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: 8296171
• 负责人: ANDREA CERUTTI
• 金额: $ 41.53万
• 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/8296171
• 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; 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）：RFA为U01规定了此申请，这将使我们能够与其他杰出的粘膜免疫学家协同作用，并合作地揭示并利用IGD的被忽视的粘膜保护功能，这是一种进化保守的抗体，是一种进化保守的抗体类别。人上呼吸道粘膜包含大量产生IgD的B细胞，这些细胞释放IgD到鼻，lachrymal，唾液，乳腺和支气管分泌物中。在过去的50年中，IGD的大量临床和免疫学观察强烈表明，IGD在呼吸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在呼吸免疫中的机制和功能，以开发疫苗，以利用IgD的功能来对抗呼吸道感染和治疗与IGD超生产相关的免疫病毒的疗法。这项研究假设来自上呼吸道粘膜的B细胞经历IgD的产生和由维生素D3控制的多样化，并且IGD对呼吸道病原体产生了反应，并通过与Heparin，Eososinophil obymomparmicatiant and obyramicatians and earlameant和proveram蛋白蛋白质蛋白质蛋白质和肥胖细胞相互作用来激活局部和全身的先天性免疫细胞，从而有助于粘膜免疫。提出了三个目标。目标1：阐明呼吸粘膜中IGD类转换和产生的调节。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。这项研究将利用健康供体和Hyper-LGD综合征患者的细胞和组织，一种自身炎症性周期性发烧综合征，作为疾病模型。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生化，分子和细胞生物学技术研究。通过单个B细胞分选，克隆和表达，高通量的下一代测序以及基于体外细胞培养的方法，将通过粘膜和全身IgD反应的反应性和保护功能和疫苗接种后的全身IgD反应。 相关性：该项目将在疫苗接种后建立有关IGD反应的临床相关信息，并导致隔离保护性IGD克隆，这些克隆可以在临床上用于抵抗呼吸道感染。它还将支持使用维生素D修饰方案在治疗免疫病理学中的使用，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。