Fc gamma RIIb on Myeloid Cells and Intrinsic Renal Cells Rather than B Cells Protects from Nephrotoxic Nephritis

Fc gamma RIIb is the sole inhibitory FcR for IgG in humans and mice, where it is involved in the negative regulation of Ab production and cellular activation. Fc gamma RIIb-deficient mice show exacerbated disease following the induction of nephrotoxic nephritis (NTN). In this study, we determined the cellular origin of the Fc gamma RIIb-knockout phenotype by inducing NTN in mice with a deficiency of Fc gamma RIIb on either B cells alone (Fc gamma RIIBfl/fl/CD19Cre(+)) or myeloid cells (Fc gamma RIIBfl/fl/CEBP alpha Cre(+)). Deletion of Fc gamma RIIb from B cells did not increase susceptibility to NTN, compared with wild-type (WT) mice, despite higher Ab titers in the Fc gamma RIIBfl/fl/CD19Cre(+) mice compared with the WT littermate controls. In contrast, mice lacking Fc gamma RIIb on myeloid cells had exacerbated disease as measured by increased glomerular thrombosis, glomerular crescents, albuminuria, serum urea, and glomerular neutrophil infiltration when compared with WT littermate controls. The role for Fc gamma RIIb expression on radioresistant intrinsic renal cells in the protection from NTN was then investigated using bone marrow chimeric mice. Fc gamma RIIb(-/-) mice transplanted with Fc gamma RIIb(-/-) bone marrow were more susceptible to NTN than WT mice transplanted with Fc gamma RIIb(-/-) bone marrow, indicating that the presence of WT intrinsic renal cells protects from NTN. These results demonstrate that Fc gamma RIIb on myeloid cells plays a major role in protection from NTN, and therefore, augmentation of Fc gamma RIIb on these cells could be a therapeutic target in human Ab-mediated glomerulonephritis. Where there was a lack of Fc gamma RIIb on circulating myeloid cells, expression of Fc gamma RIIb on intrinsic renal cells provided an additional level of protection from Ab-mediated glomerulonephritis. The Journal of Immunology, 2013, 190: 340-348.