SLE骨髓MSCs异常表达CCL2调控B细胞的作用及机制研究

Systemic lupus erythematosus (SLE) is an autoimmune disease.characterized by multiorgan involvement. Allogenic mesenchymal stem cells (MSCs).transplantation has become a new therapeutic option for refractory SLE. We have.demonstrated that bone marrow (BM) derived MSCs from MRL/lpr lupus mice were defective in inhibition on B cell activation, proliferation as well as differentiation when compared with those from normal controls. However, the underlying molecular mechanisms remain largely unclear and need to be further investigated. We have found that BMMSCs from lupus mice showed significant lower levels of CCL2 compared to normal BMMSCs, which was related to the defective function of MSC in regulating B cell maturation and antibody production in vitro. Thus, we.hypothesize that the abnormal regulation of B cells by MSCs from lupus mice may result from the dysregulated expression of CCL2. In the current study, we will determine a critical role of CCL2 in mediating B cell regulation by MSCs in vivo and in vitro. Moreover, both clinical studies and animal experiments will be conducted to confirm whether the immunomodulatory function of BMMSCs could be restored by allogenic MSCs.transplantation, which may provide further insight in understanding the mechanisms by which allogenic MSCs effectively treat lupus patients via modulating B cell functions.

系统性红斑狼疮(SLE)是一种常见的自身免疫病，异基因间充质干细胞(MSCs)移植治疗难治性SLE是一项新技术。前期动物实验已观察到狼疮鼠骨髓MSCs体外抑制B细胞活化增殖及分化的能力显著低于正常MSCs，但具体机制尚不清楚。我们发现狼疮鼠骨髓MSCs CCL2表达存在显著异常，且与其调控B细胞密切相关，推测狼疮MSCs调控B细胞异常可能与其CCL2表达减少有关。本课题拟进一步通过体内外实验探讨CCL2在MSCs调控B细胞中的关键作用，并通过临床及动物模型研究观察异基因MSCs移植对受体骨髓MSCs免疫调控功能的逆转作用，深入阐明异基因MSCs调节B细胞的分子基础及治疗SLE的具体机制。

系统性红斑狼疮（SLE）是一种常见的自身免疫病，异基因间充质干细胞（MSC）移植是治疗包括SLE在内的多种自身免疫病新技术。体外研究发现，正常人和鼠来源MSC可以抑制正常B细胞增殖、分化和抗体分泌。但是，来自SLE患者和小鼠的MSC是否具有对B细胞相同的免疫调节能力尚不清楚。如果SLE的MSC不具备这种能力，其具体分子机制如何？本项目中我们比较了SLE及正常骨髓MSC调节B细胞的差异；探索了SLE MSC对B细胞的异常调控与CC趋化因子配体2（CCL2）表达及修饰异常的关系；检测了异基因MSC移植治疗SLE时受体B细胞的功能及CCL2的作用。研究发现狼疮鼠和SLE患者来源骨髓间充质干细胞抑制正常B细胞增殖和分化的能力受损，这个现象是CCL2水平降低所致。正常来源MSC基因敲除CCL2会破坏其抑制B细胞能力，与之相反狼疮来源MSC过表达CCL2可以恢复其体外抑制B细胞的免疫调节功能、减轻狼疮性肾炎病理学和血清学表现。机制方面，研究发现MSC介导的B细胞抑制依赖于基质金属蛋白酶水解CCL2。这些发现揭示了CCL2的新功能，即在MSC调控B细胞中的作用，同时提示MSC移植可以用于B细胞活化的自身免疫病，如SLE的治疗。本项目研究结果提示，调节MSC的CCL2分子可能是增强MSC治疗B细胞活化相关自身免疫病（如SLE）的新策略，具有重要的临床意义和推广应用前景。