The discovery of the phospholipase A2 receptor 1 (PLA2R1) and thrombospondin type-1 domain-containing 7A (THSD7A) as target antigens in membranous nephropathy (MN) has led to a major progress in the understanding of the pathophysiology of the disease. The immunologic targets in the kidneys can now be investigated in more detail, while antibody levels serve as clinical markers allowing a better differential diagnosis and helping to assess treatment response and prognosis of patients with MN.
Now for almost 80% of patients with MN a pathogenesis-related diagnosis can be made. However, in the remaining 20% of patients the pathomechanisms of disease remain unclear and their clinical course is unpredictable. Thus, their pathophysiology should be better defined.
Even though PLA2R1 and THSD7A are now characterized antigens in primary MN, it is still unclear, why they serve as targets of the immune system and which roles the molecules have in the disease onset and the glomerular pathobiology. Furthermore, it is still not defined which role the IgG4 subtype plays in the activation of the complement system, which plays a dominant role in the mediation of MN. Therefore, the identification of additional target antigens in PLA2R1 and THSD7A antibody negative patients, the characterization of the pathogenetic role of these known antigens and the mechanisms, how complement is activated are the aims of this project. It is the long-term objective to characterize for each patient with MN its molecular pathogenesis in order to develop a tailored treatment strategy to make end-stage renal disease in these patients a history.
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