补体C5a与1-磷酸鞘氨醇在抗中性粒细胞胞浆抗体相关小血管炎发病机制中的协同作用研究

抗中性粒细胞胞浆抗体（ANCA）相关小血管炎（AAV）是一类进展迅速、预后凶险的自身免疫病，发病机制尚不明晰。申请者前期的工作证实补体活化在人类AAV的发病机制中起了重要作用，且补体C5a对中性粒细胞的活化是其核心环节。1-磷酸鞘氨醇（S1P）与补体C5a之间可能存在协同，后者可能在多种炎症反应中发挥致病作用。申请者前期工作证实AAV活动期患者循环S1P水平增高，S1P刺激中性粒细胞可以使其表面表达ANCA靶抗原增加，用补体C5a刺激中性粒细胞可以使其细胞内鞘氨醇激酶水平增加；本课题拟在申请者前期结果的基础上，继续深入研究补体C5a与1-磷酸鞘氨醇协同在人类AAV发病机制中的作用：在C5a刺激中性粒细胞后，S1P可能作为第一信使，以自分泌或旁分泌的方式释放到细胞外，进一步活化中性粒细胞，并在ANCA的作用下使中性粒细胞发生呼吸爆发和脱颗粒；抑制S1P受体可以减弱C5a对中性粒细胞的效应。

Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is a group of autoimmune diseases, with poor prognosis if left untreated. The pathogenesis of AAV is not fully clear yet. Our previous studies have demonstrated that activation of the complement system is crucial for the development of human AAV, and the interaction of C5a and neutrophil is the key point. In some inflammatory diseases, the synergism between C5a and sphingosine-1-phosphate (S1P) play an important role in the pathogenesis. Our pilot study found that circulating levels of S1P were elevated in patients with active AAV, as compared with those in remission as well as normal controls; S1P could prime neutrophils, i.e., the membrane expression of ANCA target antigen on neutrophils was increased; when neutrophils were stimulated by C5a, the intracellular levels of sphingosine kinase were increased. Based on these findings, we plan to further investigate the synergism between C5a and S1P in the development of human AAV, including: S1P triggered by C5a-primed neutrophils acting as an autocrine or paracrine manner, which can further activate neutrophils to develop respiratory burst and degranulation; inhibition of S1P receptor could attenuate the effect of C5a on activating neutrophils.