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（由申请方提供）：该项目将解决三个问题，以更好地了解M型磷脂酶A2受体（PLA 2 R）作为特发性膜性肾病（MN）中主要靶抗原的作用，以及在该疾病患者中特异性检测到的抗PLA 2 R抗体的特性。1. PLA 2 R1基因的变异与特发性MN的易感性有关吗？该目的基于以下发现：由抗PLA 2 R自身抗体鉴定的PLA 2 R表位是构象依赖性的;甘露糖受体/PLA 2 R家族的其他成员以弯曲或延伸构型存在的已知倾向;正常和MN肾组织中PLA 2 R之间的免疫反应性差异;以及在PLA 2 R 1中存在几种非同义SNP，包括在含有表位的N-末端区域内的8种，其中至少3种被预测影响PLA 2 R结构。 假设：PLA 2 R1的变异体可以解释MN中致病性表位的独特性质。 方法：将来自特发性MN患者的PLA 2 R1中的基因组变体与匹配的对照进行比较，以确定是否存在与疾病共分离的独特SNP。将特别注意预测影响PLA 2 R结构或功能的那些变体。2.抗PLA 2 R自身抗体是否激活补体，如果是，哪个IgG亚类负责，哪个途径被激活？这一目标将解决明显的矛盾，即IgG 4，主要IgG亚类在特发性MN和主要的抗PLA 2 R亚类，是不能激活经典的补体途径，但补体成分通常存在于肾小球免疫沉积在特发性MN。甘露聚糖结合凝集素（MBL）和激活的C4，但不存在C1 q的免疫沉积物的存在下，表明凝集素途径可能参与。值得注意的是，Fc N-连接聚糖上缺乏末端半乳糖的免疫球蛋白已显示激活MBL。 假设：IgG 4抗PLA 2 R自身抗体可通过凝集素途径激活补体。 方法：将评估PLA 2 R IgG亚类激活补体的能力。如果IgG 4激活补体，将测定其结合和激活MBL的能力，并检查其糖基化状态。3.移植肾中复发性MN是否与循环抗PLA 2 R相关？特发性MN经常在移植肾中复发，并与同种异体移植物丢失的高风险相关。目前还无法预测哪些患者可能复发。 假设：循环抗PLA 2 R的存在将预测MN的复发。 方法：将检测来自特发性MN患者的移植前和移植后系列血清，以确定抗PLA 2 R抗体的存在是否早于和预示MN的复发。 公共卫生相关性：特发性膜性肾病（MN）是一种相对常见的全球性蛋白尿性肾病，在所有种族群体中具有较高的肾移植后复发率。在我们发现M型磷脂酶受体（PLA 2 R）是高比例MN患者循环自身抗体的特异性靶抗原后，我们建议检查是否存在对该疾病的遗传易感性，并确定自身抗体的糖包被改变是否可以解释其通过激活补体系统引起肾损伤的能力。我们还计划通过检测PLA 2 R的循环抗体来确定移植后复发的可能性。