Role of PLA2R and anti-PLA2R in idiopathic membranous nephropathy

PLA2R 和抗 PLA2R 在特发性膜性肾病中的作用

• 批准号: 8181626
• 负责人: DAVID J SALANT
• 金额: $ 42.25万
• 依托单位: BOSTON MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8181626
• 关键词: Accounting; Address; Affect; Allografting; Antibodies; Antigen Targeting; Antigens; Attention; Autoantibodies; Binding; Biopsy; Classical Complement Pathway; Cleaved cell; Clinical; Complement; Complement 1q; Complement 4b; Complement Membrane Attack Complex; Control Groups; Deltastab; Deposition; Development; Diagnosis; Disease; Early Diagnosis; End stage renal failure; Epitopes; Ethnic group; Family; Fc Receptor; Galactose; Genes; Genetic Predisposition to Disease; Genomics; Human; Idiopathic Membranous Nephropathy; IgG Receptors; IgG1; IgG3; IgG4; Immune; Immunoglobulin G; Immunoglobulins; Injury; Kidney; Kidney Diseases; Kidney Transplantation; Korea; Lectin; Link; Mannose Binding Lectin; Mediating; Membranous Glomerulonephritis; Molecular Conformation; N-terminal; Oligosaccharides; Pathway interactions; Patients; Phospholipase; Phospholipase A2; Polysaccharides; Positioning Attribute; Predisposition; Property; Proteins; Proteinuria; Recurrence; Reducing Agents; Relative (related person); Reporting; Resources; Role; Serum; Structure; Taiwan; Testing; Time; Tissues; Transplantation; Urine; Variant; base; complement system; glycosylation; high risk; immunoreactivity; in vivo; mannose receptor; member; podocyte; programs; receptor; sugar

DESCRIPTION (provided by applicant): This program will address three questions in order to better understand the role of the M-type phospholipase A2 receptor (PLA2R) as a major target antigen in idiopathic membranous nephropathy (MN) and the properties of the anti-PLA2R antibodies that are specifically detected in patients with the disease. 1. Do variants in the PLA2R1 gene account for susceptibility to idiopathic MN? This aim is based on the finding that the PLA2R epitope identified by anti-PLA2R autoantibodies is conformation dependent; the known propensity for other members of the mannose receptor/PLA2R family to exist in bent or extended configurations; differences in immunoreactivity between PLA2R in normal and MN kidney tissues; and the presence of several non-synonymous SNPs in PLA2R1, including eight within the N- terminal region that contains the epitope, at least three of which are predicted to affect PLA2R structure. Hypothesis: Variants in PLA2R1 may explain the unique properties of the pathogenic epitope in MN. Approach: Genomic variants in PLA2R1 from patients with idiopathic MN will be compared to matched controls to determine if there are unique SNPs that co-segregate with the disease. Particular attention will be paid to those variants that are predicted to affect PLA2R structure or function. 2. Do anti-PLA2R autoantibodies activate complement and, if so, which IgG subclass is responsible and which pathway is activated? This aim will address the apparent paradox that IgG4, the major IgG subclass in idiopathic MN and predominant anti-PLA2R subclass, is incapable of activating the classical complement pathway, yet complement components are commonly present in the glomerular immune deposits in idiopathic MN. The presence of mannan-binding lectin (MBL) and activated C4 but absent C1q in the immune deposits suggests that the lectin pathway may be involved. It is noteworthy that immunoglobulins lacking terminal galactose on Fc N-linked glycans have been shown to activate MBL. Hypothesis: IgG4 anti-PLA2R autoantibodies may activate complement via the lectin pathway. Approach: The ability of PLA2R IgG subclasses to activate complement will be assessed. If IgG4 activates complement, its ability to bind and activate MBL will be determined and its glycosylation state examined. 3. Is recurrent MN in transplanted human kidneys associated with circulating anti-PLA2R? Idiopathic MN frequently recurs in the transplanted kidney and is associated with a high risk of allograft loss. There is presently no way to predict which patients are likely to recur. Hypothesis: The presence of circulating anti-PLA2R will predict the recurrence of MN. Approach: Pretransplant and serial post-transplant sera from patients with idiopathic MN will be tested to determine if the presence of anti-PLA2R antibodies predates and presages the recurrence of MN. PUBLIC HEALTH RELEVANCE: Idiopathic membranous nephropathy (MN) is a relatively common worldwide cause of proteinuric kidney disease in all ethnic groups with a high rate of recurrence after kidney transplantation. Following on our finding that the M-type phospholipase receptor (PLA2R) is a specific target antigen of circulating autoantibodies in a high proportion of patients with MN, we propose to examine if there is a genetic susceptibility to the disease and determine if alterations in the sugar coating of the autoantibodies might explain their ability to cause kidney damage by activating the complement system. We also plan to find out if the likelihood of recurrence after transplantation can be predicted by detecting circulating antibodies to PLA2R.

