Importance of the tyrosine phosphatase receptor type zeta (PTPRZ) and its ligands (Interleukin-34, Pleitrophin, Tenascin and Midkine) in the pathogenesis of lupus nephritis and systematic manifestations

系统性红斑狼疮(SLE)是一种病因不明的自身免疫性系统性疾病，几乎可影响任何器官系统。肾脏受累(狼疮性肾炎)对患者的发病率和死亡率至关重要。除了免疫球蛋白、肾小球和间质的沉积外，T细胞和巨噬细胞(单核细胞)对肾脏的侵袭也是狼疮性肾炎的重要组织形态特征，也具有重要的预后意义。SLE的必要免疫抑制治疗并非没有问题，因为它的不良反应和并发症主要发生在年轻女性患者(疾病高峰期为20-40岁，男女患者比例为10：1)。因此，确定导致狼疮性肾炎和系统性红斑狼疮发生和发展的因素(细胞因子、干扰素)可能导致有希望的新的、更特异的治疗方法或治疗监测选择。使用狼疮小鼠模型，我们可以证明集落刺激因子-1(CSF-1)的发病促进作用，它由肾小管上皮细胞表达，并与CSF-1受体结合。然而，IL-34也作为第二配体与CSF-1R结合。最近的研究表明，IL-34单独在狼疮性肾炎的发病机制和全身表现中起着相关的作用，而IL-34缺乏并不能通过CSF-1、CSF-1R信号通路来弥补。这些结果的原因可能是IL-34通过其第二受体--Z型酪氨酸磷酸酶受体(PTPRZ)参与狼疮性肾炎的发病。此外，PTPRZ受体还有其他与炎症过程和纤维化形成相关的配体：细胞外基质蛋白tenascin C(TNC)和肝素结合生长因子多效营养素(PTN)和中期因子(MDK)。因此，我们将研究PTPRZ受体及其配体(PTN、MDK、TNC和IL-34)在狼疮性肾炎急、慢性肾损害和系统性红斑狼疮(SLE)的发病机制中的作用。主要在小鼠模型中获得的关于PTPRZ及其配体功能作用的知识的意义将在人类SLE中进行翻译研究，以拓宽对人类SLE发病机制的理解，特别是在存在肾脏和肌肉骨骼表现的情况下。总而言之，所获得的知识将被用于开发新的治疗目标--选择以及狼疮性肾炎和全身症状的新诊断标记物。

Systemic lupus erythematosus (SLE) is an autoimmune systemic disease of unclear etiology that can affect almost any organ system. Kidney involvement (lupus nephritis) is crucial for patient morbidity and mortality. The infiltration of the kidney by T-cells and macrophages (Mø) (mononuclear cells) is, in addition to the deposition of immunoglobulins, glomerular and interstitial, an important histomorphological characteristic of lupus nephritis and also has an important prognostic significance. The necessary immunosuppressive therapy of SLE is not unproblematic due to its undesirable effects and complications in the mostly young female patients (disease peak 20-40 years of age, ratio of female to male patients 10:1). The identification of factors (cytokines, interferons) responsible for the initiation and progression of lupus nephritis and SLE could therefore lead to promising new, more specific therapy approaches or options for therapy monitoring. Using a lupus mouse model, we could demonstrate the pathogenesis-promoting role of Colony Stimulating Factor-1 (CSF-1), which is expressed by renal tubule epithelial cells and binds to the CSF-1 receptor. However, IL-34 also binds to CSF-1R as a second ligand. In recent studies we could show that IL-34 alone plays a relevant role in the pathogenesis of lupus nephritis and systemic manifestation and that IL-34 deficiency is not compensated by the CSF-1 CSF-1R signaling pathway. A hypothesis of the cause of these results could be that IL-34 is involved in the pathogenesis of lupus nephritis via its second receptor, the tyrosine phosphatase receptor type Z (PTPRZ). In addition, the PTPRZ receptor has further ligands that have already been associated with inflammatory processes and fibrosis formation: the extracellular matrix protein tenascin C (Tnc) and the heparin-binding growth factors pleiotrophin (Ptn) and midkine (Mdk). In this project we will therefore investigate the role of the receptor PTPRZ and its ligands (PTN, MdK, Tnc and IL-34) in the pathogenesis of acute and chronic renal damage in lupus nephritis and systemic manifestations in SLE. The significance of the knowledge gained primarily in the mouse model on the role of the function of PTPRZ and its ligands will be investigated translationally in human SLE in order to broaden the understanding of the pathogenesis of human SLE, especially in the presence of renal and musculoskeletal manifestations. In summary, the knowledge gained will then be used to develop new therapeutic targets-options as well as new diagnostic markers for lupus nephritis and systemic manifestations.