The identification of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type 1 domain containing 7A (THSD7A) as major target antigens in membranous nephropathy (MN) has fundamentally changed the scientific and clinical approach to this disease. The diagnosis of MN is now made based on the molecular pathogenesis of the disease. Treatment decisions and prediction of prognosis are based on the immune pathomechanisms of disease, allowing a more precise and individualized therapy. Currently, the basic treatment options for MN remain immunosuppressive and not specific for the disease itself. The development of novel treatment approaches, which are not based on a general immunosuppression, require a more profound understanding of the specific pathomechanisms leading to disease development and progression. To achieve this goal, we have the following aims in this project: 1) Identification of additional antigens in patients with MN, who are negative for PLA2R1 and THSD7A antibodies. For this purpose, we have developed new screening and antigen retrieval and detection strategies, which will allow us to detect susceptible antigens evading detection by conventional methods. 2) Characterization of B cell subsets and their role in the pathogenesis of human MN. This will allow a better prognosis of treatment success and potentially help to develop more specific treatment strategies. 3) A better understanding of the pathogenesis of PLA2R1 and THSD7A antibody mediated MN. To this end, we aim to implement an animal model for PLA2R1- associated MN in minipigs. This model will not only prove the pathogenicity of PLA2R1 antibodies, but will also be crucial for the implementation of novel treatment strategies in MN. These studies will be essential to further improve our understanding of the pathophysiology of MN, which is a prerequisite for the development of pathogenesis-based and personalized treatments.