The Journal of Experimental Medicine
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Published online 16 October 2000.
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© The Rockefeller University Press, 0022-1007/2000/10/1151/ $5.00
The Journal of Experimental Medicine, Volume 192, Number 8, October 16, 2000 1151-1164

Original Article

Immunoglobulin Heavy Chain Variable Region Gene Replacement as a Mechanism for Receptor Revision in Rheumatoid Arthritis Synovial Tissue B Lymphocytes

Kenji Itoha, Eric Meffrec, Emilia Albesianoa, Andrew Farbera, David Dinesb, Peter Steinb, Stanley E. Asnisa, Richard A. Furiea, Rita I. Jaina, and Nicholas Chiorazzia

a Department of Medicine and the Department of Surgery, North Shore University Hospital and New York University School of Medicine, Manhasset, New York 11030
b Department of Surgery, Long Island Jewish Medical Center, and the Department of Surgery, Albert Einstein College of Medicine, New Hyde Park, New York 11040
c The Laboratory of Molecular Immunology, The Rockefeller University, New York, New York 10021
North Shore University Hospital, 350 Community Dr., Manhasset, NY 11030.516-562-1683516-562-1085

Mature B cells can alter their antibody repertoires by several mechanisms, including immunoglobulin heavy chain variable region (VH) replacement. This process changes the antigen combining site by replacing a portion of the original VH/diversity/heavy chain joining region (VHDJH) rearrangement with a corresponding portion of a new VH segment. This exchange can involve cryptic heptamer-like sequences embedded in the coding regions of VH genes.

While studying the B lymphocytes that expand in the synovial tissues of patients with rheumatoid arthritis (RA), clones with VHDJH variants that were apparently generated by VH replacement were identified with surprising frequency (~8%). Examples of multiple independent VH replacement events occurring in distinct progeny clones were also identified. These secondary VH rearrangements were documented at both the cDNA and genomic DNA levels and involved several heptamer-like sequences at four distinct locations within VH (three sites in framework region 3 and one in complementarity determining region 2). The identification of blunt-ended double-stranded DNA breaks at the embedded heptamers and the demonstration of recombinase activating gene (RAG) expression suggested that these rearrangements could occur in the synovial tissues, presumably in pseudo-germinal centers, and that they could be mediated by RAG in a recognition signal sequence–specific manner. The presence of VH mutations in the clones that had undergone replacement indicated that these B cells were immunocompetent and could receive and respond to diversification signals. A relationship between these secondary VH gene rearrangements and the autoimmunity characteristic of RA should be considered.

Key Words: antibody diversity • recombinase activating genes • immune tolerance • autoimmunity • rheumatoid factor

Abbreviations used in this paper: ds, double-stranded; FR, framework region; GC, germinal center; LM, ligation-mediated; RA, rheumatoid arthritis; RAG, recombinase activating gene; RF, rheumatoid factor; RSS, recognition signal sequence(s); RT, reverse transcription.

© 2000 The Rockefeller University Press


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