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345 Deletion of the baff receptor taci fully protects against sle without reduction of b cell numbers and function
  1. F Mackay1
  1. 1University of Melbourne, School of Biomedical Sciences, University of Melbourne, Australia

Abstract

Background and aims B cell-activating factor of the TNF family (BAFF) is an essential B cell survival factor. However, high levels of BAFF promote systemic lupus erythematosus (SLE) in mice and humans. Belimumab (anti-human BAFF) limits B cell survival and is approved for use in patients with SLE. Surprisingly, the efficacy of rituximab in SLE remains controversial, despite depleting B cells more potently than belimumab. This raises the question of whether B cell depletion is really the mechanism of action of belimumab. In BAFF transgenic (BAFF-Tg) mice , SLE development is T cell-independent but relies on innate activation of B cells in cooperation with the BAFF receptor TACI. Therefore, in this study we tested whether TACI, a BAFF receptor dispensable for B cell survival may have a role in the pathogenesis of SLE.

Methods To test the role of TACI in driving BAFF-mediated autoimmunity, we reconstituted BAFF Tg mice with a TACI-deficient bone marrow and also crossed BAFF Tg mice onto TACI-/- mice.

Results We show that loss of TACI on B cells protected against BAFF-mediated autoimmune manifestations while preserving B cells, suggesting that loss of BAFF signalling through TACI, rather than loss of B cells, may underpin the effect of belimumab in the clinic. Moreover, a multimeric form of BAFF, is very effective at activating TACI, suggesting that this abnormal form of BAFF may also be a pathogenic factor in SLE.

Conclusions B cell-sparing blockade of TACI may offer a more specific and safer therapeutic alternative to broad B cell depletion in SLE.

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