摘要
本试验旨在研究不同维生素A(Vitamin,VA)水平对感染伪狂犬病毒(PseudorabiesVirus,PRV)雌鼠妊娠第9天免疫功能及繁殖性能的影响。VA缺乏模型建立后,选择体重为36.65±7.35(g)的160只雌鼠按照不完全配对试验设计分到8个处理组:其中5个VA水平(0 IU/kg、4000 IU/kg、10000 IU/kg、25000 IU/kg、50000 IU/kg)为PRV攻毒组,3个VA水平(0 IU/kg、4000 IU/kg、10000 IU/kg)为注射PBS的对照组。雌鼠于妊娠0天腹腔注射PRV或PBS。妊娠第9天屠宰收集孕鼠血清、脑、肝脏、脾脏、子宫和胚胎。利用HPLC测定肝脏中视黄醇浓度:普通PCR法检测脑组织PRV感染情况;计算脾脏指数;利用透射免疫比浊法测定血清免疫球蛋白(IgG、IgA、IgM)浓度;利用ELISA法测定血清细胞因子(IL-1β、IFN-γ、IL-4、IL-10)浓度;利用RT-PCR方法检测目的基因Toll样受体3(Toll-like receptor 3,TLR3)、7、9 mRNA在子宫和胚胎中的表达量。
结果表明:
1、肝脏中视黄醇浓度随VA水平的增加而增加。攻毒后,50000 IU/kg组孕鼠肝脏中视黄醇浓度显著高于其它VA水平组(P＜0.05)。攻毒组肝脏中视黄醇浓度低于PBS组,且4000 IU/kg攻毒组视黄醇浓度显著低于相同VA水平下PBS组(P＜0.05)。
2、攻毒后,VA缺乏组脾脏指数显著低于其它VA水平组(P＜0.05)。注射PBS条件下,0 IU/Kg和4000 IU/Kg组脾脏指数显著低于10000 IU/Kg组(P＜0.05)。4000IU/Kg攻毒组脾脏指数显著高于相同VA水平下PBS组(P＜0.05)。
3、攻毒后,50000 IU/Kg组血清IgA和IgM水平显著高于0 IU/Kg组(P＜0.05)。除VA缺乏组外,IgG水平随VA水平的增加而增加,4000 IU/Kg组显著低于10000IU/Kg组、25000 IU/Kg组和50000 IU/Kg组(P＜0.05)。注射PBS条件下,IgA、IgM和IgG水平随VA水平的增加而增加。攻毒组IgA和IgM水平低于PBS组,IgG水平高于PBS组。
4、补充VA有降低血清IL-1β、IFN-γ水平而增加IL-4、IL-10水平的趋势。攻毒后,25000 IU/Kg组血清IL-1β水平显著低于其它VA水平组(P＜0.05)。10000 IU/Kg组、25000 IU/Kg组和50000 IU/Kg组IFN-γ水平显著低于0 IU/Kg组和4000 IU/Kg组(P＜0.05)。25000 IU/Kg组IL-4水平显著高于其它VA水平组(P＜0.05)。25000 IU/Kg组IL-10水平显著高于0 IU/Kg组(P＜0.05)、4000 IU/Kg组(P＜0.05)和10000 IU/Kg组(P＜0.05);25000 IU/Kg组和50000 IU/Kg组间IL-10水平无显著差异(P＞0.05)。注射PBS条件下,10000 IU/Kg组IL-1β、IFN-γ水平显著低于0IU/Kg组(P＜0.05)。血清IL-4和IL-10水平随VA水平的增加而增加,其中10000 IU/Kg组血清IL-4水平显著高于0IU/Kg组(P＜0.05)。攻毒组血清1L-1β、IFN-γ水平高于PBS组,血清IL-4和IL-10水平低于PBS组。
5、补充VA降低妊娠9天子宫和胚胎TLR3、TLR7、TLR9相对表达量。攻毒后,25000 IU/Kg和50000 IU/Kg组子宫及胚胎TLR3、TLR7、TLR9相对表达量显著低于0 IU/Kg(P＜0.05)和4000 IU/Kg(P＜0.05)组。注射PBS条件下,10000 IU/Kg组子宫和胚胎TLR3、TLR9及胚胎TLR7相对表达量显著低于0 IU/Kg组(P＜0.05)。攻毒组子宫和胚胎TLR3、TLR7、TLR9相对表达量高于PBS组。
6、攻毒后,VA缺乏增加孕鼠死亡率和流产率,补充VA有降低死亡率和流产率趋势(P＞0.05)。
7、攻毒后,25000 IU/Kg组妊娠9天活胚数和分娩活仔数显著高于0 IU/kg组(P＜0.05)。活胚数随VA水平增加呈二次曲线变化,VA添加量为34265 IU/Kg时(正常需要量的8.5倍)达最大值。注射PBS条件下,妊娠9天活胚数和分娩活仔数随VA水平的增加而增加。攻毒组活胚数和分娩活仔数低于PBS组,且4000 IU/Kg攻毒组活胚数显著低于相同VA水平下PBS组(P＜0.05)。
结论:
1、VA临界缺乏状态下,感染PRV导致死亡率和流产率增加,活胚数和分娩活仔数降低;补充VA可降低孕鼠死亡率、流产率,提高妊娠9天活胚数和分娩活仔数;妊娠第9天活胚胎数达最大值时,孕鼠对VA的需要量达正常需要量的8.5倍。
2、VA缺乏的孕鼠感染PRV后上调TLR3、TLR7、TLR9 mRNA相对表达量,加剧Th1型促炎症细胞因子的表达,影响Th1/Th2免疫平衡状况,不利于动物繁殖性能的发挥;补充VA可降低TLR3、TLR7、TLR9 mRNA相对表达量,提高Th2型细胞因子的表达,改善Th1/Th2免疫平衡,从而对胚胎发育提供免疫保护效应。
3、补充VA可提高感染PRV孕鼠血清免疫球蛋白水平,提高孕鼠体液免疫功能,并改善胚胎发育。
