Abstract
Anti-B cell activating factor belonging to TNF-family (BAFF) antibody therapy is indicated for the treatment of patients with active systemic lupus erythematosus (SLE). We hypothesized that the BAFF receptor, transmembrane activator and calcium-modulator and cyclophilin interactor (TACI) may be responsible for the generation of antibody secreting plasma cells in SLE. To test this hypothesis, we generated TACI deficient MRL-Fas/Lpr (LPR-TACI−/−) mouse. TACI deficiency resulted in improved survival of MRL-Fas/Lpr mice and delayed production of anti-dsDNA and anti-SAM/RNP antibodies. There was also a delay in the onset of proteinuria and the accumulation of IgG and inflammatory macrophages (Mϕs) in the glomeruli of young LPR-TACI−/− mice compared to wild-type mice. Underscoring the role of TACI in influencing Mϕ phenotype, the transfer of Mϕs from 12-week-old LPR-TACI−/− mice to age-matched sick wild-type animals led to a decrease in proteinuria and improvement in kidney pathology. The fact that, in LPR-TACI−/− mouse a more pronounced delay was in IgM and IgG3 autoreactive antibody isotypes and the kinetics of follicular helper T (Tfh) cell-development was comparable between the littermates suggest a role for TACI in T cell-independent autoantibody production in MRL-Fas/Lpr mouse prior to the onset of T cell-dependent antibody production.
Highlights
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody overproduction because of dysregulated innate and adaptive immune function[1,2]
As has been shown previously in transmembrane activator and calcium-modulator and cyclophilin interactor (TACI) deficient mice on C57BL/6 background[41], TACI deficient lupus prone mice on MRL-Fas/Lpr background had an elevated number of splenic B cells at 6 weeks of age as compared to wild-type MRL-Fas/Lpr mice (Supplemental Fig. 1A)
We have previously shown that MRL strains express reduced levels of BAFF receptor (BAFFR) on B cells compared to Balb/c mice, a likely consequence of the Pro44Ser mutation in BAFFR gene, TNFRSF13C42
Summary
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by autoantibody overproduction because of dysregulated innate and adaptive immune function[1,2]. In light of these diverse outcomes regarding the role of TACI in SLE, we sought to investigate the contribution of TACI in MRL-Fas/Lpr mice, which develop SLE like autoimmune manifestation as a result of a spontaneous mutation in the fas gene[37]. The fact that spontaneous accumulation of germinal center (GC) B cells, plasma cells, follicular T helper (Tfh) cells as well as extrafollicular Tfh (Thef) cells in LPR-TACI−/− mice was not significantly different than the wild-type mice suggested that TACI deficiency does not impact the development T cell-dependent autoreactive antibodies. TACI deficiency is likely responsible for the delay in disease onset by preventing T cell-independent autoreactive antibody production and by maintaining an anti-inflammatory environment in kidneys owing to M2 phenotype of TACI deficient Mφs
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