Immunological and Microbial Mechanisms in Food Allergy

摘要 食物过敏(FA)的高流行率使许多人对食物有严重反应的风险，包括过敏反应 (1)。我们对患有FA的人类受试者和相关小鼠模型的研究发现， T(Treg)细胞群在疾病发病机制中起着关键作用。具体地说，我们确定了一个 肠道共生菌诱导的RORgT+Treg细胞在调节食物耐受性中的关键作用 过敏原(2，3)。相反，FA与RORgt+Treg的微生物区系依赖的分化缺陷有关 由于生物失调而产生的细胞。我们鉴定了抵抗素样β分子(remβ)，这是一种肠道杯状细胞细胞因子。 与对寄生虫感染的先天免疫反应有关(4-6)，作为FA发病的关键，通过促进 生物失调和扰乱RORgT+Treg细胞分化。反过来，在FA食物中出现特定的过敏原 Treg细胞具有T辅助细胞型(Th2)细胞样表型，具有高表达的转录因子 GATA3和Th2细胞因子IL-4(7，8)。这些重新编程的Treg细胞在扩增 疾病病理，在接受口服免疫治疗的患者中它们下降(7，8)。我们最近对 FA患者循环Treg细胞鉴定胸腺基质淋巴生成素受体(TSLPR)是一种 它们Th2细胞样重编程的标志。因此，这项提案的重点是确定免疫 管理FA的监管检查点以及重置检查点以促进口服耐受性的方法。我们的整体 假设FA的进化需要两个关键的检查点，每个检查点都涉及不同的Treg细胞群 在专门的先天细胞和细胞因子回路的控制下。第一个涉及依赖微生物区系的太阳神- RORgT+Treg细胞在围断乳期产生，此后加强口服耐受。这条线路 由上游簇状细胞(IL-25)-ILC2(IL-13)轴(9-11)诱导的RELMb负调控 通过促进生物失调而易患FA。第二种涉及Helios+TSLPR+Th2细胞样Treg细胞，它们是 受IgE/肥大细胞正向调节，增强FA反应。为了探索这一假设，我们将 在目标1下，检查FA Il4raF709小鼠在治疗后促耐受免疫反应的演变 带有抗RELMb单抗或RELMb基因Retnlb的急性缺失。我们还将阐明这些机制。 通过RELMb拮抗剂重置肠道微生物区系以加强口服耐受性，包括扩大 乳酸菌富含吲哚代谢物，可通过芳烃受体(AhR)抑制FA 通过诱导RORgT+Treg细胞。在目标2下，我们将剖析TSLPR在Th2细胞样重编程中的作用 Treg细胞在疾病发病机制中的作用这些发现将扩展到目标3下关于FA主题的研究 将血清RELMb和Treg细胞群的变化与生物失调和疾病严重程度联系起来。建议数 研究将提供与疾病发病机制相关的基本新见解和新的治疗方法 在FA中重建口服耐受的方法。

ABSTRACT The high prevalence of food allergy (FA) places many at risk of severe reactions to foods including anaphylaxis (1). Our studies on human subjects with FA and in relevant mouse models have identified changes in regulatory T (Treg) cell populations as playing a pivotal role in disease pathogenesis. Specifically, we have identified a critical role of RORgt+ Treg cells, induced by the gut commensal bacteria, in mediating oral tolerance to food allergens (2, 3). In contrast, FA is associated with defective microbiota-dependent differentiation of RORgt+ Treg cells due to dysbiosis. We identified Resistin like molecule beta (RELMβ), a gut goblet cell cytokine previously linked to the innate immune response to parasitic infections (4-6), as pivotal to FA pathogenesis by promoting dysbiosis and disrupting RORgt+ Treg cell differentiation. Reciprocally, there emerges in FA food allergen-specific Treg cells with a T helper cell type (Th2) cell like phenotype, with high expression of the transcription factor GATA3 and the Th2 cytokines IL-4 (7, 8). These reprogrammed Treg cells play an essential role in amplifying disease pathology, and they decline in patients receiving oral immunotherapy (7, 8). Our recent analysis of circulating Treg cells of human subjects with FA identified Thymic stromal lymphopoietin receptor (TSLPR) as a marker of their Th2 cell-like reprogramming. Accordingly, the focus of this proposal is to identify immune regulatory checkpoints that govern FA and means of resetting them to promote oral tolerance. Our overall hypothesis is that the evolution of FA entails two critical checkpoints each involving a distinct Treg cell population under control of dedicated innate cell and cytokine circuits. The first involves microbiota-dependent Helios– RORgt+ Treg cells generated at the peri-weaning period and thereafter which enforced oral tolerance. This circuit is negatively controlled by RELMb, itself induced by an upstream Tuft cell (IL-25)-ILC2(IL-13) axis (9-11), which predisposes to FA by promoting dysbiosis. The second involves Helios+TSLPR+ Th2 cell-like Treg cells that are positively regulated by IgE/Mast cells and which augment the FA responses. To explore this hypothesis, we will under Aim 1 examine the evolution of the pro-tolerogenic immune response in FA Il4raF709 mice following therapy with anti-RELMb mAb or the acute deletion of the RELMb gene Retnlb. We will also elucidate the mechanisms by which RELMb antagonism resets the gut microbiota to enforce oral tolerance, including the expansion of Lactobacilli species rich in indole metabolites that act via the aryl hydrocarbon receptor (AhR) to suppress FA by inducing RORgt+ Treg cells. Under Aim 2, we will dissect the role of TSLPR on Th2 cell-like reprogrammed Treg cell in disease pathogenesis. These findings will then be extending to studies under Aim 3 on FA subjects to relate changes in serum RELMb and Treg cell populations to dysbiosis and disease severity. The proposed studies will provide fundamental new insights relevant to disease pathogenesis and novel therapeutic approaches to re-establish oral tolerance in FA.