The Journal of Experimental Medicine
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Published online July 30, 2007
doi:10.1084/jem.20062567
The Journal of Experimental Medicine, Vol. 204, No. 8, 1959-1971
The Rockefeller University Press, 0022-1007 $30.00
© 2007 Groom et al.
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ARTICLE

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

Joanna R. Groom1, Carrie A. Fletcher1, Stacey N. Walters2, Shane T. Grey2, Sally V. Watt3, Mathew J. Sweet4,5, Mark J. Smyth3, Charles R. Mackay2, and Fabienne Mackay1

1 Autoimmunity Research Unit, 2 Inflammation and Immunology Program, The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia
3 Cancer Immunology Program, Peter MacCallum Cancer Centre, East Melbourne, 3002, Victoria, Australia
4 Institute for Molecular Bioscience and 5 School of Molecular and Microbial Sciences, University of Queensland, Brisbane, Queensland, 4072 Australia

CORRESPONDENCE Fabienne Mackay:f.mackay{at}garvan.org.au

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.

Abbreviations used: ANA, antinuclear antibodies; BAFF, B cell–activating factor of the TNF family; BAFF-R, BAFF receptor; CLN, cervical LN; ds, double-stranded; HE, hematoxylin and eosin; HEL, hen egg lysozyme; mDC, myeloid DC; MZ, marginal zone; NP, nitrophenyl; pDC, plasmacytoid DC; PerC, peritoneal cavity; PLN, peripheral LN; RF, rheumatoid factor; ss, single-stranded; SLE, systemic lupus erythematosus; SS, Sjögren's syndrome; TACI, transmembrane activator and calcium-modulator and cyclophilin ligand (CAML) interactor; Tg, transgenic.


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