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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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.
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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