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.

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Intravenous administration of rabbit anti-rat thymocyte serum (ATS) reactive with Thy-1-like antigens present on rat mesangial cells induces almost immediate (1-hr) mesangial cell injury in rats followed by sequential mesangiolytic and mesangial-proliferative/infiltrative lesions. To determine the role of complement in these ATS-induced glomerular lesions, ATS was given to Lewis rats that had been depleted of C3 by cobra venom factor (CVF). CVF treatment prevented the degenerative changes in mesangial cells and accumulation of even the few polymorphonuclear leukocytes (PMN) seen in the glomeruli (2.67 PMN/glomerulus) 1 hr after ATS-treatment in rats not given CVF. In addition, CVF prevented the mesangiolysis and mesangial hypercellularity seen at day 4. Rat C3 and late complement components identified in the mesangial of ATS-treated rats in close association with the deposition of rabbit immunoglobulin G was also absent as a result of CVF treatment. CVF treatment did not affect binding of ATS to glomeruli as studied by immunofluorescence or paired label radioisotope techniques. The depletion of leukocytes and/or PMN by irradiation or treatment with anti-I-MN serum had no effect on the induction of the acute mesangial cell damage or the mesangiolytic lesion. Irradiation did diminish the 4-day proliferative/infiltrative lesion. Complement depletion normalized the ATS-induced increase in mesangial uptake of heat-aggregated human gamma-globulin (655.0 +/- 35.2 micrograms in ATS-treated vs 20.3 +/- 2.9 micrograms/5 X 10(4) glomeruli in ATS plus CVF-treated rats; mean +/- SEM). Small immune deposits present in the mesangial areas of kidneys 4 to 5 days after CVF treatment represented CVF-anti-CVF antibody-C3 complexes. The model of mesangial cell damage induced by ATS in the rat is complement-dependent and may relate, at least in part, to complement-mediated mesangial cell lysis.

CD8-positive lymphocytes (CD8+ lym) and ICAM-1/LFA-1 interaction have been implicated in the glomerular accumulation of monocytes/macrophages (Mo/Mphi) and crescent formation in antiglomerular basement membrane (anti-GBM) glomerulonephritis of WKY rats. In the present study, the role of CD8+ lym in the expression of ICAM-1 and inflammatory cytokines as well as in the accumulation of Mo/Mphi in the glomeruli was examined by RNase protection assay and immunofluorescence microscopy. ICAM-1 expression was apparent at 1 h and markedly enhanced at day 3 in glomeruli after an anti-GBM Ab injection in parallel with glomerular accumulation of Mo/Mphi. Expression of mRNA for IL-1beta, TNF-alpha, and IFN-gamma, known to enhance ICAM-1 expression, and MIP-1alpha, MIP-1beta, and MCP-1, known to activate leukocyte integrins or to act as chemokines, were also induced in the glomeruli at a mRNA level in a profile similar to that of ICAM-1 expression. By depleting the CD8+ lym in the circulation, the increased glomerular expression of ICAM-1 and the cytokines, except IL-1beta, and the Mo/Mphi accumulation were suppressed, indicating a crucial role of CD8+ lym in the accumulation of Mo/Mphi through stimulation of ICAM-1 and induction of cytokines.