Background/Purpose: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by polyclonal B cell activation and production of class-switched antinuclear antibodies (ANA). Transgenic mice (Tg) overexpressing B cell activating factor of the TNF family (BAFF, also known as BLyS) develop an autoimmune disease resembling human SLE. Consistent with this, lupus nephritis patients have increased serum BAFF levels and the BAFF-targeted monoclonal Belimumab is an approved SLE therapy. BAFF binds to distinct receptors expressed on B cells, the BAFF receptor (BAFF-R) and transmembrane activator and CAML interactor (TACI). Because BAFF-R deletion results in a loss of mature B cells, this receptor has been suggested to explain the autoimmune phenotypes in BAFF-Tg mice. However, potential important roles for TACI in lupus pathogenesis have not been addressed.

Methods: To test the impact of TACI on BAFF-driven autoimmunity, we crossed BAFF-Tg and Taci-/- mice. Serum autoantibodies, peripheral B cell development, splenic immune activation and development of immune-complex glomerulonephritis (IC GN) was assessed by ELISA, flow cytometry and immunohistochemistry.

Results: Surprisingly, deletion of TACI abrogated serum anti-nuclear autoantibodies (ANA) in BAFF-Tg mice. In addition, lack of TACI prevented autoantibodies targeting RNA- and DNA-associated self-antigens, including Sm/RNP and dsDNA, across all immunoglobulin isotypes and subtypes, including IgM, IgG, IgA, IgG2b, IgG2c, IgG3. Lack of autoantibodies 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.

Aged BAFF-Tg mice develop prominent immune-complex glomerulonephritis, characterized by mesangial expansion, glomerular basement membrane thickening and capillary occlusion. Consistent with the lack of serum autoantibodies, Taci-/-.BAFF-Tg were completely protected from murine lupus nephritis, as evidenced by lack of albuminuria and restoration of renal histology.

Conclusion: We report the novel observation that TACI, not BAFF-R, is the predominant B cell receptor promoting BAFF-mediated murine lupus nephritis. These findings suggest that TACI may be an important therapeutic target in SLE, particularly in patients with high serum BAFF levels.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-b-cell-survival-cytokine-baff-promotes-systemic-lupus-erythematosus-via-activation-of-taci-not-baff-receptor/