Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.
Heightened Immune Activation in Fetuses with Gastroschisis May Be Blocked by Targeting IL-5.
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DOI：
10.4049/jimmunol.1502587
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发表时间：
2016-06-15
期刊：
影响因子：
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通讯作者：
MacKenzie TC
中科院分区：
文献类型：
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作者：
Frascoli M;Jeanty C;Fleck S;Moradi PW;Keating S;Mattis AN;Tang Q;MacKenzie TC
怀孕期间胎儿免疫系统的发育是一个精心策划的过程，对胎儿和新生儿的健康产生重要影响，但影响免疫激活的产前因素却知之甚少。我们假设慢性胎儿炎症可能导致胎儿免疫系统发育的改变。为了验证这一假设，我们检查了患有腹裂的新生儿，腹裂是一种先天性腹壁缺陷，会导致胎儿肠道暴露于羊水，从而导致肠道炎症。我们确定，与对照组相比，腹裂患者的炎症细胞因子和趋化因子（例如嗜酸细胞趋化因子）的全身水平较高，并且脐带血中 CD4+ 和 CD8+ 效应细胞和记忆 T 细胞的激活较早。此外，浸润发炎肠道浆膜和粘膜的 T 细胞和嗜酸性粒细胞数量增加。使用腹裂小鼠模型，我们观察到较高数量的嗜酸性粒细胞以及 2 型和 3 型先天淋巴细胞（ILC2 和 ILC3），特别是在暴露于羊水的器官部分。鉴于ILC2产生的IL-5在调节嗜酸性粒细胞发育和存活中的作用，我们确定母体或胎儿施用抗IL-5中和抗体或针对ILC的消耗抗体都可以有效减少肠道嗜酸性粒细胞增多。因此，引起慢性炎症的先天异常可以改变循环和组织驻留胎儿免疫细胞的组成。鉴于这些患者产前和新生儿并发症的发生率很高，这种变化具有临床意义，并可能成为胎儿治疗的目标。
The development of the fetal immune system during pregnancy is a well-orchestrated process with important consequences for fetal and neonatal health, but prenatal factors that affect immune activation are poorly understood. We hypothesized that chronic fetal inflammation may lead to alterations in the development of the fetal immune system. To test this hypothesis, we examined neonates with gastroschisis, a congenital abdominal wall defect that leads to exposure of the fetal intestines to amniotic fluid, with resultant intestinal inflammation. We determined that patients with gastroschisis show high systemic levels of inflammatory cytokines and chemokines such as eotaxin, and earlier activation of CD4+ and CD8+ effector and memory T cells in the cord blood compared to controls. In addition, increased numbers of T cells and eosinophils infiltrate the serosa and mucosa of the inflamed intestines. Using a mouse model of gastroschisis, we observed higher numbers of eosinophils and both type 2 and type 3 innate lymphoid cells (ILC2 and ILC3), specifically in the portion of organs exposed to the amniotic fluid. Given the role of IL-5 produced by ILC2 in regulating eosinophil development and survival, we determined that maternal or fetal administration of the anti IL-5 neutralizing antibody, or a depleting antibody against ILCs, can both effectively reduce intestinal eosinophilia. Thus, a congenital anomaly causing chronic inflammation can alter the composition of circulating and tissue-resident fetal immune cells. Given the high rate of prenatal and neonatal complications in these patients, such changes have clinical significance and might become targets for fetal therapy.