自身免疫性卵巢早衰的诊断与治疗的研究
详细信息    本馆镜像全文|  推荐本文 |  |   获取CNKI官网全文
摘要
目的探讨自身免疫性POF的免疫学诊断方法;建立自身免疫性POF动物模型,采用糖皮质激素和雄激素治疗自身免疫性POF模型小鼠为临床治疗提供理论依据。
     方法分三个部分进行。
     第一部分自身免疫性卵巢早衰的诊断的研究:52例卵巢早衰并不孕症患者为研究组,20例其他原因不孕症患者为对照组,分别检查血清抗核抗体,抗卵巢组织抗体,抗心磷脂抗体,抗甲状腺微粒体抗体,抗双链DNA抗体,免疫球蛋白IgG,IgA,IgM,IgE,补体C_3,C_4含量及抗透明带抗体浓度,并进行统计学分析。
     第二部分实验性自身免疫性卵巢早衰小鼠模型的建立:取近交系雌性小鼠(C57BL/6J),鼠龄7-9周130只,分别为模型组120只、空白对照组10只,各组小鼠均于双后脚掌掌心处进行皮下注射。模型组注射CFA—pZP3混合液0.1毫升,其中包含CFA:0.05毫升,pZP3:72.225ug;空白对照组注射三蒸水0.1毫升。建模观察指标为①各组小鼠阴道脱落细胞涂片观察性周期的改变;②采用ELISA检测小鼠外周血清中抗透明带抗体的浓度;③光学显微镜检查各组小鼠卵巢组织学改变:以生长卵泡所占比例表示卵巢萎缩受损程度;④免疫组化法检测卵巢组织中CD45阳性细胞的浸润程度判断其自身免疫性卵巢炎严重程度。模型组随机选择10只小鼠与空白组进行统计学比较和分析,评估建模是否成功。小鼠的研究:以出现明显性周期紊乱为标准,选择建模成功的自身免疫性POF小鼠80只,随机分为4组:每组20只,模型对照组同期每日腹腔注射三蒸水0.05ml,其余三组分别给以糖皮质激素、雄激素、糖皮质激素加雄激素联合治疗三个性周期,以上述建模指标进行检测作为疗效观察指标,判断其治疗效果,并进行统计学分析。
     结果
     第一部分:研究组ANA,AOAb,ds-DNA,A-TG阳性率及抗透明带抗体浓度分别为38.5%,40.4%,35.5%,44.2%和110.42±10.38pg/ml,均显著性高于对照组,P<0.05;研究组ACA、免疫球蛋白IgM、补体C_3异常率较高,分别28.8%、23.1%和25%,但与对照组无显著性差别,P>0.05;研究组免疫球蛋白IgG,IgA,IgE,补体C_4异常率较低分别为5.8%,1.9%,1.9%,3.8%,与对照组无显著性差别,P>0.05。
     第二部分:模型组小鼠80%表现为性周期紊乱,血清抗透明带抗体平均浓度高达17.55±3.52(ng/ml),生长卵泡比例低达22.44±5.88(%),出现自身免疫性卵巢炎,即CD45阳性细胞浸润的小鼠比例为90%,上述指标均较空白组有显著性差异,P<0.01。
     第三部分:①性周期正常者糖皮质激素组60%,雄激素组70%,联合治疗组65%,模型对照组仅10%。各治疗组与模型对照组均存在显著差异,P<0.01。但三个治疗组进行两组间比较,均无显著差异,P>0.05。②皮质激素组、雄激素组及联合治疗组小鼠血清抗透明带抗体平均浓度分别为(ng/ml)21.18±6.72,16.12±4.64和18.32±5.28,与模型对照组(32.61±8.77)比较均存在显著差异,P<0.01。糖皮质激素组明显高于与雄激素组,P<0.01。糖皮质激素组与联合治疗组、雄激素组与联合治疗组之间均不存在显著差异,P>0.05。③糖皮质激素组、雄激素组及联合治疗组各组小鼠组织学检查生长卵泡比例分别为(%)36.8±8.00,37.5±6.06和30.71±4.36,与模型对照组(25.72±5.31)比较均存在显著差异,P<0.01。糖皮质激素组与雄激素组无显著差异,P>0.05;糖皮质激素组与联合组、雄激素组与联合治疗组之间均存在显著差异,P<0.01。④各组出现自身免疫性卵巢炎,即CD45阳性细胞浸润的小鼠比例分别为糖皮质激素组25%,雄激素组30%,联合治疗组50%,均与模型对照组90%存在显著差异,P<0.01。三个治疗组进行两组间比较,均无显著差异,P>0.05。
     结论
     1.卵巢早衰患者存在多种自身免疫性抗体,ANA,AOAb,ds-DNA,A-TG,抗透明带抗体等检测对诊断自身免疫性卵巢早衰有临床实际意义。
     2.通过给小鼠皮下免疫注射小鼠透明带多肽片段,成功地建立了小鼠的自身免疫性卵巢早衰的实验动物模型,为进行卵巢早衰的诊断学及治疗学方面的研究提供了前提条件。
     3.糖皮质激素和雄激素均能显著改善实验性自身免疫性卵巢早衰小鼠的临床症状及免疫反应指标。且二者疗效无显著性差异。
     4.糖皮质激素和雄激素联合治疗实验性自身免疫性卵巢早衰小鼠的效果并不优于上述两者的单独治疗效果。
Objective:To establish the immunologic diagnostic methods of autoimmune premature ovary failure(POF)and to induce the animal model of autoimmune POF and provide theoretical evidence for treatment of autoimmune POF by glucocorticoids and androgen.
