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: 8515398
• 负责人: DAVID J SALANT
• 金额: $ 35.47万
• 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/8515398
• 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.

描述（由申请人提供）：该计划将解决三个问题，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 基因的变异是否导致特发性 MN 的易感性？这一目标基于以下发现：抗 PLA2R 自身抗体识别的 PLA2R 表位具有构象依赖性；已知甘露糖受体/PLA2R家族其他成员以弯曲或延伸构型存在的倾向；正常肾组织和 MN 肾组织中 PLA2R 免疫反应性的差异； PLA2R1 中存在多个非同义 SNP，其中包含表位的 N 端区域内有 8 个，预计其中至少有 3 个会影响 PLA2R 结构。 假设：PLA2R1 的变异可以解释 MN 致病表位的独特性质。 方法：将特发性 MN 患者的 PLA2R1 基因组变异与匹配对照进行比较，以确定是否存在与该疾病共分离的独特 SNP。将特别关注那些预计会影响 PLA2R 结构或功能的变体。 2. 抗 PLA2R 自身抗体是否会激活补体，如果是的话，是哪个 IgG 亚类负责以及哪个途径被激活？这一目标将解决一个明显的悖论，即 IgG4（特发性 MN 中的主要 IgG 亚类和主要抗 PLA2R 亚类）无法激活经典补体途径，但补体成分通常存在于特发性 MN 的肾小球免疫沉积物中。免疫沉积物中存在甘露聚糖结合凝集素 (MBL) 和活化的 C4，但缺乏 C1q，表明可能涉及凝集素途径。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，将确定其结合和激活 MBL 的能力并检查其糖基化状态。 3. 人移植肾中复发性 MN 与循环抗 PLA2R 相关吗？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。目前还没有办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：将对特发性 MN 患者的移植前和移植后连续血清进行检测，以确定抗 PLA2R 抗体的存在是否早于并预示着 MN 的复发。