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Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody—antigen interaction

Nature Structural Biology volume 4, pages 374–381 (1997)Cite this article

Abstract

Rheumatoid factors are the characteristic autoantibodies of rheumatoid arthritis, which bind to the Fc regions of IgG molecules. Here we report the crystal structure of the Fab fragment of a patient-derived IgM rheumatoid factor (RF-AN) complexed with human lgG4 Fc, at 3.2 Å resolution. This is the first structure of an autoantibody–autoantigen complex. The epitope recognised in IgG Fc includes the Cγ2/Cγ3 cleft region, and overlaps the binding sites of bacterial Fc-binding proteins. The antibody residues involved in autorecognition are all located at the edge of the conventional combining site surface, leaving much of the latter available, potentially, for recognition of a different antigen. Since an important contact residue is a somatic mutation, the structure implicates antigen-driven selection, following somatic mutation of germline genes, in the production of pathogenic rheumatoid factors.

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Authors and Affiliations

  1. The Randall Institute, King's College London, 26-29 Drury Lane, London, WC2B 5RL, UK

    Adam L. Corper, Maninder K. Sohi & Brian J. Sutton

  2. Department of Pediatrics, Schneider Children's Hospital of Long Island Jewish Medical Center, New Hyde Park, New York, 11042, USA

    Vincent R. Bonagura

  3. Department of Pathology, The Hebrew University, Hadassah Medical School, Jerusalem, Israel

    Michael Steinitz

  4. Department of Immunology, The Medical School, University of Birmingham, Birmingham, B15 2TT, UK

    Royston Jefferis

  5. Laboratory of Molecular Recognition, Department of Immunology, The Babraham Institute, Babraham, Cambridge, CB2 4AT, UK

    Arnold Feinstein, Dennis Beale & Michael J. Taussig

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Corper, A., Sohi, M., Bonagura, V. et al. Structure of human IgM rheumatoid factor Fab bound to its autoantigen IgG Fc reveals a novel topology of antibody—antigen interaction. Nat Struct Mol Biol 4, 374–381 (1997). https://doi.org/10.1038/nsb0597-374

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