孕期低剂量poly(I:C)暴露联合新生接种乙肝疫苗诱发小鼠持久性自闭样行为
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摘要
目的探讨低剂量聚肌苷酸胞甘酸[poly(I:C)]暴露联合新生期乙肝疫苗接种导致小鼠表现出持久性自闭症样行为的机制。方法将孕鼠随机分成4组,分别为对照(CON)组、poly(I:C)(PIC)组、乙肝疫苗(HBV)组和联合免疫干预(P/H)组。4周、8周和12周龄时,检测小鼠自闭症样行为。12周龄时,检测小鼠脾脏Th2、Th17和TH2/17细胞的比例及外周血和海马组织中IL-4和IL-17a的含量。结果与CON组比较,HBV组8周龄时出现行为学损害,12周龄时行为学损害恢复;P/H组8周、12周龄时均出现行为学损害。此外,P/H组较CON组Th2型的细胞水平有升高(P<0.05);P/H组较PIC组Th2型细胞水平升高(P<0.05)。P/H组较HBV组中的Th17型细胞水平升高(P<0.05);P/H组较CON组Th2/17型细胞水平增加(P<0.05);P/H组较PIC组中Th2/17型细胞水平增加(P<0.05)。进一步证实,分别与CON组、HBV和PIC组比较,P/H组血清和海马组织的IL-4和IL-17a的含量升高(P<0.05)。结论孕期低剂量poly(I:C)暴露联合新生期乙肝疫苗接种通过升高脑内IL-17a水平导致小鼠持久性自闭症样行为。
Objective To study the mechanism by which the offspring born to pregnant dams in pregnancy suffered with low-dose poly(I:C)exposure combined with neonatal hepatitis B vaccination exhibit long-lasting autism-like behavior.Methods Pregnant dams were randomly divided into four groups blindly:control group(CON),poly(I:C)(PIC)group,hepatitis B vaccine(HBV)group and treatment-combined(P/H)group. Mice were immunized according to the immune procedure. At 4 weeks,8 weeks and 12 weeks,three-chamber social test,forced swimming test and tail suspension test were used to evaluate autism-like behavior in offspring. At 12 weeks,the proportion of Th2,Th17 and TH2/17 cells in spleen of offspring was detected by flow cytometry. The levels of IL-4 and IL-17 a in peripheral blood and hippocampus were detected using ELISA kit. Results The results of behavioral test suggested that PIC group had no behavioral impairments at4 weeks,8 weeks and 12 weeks compared with CON group. Behavioral impairments appeared in HBV group at 8 weeks and restored to CON level at 12 weeks. Behavioral impairments appeared in P/H group at 8 weeks and was detectable till 12 weeks. The results of flow cytometry indicated that the percentage of Th2 cells in HBV group and P/H group was significantly higher than that in CON group(P<0.05);compared with PIC group,the level of Th2 cells in P/H group increased significantly(P<0.05). Compared with CON group,the level of Th17 cells in PIC group increased significantly(P<0.05);Compared with HBV group,Th17 cell level in PIC group and P/H group increased significantly(P<0.05). Compared with CON group,the level of Th2/17 cells in P/H group and HBV group increased significantly(P<0.05);compared with PIC group,the level of Th2/17 cells in P/H group increased significantly(P<0.05). Elisa results showed that the levels of IL-4 and IL-17 a in serum and hippocampus of P/H group increased significantly than that in CON group,HBV group and PIC group(P<0.05). Compared with HBV group,the levels of IL-17 a in serum of PIC group increased significantly(P<0.05). Conclusion The offspring born to pregnant dams in pregnancy suffered with low-dose poly(I:C)exposure with neonatal hepatitis B vaccination exhibit long-lasting autism-like behavior via the elevation of interleukin-17 a(IL-17 a)level.
Objective To study the mechanism by which the offspring born to pregnant dams in pregnancy suffered with low-dose poly(I:C)exposure combined with neonatal hepatitis B vaccination exhibit long-lasting autism-like behavior.Methods Pregnant dams were randomly divided into four groups blindly:control group(CON),poly(I:C)(PIC)group,hepatitis B vaccine(HBV)group and treatment-combined(P/H)group. Mice were immunized according to the immune procedure. At 4 weeks,8 weeks and 12 weeks,three-chamber social test,forced swimming test and tail suspension test were used to evaluate autism-like behavior in offspring. At 12 weeks,the proportion of Th2,Th17 and TH2/17 cells in spleen of offspring was detected by flow cytometry. The levels of IL-4 and IL-17 a in peripheral blood and hippocampus were detected using ELISA kit. Results The results of behavioral test suggested that PIC group had no behavioral impairments at4 weeks,8 weeks and 12 weeks compared with CON group. Behavioral impairments appeared in HBV group at 8 weeks and restored to CON level at 12 weeks. Behavioral impairments appeared in P/H group at 8 weeks and was detectable till 12 weeks. The results of flow cytometry indicated that the percentage of Th2 cells in HBV group and P/H group was significantly higher than that in CON group(P<0.05);compared with PIC group,the level of Th2 cells in P/H group increased significantly(P<0.05). Compared with CON group,the level of Th17 cells in PIC group increased significantly(P<0.05);Compared with HBV group,Th17 cell level in PIC group and P/H group increased significantly(P<0.05). Compared with CON group,the level of Th2/17 cells in P/H group and HBV group increased significantly(P<0.05);compared with PIC group,the level of Th2/17 cells in P/H group increased significantly(P<0.05). Elisa results showed that the levels of IL-4 and IL-17 a in serum and hippocampus of P/H group increased significantly than that in CON group,HBV group and PIC group(P<0.05). Compared with HBV group,the levels of IL-17 a in serum of PIC group increased significantly(P<0.05). Conclusion The offspring born to pregnant dams in pregnancy suffered with low-dose poly(I:C)exposure with neonatal hepatitis B vaccination exhibit long-lasting autism-like behavior via the elevation of interleukin-17 a(IL-17 a)level.
