Regulation and Function of Immunoglobulin D in Mucosal Immune Defense

免疫球蛋白 D 在粘膜免疫防御中的调节和功能

• 批准号: 8180217
• 负责人: ANDREA CERUTTI
• 金额: $ 42.38万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-15 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8180217
• 关键词: Amphibia; Antibodies; Antigen-Presenting Cells; Antigens; B-Cell Activation; B-Lymphocytes; Basophils; Binding; Biochemical; Blood Circulation; Bronchial Secretion; CD40 Ligand; Cell Culture Techniques; Cell Separation; Cells; Cholecalciferol; Cholesterol; Clinical; Cytoplasmic Granules; Disease; Disease model; Distant; Enzymes; Eosinophil cationic protein; Epithelial; Epithelial Cells; Evolution; Exclusion; Exposure to; Family; Fever; Fishes; Heparin; Home environment; Homeostasis; Human; IgA Deficiency; IgE; Immune; Immune response; Immune system; Immunity; Immunocompromised Host; Immunoglobulin A; Immunoglobulin Class Switching; Immunoglobulin D; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Recombination; Immunologist; In Vitro; Infection; Inflammation; Influenza; Interleukin-15; Interleukin-2; Intestines; Jaw; Knowledge; Lead; Ligands; Mammary gland; Mechanical Ventilators; Mediating; Methods; Mevalonate kinase; Molecular and Cellular Biology; Mucosal Immunity; Mucous Membrane; Nose; Pathway interactions; Patients; Phagocytosis; Principal Investigator; Production; Proteolytic Processing; Recurrence; Regimen; Regulation; Research; Respiratory Mucosa; Respiratory Therapy; Respiratory Tract Infections; Salivary; Signal Transduction; Site; Structure; Syndrome; T cell response; Techniques; Time; Tissues; Tropism; Tumor Necrosis Factor-alpha; Vaccinated; Vaccination; Vaccines; Vertebrates; Vitamin D; antimicrobial; arm; base; clinically relevant; combat; expression cloning; immune activation; immunopathology; indium arsenide; influenzavirus; killings; mast cell; mucosal site; neglect; next generation; pathogen; pathogen exposure; programs; receptor; respiratory; response; transcytosis; vaccination strategy

DESCRIPTION (provided by applicant): This application is mandated by the RFA for U01, which will allow us to synergize with other outstanding mucosal immunologists and cooperatively uncover and harness the neglected mucosal protective functions of IgD, an evolutionarily conserved yet mysterious class of antibody. Human upper respiratory mucosa contains abundant IgD-producing B cells that release IgD into nasal, lachrymal, salivary, mammary and bronchial secretions. Numerous clinical and immunological observations of IgD in the past 50 years strongly suggest that IgD has important functions in respiratory mucosal immune defense. The broad, long-term objectives of this project are to elucidate the regulation of IgD production as well as the mechanism and function of IgD in respiratory immunity in order to develop vaccines that harness the functions of IgD to combat respiratory infections and therapies to treat immunopathologies associated with IgD hyperproduction. This study hypothesizes that B cells from upper respiratory mucosa undergo IgD production and diversification controlled by vitamin D3 and that IgD produced reacts against respiratory pathogens and contributes to mucosal immunity by activating local and systemic innate immune cells such as basophils and mast cells through interaction with heparin, eosinophil cationic protein and inflammasomes. Three aims are proposed. Aim 1: To elucidate the regulation of IgD class switching and production in the respiratory mucosa. Aim 2: To determine the reactivity, clonal diversity, evolution and protective function of mucosal IgD. Aim 3: To dissect the mechanisms by which IgD activates mucosal and systemic immune responses. This study will take advantage of cells and tissues from healthy donors and patients with hyper-lgD syndrome, an autoinflammatory periodic fever syndrome, as a disease model. The regulation of IgD production by vitamin D3 and the mechanism by which IgD triggers immune activation will be investigated by biochemical, molecular and cellular biology techniques. The reactivity and protective functions of mucosal and systemic IgD responses upon respiratory pathogen exposure and after vaccination will by studied by single B cell sorting, cloning and expression, high-throughput next-generation sequencing and in vitro cell culture-based methods. RELEVANCE: This project will establish clinically relevant information on IgD responses after vaccination and lead to the isolation of protective IgD clones that may be used clinically to combat respiratory infections. It will also support the use of vitamin D modifying regimens in treating immunopathologies and establish that more effective vaccination strategies against respiratory pathogens should actively boost IgD responses.

描述（由申请人提供）：本申请是 RFA 对 U01 的授权，这将使我们能够与其他杰出的粘膜免疫学家协同合作，共同发现和利用 IgD（一种进化上保守但神秘的一类抗体）被忽视的粘膜保护功能。人类上呼吸道粘膜含有丰富的产生 IgD 的 B 细胞，可将 IgD 释放到鼻腔、泪液、唾液、乳腺和支气管分泌物中。过去50年对IgD的大量临床和免疫学观察强烈表明IgD在呼吸道粘膜免疫防御中具有重要功能。该项目的广泛、长期目标是阐明 IgD 产生的调节以及 IgD 在呼吸道免疫中的机制和功能，以便开发利用 IgD 功能对抗呼吸道感染的疫苗和治疗与 IgD 过度产生相关的免疫病理学的疗法。这项研究假设，上呼吸道粘膜的 B 细胞在维生素 D3 的控制下进行 IgD 产生和多样化，产生的 IgD 会与呼吸道病原体发生反应，并通过与肝素、嗜酸性粒细胞阳离子蛋白和炎性小体相互作用，激活局部和全身先天免疫细胞（如嗜碱性粒细胞和肥大细胞），从而促进粘膜免疫。提出了三个目标。目标 1：阐明呼吸道粘膜 IgD 类别转换和产生的调节。目标 2：确定粘膜 IgD 的反应性、克隆多样性、进化和保护功能。目标 3：剖析 IgD 激活粘膜和全身免疫反应的机制。这项研究将利用来自健康捐献者和高lgD综合征（一种自身炎症周期性发热综合征）患者的细胞和组织作为疾病模型。将通过生化、分子和细胞生物学技术研究维生素 D3 对 IgD 产生的调节以及 IgD 触发免疫激活的机制。将通过单 B 细胞分选、克隆和表达、高通量下一代测序和基于体外细胞培养的方法来研究呼吸道病原体暴露和疫苗接种后粘膜和全身 IgD 反应的反应性和保护功能。 相关性：该项目将建立有关疫苗接种后 IgD 反应的临床相关信息，并分离出可在临床上用于对抗呼吸道感染的保护性 IgD 克隆。它还将支持使用维生素 D 修饰方案来治疗免疫病理学，并确定针对呼吸道病原体的更有效的疫苗接种策略应积极增强 IgD 反应。