Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM

Hatfield, E. C. I., Hawkes, C. J., Payton, M. A. and Christie, Michael R. (1997) Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM. Diabetologia, 40 (11). pp. 1327-1333. ISSN 0012-186X

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Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM

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Abstract

Patients with insulin-dependent diabetes mellitus (IDDM) possess antibodies to the cytoplasmic domains of two closely related tyrosine phosphatase-like proteins, IA-2 and phogrin, previously detected as 40 kDa and 37 kDa tryptic fragments, respectively. A higher proportion of IDDM patients possess antibodies to IA-2 than to phogrin, and autoimmunity to phogrin might arise through cross-reactivity with the highly homologous IA-2. In this study, we have investigated the major regions of IA-2 recognized by antibodies in IDDM patients and examined the ability of phogrin to block antibody binding to these regions as a measure of cross-reactivity. Analysis of antibody binding to in vitro transcribed and translated polypeptides representing different regions of the cytoplasmic domain of IA-2 identified five different patterns of reactivity with antibodies in IDDM. Protein footprinting analysis, whereby polypeptide fragments generated on protease treatment of immune complexes are studied, indicated considerable heterogeneity in antibody recognition of IA-2, even between sera with similar reactivity to deletion mutants. Blocking studies with recombinant phogrin indicated that IA-2 antibodies recognize epitopes that are both unique to IA-2 and shared with phogrin. The amino-terminal 150 amino acids of the cytoplasmic domain of IA-2 encompass epitopes that are not represented on phogrin, whereas shared epitopes are localized within the carboxy-terminal 220 amino acids. The results demonstrate considerable heterogeneity between IDDM patients in autoantibody recognition of IA-2 in IDDM, whereas antibody recognition of phogrin is restricted in most patients to epitopes also present on IA-2. © 1997 Springer-Verlag.

Keywords:autoantibody, autoantigen, epitope, phosphatase, adolescent, adult, antigen binding, antigen recognition, article, autoimmunity, child, controlled study, cross reaction, etiology, human, infant, insulin dependent diabetes mellitus, major clinical study, priority journal, Adolescent, Autoantibodies, Autoantigens, Binding, Competitive, Child, Preschool, Cross Reactions, Diabetes Mellitus, Type 1, Epitopes, Humans, Membrane Glycoproteins, Membrane Proteins, Mutation, Neoplasm Proteins, Peptide Fragments, Protein-Tyrosine-Phosphatase, Recombinant Proteins
Subjects:A Medicine and Dentistry > A100 Pre-clinical Medicine
Divisions:College of Science > School of Life Sciences
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ID Code:18144
Deposited On:31 Jul 2015 09:49

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