Complement C4 maintains peripheral B-cell tolerance in a myeloid cell dependent manner

Authors

  • Priyadarshini Chatterjee,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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    • These authors contributed equally to this manuscript.

  • Amma F. Agyemang,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
    2. Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
    3. MD-PhD Program, Harvard Medical School, Boston, MA, USA
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    • These authors contributed equally to this manuscript.

  • Marat B. Alimzhanov,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Soren Degn,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Stefanos A. Tsiftsoglou,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Elisabeth Alicot,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Sarah A. Jones,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Minghe Ma,

    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
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  • Michael C. Carroll

    Corresponding author
    1. Program in Cellular and Molecular Medicine, Childrens Hospital, Boston, MA, USA
    2. Department of Pediatrics, Harvard Medical School, Boston, MA, USA
    3. Graduate Program in Immunology, Division of Medical Sciences, Harvard Medical School, Boston, MA, USA
    • Full correspondence: Prof. Michael C. Carroll, Program in Cellular and Molecular Medicine, Childrens Hospital, Rm 251 Warren Alpert Bldg, 200 Longwood Avenue, Boston, MA 02115, USA

      Fax: +1-617-713-8702

      e-mail: Michael.carroll@childrens.harvard.edu

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Abstract

The factors that allow self-reactive B cells to escape negative selection and become activated remain poorly defined. Using a BCR knock-in mouse strain, we identify a pathway by which B-cell selection to nucleolar self-antigens is complement dependent. Deficiency in complement component C4 led to a breakdown in the elimination of autoreactive B-cell clones at the transitional stage, characterized by a relative increase in their response to a range of stimuli, entrance into follicles, and a greater propensity to form self-reactive GCs. Using mixed BM chimeras, we found that the myeloid compartment was sufficient to restore negative selection in the autoreactive mice. A model is proposed in which in the absence of complement C4, inappropriate clearance of apoptotic debris promotes chronic activation of myeloid cells, allowing the maturation and activation of self-reactive B-cell clones leading to increased spontaneous formation of GCs.

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