     Methods:
     Part 1 Study of diagnosis of autoimmune POF:52 patients with POF complicating infertility were chosen for test group,and 20 patients with infertility caused by others factors were chosen for control We detect and analyze the serum levels of ANA,AoAb,AcA,A-TG,ds-DNA, immunoglobulins IgG、IgA、IgM、IgE,complement C3、C4 and AzpAb.
     Part 2 Induction of animal model of autoimmune POF:We bought 130 seven-to nine-week old female inbred line mice(C57BL/6J)from the SLACCAS animal centre,and divided them into two groups:10 mice in the control group and 120 in the model group.Each mouse accepted subcutaneous injections in both posterior sole of feet.The model group was injected with CFA—pZP3 mixed solution,which contained CFA: 0.05ml,pZP3:72.225ug.And the control group was injected with 0.1ml of distilled water.Observation indices included:①Smear of the vaginal cast-off cell of the mice for sexual cycle observation;②Detection of AzpAb serum level by ELISA;③Observation of the histological changes of the mice by HE slicing under optical microscope; ④Evaluation of the severity of autoimmune oophoritis via examining infiltration of cells expressing CD45 in the ovary by immunohistochemisty to.
     Part 3 Study of therapy methods of glucocorticoids or androgen for autoimmune POF:We choose 80 mice of autoimmune POF,and randomly distributed them into 4 groups,20 mice per group.Three groups were treated by glucocorticoids,androgen,or therapeutic alliance of glucocorticoids and androgen repsectively.We evaluated and analyzed the treatment effectiveness of these three therapeutic methods according to the index above.
     Results:
     Part 1 The serum level of AzpAb and positive rates of ANA, AoAb,ds-DNA and A-TG in the test group were 110.42±10.38pg/ml, 38.5%,40.4%,35.5%,44.2%respectively,which were all higher than the control group(P<0.05).Abnormality rates of ACA,immunogloblin IgM,complement C3 in the test group were 28.8%、23.1%and 25% respectively,which were found to be higher than the control group. However,the difference was not significant(P>0.05).Abnormality rates of immunogloblin IgG,IgA,IgE and complement C4 were 5.8%,1.9%, 1.9%,3.8%respectively,which was found to be lower than the control group,but not significantly so(P>0.05).
     Part 2 Eighty percent of mice in the model group were found to have disordered sexual cycles.The mean serum level of AzpAb was at 17.55±3.52ng/ml,whereas the proportion of growing follicles was only 22.44±5.88%.In addition,ninety percent of mice suffered from ovary infiltration of cells positively expressing CD45,which supported autoimmune oophoritis.Thus,all theindices in the model group were significantly different from the control group(P<0.01).suggesting that the animal model of autoimmune POF was successful.
     Part 3①Comparison of sexual cycles of each group after treatment: Sexual cycle of 60%of mice in the glucocorticoids group was normal, while 70%in the androgen group,65%in the therapeutic alliance group, but 10%model control group were normal.Each therapeutic group was significantly different from the control group(P<0.01)However,the differences among the three therapeutics groups were not significant(P>0.05)②Comparison of serum levels of AzpAb of each group after treatment:The serum levels of AzpAb in glucocorticoids group,androgen group and therapeutic alliance group was 21.18±6.72ng/ml,16.12±4.64 ng/ml and18.32±5.28ng/ml respectively.All of the above values were significantly different from the model control group(32.61±8.77 ng/ml)(P<0.01).The difference between the glucocorticoids group and androgen group was significant(P<0.01).But the difference between the glucocorticoids group and the therapeutic alliance group,or androgen group and the therapeutic alliance group were not significant(P> 0.05).③Comparison of the proportion of growing follicles in each group after treatment:The proportion of growing follicles in glucocorticoids group,androgen group and therapeutic alliance group was36.8±8.00%, 37.5±6.06%and30.71±4.36%respectively,all of which was significantly different from the model control group(25.72±5.31%,P<0.01).The difference between the glucocorticoids group and androgen group was not significant,(P>0.05).But the difference between the glucocorticoids group and the therapeutic alliance group,or androgen group and the therapeutic alliance group were significant,(P<0.01).④Comparison of infiltration of lymphocytes in the ovaries:Twenty five percent of mice in the glucocorticoids group suffered from oophoritis,that was,the infiltration of cells expressing CD45 in the ovaries,while 30%in the androgen group,50%in the therapeutic alliance group,90%in the model group suffered from oophoritis.Each therapeutic group was significantly different from the control group(P<0.01).But the differences among the three therapeutics groups were not significant(P>0.05).
