Interferon-γ is required for lupus-like disease and lymphoaccumulation in MRL-lpr mice

Congenic MRL-lpr mice homozygous and heterozygous for the IFN-gamma gene disruption were created to assess the role of this pleotropic cytokine on the lymphoaccumulation and lupus-like disease of Fas-defective mice. Early death was prevented, and glomerulonephritis severely reduced in IFN-gamma(-/-) mice. Hypergammaglobulinemia was maintained with a switch from IgG2a to IgG1 predominance, but the dramatic decrease in levels of the dominant IgG2a anti-dsDNA autoantibodies was not associated with a compensatory increase in T(H)2-associated IgG subclasses. Remarkably, early death and glomerulonephritis were also prevented in IFN-gamma(+/-) mice, although autoantibody levels and glomerular immune deposits were equivalent to IFN-gamma(+/+) lpr mice, indicating the importance of additional locally-exerted disease-promoting effects of IFN-gamma. IFN-gamma(-/-) mice exhibited reduced lymphadenopathy concomitant to a decrease in DN B220(+) T cells. In vivo BrdU labeling showed reduced proliferation of DN B220(+) cells in IFN-gamma(-/-) vs. IFN-gamma(+/+) lpr mice, while enhanced proliferation of all other T cell subsets was unaffected. Macrophages of IFN-gamma(-/-) lpr mice expressed markedly decreased levels of MHC class I and II molecules compared with controls. Moreover, the heightened expression of MHC class II molecules on proximal tubules of IFN-gamma(+/+) lpr mice was significantly reduced in both IFN-gamma(-/-) and IFN-gamma(+/-) mice. The data indicate that IFN-gamma hyperproduction is required for lupus development, presumably by increasing MHC expression and autoantigen presentation to otherwise quiescent nontolerant anti-self T cells, and also by promoting local immune and inflammatory processes.