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摘要:
目的 探讨乙型肝炎病毒表面抗原(hepatitis B surface antigen，HBsAg)阳性母亲外周血单个核细胞(peripheral blood monouclear cell，PBMC)中乙型肝炎病毒(hepatitis B virus，HBV)共价闭合环状DNA(covalently closed circular DNA，cccDNA)对新生儿辅助性T细胞1(T help cell 1，Th1)、辅助性T细胞2(T help cell 2，Th2)型细胞因子及Th1/Th2比值的影响。 方法 以2011年6月-2013年7月在太原市第三人民医院妇产科分娩的HBsAg阳性母亲及其新生儿作为研究对象。采用电化学发光法(electrochemiluminescence immunoassay，ECLIA)检测HBV血清学标志物，real-time PCR-TaqMan探针法检测母亲PBMC HBV cccDNA，ProcartaPlex多因子分析技术检测新生儿外周血Th1型细胞因子白介素-2(interleukin 2，IL-2)，干扰素-γ(interferon-γ，IFN-γ)和肿瘤坏死因子-α(tumor necrosis factor-α，TNF-ɑ)以及Th2型细胞因子白介素-4(interleukin 4，IL-4)，白介素-6(interleukin 6，IL-6)和白介素-10(interleukin 10，IL-10)水平。 结果 单因素分析显示：与阴性组相比，母亲PBMC HBV cccDNA阳性组IL-2、IL-6和IL-10水平升高，Th1/Th2比值降低(P=0.034；P=0.007；P=0.048；P=0.029)；经阴道分娩新生儿IL-6和IL-10明显高于剖宫产新生儿，Th1/Th2比值低于剖宫产组(均有P < 0.001)；新生儿HBsAg阳性组IL-10水平明显高于阴性组，TNF-α水平以及Th1/Th2比值明显低于阴性组(P=0.011；P < 0.001；P=0.027)。以Th1/Th2比值反映新生儿Th2优势应答程度，分析母亲PBMC HBV复制对新生儿Th2优势应答的影响，调整相关因素后，logistic回归分析结果显示母亲PBMC HBV cccDNA阳性新生儿发生Th2强优势应答的风险是母亲PBMC HBV cccDNA阴性新生儿的2.42倍(OR=2.42，95%CI：1.16~5.04，P=0.018)，经阴道分娩新生儿发生Th2强优势应答的风险是剖宫产新生儿的5.06倍(OR=5.06，95%CI：2.95-8.67，P < 0.001)。 结论 HBsAg阳性母亲PBMC HBV复制和阴道产可能加重新生儿Th2优势应答程度，提示需注重母亲PBMC HBV复制和分娩方式对新生儿Th1/Th2型细胞因子的影响。 Abstract:Objective To explore the effect of PBMC HBV cccDNA in HBsAg-positive mothers on neonatal Th1, Th2 cytokines and the ratio of Th1/Th2. Methods HBsAg-positive mothers and their neonates delivered in the Third People's Hospital of Taiyuan between June 2011 and July 2013 were recruited. Questionnaires on general information were collected by an in-person interview. Electrochemiluminescence immunoassay (ECLIA) were utilized to detect HBV serological markers.HBV cccDNA in PBMC was detected with real-time PCR-TaqMan Probe method, Th1 cytokines (interleukin 2, interferon-γ and tumor necrosis factor-α) and Th2 cytokines (interleukin 4, interleukin 6 and interleukin 10) were detected with Procarta Plex Multiplex Immunoassays. Results Univariate analysis showed that the levels of IL-2, IL-6 and IL-10 in the positive group were significantly higher than those in the negative group, while the ratio of Th1/Th2 was lower than that in the negative group (P=0.034, P=0.007, P=0.048, P=0.029). The levels of IL-6 and IL-10 in neonates delivered by vagina were significantly higher than those by cesarean section, while the ratio of Th1/Th2 was lower than that by cesarean section (P < 0.001). The level of IL-10 in positive group of neonatal HBsAg was significantly higher than that in negative group, while TNF-α and Th1/Th2 ratio were lower than negative group (P=0.011, P < 0.001, P=0.027). The degree of Th2 predominant response was reflected by ratio of Th1/Th2. After adjusting potential confounding factors in non-conditional logistic regression analysis, compared to those born to mothers with PBMC HBV cccDNA negative, neonates whose mother with PBMC HBV cccDNA positive had an increased risk of having a strong Th2 predominant response (OR=2.42, 95% CI: 1.16-5.04, P=0.018). The risk of a strong Th2 predominant response in neonates delivered by vagina was 5.49 times higher than those by cesarean section (OR=5.06, 95% CI: 2.95-8.67, P < 0.001). Conclusion HBsAg-positive mothers' PBMC HBV replication and vaginal delivery may increase the risk of having a Th2 predominant response in neonates. It is suggested that we should pay attention to the effect of maternal PBMC HBV replication and the mode of delivery on neonatal Th1/Th2 cytokines. -
