Mice overexpressing BAFF develop a commensal flora–dependent, IgA-associated nephropathy
Douglas D. McCarthy, … , Jennifer L. Gommerman, Jeffrey L. Browning
Douglas D. McCarthy, … , Jennifer L. Gommerman, Jeffrey L. Browning
Published September 1, 2011
Citation Information: J Clin Invest. 2011;121(10):3991-4002. https://doi.org/10.1172/JCI45563.
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Research Article Immunology

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.

Authors

Douglas D. McCarthy, Julie Kujawa, Cheryl Wilson, Adrian Papandile, Urjana Poreci, Elisa A. Porfilio, Lesley Ward, Melissa A.E. Lawson, Andrew J. Macpherson, Kathy D. McCoy, York Pei, Lea Novak, Jeannette Y. Lee, Bruce A. Julian, Jan Novak, Ann Ranger, Jennifer L. Gommerman, Jeffrey L. Browning

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Figure 1

Gender-biased development of fatal nephropathy associated with dominant IgA and IgM glomerular deposits in the BAFF-Tg mice.

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Gender-biased development of fatal nephropathy associated with dominant ...
(A) Cohorts of male and female BAFF-Tg mice and WT controls (n = 13–20 each) were observed for up to 21 months. Cohorts of BAFF-Tg mice for the survival experiments were derived from 2 homozygous founders called BAFF-1 (original 816 line) and BAFF-2 (original 823 line) (35), which had been rederived after receipt from the Garvan Institute. Genome scanning showed that both lines retained some DBA2 from the original transgenic derivation using DBA2 × B6 F1 mice (BAFF-1, 10%; BAFF-2, 18%). The longitudinal study shown here was conducted from 2003 to 2005. This study was repeated from 2006 to 2008, and although onset of severe nephropathy was roughly equivalent (30–40 weeks) and the gender bias was present, we observed enhanced survival at the experiment end compared with that of the 2003 to 2005 cohort (data not shown). The improved survival was also recapitulated in BAFF-1 homozygous mice that retained only 4% DBA2 (see further discussion of this topic in the Methods). (B) Representative WT (6 months) and BAFF-2 Tg kidney tissues reveal increased mesangial matrix in BAFF-Tg mice (PAS stain; original magnification, ×200). (C) Representative IgA, IgG, and IgM deposits in BAFF-1 Tg mice versus WT mice (original magnification, ×200).