妊娠期间补充维生素D可改善新生儿免疫力、防止哮喘和呼吸道感染

　　胎儿发育期间的免疫系统可以影响胎儿发育后期的生活结局和哮喘相关风险因素。维生素D是一种公认的免疫调节剂，妊娠期间该营养素缺乏可能影响后代的疾病发展。迄今为止，调查维生素D与婴幼儿免疫力之间相关性的研究很少。

　　2017年5月16日，美国过敏、哮喘与免疫学会（AAAAI）《过敏与临床免疫学杂志》在线发表英国伦敦国王学院医学院、美国波士顿布莱根女子医院、波士顿大学医学院、哈佛大学医学院的产前维生素D减少哮喘研究（VDAART）报告，发现妊娠期间补充维生素D可积极改变新生儿免疫系统，有助于新生儿防止哮喘和呼吸道感染。

　　该随机双盲安慰剂对照临床研究（VDAART）入组51位妊娠中后期（妊娠10～18周后）女性，观察随机补充维生素D3高剂量（26例4400IU/d）或低剂量（25例400IU/d）对新生儿免疫力的影响情况，使用脐带血样本，通过流式细胞计数、定量PCR、细胞计数微球阵列法对脐带血样本进行免疫细胞组成、Toll样受体（TLR）表达、促有丝分裂TLR和T细胞刺激后的细胞因子分泌进行分析，并检测对糖皮质激素地塞米松的反应，以评定新生儿先天免疫系统的反应性。先天免疫系统的反应性是指人体对感染的第一道防线、人体针对感染产生持久保护的T淋巴细胞反应。

　　结果发现，母亲补充4400IU维生素D3可使脐带血单核细胞对先天和有丝分裂刺激广谱促炎细胞因子反应增强（P=0.0009），若干促炎细胞因子（GM-CSF、IFN-γ、IL-1β、IL-6、IL-8）受到刺激后平均水平提高1.7～2.1倍，TLR2、TLR9基因表达水平较高（P=0.02、P=0.02），多克隆T细胞刺激后IL-17A产量增加大于4倍（P=0.03），脐带血单核细胞对地塞米松处理培养物的IL-10反应增强（P=0.018）。这些反应可以改善新生儿受感染时的免疫系统抵抗力。

　　大多数哮喘病例在患者处于儿童时期就被诊断，这意味着该病起源于胎儿生命早期。由于婴儿生命早期的强烈免疫反应与哮喘发展有相关性，故该研究首次表明，妊娠期间较高水平维生素D可能有效改变新生儿免疫系统反应，这些反应可能改善儿童呼吸系统健康状况，有助于降低儿童哮喘发生率。

　　研究结果表明，维生素D是很有前途的哮喘研究方向，在胎儿发育过程中对妊娠女性补充维生素D可能改善胎儿免疫反应、影响新生儿免疫系统，可能有助改善生命早期哮喘相关（包括感染）的结局。不过，该研究仅仅初步揭示二者关系，仍然需要更多研究直接证明维生素D是否能够影响胎儿以后哮喘的发生情况。

J Allergy Clin Immunol. 2017 May 16. [Epub ahead of print]

Vitamin D supplementation during pregnancy: Effect on the neonatal immune system in a randomized controlled trial.

Hornsby E, Pfeffer PE, Laranjo N, Cruikshank W, Tuzova M, Litonjua AA, Weiss ST, Carey VJ, O'Connor G, Hawrylowicz C.

King's College London School of Medicine, London, United Kingdom; Brigham and Women's Hospital, Boston, Mass; Boston University School of Medicine, Boston, Mass; Harvard Medical School, Boston, Mass.

BACKGROUND: Programming of the immune system during fetal development can influence asthma-related risk factors and outcomes in later life. Vitamin D is a well-recognized immune modulator, and deficiency of this nutrient during pregnancy is hypothesized to influence disease development in offspring.

OBJECTIVE: We sought to investigate the effect on neonatal immunity of maternal supplementation with 4400 IU/d vitamin D3 during the second and third trimesters of pregnancy by using a subset of cord blood samples from a randomized, double-blind, placebo-controlled clinical trial (the Vitamin D Antenatal Asthma Reduction Trial).

METHODS: Cord blood samples from neonates born to mothers supplemented with 4400 IU/d (n = 26) or 400 IU/d (n = 25) of vitamin D3 were analyzed for immune cell composition by flow cytometry, Toll-like receptor (TLR) expression by quantitative PCR, and cytokine secretion after stimulation with mitogenic, TLR, and T-cell stimuli by cytometric bead array. Responsiveness to the glucocorticoid dexamethasone was determined.

RESULTS: Supplementation of mothers with 4400 IU of vitamin D3 resulted in an enhanced broad-spectrum proinflammatory cytokine response of cord blood mononuclear cells to innate and mitogenic stimuli (P = .0009), with an average 1.7- to 2.1-fold increase in levels of several proinflammatory cytokines (GM-CSF, IFN-γ, IL-1β, IL-6, and IL-8) across stimuli, a higher gene expression level of TLR2 (P = .02) and TLR9 (P = .02), a greater than 4-fold increase in IL-17A (P = .03) production after polyclonal T-cell stimulation, and an enhanced IL-10 response of cord blood mononuclear cells to dexamethasone treatment in culture (P = .018).

CONCLUSION: Vitamin D exposure during fetal development influences the immune system of the neonate, which can contribute to protection from asthma-related, including infectious, outcomes in early life.

KEYWORDS: Vitamin D; asthma; innate immunity; pregnancy

PMID: 28552588

PII: S0091-6749(17)30575-4

DOI: 10.1016/j.jaci.2017.02.039