IFN-GAMMA RECEPTOR DELETION PREVENTS AUTOANTIBODY PRODUCTION AND GLOMERULONEPHRITIS IN LUPUS-PRONE (NZB X NZW)F-1 MICE

(NZB x NZW)F-1 female (BW) mice spontaneously develop an autoimmune di sease, characterized by the production of autoantibodies (autoAbs) and glomerulonephritis, which can be delayed by neutralizing IFN-gamma Ab s and accelerated by IFN-gamma injections, To define the role of IFN-g amma in the pathogenesis of glomerulonephritis, we established a popul ation of EW mice deficient in IFN-gamma R (BW gamma R-/-) by repeated crossing; these mice were compared with BW gamma R+/+ and +/- litterma tes, Of the BW gamma R+/+ and +/- mice, 50% showed immune complex-glom erulonephritis with heavy proteinuria at 8 mo of age, while only 10% o f the BW gamma R-/- mice were affected at 14 mo, The serum concentrati on of anti-dsDNA and anti-histone Abs was dramatically reduced in BW g amma R-/- mice, The role of IFN-gamma in promoting class switch to IgG 2a and IgG3 could not fully account for the impaired production of ant i-dsDNA in BW gamma R-/- animals since, IgM and IgG1 levels were also reduced, There was a high incidence of B cell lymphoma in the BW gamma R-/- mice, which might be related to the suppression of autoAb produc tion, Thus, the absence of glomerulonephritis in BW gamma R-/- mice is likely due to a dramatic get unexplained effect of the inactivation o f IFN-gamma signaling on autoAb production.