This study was conducted to investigate effects of vitamin A on immunity and reproductive performance on 9~(th) pregnancy of mice infected Pseudorabies Virus.The mice model with vitamin A deficiency was established,160 mice weighted 36.65±7.35(g) were assigned to 8 treatments according to an incomplete paired design.Mice in the three control groups were injected with PBS and supplied with vitamin A at 0,4000 and 10000 IU/kg, respectively;mice in the five experimental groups were infected Pseudorabies Virus and supplied with Vitamin A at 0,4000,10000,25000 and 50000 IU/kg,respectively.Female mice were injected Pseudorabies Virus or PBS on 0~(th) pregnancy and mice were killed on 9~(th) pregnancy to collect serum、brain、liver、spleen、uterus and embryos.Hepatic retinol concentration was determinted by HPLC,Ordinary PCR was used to determine PRV infection in brain,calculation spleen index,Immunity Transmission Turbidimetry was applied to determine maternal immunoglobulins(IgG、IgA、IgM) concentration in serum,ELISA was applied to determin cytokine(IL-1β、IFN-γ、IL-4、IL-10) concentration in serum,and real time-quantitative RT-PCR was applied to determine the expression of genes(TLR3、TLR7、TLR9) in uterus and embryos.
The results were as follows:
1、Hepatic retinol concentration increased with vitamin A level and was lower in the challenged than in the PBS group.Among challenged groups,hepatic retinol concentration in the 50000 IU/kg group was significantly higher than other vitamin A groups(P＜0.05), and between 4000 IU/kg groups,it was significantly lower in the challenged than in the PBS group(P＜0.05).
2、Among challenged groups,spleen index was significantly lower in the 0 IU/kg than in other groups(P＜0.05),among PBS groups,it was significantly lower in the 0 and 4000 IU/kg group than in the 10000 IU/kg group(P＜0.05).and between 4000 IU/kg groups,it was significantly higher in the challenged than in the PBS group(P＜0.05).
3、Among challenged groups,IgA and IgM concentration in the 50000 IU/Kg group was significantly higher than in the 0IU/Kg group(P＜0.05).IgG concentration increased with vitamin A level except 0 IU/Kg group,and it was significantly lower in the 0 IU/Kg group than in the 10000 IU/kg,25000 IU/Kg and 50000 IU/Kg group(P＜0.05).Among PBS groups,IgA、IgM、IgG concentration increased with vitamin A level increased.Compared with PBS groups,IgG concentration increased and IgA、IgM concentration decreased in challenged groups at the same vitamin A level.
