应用CAAR-T细胞特异性靶向自身反应性B细胞探讨anti-MDA5皮肌炎的致病机理

Anti-MDA5 dermatomyositis (DM) is a newly classified subset of dermatomyositis. The characteristic feature of this disease is the high incidence of interestial lung disease (ILD). Anti-MDA5 DM patients with ILD, especially in Asia, usually run an aggressive course and respond poorly to the current treatment. The problem of high mortality is challenged to be resolved. The pathogenesis of anti-MDA5 DM is largely unknown. Although anti-MDA5 autoantibody is shown to be associated with ILD, there has been a lack of direct evidence of autoantibody-induced pathology. Based on our previous work, self-reactive B cells will be the object of the current research project. The aim is to explore whether self-reactive B cells are the core in the pathogenesis of anti-MDA5 DM. Therefore, MDA5-specific B cells will be analyzed in terms of both the changes before and after onset. The relationship between MDA5-specific B cells and other clinical features of anti-MDA5 DM will be determined. More importantly, MDA5 CAAR (Chimeric Autoantibody Receptor) T cells will be engineered to eliminate MDA5-specific B cells. The effect of MDA5-specific B cells elimination will be investigated in a model of anti-MDA5/ILD. The implementation of this project is expected not only to fill the gap of B cell research in the pathogenesis of anti-MDA5 DM, but also to find a new therapeutic strategy for ILD associated with anti-MDA5 autoantibody.

anti-MDA5皮肌炎是新近被认识的一种皮肌炎亚型；该病症因肺间质病变发生率高、进展快、临床治疗乏术而病死率高。目前虽已证明anti-MDA5自身抗体与肺间质病变明显相关，但缺乏抗体致病的直接证据。鉴于此并结合既往的工作基础，我们在本项目中将以自身反应性B细胞为研究对象，不仅观察MDA5-specific B cells在疾病消长各阶段的动态变化，鉴定其临床意义；而且将设计制备MDA5 CAAR（Chimeric Autoantibody Receptor）-T细胞，精准杀伤MDA5-specific B cells，在动物模型身上观察对肺间质病变的影响效应，旨在探讨确立“自身反应性B细胞是anti-MDA5皮肌炎致病机制中的核心因素”。本项目的实施，预期将填补anti-MDA5皮肌炎致病机理中B细胞研究领域的空白；更为抢救治疗anti-MDA5相关性肺间质病变患者发掘新的治疗方法。

anti-MDA5皮肌炎是近20余年新认识的皮肌炎亚型，尤其在亚裔人群中以高发致命性的肺间质病变成为风湿科的危重症之一；寻求有效的治疗手段有待于对疾病发病机制的深入剖析。延续前期研究工作，我们在本项目中首先完善论证了“I型干扰素通路异常活化是anti-MDA5皮肌炎的核心发病机制”。在高I型干扰素背景下，anti-MDA5 皮肌炎患者血清中 BAFF（B-cell-activating factor）水平明显上调，且与疾病的严重度和anti-MDA5自身抗体滴度呈正相关，进而影响到自身反应性B细胞（MDA5-specific B cells）。通过检测MDA5-specific B cells在病程发展中的动态变化，分析其与疾病主要临床指标和不良预后因素之间的相关性，我们确立了“自身反应性B细胞在anti-MDA5皮肌炎致病机理中的重要地位”，为疾病的干预治疗发掘出新的靶点。另一方面，我们筛选出MDA5的B细胞抗原决定簇，组装构建MDA5 CAAR-T细胞（通用型），旨在通过MDA5 CAAR-T细胞选择性杀伤MDA5-specific B cells的干预效应再反向论证自身反应性B细胞的重要作用，亦为疾病的治疗提出新的治疗方法。