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Investigating the functional capacity of autoantibodies in primary membranous nephropathy

研究原发性膜性肾病自身抗体的功能能力

基本信息

批准号：
10297617
负责人：
Laurence H Beck
金额：
$ 26.25万
依托单位：
BOSTON MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-20 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10297617
关键词：
Achievement Activities of Daily Living Address Animals Antibodies Antibody titer measurement Antigen Targeting Antigen-Antibody Complex Antigens Autoantibodies Autoimmune Binding Biological Assay Biopsy Blood Tests Cell Line Cells Clinical Clinical Data Complement Complement 3c Complement Activation Cox Proportional Hazards Models Deposition Development Diagnosis Disease Disease Outcome Disease Pathway Disease remission Elements End stage renal failure Enzyme-Linked Immunosorbent Assay Epitope spreading Epitopes Event Extracellular Matrix Filtration Gene Expression Generations Glomerulonephritis Goals Guidelines Human Immune Immune System Diseases Immunoblotting Immunodominant Epitopes Immunoglobulin G Immunologic Monitoring Immunological Diagnosis Immunosuppression Immunotherapy Injury Kidney Kidney Diseases Knowledge Laboratories Lead Measures Mediating Medical Membranous Glomerulonephritis Methods Molecular Monitor N-terminal Nephrology Nephrotic Syndrome Outcome Pathogenicity Pathologic Patients Production Property Proteins Proteinuria Reaction Recombinants Recovery Renal function Risk Sampling Serology Serology test Serum Severities Severity of illness Specificity Specimen Spontaneous Remission Survival Analysis Testing Time Tissues Transforming Growth Factor beta Work aggressive therapy base care providers cell injury clinical predictors clinical remission cohort crosslink glomerular basement membrane human disease in vitro Model in vivo individual patient injured insight kidney biopsy novel podocyte primary outcome prognostic targeted treatment treatment response

项目摘要

PROJECT SUMMARY / ABSTRACT Membranous nephropathy (MN) is an autoimmune kidney disease in which antibodies against intrinsic glomerular proteins expressed by the podocyte lead to sublethal podocyte cell injury, loss of the filtration barrier, and ultimately the nephrotic syndrome. The overall disease course can be quite protracted and the duration and extent of proteinuria are risks for progressive decline of kidney function and end-stage kidney disease. PLA2R is the major target in 80% of primary MN cases and the monitoring of circulating anti-PLA2R antibodies (PLA2R- ab) has been instrumental in following immunologic disease activity and allowing for more rapid treatment decisions. Yet despite the existence of guidelines for such use of PLA2R-ab serology, nephrologists continue to have substantial ambiguity about whom to treat with immunosuppression, and when, due to significant variability in outcome. Patients may develop severe nephrotic syndrome with relatively low titers of PLA2R-ab or relatively mild disease with very high levels, an observation which remains unexplained. The goal of this proposal is to identify novel predictors of disease outcome associated with the variable repertoire of PLA2R-ab (which differ in subclass and epitope specificity) and to better understand the functional consequences of PLA2R-ab-mediated injury. Aim 1 describes the development of two novel assays that may add to total PLA2R-ab titer in determining likelihood of clinical remission. One assay will be a simple ELISA to assess the absence or presence of epitope spreading beyond the N-terminal immunodominant epitope of PLA2R. The second will be a measure of C3c generation (complement activation) by PLA2R-ab to summate the functional effects of all the IgG subclasses and epitope specificities. Cox proportional hazards models (survival analysis) will be used to test the associations between PLA2R-ab levels, C3c generation and epitope spreading with time to the primary outcome (achievement of partial or complete remission), using two well-characterized MN cohorts. Aim 2 will use IgG eluted from remnant kidney biopsies from patients with MN to ask whether or not the repertoire of PLA2R-ab that is bound within the immune deposits mirrors the circulating forms. The manner by which PLA2R is attached within the glomerular basement membrane (GBM) will also be assessed. Understanding the pathogenic PLA2R-ab that accumulate with antigen in the kidney deposits, as well as knowing how PLA2R is incorporated into deposits may offer new insights into disease pathways that could be targeted therapeutically. It has been suggested from animal studies that the extracellular matrix produced in reaction to the immune injury in MN contains ectopic elements not usually present in healthy GBM; these have not been extensively studied in human disease. In Aim 3, PLA2R-expressing human podocytes will serve as an in vitro model of PLA2R-ab-induced cell injury to assess early events that lead to antibody-mediated release of PLA2R from the cell, its binding to conventional and more novel matrix elements, and to broadly look at changes in extracellular matrix production. The new knowledge gained from these studies will expand our knowledge of how deposits form and persist in human MN.

项目摘要/摘要