title: Inhibition of B cell death causes the development of an IgA nephropathy in (New Zealand white x C57BL/6)F(1)-bcl-2 transgenic mice.
abstract: Little is known about the pathogenic mechanisms of IgA nephropathy, despite being the most prevalent form of glomerulonephritis in humans. We report in this study that in (New Zealand White (NZW) x C57BL/6)F(1) mice predisposed to autoimmune diseases, the expression of a human bcl-2 (hbcl-2) transgene in B cells promotes a CD4-dependent lupus-like syndrome characterized by IgG and IgA hypergammaglobulinemia, autoantibody production, and the development of a fatal glomerulonephritis. Histopathological analysis of glomerular lesions reveals that the glomerulonephritis observed in these animals resembles that of human IgA nephropathy. The overexpression of Bcl-2 in B cells selectively enhances systemic IgA immune responses to T-dependent Ags. Significantly, serum IgA purified from (NZW x C57BL/6)F(1)-hbcl-2 transgenic mice, but not from nontransgenic littermates, shows reduced levels of galactosylation and sialylation and an increased ability to deposit in the glomeruli, as observed in human patients with IgA nephropathy. Our results indicate that defects in the regulation of B lymphocyte survival associated with aberrant IgA glycosylation may be critically involved in the pathogenesis of IgA nephropathy, and that (NZW x C57BL/6)F(1)-hbcl-2 Tg mice provide a new experimental model for this form of glomerulonephritis.
authors.affiliation: Laboratory of Immunology, Department of Molecular Biology, Unit Associated with Centro de Investigaciones Biologicas/Consejo Superior de Investigaciones Cientificas, University of Cantabria, Santander, Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Marquina
authors.forename: Miguel A
authors.initials: MA
authors.lastname: Díez
authors.forename: Marcos
authors.initials: M
authors.lastname: López-Hoyos
authors.forename: Luis
authors.initials: L
authors.lastname: Buelta
authors.forename: Aki
authors.initials: A
authors.lastname: Kuroki
authors.forename: Shuichi
authors.initials: S
authors.lastname: Kikuchi
authors.forename: Juan
authors.initials: J
authors.lastname: Villegas
authors.forename: Maria
authors.initials: M
authors.lastname: Pihlgren
authors.forename: Claire-Anne
authors.initials: CA
authors.lastname: Siegrist
authors.forename: Manuel
authors.initials: M
authors.lastname: Arias
authors.forename: Shozo
authors.initials: S
authors.lastname: Izui
authors.forename: Jesús
authors.initials: J
authors.lastname: Merino
authors.forename: Ramón
authors.initials: R
authors.lastname: Merino
mesh_terms: D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000502:physiology*; D005260:Female; D005922:Glomerulonephritis, IGA / Q000209:etiology*; D006031:Glycosylation; D007070:Immunoglobulin A / Q000378:metabolism; D008180:Lupus Erythematosus, Systemic / Q000209:etiology; D051379:Mice; D008810:Mice, Inbred C57BL; D008814:Mice, Inbred NZB; D008822:Mice, Transgenic; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*
chemical_list: D007070:Immunoglobulin A; D019253:Proto-Oncogene Proteins c-bcl-2