子宫内膜异位症患者Th1/Th2细胞因子免疫反应的研究
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摘要
目的 探讨Th1/Th2细胞因子免疫反应状态与子宫内膜异位症的关系
方法 用双抗体夹心酶联免疫吸附实验(ELISA法)对30例子宫内膜异位症患者及20例非内异症患者血清及腹腔液中Th1型细胞因子IL-2和Th2型细胞因子IL-10的含量进行检测，用免疫组化法检测30例内异症患者异位内膜及10例正常子宫内膜中IL-2及IL-10的表达，结果采用SPSS10.0统计软件包进行，包括非参数Mann-Whitney U检验、卡方检验、Spearman等级相关检验。
结果 (1)内异症患者血清及腹腔液中IL-10水平较对照组明显升高，且随临床期别的增高而增高，差异有显著性(P＜0.05)。(2)内异症Ⅰ-Ⅱ期患者IL-10水平与对照组比较差异无显著性(P＞0.05)。(3)在正常月经周期中，细胞因子水平无明显变化。在内异症患者的增生期与分泌期比较，IL-10水平亦无明显差异(P＞0.05)。但无论在增生期还是分泌期，内异症组IL-10水平均较对照组升高，差异有显著性(P＜0.05)。(4)IL-2水平无论是临床分期还是月经周期分期，与对照组比较均无明显差异(P＞0.05)。(5)IL-2/IL-10比值在内异症患者明显下降，且临床期别越高，下降越明显(P＜0.05)。(6)正常子宫内膜组织中IL-2、IL-10的表达为阴性，内异症异
中文摘要
位内膜中几.2、IL一10均有表达，份10的表达阳性率(6仔yO)较12(57%)
高，差异无显著性。
结论(1) Thl八112细胞因子在体内的平衡状态对于免疫系统发挥正常
功能起重要作用，内异症患者几.2/IL一10比值的明显下降，且临床期别越高，
下降越明显，说明T七2因子表达增强，Thl因子表达受抑制，机体处于1七2倾
向，Thl厂1，h2平衡向ThZ漂移，细胞免疫功能下降，体液免疫功能增强。
(2)IL一10在内异症的发生中起重要作用。内异症患者血清、腹腔液中高水平
的几.10可在各个环节均造成细胞免疫功能低下，导致自然杀伤(NK)细胞
活性的降低，对异位内膜的吞噬作用降低，巨噬细胞的激活引起细胞因子含量
增加，刺激异位的内膜生长引起内异症的发生和发展。(3)1一n期内异症患
者IL一10水平与对照组比较差异无显著性(P>0.05)，提示轻度内异症患者免
疫功能损伤较轻，机体尚有清除异位内膜的能力。(4)在正常月经周期
细胞因子水平不随月经周期的改变而变化，可能因为异位内膜本身缺乏典型的
周期性变化，或者可能是细胞因子本身就不受性激素的影响。
Objective To investigate the relationship between immune reaction state of Thl and Th2 cytokine and endometriosis.
Methods Interleukin-2 and interleukin-10 contents in serum and peritoneal fluid of 30 cases with endometriosis were detected by enzyme linked immunoabsorbent assay (ELISA) and compared with the counterparts of 20 cases without endometriosis (controls). Immunohistochemistry was used to evaluate the expression of Interleukin-2 and interleukin-10 in ectopicendometrium of 30 patients with endometriosis and in eutopicendometrium of 10 cases without endometriosis (controls).
Results (1) The serum and peritoneal fluid from patients with endometriosis contained significantly greater amounts of IL-10 (PO.05) than those in controls, and there was a significant positive correlation between IL-10 contents and different clinical stages (P<0.05). (2) There was no different amount of IL-10 between patients with mild endometriosis and controls (P>0.05). (3) The level of IL-10 between the proliferative phase and the secretory phase of patients with endometriosis was not significantly different (P>0.05). (4) As a result, the ratio of IL-2/IL-10 decreased in patients with endometriosis (P<0.05). (5) The level of EL-2 was not significantly different between patients with endometriosis and controls (P>0.05). (6) All samples of normal eutopicendometrium were not found to express IL-2 and IL-10 protein, hi ectopicendometrium of 30 patients with endometriosis, the total rate of IL-10 expression was 60%, and IL-2 was 57%, there was no significantly different between themP>0.05).