引文
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[18]Wu Y,Qi F,Song D,et al. Prenatal influenza vaccination rescues impairments of social behavior and lamination in a mouse model of autism[J]. J Neuroinflammation,2018,15(1):228.
[19]Xia YC,Qi FF,Zou JT,et al. Influenza vaccination during early pregnancy contributes to neurogenesis and behavioral function in offspring[J]. Brain Behavior and Immunity,2014,42:212-221.
[20]Moon SH,Shin EC,Noh YW,et al. Evaluation of hyaluronic acid-based combination adjuvant containing monophosphoryl lipid A and aluminum salt for hepatitisBvaccine[J].Vaccine,2015,33(38):4762-4769.
[2] Lee BK,Magnusson C,Gardner RM,et al. Maternal hospitalization with infection during pregnancy and risk of autism spectrum disorders[J]. Brain Behav Immun,2015,44:100-105.
[3] Atladottir HO,Thorsen P,Ostergaard L,et al. Maternal infection requiring hospitalization during pregnancy and autism spectrum disorders[J]. J Autism Dev Disord,2010,40(12):1423-1430.
[4] Wong H,Hoeffer C. Maternal IL-17A in autism[J].Exp Neurol,2018,299:228-240.
[5] Kim S,Kim H,Yim Y S,et al. Maternal gut bacteria promote neurodevelopmental abnormalities in mouse offspring[J]. Nature,2017,549(7673):528-532.
[6] Choi G B,Yim YS,Wong HL,et al. The maternal interleukin-17a pathway in mice promotes autismlike phenotypes in offspring[J]. Science,2016,351(6276):933-939.
[7] Malkova NV,Yu CZ,Hsiao EY,et al. Maternal immune activation yields offspring displaying mouse versions of the three core symptoms of autism[J].Brain Behavior and Immunity,2012,26(4):607-616.
[8] Vanderende K,Gacic-Dobo M,Diallo MS,et al.Global routine vaccination coverage-2017[J]. Mmwr Morbidity and Mortality Weekly Report,2018,67(45):1261-1264.
[9] Gallagher CM,Goodman MS. Hepatitis B vaccination of male neonates and autism diagnosis,NHIS1997-2002[J]. J Toxicol Env Heal A,2010,73(24):1665-1677.
[10]Stubgen JP. Immune-mediated myelitis following hepatitis B vaccination[J]. Autoimmun Rev,2012,12(2):144-149.
[11]Hernan MA,Jick SS,Olek MJ,et al. Recombinant hepatitis B vaccine and the risk of multiple sclerosisA prospective study[J]. Neurology,2004,63(5):838-842.
[12]Wang X,Yang JH,Xing ZW,et al. IL-4 mediates the delayed neurobehavioral impairments induced by neonatal hepatitis B vaccination that involves the down-regulation of the IL-4 receptor in the hippocampus[J]. Cytokine,2018,110:137-149.
[13]Yang JH,Qi FF,Yang Y,et al. Neonatal hepatitis B vaccination impaired the behavior and neurogenesis of mice transiently in early adulthood[J]. Psychoneuroendocrinology,2016,73:166-176.
[14]Cosmi L,Maggi L,Santarlasci V,et al. Identification of a novel subset of human circulating memory CD4(+)T cells that produce both IL-17A and IL-4[J]. J Allergy Clin Immun,2010,125(1):222-230.
[15]Meyer U,Feldon J,Schedlowski M,et al. Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia[J]. Neurosci Biobehav R,2005,29(6):913-947.
[16]Meyer U,Feldon J. To poly(I:C)or not to poly(I:C):advancing preclinical schizophrenia research through the use of prenatal immune activation models[J]. Neuropharmacology,2012,62(3):1308-1321.
[17]Fortier ME,Luheshi GN,Boksa P. Effects of prenatal infection on prepulse inhibition in the rat depend on the nature of the infectious agent and the stage of pregnancy[J]. Behav Brain Res,2007,181(2):270-277.
[18]Wu Y,Qi F,Song D,et al. Prenatal influenza vaccination rescues impairments of social behavior and lamination in a mouse model of autism[J]. J Neuroinflammation,2018,15(1):228.
[19]Xia YC,Qi FF,Zou JT,et al. Influenza vaccination during early pregnancy contributes to neurogenesis and behavioral function in offspring[J]. Brain Behavior and Immunity,2014,42:212-221.
[20]Moon SH,Shin EC,Noh YW,et al. Evaluation of hyaluronic acid-based combination adjuvant containing monophosphoryl lipid A and aluminum salt for hepatitisBvaccine[J].Vaccine,2015,33(38):4762-4769.