MIF/CD74在IgA肾病发病机制中作用的研究以及针对性干预手段的建立

Immunoglobulin A Nephropathy is characterized by immune deposits predominantly containing polymeric IgA in the glomerular mesangium on renal biopsy. In IgAN, the IgA+ B cells and plasma cells originally primed at mucosal sites have mis-homed to systemic sites, ectopicly producing IgA1. We propose to study the roles of pro-inflammatory molecule MIF and CD74 siganling in the pathogenesis of IgAN using MBP-20-Peptide immunized mouse model. MIF may regulate the migration of mucosally primed B cells into systemic sites, while the activation of CD74 signaling may contribute to the survival of ectopic B cells, germinal center formation and high-efficiency antigen presentation. Indeed through our early studies, we have already shown that CD74 signaling can boost germinal center B cell survival and enhance antigen presentation. Based on these hypotheses, we propose two distinct therapeutic models: Firstly we administrate MIF antagonist ISO-1 in the early stage post infection of IgAN development, and anticipate that the inactivation of MIF tautomerase activity will restrict the mis-homing of mucosal B cells; Secondly we have designed soluble receptor for MIF to neutralize the excess of MIF in blood during inflammation. As a result, CD74 signaling will be blocked. We hope the activity of ectopic mucosal B cells will be limited by applying the second therapeutic approach leading to the release of disease symptons. Finally, we aim to proove that MIF can regulate the expression of CD74 during IgAN pathogensis.

IgA肾病是以肾小球系膜区IgA沉积为特征的原发性肾小球疾病。粘膜IgA+细胞的异常迁移和IgA1异位分泌可导致IgAN发生，但具体机制仍不清楚。巨噬细胞迁移抑制因子（MIF）参与调控炎症细胞迁移并可上调其受体CD74的表达。我们的前期研究发现MIF/CD74信号通路对维持生发中心B细胞的存活，加强抗原递呈都起到重要作用，由此推断MIF/CD74可能参与了IgAN的发生。本项目首先探讨MIF/CD74对IgAN小鼠粘膜IgA+细胞迁移的影响及对迁移后IgA+细胞活性的调节作用，并进一步通过运用小分子化合物ISO-1及前期自行设计的MIF可溶性受体，分别抑制MIF活性及中和IgAN小鼠体内过度分泌的MIF，以达到限制粘膜B细胞迁移及其活性，从而预防IgAN的发生或延缓疾病进展的目的，为IgAN防治提供了新思路。

IgA 肾病（IgA nephropathy, IgAN）是一种常见的肾小球疾病，全球各国所报道的原发性 IgAN 发病率不一，具有较明显的地域差异，亚太地区的发病率远高于北美、欧洲等地，该病约占亚太地区原发性肾小球肾炎病例的 30~50%。但其发病机制至今尚未阐明。动物模型的建立对于探究其发病机制和寻求针对性治疗手段具有重要作用。本课题针对MIF（Macrophage Inhibitory Factor）细胞因子在IgAN病人中大量表达的现象，通过设计、表达、纯化和使用MIF可溶性受体，在IgAN发病早期的小鼠模型中探索MIF的重要作用。我们成功建立MBP-20-Peptide免疫小鼠模型；成功制备MIF可溶性纯化受体；并利用MBP-20-Peptide免疫小鼠模型开展MIF干预实验，结果显示干预组IgA小鼠的肾脏病理学改变有所减轻或缓解，推断MIF可溶性受体可以有效抑制MIF的互变异构酶活性，进而推断其可在一定程度上限制免疫细胞的迁移。该小鼠模型的成功建立具有重要的科研价值和临床意义，同时可以为新的临床药物的检测提供很好的实验平台。