4、With vitamin A level increased,IL-1β、IFN-γconcentration tended to decrease and IL-4、IL-10 concectration tended to increase.Among challenged groups,IL-1βconcentration in the 25000 IU/Kg group was significantly lower than in other vitamin A groups(P＜0.05). IFN-γconcentration in the 10000 IU/Kg group、25000 IU/Kg group and 50000 IU/Kg group were significantly lower than in the 0 IU/Kg and 4000 IU/Kg group(P＜0.05).IL-4 concentration in the 25000 IU/Kg group was significantly higher than in other vitamin A groups(P＜0.05).IL-10 concentration in the 25000 IU/Kg group was significantly higher than in the 0 IU/Kg、4000 IU/Kg and 10000 IU/Kg group(P＜0.05),and there were no significant differences between 25000IU/Kg group and 50000 IU/Kg group(P＞0.05). Among PBS groups,IL-1β、IFN-γconcentration in the 10000 IU/Kg group was significantly lower than in the 0 IU/Kg group(P＜0.05).IL-4 and IL-10 concentration increased with vitamin A level increased,and IL-4 concentration in the 10000 IU/Kg group was significantly higher than in the 0 IU/Kg group(P＜0.05).Compared with PBS groups, IL-1β、IFN-γconcentration increased and IL-4、IL-10 concentration decreased in challenged groups at the same vitamin A level.
5、With vitamin A level increased,expression of TLR3/TLR7/TLR9 decreased.Among challenged groups,they were significantly lower in the 25000 IU/Kg and 50000 IU/Kg group than in the 0 IU/Kg and 4000 IU/Kg group(P＜0.05).Among PBS groups,expression of TLR3、TLR9 in uterus and embryos and TLR7 in embryos in the 10000 IU/Kg group were significantly lower than in the 0 IU/Kg group(P＜0.05).Expression of TLR3、TLR7、TLR9 was higher in challenged group than in the PBS group at the same vitamin A level.
6、Morality and abortion rate increased postchallenged,and tended to decrease with vitamin A level increased(P＞0.05).
7、Among challenged groups,live embryos and live litter size in the 25000 IU/Kg group were significantly higher than in the 0 IU/Kg group(P＜0.05).Regression analysis revealed that there was a quadratic increase in live embryos on 9~(th) pregnancy,with the highest values observed at 34265 IU/kg(8.5 times that of mice with normal live embryos).Among PBS group,live embryos on 9~(th) pregnancy and live litter size increased with vitamin A level increased.Live embryos and live litter size decaresed when infected PRV,and between 4000 IU/kg groups,it was significantly lower in the challenged than in the PBS group(P＜0.05).
Conclusion:
1、When vitamin A level was in marginal deficiency,Pseudorabies Virus infection resulted in increased abortion rate and mortality and decreased live embryos and live litter size;However,abortion rate and mortality decreased and live embryos and live litter size increased when supplied vitamin A,and vitamin A requirement of female mice with highest live embryos on 9~(th) pregnancy was 8.5 times that of mice with normal live embryos.
2、When vitamin A level was in marginal deficiency,Pseudorabies Virus infection resulted in increased expression of TLR3、TLR7、TLR9,then aggvarated expression of Th1 inflammatory factors,then affected Th1/Th2 immune balance,which was harmful to reproductive performance;However,expression of TLR3、TLR7、TLR9 decreased and level of Th2 antiinflammatory factor increased when supplied vitamin A,then Th1/Th2 immune balance improved which provided protective effect to embryonic development.
3、Spplied vitamin A to pregnant mice infected PRV can increase serum immunoglobulin concentration,increase humoral immunity and improve embryos development.
