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OP0215 Role of inhibitory igg fc receptor iib on b cells and monocytes in yaa-related murine lupus
  1. S Hirose1,
  2. L Qingshun1,
  3. M Ohtsuji1,
  4. H Nishimura1,
  5. H Amano2,
  6. SJ Verbeek3
  1. 1Biomedical Engineering, Toin University of Yokohama, Yokohama
  2. 2Rheumatology and Internal Medicine, Juntendo University School of Medicine, Tokyo, Japan
  3. 3Human Genetics, Leiden University Medical Center, Leiden, Netherlands

Abstract

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.

References

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

References

Disclosure of Interest None declared

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