Immune mechanisms regulating allergy

调节过敏的免疫机制

基本信息

批准号：
10548673
负责人：
Stephanie Caroline Eisenbarth
金额：
$ 60.4万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-17 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10548673
关键词：
Immune mechanisms regulating allergy

项目摘要

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 的交联会导致最危及生命的过敏反应之一，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。据了解，滤泡辅助 T (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存在于小鼠和人类中， Tfh2 细胞主要通过细胞因子和趋化因子受体表达的差异来定义。 IL-4 在 2 型免疫反应期间表达并可促进 IgE 是否需要 Tfh2 细胞。通过研究一种罕见的单基因形式的 IgE- 的小鼠模型，低亲和力和高亲和力 IgE 都是未知的。介导的过敏、DOCK8（胞质分裂 8 的贡献者）缺陷，我们最近发现了 Tfh2 的一个新子集我们将这种新的细胞亚群称为“TfhE”细胞，并通过 Tfh 细胞通常不产生的一系列细胞因子和转录因子的表达。在野生型小鼠中诱导相同的子集，但仅在高亲和力时的气源过敏原驱动的反应期间相反，TfhE 细胞在低亲和力 IgE 反应期间不会被诱导。 TfhE 细胞的发育受到调节或它们如何发挥诱导 IgE 的作用，尽管 IL-4 对于 TfhE 细胞的发育是必需的。 IgE 类别转换，在体内还不够，低亲和力和高亲和力产生之间的解离。在不同的 2 型免疫反应期间，表明直接与顺序 B 细胞转换为 IgE 可能我们提出的实验的目标是填补这些关键的空白。知识，从而阐明驱动高亲和力 IgE 产生的途径以及随之而来的这些进步的广泛影响可能是巨大的，从而可以定义过敏性反应。决定哮喘和其他疾病患者高亲和力 IgE 反应的遗传和环境因素我们开发了包括 Tfh 限制性基因敲除小鼠在内的工具来确定 1) 是否存在。 DOCK8 以细胞固有的方式调节 Tfh 分化，并且在人类 Tfh 细胞中具有类似的功能 2) 野生型小鼠中高亲和力和低亲和力 IgE 是否由不同的 Tfh 细胞亚群驱动；3) 分子；控制野生型 TfhE 发育和功能的机制，包括共同作用的因素的身份与 IL4 一起，由 TfhE 细胞产生，驱动 IgE 类别转换和决定 TfhE 的转录因子如果成功，这些实验将确定 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，抑制这些关键途径的运作。 TfhE 细胞可用于促进过敏原特异性抗体同种型的产生，从而可能阻止过敏反应。 1