引文
[1]Takeda,K.,Kaisho,T.,and Akira,S.Toll-like receptors.Annu Rev.Immunol,2003,21:335-376
[2]Bry K,Lappalainen U.Interleukin-4 and transforming growth factor-beta 1 modulate the production of interleukin-1 receptor antagonist and of prostaglandin E2 by decidual cells[J].American Journal of Obstetrics and Gynecology,1994,170(4):1194-1198
[3]Robertson SA,Care AS,Skinner BJ.Interleukin 10 Regulates inflammatory Cytokine Synthesis to Protect Against Lipopolysaccharide-Induced Abortion and Fetal Growth Restriction in Mice[J].Biology of Reproduction,2007,76:738-748
[4]Bianchi A.T.J.,Moonen-Leusen H.W.M.,van Milligen F.J.,et al.A mouse model to study immunity against pseudorabies virus infection:significance of CD4+ and CD8+ cells in protective immunity.Vacdine,1998,16(16):1550-1558
[5]喻丽雅,王若光,尤昭玲等.黄芪丹参复方成分对一氧化氮合成阻滞孕鼠模型血浆IL-1、IL-10变化的影响.湖南中医学院学报,2005,25(5):8-11
[6]Cui D,Moldoveanu Z and Stephensen CB.High-Level Dietary Vitamin A Enhances T-Helper Type 2 Cytokine Production and Secretory Immunoglobulin A Response to Influenza A Virus Infection in BALB/c Mice.J.Nutr,2000,130:1132-1139
[7]Mueller,Tobias,Terada,et al.Th2 cytokines down-regulate TLR expression and function in human intestinal epithelial cells.J.Immunol,2006,176:5805-5814
[8]Lin Y,Liang Z,Chen Y,et al.TLR3-Involved Modulation of Pregnancy Tolerance in Double-Stranded RNA-Stimulated NOD/SCID Mice.The Journal of Immunology,2006,176:4147-4154
[9]Reyes H,Villalpando S,Cuevas RP,et al.Frequency and Determinants of Vitamin A Deficiency in Children Under 5 Years of Age with Pneumonia[J].Archives Medical Research,2002,33(2):180-185
[10]Abbas AK,Murphy KM and Sher A.Functional diversity of helper T lymphocytes.Nature,1996,383(6603):787-793
[11]Pasatiempo AM,Abaza M,Taylor CE,et al.Effects of timing and dose of vitamin A on tissue retinol concentrations and antibody production in the previously vitamin A-depleted rats.Am J Clin Nutr,1992,55:443-51
[12]Nikawa T,Odahara K,Koizumi H,et al.Vitamin A Prevents the Decline in Immunoglobulin A and Th2 Cytokine Levels in Small Intestinal Mucosa of Protein-Malnourished Mice.J.Nutr,1999,129:934-941
[13]Satre M A,Ugen KE,Kochhar DM.Developmental changes in endogenous retinoids during pregnancy and embryogenesis in the mouse[J].Biology of Reproduction,1992,46(5): 802-810
[14]Broek NVD.Anaemia and micronutrient deficiencies.British Medical Bulletin,2003,67:149-160
[15]White JC,Shankar VN,Highland M,et al.Defects in embryonic hindbrain development and fetal resorption resulting from Vitamin A deficiency in the rat are prevented by feeding pharmacological levels of all-trans-retinoic acid.Proc.Natl.Acad.Sci.USA,1998,95:13459-13464
[16]李娜,孙珊珊,王迪等.维生素A缺乏对雌性大鼠生长发育及胚胎影响.中国公共卫生,2007,23(10):1173-1175
[17]Coffey MT,et al.Enhancement of sow reproductive performance by beta-carotene or vitamin A,J.of Anim.Sci,1993,71(5):1198-1202
[18]刘光芒,吴德,张明等.铁与维生素A水平对小鼠子宫分泌蛋白及胚胎存活率影响.动物营养学报.2007,19(4):392-400
[19]樊建设,朱清华,刘烈刚.维生素A缺乏对小鼠胚胎Hox基因表达的影响.营养学报,1999,21(4):384-387
[20]何中滇,何婉蓉.视黄醇类对细胞生长的调节.国外医学卫生学分册,1985,12:150-153
[21]West KJ,Katz J,Khatry K,et al.Double blind,cluster randomized trial of low dose supplementation with vitamin A or B carotene on mortality related to pregnancy in Nepal.BMJ.1999;318:570-575
[22]Friedman.Decreased Resistance and Immune Response to Escherichia coli Infection in Chicks with Low or High Intakes of Vitamin A.Aharon Friedman,Amit Meidovsky,Gabriel Leitned and David Sklan.J.Nutr,1991,121:395-400
[23]Yu S,Xia M,Xu W,et al.All-trans retinoic acid biases immune response induced by DNA vaccine in a Th2 direction.Vaccine,2005,23:5160-5167
[24]Smith SM and Hayes CE.Contrasting impairments in IgM and IgG responses of vitamin A-deficient mice.Proc.Natl.Acad.Sci.USA.1987,84:5878-5882
[25]Walf G,et al.Recent evidence for the participation of vitamin A in glycoprotein synthesis.Fed Proc,1979,38:2540
[26]Lomo J,Smeland EB,Ulven S,et al.RAR-,not RXR,ligands inhibit cell activation and prevent apoptosis in B-lymphocytes[J].Journal of Cellular Physiology,1998,175(1):68-77
[27]陈晓,邓昌辉,陈莉.Th1、Th2型细胞因子对妊娠免疫调节的研究.医学综述,2002,8(9):540-541
[28]Agarwal RK,Chan CC,Wiggert B.et al.Pregnancy ameliorates induction and expression of experimental autoimmune uveitis,Journal of Immunology,1999,162(5):2648-2654
[29]刘富强、黄忆明.大鼠孕期、哺乳期维生素A水平对仔鼠细胞免疫功能的影响.实用 项防医学,2002,9(2):141-144
[30]Stoltzfus.RJ,Jalal.F,Harvey.PWJ,et al.Interactions between Vitamin A Deficiency and Plasmodium berghei Infection in the Rat.Journal of Nutrition,1989,119(12):2030-2037
[31]刘雅明,华春珍,黄先玫.维生素A对动物器官影响的实验研究.中国实验临床免疫学杂志,1997,9(2):24-26
[32]周源苑,王玉,马剑华.维生素A和锌过量摄人对大鼠脾脏的损伤作用.中国公共卫生,2006,22(9):1055-1056
[33]Chun TY,Carman JA and Colleen E.Hayes.Retinoid Repletion of Vitamin A-Deficient Mice Restores IgG Responses.J.Nutr,1992,122:1062-1069.