Conclusion (1) The balance of Thl and Th2 played an important role in immune system. The ratio of IL-2/IL-10 decreased in patients with endometriosis, and
decreased more in heavy endometriosis. The high level cytokines of Th2 cells resulted in a shift towards Th2 polarization, which earned inhibition of immune regulation. (2) High level of IL-10 was an important role in the process of endometriosis. It caused macrophage activity enhanced and cytokines increased. At the same time, as natural killer activity decreased, the ectopic endometrium could not be cleared, it grew, planted and spread. (3) The level of IL-10 in mild endometriosis was not higher than controls. It suggested that immune injury was light in mild endometriosis. (4) Cytokine contents had no changes in normal menstrual cycle, perhaps sex hormone had no effect on cytokines.
方法 用双抗体夹心酶联免疫吸附实验(ELISA法)对30例子宫内膜异位症患者及20例非内异症患者血清及腹腔液中Th1型细胞因子IL-2和Th2型细胞因子IL-10的含量进行检测，用免疫组化法检测30例内异症患者异位内膜及10例正常子宫内膜中IL-2及IL-10的表达，结果采用SPSS10.0统计软件包进行，包括非参数Mann-Whitney U检验、卡方检验、Spearman等级相关检验。
结果 (1)内异症患者血清及腹腔液中IL-10水平较对照组明显升高，且随临床期别的增高而增高，差异有显著性(P＜0.05)。(2)内异症Ⅰ-Ⅱ期患者IL-10水平与对照组比较差异无显著性(P＞0.05)。(3)在正常月经周期中，细胞因子水平无明显变化。在内异症患者的增生期与分泌期比较，IL-10水平亦无明显差异(P＞0.05)。但无论在增生期还是分泌期，内异症组IL-10水平均较对照组升高，差异有显著性(P＜0.05)。(4)IL-2水平无论是临床分期还是月经周期分期，与对照组比较均无明显差异(P＞0.05)。(5)IL-2/IL-10比值在内异症患者明显下降，且临床期别越高，下降越明显(P＜0.05)。(6)正常子宫内膜组织中IL-2、IL-10的表达为阴性，内异症异
中文摘要
位内膜中几.2、IL一10均有表达，份10的表达阳性率(6仔yO)较12(57%)
高，差异无显著性。
结论(1) Thl八112细胞因子在体内的平衡状态对于免疫系统发挥正常
功能起重要作用，内异症患者几.2/IL一10比值的明显下降，且临床期别越高，
下降越明显，说明T七2因子表达增强，Thl因子表达受抑制，机体处于1七2倾
向，Thl厂1，h2平衡向ThZ漂移，细胞免疫功能下降，体液免疫功能增强。
(2)IL一10在内异症的发生中起重要作用。内异症患者血清、腹腔液中高水平
的几.10可在各个环节均造成细胞免疫功能低下，导致自然杀伤(NK)细胞
活性的降低，对异位内膜的吞噬作用降低，巨噬细胞的激活引起细胞因子含量
增加，刺激异位的内膜生长引起内异症的发生和发展。(3)1一n期内异症患
者IL一10水平与对照组比较差异无显著性(P>0.05)，提示轻度内异症患者免
疫功能损伤较轻，机体尚有清除异位内膜的能力。(4)在正常月经周期
细胞因子水平不随月经周期的改变而变化，可能因为异位内膜本身缺乏典型的
周期性变化，或者可能是细胞因子本身就不受性激素的影响。
Objective To investigate the relationship between immune reaction state of Thl and Th2 cytokine and endometriosis.
Methods Interleukin-2 and interleukin-10 contents in serum and peritoneal fluid of 30 cases with endometriosis were detected by enzyme linked immunoabsorbent assay (ELISA) and compared with the counterparts of 20 cases without endometriosis (controls). Immunohistochemistry was used to evaluate the expression of Interleukin-2 and interleukin-10 in ectopicendometrium of 30 patients with endometriosis and in eutopicendometrium of 10 cases without endometriosis (controls).
Results (1) The serum and peritoneal fluid from patients with endometriosis contained significantly greater amounts of IL-10 (PO.05) than those in controls, and there was a significant positive correlation between IL-10 contents and different clinical stages (P<0.05). (2) There was no different amount of IL-10 between patients with mild endometriosis and controls (P>0.05). (3) The level of IL-10 between the proliferative phase and the secretory phase of patients with endometriosis was not significantly different (P>0.05). (4) As a result, the ratio of IL-2/IL-10 decreased in patients with endometriosis (P<0.05). (5) The level of EL-2 was not significantly different between patients with endometriosis and controls (P>0.05). (6) All samples of normal eutopicendometrium were not found to express IL-2 and IL-10 protein, hi ectopicendometrium of 30 patients with endometriosis, the total rate of IL-10 expression was 60%, and IL-2 was 57%, there was no significantly different between themP>0.05).
