We have generated a new model for systemic autoimmune disease in mice deficient in FcgammaRIIB, an IgG-binding receptor that inhibits antibody production and inflammatory responses. These mice develop a spontaneous disease that resembles lupus in humans but only in certain genetic backgrounds. Our goal is to identify susceptibility/resistance genetic loci that are responsible for the background differences in this system. We have performed an analysis of 200 mice derived from the cross between a resistant strain and a lupus susceptible strain and have identified three new resistance loci. New mouse lines have been generated in which these resistance loci are transferred to the RII-/-B6 background to allow further genetic mapping and eventual gene identification. In the characterization of the autoimmune-prone RII-/-B6 mice, we have observed that they can be aggravated or attenuated in their disease by crossing to certain modifier strains. We have observed enhanced disease in RII-/- B6 Yaa mice and decreased disease in RII-/- lpr-/-B6 mice. By comparing these new models of disease we aim to dissect the requirements for the autoimmune pathology. These newly discovered genes will possibly uncover potential routes for modifying ongoing disease in lupus or other autoimmune diseases and will serve as predictors of disease susceptibility, progression and severity.
