Cross reactivity between IA-2 and phogrin/IA-2β in binding of autoantibodies in IDDM |
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Authors: | E C I Hatfield C J Hawkes M A Payton M R Christie |
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Institution: | (1) Department of Medicine, King's College School of Medicine and Dentistry, London, UK, GB |
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Abstract: | Summary 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. Diabetologia (1997) 40: 1327–1333]
Received: 4 April 1997 and in revised form: 2 July 1997 |
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Keywords: | Autoantibodies Autoantigens Tyrosine phosphatase Epitopes Insulin-dependent diabetes |
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