SHIP-1 Deficiency in AID + B Cells Leads to the Impaired Function of B10 Cells with Spontaneous Autoimmunity

• Published in: The Journal of immunology (1950) Vol. 199; no. 9; pp. 3063 - 3073
• Main Authors: Chen, Yingjia, Hu, Fanlei, Dong, Xuejiao, Zhao, Meng, Wang, Jing, Sun, Xiaolin, Kim, Tae Jin, Li, Zhanguo, Liu, Wanli
• Format: Journal Article
• Language: English
• Published: United States American Association of Immunologists 01-11-2017
• Subjects: Activation-induced cytidine deaminase; Adoptive Transfer; AKT protein; Animals; Anti-DNA antibodies; Antigen-antibody complexes; Autoimmune diseases; B-Lymphocyte Subsets - immunology; B-Lymphocyte Subsets - pathology; Cytidine deaminase; Cytidine Deaminase - genetics; Cytidine Deaminase - immunology; Extracellular Signal-Regulated MAP Kinases - genetics; Extracellular Signal-Regulated MAP Kinases - immunology; Germinal Center - immunology; Germinal Center - pathology; Germinal centers; Immunoglobulin G; Immunosuppression; Inositol; Interleukin 10; Interleukin-10 - genetics; Interleukin-10 - immunology; Kidneys; Lupus Erythematosus, Systemic - genetics; Lupus Erythematosus, Systemic - immunology; Lupus Erythematosus, Systemic - pathology; Lupus Erythematosus, Systemic - therapy; Lymphocytes B; MAP kinase; Medical treatment; Mice; Mice, Transgenic; myo-Inositol-1 (or 4)-monophosphatase; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - deficiency; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases - immunology; Proto-Oncogene Proteins c-akt - genetics; Proto-Oncogene Proteins c-akt - immunology; Ships; Transcription factors
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1700138

Unlike conventional B cells, regulatory B cells exhibit immunosuppressive functions to downregulate inflammation via IL-10 production. However, the molecular mechanism regulating the production of IL-10 is not fully understood. In this study, we report the finding that activation-induced cytidine deaminase (AID) is highly upregulated in the IL-10-competent B cell (B10) cell from Innp5d
Aicda
mice, whereas the 5' inositol phosphatase SHIP-1 is downregulated. Notably, SHIP-1 deficiency in AID
B cells leads to a reduction in cell count and impaired IL-10 production by B10 cells. Furthermore, the Innp5d
Aicda
mouse model shows B cell-dependent autoimmune lupus-like phenotypes, such as elevated IgG serum Abs, formation of spontaneous germinal centers, production of anti-dsDNA and anti-nuclear Abs, and the obvious deposition of IgG immune complexes in the kidney with age. We observe that these lupus-like phenotypes can be reversed by the adoptive transfer of B10 cells from control Innp5d
mice, but not from the Innp5d
Aicda
mice. This finding highlights the importance of defective B10 cells in Innp5d
Aicda
mice. Whereas p-Akt is significantly upregulated, MAPK and AP-1 activation is impaired in B10 cells from Innp5d
Aicda
mice, resulting in the reduced production of IL-10. These results show that SHIP-1 is required for the maintenance of B10 cells and production of IL-10, and collectively suggests that SHIP-1 could be a new potential therapeutic target for the treatment of autoimmune diseases.