Characterization of inflammatory cells and mediators in human glomerulonephritis

点击翻译按钮获取中文摘要

Rapidly progressive glomerulonephritis (RPGN) and membranous nephropathy (MN) are two human renal diseases which are at the opposite ends of a spectrum of glomerular autoimmune injuries. Whereas RPGN is an acute inflammatory lesion, which leads to end-stage renal disease (ESRD) when left untreated, MN is an injury which usually presents with normal renal function and a nephrotic syndrome. Both diseases are regarded as autoimmune injuries. Therefore both diseases periodically need immunosuppressive therapies, which may induce immunologic or clinical remission. However, a risk of relapse remains when therapy is stopped. So far there are no good clinical or laboratory parameters which indicate remission or relapse. Based on our previous work in this project, we will focus on inflammatory mediators, which might be relevant in disease induction and serve as biomarkers for clinical activity. RNA levels of the chemokine CCL18, predominantly produced in M2 macrophages, are strongly up-regulated in renal tissue of patients with RPGN when compared to controls. Additionally, patients with cANCA associated RPGN have 8 times higher expression levels than patients with pANCA associated RPGN. CCL18 serum levels were also significantly higher in patients with RPGN when compared with healthy volunteers. We will assess in more detail the site of CCL18 expression in the kidney, the potential inducers of expression, the expression and cellular localization of the receptor, and its role in the regulation of the cellular infiltrate. Furthermore, the potential role of CCL18 as marker of disease activity will be assessed in patients with RPGN. In patients with MN the role of the Phospholipase A2-Receptor antibody (PLA2R-AB) as biomarker for disease activity will be studied. In addition, the potential mechanisms of the enhanced PLA2R expression in glomeruli of patients with primary MN will be evaluated. The project will also focus on the search for other potential antigen-antibody interactions in patients with secondary MN. These studies might lead to a better clinical management of patients with RPGN and MN and could also lead to more specific therapies.