[34]Gajewski TF and Fithc FW.Anti-proliferative effect of IFN-γ in immune regulation.I.IFN-γinhibits the proliferation of Th2 but not Th1 murine helper T lymphocyte clones.J.Immunol,1998,140:4245-4252
[35]Keelan JA,Sato TA.,Hansen WR.,et al.Interleukin-4 differentially regulates prostaglandin production in amnionderived WISH cells stimulated with pro-inflammatory cytokines and epidermal growth factor.Prostaglandins,Leukotrienes and Essential Fatty Acids,1999,60(4):255-262
[36]Carman JA,Smith SM,and Hayes CE.Characterization of a helper T lymphocyte defect in vitamin A-deficient mice.J.Immunol,1989,142:388-393
[37]Dudley DJ.Pre-term labor:an intra-uterine inflammatory response syndrome? Journal of Reproductive Immunology,1997,35:93-109
[38]Blackwell TS,Christman JW.The role of nuclear factor-kappa B in cytokine gene regulation.Am J Respir Cell Mol Biol,1997,17(1):3-9.
[39]Sergerie Y,Rivest S,and Boivin G.Tumor Necrosis Factor-alpha and Interleukin-1beta Play a Critical Role in the Resistance against Lethal Herpes Simplex Virus Encephalitis.The Journal of Infectious Diseases,2007,196(6):853-60
[40]Reznikov LL,Fantuzzi G,Selzman CH,et al.Utilization of Endoscopic Inoculation in a Mouse Model of Intrauterine Infection-Induced Preterm Birth:Role of Interleukin 1β.BIOLOGY OF REPRODUCTION,1999,60:1231-1238
[41]Clifford L.Libraeh,Seth L.Feigenbaum,Kathryn E.Bass,et al.Interleukin-1β Regulates Human Cytotrophoblast Metalloproteinase Activity and Invasion in Vitro.The Journal of Biological Chemistry,1994,269(25):17125-17131
[42]Karagouni EE,Chryssikopoulos A,Mantzavinos T,et al.Interleukin-1 beta and interleukin 1alpha may affect the implantation rate of patients undergoing in vitro fertilization-embryo transfer.Fertil Steril,1998,70(3):553-559
[43]Hoag KA,Nashold FE,Goverman J,et al.Retmoie Acid Enhances the T Helper 2 Cell Development That Is Essential for Robust Antibody Responses through Its Action on Antigen-Presenting Cells.J.Nutr,2002,132:3736-3739
[44]Long KZ,Garcia TE,Rosado JL,et al.The Effect of Vitamin A Supplementation on the Intestinal Immune Response in Mexican Children Is Modified by Pathogen Infections and Diarrhea.J.Nutr,2006,136:1365-1370
[45]Long MT,Baszler TV.Neutralization of maternal IL-4 modulates congenital protozoal transmission:comparison of innate versus acquired immune responses.Journal of Immunology,2000,164(9):4768-4774
[46]陶月红,杨毅,王卫平.维生素A对树突状细胞的调节及其在粘膜免疫中的作用[D].上海:复旦大学,2006
[47]Stephensen CB.Vitamin A,Infection,and Immune Function.Annual Review of Nutrition,2001,21:167-92
[48]Stephensen CB,Rasooly R,Jiang XW,et al.Vitamin A Enhances in Vitro Th2 Development Via Retinoid X Receptor Pathway.The Journal of Immunology,2002,168:4495-4503
[49]Racke MK,Burnett D,Pak SH,et al.Retinoid treatment of experimental allergic encephalomyelitis lL-4 prodiction correlates with improved disease course.Journal of lmmunology,1995,154(1):450-458
[50]Sarkar J,Gangopadhyay NN,Moldoveanu Z,et al.Vitamin A Is Required for Regulation of Polymeric Immunoglobulin Receptor(pIgR) Expression by Intedeukin-4 and Interferon-γ in a Human Intestinal Epithelial Cell Line.J.Nutr,1998,128:1063-1069
[51]Ramphal R,Cogliano RC.,Shands JW,Jr.et al.Serum antibody prevents lethal murine influenza pneumonitis but not tracheitis.Infect Immun,1979,25:992-997
