Susceptibility loci for the defective foreign protein-induced tolerance in New Zealand Black mice: implication of epistatic effects of Fcgr2b and Slam family genes.

In contrast to normal mice, autoimmune-prone New Zealand Black (NZB) mice are defective in susceptibility to tolerance induced by deaggregated bovine γ globulin (DBGG). To examine whether this defect is related to the loss of self-tolerance in autoimmunity, susceptibility loci for this defect were examined by genome-wide analysis using the F(2) intercross of nonautoimmune C57BL/6 (B6) and NZB mice. One NZB locus on the telomeric chromosome 1, designated Dit (Defective immune tolerance)-1, showed a highly significant linkage. This locus overlapped with a locus containing susceptibility genes for autoimmune disease, namely Fcgr2b and Slam family genes. To investigate the involvement of these genes in the defective tolerance to DBGG, we took advantage of two lines of Fcgr2b-deficient B6 congenic mice: one carries autoimmune-type, and the other carries B6-type, Slam family genes. Defective tolerance was observed only in Fcgr2b-deficient mice with autoimmune-type Slam family genes, indicating that epistatic effects of both genes are involved. Thus, common genetic mechanisms may underlie the defect in foreign protein antigen-induced tolerance and the loss of self-tolerance in NZB mouse-related autoimmune diseases.