     Conclusion:
     1.We found many kinds of autoimmune antibodies in patients with POF.Detection of ANA,AOAb,ds-DNA,A-TG and AzpAb was of clinical significance to diagnosing autoimmune premature ovary failure.
     2.We successfully developed animal model of autoimmune premature ovary failure by active immunization of adult mouse with a murine ZP3 peptide(pZP3)in complete Freund's adjuvant(CFA),and provided conditions for further research of POF in diagnostics and therapeutics.
     3.We found that both glucocortcoids and androgen could significantly redress the clinical symptons and immunical indicators of autoimmune POF.But the differences between them were not significant (P>0.05).
     4.We found that the therapeutic alliance of glucocorticoids and androgen was not better than either glucocorticoids or androgen alone.
引文
[1]王伟,李继俊.卵巢早衰的病因学研究进展.现代妇产科进展,2002,11(2):136-137.
    [2]Irvine WJ,Chan MM,Scarthage L,et al.Immunological aspects of premature ovarian failure associated with idiopathic Addison's disease.Lancet,1968,2(7574):883-887.
    [3]Chang DM,Chu SJ,Chen HC,et al.Dehydroepiandrosterone suppresses Interleukin-10 synthesis in women with systemic lupus erythematosus[J].Ann Rheum Dis,2004,63(12):1623-1626.
    [4]莫中福,徐素欣.卵巢早衰病因及诊治的研究进展.河北医科大学学报,2006,27(3)230-233.
    [5]李诵絃,于传鑫主编.实用妇科内分泌学.第1版.上海:上海医科大学出版社,1997,64-68.
    [6]王一峰,欧汝强,杨宁等.卵巢早衰表明血清抗透明带抗体和肿瘤坏死因子-a,γ-干扰素及白细胞介素-2的分析.生殖医学杂志,2002,11(2):7-10.
    [7]Coulam JB,The prevalence of autoimmune disorders among patientes with primary ovarian failure.Am J Reprod Immunol,4:63-66.
    [8]Luborsky JL,Meyer P,Sowers MF,et al.Premature menopause in a multi-ethnic population study of the menopause transition.Hum Reprod,2003,18(1):199-206.
    [9]Fenichel P,Sosset C,Barbarino M,et al.Prevalence specificity and significance of ovarian antibodies during spontaneous premature ovarian failure[J].Hum Reprod,1997,12(12):2623-2628.
    [10]Alper MM and Garner PR.Premature ovarian failure:its relationship to autoimmune disease.Obstet Gynecol,66:27-30.
    [11]张学武,粟占国,郭嘉玲等.系统性红斑狼疮患者抗卵巢细胞抗体与月经不调的相关性研究.中华风湿病学杂志,2006,10(2):69-67.
    [12]Ishizuka B,Kudo Y,Ameniya A,et al.Anti-nuclear antibodies in patients with premature ovarian failure[J].Hum Reprod,1999,14:70-75.
    [13]任平,卢坚贞,马艳萍.生殖免疫自身抗体多项检测和复查与不孕的临床分析.中国优生与遗传杂志,2005,13(3):96-97.
    [1]Bagavant H,Adams S,Terranova P,et al.Autoimmune ovarian inflammation triggered by proinflammatory(Th1)T cells is compatible with normal ovarian function in mice[J].Biol Reprod,1999,61(3):635-642.
    [2]付莉,赵怡璇,李守柔.卵巢早衰实验动物模型的建立.生殖医学杂志,2006,15(6):179-183.
    [3]K Tung,S Agersborg,H Bagavant,et al.Autoimmune ovarian disease induced by immunization with zona pellucida(ZP3)peptide.Curr Protoc Immunol,2002,15:15-17.
    [4]林其德等。现代生殖免疫学,2006年12月第一版,人民卫生出版社,355-356.
    [5]林建化,严隽鸿。自身免疫性卵巢衰退小鼠动物模型的建立。上海医学,1999,22(12):747-748.
    [6]Sjokin,K.,Dalmasso,A.P.,Smith,J.P.and Martinez,C.Thymectomy in newborn and adult mice.Transplantation,1963,1:521.
    [1]Burnstein KI,Cidlowski JA.The down side of glucocorticoid receptor.Mol Cell Endocrinol,1992,83:1-8.
    [2]Chang DM,Chu SJ,Chen HC,et al.Dehydroepiandrosterone suppresses Interleukin-10 synthesis in women with systemic lupus erythematosus[J].Ann Rheum Dis,2004,63(12):1623-1626.
    [3]Cowchock FS,McCabe JL and Montgomery BB Pregnancy after corticosteroid administration in premature ovarian failure (polyglandular endocrinopathy syndrome).Am J Obstet Gynecol,1988,158:118-119.
