Understanding Interleukin-18 Mediated Susceptibility to Systemic Hyperinflammation

项目摘要/摘要 尽管进行了重大投资，免疫疗法对全身炎症反应的承诺 综合征(SIRS)仍未得到满足。高炎症性SIRS亚群的死亡率要高得多。 因此，最需要新的治疗方法来限制免疫病理学。临床因素用来定义 高炎性SIRS是由一种危及生命的儿科风湿病并发症引起的 巨噬细胞激活综合征(MAS)。最近，MAS在基因上与多动症有关。 NLRC4炎症体和过度的白介素18，强烈表明过度的白介素18是一个基本的 高炎性SIRS的宿主易感因素。这项提案的目标是确定相关的 推动IL-18过度产生的机制和确定IL-18促进的途径 过度炎症。我们的中心假设是肠道IL-18的过度产生促进了这两个淋巴细胞 过度激活和功能障碍导致过度炎症和MAS表型。我们的指导思想是 了解导致高炎症性SIRS的机制将使我们能够理性地识别高危 患者，确定潜在的预防策略，并促进必要的靶向免疫疗法的使用 以防止器官功能障碍和死亡。 为了实现我们的目标，我们首先的目标是确定MAS中IL-18升高的原因。这将是 涉及(I)确定炎症小体驱动的肠道过度生产所必需的分子机制 IL-18的产生；(Ii)分离影响肠道IL-18产生的特定微生物因子并检测其作用 关于实验性MAS；(Iii)在模型中确定诱导性IL-18的细胞来源(肠道与髓系) 系统性炎症；以及(Iv)系统性IL-18水平与儿童粪便定植的相关性 系统性青少年特发性关节炎，是MAS的高危人群。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；以及(Iii)确定NLRC4过度活动和 过量的IL-18会增加感染的易感性。 这些实验将大大有助于定义新的遗传和机制驱动因素 高度炎症，他们将指导精确的诊断、预防策略和有针对性的治疗 预防高炎症性SIRS的发病率和死亡率。这项拟议的研究具有创新性，因为它 起源于单基因人类高炎性疾病的机制，以了解和 更广泛地操纵SIRS生理。最终，我们预期建议的研究完成后，可提供 有助于指导早期发现高炎症性SIRS表型和新方法的具体见解 扰乱危及生命的免疫病理。

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.