BAFF and MyD88 signals promote a lupuslike disease independent of T cells

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Groom, JR; Fletcher, CA; Walters, SN; Grey, ST; Watt, SV; Sweet, MJ; Smyth, MJ; Mackay, CR; Mackay, FDate
2007-08-06Source Title
Journal of Experimental MedicinePublisher
ROCKEFELLER UNIV PRESSAffiliation
Medical Biology (W.E.H.I.)Microbiology and Immunology
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Groom, J. R., Fletcher, C. A., Walters, S. N., Grey, S. T., Watt, S. V., Sweet, M. J., Smyth, M. J., Mackay, C. R. & Mackay, F. (2007). BAFF and MyD88 signals promote a lupuslike disease independent of T cells. JOURNAL OF EXPERIMENTAL MEDICINE, 204 (8), pp.1959-1971. https://doi.org/10.1084/jem.20062567.Access Status
Open AccessAbstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by the production of autoantibodies. However, the underlying cause of disease appears to relate to defects in T cell tolerance or T cell help to B cells. Transgenic (Tg) mice overexpressing the cytokine B cell-activating factor of the tumor necrosis factor family (BAFF) develop an autoimmune disorder similar to SLE and show impaired B cell tolerance and altered T cell differentiation. We generated BAFF Tg mice that were completely deficient in T cells, and, surprisingly, these mice developed an SLE-like disease indistinguishable from that of BAFF Tg mice. Autoimmunity in BAFF Tg mice did, however, require B cell-intrinsic signals through the Toll-like receptor (TLR)-associated signaling adaptor MyD88, which controlled the production of proinflammatory autoantibody isotypes. TLR7/9 activation strongly up-regulated expression of transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), which is a receptor for BAFF involved in B cell responses to T cell-independent antigens. Moreover, BAFF enhanced TLR7/9 expression on B cells and TLR-mediated production of autoantibodies. Therefore, autoimmunity in BAFF Tg mice results from altered B cell tolerance, but requires TLR signaling and is independent of T cell help. It is possible that SLE patients with elevated levels of BAFF show a similar basis for disease.
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