Conclusion (1) The balance of Thl and Th2 played an important role in immune system. The ratio of IL-2/IL-10 decreased in patients with endometriosis, and
decreased more in heavy endometriosis. The high level cytokines of Th2 cells resulted in a shift towards Th2 polarization, which earned inhibition of immune regulation. (2) High level of IL-10 was an important role in the process of endometriosis. It caused macrophage activity enhanced and cytokines increased. At the same time, as natural killer activity decreased, the ectopic endometrium could not be cleared, it grew, planted and spread. (3) The level of IL-10 in mild endometriosis was not higher than controls. It suggested that immune injury was light in mild endometriosis. (4) Cytokine contents had no changes in normal menstrual cycle, perhaps sex hormone had no effect on cytokines.
引文
1 Timthy R Mosmann,Huy Cherwinski,Marthaw,et al. Two types of murine helper T cell clone. J Immunol.1986;137(7) :2384-2363
2 Sergi Romagnani. Human Th1 and Th2 Subset: doubt no more. Immunol Today.1991;12(8) :256-257
3 Fan XG,Yakoob J,Fan XJ,et al. Enhanced T helper 2 lymphocyte responses: immune mechanisms of helicobater pylori infection. Ir J Med Sci.l996;165:37-39
4 Clerici M,Shearer GM. A Th1---->>Th2 swith is a critical step in the etiology of HTV infection. Immunol Today.1993;14:107-111
5 Heinzel FP,Sadick MD,Holaday BJ,et al. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for distinct helper T cell subsets. J Exp Med.1989;169(1) :59-72
6 Taneja V,Hansen J,Smart M,Griffiths M,et al. Expression of H2-E molecule mediates protection to collagen induced arthritis in HLA-DQ8 transgenic mine: role of cytokines. Int Immunol.1997 Aug;9(8) :1213-1219
7 Kennedy MK,Picha KS,Shanebeck KD,et al.Interleukin-12 regulates the proliferation of Th1 ,but not Th2 or Th0 clones. Eur J Immunol.1994;4(10) :2271-2278
8 Modlin RL,Nutman TB. Type 2 cytokines and negative immune regulation in human infection. Current opinion of immunology. 1993 ;5:511-517
9 Liblan-RS,Singer SM,Mcdertitt HO. Th1 and Th2 CD4+T cell in the pathogenesis of organ-specific autoimmune disease. Immunol Today.l995;16(1) :34-38
10 孙卫民、王惠琴主编，细胞因子研究方法学。北京：人民卫生出版社， 1999：5-7：18-20
11 Constant SL, Bottomry K. Induction of Th1 and Th2 CD4+ T cell response: the alternative approaches. Ann Rev Immunol,1997,15:297-322
12 Edwark K, Janice W, Paul G, et al. Rhen Dis Clin Noth Am,1998,24(3) :629-639
13 张道杰、段朝霞。IL-10的研究进展。国外医学免疫学分册，2003，26(1)：39-41
14 Fiorentino DF, Zlotnik A, Mosmann TR, et al. IL-10 inhibits cytokine production by activated marcrophages. J Immunol,1991,147:3815
15 D'Andrea AM, Aste-Amezaga M, Valiante NM, et al. Interleukine 10(IL-10) inhibits human lymhocyte interferon-gamma production by suppressing nature killer cell stimulatory factor IL-12synthesis in accessory cells. J Exp Med, 1993,178:1041-1049
16 De Wool Malefyt, Abrams J, Bennet B, et al.IL-10 inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J Exp Med, 1991;124:1209
17 Dcruz OJ, Wild RA. Evaluation of endometrial tissue specific complement activation in women with endometriosis. Fertil Steril, 1992,57:787-795
18 D'Hooghe TM, Xiao L, Hill JA. Cytokine profiles in autologous peritoneal fluid and peripheral blood of women with deep and superficial endometriosis. Arch Gynecol Obstet 2001 Mar;265(1):40-44
