Caspase 8: A Novel Suppressor of Dendritic Cell-Mediated Autoimmunity

描述（由申请人提供）：揭示免疫细胞介导的自身免疫性风湿性疾病发病机制的新机制途径是我研究生涯中始终如一的主题。系统性红斑狼疮（SLE）是一种以致病性自身抗体为特征的多器官、破坏性自身免疫性疾病。虽然树突状细胞在疾病的发生中起着重要作用，但直到最近才有研究表明树突状细胞是SLE持续存在的主要因素。SLE患者的树突状细胞表现出激活标记物的表达升高，包括共刺激分子和促炎细胞因子；然而，导致异常激活的因素尚不清楚。Caspase 8是一种已知在死亡受体信号传导中起作用的天冬氨酸酶，可以在多种细胞中启动细胞凋亡和/或抑制坏死坏死（通过抑制RIPK1/3信号传导）。初步研究表明，dc （CreCD11cCasp8flox/flox）中缺乏caspase 8的小鼠，早在2-3个月大时就表现出耐受性的中断。CreCD11cCasp8flox/flox小鼠表现为脾肿大、淋巴结病变、dsdna反应性自身抗体、肾小球肾炎、肾脏免疫复合物沉积、蛋白尿水平加重、血清促炎细胞因子（IL-12、IL-1和IFN）水平升高和早期死亡。dc中caspase 8的缺失并不影响其存活，但它们被高度激活，导致旁分泌方式激活淋巴细胞水平升高。CreCD11cCasp8flox/flox DCs激活电位的增加可能受到toll样受体7和9 （TLR7/9）的控制，因为caspase 8缺陷DCs对TLR7/9连接表现出高反应性，干扰素调节因子（IRF）的DNA结合活性增加。此外，阻断RIPK1信号可以抑制tlr7 /9诱导的caspase 8缺陷dc中促炎细胞因子的分泌。总的来说，这些数据表明，dc中完整的caspase 8信号对于预防和/或限制dc的过度刺激和诱导sle样疾病至关重要。我的进步和职业发展将在整个五年计划中由一个咨询委员会监督，该委员会将包括我的导师和其他四名成员，这个小组已经在帮助我制定研究计划方面发挥了重要作用。我的长期职业目标是建立一个学术研究小组，专注于了解风湿性疾病发展的免疫机制，重点是系统性红斑狼疮（SLE）。我相信这个提案是获得K01指导研究科学家发展奖的理想培训工具，因为我将精通DC生物学，以及信号转导，从而在我开始建立独立的学术生涯的同时，在风湿病方面发展自己的利基。

DESCRIPTION (provided by applicant): Uncovering novel mechanistic pathways involved in immune cell-mediated pathogenesis of autoimmune rheumatic diseases has been a consistent theme throughout my research career. Systemic lupus erythematosus (SLE) is a multi-organ and destructive autoimmune disease characterized by pathogenic autoantibodies. While it has been accepted that dendritic cells play an important role in the initiation of the disease, only recently have studies now implicated DCs as a major factor in the persistence of SLE. DCs from patients with SLE exhibit elevated expression of activation markers including co-stimulatory molecules and pro- inflammatory cytokines; however, the factors that are responsible for the aberrant activation is unknown. Caspase 8, an aspartic enzyme known to function in death receptor signaling, can initiate apoptosis and/or suppress necroptosis (through inhibition of RIPK1/3 signaling) in a multitude of cells. Preliminary studies show that mice lacking caspase 8 in DCs (CreCD11cCasp8flox/flox), exhibit a break in tolerance at as early as 2-3 months of age. CreCD11cCasp8flox/flox mice display splenomegaly, lymphadenopathy, dsDNA-reactive autoantibodies, glomerulonephritis, immune complex deposition in the kidney, exacerbated proteinuria levels, heightened amounts of serum pro-inflammatory cytokines (IL-12, IL-1¿, and IFN¿/¿)and early mortality. Loss of caspase 8 in DCs does not affect their survival, but they are highly activated, leading to elevated levels of activated lymphocytes in a paracrine manner. The increased activation potential of CreCD11cCasp8flox/flox DCs may be controlled by toll-like receptos 7 and 9 (TLR7/9) since caspase 8-deficient DCs display a hyper- responsiveness to TLR7/9 ligation with increased DNA binding activity of interferon regulatory factor (IRF). Additionally, blocking RIPK1 signaling dampens the TLR7/9-induced secretion of pro-inflammatory cytokines in caspase 8-deficient DCs. Collectively, these data suggest that intact caspase 8 signaling in DCs is crucial for preventing and/or limiting the hyper stimulation of DCs and induction of SLE-like disease. My progress and career advancement will be monitored throughout the five-year program by an Advisory Committee, which will include my mentor and four other members, and this group has already been instrumental in helping me develop my research proposal. My long-term career goal has been to build an academic research group focused on understanding immunologic mechanisms underlying the development of rheumatic diseases, with an emphasis on systemic lupus erythematosus (SLE). It is my belief that this proposal is an ideal training vehicle for a K01 Mentored Research Scientist Development Award, as I will become proficient in DC biology, as well as signal transduction, thereby developing my own niche in rheumatic disease as I begin to establish an independent academic career.