Immune mechanisms regulating allergy

肥大细胞上高亲和力的IgE的交联会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 明白了。T滤泡辅助细胞(TFH)是主要的T细胞亚群，负责引导亲和力， B细胞产生的抗体的长寿和同型。在小鼠和人中都存在TFH细胞亚群， 由它们不同的细胞因子和趋化因子受体的表达来定义。Tfh2细胞主要由 IL-4在2型免疫反应中的表达，并能促进IgE。Tfh2细胞是否需要用于 目前尚不清楚低亲和力和高亲和力的IgE。通过研究一种罕见的单基因形式的IgE- 介导性变态反应，DOCK8(细胞质分裂贡献者8)缺乏，我们最近发现了一个新的Tfh2亚群 体内促进高亲和力IgE的细胞。我们将这个新的子集称为“TfhE”细胞，并通过 一系列细胞因子和转录因子的表达，通常不是由TFH细胞产生的。此外， 同样的亚群在野生型小鼠中被诱导，但仅在高亲和力时空气变应原驱动的反应中诱导 产生了IGE。相反，TfhE细胞在低亲和力IgE反应中不被诱导。我们不知道如何 TfhE细胞的发育受到调控，或者它们如何发挥诱导IgE的功能。尽管IL-4是必要的 IGE类切换，在活体内是不够的。此外，低亲和力产物和高亲和力产物之间的解离 在不同的2型免疫反应期间提示，直接与顺序B细胞向IgE的转换可能 受不同的Tfh2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及其伴随物产生的途径 过敏性过敏反应。这些进步的广泛影响可能是巨大的，使得能够定义 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 过敏症。我们已经开发了包括Tfh限制性基因敲除小鼠在内的工具来确定1) DOCK8以细胞固有的方式调节Tfh的分化，并且在人Tfh细胞中的功能类似；2) 野生型小鼠高、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同一性 与IL4一起，由TfhE细胞产生，以驱动Ig E类转换和决定TfhE的转录因子(S) 差异化。如果成功，这些实验将确定TfhE细胞如何特异性地促进高亲和力IgE 并将定义调节TfhE诱导的分子途径。抑制在这些区域中运行的关键通路 TfhE细胞可用于促进可能阻止过敏反应的过敏原特异性抗体同型。 1

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