    [4]Fernandes AM,Arruda Mde S,Bedone AJ.Twin gestation two years after the diagnosis of premature ovarian failure in a woman on hormone replacement therapy. A case report [J] . J Reprod Med , 2002 ,47(6) : 504-506.
    [5] Kalantaridou, S. N., Davis SR and Nelson LM Premature ovarian failure. Endocrinol Metab Clin North Am, 1998,27:989-1006.
    [6] Korczowska I, Lacki JK, Leszczynski P, et al. Bone tissue metabolism in systematic lupus erythematosus patients treated with glucocorticosteroids [J].Pol Arch Med Wewn, 2001, 106(4):901-907.
    [7] Jacobson DL , Grange SJ , Rose NR , et all Epidemiology and estimated population burden of selected autoimmune diseases in the United States [J]. Clin Immunol Immunopathol, 1997 ,54 :22-31.
    [8] Cutolo M, Seriolo B, Villaggio B, et all Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis[J].Ann N YAcad Sci,2002, 966:1311.
    [9] Loria RM. Immune up-regulation and tumor apoptosis by androstene steroids[J]. Steroids, 2002,67:9531.
    [10] Kazem Ahmadi, Alan B. McCruden, Macrophage may responses to androgen via its Receptor. Med Sci Monit, 2006, 12(1): 15-20.
    [11] BentenW P, BeckerA, Peter H, et al. Developmental regulation of intracellular and surface androgen recep tors in T cells[J]. Steroids, 2002,67 (11):925-931.
    [12]姚根宏.雄激素对免疫系统的影响.中华男科学,2001,7(6):401-403.
    [1] Baugh JA, Bucala R. Macrophage migration inhibitory factor [J]. Crit CareMed, 2002, 30(1 Supp): 27-35.
    [2] Denkinger CM,Denkinger M, Kort JJ. In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System.The Journal of Immunology,2003,170:1274-1282.
    [3]Atluru D,Gudapaty S.Evidencethatgenistein,aprotein-tyrosineki-naseinhibitor,inhibits CD28 monoclonal-antibody-stimulated human T cell proliferation[J].Transplantation,1991,51:448-450.
    [4]Wagle NM,Kim JH,Pierce SK.Signaling through the B cell antigen Receptor regulates discrete steps in the antigen processing pathway[J].Cell Immunol,1998,184:1-11.
    [5]Xagorari A,Papapetropoulos A.Luteolin inhibits an endotoxin-stimu-Lated phosphory lation cascade and proin flammatory cytokine production in macrophages[J].J Pharm acol Expher,2001,296:181-187.
    [6]朱国超,陈知水.染料木黄酮的免疫调节作用及其在器官移植中的应用[J].细胞与分子免疫学杂志,2006,22(5):689-691.
    [7]Horwitz DA,Zheng SG,Gray JD,et al.Regulatory T cell generated ex vivo as an approach for the therapy of autoim mune disease[J].Semin Immunol,2004,16(2):135.143.
    [8]Sakaguchi S.Naturally arising CD4 T regulatory cell for immunologic self-tolerance and negative control of immune responses[J].Annu Rev Immunol,2004,22:231-262.
    [9]Ansell SM,Tschumper RC.Chemokine upregulation in response to ritucimab in B-cell non-Hodgkin lymphoma[J].Blood,1999,(94):377-383.
    [10]Jonathan CW,Ewards JCW,Szczepanski L,et af.Efficacy of B cell targeted therapy with ritucimab in patients with rheumatoid arthritis[J].New Engl J Med,2004.350(25):2572-2581.
    [11]Lipsky PE,van der Heijde Desiree MFM,Clair EWS,et al.Infliximab and methotrexate in the treatment of rheumatoid arthritis.antitumor necrosis factor trial in rheumatoid arthritis with Concomitant therapy study group[J].New Engl J Med,2000, 343(22):1594-1602.
    [12]Su X,Zhou T,Yang P.et al.Reduction of arthritis and pneumonitis in m otheaten m ice by soluble tumor necrosis factor receptor[J].Arthritis Rheum,1998,41(1):139-149.
    [13]史进方,顾国浩,陈见奇,等.蛋白芯片技术对8种自身抗体的检测及评价[J].西安交通大学学报(医学版),2005,26(1):57-60.
    [1]Christin Maitre S,Bouchard P.Genes and ovarian insufficiency.Ann Endocrinol,1999,60(2):118-122.
    [2]Alzubaidi NH,Chap in HL,Vanderhoof VH,et al.Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure.Obstet Gynecol,2002,99(5):720-725.
    [3]徐苓,宋亦军.卵巢早衰的临床表现和诊断标准.实用妇产科杂志,2003,19(4):195-196.
    [4]Stanley J.Robboy,Malcolm C.Anderson,Peter Russell.PATHOLOGY of the FEMALE REPRODUCTIVE TRACT.Elsevier,2004.
