective HLA molecules, although some exceptions were observed. The binding inventory presented here for GAD and IA-2 peptides can be useful for mapping natural epitopes and predicting peptide-specific responses induced by preventive immunization.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. C. Tong, G. L. Zhang, T. W. Tan, J. T. August, V. Brusic, and S. Ranganathan Prediction of HLA-DQ3.2{beta} Ligands: evidence of multiple registers in class II binding peptides Bioinformatics, May 15, 2006; 22(10): 1232 - 1238. [Abstract] [Full Text] [PDF]

				J. Endl, S. Rosinger, B. Schwarz, S.-O. Friedrich, G. Rothe, W. Karges, M. Schlosser, T. Eiermann, D. J. Schendel, and B. O. Boehm Coexpression of CD25 and OX40 (CD134) Receptors Delineates Autoreactive T-cells in Type 1 Diabetes Diabetes, January 1, 2006; 55(1): 50 - 60. [Abstract] [Full Text] [PDF]

				J. Sidney, M.-F. del Guercio, S. Southwood, and A. Sette The HLA Molecules DQA1*0501/B1*0201 and DQA1*0301/B1*0302 Share an Extensive Overlap in Peptide Binding Specificity J. Immunol., November 1, 2002; 169(9): 5098 - 5108. [Abstract] [Full Text] [PDF]

				N. S. Patil, F. C. Hall, S. Drover, D. R. Spurrell, E. Bos, A. P. Cope, G. Sonderstrup, and E. D. Mellins Autoantigenic HCgp39 Epitopes Are Presented by the HLA-DM-Dependent Presentation Pathway in Human B Cells J. Immunol., January 1, 2001; 166(1): 33 - 41. [Abstract] [Full Text] [PDF]