PKCdelta as a key molecule in human (auto)immunity

• Applicant: Professor Dr. Klaus Warnatz
• Subject Area: Rheumatology
• Term: from 2015 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 272598126

Human autoimmune disorders present in various forms, often with a life long burden of high morbidity and even mortality. Many different ways lead to the loss of immune tolerance and often the origin is multifactorial impeding our good comprehension of it. Recently, patients with a mutation in PRKCD encoding Protein kinase c delta (PKCdelta) have been identified as a monogenic prototype for one of the most prominent forms of humoral systemic autoimmune diseases, systemic lupus erythematosus (SLE). PKCdelta is a signaling protein with multiple downstream target proteins and functions in various signaling pathways. Interestingly, mouse models have indicated a special role of the ubiquitously expressed protein in the control of B cell tolerance revealed by the severe autoimmunity in Prkcd knock out mice as the major phenotype. Therefore the newly identified PKCdelta-deficient patients and their lymphocytes grant a unique opportunity to investigate the role of PKCdelta in the control of immune tolerance in humans. Based on their complementary long-term expertise in the field of human immune mediated diseases the laboratories of K. Warnatz (CCI Freiburg, Germany) and K. Boztug (CeMM Vienna, Austria) will screen large European SLE cohorts for mutations in PRKCD. We will investigate lymphocyte and especially B cell development and homeostasis in the affected patients. The analysis of signaling pathways in the absence of PKCdelta will shed light on the role of PKCdelta in the signaling networks downstream of different receptors in human B-, T- and NK cells. New interaction partners shall be identified by proteomics. This altered signaling cumulates in a disturbed cell cycle control, survival and proliferation of B cells possibly underlying the autoimmune process in PKCdelta deficiency. Functional studies of primary B cells will be used to dissect the contributing factors. Finally, the combined genetic and proteomic analysis of this study allows for the discovery of new PKCdelta-related proteins involved in human autoimmunity. Integrating the signaling, proteomic and functional data this human model of systemic autoimmune disease will not only provide a better insight into the underlying pathomechanism in the enhanced B cell growth and loss of tolerance in PKCdelta deficiency, but also into the more general pathomechanisms relevant for the development of SLE and implicate thereby new targeted therapeutic options for human autoimmune disease in order to re-establish tolerance.

• DFG Programme: Research Grants
• International Connection: Austria, France
• Partner Organisation: Fonds zur Förderung der wissenschaftlichen Forschung (FWF)
• Co-Investigator: Professor Dr. Kaan Boztug
• Cooperation Partner: Professor Dr. Jean-Lois Pasquali