牛乳IgG在人类免疫中的作用

Ulfman 等人2018 (1)的回顾显示,涉及到婴儿和成人的研究发现,牛免疫球蛋白G(IgG)和富含IgG的牛初乳在预防胃肠道(GIT)感染(2-7)和上呼吸道(URT)感染中有重要作用(8-17)。然而这些研究在目标人群、设计、牛IgG来源、剂量和终点设定上有不同,这使之很难得出强有力的结论。基于这些考虑,此回顾集中于经口服用牛IgG的效果,以及其对儿童和成人免疫系统的潜在作用机理上。

总结 | 这项回顾分析了对牛IgG和初乳的研究,结果显示IgG对GIT和URT感染有预防和治疗作用(2-28)。牛IgG也可减少中耳炎(29,30)和过敏(31,32)的风险。牛IgG通过粘附病原体和过敏源、提高它们的清除力、限制胃肠炎症、在某些状况下中和感染而作用于免疫系统。在体外模型中,牛IgG通过靶向病原体表达IgG受体的吞噬细胞提高吞噬作用;杀死细菌;抗原提呈(33,34),和支持胃肠屏蔽功能(35-41)。

研究者还发现口服摄入牛IgG可在粪便中被发现,表明它能够通过胃肠道保持其活性。婴儿粪便中IgG数值比成年人高,这很可能是由于胃肠道的状态如pH值不同。涉及到婴儿和成年人的研究显示牛IgG能够预防胃肠道感染(2-7)和上呼吸道感染(8-17)。

研究特征

这是一次对含有牛IgG产品的机理和营养性研究的最顶尖的回顾。这项回顾涉及了大多数人体研究,有使用血清分离IgG、初乳、初乳和牛奶分离IgG,也有采用从血清分离的免疫球蛋白作为牛IgG来源,还包括从接种过的牛和没有免疫接种过的动物来源的IgG,这都取决于研究目的和设计。

结论

牛IgG对免疫系统的作用

胃肠道(GIT)感染

牛乳IgG在人类免疫中的作用四个对持续GIT感染的婴儿和儿童的研究提示,牛IgG–从接种过特定微生物的牛分离出来–在减少GIT感染持续时间上有作用(18,20)。除了它的治疗作用(18-24),也对其预防作用(2-7)进行了仔细观察。使用特定病原体免疫的牛免疫球蛋白来预防婴儿GIT感染的概念,已经在几个致病源如大肠杆菌和幽门螺旋杆菌上进行了试验(44-47)。这个领域被最广泛研究的肠道病原体是轮状病毒,并且动物和人体研究都支持服用特异轮状病毒的牛免疫球蛋白能预防轮状病毒腹泻(7,18021,42,43)。牛IgG对免疫缺陷个体的GIT感染的预防也有作用(48-54)。对反复发作腹泻的HIV感染个体的研究发现,服用牛IgG减少其大便频率、降低疲劳评分、并增加体重和CD4+T细胞计数。

呼吸道感染

对比使用配方奶喂养的婴儿,母乳喂养儿更少发生呼吸道感染和中耳炎。然而,需要有更多的研究来确定最佳的母乳喂养持续时间和数量以确认其对呼吸道感染和中耳炎的保护作用。

有11个研究显示牛IgG和初乳能够预防儿童、成人、老年人和运动员的URT感染(8-17, 55, 56)。这些研究大多数使用来自于没有接种过疫苗的正常牛IgG,并仅针对胃肠道致病原。有意思的是,流行病学研究显示,对比使用超高温处理(UHT)的牛奶,摄入没有处理过的牛奶作为生后第一年的辅食,减少了呼吸道感染和中耳炎的风险。一个可能的解释是存在于没有处理过的牛奶中的完整蛋白质起到了保护作用(57-59)。

过敏

早期的呼吸道感染和过敏的发展之间有着复杂的联系,卫生学假说提及早期的感染与过敏和过敏性疾病的减少相关(60)。可能的免疫机理是感染期间产生的干扰素(IFN-g)下调了T辅助细胞2(Th2)的活性,而此活性与促进IgE产生的白细胞介素-4(IL-4)的生成相关。另外,感染也上调了T-调节细胞(T-reg)的活性,这对Th2和Th1的反应有额外的控制效应。后者解释了为什么与Th2反应有关的过敏、和与Th1反应有关的自身免疫疾病更常见并在富裕社区相应存在。在一些感染活跃如有麻疹的社区,与更少的过敏相关,可能原因是人类共生菌在促进正常免疫调节中扮演了主要角色。这样,创新了一个更加精确的名称:“微生物暴露假说”。

与微生物暴露假说相应,流行病学队列研究的发现显示,后续发展为过敏性致敏和疾病的儿童呼吸道感染频率增高,对这个发现的解释需要谨慎。增加感染风险的潜在免疫反应缺陷可能也与过敏的发生有关;这个提示感染和过敏之间的关系不一定是因果关系。

尽管如此,某些婴儿病毒感染跟今后哮喘的发展特别相关。例如鼻病毒诱发的婴儿期喘息预示着以后发展为哮喘的可能性高;可能性稍低一些的是,哮喘也与由呼吸道合胞病毒感染(RSV)引起的婴儿支气管炎症有关。 一个特别有意思的事实是,牛IgG能够与人RSV紧密结合、并在体内试验中显示能够预防人细胞感染人RSV,因此推测牛IgG与减少RSV感染从而降低后续哮喘的发生相关(61)。

一般来说,婴儿急性胃肠炎增加了婴儿对食物蛋白过敏致敏的风险,特别在有严重消化道炎症时发生暴露于过敏蛋白的情况下,后者提供了一个协同刺激信号激发了致敏反应。因此,母乳喂养对胃肠道和RSV感染的保护作用减少了这种状况的发生。

作用机理

牛IgG可与许多人类的致病原结合,阻止它们粘附在肠道上皮上。进而,牛IgG能够中和人细胞试验性的感染、并限制胃肠道的炎症。IgG在肠道上皮上直接发挥了抗感染作用,并阻止了细菌成分穿过上皮细胞层。牛IgG也跟人Fc受体绑定,从而提高了吞噬作用,杀死细菌和抗原提呈。在体外模型中,牛IgG也显示出对胃肠道屏障功能的支持(33-41)。

结论

这项回顾提示,当经口服用时,牛IgG对支持脆弱人群如婴儿、儿童、老年人和免疫缺陷者的免疫功能可能有作用。

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