Constitutive overexpression of BAFF in autoimmune‐resistant mice drives only some aspects of systemic lupus erythematosus–like autoimmunity

Abstract

Objective. To determine whether overexpression of BAFF can promote systemic lupus erythematosus (SLE)-like autoimmunity in mice that are otherwise autoimmune-resistant.Methods. We used class II major histocompatibility complex (MHC)-deficient C57BL/6 (B6) mice as a model of resistance to SLE and Sles1-bearing B6 mice as a model of resistance to the autoantibody-promoting capacity of the Sle1 region. We generated BAFFtransgenic (Tg) counterparts to these respective mice and evaluated lymphocyte phenotype, serologic autoimmunity, renal immunopathology, and clinical disease in the BAFF-Tg and non-Tg mouse sets.Results. Although constitutive BAFF overexpression did not lead to B cell expansion in class II MHC-deficient B6 mice, it did lead to increased serum IgG autoantibody levels. Nevertheless, renal immunopathology was limited, and clinical disease did not develop. In B6 and B6.Sle1 mice, constitutive BAFF overexpression led to increased numbers of B cells and CD4؉ memory cells, as well as increased serum IgG and IgA autoantibody levels. Renal immunopathology was modestly greater in BAFF-Tg mice than in their non-Tg counterparts, but again, clinical disease did not develop.

Effects of belimumab, a B lymphocyte stimulator-specific inhibitor, on disease activity across multiple organ domains in patients with systemic lupus erythematosus: combined results from two phase III trials

“…Post-hoc analysis suggested that patients with high serological activity (ie, both anti-dsDNA positivity and low complement 3 or 4 levels; 52% of the study population) have higher disease activity, and may have greater magnitudes of SRI response and individual organ domain improvement with belimumab than with standard therapy alone. These results are consistent with the improvement noted in the immunological domain (decrease in anti-dsDNA autoantibodies, or increase in complement 3 or 4 levels), as well as the reductions in other autoantibodies, or selected B-cell and plasma cell subsets observed in the BLISS trials 13. Although the most commonly affected organ domains (ie, mucocutaneous, musculoskeletal and immunological) improved with belimumab therapy, there were also responses detected in the CNS, renal and vasculitis domains that are often associated with high disease activity (SELENA–SLEDAI score ≥10), which supports the observations in the multivariate analysis 7…”

Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy

“…In the current colonies (both at Biogen Idec and University of Toronto), substantial titers of IgG or IgA directed against antichromatin, dsDNA, ssDNA, and extractable nuclear antigen were not observed in either BAFF-Tg line ( Figure 2, C and D, Supplemental Figure 3, and data not shown), especially when compared with autoimmune sera from the MRL/lpr mouse. Only IgM autoreactivity was observed in ELISA and crithidia formats, consistent with the observation that IgG autoreactivity may require collaboration between BAFF and other autoimmune loci (34). Therefore, in contrast to the original BAFF-Tg mice with more severe autoimmune manifestations (35), mice in the current colony did not exhibit hallmarks of classical autoreactive IgG-driven lupus nephritis but rather develop an IgA-associated kidney disease.…”

The role of BAFF in the progression of rheumatoid arthritis

“…In collagen-induced arthritis (CIA) rats, the production of antibodies was found to be related to the level of BAFF [31,63]. Transgenic animal studies and clinical research have shown that the increased expression of BAFF results in the presence of anti-DNA antibodies, RF, and circulating immune complexes [64][65][66]. Of note, the plasma BAFF level in sero-positive (positive for RF and/or anti-cyclic citrullinated peptide) RA patients was higher compared to that of sero-negative patients [67].…”