BAFF and MyD88 signals promote a lupuslike disease independent of T cells
AuthorGroom, JR; Fletcher, CA; Walters, SN; Grey, ST; Watt, SV; Sweet, MJ; Smyth, MJ; Mackay, CR; Mackay, F
Source TitleJournal of Experimental Medicine
PublisherROCKEFELLER UNIV PRESS
AffiliationMedical Biology (W.E.H.I.)
Microbiology and Immunology
Document TypeJournal Article
CitationsGroom, 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 StatusOpen Access
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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