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) Alert me when this article is cited Alert me if a correction is posted Citation Map Services 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 Bearzatto, M. Articles by Bonifacio, E. Search for Related Content PubMed PubMed Citation Articles by Bearzatto, M. Articles by Bonifacio, E.

Two Distinctly HLA-Associated Contiguous Linear Epitopes Uniquely Expressed Within the Islet Antigen 2 Molecule Are Major Autoantibody Epitopes of the Diabetes-Specific Tyrosine Phosphatase-Like Protein Autoantigens¹

Massimo Bearzatto^*, Heike Naserke, Sandra Piquer^*, Kerstin Koczwara, Vito Lampasona, Alistair Williams, Michael R. Christie^¶, Polly J. Bingley, Anette-G. Ziegler and Ezio Bonifacio^2,*

Departments of ^* Medicine 1 and Medicine Laboratory, Istituto Scientifico San Raffaele, Milan, Italy; Institut fur Diabetesforshung, Munich, Germany; Division of Medicine, University of Bristol, Bristol, United Kingdom; and ^¶ Department of Medicine, King’s College School of Medicine, London, United Kingdom

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2 are autoantigens of type 1 diabetes in humans. Autoantibodies are predominantly against IA-2, and IA-2-specific epitopes are major autoantibody targets. We used the close homology of IA-2 and IA-2 to design chimeras and mutants to identify humoral IA-2-specific epitopes. Two major IA-2 epitopes that are absent from the related autoantigens IA-2 and IA-2 13 splice variant ICA512.bdc were found contiguous to each other within IA-2 juxtamembrane amino acids 611–620 (epitope JM1) and 621–630 (epitope JM2). JM1 and JM2 are recognized by sera from 67% of patients with IA-2 Abs, and relatives of patients with type 1 diabetes having Abs to either JM epitope had a >50% risk for developing type 1 diabetes within 6 years, even in the absence of diabetes-associated HLA genotypes. Remarkably, the presence of Abs to one of these two epitopes was mutually exclusive of the other; JM2 Abs and not JM1 Abs were found in relatives with HLA DR3/4, DR4/13, or DR1/4 genotypes; and the binding of autoantibodies to the JM2 epitope, but not the JM1 epitope, markedly affected proteolysis of IA-2. This is a unique demonstration of HLA-associated B cell responses to epitopes within a single autoantigen in humans and is consistent with modification of Ag processing by specific Ab-influencing peptide presentation by HLA molecules.

This article has been cited by other articles:

				C. Pihoker, L. K. Gilliam, C. S. Hampe, and A. Lernmark Autoantibodies in Diabetes Diabetes, December 1, 2005; 54(suppl_2): S52 - S61. [Abstract] [Full Text] [PDF]

				J. A. Dromey, S. M. Weenink, G. H. Peters, J. Endl, P. J. Tighe, I. Todd, and M. R. Christie Mapping of Epitopes for Autoantibodies to the Type 1 Diabetes Autoantigen IA-2 by Peptide Phage Display and Molecular Modeling: Overlap of Antibody and T Cell Determinants J. Immunol., April 1, 2004; 172(7): 4084 - 4090. [Abstract] [Full Text] [PDF]

				S. E. Starwalt, E. L. Masteller, J. A. Bluestone, and D. M. Kranz Directed evolution of a single-chain class II MHC product by yeast display Protein Eng. Des. Sel., February 1, 2003; 16(2): 147 - 156. [Abstract] [Full Text] [PDF]