Key words:
- Hepatitis B virus /
- Covalently closed circular DNA /
- Neonate /
- Cytokines /
- Th1/Th2
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表 1 HBsAg母亲及新生儿一般情况描述[n(%)]
Table 1. Description of the general information in HBsAg -positive mothers and their neonate [n(%)]
变量 人数 构成比(%) 母亲基本特征 年龄(岁) < 25 75 23.22 25~ 158 48.92 30~ 69 21.36 ≥35 21 6.50 受教育程度 高中及以下 186 57.59 专科 75 23.21 本科及以上 62 19.20 家庭年收入(元) < 30 000 102 31.58 30 000~ 185 57.28 50 000~ 36 11.14 孕期在职 在职 80 24.77 无业 243 75.23 孕周(周) < 37 6 1.86 37~41 317 98.14 乙型肝炎家族史 有 92 28.48 无 231 75.52 既往孕产史 有 161 49.85 无 162 50.15 分娩方式 阴道产 144 44.58 剖宫产 179 55.42 新生儿基本特征 出生身长(cm) 45~ 319 98.76 54~ 4 1.24 出生体重(g) 2 500~ 288 89.16 4 000~5 000 35 10.84 新生儿性别 女 151 46.75 男 172 53.25 Apgar评分(分) 6~7 3 0.93 7~10 320 99.07 母亲HBV复制 PBMC HBV cccDNA 阳性 57 17.65 阴性 266 82.35 血清HBeAg 阳性 154 47.68 阴性 169 52.32 血清HBV DNA (copies/ml) < 500 132 40.87 500~ 101 31.27 106~ 90 27.86 新生儿HBV感染及复制 血清HBsAg 阳性 43 13.31 阴性 280 86.69 血清HBV DNA 阳性 5 1.55 阴性 318 98.45 血清HBeAg 阳性 141 43.65 阴性 182 56.35 
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表 2 单因素分析新生儿Th1、Th2型细胞因子水平及Th1/Th2比值的影响因素
Table 2. Univariate analysis of factors affecting neonatal Th1, Th2 cytokine levels and the ratio of Th1/Th2
变量 Th1型细胞因子M (QR) Th2型细胞因子M (QR) Th1/Th2比值M (QR) IL-2 (pg/ml) IFN-γ(pg/ml) TNF-α(pg/ml) IL-4(pg/ml) IL-6(pg/ml) IL-10(pg/ml) 母亲PBMC HBV cccDNA 阳性(n=57) 13.96(4.30) 1.47(0.97) 2.18(3.83) 8.09(6.32) 117.66(363.30) 2.84(8.11) 0.12(0.36) 阴性(n=266) 13.86(8.08) 1.33(0.91) 1.79(2.33) 8.45(9.68) 43.22(167.60) 1.86(6.26) 0.22(0.49) Z值 2.12 1.04 1.60 0.48 2.66 1.97 -2.18 P值 0.034 0.298 0.109 0.634 0.007 0.048 0.029 分娩方式 阴道产(n=144) 13.86(8.08) 1.29(0.95) 1.66(2.19) 8.12(9.68) 104.73(257.07) 6.88(16.08) 0.10(0.23) 剖宫产(n=179) 13.86(8.77) 1.40(0.93) 1.79(3.15) 8.45(9.68) 31.22(128.09) 0.90(1.49) 0.34(0.62) Z值 -0.86 -0.78 -1.26 -0.46 -4.85 -10.99 -6.05 P值 0.390 0.433 0.207 0.643 < 0.001 < 0.001 < 0.001 新生儿HBsAg 阳性(n=43) 13.86(8.97) 1.40(0.95) 1.12(1.04) 8.45(9.24) 117.30(304.08) 10.16(19.51) 0.10(0.25) 阴性(n=280) 13.86(7.88) 1.35(0.91) 1.79(2.33) 8.45(9.68) 45.58(192.16) 1.71(5.13) 0.21(0.49) Z值 0.01 0.26 -2.53 -0.18 1.80 4.00 -2.22 P值 0.991 0.797 0.011 0.861 0.072 < 0.001 0.027
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表 3 新生儿Th2优势应答程度影响因素的非条件logistic回归分析
Table 3. Non-conditional logistic regression analysis of influencing factors of Th2 predominant immune response
变量 β值 S.E. Wald χ2值 P值 OR值(95% CI) OR值(95% CI)a 母亲PBMC HBV cccDNA 阴性 1.00 1.00 阳性 0.884 0.374 5.570 0.018 1.85(1.02, 3.35)a 2.42(1.16, 5.04)a 分娩方式 剖宫产 1.00 1.00 阴道产 1.621 0.275 34.771 < 0.001 4.72(2.93, 7.61)a 5.06(2.95, 8.67)a 注：a调整因素包括母亲相关因素(年龄、孕周、孕期在职情况、血清HBeAg及HBV DNA)和新生儿相关因素(血清HBsAg、HBeAg及HBV DNA)。
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