    [5]Hoek A,Schoemaker J,Drexhage HA.Premature ovarian failure and ovarian autoimmunity.Endocr in Rev,1997,18(1):107-134.
    [6]Nanette S.Research on the mechanisms of premature ovarian failure.J Soc Gynecol Investig.2001,8(1):10-12.
    [7]Jaroudi KA,Arora M,Sheth KV,et al.Human leukocyte antigen typing and associated abnormalities in premature ovarian failure[J].Hum Reprod, 1994,9(11):2006-2009.
    [8]Hak AE,Pols HA,Visser T J,et al.Subclinical hypothyroidism is an independent risk factor for atherosclerosis and myocardial infarction in elderly women:The Rotterdam Study.Ann Intern Med,2000,132:270-278.
    [9]KimJG,Moon SY,Chang YS,et al.Autoimmune premature ovarian failure[J].J Obstet Gynecol,1995,21(1):59-66.
    [10]Betterle C,Volpato M.Adrenal and ovarian autoimmunity[J]Eur J Endocrinol,1998,138(1):16-25.
    [11]Weetman AP.Autoimmunity and endocrinology[J].Exp Clin Endo Diabetes,1999,107(3):63-66.
    [12]Santoro N.Research on the mechanisms of premature ovarian failure[J].J Soc Gyn Inves,2001,8(1):10-12.
    [13]Yan G,Schoenfeld D,Penney C,et al.Identification of premature ovarian failure patients with underlying autoimmunity[J].J Women's Health Gend Based Med,2000,9(3):275-287.
    [14]van Kasteren YM,von Blomberg M,Hoek A,et al.Incipient ovarian failure and premature ovarian failure show the same immunological profile[J].Am J Reprod Immunol,2000,43(6):359-366.
    [15]Chernyshov VP,Radysh TV,Gura IV,et al.Immune disorders in women with premature ovarian failure in initial period[J].Am J Reprod Immunol,2001,46(3):220-225.
    [16]杨桂艳,王一理,曹缵等.卵巢早衰患者外周血CD4~+、Th1/Th2细胞分布研究.生殖医学杂志,1998,7(4):722-032.
    [17]Maity R,Nair SR,Caspi RR,et al.Post-thymectomy murine experimental autoimmune oophoritis is associated with reduced natural killer cell activity[J].Am J Reprod Immunol,1997,38(5):360-365.
    [18]Hoek A,van Kasteren Y,de Haan-Meulman M,et al.Analysis of peripheral blood lymphocyte subsets,NK cells,and delayed type hypersensitivity skin test in patients with premature ovarian failure[J].Am J Reprod Immunol,1995,33(6):495-502.
    [19]Naz PK,Thurston D,Santoro N.Circulating tumor necrosis factor(TNF)-alpha in normally cycling women and patients with premature ovarian failure and polycystic ovaries.Am J Reprod Immunol,1995,34(3):170.
    [20]Coulam JB,The prevalence of autoimmune disorders among patientes with primary ovarian failure.Am J Reprod Immunol,4:63-66.
    [21]Grasso G,Muscettola M.Possible role of interferon-gamma in ovarian function.Ann N Y Acad Sci,1992,650:191-6.
    [22]谢端薇,欧汝强,杨宁.卵巢早衰与细胞因子TNF-α,IFN-γ和IL-2的相关性研究.广东医学,1999,20(11):138-238.
    [23]Russell P.The clinicpathological features premature ovarian failure.Verh Dtsch Ges Pathol,1997,81:197
    [24]Luborsky J.Ovarian autoimmune disease and ovarian autoantibodies[J].J Womens Health Gend Based Med,2002,11(7):585-599.
    [25]Fenichel P,Sosset C,Barbarino M,et al.Prevalence specificity and significance of ovarian antibodies during spontaneous premature ovarian failure[J].Hum Reprod,1997,12(12):2623-2628.
    [26]Ishizuka B,Kudo Y,Ameniya A,et al.Anti-nuclear antibodies in patients with premature ovarian failure[J].Hum Reprod,1999,14:70-75.
    [27]任平,卢坚贞,马艳萍.生殖免疫自身抗体多项检测和复查与不孕的临床分析.中国优生与遗传杂志,2005,13(3):96-97.
    [28]van Weissenbruch,A Hoek,I van Vliet-Bleeker,et al.Evidence for existence of immunoglobulins that block ovarian granulosa cell growth in vitro.A putative role in resistant ovary syndrome? Journal of Clinical Endocrinology &Metabolism,Vol 73,360-367.
    [29]Anasti J N,Flack MR,Froehlich J The use of human recombinant gonadotropin receptors to search for immunoglobulin G2mediated premature ovarian failure[J].J Clin Endocrinol Metab,1995,80(3):824-828.
    [30]马良坤,马莉,林守清.卵巢早衰与自身免疫.生殖医学杂志,2004,13(2):123-126.
    [31]Coulam CB,SternJJ.Immunology of ovarian failure[J].Am J Reprod Immunol,1991,25(4):169-174.
