Immunological and Microbial Mechanisms in Food Allergy

摘要 不断恶化的食物过敏疫情被归因于环境因素的汇合 现代生活方式的一部分，包括改变肠道微生物区系，作用于遗传易感个体。中环 食物过敏的发展是口服耐受性的崩溃，通常是由食物过敏原- 特异性T调节(TR)细胞。然而，口服耐受性崩溃的机制是 默默无闻。通过使用一种创新的人类食物过敏小鼠模型，涉及到功能突变的获得 在IL-4受体α链免疫酪氨酸抑制基序(Il4raF709)中，我们已经证明了食物 过敏与过敏原特异性诱导的TR(ITR)细胞的形成减少有关。这些ITR细胞是 产生的是功能障碍，无法防止敏感化或抑制活动性疾病。这一失败是 与它们重新编程为表达IL-4的Th2细胞样受体细胞有关，GATA3和GATA3水平升高 Tgfb1转录本减少。我们还观察到变应原特异的tr细胞中的Th2细胞样重编程。 人类食物过敏受试者。食物过敏性Il4raF709小鼠表现出先天淋巴样细胞调节失调 2型(ILC2s)，通过分泌IL-4在疾病的发病机制中发挥必要的作用。他们还展示了 致病的非生物共生菌群，当它们促进食物过敏时就是证据 转移到无菌(GF)小鼠体内。反过来，耐受食物的小鼠的菌群可以防止疾病的诱发 移植到GF-Il4raF709小鼠体内。用最小梭状芽胞杆菌或类杆菌联合保护治疗 对抗食物过敏。因此，在目标1中，我们提出Th2细胞样受体细胞在疾病中起关键作用。 通过指导IgE的产生和肥大细胞的扩张，以及抑制 Th2细胞样的tr细胞通过tr细胞特异性的IL4/IL13缺失来编程，挽救已建立的疾病。我们还将 检测TR细胞中Tgfb1表达的改变在TR细胞小鼠疾病发病机制中的作用 特异性Tgfb1缺失或转基因表达。在目标2中，我们将检验这样的假设：IL-4通过 ILC2通过抑制ITR细胞的形成和诱导Th2细胞样细胞在疾病发病机制中发挥重要作用 并通过依赖IL-33机制来调节ILC。最后，在 目的3，我们假设最小的一组梭状芽胞杆菌和拟杆菌可以拯救活动性疾病， 抑制生物失调和恢复共生，部分是通过在TR细胞中通过MyD88信号传递，这将 促进ITR细胞的形成，并将肠道免疫球蛋白的产生从IgE重定向到IgA。 我们建议的研究将确定口服的基本免疫学和微生物机制 耐受性在食物过敏中被颠覆，并将使治疗方法的发展成为可能。

ABSTRACT The worsening epidemic of food allergy has been attributed to a confluence of environmental factors reflective of a modern life style, including altered gut microbiota, acting upon genetically susceptible individuals. Central to the development of food allergy is the breakdown of oral tolerance, normally enforced by food allergen- specific T regulatory (TR) cells. However, the mechanisms involved in the breakdown of oral tolerance are obscure. By employing an innovative murine model of human food allergy involving a gain of function mutation in the IL-4 receptor alpha chain immunotyrosine inhibitory motif (Il4raF709), we have demonstrated that food allergy is associated with reduced formation of allergen-specific induced TR (iTR) cells. Those iTR cells that are generated are dysfunctional and fail to prevent sensitization or to suppress active disease. This failure is related to their reprogramming into Th2-cell like TR cells that express IL-4, elevated levels of GATA3 and decreased Tgfb1 transcripts. We have also observed Th2 cell-like reprogramming in allergen-specific TR cells of human food allergic subjects. Food allergic Il4raF709 mice manifest dysregulation of innate lymphoid cells type 2 (ILC2s), which play a requisite role in disease pathogenesis by secreting IL-4. They also exhibit dysbiotic commensal flora that are pathogenic, as evidenced by their promotion of food allergy when transferred into germ-free (GF) mice. Reciprocally, flora of food tolerant mice prevented disease induction when transplanted into GF Il4raF709 mice. Therapy with minimal Clostridia or Bacteroidetes consortia protect against food allergy. Accordingly, in Aim 1, we propose that Th2 cell-like TR cells play a critical role in disease pathogenesis and persistence by directing IgE production and mast cell expansion, and that suppression of the Th2 cell-like TR cell program by TR cell-specific Il4/Il13 deletion rescues established disease. We will also examine the contribution of altered Tgfb1 expression in TR cells to disease pathogenesis in mice with TR cell- specific Tgfb1 deletion or transgene expression. In Aim 2, We will test the hypothesis that IL-4 production by ILC2 plays a crucial role in disease pathogenesis by suppressing iTR cell formation and inducing Th2 cell-like reprogramming of TR cells, and that TR cells in turn regulate ILC by IL-33-dependent mechanisms. Finally, in Aim 3, we hypothesize that a minimal set of Clostridia and Bacteroidetes consortia rescues active disease, suppresses dysbiosis and restores commensalism in part by signaling via MyD88 in TR cells, which would promote iTR cell formation and redirect intestinal immunoglobulin production away from IgE and towards IgA. Our proposed studies will identify fundamental immunological and microbial mechanisms by which oral tolerance is subverted in food allergy, and will enable the development of curative therapies.