IFN-gamma receptor deletion prevents autoantibody production and glomerulonephritis in lupus-prone (NZB x NZW)F1 mice.
(NZB x NZW)F1 female (BW) mice spontaneously develop an autoimmune disease, characterized by the production of autoantibodies (autoAbs) and glomerulonephritis, which can be delayed by neutralizing IFN-gamma Abs and accelerated by IFN-gamma injections. To define the role of IFN-gamma in the pathogenesis of glomerulonephritis, we established a population of BW mice deficient in IFN-gammaR (BWgammaR[-/-]) by repeated crossing; these mice were compared with BWgammaR(+/+) and +/- littermates. Of the BWgammaR(+/+) and +/- mice, 50% showed immune complex glomerulonephritis with heavy proteinuria at 8 mo of age, while only 10% of the BWgammaR(-/-) mice were affected at 14 mo. The serum concentration of anti-dsDNA and anti-histone Abs was dramatically reduced in BWgammaR(-/-) mice. The role of IFN-gamma in promoting class switch to IgG2a and IgG3 could not fully account for the impaired production of anti-dsDNA in BWgammaR(-/-) animals since, IgM and IgG1 levels were also reduced. There was a high incidence of B cell lymphoma in the BWgammaR(-/-) mice, which might be related to the suppression of autoAb production. Thus, the absence of glomerulonephritis in BWgammaR(-/-) mice is likely due to a dramatic yet unexplained effect of the inactivation of IFN-gamma signaling on autoAb production.
Haas
C
C
Institute of Anatomy of the University of Zürich, Switzerland.
Ryffel
B
B
Le Hir
M
M
D000818:Animals; D000974:Antibodies, Antinuclear / Q000096:biosynthesis; D001323:Autoantibodies / Q000096:biosynthesis*; D001483:Base Sequence; D017931:DNA Primers / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000097:blood; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D008181:Lupus Nephritis / Q000209:etiology / Q000473:pathology / Q000517:prevention & control*; D008223:Lymphoma / Q000209:etiology / Q000473:pathology; D008297:Male; D051379:Mice; D008814:Mice, Inbred NZB; D018345:Mice, Knockout; D016133:Polymerase Chain Reaction; D017471:Receptors, Interferon / Q000235:genetics* / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology; D000096743:Interferon gamma Receptor
D000974:Antibodies, Antinuclear; D001323:Autoantibodies; D017931:DNA Primers; D007074:Immunoglobulin G; D007371:Interferon-gamma; D015847:Interleukin-4; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor