Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation

项目概要/摘要 尽管有重大投资，但全身炎症反应免疫治疗的前景 SIRS（全身炎症综合征）仍然没有实现。炎症性SIRS亚群的死亡率要高得多， 因此最需要新的疗法来限制免疫病理学。用于定义的临床因素 高度炎症性全身炎症反应综合征的灵感来自于小儿风湿性疾病的一种危及生命的并发症， 巨噬细胞活化综合征（MAS）。最近，MAS在遗传上与多动性相关， NLRC 4炎性小体和过量的白细胞介素（IL）-18，强烈表明过量的IL-18是一种基本的炎症反应。 高度炎症性SIRS宿主易感因子本建议的目的是确定相关的 驱动IL-18过度产生的机制，并确定IL-18促进 过度炎症我们的中心假设是，肠道IL-18的过度产生促进淋巴细胞 过度活化和功能障碍以驱动过度炎症和MAS表型。我们的指导思想是 了解导致炎症性SIRS的机制将有助于合理识别高危患者， 患者，确定潜在的预防策略，并促进必要的靶向免疫治疗的使用 以防止器官功能障碍和死亡。 为了实现我们的目标，我们首先旨在确定MAS中IL-18升高的原因。这将 涉及（i）确定炎性小体驱动的肠道过度生产所必需的分子机制 （ii）分离影响肠IL-18产生的特定微生物因子并测试它们的作用 （iii）确定模型中诱导型IL-18的细胞来源（肠相对于骨髓） （iv）将全身性IL-18水平与儿童中的粪便定殖相关联， 全身性青少年特发性关节炎，谁是在高风险的MAS。我们的第二个目标是定义 IL-18促进过度炎症的机制。这将涉及（i）确定免疫学 IL-18促进过度炎症模型的机制;（ii）确定细胞毒性损伤如何 和过量的IL-18协同促进免疫病理学;和（iii）确定NLRC 4活性亢进和 过量的IL-18促进对感染的易感性。 这些实验将大大有助于确定新的遗传和机械驱动因素， 他们将指导精确的诊断，预防策略和有针对性的治疗， 预防炎症性SIRS的发病率和死亡率。这项研究是创新的，因为它 起源于单基因人类炎症性疾病的机制，以了解和 更广泛地操纵SIRS生理学。最终，我们预计完成拟议的研究， 用于指导早期检测炎症性SIRS表型和新方法的特定见解 破坏危及生命的免疫病理学

PROJECT SUMMARY/ABSTRACT Despite major investments, the promise of immunotherapy for Systemic Inflammatory Response Syndrome (SIRS) remains unfulfilled. A hyperinflammatory SIRS subset suffers much higher mortality, and thus is in greatest need of new therapies to limit immunopathology. The clinical factors used to define hyperinflammatory SIRS were inspired by a life-threatening complication of pediatric rheumatic disease called Macrophage Activation Syndrome (MAS). Recently, MAS was genetically associated with hyperactivity of the NLRC4 inflammasome and excess Interleukin (IL)-18, strongly suggesting that excess IL-18 is a fundamental host susceptibility factor for hyperinflammatory SIRS. The objectives of this proposal are to identify the relevant mechanisms driving IL-18 overproduction and to define the pathways by which IL-18 promotes hyperinflammation. Our central hypothesis is that intestinal IL-18 overproduction promotes both lymphocyte hyperactivation and dysfunction to drive hyperinflammation and the MAS phenotype. Our guiding rationale is that understanding the mechanisms driving hyperinflammatory SIRS will enable rational identification of at-risk patients, identify potential prevention strategies, and facilitate the use of targeted immunotherapies necessary to prevent organ dysfunction and death. To accomplish our objectives, we first aim to identify the causes of elevated IL-18 in MAS. This will involve (i) determining the molecular machinery necessary for inflammasome-driven intestinal overproduction of IL-18; (ii) isolating the specific microbial factors affecting intestinal IL-18 production and testing their effects on experimental MAS; (iii) determining the cellular sources (intestinal vs. myeloid) of inducible IL-18 in models of systemic hyperinflammation; and (iv) correlating systemic IL-18 levels with fecal colonization in children with Systemic Juvenile Idiopathic Arthritis, who are at high risk for MAS. Our second aim is to define the mechanisms by which IL-18 promotes hyperinflammation. This will involve (i) determining the immunologic mechanisms by which IL-18 promotes models of hyperinflammation; (ii) determining how cytotoxic impairment and excess IL-18 synergistically promote immunopathology; and (iii) determining how NLRC4 hyperactivity and excess IL-18 promote susceptibility to infection. These experiments will contribute significantly to defining new genetic and mechanistic drivers of hyperinflammation, and they will guide precision diagnostics, prevention strategies, and targeted treatments to prevent morbidity and mortality in hyperinflammatory SIRS. The proposed research is innovative because it originates with mechanisms derived from monogenic human hyperinflammatory diseases to understand and manipulate SIRS physiology more broadly. Ultimately, we expect completion of the proposed studies to provide specific insights useful for guiding early detection of the hyperinflammatory SIRS phenotype and novel means to disrupt life-threatening immunopathology.