Pro-Inflammatory Immune Complexes Are Sufficient To Induce A Lupus-Like Phenotype In R4axfcriib-/- Balb/C Mice

FcRIIb, a low-affinity inhibitory receptor for the Fc portion of IgG, is expressed on B cells and is required for the elimination of long-lived plasma cells. FcRIIb−/− C57BL/6 mice spontaneously develop high titers of pathogenic IgG anti-DNA antibodies and die prematurely of immune complex (IC)-mediated renal failure, whereas BALB/c mice deficient in FcRIIb show no evidence of autoimmune disease. We have developed a mouse that is transgenic (Tg) for the heavy (H) chain of a nephritogenic anti-DNA antibody (R4A-γ2b) that maintains B cell tolerance when expressed on a non-autoimmune background. Since the R4A H chain can generate pro-inflammatory anti-DNA antibodies, we hypothesized that the R4A Tg may be sufficient to break tolerance in FcRIIb−/− BALB/c mice. Young R4A Tg BALB/c FcRIIb−/− mice displayed negligible anti-DNA titers; however by 6 months of age they developed elevated anti-DNA antibodies, proteinuria and IC deposition in the kidney. An increase in the number of Tg-expressing plasma cells was observed. In addition IFN-α inducible genes, IFI202b and OASLE were upregulated in spleen consistent with the presence of pro-inflammatory DNA-containing ICs. Interestingly, splenic BAFF mRNA and serum BAFF protein levels were significantly increased. We propose that FcRIIb deficiency induces a feedback loop wherein the failure to eliminate plasma cells facilitate the generation of DNA-containing pro-inflammatory ICs, which induce BAFF, and enhance the maturation of high affinity anti-DNA B cells.