Role of IgM and Complement Activation in Glomerular Disease

描述（由申请人提供）：慢性肾脏疾病（CKD）的主要原因之一是肾小球疾病。慢性肾病常发展为终末期肾病，需要透析。肾小球疾病的整体机制尚不清楚。然而，多种肾小球疾病的一个共同点是肾小球内IgM和补体蛋白C3的沉积。许多临床医生认为IgM和C3的存在并不是疾病过程中的因果因素。然而，我们有证据表明IgM和C3可能在肾小球疾病中发挥积极作用。这一观察结果也提高了肾小球疾病通过IgM和C3共同途径进展的可能性。这个项目涉及使用疾病模型来解决这个问题。具体来说，我们将使用小鼠模型来研究IgM和补体蛋白C3是否引起肾小球疾病。这是一个重要的研究领域，因为它提供了肾小球疾病的新机制，并有可能完全改变我们目前对肾小球疾病患者的临床治疗。具体目标1将探讨IgM是否是补体介导的进行性肾小球疾病的触发因素。我们已经证明补体蛋白C3沉积在补体调节蛋白，因子H（因子H敲除小鼠）缺乏的小鼠中。我们有一群同样缺乏制造B细胞能力的老鼠，因此没有内源性IgM。我们的初步数据显示，当B细胞缺乏时，因子H敲除小鼠的肾小球C3沉积减弱。特异性目的2将研究抗b细胞治疗剂是否阻断肾小球内补体活化并预防肾小球疾病。我们将使用抗b细胞剂，抗cd20抗体，来确定其在我们的疾病模型中的效果。抗cd20是一种有吸引力的治疗药物，因为它是商业上可用于临床的。我们预计给予抗cd20将阻断补体介导的肾小球疾病。

DESCRIPTION (provided by applicant): One of the prominent causes of chronic kidney disease (CKD) is due to glomerular disease. CKD often progresses to end stage renal disease and need for dialysis. The overall mechanism of glomerular disease is not well understood. However, one commonality seen in a variety of glomerular disease is deposition of IgM and the complement protein C3 within the glomerulus. Many clinicians believe the presence of IgM and C3 is not a causal factor in the disease process. However, we have evidence that IgM and C3 may play an active role in glomerular disease. This observation also raises the possibility of glomerular disease progressing through a common pathway involving IgM and C3. This project involves the use of a disease model to address this question. Specifically, we will use a mouse model to investigate if IgM and complement protein C3 cause glomerular disease. This is an important area of investigation because it provides a novel mechanism for glomerular disease and has the potential to completely alter our current clinical treatment of glomerular disease in patients. Specific aim 1 will address if IgM is a trigger of complement mediated progressive glomerular disease. We have demonstrated complement protein C3 deposition in mice deficient in the complement regulatory protein, factor H (factor H knockout mice). We have a colony of these same mice that also lack the ability to make B cells and therefore have no endogenous IgM. Our preliminary data show the novel finding that the glomerular C3 deposition seen in factor H knockout mice is attenuated when the mice are deficient in B cells. Specific aim 2 will investigate if anti-B cell therapeutic agents block complement activation within the glomerulus and prevent glomerular disease. We will administer an anti-B cell agent, anti-CD20 antibody, to determine its effect in our disease model. Anti-CD20 is an attractive therapeutic agent because it is commercially available for clinical use. We anticipate that administering anti-CD20 will bloc complement mediated glomerular disease. PUBLIC HEALTH RELEVANCE: Chronic kidney disease is a growing public health burden, which often leads to kidney failure and need for dialysis. Currently there are few therapeutic options available to patients to prevent progression of kidney disease. This research seeks to unravel the disease process between the immune system and the kidney and investigates the role for novel anti-inflammatory therapeutics in kidney disease.