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

JR Groom, CA Fletcher, SN Walters, ST Grey… - The Journal of …, 2007 - rupress.org
JR Groom, CA Fletcher, SN Walters, ST Grey, SV Watt, MJ Sweet, MJ Smyth, CR Mackay…
The Journal of experimental medicine, 2007rupress.org
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 …
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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