PKCdelta as a key molecule in human (auto)immunity

PKCdelta 作为人类（自身）免疫的关键分子

• 批准号: 272598126
• 负责人: Professor Dr. Klaus Warnatz
• 金额: --
• 依托单位: Klinik für Rheumatologie und Klinische Immunologie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2015
• 资助国家: 德国
• 起止时间: 2014-12-31 至 2019-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/272598126?language=en
• 关键词: PKCdelta; key; molecule; human; auto

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.

人类自身免疫性疾病以各种形式存在，往往伴随着高发病率甚至死亡率的终生负担。许多不同的方式导致免疫耐受性的丧失，其根源往往是多因素的，阻碍了我们对它的良好理解。最近，编码蛋白激酶C增量(PKCDelta)的PRKCD突变的患者被确定为体液系统自身免疫性疾病中最突出的形式之一的单基因原型，系统性红斑狼疮(SLE)。PKCDelta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，小鼠模型表明，这种普遍表达的蛋白在控制B细胞耐受中具有特殊的作用，PRKCD基因敲除小鼠以严重的自身免疫为主要表型。因此，新发现的PKC Delta缺陷患者和他们的淋巴细胞为研究PKC Delta在人类免疫耐受控制中的作用提供了一个独特的机会。基于他们在人类免疫介导性疾病领域的长期互补专业知识，K.Warnatz(CCI Freiburg，德国)和K.Boztug(CeMM维也纳，奥地利)的实验室将筛查欧洲大型SLE队列中PRKCD的突变。我们将研究受影响患者的淋巴细胞，特别是B细胞的发育和动态平衡。在没有PKC Delta的情况下对信号通路的分析将有助于阐明PKC Delta在人类B-、T-和NK细胞不同受体下游的信号网络中的作用。蛋白质组学将确定新的相互作用伙伴。这种改变的信号累积在细胞周期控制、B细胞的存活和增殖的紊乱中，这可能是PKC Delta缺乏症自身免疫过程的基础。对原代B细胞的功能研究将被用来剖析其影响因素。最后，这项研究的遗传学和蛋白质组学的结合分析允许发现与人类自身免疫有关的新的PKCDelta相关蛋白。结合信号、蛋白质组和功能数据，这一系统性自身免疫性疾病的人类模型不仅可以更好地了解PKCDelta缺乏症B细胞生长增强和耐受性丧失的潜在病理机制，而且还可以了解与SLE发展相关的更一般的病理机制，从而为人类自身免疫性疾病提供新的靶向治疗选择，以重建耐受性。