Autoantigen glycoprotein 70 expression is regulated by a single locus, which acts as a checkpoint for pathogenic anti-glycoprotein 70 autoantibody production and hence for the corresponding development of severe nephritis, in lupus-prone BXSB mice

Retroviral envelope glycoprotein gp70 is present in the sera of immunologic ally normal and autoimmune-prone strains of mice. However, only lupus-prone mice spontaneously develop gp70-anti-gp70 immune complexes (gp70IC), and t hese have been implicated in the development of nephritis. We investigated the genetic factors that affect the production of both free serum gp70 and gp70IC in the lupus-prone BXSB mouse strain by analyzing (BXSB X (C57BL/10 X BXSB)F-1)- and (C57BL/10 X (C57BL/10 X BXSB)F-1)-backcrossed male mice. P roduction of gp70 mapped to a single major locus located on chromosome 13 ( Bxs6) with a maximum log likelihood of the odds of 36.7 (p = 1.6 X 10(-38)) . The level of gp70IC was highly dependent on Bxs6-related gp70 production, and high titer autoantibody production only occurred when serum gp70 level s were greater than a threshold value of similar to4.0 mug/ml. The subdivis ion of the (BXSB X (C57BL/10 X BXSB)F-1)-backcrossed mice into those homozy gous or heterozygous for Bxs6 enabled a remarkable association to be observ ed between high levels of gp70IC and severe nephritis in the Bxs6 homozygot e population. A further mapping study in these two subgroups identified a p reviously unrecognized interval associated with the production of autoantib odies.