OP0059 Importance of the protein tyrosine phosphatase SHP1 in dendritic cells for prevention of TH1 cell differentiation and autoimmunity: A potential target for the therapy
Authors: T. Kaneko, Y. Saito, T. Kotani, H. Ohnishi, Y. Murata, Y. Yonemoto, K. Okamura, T. Matozaki, K. Takagishi
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> Dendritic cells (DCs) are professional antigen-presenting cells crucial for initiating immune response to pathogens as well as for maintaining immune tolerance to self-antigens. Dysregulation of the function of DCs is thought to cause abnormal immune responses to self-antigens, which in turn cause autoimmunity. Src homology 2 domain-containing protein tyrosine phosphatase-1 (Shp1) is a nonreceptor-type protein tyrosine phosphatase expressed in a wide variety of immune cells<sup>1)</sup>. Spontaneous mutations in the <i>Shp1</i> gene in mice produce the <i>motheaten</i> phenotypes that exhibit multiple inflammatory and autoimmune disorders<sup>1)</sup>. Previous studies with the <i>motheaten</i> mice suggest that Shp1 negatively regulates the function of lymphocytes<sup>2),3)</sup>. Recent studies appeared that Shp1 also negatively regulate DC fucnctions such as production of proinflammatory cytokines<sup>4),5)</sup>. However, physiological and pathological roles of Shp1 in DCs remain to be elucidated. <h3>Objectives</h3> Investigation of Shp1 in DCs <i>in vivo</i> for development of autoimmunity <h3>Methods</h3> We generated Shp1 conditional knock out (CKO) mice, in which the <i>Shp1</i> gene was specifically deleted in CD11c<sup>+</sup> DCs by crossing Shp1-flox mice and CD11c-Cre mice. <h3>Results</h3> CKO mice showed marked splenomegaly, which was due to hypercellularity with increased number of DCs. Splenic DCs from CKO mice showed up-regulation of CD86 and CCR7 expression as well as LPS-induced production of proinflammatory cytokines. The mice manifested an increased number of splenic Th1 cells, consistent with the increased ability of their DCs to induce production of IFN-γ by Ag-specific T cells in vitro. The number of splenic CD5<sup>+</sup>CD19<sup>+</sup> B-1a cells as well as the serum concentrations of IgM and IgG2a were also increased in CKO mice. Moreover, CKO mice spontaneously developed age-related glomerulonephritis, which was characterized by massive leukocyte accumulation and hypercellularity in renal glomeruli and immune complex deposition in glomeruli, as well as interstitial pneumonitis together with increased serum concentrations of ANA and anti-ds DNA antibodies. <h3>Conclusions</h3> Our results thus suggest that Shp1 negatively regulates various functions of DCs and suppresses proliferation or differentiation of autoreactive T cells and B cells, thereby protecting against autoimmunity. Development of an approach to activate Shp1 specifically in DCs may provide the basis for a potential new therapy for autoimmune diseases like SLE. <h3>References</h3> [1]Green, M. C., et al. 1975. J. Hered. 66: 250–258. [2]Pao, L. I., et al. 2007. Immunity 27: 35–48. [3]Neel, B. G., et al. 2003. Trends Biochem. Sci. 28: 284–293. [4]An, H., et al. 2008. Nat. Immunol. 9: 542-550. [5]Ramachandran, I.R., et al. 2011. J. Immunol. 186:3934-3945. <h3>Disclosure of Interest</h3> None Declared