    [32]Mok CC,Lau CS,Wong RW.Risk factors for ovarian failure in patients with systemic lupus erythematosus receiving cyclophosphamide therapy[J].Arthritis Rheum,1998,41(5):831-837.
    [33]Pasoto SG,Mendonca BB,Bonfa ESO1Menstrual disturbances in patients with systemic lupus erythematosus without alkylating therapy:clinical,hormonal and therapeutic associations[J].Lupus,2002,11(3):175-180.
    [34]谷春霞,陶学濂,葛秦生等.雷公藤多甙片所致闭经原因的探讨.中国医学科学院学报,1989,11(2):151-153.
    [35]Edmonds SE,Montgomery JC.Reversible ovarian failure induced by a Chinese herbal medicine:lei gong teng[J].B JOG,2003,110(1):77-78.
    [36]张学武,粟占国,郭嘉玲等.系统性红斑狼疮患者抗卵巢细胞抗体与月经不调的相关性研究.中华风湿病学杂志,2006,10(2):69-67.
    [37]郑莉.超抗原与自身免疫性疾病,国外医学生理、病理科学与临床分册1997,17(3).
    [38]R Bunikowski,MEA Mielke,H Skarabis,et al.Evidence for a disease-promoting effect of Staphylococcus aureus-derived exotoxins in atopic dermatitis.J Allergy Clin Immunol 2000,105:814-9.
    [39]哈提古丽,阿也提,卵巢早衰的诊断与治疗,中华现代妇产科学杂志,2006,2(3):255.
    [40]施晓波,舒晴,张晶.卵巢早衰患者自身免疫反应性指标的检测及其意义.2007,16(8):591-593.
    [41]黄邱朝,刘琦,武建国等.卵巢功能早衰患者抗卵巢抗体及细胞免疫功能的测定,中华妇产科杂志1996年10月第31卷第10期.
    [42]Adashi EY,Resnick CE,Packman JN,et al.Cytokine-mediated regulation of ovarian function:tumor necrosis factor alpha inhibits gonadotropin-supported progesterone accumulation by differentiating and luteinized murine granulosa cells.Am J Obstet Gynecol,1990,162(4):889-96.
    [43]Adashi EY,Resnick CE,Hernandez ER,et al.Ovarian granulosa cell-derived insulin-like growth factor(IGF)binding proteins:release of low molecular weight,high-affinity IGF-selective species.Mol Cell Endocrinol,1990,74(3):175-84.
    [44]许坤、张永亮、张敬然.系统性红斑狼疮患者外周血T淋巴细胞亚群的变化.实用医技杂志,2007,14(29):3991-3992.
    [45]王飞、GfifithsCEM等.自然杀伤细胞和T淋巴细胞在银屑病发病中作用的研究.临床皮肤科杂志,2002,3 1(8):489-490.
    [46]Bossowski A,Urban M,Stasiak-Barmuta A.Analysis of changes in the percentage of B(CD19)and T(CD3)lymphocytes,subsets CD4,CD8 and their memory(CD45RO),and native(CD45RA)T cells in children with immune and non-immune thyroid diseases.J Pediatr Endocrino Metab,2003,16:63-70.
    [47]Corenblum B.Large dose and short course of glucocorticoids therapy for infertility caused by POF.Fertil Steril,1993,59(5):988-991.
    [48]Blumenfeld Z,Halachmi S,Alik Peretz B,Shmuel Z,Golan D,Makler A and Brandes JM(1993)Premature ovarian failureDthe prognostic application of autoimmunity on conception after ovulation induction.Fertil Steril,59:750-755.
    [49]Cowchock FS,McCabe JL and Montgomery BB(1988)Pregnancy after corticosteroid administration in premature ovarian failure(polyglandular endocrinopathy syndrome).Am J Obstet Gynecol,158:118-119.
    [50]Fernandes AM,Arruda Mde S,Bedone AJ.Twin gestation two years after the diagnosis of premature ovarian failure in a woman on hormone replacement therapy.A case report[J].J Reprod Med,2002,47(6):504-506.
    [51]Burnstein KI,Cidlowski JA.The down side of glucocorticoid receptor.Mol Cell Endocrinol,1992,83:1-8.
    [52]Chang DM,Chu SJ,Chen HC,et al.Dehydroepiandrosterone suppresses Interleukin-10 synthesis in women with systemic lupus erythematosus[J].Ann Rheum Dis,2004,63(12):1623-1626.
    [53]Korczowska I,Lacki JK,Leszczynski P,et al.Bone tissue metabolism insystematic lupus erythematosus patients treated with glucocorticosteroids[J].Pol Arch Med Wewn,2001,106(4):901-907.
    [54]马小红.卵巢早衰与自身免疫机制的研究进展.中国计划生育学杂志,2007,3(137):186-188.
    [55]Jacobson DL,Grange SJ,Rose NR,et all Epidemiology and estimated population burden of selected autoimmune diseases in the United States[J].Clin Immunol Immunopathol,1997,54:22-31.
