Intestinal mast cell-derived leukotrienes mediate the anaphylactic response to ingested antigens

Anaphylaxis is a life-threatening complication of allergen exposure. While mechanisms governing anaphylaxis after intravenous injection have been defined in mice, these models neglect mucosal exposure that accompanies food ingestion. We investigated the role of mast cell populations within the intestine of mice in response to antigens delivered orally. Oral anaphylaxis required IgE-FceR1 signaling, and profiling of intestinal mast cells revealed a rapidly developing population shaped by epithelial cues. Intestinal mast cells were largely epithelium-resident and displayed divergent transcriptomes and effector functions from connective tissue mast cells found throughout the body. Histamine synthesis was diminished and leukotriene generation enhanced. Mice genetically deficient in cysteinyl leukotriene synthesis, or those treated with aLOX5 antagonist, Zileuton, were protected from oral anaphylaxis whereas that elicited by intravenous injection was unaltered. Overall design: BALB/cJ female mice were sensitized subcutaneously with OVAxAlum on d0 and d7 . Mice were challenged intragastrically with 20mg of OVA (Sigma grade III) in 200ul water on d14. MCs were sorted 24 hr later

全身性过敏反应（Anaphylaxis）是过敏原暴露后引发的致命并发症。目前，小鼠静脉注射过敏原后引发全身性过敏反应的调控机制已得到阐明，但此类模型均忽略了进食过程中伴随的黏膜暴露问题。本研究针对小鼠肠道内肥大细胞（mast cell）群在口服抗原刺激下的作用展开了探究。
口服型全身性过敏反应依赖IgE-FceR1信号通路；对肠道肥大细胞的转录组谱分析显示，存在一类由上皮细胞信号调控的快速发育细胞群。
肠道肥大细胞大多为上皮驻留型，与全身各处的结缔组织肥大细胞相比，其转录组和效应功能均存在显著差异。该类细胞的组胺合成能力减弱，而白三烯生成则有所增强。
半胱氨酰白三烯合成基因缺陷小鼠，或经5-脂氧合酶（aLOX5）拮抗剂齐留通（Zileuton）处理的小鼠，可免受口服型全身性过敏反应的影响，但静脉注射诱导的全身性过敏反应并未出现改变。
实验整体设计：于第0天和第7天，对BALB/cJ品系雌性小鼠皮下注射卵清蛋白-明矾复合物（OVAxAlum）进行致敏；于第14天，以200μl水溶液中含20mg卵清蛋白（OVA，Sigma III级）的溶液对小鼠进行灌胃攻击；24小时后对肥大细胞（MCs）进行分选。