[52]Kinoshita M,Pasatiempo AMG.,Taylor CE.et al.Immunological memory to tetanus toxoid is established and maintained in the vitamin A-depleted rat.FASEB J,1991,5(10):2473-2481
[53]Akira S,Takeda K.Toll-like receptor signaling.Nat Rev Immnol,2004,4(7):499-511
[54]Akira S,Uematsu S,Takeuchi O.Pathogen recognition and innate immunity[J].Cell,2006,124(4):783-801
[55]张建红.Toll样受体对子宫NK细胞的调控特征及其与母胎耐受的关系.中国科技大学,2007
[56]Jorgenson RL,Yonng SL,Lesmeister MJ,et al.Human Endometrial Epithelial Cells Cyclically Express Toll-Like Receptor 3(TLR3) and Exhibit TLR3-Dependent Responses to dsRNA.Human Immunology,2005,66,469-482
[57]Le Goffic R.,Balloy V,Lagranderie M,et al..Detrimental contribution of the Toll-like receptor(TLR)3 to influenza A vires-induced acute pneumonia.PLoS Pathogens,2006,2(6): 526-535
[58]Vercammen E,Staal J,and Beyaert R.Sensing of Viral Infection and Activation of Innate Immunity by Toll-Like Receptor 3.Clincal Microbiology Reviews,2008,21(1):13-25
[59]Elovitz MA,Wang Z,Chien EK,et al.A New Model for Inflammation -Induced Preterm Birth:The Role of Platelet-Activating Factor and Toll-Like Receptor-4.American Journal of Pathology,2003,163(5):2103-2111
[60]Nishiya T,Kajita E,Miwa S,et al.TLR3 and TLR7 Are Targeted to the Same Intracellular Compartments by Distinct Regulatory Elements.Journal of Biological Chemistry,2005,280(44):37107-37117
[61]唐宗青.TLR7配体Loxoribine对调节性T细胞抑制作用的解除.上海交通大学学报(农业科学版,2007,25(6):525-530
[62]Fransen F,Boog C J,van Putten J P,et al.Agonists of Toll-like receptor 3,4,7,and 9 are candidates for use in an outer membrane vaccine against Neisseria meningitidis serogroup B [J].Infection and Immunity,2007,75(12):5939-5946
[63]Fili L,Ferri S,Guaina F,et al.Redirection of allergen-specific Th2 response by a modified adenine through toll-like receptor 7 interaction and IL-12/IFN release[J].J Allergy Clin Immunol,2006,118:511-517
[64]Schlaepfer E,Audige A,Joller H,et al.TLR7/8 Triggering Exerts Opposing Effects in Acute versus Latent HIV Infection.The Journal of Immunology,2006,176:2888-2895
[65]Schlender J,Homung V,Finke S,et al.Inhibition of toll-like receptor 7-and 9-mediated alpha/beta interferon production in human plasmacytoid dendritic cells by respiratory syncytial virus and measles virus[J].Journal of Virology,2005,
[66]Lund J,Sato A,Akira S,Medzhitov.R,lwasaki.A.Toll-like receptor 9-mediated recognition of herpes simplex virus-2 by plasmacytoid dendritic cells[J].Journal of Experimental Medicine,2003,198(3):513-520
[67]徐佩红,袁定芬,薛峰等.生殖器疱疹患者外周血单个核细胞TLR9的表达及血清IL-12、IFN-γ水平的研究.诊断学理论与实践,2007,6(4):366-368
[68]丁歆,付琳琳,苏稚辉等.葡萄膜炎患者外周血单个核细胞TLR9、TLR7 mRNA的表达及意义.徐州医学院学报,2008,28(4):222-224
[69]Tudor D,Dubuquoy C,Gaboriau V,et al.TLR9 pathway is involved in adjuvant effects of plasmid DNA-based vaccines.Vaccine,2005,23:1258-1264
[70]Bernasconi NL,Onai N,Lanzavecchia A.A role for Toll-like receptors in acquired immunity:up regulation of TLR9 by BCR triggering in naive B cells and constitutive expression in memory B cells.Blood,2003,101:4500-4504
[71]Eisenacher K,Steinberg C,Reindl W,et al.The role of viral nucleic acid recognition in dendritic cells for innate and adaptive antiviral immunity.Immunobiology,2008,212:701-714
