The Role of GDF-15 in the Lupus Nephritis

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Systemic lupus erythematosus (SLE) leads to an increased extracellular presence of nuclear autoantigens and the activation and proliferation of autoreactive B and T cells and consequently to severe kidney phenotype: lupus nephritis (LN). Our work has shown that RNA- and DNA-containing lupus autoantigens mediate the progression of SLE and lupus nephritis by activation of toll-like receptor-7 and -9, and that this process is mediated by various molecules, e.g. SIGIRR, IRAK-3, PTX3, IRF-4, NLRP3 or ASC. These molecules are responsible for regulation of immune responses in dendritic cells and B cells, which are crucial for the development of the disease. Such molecules that modulate the immune response play an important role in inflammatory diseases.The role of GDF15 in the pathology of SLE and LN is still unknown. We hypothesize that GDF15 deficiency can affect the pathogenesis of SLE for example by increased antigen presentation, cell death and/or other mechanisms which favor a dysregulation of the immune system. Therefore, the aim of this project is to investigate whether 1.) GDF-15 deficient C57BL/6 mice show signs of autoimmunity, 2.) How the SLE and the LN develop in GDF-15-deficient C57BL/6lpr/lpr mice, as well as a clarification of the GDF-15-associated mechanisms which are responsible for the development of the disease 3.) Which functional role has this protein and whether it is suitable for a therapeutic use and 4.) Whether GDF15 is involved in the human LN or whether it can be used as a prognostic marker for the course of the disease.