Membranous nephropathy (MN) is the most common cause of nephrotic syndrome in Caucasian adults. It is considered as a model of organ-specific autoimmune disease which targets the kidney glomerulus, resulting in the formation of immune deposits on the outer aspect of the glomerular basement membrane and complement-mediated proteinuria. Although spontaneous remission occurs in up to 40% of patients, 30 to 40% of patients will progress to end-stage kidney disease in 5 to 15 years, requiring renal replacement therapy with increased patient comorbidity and substantial economic healthcare burden. Fourty % of grafted patients will develop recurrence, a cause of graft loss. Treatment of MN is controversial and challenging, partly because of toxicity of immunosuppressants, long ignorance of the pathological antibodies, and lack of biomarkers apart from proteinuria. The key to rationalized therapy is the identification of pathogenic mechanisms. Several antigens such as PLA2R1, the type-M phospholipase A2 receptor, and the immune response gene HLA-DQA1 have been identified. However, molecular bases of PLA2R1 antigenicity are unknown, and the concept of only one target podocyte antigen is challenged by our own data and those of other teams. It is more likely that several antigen-antibody systems are involved at different stages of the disease in the same patient, or in different subgroups of patients. Our project aims to personalized medicine based on molecular (immunologic and genetic) signatures. In the wake of our prior studies that led to the identification of two of the three causative antigens (neutral endopeptidase, cationic bovine serum albumin) and two major predisposing genes (PLA2R, HLA-DQA1), we will further dissect the heterogeneity of MN in order to provide a novel comprehensive view of the antigens, epitopes and gene variants involved in the disease pathogenesis. Based on these new data, we will develop a set of epitope-and antigen-based assays and gene arrays for personalized diagnostic, monitoring and prediction of disease recurrence. In this innovative project at the frontier of immunology, genetics and clinical medicine, we will: 1. identify pathogenic epitopes and new antigens (particularly in the 20 to 30% PLA2R1-negative patients with idiopathic MN) by using random peptide libraries ; 2. determine the functional role of antibodies against disease-related antigens and epitopes, by a combination of in vitro (cultured podocytes) and in vivo (immunized animals) approaches ; 3. unravel the mechanisms of MN development and recurrence in the renal graft, by next generation sequencing of PLA2R1 and HLA-DQA1 loci and other relevant genes (TNF, TNFd, NPHS1, PAI1, IL-6 and STAT4) in pairs of donors and recipients with or without recurrence; 4. deliver proprietary antigen- and epitope-based assays and gene arrays, allowing personalized profiling, monitoring and care ; 5. establish correlations between gene variants, serology, immunohistological data, response to treatment and outcome in large cohorts of deeply phenotyped patients that are already available. Based on the correlations between molecular signatures, response to treatment and outcome, we will be able to determine which patient to treat, how long we should treat, when treatment should be resumed and which donor kidneys should be excluded because of high risk of recurrence. We also aim to move towards a molecular-based phenotyped ontology by substituting molecular signatures for the uniform histological definition of MN.