    [56]Cutolo M,Seriolo B,Villaggio B,et all Androgens and estrogens modulate the immune and inflammatory responses in rheumatoid arthritis[J].Ann N YAcad Sci,2002,966:1311.
    [57]Loria RM.Immune up-regulation and tumor apoptosis by androstene steroids[J].Steroids,2002,67:9531.
    [58]Kazem Ahmadi,Alan B.McCruden,Macrophage may responses to androgen via its Receptor.Med Sci Monit,2006,12(1):15-20.
    [59]BentenW P,BeckerA,Peter H,et al.Developmental regulation of intracellular and surface androgen receptors in T cells[J].Steroids,2002,67(11):925-931.
    [60]姚根宏.雄激素对免疫系统的影响.中华男科学,2001,7(6):401-403.
    [61]蔡立荣,李大金,孙晓溪等.补肾活血方对小鼠实验性卵巢早衰防治作用的研究.中国中西医结合杂志,2001,21(2):126-129.
    [62]Baugh JA,Bucala R.Macrophage migration inhibitory factor[J].Crit CareMed,2002,30(1 Supp):27-35.
    [63]Denkinger CM,Denkinger M,Kort JJ.In Vivo Blockade of Macrophage Migration Inhibitory Factor Ameliorates Acute Experimental Autoimmune Encephalomyelitis by Impairing the Homing of Encephalitogenic T Cells to the Central Nervous System.The Journal of Immunology,2003,170:1274-1282.
    [64]Horwitz DA,Zheng SG,Gray JD,et al.Regulatory T cell generated ex vivo as an approach for the therapy of autoim mune disease[J].Semin Immunol,2004,16(2):135.143.
    [65]Sakaguchi S.Naturally arising CD4 T regulatory cell for immunologic self-tolerance and negative control of immune responses[J].Annu Rev Immunol,2004,22:231-262.
    [66]Ansell SM,Tschumper RC.Chemokine upregulation in response to ritucimab in B-cellnon-Hodgkinlymphoma[J].Blood,1999,(94):377-383.
    [67]Jonathan CW,Ewards JCW,Szczepanski L,et af.Efficacy of B cell targeted therapy with ritucimab in patients with rheumatoid arthritis[J].New Engl J Med,2004.350(25):2572-2581.
    [68]Lipsky PE,van der Heijde Desiree MFM,Clair EWS,et al.Infliximab and methotrexate in the treatment of rheumatoid arthritis,antitumor necrosis factor trial in rheum atoid arthritis with Concomitant therapy study group[J].New Engl J Med,2000,343(22):1594-1602.
    [69]Su X,Zhou T,Yang P.et al.Reduction of arthritis and pneumonitis in m otheaten m ice by soluble tumor necrosis factor receptor[J].Arthritis Rheum,1998,41(1):139-149.
    [70]史进方,顾国浩,陈见奇,等.蛋白芯片技术对8种自身抗体的检测及评价[J].西安交通大学学报(医学版),2005,26(1):57-60.
    [1]Bloom BR,Bennett B.Mechanism of a reaction in vitro associated with delayed-type hypersensitivity.Science 1966;153:80-2.
    [2]Calandra T,Roger T.Macrophage migration inhibitory factor:a regulator of innate immunity.Nat Rev Immunol,2003,3(10):791-800.
    [3]Powell ND,Papenfuss TL,McClain MA,Gienapp IE,Shawler TM,Satoskar AR,et al.Macrophage migration inhibitory factor is necessary for progression of experimental autoimmune encephalomyelitis.J Immunol 2005;175:5611-4.
    [4]Mizue Y,Ghani S,Leng L,McDonald C,Kong P,Baugh J,et al.Role for macrophage migration inhibitory factor in asthma.Proc Natl Acad Sci U S A 2005;102:14410-5.
    [5]Nakamaru Y,Oridate N,Nishihira J,Takagi D,Furuta Y,Fukuda S.Macrophage migration inhibitory factor(MIF)contributes to the development of allergic rhinitis.Cytokine 2005;31:103-8.
    [6]Morand EF.New therapeutic target in inflammatory disease:macrophage migration inhibitory factor.Intern Med J 2005;35:419-26.
    [7]Leech M,Metz C,Hall P,Hutchinson P,Gianis K,Smith M,et al.Macrophage migration inhibitory factor in rheumatoid arthritis:evidence of proinflammatory function and regulation by glucocorticoids. Arthritis Rheum 1999;42:1601-8.
    [8] Kats R, Metz CN, Akoum A. Macrophage migration inhibitory factor is markedly expressed in active and early-stage endometriotic lesions. Clin Endocrinol Metab 2002;87:883-9.
    [9] Lan HY, Yang N, Nikolic-Paterson DJ, Yu XQ, MuW, Isbel NM, et al. Expression of macrophage migration inhibitory factor in human glomerulonephritis. Kidney Int 2000;57:499-509.
