外周血浆细胞在无肌病性皮肌炎中的功能和致病机理研究

无肌病性皮肌炎(ADM)是皮肌炎的一种特殊亚型，患者易并发快速进展型间质性肺炎，死亡率居高不下。目前治疗上尚无推荐方案，关键原因是对发病机制缺乏认识，缺乏特异性治疗靶点，因此ADM诊治是当前风湿病领域面临的一大挑战。我们应用细胞免疫学整体研究策略发现重症ADM患者外周血中存在异常增多的浆细胞，其比例与病情严重性呈显著正相关。在此基础上本研究拟开展下列研究：1)采用流式细胞术鉴定ADM患者浆细胞的表型，探索浆细胞的分化途径及其关键调控因子；2)采用RNA测序、细胞共培养及信号通路分析等方法探索患者浆细胞的天然免疫特性和免疫调节功能；3)在前瞻性的队列中验证浆细胞及相关指标的诊断和预后价值；4)开展蛋白酶体抑制剂硼替佐米治疗重症ADM患者的小规模临床试验，初步明确浆细胞靶向治疗对ADM的疗效和安全性。本研究不但对于阐明ADM的免疫状态及发病机制有重要意义，而且也可为疾病治疗提供新的策略和思路。

Amyopathic dermatomyositis (ADM) is a special subtype of dermatomyositis, and tends to be complicated with rapidly progressive interstitial lung disease, which resulted in high mortality. Currently the research on the pathogenesis of ADM is limited, and there are no recommended drugs for the treatment of severe ADM beyond supportive care. In the preliminary study, we have applied a novel systemic strategy to study the immune status of ADM. To our surprise, we have found that the percentage of plasma cells (PC) was increased obviously in peripheral blood of patients with severe ADM, and was positively correlated with the severity of disease. On the basis of this finding, 1) the aim of this study is to identify the phenotype of PC in patients with ADM by flow cytometry, and to identify the source of PC and key transcription factors in the established PC differentiation system. 2) And then we will use RNA sequence, cell co-culture and signal pathway analysis to explore the innate immune features and immunoregulatory effect of PC in ADM patients. 3) Furthermore, we will verify the value of the PC relevant parameters and new specific autoantibodies as diagnosis and prognostic biomarkers in the ADM prospective cohort. 4) Finally, severe patients will be administrated with proteasome inhibitor bortezomib in order to clear the efficacy and safety of PC targerted therapy. In short, this project will not only provide critical information to help to uncover the complex nature of immune disorder of ADM, but also constitute a strong basis to develop novel strategies for the treatment of this severe disease.