Mechanisms of immune dysregulation in human PI3Kgamma deficiency

人类 PI3Kgamma 缺乏症免疫失调的机制

• 批准号: 10265763
• 负责人: Carrie L. Lucas
• 金额: $ 12.56万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-08-14 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10265763
• 关键词: Antibodies; Antibody Formation; Antibody Response; Asthma; Autoimmune; Autoimmune hemolytic anemia; Autoimmunity; BLR1 gene; Binding; Biochemical; Biology; CD3 Antigens; CD4 Positive T Lymphocytes; CXCL10 gene; CXCL9 gene; CXCR3 gene; Catalytic Domain; Cell Line; Cells; Chemotactic Factors; Clinical; Complex; Critical Pathways; Defect; Development; Disease; Equilibrium; Exhibits; Exposure to; G-Protein-Coupled Receptors; Genes; Genomic DNA; Goals; Housing; Human; Human Biology; Hypersensitivity; Immune; Immune System Diseases; Immune system; Immunocompetence; Immunologic Deficiency Syndromes; In Vitro; Individual; Infection; Infiltration; Inflammation; Inflammatory; Inherited; Interleukin-12; Investigation; Letters; Leukocytes; Light; Link; Loss of Heterozygosity; Lung; Lymphocyte; Maintenance; Modeling; Mononuclear; Mus; Mutation; Myeloid Cells; Nature; PASLI disease; PIK3CG gene; Pathologic; Pathway interactions; Patients; Pattern; Phagocytes; Phenotype; Phosphatidylinositols; Phosphotransferases; Physiological; Play; Process; Production; Proteins; Reporting; Resources; Role; Serum; Signal Pathway; Signal Transduction; Stimulus; Structure of germinal center of lymph node; Syndrome; T cell differentiation; T cell response; T-Cell Activation; T-Lymphocyte; Testing; Th1 Cells; Therapeutic; Tissues; Translational Research; Tumor-infiltrating immune cells; Work; cell behavior; chemokine; clinical phenotype; congenital immunodeficiency; cytokine; cytopenia; exome sequencing; forward genetics; gain of function; gain of function mutation; genetic manipulation; human disease; human model; hypogammaglobulinemia; immune health; immunoregulation; improved; in vivo; innovation; insight; interleukin-23; loss of function mutation; macrophage; monocyte; mouse model; next generation sequencing; novel; pathogen; pathogen exposure; patient response; peripheral blood; polarized cell; profiles in patients; public health relevance; response; translational model; unpublished works

Project Summary Primary immunodeficiency diseases (PIDs) have great potential to provide mechanistic insights into the molecules and pathways fundamentally important for maintenance of human immune health, and the unbiased nature of forward genetics makes these studies particularly exciting to pursue. The phosphoinositide 3-kinase (PI3K) signaling pathway plays important roles in many aspects of cell behavior within and outside the immune system. Both gain-of-function and loss-of-function mutations in the genes encoding the p110δ and p85α PI3K subunits have been identified in PID patients and have shed light on basic PI3K biology and underpinnings of inherited immunodeficiency. However, no mutations in the other PI3K genes have been described in inherited human disorders. We have now identified novel loss-of-function mutations in a new PI3K gene, PIK3CG, and our preliminary studies highlight its importance in immune competence and regulation of tissue inflammation in this disorder we have termed Inactivated PI3Kγ Syndrome (IPGS). Using primary human cells and cutting-edge `dirty' mouse modeling approaches that recapitulate human disease by combining genetic manipulation and natural pathogen exposure, two specific aims will be pursued. Aim 1) To define the roles for PI3Kγ in regulating T cell-intrinsic and -extrinsic signals that modulate T cell activation and differentiation. Aim 2) To dissect the mechanistic basis for antibody defects. The results of these investigations will provide significant insights into this novel PID and PI3K signaling in general and will lay the groundwork to improve physiologically relevant models for translational research in PIDs and other human disease contexts.

项目摘要 原发性免疫缺陷疾病（PIDS）具有提供机械见解的巨大潜力 分子和途径对于维持人类免疫健康至关重要，无偏见 远期遗传学的性质使这些研究特别令人兴奋。磷酸肌醇3-激酶 （PI3K）信号通路在免疫内外的细胞行为的许多方面都起着重要作用 系统。编码p110Δ和p85αpi3K的基因中的功能丧失和功能丧失突变 PID患者已经确定了亚基，并阐明了基本的PI3K生物学和基础 继承的免疫缺陷。但是，在遗传中尚未描述其他PI3K基因中的突变 人类疾病。现在，我们已经确定了新的PI3K基因，PIK3CG和 我们的初步研究强调了其在免疫能力和组织炎症调节中的重要性 我们称这种疾病已被灭活的PI3Kγ综合征（IPG）。使用原代人类细胞和尖端 “肮脏”小鼠建模方法通过结合基因操纵和 自然病原体暴露，将追求两个具体的目标。目标1）定义PI3Kγ调节的作用 调节T细胞激活和分化的T细胞中心和 - 超支信号。目标2）剖析 抗体缺陷的机械基础。这些调查的结果将为您提供重大见解 这个新颖的PID和PI3K信号通常会为改善物理相关的基础奠定基础 PID和其他人类疾病环境中翻译研究的模型。

项目成果

The role of PI3Kγ in the immune system: new insights and translational implications.

• DOI: 10.1038/s41577-022-00701-8
• 发表时间: 2022-11
• 期刊: Nature reviews. Immunology

Editorial: Human Disorders of PI3K Biology.

• DOI: 10.3389/fimmu.2020.617464
• 发表时间: 2020
• 期刊: Frontiers in immunology
• 影响因子: 7.3
• 作者: Lucas CL;Tangye SG
• 通讯作者: Tangye SG

Maximizing insights from monogenic immune disorders.

• DOI: 10.1016/j.coi.2021.09.008
• 发表时间: 2021-12
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: Barmada A;Ramaswamy A;Lucas CL
• 通讯作者: Lucas CL