Characterization of inflammatory cells and mediators in human glomerulonephritis

快速进行性肾小球肾炎（RPGN）和膜性肾病（MN）是两种人类肾脏疾病，处于肾小球自身免疫性损伤谱的两端。RPGN是一种急性炎性病变，如果不及时治疗，可导致终末期肾病（ESRD），而MN则是一种通常表现为肾功能正常和肾病综合征的损伤。这两种疾病都被认为是自身免疫性损伤。因此，这两种疾病都需要周期性的免疫抑制治疗，这可能会导致免疫或临床缓解。然而，当停止治疗时，复发的风险仍然存在。到目前为止，还没有好的临床或实验室参数来指示缓解或复发。在本项目前期工作的基础上，我们将重点关注炎症介质，炎症介质可能与疾病诱导相关，并作为临床活性的生物标志物。与对照组相比，趋化因子CCL18的RNA水平在RPGN患者的肾组织中明显上调，CCL18主要产生于M2巨噬细胞。此外，cANCA相关RPGN患者的表达水平是pANCA相关RPGN患者的8倍。与健康志愿者相比，RPGN患者血清CCL18水平也显著升高。我们将更详细地评估CCL18在肾脏中的表达部位、潜在的表达诱导剂、受体的表达和细胞定位，以及它在细胞浸润调节中的作用。此外，CCL18作为RPGN患者疾病活动性标志物的潜在作用将被评估。在MN患者中，磷脂酶a2受体抗体（PLA2R-AB）作为疾病活动性生物标志物的作用将被研究。此外，还将评估原发性MN患者肾小球中PLA2R表达增强的潜在机制。该项目还将专注于寻找继发性MN患者中其他潜在的抗原-抗体相互作用。这些研究可能会导致RPGN和MN患者更好的临床管理，也可能导致更具体的治疗方法。

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.