The cell-type specific regulatory role of FcγRIIb in immune-complex-mediated inflammatory diseases

Abstract

The analysis of the complex role of the inhibiting receptor for the Fc part of IgG, Fc__RIIb, was performed in various autoimmune diseases in murine models: Systemic Lupus Erythematosus (SLE), Goodpasture__s Syndrome (GPS), and arthritis.The crucial question is whether FcgRIIb plays a role in the maintenance of immunological tolerance. The important role of Fc__RIIb in the negative regulation of activating Fc receptors on myeloid effector cells and in a negative feedback mechanism in B cells, regulating antibody production, was confirmed by the immune hyperactive phenotype of Fc__RIIB KO mice. We demonstrate that Fc__RIIB-/- mice generated by gene targeting in B6-derived ES cells (Fc__RIIBB6 -/-), lacking the 129 derived flanking Sle16 region, exhibit a hyperactive phenotype, but fail to develop lupus. This fact indicates that in Fc__RIIB129 -/- mice, not the deficiency of Fc__RIIB, but the presence of the 129-derived fc__r2b flanking region, causes loss of tolerance. The contribution to the autoimmune-disease development by the resulting auto-reactive B cells is magnified by the Fc__RIIB absence, culminating in lethal lupus. We confirmed that Fc__RIIb deficiency renders B6 mice susceptible to CIA. Fc_RIIb on myeloid cells, but not B cells, manifests a dominant role in the predisposition to CIA. Regarding the role of Fc__R2b in autoimmune disease, all observations along the different autoimmune disease models (NTN, GPS, SLE, CIA) indicate towards the same direction: Fc__R2b possesses a minor function, if any, in the maintenance of the immunological tolerance.