19 Polak G, Koziol Montewka M, et al. Lipid peroxides, tumor necrosis factor alpha (TNF-alphu) and interferon gamma (IFN-gamma) in peritoneal fluid from infertile women with minimal and mild endometriosis. Ginekol Pol 2002 May; 72(5):422-426
20 Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002 Feb;17(2):426-431
21 郝敏、石一复等。子宫内膜异位症患者腹腔液白细胞介素6、8及转化生长因子β1的测定。中华妇产科杂志，2000，35(6)：329-331
22 程凯灵、令狐华。子宫内膜异位症患者血清细胞因子水平的测定。中华医学检验杂志，1998，21(1)
23 殷红梅、王苏荣、戴淑真等。子宫内膜异位症患者T辅助细胞亚群功能失调的研究。中华妇产科杂志，2000，35(6)：327-328
24 张淑芝、王慧贤等。子宫内膜异位症不孕患者腹腔液淋巴细胞及其白细胞介素2的变化。中华妇产科杂志，1998，33(1)
25 Chao-Chin Hsu, Bei-Chang Yang, Meng-Hsing WU et al. Enhanced interleukin-4 expression in patients with endometriosis. Fertility and Sterility. 1997;67(6): 1059-1064
26 Oral E, Arici A, De Cecco L. The biological basis of medical treatment of endometriosis. Gynecol Endocrinol, 1995,9:259-266
27 Dmowski WP. Immunological aspects of endometriosis. Int J Gynaecol Obstet, 1995,50 (Suppl 1):3-10
28 Fernandez-Shaw S, Hicks BR, Yudkin PL, et al. Anti-endometrial and antiendothelial auto-antibodies in women with endometriosis. Hum Reprod, 1993,8:310-315
29 Keenan JA, Chen TT, Chadwell NL, et al. IL-1 beta, TNT-alpha, and IL-2 in peritoneal fluid and macrophage-conditioned media of women with endometriosis. Am J Reprod Immunol, 1995,34:381-385
30 Rana N, Braun DP, House R, et al. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril, 1996,65:925-930
31 Pellicer A, Albert C, Mercadeer A, et al. The follicular and endocrine environment in women with endometriosis:local and systemic cytokine production. Fertil Steril, 1998,70:425-431
32 孔北华、崔保霞等。卵巢癌患者Th1／Th2类细胞因子的检测。现代妇产科进展。2000，9(2)：104-105
33 Brinda RK, Peter GI.. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. Am J Pathol, 1987,127:66-73
34 王悦、张丽珠等。子宫内膜异位症在位、异位内膜淋巴细胞亚群分布的研究。中华妇产科杂志，2001，36(2)：85-87
2 Sergi Romagnani. Human Th1 and Th2 Subset: doubt no more. Immunol Today.1991;12(8) :256-257
3 Fan XG,Yakoob J,Fan XJ,et al. Enhanced T helper 2 lymphocyte responses: immune mechanisms of helicobater pylori infection. Ir J Med Sci.l996;165:37-39
4 Clerici M,Shearer GM. A Th1---->>Th2 swith is a critical step in the etiology of HTV infection. Immunol Today.1993;14:107-111
5 Heinzel FP,Sadick MD,Holaday BJ,et al. Reciprocal expression of interferon gamma or interleukin 4 during the resolution or progression of murine leishmaniasis. Evidence for distinct helper T cell subsets. J Exp Med.1989;169(1) :59-72
6 Taneja V,Hansen J,Smart M,Griffiths M,et al. Expression of H2-E molecule mediates protection to collagen induced arthritis in HLA-DQ8 transgenic mine: role of cytokines. Int Immunol.1997 Aug;9(8) :1213-1219
7 Kennedy MK,Picha KS,Shanebeck KD,et al.Interleukin-12 regulates the proliferation of Th1 ,but not Th2 or Th0 clones. Eur J Immunol.1994;4(10) :2271-2278
8 Modlin RL,Nutman TB. Type 2 cytokines and negative immune regulation in human infection. Current opinion of immunology. 1993 ;5:511-517
9 Liblan-RS,Singer SM,Mcdertitt HO. Th1 and Th2 CD4+T cell in the pathogenesis of organ-specific autoimmune disease. Immunol Today.l995;16(1) :34-38
10 孙卫民、王惠琴主编，细胞因子研究方法学。北京：人民卫生出版社， 1999：5-7：18-20
