BAFF and MyD88 signals promote a lupuslike disease independent of T cells.
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.
Autoimmunity Research Unit, The Garvan Institute of Medical Research, Darlinghurst, NSW 2010, Australia.
Joanna R
JR
Groom
Carrie A
CA
Fletcher
Stacey N
SN
Walters
Shane T
ST
Grey
Sally V
SV
Watt
Mathew J
MJ
Sweet
Mark J
MJ
Smyth
Charles R
CR
Mackay
Fabienne
F
Mackay
D000818:Animals; D001323:Autoantibodies / Q000737:chemistry; D053264:B-Cell Activating Factor / Q000378:metabolism / Q000502:physiology*; D002454:Cell Differentiation; D002469:Cell Separation; D005786:Gene Expression Regulation; D007070:Immunoglobulin A / Q000378:metabolism; D007075:Immunoglobulin M / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D053594:Myeloid Differentiation Factor 88 / Q000378:metabolism / Q000502:physiology*; D013601:T-Lymphocytes / Q000378:metabolism
D001323:Autoantibodies; D053264:B-Cell Activating Factor; D007070:Immunoglobulin A; D007075:Immunoglobulin M; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C505720:Tnfsf13b protein, mouse