ICs微环境来源活性多肽ICMRP调控自身抗体亚类转换在原发性膜性肾病中的作用机制研究

ICMRP是我们基于ICs微环境降解产物介导肾-脾对话的新思想，从原发性膜性肾病（PMN）患者血清中筛选发现的一条与PMN病程密切相关的活性多肽。前期研究发现，该多肽具有活化MZB细胞、调控免疫球蛋白类（亚）别转换（CSR）的生物学功能，Blimp1可能是其直接靶标，而Blimp1是CSR的关键开关基因。提示：ICMRP可能通过Blimp1促进CSR而过量合成IgG4亚类自身抗体影响PMN的疾病进程。本课题拟借助临床样本、cBSA-PMN动物模型及Blimp1条件敲除小鼠，应用多肽探针、免疫荧光、FACS、ChIP等实验，探索ICMRP结合Blimp1、激活MZB分泌病理性IgG4自身抗体、加速PMN病程的分子机制，并系统评估ICMRP作为PMN临床进程新型分子标志物的可行性。本研究具有思想先进性和源头创新性，若获成功，将为PMN的自身免疫致病机制提供新理论，因此具有重要的临床研究意义。

From a novel perspective, based on the cross-talking between kidney and spleen mediating by ICs microenvironment related peptides, we screened an active peptides ICMRP, which is associated with the course of PMN consistently. In vivo and in vitro experiments demonstrated that the peptides have biological functions of activating MZB cells preferentially and immunoglobulin class (subclass) switch recombination (CSR) ensues. Blimp1 may be its direct binding target, also the key switch gene of CSR after MZB cells transforming into plasma cells. It suggested that ICMRP might aggravate the course of PMN by over-expressing pathological IgG4 subclass autoantibodies through Blimp1 promoting CSR process. On this basis, via clinical samples and cBSA-PMN animal model with wild type and Blimp1 knockout mice, we adopted polypeptide probes, immunofluorescence, flow cytometry, ChIP and other methodologies to explore the molecular mechanism through ICMRP binding to Blimp1, transforming MZB to plasmablast and secreting IgG4 subclass autoantibodies, which accelerate the course of PMN in turns, meanwhile evaluated the feasibility of ICMRP as a dynamic biomarker reflecting PMN systematically. This study is original and advanced. So, it will provide new autoimmune perspective of pathogenesis for PMN and yield new targets for precise intervention of PMN. Therefore, it has great clinical translational research significance.