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

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 lev...

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Bibliographic Details
Published in:The Journal of clinical investigation 2011-10, Vol.121 (10), p.3991-4002
Main Authors: 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
Format: Article
Language:English
Subjects:
Animals
Antibodies
Antibodies, Antinuclear - blood
Antibodies, Bacterial - blood
Antigens
Autoimmune diseases
B cells
B-Cell Activating Factor - blood
B-Cell Activating Factor - genetics
B-Cell Activating Factor - immunology
Biomedical research
Development and progression
Disease
Disease Models, Animal
DNA-Binding Proteins - blood
Female
Gene Expression
Glomerulonephritis, IGA - etiology
Glomerulonephritis, IGA - genetics
Glomerulonephritis, IGA - immunology
Glomerulonephritis, IGA - pathology
Humans
IgA glomerulonephritis
Immunoglobulin A - blood
Immunoglobulin G - blood
Immunology
Kidney - immunology
Kidney - pathology
Male
Mice
Mice, Transgenic
Microbiota
Pathology
Physiological aspects
Transcription Factors - blood
Transgenic animals
Tumor necrosis factor
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI45563