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AI-17 Baff promotes systemic autoimmunity via taci-dependent activation of transitional B cells
  1. Holly M Jacobs1,
  2. Christopher D Thouvenel1,
  3. Sarah Leach1,
  4. Tanvi Arkatkar1,
  5. David J Rawlings1,2,3,4 and
  6. Shaun W Jackson1,3,4
  1. 1Seattle Children’s Research Institute
  2. 2Departments of Immunology
  3. 3Departments of Immunologyand Pediatrics
  4. 4University of Washington School of Medicine Seattle, WA, USA


Background Although excess levels of B cell activating factor of the TNF family (BAFF, also known as BLyS) have been implicated in the pathogenesis of SLE, how excess BAFF promotes breaks in B cell tolerance is not completely understood. Transgenic mice (Tg) overexpressing BAFF develop an autoimmune disease resembling human SLE. BAFF binds to distinct receptors expressed on B cells, the BAFF receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI). Since BAFF-R deletion results in loss of mature B cells, BAFF-R-dependent signals are presumed to explain BAFF-mediated autoimmunity. However, potential important roles for TACI in lupus pathogenesis have not been addressed.

Materials and methods After crossing BAFF-Tg and Taci-/- mice, we used standard immunologic techniques to test the impact of TACI on BAFF-driven autoimmunity.

Results Despite prior evidence of a negative role for TACI in B cell activation, we discovered that TACI deletion resulted in a striking loss of class-switched serum autoantibodies. Loss of serum autoantibodies also correlated with protection from immune-complex glomerulonephritis in Taci-/-.BAFF-Tg mice. Importantly, lack of autoimmunity was not explained by alterations in peripheral B cell development, since both BAFF-Tg and Taci-/-.BAFF-Tg mice exhibited similar B cell hyperplasia, with equivalent expansion of the follicular (FM) and marginal zone (MZ) compartments. Rather, whereas surface TACI expression is usually limited to mature B cells, we discovered that excess BAFF integrates with dual B cell receptor (BCR)- and MyD88-dependent signals to promote TACI upregulation on transitional B cells. The novel TACIhi subset of transitional B cells from BAFF-Tg mice are characterised by an activated, cycling phenotype and expressed activation-induced cytidine deaminase (AID) and T-bet. Single-cell cloning of B cell receptors from TACIhi vs TACIlo transitional B cells demonstrated that the TACIhi cell subset is specifically enriched for autoreactivity and exhibits evidence of somatic hypermutation. Finally, consistent with a direct role in autoimmune pathogenesis, TACIhi transitional B cells from BAFF-Tg mice spontaneously produce class-switched autoantibodies ex vivo.

Conclusion Our combined findings highlight a novel mechanism whereby BAFF promotes humoral autoimmunity via TACI-dependent activation of transitional B cells. In addition to SLE and other autoimmune disorders characterised by elevated BAFF, dysregulated transitional B cell activation is likely to be relevant a range of other clinical scenarios, including: autoimmune disease relapse after treatment with B cell-depletion therapies; de novo humoral autoimmunity following stem cell transplantation; and, rapid IgM- and IgG-mediated antibody responses during pathogen challenges.

Acknowledgements This work was supported by the National Institutes of Health (NIH) under award numbers: R01HL075453 (DJR), R01AI084457 (DJR), R01AI071163 (DJR), DP3DK097672 (DJR) and K08AI112993 (SWJ). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH. Additional support provided by the Benaroya Family Gift Fund (DJR); by the ACR REF Rheumatology Scientist Development Award (SWJ); and by the Arnold Lee Smith Endowed Professorship for Research Faculty Development (SWJ).

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