[72]Liu P T,Stenger S,Li H,et al.Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response.Science,2006,311(5768):1770-1773
[73]Sadeghi K,Wessner B,Laggner U,et al.Vitamin D3 down-regulates monocyte TLR expression and triggers hyporesponsiveness to pathogen-associated molecular patterns.Eur.J.Immunol,2006,36:361-370
[74]Skj(?)veland I,Iliev DB,Zou J,et al.A TLR9 homolog that is up-regulated by IFN-γ in Atlantic salmon(Salmo salar).Developmental and Comparative Immunology,2008,32:603-607
[75]SMITH SM,LEVY NS AND COLLEEN E.HAYES.Impaired Immunity in Vitamin A-Deficient Mice.J.Nutr,1987,117:857-865
[76]Stephensen CB,Blount SR,Schoeb TR,et al.Vitamin A Deficiency Impairs Some Aspects of the Host Response to Influenza A Virus Infection in BALB/c Mice.J.Nutr,1993,123:823-833
[77]Reeves PH,Nielsen FH,Fahey GC.AIN-93 Purified Diets for Laboratory Rodents:Final Report of the American Institute of Nutrition AdHoc Writing Committee on the Reformulation of the AIN-76A Rodent Diet.Journal of Nutrition,1993,123:1939-1951
[78]Pasatiempo AMG,Bowman TA,Taylor CE,et al.Vitamin A depletion and repletion:effects on antibody response to the capsular polysaccharide of Streptococcus pneumoniae,type III(SSS-III).American Journal of Clincal Nutrition,1989,49:501-10
[79]许蕴,马经野,付林等.反相高效液相色谱法测定人血清中维生素A含量.深圳中西医结合杂志,2005,15(3):175-177,182
[80]谭青松,付洁,何瑞国.高效液相色谱法测定鱼样中的维生素A、维生素D3和维生素E.动物营养学报,2007,19(5):636-640
[81]梁鸿雁,王玉海,高宏伟等.日粮锌与维生素A水平对维生素A代谢的影响.辽宁畜牧兽医,2004(4):8-10
[82]West CE,Sutsma SR,Kouwenhoven B,et al.Epithelia-Damagingg Virus Infections Affect Vitamin A Status in Chickens.Journal of Nutrition,1992,122:333-339.
[83]Athanassakis I,Aifantis I,Ranella A,et al.Inhibition of Nitric Oxide Production Rescues LPS-Induced Fetal Abortion in Mice.Biology and Chemistry,1999,3(3):216-224
[84]Kang MK,Yoon YE,Yang JY,et al.Protective effect of retinoic acid on interleukin-1-β-induced cytotoxicity of pancreatic -β-cells.Mechanisms of Ageing and Development,2004,125(7):483-490
[85]Somi SS.Cytokines during early pregnancy of mammals:a review.Anim Reprod sci,2003, 75:73-94
[86]Hart OM,Athie-Morales V,O'Connor GM,et al.TLR7/8-Mediated Activation of Human NK Cells Results in Accessory Call-Dependent IFN-γ Production.The Journal of Immunology,2005,175:1636-1642
[87]Dugas B,Debre P,and Moncada S.Nitric oxide,a vital poison~-inside the immune and inflammatory network,Res.Immunol,1995,146:664-670
[88]Zhang JH,Croy BA,Tian ZG.Uterine natural killer cells:their xhoices,rtheir missions[J].Cel Mole Immunol,2005,2:124-129
[89]Klugcr MJ.Fever:role of pyrogens and cryogens.Physiol.Rev,1991(1),71:93-127
[90]Rothwell NJ,Luheshi G,Toulmond S.Cytokines and their receptors in the central nervous system:physiology,pharmacology,and pathology.Pharmacology &Therapeutics,1996,69(2):85-95
[91]Taylor AN,Tio DL,Yirmiya R.Fetal alcohol exposure attenuates interleukin-1β-induced fever:neuroimmune mechanisms.Journal of Neuroimmunology 1999,99(1):.44-52
[92]盛晓蓉,吴纳新,刁慧敏等.丹参治疗单纯疱疹病毒性脑炎小鼠脑损伤实验研究.中国临床药理学与治疗学,2006,11(3):336-338
[93]Kauma SW.Interleukin-1β Stimulates Colony-Stimulating Factor-1 Production in Human Term Placenta.Journal of Clinical Endocrinology Metabolism,1993,76:701-703
[94]李风雷.白细胞介素-10和急性肺损伤[J].国外医学:呼吸系统分册,2001,21(2):57-58
[95]石增立,刘凤,石磊等.油酸型急性呼吸窘迫综合征大鼠血清及肺组织IL-4、IL-10、IL-12水平的变化.中国病理生理杂志,2003,19(7):939-941
