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（由申请人提供）：该程序将解决三个问题，以便更好地了解M型磷脂酶A2受体（PLA2R）作为特发性膜肾病（MN）中的主要靶抗原，以及在患者中指定的抗PLA2R抗体的特性和抗Pla2R抗体的特性。 1。pla2r1基因中的变体对特发性mn的敏感性说明了吗？该目标是基于以下发现：抗Pla2r自身抗体鉴定的PLA2R表位取决于构象。 Mannose受体/PLA2R家族的其他成员的已知倾向存在于弯曲或扩展的构型中；正常和MN肾脏组织中PLA2R之间免疫反应性的差异； PLA2R1中存在几个非同义SNP，其中包括包含表位的N末端区域中的八个，其中至少三个被预测会影响PLA2R结构。 假设：PLA2R1中的变体可以解释MN中致病性表位的独特特性。 方法：将比较特发MN患者的PLA2R1中的基因组变异与匹配的对照组进行比较，以确定是否存在与该疾病共隔离的独特SNP。将特别注意那些预测会影响PLA2R结构或功能的变体。 2。抗Pla2r自身抗体是否激活补体，如果是，哪个IgG亚类负责并激活哪种途径？这个目的将解决明显的悖论，即特发症MN中的主要IgG子类和主要的抗Pla2r子类是无法激活经典补体途径，但补体组件通常存在于特发育MN中的肾小球沉积物中。 Mannan结合凝集素（MBL）和激活的C4的存在，但免疫沉积中不存在C1q，这表明凝集素途径可能涉及。值得注意的是，在FC N连接的聚糖上缺乏末端半乳糖的免疫球蛋白已被证明可以激活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 IgG亚类激活补体的能力。如果IgG4激活补体，则将确定其结合和激活MBL的能力，并检查其糖基化状态。 3。在与循环抗Pla2r相关的移植人肾脏中是否复发Mn？特发性MN经常在移植的肾脏中复发，并且与同种异体移植丧失的高风险有关。目前无法预测哪些患者可能会复发。 假设：循环抗Pla2R的存在将预测MN的复发。 方法：将测试来自特发性MN患者的移植前和序列化移植后血清，以确定是否存在抗Pla2R抗体的存在是否早于MN的复发。 公共卫生相关性：特发性膜性肾病（MN）是所有种族中蛋白尿肾脏疾病的相对常见原因，肾移植后复发率很高。遵循我们发现，M型磷脂酶受体（PLA2R）是在高比例的MN患者中循环自身抗体的特定靶抗原，我们建议检查是否存在对疾病的遗传敏感性，并确定是否会造成自动抗体的糖涂层来解释其能力损害卵形系统的能力。我们还计划找出通过检测到PLA2R的循环抗体来预测移植后复发的可能性。