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 autoantigens

Bearzatto, Massimo, Naserke, Heike, Piquer, Sandra , Koczwara, Kerstin, Lampasona, Vito, Williams, Alistair, Christie, Michael R., Bingley, Polly J., Ziegler, Annette-G. and Bonifacio, Ezio (2002) 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 autoantigens. Journal of Immunology, 168 (8). pp. 4202-4208. ISSN 0022-1767

Full content URL: http://www.jimmunol.org/content/168/8/4202.full

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Abstract

The related tyrosine phosphatase-like proteins islet Ag (IA)-2 and IA-2β� 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-2β� 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-2β� and IA-2Δ� 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.

Keywords:amino acid, autoantibody, autoantigen, epitope, HLA antigen, HLA DR1 antigen, HLA DR13 antigen, HLA DR3 antigen, HLA DR4 antigen, Ia 2 antigen, Ia antigen, protein tyrosine phosphatase, unclassified drug, adolescent, adult, antigen binding, antigen presentation, antigen specificity, article, B lymphocyte, child, clinical article, diabetes mellitus, genotype, human, insulin dependent diabetes mellitus, priority journal, protein degradation, Antigen-Antibody Reactions, Autoantibodies, Autoantigens, Binding Sites, Antibody, Binding, Competitive, Diabetes Mellitus, Type 1, HLA-DR Antigens, Humans, Hydrolysis, Immunodominant Epitopes, Islets of Langerhans, Membrane Proteins, Peptide Fragments, Protein Footprinting, Protein-Tyrosine-Phosphatase, Recombinant Fusion Proteins, Risk Factors, Trypsin
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > School of Life Sciences
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ID Code:18135
Deposited On:07 Aug 2015 08:51

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