FcγRIIb on B Cells and Myeloid Cells Modulates B Cell Activation and Autoantibody Responses via Different but Synergistic Pathways in Lupus-Prone Yaa Mice

Abstract

C57BL/6 (B6).FcγRIIb^-/- Yaa mice spontaneously develop lethal lupus nephritis. To define the cell type-specific role of FcγRIIb in Yaa-associated lupus, we established B cell- (CD19^Cre Yaa), myeloid cell- (C/EBPα^Cre Yaa), and dendritic cell- (DC) (CD11c^Cre Yaa) specific FcγRIIb-deficient B6.Yaa mouse strains. CD19^Cre Yaa mice developed milder lupus than B6.FcγRIIb^-/- Yaa mice, indicating that FcγRIIb deficiency on B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα^Cre Yaa mice also showed autoantibody production and mild lupus similar to that in CD19^Cre Yaa mice, whereas CD11c^Cre Yaa mice stayed disease free. These observations indicate that FcγRIIb deficiency in B cells and myeloid cells, but not DCs, contributes to the severe disease in B6.FcγRIIb^-/- Yaa mice. Flow cytometric analysis showed that the frequency of peripheral Gr-1^- but not Gr-1⁺ monocyte was increased in B6.FcγRIIb^-/- Yaa and C/EBPα^Cre Yaa but not CD19^Cre Yaa mice, suggesting a link between FcγRIIb deficiency on myeloid cells and the high frequency of Gr-1^- monocytes. RNA sequencing revealed that compared with Gr-1⁺ monocytes, Gr-1^- monocytes expressed higher levels of the B cell-stimulating cytokines BSF-3, IL-10, and IL-1β, the DC markers CD11c, CD83, and Adamdec1, and the antiapoptotic factors Bcl2 and Bcl6. In conclusion, in Yaa-associated lupus nephritis, FcγRIIb on B cells and myeloid cells modulates B cell activation via different but synergistic pathways. Gr-1^- monocytes are the most likely candidate myeloid cells involved.