ROLES OF INTERFERON-GAMMA AND INTERLEUKIN-4 IN MURINE LUPUS

The systemic autoimmune syndrome of MRL/Mp-lpr/lpr (MRL/lpr) mice cons ists of severe pan-isotype hypergammaglobulinemia, autoantibody produc tion, lymphadenopathy, and immune complex-associated end-organ disease . Its pathogenesis has been largely attributed to helper alpha beta T cells that may require critical cytokines to propagate pathogenic auto antibody production, To investigate the roles of prototypical Th1 and Th2 cytokines in the pathogenesis of murine lupus, IFN-gamma -/- and I L-4 -/- lupus-prone mice were generated by backcrossing cytokine knock out animals against MRL/lpr breeders, IFN-gamma -/- animals produced s ignificantly reduced titers of IgG2a and IgG2b serum immunoglobulins a s well as autoantibodies, but maintained comparable levels of IgG1 and IgE in comparison to cytokine-intact controls; in contrast, IL-4 -/- animals produced significantly less IgG1 and IgE serum immunoglobulins , but maintained comparable levels of IgG2a and IgG2b as well as autoa ntibodies in comparison to controls. Both IFN-gamma -/- and IL-4 -/- m ice, however, developed significantly reduced lymphadenopathy and end- organ disease. These results suggest that IFN-gamma and IL-4 play oppo sing but dispensable roles in the development of lupus-associated hype rgammaglobulinemia and autoantibody production; however, they both pla y prominent roles in the pathogenesis of murine lupus-associated tissu e injury, as well as in lpr-induced lymphadenopathy.