描述(申请人提供)：这个项目将解决三个问题，以便更好地了解M型磷脂酶A2受体(PLA2R)作为特发性膜性肾病(MN)主要靶抗原的作用，以及在该疾病患者中特异性检测到的抗PLA2R抗体的特性。1.PLA2R1基因变异是否与特发性MN的易感性有关？这一目标基于以下发现：由抗PLA2R自身抗体识别的PLA2R表位是构象依赖的；已知甘露糖受体/PLA2R家族的其他成员存在弯曲或延伸构型的倾向；正常肾组织和MN肾组织中PLA2R之间的免疫反应性差异；以及PLA2R1中存在几个非同义SNP，包括包含该表位的N-末端区域内的八个，其中至少三个被预测影响PLA2R结构。假设：PLA2R1的变异可能解释了MN中致病表位的独特性质。方法：来自特发性MN患者的PLA2R1的基因组变异将与匹配的对照组进行比较，以确定是否存在与疾病共分离的独特SNPs。将特别关注那些被预测会影响PLA2R结构或功能的变体。2.抗PLA2R自身抗体能激活补体吗？如果是的话，哪个免疫球蛋白亚类负责，哪个途径被激活？这一目标将解决一个明显的悖论，即特发性MN中主要的免疫球蛋白G亚类和主要的抗PLA2R亚类IgG4不能激活经典的补体途径，而补体成分普遍存在于特发性MN的肾小球免疫沉积中。免疫沉淀物中存在甘露聚糖结合凝集素(MBL)和活化的C4，但不存在C1q，提示凝集素途径可能参与了这一过程。值得注意的是，Fc-N连接的糖链上缺少末端半乳糖的免疫球蛋白可以激活MBL。假设：IgG4抗PLA2R自身抗体可能通过凝集素途径激活补体。方法：将评估PLA2R免疫球蛋白亚类激活补体的能力。如果IgG4激活补体，将测定其结合和激活MBL的能力，并检测其糖基化状态。3.移植肾复发MN是否与循环抗PLA2R有关？特发性肾小球肾炎在移植肾中经常复发，并与移植肾丢失的高风险有关。目前还没有办法预测哪些患者可能复发。假设：循环中抗PLA2R抗体的存在将预测MN的复发。方法：将检测特发性MN患者移植前和移植后的一系列血清，以确定抗PLA2R抗体的存在是否早于并预示着MN的复发。 公共卫生相关性：特发性膜性肾病(MN)是一种在全世界范围内相对常见的引起蛋白尿肾病的原因，在所有民族中都有，肾移植后复发率高。根据我们的发现，在高比例的MN患者中，M型磷脂酶受体(PLA2R)是循环自身抗体的特异性靶抗原，我们建议检查是否存在疾病的遗传易感性，并确定自身抗体糖衣的变化是否可以解释它们通过激活补体系统导致肾脏损害的能力。我们还计划找出是否可以通过检测循环中的PLA2R抗体来预测移植后复发的可能性。