title: 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: Department of Immunology, University of Toronto, Toronto, Ontario, Canada.
authors: Douglas D
authors: DD
authors: McCarthy
authors: Julie
authors: J
authors: Kujawa
authors: Cheryl
authors: C
authors: Wilson
authors: Adrian
authors: A
authors: Papandile
authors: Urjana
authors: U
authors: Poreci
authors: Elisa A
authors: EA
authors: Porfilio
authors: Lesley
authors: L
authors: Ward
authors: Melissa A E
authors: MA
authors: Lawson
authors: Andrew J
authors: AJ
authors: Macpherson
authors: Kathy D
authors: KD
authors: McCoy
authors: York
authors: Y
authors: Pei
authors: Lea
authors: L
authors: Novak
authors: Jeannette Y
authors: JY
authors: Lee
authors: Bruce A
authors: BA
authors: Julian
authors: Jan
authors: J
authors: Novak
authors: Ann
authors: A
authors: Ranger
authors: Jennifer L
authors: JL
authors: Gommerman
authors: Jeffrey L
authors: JL
authors: Browning
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D000907:Antibodies, Bacterial / Q000097:blood; D053264:B-Cell Activating Factor / Q000097:blood / Q000235:genetics* / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000097:blood; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D005922:Glomerulonephritis, IGA / Q000209:etiology* / Q000235:genetics / Q000276:immunology / Q000473:pathology; D006801:Humans; D007070:Immunoglobulin A / Q000097:blood; D007074:Immunoglobulin G / Q000097:blood; D007668:Kidney / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D014157:Transcription Factors / Q000097:blood
chemical_list: D000974:Antibodies, Antinuclear; D000907:Antibodies, Bacterial; D053264:B-Cell Activating Factor; D004268:DNA-Binding Proteins; D007070:Immunoglobulin A; D007074:Immunoglobulin G; C118660:PDS5B protein, human; C505719:TNFSF13B protein, human; C505720:Tnfsf13b protein, mouse; D014157:Transcription Factors