Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity
Vitamin D deficiency may be a risk factor for recurrent pregnancy losses by increasing cellular immunity and autoimmunity
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DOI：
10.1093/humrep/det424
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发表时间：
2014-02-01
影响因子：
6.1
通讯作者：
Kwak-Kim, Joanne
中科院分区：
文献类型：
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作者：
Ota, Kuniaki;Dambaeva, Svetlana;Kwak-Kim, Joanne
与维生素D正常的RPL女性相比，复发性妊娠丢失（RPL）和低维生素D的女性自身免疫和细胞免疫异常的患病率是否增加？维生素D对体外细胞免疫是否有任何影响？有很大比例的RPL妇女缺乏维生素D，并且在RPL和维生素D缺乏的妇女中，自身和细胞免疫异常的风险增加。孕妇缺乏维生素D与产科并发症的风险增加有关，如先兆子痫、细菌性阴道病相关的早产、妊娠期糖尿病和小胎龄分娩。对133名女性RPL患者进行了为期2年的回顾性横断面研究，并进行了实验室实验。在大学诊所登记的怀孕20周前连续三次或以上自然流产的妇女。测定小鼠体内、体外血清维生素D水平、细胞活性和自身免疫参数。133名女性中有63名（47.4名）维生素D含量低（30 ng/ml）。低维生素D组（VDlow）抗磷脂抗体（APA）阳性率（39.7）显著高于正常维生素D组（VDnl） （22.9） （P < 0.05），校正比值比（OR）为2.22,95可信区间（CI）为1.04.7。VDlow组抗核抗原抗体（VDlow vs VDnl; 23.8 vs 10.0, OR 2.81, 95 CI 1.17.4）、抗ssdna （19.0 vs 5.7, OR 3.76, 95 CI 1.112.4）和甲状腺过氧化物酶抗体（33.3 vs 15.7, OR 2.68, 95 CI 1.26.1）的患病率均显著高于VDnl组（P均0.05）。VDlow组外周血CD19 B和CD56 NK细胞水平及NK细胞效应靶细胞毒性（E:T）比为25:1，显著高于VDnl组（P均为0.05）。IgG （12.5 mg/dl）对VDlow小鼠NK细胞毒性（E:T比为50:1和25:1）的降低作用显著低于VDnl （P < 0.05, P < 0.01）。VDlow与VDnl的Th1/Th2比值无显著差异。体外NK细胞毒实验中，添加维生素D-3后，10 nMol/L (nM)（11.9 3.3）和100 nM（10.9 3.7）的维生素D-3能显著抑制E:T比为50:1的NK细胞毒，与对照组（15.3 4.7）比较，差异均有统计学意义（P均0.01）。与对照组（40.4 11.3）相比，100 nM维生素D-3显著降低TNF-/IL-10表达CD3/4的细胞比例（31.3 9.4,P 0.05）。此外，与对照组（14.8 4.6）相比，100 nM维生素D-3显著降低了INF-/IL-10表达CD3/4的细胞比例（12.1 4.0,P 0.05）。与对照组相比，维生素D-3 100 nM显著降低了NK细胞的IFN-和TNF-分泌（P < 0.01），显著提高了IL-10、IL-1、血管内皮生长因子和粒细胞集落刺激因子水平（P < 0.01）。由于补充维生素D的女性被排除在本研究之外，因此本研究中RPL女性维生素D缺乏症的患病率可能存在I型错误。建议对患有RPL的妇女进行维生素D水平评估。补充维生素D作为RPL的一种可能的治疗选择应进一步探索。这项工作得到了罗莎琳德富兰克林医学与科学大学芝加哥医学院微生物与免疫学系的校内资助。所有作者均无任何利益冲突需要声明。
Do women with recurrent pregnancy losses (RPL) and low vitamin D have increased prevalence of auto- and cellular immune abnormalities when compared with women with RPL who have normal vitamin D, and does vitamin D have any effect on cellular immunity in vitro?A high proportion of women with RPL have vitamin D deficiency and the risk of auto- and cellular immune abnormalities is increased in women with RPL and vitamin D deficiency.Vitamin D deciency in pregnant women is associated with increased risk of obstetrical complications such as pre-eclampsia, bacterial vaginosis associated preterm delivery, gestational diabetes mellitus and small-for-gestational age births.A retrospective cross-sectional study of 133 women with RPL who were enrolled in a 2-year period, together with laboratory experiments.Women with three or more consecutive spontaneous abortions prior to 20 weeks of gestation who were enrolled at the University clinic. Serum vitamin D level, cellular activity and autoimmune parameters in vivo and in vitro were measured.Sixty-three out of 133 women (47.4) had low vitamin D (30 ng/ml). The prevalence of antiphospholipid antibody (APA) was significantly higher in low vitamin D group (VDlow) (39.7) than in the normal vitamin D group (VDnl) (22.9) (P 0.05) and the adjusted odds ratio (OR) for APA in VDlow was 2.22 with the 95 confidence interval (CI) of 1.04.7. The prevalence of antinuclear antigen antibody (VDlow versus VDnl; 23.8 versus 10.0, OR 2.81, 95 CI 1.17.4), anti-ssDNA (19.0 versus 5.7, OR 3.76, 95 CI 1.112.4) and thyroperoxidase antibody (33.3 versus 15.7, OR 2.68, 95 CI 1.26.1) was significantly higher in VDlow than those of VDnl (P 0.05 each). Peripheral blood CD19 B and CD56 NK cell levels and NK cytotoxicity at effector to target cell (E:T) ratio of 25:1 were significantly higher in VDlow when compared with those of VDnl (P 0.05 each). Reduction () of NK cytotoxicity (at E:T ratio of 50:1 and 25:1) by IgG (12.5 mg/dl) was significantly lower in VDlow than those of VDnl (P 0.05, P 0.01, respectively). There were no differences in Th1/Th2 ratios between VDlow and VDnl. When vitamin D-3 was added in NK cytotoxicity assay in vitro, NK cytotoxicity at E:T ratio of 50:1 was significantly suppressed with 10 nMol/L (nM) (11.9 3.3) and 100 nM (10.9 3.7) of vitamin D-3 when compared with controls (15.3 4.7) (P 0.01 each). TNF-/IL-10 expressing CD3/4 cell ratios were significantly decreased with 100 nM of vitamin D-3 (31.3 9.4, P 0.05) when compared with controls (40.4 11.3) in vitro. Additionally, INF-/IL-10 expressing CD3/4 cell ratio was significantly decreased with 100 nM of vitamin D-3 (12.1 4.0, P 0.05) when compared with controls (14.8 4.6). IFN- and TNF- secretion from NK cells were significantly decreased (P 0.01 each), and IL-10, IL-1, vascular endothelial growth factor and granulocyte colony stimulating factor levels were significantly increased (P 0.01 each) with vitamin D-3 100 nM when compared with those of controls.The prevalence of vitamin D deficiency in women with RPL in this study is open to a possible type I error since women with vitamin D supplementation were excluded from this study.Assessment of vitamin D level is recommended in women with RPL. Vitamin D supplementation should be explored further as a possible therapeutic option for RPL.This work was supported by the intramural funding from Department of Microbiology and Immunology, Chicago Medical School at Rosalind Franklin University of Medicine and Science. None of the authors has any conflict of interest to declare.N/A.