DCs、T细胞异常在ITP发病中起关键作用。课题组前期发现：ITP患者CD4+CD25- T细胞可成功诱导为GP特异性CD4+CD25+ Tregs，该Tregs可进一步诱导致耐受性DCs，但其分子机制尚不明确。sFGL2是Tregs的重要效应因子，通过作用于DCs FcγRIIb发挥抑制效应。课题申请者最新发现：ITP患者存在FcγRIIb表达下调，伴单核/巨噬细胞吞噬提呈血小板能力增强。本研究首先提出sFGL2/FcγRIIb/Btk信号通路在Tregs诱导DCs致耐受性过程中发挥关键作用这一假说，为验证该假说，本研究拟应用基因工程等技术中和/阻断/上调sFGL2、FcγRIIb、Btk基因表达，或阻断Btk磷酸化，观察其对DCs免疫致耐受效应的影响，双向验证该通路调节DCs分化的作用；同时探讨外源性sFGL2或上调FcγIIb对临床干预ITP发生发展的可能性，为ITP治疗提供新思路。

Functional abnormalities of dendritic cells (DCs) and T cells play important roles in the pathophysiology of ITP. Our previous study demonstrated that CD4+CD25- T cells could be successfully induced into GP-specific CD4+CD25+ regulatory T cells (Tregs) in vitro, which could further drive DCs to differentiate into tolerogenic DCs, and the precise mechanisms remain to be elucidated. Soluble fibrinogen-like protein 2 (sFGL2) is one of the most important inhibitory effector cytokines secreted by Tregs. It has been demonstrated that sFGL2 exerted the inhibitory effect on DCs via acting on the inhibitory FcγRIIb. In addition, our recently published article on Blood revealed that ITP had decreased expression of inhibitory FcγRIIb, which in parallel with the decreased ability of phagocytosing and presenting autologous oposinized platelets by APCs. Based on our above-mentioned study, we speculate that sFGL2/FcγRIIb/Btk signaling pathway played pivotal roles in the induction of tolerogenic DCs by GP-specific regulatory T cells. To test the hypothesis, we intend to use a variety of molecular biological methods, such as blocking antibodies, engineering technologies, to neutralize, downregulate or upregulate the expression of sFGL2, FcγRIIb, Btk, or inhibit the phosphorylation of Btk, and next evaluate the effect of these interventions on the GP-specific tolerogenicity of DCs. Moreover, the feasibility of exogenous sFGL2 or FcγRIIb upregulation for disrupting the pathophysilolgy process of ITP will be evaluated, thus providing new clues for the management of ITP.