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Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors

Nature volume 416, pages 603–607 (2002)Cite this article

Abstract

Autoreactive B cells are present in the lymphoid tissues of healthy individuals, but typically remain quiescent. When this homeostasis is perturbed, the formation of self-reactive antibodies can have serious pathological consequences. B cells expressing an antigen receptor specific for self-immunoglobulin-γ (IgG) make a class of autoantibodies known as rheumatoid factor (RF). Here we show that effective activation of RF+ B cells is mediated by IgG2a–chromatin immune complexes and requires the synergistic engagement of the antigen receptor and a member of the MyD88-dependent Toll-like receptor (TLR) family. Inhibitor studies implicate TLR9. These data establish a critical link between the innate and adaptive immune systems in the development of systemic autoimmune disease and explain the preponderance of autoantibodies reactive with nucleic acid–protein particles. The unique features of this dual-engagement pathway should facilitate the development of therapies that specifically target autoreactive B cells.

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Figure 1: Anti-nucleosome antibody stimulation of RF+ B cells is DNase sensitive.
Figure 2: Anti-TNP–TNP-BSA immune complexes fail to efficiently stimulate proliferation of RF+ B cells.
Figure 3: Stimulation of RF+ B cells by autoantibody–autoantigen immune complex is not dependent on the complement receptor.
Figure 4: Stimulation of RF+ B cells by autoantibody–autoantigen immune complex is dependent on MyD88.
Figure 5: Stimulation of RF+ B cells by autoantibody–autoantigen immune complexes can be blocked by inhibitors of the TLR9 signalling pathway.

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Acknowledgements

We thank M. Carroll, S. Akira and D. Golenbock for providing the Cr2-deficient and MyD88-deficient mice; M. Boulé, C. Chi, C. Lau and G. Yospin for technical assistance; L. Wetzler and D. Golenbock for providing TLR ligands; H. Ploegh for providing concanamycin B; M. Fenton, L. Wetzler, R. Corley, R. Medzhitov, T. Rothstein and D. Stollar for reviewing the manuscript and/or discussions. This work was supported by grants from the National Institutes of Health, the Arthritis Foundation, and the National Kidney Foundation.

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  1. Correspondence and requests for materials should be addressed to A.M.-R. (e-mail: amrothst@bu.edu).

Authors and Affiliations

  1. Department of Microbiology, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Elizabeth A. Leadbetter, Andreas M. Hohlbaum, Britte C. Beaudette & Ann Marshak-Rothstein

  2. Department of Medicine, Boston University School of Medicine, Boston, 02118, Massachusetts, USA

    Ian R. Rifkin

  3. Departments of Laboratory Medicine and Immunobiology, Yale University School of Medicine, New Haven, 06520, Connecticut, USA

    Mark J. Shlomchik

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A provisional patent on the use of TLR inhibitors in the treatment of autoimmune disease.

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Leadbetter, E., Rifkin, I., Hohlbaum, A. et al. Chromatin–IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416, 603–607 (2002). https://doi.org/10.1038/416603a

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