Immune mechanisms regulating allergy

调节过敏的免疫机制

• 批准号: 10240308
• 负责人: Stephanie Caroline Eisenbarth
• 金额: $ 2.6万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2021-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10240308
• 关键词: Affinity; Allergens; Allergic; Allergic Reaction; Anaphylaxis; Antibodies; Antibody Response; Asthma; Automobile Driving; B-Lymphocyte Subsets; B-Lymphocytes; Cell Differentiation process; Cell physiology; Cells; Cytokine Receptors; Cytokinesis; Development; Disease; Dissociation; Environmental Risk Factor; Experimental Models; GATA3 gene; Genetic; Goals; Helper-Inducer T-Lymphocyte; Human; Hypersensitivity; IL4 gene; IgE; IgG1; Immune; Immune response; Immunization; Immunize; Immunoglobulin Class Switching; Immunoglobulin M; Immunologics; Interleukin-13; Interleukin-4; Interleukin-5; Knockout Mice; Knowledge; Life; Longevity; Mediating; Modeling; Molecular; Mus; Pathologic; Pathway interactions; Phenotype; Production; Role; STAT3 gene; Signal Transduction; Stimulus; System; T-Lymphocyte; T-Lymphocyte Subsets; Testing; Wild Type Mouse; Work; airborne allergen; base; chemokine receptor; conditional knockout; crosslink; cytokine; experimental study; helminth infection; in vivo; man; mast cell; mouse model; prevent; receptor expression; response; tool; transcription factor

Cross-linking of high affinity IgE on mast cells results in one of the most life-threatening allergic reactions, anaphylaxis. Yet the cellular mechanisms that induce B cells to produce IgE to allergens remain poorly understood. T follicular helper (Tfh) cells are the primary T cell subset responsible for directing the affinity, longevity and isotype of antibody produced by B cells. Subsets of Tfh cells exist in both mouse and man, defined by their differential cytokine and chemokine receptor expression. Tfh2 cells are primarily identified by IL-4 expression during a type 2 immune response and can promote IgE. Whether Tfh2 cells are required for both low and high affinity IgE is not know. By studying a murine model of a rare monogenic form of IgE- mediated allergy, DOCK8 (dedicator of cytokinesis 8) deficiency, we recently discovered a new subset of Tfh2 cells that promotes high affinity IgE in vivo. We call this new subset “TfhE” cells and identify them by the expression of a constellation of cytokine and transcription factors not normally produced by Tfh cells. Further, the same subset is induced in wild type mice, but only during aeroallergen-driven responses when high affinity IgE is produced. In contrast, TfhE cells are not induced during low affinity IgE responses. We do not know how the development of TfhE cells is regulated or how they function to induce IgE. Although IL-4 is necessary for IgE class switching, it is not sufficient in vivo. Further, the dissociation between low and high affinity production during different type 2 immune responses suggests that direct versus sequential B cell switching to IgE might be regulated by different Tfh2 subsets. The goal of our proposed experiments is to fill these crucial gaps in knowledge and thereby illuminate the pathways that drive production of high affinity IgE and the attendant anaphylactic allergic reactions. The broad impact of these advances could be substantial, enabling definition of the genetic and environmental factors that dictate high affinity IgE responses in those with asthma and other allergic conditions. We have developed tools including Tfh-restricted knockout mice to determine 1) whether DOCK8 regulates Tfh differentiation in a cell-intrinsic manner and functions similarly in human Tfh cells; 2) whether high and low affinity IgE are driven by different Tfh cell subsets in wild type mice; 3) molecular mechanisms controlling wild type TfhE development and function, including the identity of factors that, together with IL4, are produced by TfhE cells to drive IgE class switching and transcription factor(s) that dictate TfhE differentiation. If successful, these experiments will define how TfhE cells specifically promote high affinity IgE and will define molecular pathways that regulate TfhE induction. Inhibition of key pathways operational in these TfhE cells could be used to promote allergen-specific antibody isotypes that potentially block anaphylaxis. 1

肥大细胞上高亲和力IgE的交联导致最危及生命的过敏反应之一， 过敏反应然而，诱导B细胞产生针对过敏原的IgE的细胞机制仍然很差 明白T滤泡辅助（Tfh）细胞是负责指导亲和力的主要T细胞亚群， B细胞产生的抗体的寿命和同种型。Tfh细胞的亚群存在于小鼠和人中， 由它们的差异细胞因子和趋化因子受体表达来定义。Tfh 2细胞主要通过以下方法鉴定： IL-4在2型免疫应答期间表达，并可促进IgE。是否需要Tfh 2细胞 低亲和力和高亲和力IgE都是未知的。通过研究一种罕见的IgE单基因形式的小鼠模型， 介导的变态反应，DOCK 8（胞质分裂奉献者8）缺陷，我们最近发现了一个新的Tfh 2亚群 在体内促进高亲和力IgE的细胞。我们将这种新的亚群称为“TfhE”细胞，并通过 表达一系列通常不由Tfh细胞产生的细胞因子和转录因子。此外，本发明还 在野生型小鼠中诱导了相同的亚群，但仅在当高亲和力 IgE的产生。相反，TfhE细胞在低亲和力IgE应答期间不被诱导。我们不知道如何 TfhE细胞的发育受到调节或它们如何起作用以诱导IgE。虽然IL-4是必需的， IgE类转换，它是不够的，在体内。此外，低亲和力和高亲和力生产之间的解离 在不同的2型免疫反应中，直接与顺序的B细胞转换为IgE可能 由不同的Tfh 2亚群调控。我们提出的实验的目标是填补这些关键的空白， 知识，从而阐明了驱动高亲和力IgE和伴随物产生的途径 过敏性过敏反应这些进展的广泛影响可能是实质性的， 遗传和环境因素决定了哮喘和其他疾病患者的高亲和力IgE反应， 过敏状况。我们已经开发了包括Tfh限制性敲除小鼠在内的工具来确定1）是否 DOCK 8以细胞内在方式调节Tfh分化，并且在人Tfh细胞中具有类似的功能; 2） 高和低亲和力IgE是否由野生型小鼠中的不同Tfh细胞亚群驱动; 3）分子水平 控制野生型TfhE发育和功能的机制，包括共同 与IL 4一起，由TfhE细胞产生，以驱动IgE类别转换和决定TfhE的转录因子 分化如果成功，这些实验将定义TfhE细胞如何特异性促进高亲和力IgE 并将定义调节TfhE诱导的分子途径。抑制关键途径的运作，在这些 TfhE细胞可用于促进可能阻断过敏反应的过敏原特异性抗体同种型。 1