Mechanistic elucidation of pathogenic CBM complex mutations associated with atopic disease

与特应性疾病相关的致病性 CBM 复合体突变的机制阐明

• 批准号: 10737122
• 负责人: Joshua D. Milner
• 金额: $ 71.47万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-07-05 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10737122
• 关键词: Affect; Allergic; Allergic Disease; Antigen Receptors; Asthma; Atopic Dermatitis; Attenuated; Automobile Driving; B-Lymphocytes; BCL10 gene; Biochemical; Biochemical Pathway; Cell Line; Cell Signaling Process; Cell physiology; Cell surface; Cells; Child; Chronic; Code; Collection; Communication; Complex; Coupled; Data; Defect; Developed Countries; Development; Diagnosis; Diagnostic; Disease; Dominant-Negative Mutation; Eczema; Effector Cell; Essential amino acids supplementation; Food Hypersensitivity; Gene Mutation; Genes; Genetic; Genetic Predisposition to Disease; Glean; Glutamine; Heterozygote; Human; Hypersensitivity; IgE; Immune; Immune System Diseases; Immune response; Immunology; Impairment; In Vitro; Individual; Infectious Skin Diseases; Inflammatory; Interferon Type II; Interleukin-13; Interleukin-4; Intervention; Investigation; Knowledge; Lesion; Leukocytes; Ligation; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoma; MAPK8 gene; Maintenance; Metabolic Pathway; Molecular; Molecular Abnormality; Mucosa- associated lymphoid tissue lymphoma translocation protein-1; Mus; Mutant Strains Mice; Mutation; National Institute of Allergy and Infectious Disease; Pathogenesis; Pathogenicity; Pathology; Pathway interactions; Patients; Phenotype; Play; Population; Predisposition; Prevalence; Prevention; Process; Production; Proliferating; Proteins; Receptor Signaling; Recording of previous events; Research; Resources; Respiratory Tract Infections; Role; STAT3 gene; STAT5B gene; Severe Combined Immunodeficiency; Signal Pathway; Signal Transduction; Signaling Protein; Skin; Structure; Supplementation; System; T cell differentiation; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Transfection; Transplantation; Validation; Variant; Work; adaptive immune response; allergic response; atopy; clinical phenotype; cohort; cytokine; gain of function mutation; genetic analysis; genome wide association study; in vivo; innovation; insight; interest; new therapeutic target; novel; null mutation; scaffold; skin barrier; tool; treatment strategy; uptake

PROJECT ABSTRACT The study of primary atopic disorders (PADs) has provided important and surprising knowledge about specific genes that control the function of white blood cells involved in driving allergic responses. Over the last several years, our groups have played a leading role in the discovery and characterization of human immune disorders linked to mutations in CARD11, which encodes a critical signaling protein in lymphocytes. CARD11 partners with two other proteins (BCL10 and MALT1) to form the “CBM complex”, which communicates key signals that dictate lymphocyte activation, differentiation and function. Most recently, we described numerous patients with severe eczema, asthma/food allergies, and skin/respiratory infections that carried debilitating CARD11 mutations that disrupt normal CBM function. These variants attenuate CBM signaling in patient lymphocytes and cause them to differentiate abnormally into effector cells associated with allergy/atopy. The long-term objective of this project is to precisely define which cell signaling processes are disrupted by mutations in CBM complex genes, and elucidate how these defects adversely affect B and T cell function to ultimately manifest as in atopy, including assessment of glutamine as a potential treatment strategy. We will also define the broader scope and burden of pathogenic CBM complex mutations that influence atopic predisposition in both rare PADs and common cohorts of allergy disease patients. Built upon an extensive panel of atopy-associated, damaging mutations spanning the CARD11 gene, and extending to other CBM gene mutations identified from allergic patient cohorts, our studies will better define how these mutations disrupt normal CBM-dependent signaling pathways in lymphocytes. Using well- established cell transfection systems AND primary murine and patient cells, we will elucidate the molecular and cellular mechanisms through which impaired CARD11 signaling drives the preferential production of allergy- associated cytokines and IgE. Based on compelling preliminary data, our analyses will pinpoint specific biochemical and metabolic pathways that are disrupted by defective CARD11 signaling directly in primary cells from affected patients, an invaluable resource that we have unique access to. Defining these molecular abnormalities will enhance our understanding of disease pathogenesis and illuminate mechanisms by which simple interventions, such as supplementation with the essential amino acid glutamine, can restore the proper function of T and B cells harboring CBM mutations. Our innovative approach has the potential to significantly revise our understanding of how the CBM complex regulates adaptive immune responses. Insights gleaned from a more thorough investigation of CBM gene mutations, derived from both rare and common allergy patient cohorts, will better define their contribution to atopic susceptibility and inform new targeted therapeutic approaches for treating a broader spectrum of patients suffering from allergic disease.

