美国波士顿儿童医院Talal A. Chatila和Seth Rakoff-Nahoum共同合作，近期取得重要工作进展。他们研究发现，RELMβ设定了依赖微生物群的口服耐受阈值。相关研究成果2025年1月22日在线发表于《自然》杂志上。

据介绍，对食物抗原产生耐受对于避免引发食物过敏（FA）和过敏反应的有害2型免疫反应至关重要。然而，目前人们对维持和丧失食物抗原耐受性的机制仍知之甚少。

研究人员证实杯状细胞来源的抵抗素样分子β（RELMβ）是口服耐受的关键调节因子。在食物过敏患者的血清以及食物过敏小鼠模型中，RELMβ的含量都很高。敲除RELMβ能够保护小鼠免受食物过敏的影响，防止食物抗原特异性免疫球蛋白E（IgE）的产生和过敏反应的发生。RELMβ通过调节肠道微生物群，减少能够产生吲哚代谢物的乳杆菌属和另枝菌属细菌的数量，从而破坏食物耐受性。

而吲哚衍生物在局部的产生能够激活芳香烃受体，驱动对食物过敏具有保护作用的表达视黄酸相关孤儿受体γt（RORγt⁺）的调节性T细胞（T_reg），进而维持耐受性。在断奶前后时期拮抗RELMβ能够恢复口服耐受性，并保护具有遗传易感性的后代在日后的生活中免受食物过敏的困扰。

总之，研究人员发现RELMβ介导了一个肠道免疫-上皮回路，该回路可调节对食物抗原的耐受性，这是一种通过编辑微生物群来实现先天性免疫对适应性免疫调控的新模式。研究人员确定了这个回路中可作为靶点的候选因素，用于食物过敏的预防和治疗。

附：英文原文

Title: RELMβ sets the threshold for microbiome-dependent oral tolerance

Author: Stephen-Victor, Emmanuel, Kuziel, Gavin A., Martinez-Blanco, Monica, Jugder, Bat-Erdene, Benamar, Mehdi, Wang, Ziwei, Chen, Qian, Lozano, Gabriel L., Abdel-Gadir, Azza, Cui, Ye, Fong, Jason, Saint-Denis, Elisa, Chang, Iris, Nadeau, Kari C., Phipatanakul, Wanda, Zhang, Angela, Farraj, Farida Abi, Holder-Niles, Faye, Zeve, Daniel, Breault, David T., Schmitz-Abe, Klaus, Rachid, Rima, Crestani, Elena, Rakoff-Nahoum, Seth, Chatila, Talal A.

Issue&Volume: 2025-01-22

Abstract: Tolerance to dietary antigens is critical for avoiding deleterious type 2 immune responses resulting in food allergy (FA) and anaphylaxis1,2. However, the mechanisms resulting in both the maintenance and failure of tolerance to food antigens are poorly understood. Here we demonstrate that the goblet-cell-derived resistin-like molecule β (RELMβ)3,4 is a critical regulator of oral tolerance. RELMβ is abundant in the sera of both patients with FA and mouse models of FA. Deletion of RELMβ protects mice from FA and the development of food-antigen-specific IgE and anaphylaxis. RELMβ disrupts food tolerance through the modulation of the gut microbiome and depletion of indole-metabolite-producing Lactobacilli and Alistipes. Tolerance is maintained by the local production of indole derivatives driving FA protective RORγt+ regulatory T (Treg) cells5 through activation of the aryl hydrocarbon receptor. RELMβ antagonism in the peri-weaning period restores oral tolerance and protects genetically prone offspring from developing FA later in life. Together, we show that RELMβ mediates a gut immune–epithelial circuit regulating tolerance to food antigens—a novel mode of innate control of adaptive immunity through microbiome editing—and identify targetable candidates in this circuit for prevention and treatment of FA.

DOI: 10.1038/s41586-024-08440-7

Source: https://www.nature.com/articles/s41586-024-08440-7