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.
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.
Marquina
Regina
R
Laboratory of Immunology, Department of Molecular Biology, Unit Associated with Centro de Investigaciones Biologicas/Consejo Superior de Investigaciones Cientificas, University of Cantabria, Santander, Spain.
Díez
Miguel A
MA
López-Hoyos
Marcos
M
Buelta
Luis
L
Kuroki
Aki
A
Kikuchi
Shuichi
S
Villegas
Juan
J
Pihlgren
Maria
M
Siegrist
Claire-Anne
CA
Arias
Manuel
M
Izui
Shozo
S
Merino
Jesús
J
Merino
Ramón
R
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*
D007070:Immunoglobulin A; D019253:Proto-Oncogene Proteins c-bcl-2