[96]Sanders CM,Cruse JM,Lewis RE.Toll-like receptors,cytokines and HIV-1.Experimental and Molecular Pathology,2008,84:31-36
[97]Rivera DL,Olister SM,Liu X,et al.Interleukin-10 attenuates experimental fetal growth restriction and demise[J].Faseb J,1998,12:189-197
[98]Vigano P,Gaffuri B,Somigliana E,et al.Interleukin -10 is produced by human uterine natural killer cells but does not affect their production of interferon-γ.Molecular Human Reproduction,2001,7(10):971-977
[99]Stephensen CB,Moldoveanu Z and Gangopadhyay NN.Vitamin A Deficiency Diminishes the Salivary Immunoglobulin A Response and Enhances the Serum Immunoglobulin G Response to Influenza A Virus Infection in BALB/c Mice.J.Nutr,1996,126:94-102
[100]Burgos JS,Ramirez C,Brachet A,et al.Changes in immunoglobulin levels related to herpes simplex virus type 1 brain infection in pregnant mice.Journal of NeuroVirology,2007,13:233-241
[101]TANAKA S and MANNEN K.Pregnancy and Parturition of Mice Latently Infected with Pseudorabies Virus.Exp. Anim, 2008, 57 (2 ): 149-152
[102] Chinsakchai S, Molitor TW. Immunobiology of pseudorabies virus infection in swine. Veterinary Immunology and Immunopathology, 1994,43: 107-116
[103] Miyajima T, Hirata AA, Terasaki PI. Escape from sensitization to HL-A antibodies[J]. Tissue Antigens, 1972,2:64-73
[104] Bansal SC. Cytotoxicity and blocking factors in neoplasia. Progress in Immunology II[J], 1974, 3: 394-397
[105] Sjogren HO., Hellstrm I, Bansal SC, et al. Suggestive evidence that the "blocking antibodies" of tumor-bearing indivuduals may be antigen-antibody complexes[J]. Proc.Natl Acad. Sci, 1971,68: 1372-1375
[106] Linscott WD. Effect of cell surface antigen density on immunological enhancement[J]. Nature, 1970,228: 824-827
[107] West J and Damania B. Upregulation of the TLR3 Pathway by Kaposi's Sarcoma-Associated Herpesvirus during Primary Infection. JOURNAL OF VIROLOGY, 2008: 5440-5449
[108] Quayle AJ. The innate and early immune response to pathogen challenge in the female genital tract and the pivotal role of epithelial cells. J. Reprod.Immunol, 2002,57: 61-79
[109] Zhang JH, Wei HM, Wu DM, et al. Toll-like receptor 3 agonist induces impairment of uterine vascular remodeling and fetal losses in CBAxDBA/2 mice. Journal of Reproductive Immunology. 2007, 74: 61-67
[110] Diebold SS, Kaisho T, Hemmi H, et al. Innate Antiviral Responses by Means of TLR7-Mediated Recognition of Single-Stranded RNA.Science, 2004, 303: 1529-1531
[111] Sergerie Y, Boivin G, Gosselin D,et al. Delayed but not early glucocorticoid treatment protects the host during experimental herpes simplex virus encephalitis in mice. J Infect Dis ,2007, 195(6): 817-25.
[112] Martin-Armas M, Simon-Santamaria J, Pettersen I, et al. Toll-like receptor 9 (TLR9) is present in murine liver sinusoidal endothelial cells (LSECs) and mediates the effect of CpG-oligonucleotides. Journal of Hepatology, 2006,44:939-946
[113] Chaturvedi A, Dorward D, and Pierce SK. The B Cell Receptor Governs the Subcellular Location of Toll-like Receptor 9 Leading to Hyperresponses to DNA-Containing Antigens. Immuunity, 2008, 28: 799-809
[114] Takeda K and Akira S. Roles of Toll-like receptors in innate immune responses. Genes to Cells, 2001, 6(9): 733-742