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

McCarthy, Douglas D; Kujawa, Julie; Wilson, Cheryl; Papandile, Adrian; Poreci, Urjana; Porfilio, Elisa A; Ward, Lesley; Lawson, Melissa A E; Macpherson, Andrew J; McCoy, Kathy D; Pei, York; Novak, Lea; Lee, Jeannette Y; Julian, Bruce A; Novak, Jan; Ranger, Ann; Gommerman, Jennifer L; Browning, Jeffrey L (2011). Mice overexpressing BAFF develop a commensal flora-dependent, IgA-associated nephropathy. Journal of clinical investigation, 121(10), pp. 3991-4002. Ann Arbor, Mich.: American Society for Clinical Investigation 10.1172/JCI45563

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Gastroenterology
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery

UniBE Contributor:

Macpherson, Andrew and McCoy, Kathleen

ISSN:

0021-9738

Publisher:

American Society for Clinical Investigation

Language:

English

Submitter:

Factscience Import

Date Deposited:

04 Oct 2013 14:22

Last Modified:

22 Jul 2015 09:53

Publisher DOI:

10.1172/JCI45563

PubMed ID:

21881212

Web of Science ID:

000295601000027

BORIS DOI:

10.7892/boris.7753

URI:

https://boris.unibe.ch/id/eprint/7753 (FactScience: 213079)

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