Maternal influence on offspring food allergy

项目摘要 食物过敏(FA)是一个日益严重的公共卫生问题。母体免疫反应对诱导的影响 调节性T(Treg)细胞介导的食物耐受性在后代中的作用还知之甚少。我们发现这是母性的 过敏原[卵清蛋白(OVA)或花生]的“保护性”致敏可阻止子代的FA反应 对相同过敏原的皮肤表面致敏和口服刺激的反应，如下降所示 在食物过敏反应、变应原特异性免疫球蛋白(Ig)E、血清肥大细胞蛋白酶1、 和肠道肥大细胞的扩张。新生儿Fc受体(FcRN)依赖母体免疫球蛋白和变应原的转移 乳汁免疫复合物(Ig-IC)及新生儿CD11c+细胞诱导的过敏原特异性递呈 后代体内的Treg细胞。未致敏的母亲的后代由卵子致敏的母亲或母亲的免疫球蛋白- IC补充剂诱导新生儿耐受。始终如一地，来自非过敏症母亲的母乳含有 人源化FcRN小鼠的免疫球蛋白IC及其诱导耐受这些结果表明，母乳中的Ig G-IC-FcRN Axis建立了Treg细胞介导的新生儿食物耐受性，这种耐受性可能延伸到人类。作为对 我们之前的研究，这项提议的目标是以前调查不足的机制，通过这些机制 哺乳期间特定断奶前间隔中的乳因子(微生物区系)除了免疫球蛋白-IC外，还关键地调节 维甲酸受体相关孤儿受体γt(Rorγt)+Treg细胞介导的新生儿耐受诱导 对阵英足总。有选择地删除 RORC，编码Rorγt的基因， 叉头盒蛋白3(Foxp3)+Treg细胞 在野生型(WT)小鼠中易患FA。 OVA致敏的WT母亲的后代出现更高的频率 OVA特异性RORγT+Treg细胞与对照组比较。Il4raF709小鼠，FA的小鼠模型，携带有- 白细胞介素4受体(IL-4R)α链等位基因功能突变。Il4raF709卵白蛋白致敏后代 在免疫球蛋白-IC存在的情况下，与对照组相比，Il4raF709母亲对FA的耐受性失败。 与RORγT+Treg细胞频率降低相关。梭状芽胞杆菌或类杆菌的细菌治疗 不同物种诱导的RoRγt+Treg细胞抑制Il4raF709小鼠FA，提示RoRγt+Treg细胞介导 对FA的保护和易位基因可能阻碍新生儿耐受性的最佳诱导 通过对RoRγT+Treg细胞的重新编程 。OVA致敏的无菌母亲的后代和 卵子--哺乳期接受抗生素治疗的母亲未能显示出对FA的保护作用，即使在 存在免疫球蛋白IC。我们的初步研究确定了牛奶细菌分类群与人奶的不同。 低聚糖在非特应组和FA组之间的差异。这些结果表明，母体微生物区系在 哺乳期是成功诱导新生儿食物耐受所必需的。我们假设新的 在新生儿肠道中形成的过敏原特异性的rorγt+Treg细胞抑制了对食物过敏原的Th2反应，以及 这一过程受到高Th2信号的影响。我们还假设母体微生物区系在 哺乳期塑造新生儿肠道微生物区系，诱导Treg细胞介导的新生儿食物耐受性。

Project Summary Food allergy (FA) is a growing public health concern. The effects of maternal immune responses on the induction of regulatory T (Treg) cell-mediated food tolerance in offspring are poorly understood. We found that maternal “protective” sensitization with allergen [ovalbumin (OVA) or peanut] prevented FA responses in murine offspring in response to epicutaneous sensitization and oral challenge with the same allergen, as indicated by a decrease in the levels of food anaphylaxis, allergen-specific immunoglobulin (Ig) E, serum mouse mast cell proteinase 1, and intestinal mast cell expansion. Neonatal Fc receptor (FcRn)-dependent transfer of maternal IgG and allergen immune complexes (IgG-IC) via milk and IgG-IC presentation by neonatal CD11c+ cells induced allergen-specific Treg cells in offspring. Offspring of unsensitized mothers fostered by OVA-sensitized mothers or maternal IgG- IC supplementation induced neonatal tolerance. Consistently, human milk from non-atopic mothers contained IgG-IC and induced tolerance in humanized FcRn mice. These results indicate that maternal milk IgG-IC-FcRn axis establishes Treg cell-mediated neonatal food tolerance, which may extend to humans. As an extension of our prior study, the goals of this proposal are the previously underinvestigated mechanisms by which additional milk factor (microbiota) besides IgG-ICs in a specific preweaning interval during lactation critically regulate the induction of retinoic acid receptor related orphan receptor γt (Rorγt)+ Treg cell-mediated neonatal tolerance against FA. Selective deletion of Rorc, the gene encoding Rorγt, in Forkhead box protein 3 (Foxp3)+ Treg cells predisposes to FA in wild-type (WT) mice. Offspring of OVA-sensitized WT mothers show higher frequencies of OVA-specific Rorγt+ Treg cells as compared to controls. Il4raF709 mice, a murine model of FA, carry a gain-of- function mutation in the interleukin (IL)-4 receptor (IL-4R) α chain allele. Il4raF709 offspring of OVA-sensitized Il4raF709 mothers showed failure of tolerance towards FA as compared to controls in the presence of IgG-IC, associated with decreased frequencies of Rorγt+ Treg cells. Bacteriotherapy with Clostridiales or Bacteroidales species induced Rorγt+ Treg cells that suppressed FA in Il4raF709 mice, suggesting that Rorγt+ Treg cells mediate protection against FA and that pro-atopic genotype may hinder the optimal induction of neonatal tolerance through the reprogramming of Rorγt+ Treg cells . Offspring of OVA-sensitized germ-free mothers and offspring of OVA-mothers treated with antibiotics during the lactation period failed to show protection against FA, even in the presence of IgG-IC. Our pilot study identified the differences in milk bacterial taxa and human milk oligosaccharides between non-atopic and FA groups. These results imply that the maternal microbiota during the lactation period is necessary to successfully induce neonatal food tolerance. We hypothesize that newly developed allergen-specific Rorγt+ Treg cells in the neonatal gut suppress Th2 responses to food allergen, and that this process is compromised by high Th2 signaling. We also hypothesize that the maternal microbiota during the lactation period shape the neonatal gut microbiota that induce the Treg cell-mediated neonatal food tolerance.