Cd72(c) is a modifier gene that regulates Fas(lpr)-induced autoimmune disease.

Although modifier genes are extensively studied in various diseases, little is known about modifier genes that regulate autoimmune diseases. Autoimmune disease caused by the Fas(lpr) mutation depends on the genetic background of mouse strains, suggesting a crucial role of modifier genes. MRL/MpJ-Fas(lpr) (MRL/lpr) and AKR/lpr mice develop severe and mild lupus-like autoimmune disease, respectively, whereas this mutation does not cause disease on C57BL/6 (B6) or C3H background. Both MRL and AKR carry the same haplotype of the Cd72 gene encoding an inhibitory BCR coreceptor (CD72(c)), and CD72(c) contains several amino acid substitutions and a deletion in the extracellular region compared with CD72(a) and CD72(b). To address the role of Cd72(c) locus in the regulation of Fas(lpr)-induced autoimmune disease, we generated B6.CD72(c)/lpr and MRL.CD72(b)/lpr congenic mice. Introduction of the chromosomal interval containing Cd72(c) did not cause disease in B6 mice by itself, but caused development of lupus-like disease in the presence of Fas(lpr) on B6 background, clearly demonstrating that this interval contains the modifier gene that regulates Fas(lpr)-induced autoimmune disease. Conversely, MRL.CD72(b)/lpr congenic mice showed milder disease compared with MRL/lpr mice. We further demonstrated that Cd72(c) is a hypofunctional allele in BCR signal inhibition and that CD72 deficiency induces severe autoimmune disease in the presence of Fas(lpr). These results strongly suggest that the Cd72(c) is a crucial modifier gene that regulates Fas(lpr)-induced autoimmune disease due to its reduced activity of B cell signal regulation.

Presumptive role of 129 strain-derived Sle16 locus in rheumatoid arthritis in a new mouse model with Fcγ receptor type IIb-deficient C57BL/6 genetic background.

OBJECTIVE: Fcγ receptor type IIb (FcγRIIb) is a major negative regulator of B cells, and the lack of FcγRIIb expression has been reported to induce systemic lupus erythematosus (SLE) in mice of the C57BL/6 (B6) genetic background. The 129 strain-derived Sle16 locus on the telomeric region of chromosome 1 including polymorphic Fcgr2b confers the predisposition to systemic autoimmunity when present on the B6 background. We undertook this study to examine the effect of the Sle16 locus on autoimmune disease in FcγRIIb-deficient B6 mice. METHODS: We established 2 lines of FcγRIIb-deficient B6 congenic mouse strains (KO1 and KO2) by selective backcrossing of the originally constructed FcγRIIb-deficient mice on a hybrid (129×B6) background into a B6 background. Although both lack FcγRIIb expression, the KO1 and KO2 strains carry different lengths of the 129 strain-derived telomeric chromosome 1 segment flanked to the null-mutated Fcgr2b gene; the KO1 strain carries a 129 strain-derived ∼6.3-Mb interval distal from the null-mutated Fcgr2b gene within the Sle16 locus, while this interval in the KO2 strain is of B6 origin. RESULTS: Unexpectedly, both strains failed to develop SLE; instead, the KO1 strain, but not the KO2 strain, spontaneously developed severe rheumatoid arthritis (RA) with an incidence reaching >90% at age 12 months. CONCLUSION: The current study shows evidence that the epistatic interaction between the Fcgr2b-null mutation and a polymorphic gene(s) in the 129 strain-derived interval located in the distal Sle16 locus contributes to RA susceptibility in a new mouse model with the B6 genetic background, although the participation of other genetic polymorphisms cannot be totally excluded.

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.