The Role of GDF-15 in the Lupus Nephritis

系统性红斑狼疮（SLE）导致核自身抗原的细胞外存在增加，自身反应性B细胞和T细胞的激活和增殖，从而导致严重的肾脏表型：狼疮肾炎（LN）。我们的工作表明，含有RNA和dna的狼疮自身抗原通过激活toll样受体-7和-9介导SLE和狼疮肾炎的进展，并且这一过程是由各种分子介导的，例如SIGIRR， IRAK-3, PTX3, IRF-4， NLRP3或ASC。这些分子负责调节树突状细胞和B细胞的免疫反应，这对疾病的发展至关重要。这些调节免疫反应的分子在炎症性疾病中起着重要作用。GDF15在SLE和LN病理中的作用尚不清楚。我们假设GDF15缺乏可以影响SLE的发病机制，例如通过增加抗原呈递、细胞死亡和/或其他有利于免疫系统失调的机制。因此，这个项目的目的是调查是否1.)GDF-15缺陷C57BL/6小鼠表现出自身免疫迹象，2)。在gdf -15缺陷的C57BL/6lpr/lpr小鼠中SLE和LN是如何发展的，以及gdf -15相关的疾病发展机制的澄清。这种蛋白质的功能作用是什么，它是否适合用于治疗？GDF15是否参与人类LN，或者它是否可以作为疾病进程的预后标记物。

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.