Background FcγRIIB-deficient C57BL/6 (B6) mice spontaneously develop severe lupus nephritis in combination with Yaa locus (TLR7-duplication).

Objectives The aim of this study is to clarify the cell type-specific roles of FcγRIIB for the pathogenesis of Yaa-related lupus.

Methods We established B cell-specific (CD19^Cre.Yaa), myeloid-derived cell-specific (C/EBPα^Cre.Yaa), and dendritic cell (DC)-specific (CD11c^Cre.Yaa) FcγRIIB-deficient mice on B6.Yaa background, and compared the disease features of these mice with full FcγRIIB-deficient B6.FcγRIIB^-/-.Yaa mice.

Results CD19^Cre.Yaa mice developed milder lupus nephritis compared to B6.FcγRIIb^-/-.Yaa mice, indicating that FcγRIIB deficiency on only B cells is not sufficient for the development of severe disease. Surprisingly, C/EBPα^Cre.Yaa mice developed similar mild disease as CD19^Cre.Yaa mice whereas CD11c^Cre.Yaa stayed disease free. These observations indicate that, in B6. FcγRIIB^-/-.Yaa mice, FcγRIIB deficiency on both B cells and myeloid cells, but not on DCs, contribute to the development of severe lupus with high autoantibody titers. Flow cytometric analysis showed that the frequency of peripheral Gr-1^-, but not Gr-1⁺, monocytes was increased and correlated positively with the frequency of splenic PNA⁺ activated B cells in B6.FcγRIIB^-/-.Yaa and C/EBPa^Cre.Yaa, but not CD19^Cre.Yaa, mice. This suggests a link between FcγRIIB deficiency on monocytes, the high frequency of Gr-1^- monocytes and B cell activation. Transcriptome analysis of Gr-1⁺ and Gr-1^- monocytes revealed that B cell-stimulating factor-3 (BSF-3), IL-10, and IL-1β were all up-regulated in Gr-1^- monocytes.

Conclusions FcγRIIB on B cells and monocytes controls B cell activation and autoimmune responses via different but synergistic pathways in Yaa-related lupus nephritis.

References

1. Boross P, et al. J. Immunol. 187:1304–1313, 2011.

References

Disclosure of Interest None declared