PKCdelta as a key molecule in human (auto)immunity

人类自身免疫性疾病以各种形式存在，通常具有高发病率甚至死亡率的终身负担。许多不同的方式导致免疫耐受的丧失，并且起源通常是多因素的，阻碍了我们对它的良好理解。最近，编码蛋白激酶c δ（PKC δ）的PRKCD突变的患者已被确定为最突出的体液系统性自身免疫疾病形式之一系统性红斑狼疮（SLE）的单基因原型。PKC δ是一种具有多个下游靶蛋白的信号蛋白，在多种信号通路中发挥作用。有趣的是，小鼠模型已经表明普遍表达的蛋白质在控制B细胞耐受性中的特殊作用，这通过Prkcd敲除小鼠中的严重自身免疫性作为主要表型来揭示。因此，新发现的PKC δ缺陷患者及其淋巴细胞为研究PKC δ在人类免疫耐受控制中的作用提供了独特的机会。基于他们在人类免疫介导疾病领域的互补性长期专业知识，K。Warnatz（CCI弗赖堡，德国）和K. Boztug（CeMM维也纳，奥地利）将筛选大型欧洲SLE队列的PRKCD突变。我们将研究淋巴细胞，特别是B细胞的发展和稳态在受影响的患者。在不存在PKC δ的情况下对信号通路的分析将阐明PKC δ在人类B-、T-和NK细胞中不同受体下游的信号网络中的作用。新的相互作用伙伴应通过蛋白质组学鉴定。这种改变的信号传导累积在B细胞的受干扰的细胞周期控制、存活和增殖中，可能是PKC δ缺陷中的自身免疫过程的基础。原代B细胞的功能研究将用于剖析促成因素。最后，本研究的遗传学和蛋白质组学相结合的分析允许发现参与人类自身免疫的新的PKCdelta相关蛋白。整合信号传导、蛋白质组学和功能数据，该系统性自身免疫性疾病的人类模型将不仅提供对增强的B细胞生长和PKC δ缺陷中的耐受性丧失的潜在病理机制的更好的洞察，而且提供对与SLE的发展相关的更一般的病理机制的更好的洞察，并且由此暗示人类自身免疫性疾病的新的靶向治疗选择，以便重建耐受性。

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.