自身抗原SFPQ在皮肌炎合并急进型肺间质病变中的作用及机制研究

Due to the complexity and heterogeneity of clinical manifestations in DM/CADM patients, the current treatment disorder is overgrown. For providing early diagnosis and assessment, there is an urgent need for sensitive and specific antibody detection programs. We have taken the lead in the detection of anti-MDA5 antibodies in patients with DM/CADM. And we found that all of them have rapidly progressive ILD, but they were different in response to treatment, leading to a very different prognosis. It may be related to the identification of antigen polypeptide SFPQ with partial anti-MDA5 antibody. On this basis, the project tries to study:①Serum anti- SFPQ antibody was detected by ELISA and antigenic specification analysis of SFPQ using recombinant SFPQ protein.②The pathogenicity of anti-SFPQ antibody was studied through in vitro experiments and animal models.③Whether the intervention by NEAT1 can improve the symptoms and course of autoimmune myositis model. This project not only intends to establish a series of rapid and non-traumatic serological diagnosis, but also can expatiate the regulation mechanism of NEAT1-SFPQ in autoimmune disease. The understanding and integration of the physiological function of NEAT1-SFPQ and its role in disease will have a deeper understanding of the development of innate immune diseases as well as providing new research ideas and treatment strategies for disease treatment.

DM/CADM临床表现的复杂性和异质性导致治疗乱象丛生，临床迫切需要敏感性和特异性较高的抗体检测项目，为及时诊断和病情评估提供依据。我们已率先开展皮肌炎患者血清抗MDA5抗体的检测，并观察到抗MDA5抗体阳性的DM/CADM患者都出现急进型ILD，但对治疗反应不同，导致预后截然不同。可能与部分抗MDA5抗体阳性血清所识别抗原多肽SFPQ有关，在此基础上本课题：①重组SFPQ蛋白，检测皮肌炎患者血清中抗SFPQ抗体水平和抗原特异性；②通过体外实验和构建动物模型研究抗SFPQ抗体的致病性；③对NEAT1的干预能否改善自身免疫性肌炎鼠模型的症状和病程。本课题不仅拟建立一系列快速、无创伤的血清学诊断，而且可阐述NEAT1-SFPQ在自身免疫病中的调控机制。对NEAT1-SFPQ生理功能及其在疾病中作用的认识和整合，将对免疫相关性疾病的发生发展有着更深的理解，为疾病治疗提供新的研究思路和治疗策略。

根据细胞因子/趋化因子的表达谱，抗TIF1-γ阳性DM/CADM患者被分为“皮肤主导型”和“过度炎症型”。抗TIF1-γ阳性DM/CADM患者的细胞因子/趋化因子表达谱可以识别具有不同疾病类型、器官受累和临床转归的患者。DM/CADM患者皮肤中JAK-STAT信号通路活化，提示JAK-STAT通路可能为皮损的有效治疗靶点；JAK1/2抑制剂通过抑制多条信号通路和免疫分子发挥治疗作用；血清CCL2、CXCL10和Galectin-9可用于评估疗效。血清中Galectin-9在DM/CADM患者中高表达，特别是合并恶性肿瘤患者Galectin-9水平显著高于无肿瘤患者，Galectin-9是预测DM/CADM合并肿瘤的血清标记物。动态监测Galectin-9可以有效判断肿瘤治疗效果，提高恶性肿瘤检出率，有助于早发现早干预，降低患者死亡风险，改善患者预后，为将来临床提供可能的新靶点和思路。色氨酸-犬尿氨酸高代谢即高IDO1活性的初发皮肌炎患者疾病活动性高、严重程度高和生存率低。IDO1催化的色氨酸-犬尿氨酸代谢途径所介导的免疫调节作用可能成为皮肌炎治疗的新靶点。