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

• Applicant: Professorin Dr. Julia Weinmann-Menke
• Subject Area: Rheumatology ; Nephrology
• Term: since 2014
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 261683854

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.

• DFG Programme: Research Grants