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

Abstract

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.

Type Journal
ISBN 0022-1007 (Print)
Authors 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. :
Publisher Name J EXP MED
Published Date 2007-01-01 00:00:00
Published Volume 204
Published Issue 8
Published Pages 1959-71
URL http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17664289
Status Published In-print
OpenAccess Link https://publications.gimr.garvan.org.au/download.php?2204_11129/07 Groom JEM 1959.pdf