Mechanisms of immune dysregulation in human PI3Kgamma deficiency

项目摘要 感染易感性和/或免疫介导的年轻患者中的许多严重免疫性疾病 组织损伤是由单基因缺陷导致的先天免疫错误引起的。我们有很长一段时间- 对儿童严重免疫疾病的深入调查保持兴趣。我们的做法是追求 严格的遗传学和免疫学研究，定义了基因、细胞类型和潜在的病理途径 直接从患者那里收集与临床相关的对基础人类生物学的见解。目前，基因， 罕见严重SARS-CoV2相关病例的易感性和发病机制的分子、细胞和细胞驱动因素 疾病发生在年轻人身上，否则健康的个体是未知的。定义这些驱动因素不仅可以解决 受最近激增的多系统炎症性疾病困扰的儿童和青少年的迫切健康需求 与SARS-CoV2感染相关的儿童综合征(MIS-C)和严重呼吸道症状，但 还将提供有关免疫病理机制的基本知识，这些机制是 新冠肺炎涵盖了各个年龄段。我们已经建立了越来越多的年轻新冠肺炎患者并将其存入银行 从唾液和外周血液样本中提取DNA、细胞和血清，使我们能够应对这一紧急危机。我们的 初步数据表明，获取合适的样本用于白细胞多维分析是可行的 并提出了关于MISC的启动和触发事件的可检验假设。vbl.使用 在原代人体细胞和尖端技术方面，将追求两个具体目标。目标1)定义基因 其他方面健康的年轻受试者对严重新冠肺炎的易感性。目的2)阐明免疫 调节这些儿童和青少年严重炎症反应的机制。这些研究的结果 调查将为新冠肺炎的遗传学和炎症提供重要的见解，并将为 帮助推进我们对这一世界性大流行的理解和治疗战略的基础工作。

Project Summary Many severe immune diseases in young patients with infection susceptibility and/or immune-mediated tissue damage are caused by a single-gene defect resulting in an inborn error of immunity. We have a long- standing interest in intensive investigation of severe immune diseases of childhood. Our approach is to pursue rigorous genetic and immunologic studies that define the genes, cell types, and pathways underlying pathology to glean clinically relevant insights into fundamental human biology directly from patients. Currently, the genetic, molecular, and cellular drivers of susceptibility and pathogenesis in rare cases of severe SARS-CoV2-related disease in young, otherwise healthy individuals are unknown. Defining these drivers will not only address the urgent health needs of children and teenagers afflicted with the recently surging ‘multisystem inflammatory syndrome in children’ (MIS-C) and severe respiratory manifestations associated with SARS-CoV2 infection but will also provide fundamental knowledge about immunopathology mechanisms that are a general feature of COVID-19 across the age spectrum. We have built an growing cohort of young COVID-19 patients and banked DNA, cells, and serum from saliva and peripheral blood samples to enable us to tackle this urgent crisis. Our preliminary data demonstrate feasibility to obtain suitable samples for multi-dimensional analysis of leukocytes from these patients and also raise testable hypotheses about the initiating and triggering events in MIS-C. Using primary human cells and cutting-edge technologies, two specific aims will be pursued. Aim 1) To define genetic susceptibility to severe COVID-19 in young, otherwise healthy subjects. Aim 2) To elucidate immune mechanisms mediating severe inflammatory responses in these children and teenagers. The results of these investigations will provide significant insights into COVID-19 genetics and inflammation and will lay the groundwork to help advance our understanding and treatment strategies for this world-wide pandemic.