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Apoptotic marginal zone deletion of anti-Sm/ribonucleoprotein B cells.

Abstract

CD40L is excessively produced in both human and murine lupus and plays a role in lupus pathogenesis. To address how excess CD40L induces autoantibody production, we crossed CD40L-transgenic mice with the anti-DNA H-chain transgenic mouse lines 3H9 and 56R, well-characterized models for studying B-cell tolerance to nuclear antigens. Excess CD40L did not induce autoantibody production in 3H9 mice in which anergy maintains self-tolerance, nor did it perturb central tolerance, including deletion and receptor editing, of anti-DNA B cells in 56R mice. In contrast, CD40L/56R mice restored a large number of marginal zone (MZ) B cells reactive to Sm/ribonucleoprotein (RNP) and produced autoantibody, whereas these B cells were deleted by apoptosis in MZ of 56R mice. Thus, excess CD40L efficiently blocked tolerance of Sm/RNP-reactive MZ B cells, leading to production of anti-Sm/RNP antibody implicated in the pathogenesis of lupus. These results suggest that self-reactive B cells such as anti-Sm/RNP B cells, which somehow escape tolerance in the bone marrow and migrate to MZ, are tolerized by apoptotic deletion in MZ and that a break in this tolerance may play a role in the pathogenesis of lupus.

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    • Authors

    Kishi Y, Higuchi T, Phoon S, Sakamaki Y, Kamiya K, Riemekasten G, Akiyoshi K, Weigert MG, Tsubata T

    Institution

    Laboratory of Immunology, Graduate School of Biomedical Sciences, and Department of Immunology, Medical Research Institute, Tokyo Medical and Dental University, Tokyo 113-8510, Japan.

    Source

    Proceedings of the National Academy of Sciences of the United States of America 109:20 2012 May 15 pg 7811-6

    MeSH

    Animals
    Antibodies, Antinuclear
    Apoptosis
    Autoantibodies
    B-Lymphocytes
    CD40 Ligand
    Clodronic Acid
    Crosses, Genetic
    Enzyme-Linked Immunosorbent Assay
    Female
    Flow Cytometry
    Immune Tolerance
    Immunohistochemistry
    Indoles
    Liposomes
    Lupus Erythematosus, Systemic
    Mice
    Mice, Transgenic

    Pub Type(s)

    Journal Article
    Research Support, Non-U.S. Gov't

    Language

    eng

    PubMed ID

    22547827