MSC对SLE骨髓前体B细胞异常分化的干预作用及机制研究

Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease characterized by the overactivation of B cells and the production of a large number of autoantibodies. The pathogenesis of SLE remains unclear. Previous studies have focused on detecting the role of peripheral B cells in disease onset; however, it may be more valuable to clarify the mechanism of aberrant early B cell differentiation in SLE as the central checkpoint in bone marrow is more important for B cell tolerance. Mesenchymal stem cells (MSC) are the main cell type involved in the regulation of precursor B cell development in bone marrow microenvironment. Previously, we have demonstrated that bone marrow MSC from SLE patients exhibited defects in various aspects and their immunoregulatory abilities were greatly impaired. In this project, we are planning to delineate the regulatory effect of MSC on precursor B cells as well as the molecular mechanism of MSC malfunction in SLE bone marrow though in vivo and in vitro studies, and based on animal models and clinical applications, to explore whether allogeneic MSC transplantation improves the development of bone marrow precursor B cells to exert a therapeutic role. The results may not only give a new explanation for SLE pathogenesis, but also provide more solid evidence for the clinical application of allogeneic MSC in autoimmune diseases.

系统性红斑狼疮(SLE)这一自身免疫病原型疾病以B细胞高度活化和大量自身抗体产生为特征，发病机理尚不明确。既往研究多侧重于探讨外周B细胞在疾病发生中的作用，但由于B细胞耐受主要在中枢(骨髓)中进行，阐明SLE中B细胞早期分化异常的机制可能更有意义。间充质干细胞(MSC)是骨髓微环境中主要参与调控前体B细胞分化的细胞类型，前期我们已发现SLE患者骨髓前体B细胞存在异常；同时其MSC具有多方面缺陷，且调控多种免疫细胞的能力显著降低。在本项目中，拟通过体内外实验解析骨髓MSC对前体B细胞的调控作用及狼疮MSC功能异常的具体机制，并结合动物模型和临床应用研究探讨异体MSC改善骨髓前体B细胞分化与其疗效的关系，在此基础上尝试修饰MSC以增强其功能。相关结果可望为疾病发生机制提出新的解释，同时也为应用异体MSC进行免疫干预提供新的依据。

系统性红斑狼疮(SLE)这一自身免疫病原型疾病以B细胞高度活化和大量自身抗体产生为特征，发病机理尚不明确。在本项目中，我们观察到狼疮患者及不同狼疮动物模型中早期B细胞分化均存在异常，尤其是祖B细胞（pro-B）比例降低；且随着小鼠周龄的增加，这一紊乱愈发明显。结合高通量测序及候选基因研究策略，筛选出多个可能参与调控的B细胞相关基因；沉默和过表达实验揭示非受体型蛋白酪氨酸磷酸酶22（Ptpn22）在减少总pro-B细胞数量的同时，却可以促进其中与自身抗体相关的双阴性B细胞的产生，提示该基因是导致狼疮早期B细胞异常分化的重要靶点；布鲁东氏酪氨酸激酶（Btk）抑制剂可阻断Ptpn22的沉默效应，提示Btk在Ptpn22下游发挥作用；间充质干细胞（MSC）治疗后狼疮小鼠Ptpn22表达下降，骨髓pro-B增多，有望纠正这一紊乱。这一研究不仅为阐明了新的狼疮致病机制，提出新的治疗靶点，也为MSC治疗狼疮提供了更多的理论依据。