Role of IgM and Complement Activation in Glomerular Disease

点击翻译按钮获取中文摘要

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.