11 Constant SL, Bottomry K. Induction of Th1 and Th2 CD4+ T cell response: the alternative approaches. Ann Rev Immunol,1997,15:297-322
12 Edwark K, Janice W, Paul G, et al. Rhen Dis Clin Noth Am,1998,24(3) :629-639
13 张道杰、段朝霞。IL-10的研究进展。国外医学免疫学分册，2003，26(1)：39-41
14 Fiorentino DF, Zlotnik A, Mosmann TR, et al. IL-10 inhibits cytokine production by activated marcrophages. J Immunol,1991,147:3815
15 D'Andrea AM, Aste-Amezaga M, Valiante NM, et al. Interleukine 10(IL-10) inhibits human lymhocyte interferon-gamma production by suppressing nature killer cell stimulatory factor IL-12synthesis in accessory cells. J Exp Med, 1993,178:1041-1049
16 De Wool Malefyt, Abrams J, Bennet B, et al.IL-10 inhibits cytokine synthesis by human monocytes: An autoregulatory role of IL-10 produced by monocytes. J Exp Med, 1991;124:1209
17 Dcruz OJ, Wild RA. Evaluation of endometrial tissue specific complement activation in women with endometriosis. Fertil Steril, 1992,57:787-795
18 D'Hooghe TM, Xiao L, Hill JA. Cytokine profiles in autologous peritoneal fluid and peripheral blood of women with deep and superficial endometriosis. Arch Gynecol Obstet 2001 Mar;265(1):40-44
19 Polak G, Koziol Montewka M, et al. Lipid peroxides, tumor necrosis factor alpha (TNF-alphu) and interferon gamma (IFN-gamma) in peritoneal fluid from infertile women with minimal and mild endometriosis. Ginekol Pol 2002 May; 72(5):422-426
20 Bedaiwy MA, Falcone T, Sharma RK, Goldberg JM, et al. Prediction of endometriosis with serum and peritoneal fluid markers: a prospective controlled trial. Hum Reprod 2002 Feb;17(2):426-431
21 郝敏、石一复等。子宫内膜异位症患者腹腔液白细胞介素6、8及转化生长因子β1的测定。中华妇产科杂志，2000，35(6)：329-331
22 程凯灵、令狐华。子宫内膜异位症患者血清细胞因子水平的测定。中华医学检验杂志，1998，21(1)
23 殷红梅、王苏荣、戴淑真等。子宫内膜异位症患者T辅助细胞亚群功能失调的研究。中华妇产科杂志，2000，35(6)：327-328
24 张淑芝、王慧贤等。子宫内膜异位症不孕患者腹腔液淋巴细胞及其白细胞介素2的变化。中华妇产科杂志，1998，33(1)
25 Chao-Chin Hsu, Bei-Chang Yang, Meng-Hsing WU et al. Enhanced interleukin-4 expression in patients with endometriosis. Fertility and Sterility. 1997;67(6): 1059-1064
26 Oral E, Arici A, De Cecco L. The biological basis of medical treatment of endometriosis. Gynecol Endocrinol, 1995,9:259-266
27 Dmowski WP. Immunological aspects of endometriosis. Int J Gynaecol Obstet, 1995,50 (Suppl 1):3-10
28 Fernandez-Shaw S, Hicks BR, Yudkin PL, et al. Anti-endometrial and antiendothelial auto-antibodies in women with endometriosis. Hum Reprod, 1993,8:310-315
29 Keenan JA, Chen TT, Chadwell NL, et al. IL-1 beta, TNT-alpha, and IL-2 in peritoneal fluid and macrophage-conditioned media of women with endometriosis. Am J Reprod Immunol, 1995,34:381-385
30 Rana N, Braun DP, House R, et al. Basal and stimulated secretion of cytokines by peritoneal macrophages in women with endometriosis. Fertil Steril, 1996,65:925-930
31 Pellicer A, Albert C, Mercadeer A, et al. The follicular and endocrine environment in women with endometriosis:local and systemic cytokine production. Fertil Steril, 1998,70:425-431
32 孔北华、崔保霞等。卵巢癌患者Th1／Th2类细胞因子的检测。现代妇产科进展。2000，9(2)：104-105
33 Brinda RK, Peter GI.. The immunocytochemical distribution of leukocytic subpopulations in human endometrium. Am J Pathol, 1987,127:66-73
34 王悦、张丽珠等。子宫内膜异位症在位、异位内膜淋巴细胞亚群分布的研究。中华妇产科杂志，2001，36(2)：85-87
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