Membranous Nephropathy (MN) is an autoimmune kidney disease caused by circulating autoantibodies binding to antigens on kidney glomerular epithelial cells. To date, the only therapeutic options are unspecific and toxic immunosuppressants which, however, are unsuccessful in 20-40% of patients. PLA₂R1 and THSD7A have been identified as the pathogenic target antigens in 70-80% and 2-3% of patients with MN, respectively. Further potential target antigens in MN include NELL1, SEMA3B, PCDH7, HTRA1, and NTNG1. The identification of target antigens and the characterization of their clinical relevance in patients with MN by our group and others represent an important step for the understanding of the antigen-based pathogenesis of MN, which is vital for the improvement of patient care.
To achieve this, we will address the following topics in this project: 1) Establishment of a translational platform to transfer antigen-based MN diagnosis and management into clinical routine on a single-patient level. This approach will help individualize treatment of patients with MN. 2) Characterization of antigen-specific pathomechanisms of disease initiation, development and injury mediation in patients with MN. 3) Investigation of the pathomechanisms responsible for the development of the antigen-specific immune-response in PLA₂R1-induced MN. This includes the mechanisms of kidney injury mediation upon antibody binding and complement activation, the physiologic response of the kidneys’ glomeruli to injury as well as how clearance of immune complexes, and cell-specific injury-response in the glomeruli are regulated. To this end, we will use an active minipig model of PLA₂R1-induced MN.
These studies will be essential to further improve our understanding of the antigen-based pathophysiology of MN and lead to more precise and less toxic antigen-specific treatment strategies in MN.