项目摘要 原发性特应性疾病 (PAD) 的研究提供了重要且令人惊讶的知识 控制白细胞功能的特定基因参与驱动过敏反应。 多年来，我们的团队在人类免疫的发现和表征方面发挥了主导作用 与 CARD11 突变相关的疾病，CARD11 编码淋巴细胞中的关键信号蛋白。 与其他两种蛋白质（BCL10 和 MALT1）合作形成“CBM 复合物”，该复合物传达关键信息 最近，我们描述了许多决定淋巴细胞激活、分化和功能的信号。 患有严重湿疹、哮喘/食物过敏以及导致衰弱的皮肤/呼吸道感染的患者 CARD11 突变会破坏正常的 CBM 功能，这些变异会减弱患者的 CBM 信号传导。 淋巴细胞并导致它们异常分化为与过敏/特应性相关的效应细胞。 该项目的长期目标是精确定义哪些细胞信号传导过程被破坏 通过 CBM 复杂基因的突变，并阐明这些缺陷如何对 B 和 T 细胞产生不利影响 最终表现为特应性的功能，包括评估谷氨酰胺作为潜在治疗方法 我们还将定义致病性 CBM 复合体突变的更广泛范围和负担。 影响罕见 PAD 和常见过敏性疾病患者的特应性倾向。 基于涵盖 CARD11 基因的一系列与特应性相关的破坏性突变， 并扩展到从过敏患者群体中发现的其他 CBM 基因突变，我们的研究将更好 定义这些突变如何破坏淋巴细胞中正常的 CBM 依赖性信号通路。 建立细胞转染系统以及原代小鼠和患者细胞，我们将阐明分子和 受损的 CARD11 信号传导驱动优先产生过敏的细胞机制 基于令人信服的初步数据，我们的分析将确定具体的细胞因子和 IgE。 原代细胞中的 CARD11 信号缺陷直接破坏生化和代谢途径 来自受影响患者的信息，这是我们可以独特获取的宝贵资源。 异常将增强我们对疾病发病机制的理解并阐明疾病的机制 简单的干预措施，例如补充必需氨基酸谷氨酰胺，可以恢复正常的功能 我们的创新方法有可能显着改善携带 CBM 突变的 T 细胞和 B 细胞的功能。 修改我们对 CBM 复合物如何调节适应性免疫反应的理解。 来自对源自罕见和常见过敏的 CBM 基因突变的更彻底研究 患者群体将更好地确定他们对特应性易感性的贡献，并为新的靶向治疗提供信息 治疗更广泛的过敏性疾病患者的方法。

项目成果

ERBIN and phosphoglucomutase 3 deficiency.

ERBIN 和磷酸葡萄糖变位酶 3 缺乏症。

• DOI: 10.1016/j.coi.2023.102353
• 发表时间: 2023-06-25
• 期刊: Current opinion in immunology
• 影响因子: 7
• 作者: J. Milner