HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Hassainya, Y. Articles by van Endert, P. M. Search for Related Content PubMed PubMed Citation Articles by Hassainya, Y. Articles by van Endert, P. M. Social Bookmarking                What's this?

Identification of Naturally Processed HLA-A2—Restricted Proinsulin Epitopes by Reverse Immunology

¹ Institut National de la Santé et de la Recherche Médicale Unité 580, Université René Descartes, Paris, France
² Unité d’Immunité Cellulaire Antivirale, Département d’Immunologie, Institut Pasteur, Paris, France
³ M-SCAN, Wokingham, U.K
⁴ Department of Cellular Immunology, Max Planck Institute of Immunobiology, Freiburg, Germany

Type 1 diabetes is thought to result from the destruction of ß-cells by autoantigen-specific T-cells. Observations in the NOD mouse model suggest that CD8⁺ cytotoxic T-cells play an essential role in both the initial triggering of insulitis and its destructive phase. However, little is known about the epitopes derived from human ß-cell autoantigens and presented by HLA class I molecules. We used a novel reverse immunology approach to identify HLA-A2–restricted, naturally processed epitopes derived from proinsulin, an autoantigen likely to play an important role in the pathogenesis of type 1 diabetes. Recombinant human proinsulin was digested with purified proteasome complexes to establish an inventory of potential COOH-terminals of HLA class I–presented epitopes. Cleavage data were then combined with epitope predictions based on the SYFPEITHI and BIMAS algorithms to select 10 candidate epitopes; 7 of these, including 3 with a sequence identical to murine proinsulin, were immunogenic in HLA-A2 transgenic mice. Moreover, six of six tested peptides were processed and presented by proinsulin-expressing cells. These results demonstrate the power of reverse immunology approaches. Moreover, the novel epitopes may be of significant interest in monitoring autoreactive T-cells in type 1 diabetes.

Abbreviations: CTL, cytotoxic T-cell; MHC, major histocompatibility complex; TAP, transporter associated with antigen processing

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				B. O. Roep Islet Autoreactive CD8 T-cells in Type 1 Diabetes: Licensed to Kill? Diabetes, May 1, 2008; 57(5): 1156 - 1156. [Full Text] [PDF]

				E. Martinuzzi, G. Novelli, M. Scotto, P. Blancou, J.-M. Bach, L. Chaillous, G. Bruno, L. Chatenoud, P. van Endert, and R. Mallone The Frequency and Immunodominance of Islet-Specific CD8+ T-cell Responses Change after Type 1 Diabetes Diagnosis and Treatment Diabetes, May 1, 2008; 57(5): 1312 - 1320. [Abstract] [Full Text] [PDF]

				L. T. Mars, J. Bauer, D. A. Gross, F. Bucciarelli, H. Firat, D. Hudrisier, F. Lemonnier, K. Kosmatopoulos, and R. S. Liblau CD8 T Cell Responses to Myelin Oligodendrocyte Glycoprotein-Derived Peptides in Humanized HLA-A*0201-Transgenic Mice J. Immunol., October 15, 2007; 179(8): 5090 - 5098. [Abstract] [Full Text] [PDF]

				I. Jarchum, J. C. Baker, T. Yamada, T. Takaki, M. P. Marron, D. V. Serreze, and T. P. DiLorenzo In Vivo Cytotoxicity of Insulin-Specific CD8+ T-Cells in HLA-A*0201 Transgenic NOD Mice Diabetes, October 1, 2007; 56(10): 2551 - 2560. [Abstract] [Full Text] [PDF]

				P. Blancou, R. Mallone, E. Martinuzzi, S. Severe, S. Pogu, G. Novelli, G. Bruno, B. Charbonnel, M. Dolz, L. Chaillous, et al. Immunization of HLA Class I Transgenic Mice Identifies Autoantigenic Epitopes Eliciting Dominant Responses in Type 1 Diabetes Patients J. Immunol., June 1, 2007; 178(11): 7458 - 7466. [Abstract] [Full Text] [PDF]

				R. Mallone, E. Martinuzzi, P. Blancou, G. Novelli, G. Afonso, M. Dolz, G. Bruno, L. Chaillous, L. Chatenoud, J.-M. Bach, et al. CD8+ T-Cell Responses Identify {beta}-Cell Autoimmunity in Human Type 1 Diabetes Diabetes, March 1, 2007; 56(3): 613 - 621. [Abstract] [Full Text] [PDF]

				N. E. Standifer, Q. Ouyang, C. Panagiotopoulos, C. B. Verchere, R. Tan, C. J. Greenbaum, C. Pihoker, and G. T. Nepom Identification of Novel HLA-A*0201-Restricted Epitopes in Recent-Onset Type 1 Diabetic Subjects and Antibody-Positive Relatives Diabetes, November 1, 2006; 55(11): 3061 - 3067. [Abstract] [Full Text] [PDF]

				T. Takaki, M. P. Marron, C. E. Mathews, S. T. Guttmann, R. Bottino, M. Trucco, T. P. DiLorenzo, and D. V. Serreze HLA-A*0201-Restricted T Cells from Humanized NOD Mice Recognize Autoantigens of Potential Clinical Relevance to Type 1 Diabetes. J. Immunol., March 1, 2006; 176(5): 3257 - 3265. [Abstract] [Full Text] [PDF]