Immunologic Mechanisms of Progressive Glomerulosclerosis

慢性肾脏疾病(CKD)影响着超过13%的人口，其患病率在 美国正在增加。不管潜在的病因是什么，CKD倾向于一旦肾脏疾病进展 函数降至50%以下。肾小球硬化是所有病因的慢性肾脏病的标志，提示 原发疾病涉及疾病发展的共同最终途径。不幸的是，目前有 没有特定的治疗方法可以延缓慢性肾脏病和肾小球硬化的进展。有趣的是，它一直是 几十年来，人们知道一些CKD患者的肾小球中有IgM和C3的沉积， 尽管这些矿藏的重要性仍然难以捉摸。最近的研究表明，自然界 免疫球蛋白(即未发生体细胞突变的免疫球蛋白M)与损伤细胞上表达的新表位结合。 与组织结合的IgM激活补体系统，导致进一步的损伤。这一发现 促使我们重新审视CKD患者肾小球IgM沉积的意义。我们发现了 免疫球蛋白M与小鼠肾小球中表达的特定表位结合，在化学、炎症和 缺血性损伤。肾小球免疫球蛋白M触发补体激活，导致进一步的肾脏损伤。我们的 初步数据还表明，补体激活片段在血浆中升高。 人类慢性肾脏病患者。目前提议的总体假设是天然抗体IgM结合 在广泛的侮辱后，新表位在肾小球中表达，结合的IgM激活 补充级联。一旦这种伤害性免疫过程开始，它就会产生更多的新表位 天然的IgM，即使原发病过程停止，肾脏损伤也会持续。为了测试这一点 假设，将追求以下具体目标。1)检测天然免疫球蛋白M是否导致进行性 肾小球硬化。为了达到这个目的，我们将测试缺乏可溶性IgM的小鼠是否可以预防慢性肾脏病 在两个动物模型中的进展，我们将测试特定的单抗IgM是否有能力 恢复伤势。2)探讨补体介导的肾小球损伤机制。假说 因为这个目的是C3a和C5a在CKD受试者的肾小球中产生并促进 肾小球硬化。我们将检查这些补体激活片段对不同 体外和体内肾小球细胞类型。3)开发治疗进展性慢性肾脏病的新疗法。 这一目标的假设是一种新的补体抑制剂，它专门针对与损伤相关的 肾小球表位将减缓肾脏疾病的进展。这项提案中的实验将 提高对CKD发病机制的认识，促进改良CKD的发展 这种疾病的免疫调节疗法。

Chronic kidney disease (CKD) affects more than 13% of the population, and its prevalence in the United States is increasing. Regardless of the underlying etiology, CKD tends to progress once renal function falls below 50%. Glomerulosclerosis is a hallmark of CKD of all etiologies, suggesting that diverse primary diseases engage common final pathways of disease progression. Unfortunately, there are currently no specific therapies for slowing the progression of CKD and glomerulosclerosis. Interestingly, it has been known for decades that IgM and C3 are deposited in the glomeruli of some patients with CKD, although the significance of these deposits has remained elusive. Recent work has revealed that natural IgM (i.e. IgM that has not undergone somatic mutation) binds to neoepitopes expressed on injured cells. The tissue-bound IgM activates the complement system, contributing to further injury. This discovery prompted us to reexamine the significance of glomerular IgM deposits in patients with CKD. We have found that IgM binds to specific epitopes expressed in the glomeruli of mice after chemical, inflammatory, and ischemic injury. The glomerular IgM triggers complement activation, causing further renal injury. Our preliminary data also demonstrates that complement activation fragments are elevated in the plasma of human patients with CKD. The overall hypothesis of the current proposal is that natural antibody IgM binds to neoepitopes expressed in the glomerulus after a wide range of insults, and bound IgM activates the complement cascade. Once this injurious immune process starts, it generates additional neoepitopes for natural IgM, perpetuating the renal injury even if the primary disease process ceases. To test this hypothesis, the following specific aims will be pursued. 1) Test whether natural IgM causes progressive glomerulosclerosis. In this aim we will test whether mice deficient in soluble IgM are protected from CKD progression in two animal models, and we will test the ability of specific monoclonal IgM antibodies to restore injury. 2) Investigate the mechanisms of complement-mediated glomerular injury. The hypothesis for this aim is that C3a and C5a are generated in the glomeruli of subjects with CKD and promote glomerulosclerosis. We will examine the effects of these complement activation fragments on the different glomerular cell types in vitro and in vivo. 3) Develop novel therapies for the treatment of progressive CKD. The hypothesis for this aim is that a novel complement inhibitor that specifically targets injury-associated glomerular epitopes will slow the progression of renal disease. The experiments in this proposal will advance our understanding of the pathogenesis of CKD and foster the development of improved immunomodulatory treatments for this disease.