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

Abstract

B cell activation factor of the TNF family (BAFF) is a potent B cell survival factor. BAFF overexpressing transgenic mice (BAFF-Tg mice) exhibit features of autoimmune disease, including B cell hyperplasia and hypergammaglobulinemia, and develop fatal nephritis with age. However, basal serum IgA levels are also elevated, suggesting that the pathology in these mice may be more complex than initially appreciated. Consistent with this, we demonstrate here that BAFF-Tg mice have mesangial deposits of IgA along with high circulating levels of polymeric IgA that is aberrantly glycosylated. Renal disease in BAFF-Tg mice was associated with IgA, because serum IgA was highly elevated in nephritic mice and BAFF-Tg mice with genetic deletion of IgA exhibited less renal pathology. The presence of commensal flora was essential for the elevated serum IgA phenotype, and, unexpectedly, commensal bacteria-reactive IgA antibodies were found in the blood. These data illustrate how excess B cell survival signaling perturbs the normal balance with the microbiota, leading to a breach in the normal mucosal-peripheral compartmentalization. Such breaches may predispose the nonmucosal system to certain immune diseases. Indeed, we found that a subset of patients with IgA nephropathy had elevated serum levels of a proliferation inducing ligand (APRIL), a cytokine related to BAFF. These parallels between BAFF-Tg mice and human IgA nephropathy may provide a new framework to explore connections between mucosal environments and renal pathology.

Re-thinking the functions of IgA+plasma cells

“…153 Our work has implicated IgA in kidney pathogenesis, and an important question is whether IgA C PC themselves are found in this location. 63 Moreover, although the cecum and colon are relatively poor in IgA C PC in the steady-state, in responses to Citrobacter rodentium IgA C PC quickly accumulate in the cecum/colon in as little as 36 hours. 1 The fact that in the steady state approximately 40% of PC in human BM are IgA C PC that express CCR4 as well as the b7 integrin and CCR10 may suggest a contribution of mucosal PC to the BM compartment, however more research is needed to unambiguously determine where these PC were originally generated.…”

“…This results in a massive increase in IgA levels in the serum, and interestingly, a portion of this serum IgA appears to be specific for commensal organisms. 63 Mice that over-express BAFF exhibit kidney dysfunction resulting in hematuria, proteinuria and premature death. 64,65 We observed that if BAFF-transgenic mice were crossed to an IgA-deficient background, kidney pathology was largely attenuated, suggesting that over-production of IgA may have a pathological consequence not unlike in the human disease IgA nephropathy.…”

“…We further showed that for patients with IgA nephropathy, the related cytokine APRIL was significantly elevated in their serum. 63 APRIL was subsequently implicated as a top hit in a large-scale genome wide analysis of IgA nephropathy patients. 66 Thus, inappropriate survival of IgA C PC, driven by aberrantly elevated levels of BAFF or APRIL, can have pathological consequences for kidney health.…”

Deficiency of the B Cell-Activating Factor Receptor Results in Limited CD169+ Macrophage Function during Viral Infection

“…Based on our results, BAFF production by neutrophil B helper cells, by promoting B cellmediated lymphotoxin production, may also affect CD169 ϩ cell survival and subsequently enforce antigen amplification and presentation. Furthermore, BAFF overexpression has been linked to a variety of autoimmune diseases, such as rheumatoid arthritis, lupus erythematosus, and Sjögren syndrome (5,(43)(44)(45). A clinically used BAFF-blocking antibody, belimumab, is effective in treating some lupus patients (46), and potentially, some clinical efficacy of BAFF neutralization in lupus patients may be due to effects on CD169 ϩ macrophages.…”

Update on immunoglobulin A nephropathy, Part I: Pathophysiology

“…This locus contains the gene TNFS 13 that codes a proliferation-inducing ligand (APRIL). APRIL might determine the proliferation of IgA-producing cells [29,30] and APRIL serum levels may be higher in subjects affected by IgAN [31] . A second locus on chromosome 22q12 affects the circulatory IgA load and the susceptibility to develop IgAN [19] .…”