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Type: Journal article
Title: An immunodominant La/SSB autoantibody proteome derives from public clonotypes
Author: Thurgood, L.
Arentz, G.
Lindop, R.
Jackson, M.
Whyte, A.
Colella, A.
Chataway, T.
Gordon, T.
Citation: Clinical and Experimental Immunology, 2013; 174(2):237-244
Publisher: Wiley
Issue Date: 2013
ISSN: 0009-9104
Statement of
L. A. Thurgood, G. Arentz, R. Lindop, M. W. Jackson, A. F. Whyte, A. D. Colella, T. K. Chataway, and T. P. Gordon
Abstract: The La/SSB autoantigen is a major target of long-term humoral autoimmunity in primary Sjögren's Syndrome (SS) and systemic lupus erythematosus. A majority of patients with linked anti-Ro60/Ro52/La responses target an NH2-terminal epitope designated LaA that is expressed on Ro/La ribonucleoprotein complexes and the surface membrane of apoptotic cells. In this study, we used high-resolution Orbitrap mass spectrometry to determine the clonality, isotype and V-region sequences of LaA-specific autoantibodies in seven patients with primary SS. Anti-LaA immunoglobulin (Ig)Gs purified from polyclonal sera by epitope-specific affinity chromatography were analysed by combined database and de-novo mass spectrometric sequencing. Autoantibody responses comprised two heavily mutated IgG1 kappa-restricted monoclonal species that were shared (public) across unrelated patients; one clonotype was specified by an IGHV3-30 heavy chain paired with IGKV3-15 light chain and the second by an IGHV3-43/IGKV3-20 pairing. Shared amino acid replacement mutations were also seen within heavy and light chain complementarity-determining regions, consistent with a common breach of B cell tolerance followed by antigen-driven clonal selection. The discovery of public clonotypic autoantibodies directed against an immunodominant epitope on La, taken together with recent findings for the linked Ro52 and Ro60 autoantigens, supports a model of systemic autoimmunity in which humoral responses against protein-RNA complexes are mediated by public sets of autoreactive B cell clonotypes.
Keywords: La/SSB; mass spectrometry; primary Sjögrens syndrome; public clonotypes
Rights: © 2013 British Society for Immunology
DOI: 10.1111/cei.12171
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Microbiology and Immunology publications

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