Hydronephrosis associated with antiurothelial and antinuclear autoantibodies in BALB/c-Fcgr2b−/−Pdcd1−/− mice

Because most autoimmune diseases are polygenic, analysis of the synergistic involvement of various immune regulators is essential for a complete understanding of the molecular pathology of these diseases. We report the regulation of autoimmune diseases by epistatic effects of two immunoinhibitory receptors, low affinity type IIb Fc receptor for IgG (Fc γ RIIB) and programmed cell death 1 (PD-1). Approximately one third of the BALB/c- Fcgr2b − / − Pdcd1 − / − mice developed autoimmune hydronephrosis, which is not observed in either BALB/c- Fcgr2b − / − or BALB/c- Pdcd1 − / − mice. Hydronephrotic mice produced autoantibodies (autoAbs) against urothelial antigens, including uroplakin IIIa, and these antibodies were deposited on the urothelial cells of the urinary bladder. In addition, ∼15% of the BALB/c- Fcgr2b − / − Pdcd1 − / − mice produced antinuclear autoAbs. In contrast, the frequency of the autoimmune cardiomyopathy and the production of anti–parietal cell autoAb, which were observed in BALB/c- Pdcd1 − / − mice, were not affected by the additional Fc γ RIIB deficiency. These observations suggest cross talk between two immunoinhibitory receptors, Fc γ RIIB and PD-1, on the regulation of autoimmune diseases.