T淋巴细胞在抗LEG3抗体介导的系统性红斑狼疮皮肤血管炎发病机制中的作用

Vasculitis is one of the prominent syndromes in systemic lupus erythematosus patients (SLE), of which , about 90% presents as cutaneous vasculitis. Our previous researches demonstrated that 80% of SLE patients with skin lesions were detected with anti-LEG3 antibodies, which decreased with skin recovery. Affinity purified anti-LEG3 antibodies induced cutaneous vasculitis after intradermal injection into mouse skin. These findings for the first time to provide direct evidences for immune complex mediated vasculitis. T cell is a key regulator in antibody induced tissue damages. In this project, we will investigate the T cell effect on anti-LEG3 antibody mediated cutaneous vasculitis in SLE. Using the animal model, we'll characterize the adhesion molecules and cytokines produced by endothelial cells in the presence of anti-LEG3 antibody by flow cytometry and real-time PCR, evaluate the subsets of T cells infiltrating in the skin lesions by immunohistochemistry, test the pathogenic effect of cytokines produced by the subsets of T cell by histological examination, and determine the effect of these T cells and cytokines on the initiation, development and prognosis of cutaneous vasculitis by adding exogenous or neutralizing the endogensous molecules. With this project, we are hoping to reveal the mechanism of T cells in regulating anti-LEG3 antibody mediated cutaneous vascuilitis, and to provide evidences for developing new topical reagents to manage skin vasculitis.

大约54%的系统性红斑狼疮（SLE）患者有血管炎改变，90%表现为皮肤血管炎。 我们前期研究发现，80%有皮疹的SLE患者抗LEG3抗体阳性，抗体滴度随皮疹好转逐渐下降；纯化血清抗LEG3抗体经皮内注射引起皮肤血管炎，为免疫复合物介导血管炎理论提供了直接证据。任何抗体介导的靶器官免疫性损伤都离不开T细胞的调节。本课题利用我们已经建立的动物模型，深入研究T细胞在抗LEG3抗体介导的皮肤血管炎发生机制中的作用：①LEG3抗体对血管内皮细胞表面分子和分泌细胞因子的影响；② 上述内环境决定炎症组织内T细胞亚群构成；③ T细胞亚群分泌相关细胞因子促进血管炎发生；④改变T细胞亚群；局部皮肤内补充外源性或中和内源性关键细胞因子，可以调节抗LEG3抗体所介导的皮肤血管炎的发生、发展和炎症消褪过程， 为皮肤血管炎的局部治疗提供理论和实验依据。

大约 54%的系统性红斑狼疮（SLE）患者有血管炎改变，90%表现为皮肤血管炎。.我们前期研究发现，80%有皮疹的 SLE 患者抗 LEG3 抗体阳性，抗体滴度随皮疹好转逐渐下降；纯化血清抗 LEG3 抗体经皮内注射引起局部皮肤血管炎，为免疫复合物介导血管炎理论提供了直接证据。本课题深入研究了LEG3 抗体介导皮肤血管炎的机制：LEG3抗体通过活化NLRP3-IL1β通路导致皮肤血管炎的发生。更为重要的是，该课题创造性地建立LEG3诱导的系统性红斑狼疮模型，该动物模型具有与人类SLE相类似的器官损害和免疫学改变，包括脱发、皮肤损害、肾脏损害、肺脏损害、抗dsDNA抗体阳性、抗ANA抗体阳性等，因此该模型可作为一种新的狼疮模型应用于SLE的研究。