Human B Cell Tolerance and Its Failure in Rheumatoid Arthritis

Authors

  • JONATHAN SAMUELS,

    1. Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA
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  • YEN-SHING NG,

    1. Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA
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  • CLAIRE COUPILLAUD,

    1. Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA
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  • DANIEL PAGET,

    1. Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA
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  • ERIC MEFFRE

    Corresponding author
    1. Laboratory of Biochemistry and Molecular Immunology, Hospital for Special Surgery, New York, New York 10021, USA
    2. Weill Medical College of Cornell University, New York, New York 10021, USA
      Address for correspondence: Eric Meffre, Hospital for Special Surgery, Research Department, 535 E. 70th St., New York, NY 10021. Voice: 212-774-2347; fax: 212-717-1192. meffree@hss.edu
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Address for correspondence: Eric Meffre, Hospital for Special Surgery, Research Department, 535 E. 70th St., New York, NY 10021. Voice: 212-774-2347; fax: 212-717-1192. meffree@hss.edu

Abstract

Abstract: Random V(D)J gene assembly generates many autoreactive B cell receptors (BCRs). In healthy donors, most autoreactive developing B cells are removed either in the bone marrow or in the periphery, revealing two B cell tolerance checkpoints. The regulation and the mechanisms that ensure this human B cell tolerance are poorly characterized, but they require proper BCR signaling. Indeed, patients with X-linked agammaglobulinemia who carry mutations in the BTK gene, which encodes an essential BCR signaling component, fail to establish proper central B cell tolerance, as demonstrated by the release of self-reactive B cells in the periphery. In autoimmune diseases such as rheumatoid arthritis (RA), B cell tolerance is broken and autoantibodies are secreted. Our recent results show that RA patients suffer from defective central and peripheral B cell tolerance checkpoints, which may favor the development of autoimmunity. Also, about half of our RA patients display unusual immunoglobulin light chain repertoires showing impaired secondary recombination regulation, which indicates that receptor editing, one of the mechanisms that normally ensures B cell tolerance, may often be defective in RA.

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