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 (CD19Cre.Yaa), myeloid-derived cell-specific (C/EBPαCre.Yaa), and dendritic cell (DC)-specific (CD11cCre.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 CD19Cre.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/EBPαCre.Yaa mice developed similar mild disease as CD19Cre.Yaa mice whereas CD11cCre.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/EBPaCre.Yaa, but not CD19Cre.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.
Boross P, et al. J. Immunol. 187:1304–1313, 2011.
Disclosure of Interest None declared
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