    [10] Steinhoff M, Meinhardt A, Steinhoff A, Gemsa D, Bucala R, Bacher M. Evidence for a role of macrophage migration inhibitory factor in psoriatic skin disease. Br J Dermatol 1999;141:1061-6.
    [11] Bernhagen J, Bacher M, Calandra T, Metz CN, Doty SB, Donnelly T, et al. An ssential role for macrophage migration inhibitory factor in the tuberculin delayed-type hypersensitivity reaction. J Exp Med 1996; 183:277-82.
    [12] Calandra T, Echtenacher B, Roy DL, Pugin J, Metz CN, Hultner L, et al. Protection from septic shock by neutralization of macrophage migration inhibitory factor. Nat Med 2000;6:164-70.
    [13] Burger-Kentischer A, Gobel H, Kleemann R, Zernecke A, Bucala R, Leng L, et al. Reduction of the aortic inflammatory response in spontaneous atherosclerosis by blockade of macrophage migration inhibitory factor (MIF). J Atheroscler Res 2006; 184:28-38.
    [14] Lan HY, Bacher M, Yang N, Mu W, Nikolic-Paterson DJ, Metz C, et al. The pathogenic role of macrophage migration inhibitory factor in immunologically induced kidney disease in the rat. J Exp Med 1997;185:1455-65.
    [15] Santos L,Hall P,Metz C, Bucala R,Morand EF. Role ofmacrophage migration inhibitory factor (MIF) in murine antigen-induced arthritis: interaction with glucocorticoids. Clin Exp Immunol 2001;123:309-14.
    [16] Denkinger CM, Metz C, Fingerle-Rowson G, Denkinger MD, Forsthuber T. Macrophage migration inhibitory factor and its role in autoimmune diseases. Arch Immunol Ther Exp (Warsz) 2004;52:389-400.
    [17] Matsui Y, Okamoto H, Jia N, AkinoM, Uede T, Kitabatake A, et al. Blockade of macrophage migration inhibitory factor ameliorates experimental autoimmune myocarditis. J Mol Cell Cardiol 2004;37: 557-66.
    [18] Nicoletti F, Creange A, Orlikowski D, Bolgert F,Mangano K,Metz C, et al. Macrophage migration inhibitory factor (MIF) seems crucially involved in Guillain-Barre syndrome and experimental allergic neuritis. J Neuroimmunol 2005; 168:168-74.
    [19] Lubetsky JB, Dios A, Han J, Aljabari B, Ruzsicska B, Mitchell R, et al. The tautomerase active site of macrophage migration inhibitory factor is a potential target for discovery of novel anti-inflammatory agents. J Biol Chem 2002;277:24976-82.
    [20] Cvetkovic I, Al-Abed Y, Miljkovic D, Maksimovic-Ivanic D, Roth J, Bacher M, et al. Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes. Endocrinology 2005; 146:2942-51.
    [21] XagorariA, PapapetropoulosA. Luteolin inhibits an endotoxin-stimu- lated phosphorylation cascade and proinflammatory cytokine production inmacrophages[J].J Pharm acol Exp Ther, 2001,296: 181-187.
    [22] Atluru D, Gudapaty S. Evidence thatgenistein, a protein-tyrosine ki- nase inhibitor, inhibits CD28 monoclonal-antibody-stimulated human T cell proliferation[J].Transplantation, 1991, 51: 448-450.
    1 史文籽、赵怡理 卵巢早衰 国外医学妇幼保健分册,2002;13(1):7-9
    2 李诵絃,于传鑫主编.实用妇科内分泌学.第1版.上海:上海医科大学出版社,1997,64-68.
    3 王一峰,欧汝强,杨宁,等.卵巢早衰表明血清抗透明带抗体和肿瘤坏死因子—a,r一干扰素及白细胞介素一2的分析.生殖医学杂志,2002,(11)2:7-10.
    4 Fenichel P,Sosset C,Barbarino M,etal.Prevalence specificity and significance of ovarian antibodies during spontaneous premature ovarian failure[J].Hum Reprod.1997,12(12):2623-2628.
    5 王伟,李继俊.卵巢早衰的病因学研究进展.现代妇产科进展,2002,11(2)136-137
    6 张学武,粟占国,郭嘉玲,等.系统性红斑狼疮患者抗卵巢细胞抗体与月经不调的相关性研究.中华风湿病学杂志2006,10(2):69-67
    7 Ishizuka B,Kudo Y,Ameniya A,etal.Anti-nuclear antibodies in patients with premature ovarian failure[J].Hum Reprod,1999,14:70-75
    8 任平,卢坚贞,马艳萍.生殖免疫自身抗体多项检测和复查与不孕的临床分析.中国优生与遗传杂志2005,13(3):96-97

© 2004-2018 中国地质图书馆版权所有 京ICP备05064691号 京公网安备11010802017129号

地址:北京市海淀区学院路29号 邮编:100083

电话:办公室:(+86 10)66554848;文献借阅、咨询服务、科技查新:66554700