Th1/Th2平衡调控对妇产科疾病影响的研究进展

近年来研究发现辅助性T细胞1型(Th1)/Th2的平衡调控与妇产科疾病的发生、发展、治疗和转归有密切的关系。Th1细胞调节细胞免疫,主要促进炎症反应和细胞毒性活动;Th2细胞调节体液免疫,主要刺激细胞的分化与增殖。Th1细胞通过合成γ干扰素(IFN-γ)抑制Th2细胞功能,Th2细胞通过合成白细胞介素4(IL-4)抑制Th1细胞的功能,二者相互作用、相互调节。正常妊娠情况下Th1/Th2细胞应答存在生理性失衡,母体Th2型细胞因子抑制Th1型细胞因子的产生,这种生理性失衡被破坏可导致复发性流产、早产、子痫前期及不孕症等妊娠相关疾病。而宫颈癌、卵巢癌、子宫内膜异位症等妇科疾病与Th1/Th2平衡调控有关,但其确切免疫学机制尚不明确,尚需进一步深入研究,以期为多种妇产科疾病的免疫学治疗开辟新的前景。     

不明原因反复自然流产患者Th1/Th2型细胞因子的检测

反复自然流产是一种常见的病理性妊娠,但有60％~70％患者病因不明,临床上称之为原因不明反复自然流产（unexplainedURSA）。近年免疫学领域Th1／Th2型细胞因子的发现及其研究进展,为探讨URSA的免疫学发病机制开辟了新途径。本研究选取IL-2、IFN－γ代表Th1型细胞因子,IL－4、IL-10代表Th2型细胞因子,通过检测URSA患者外周血单个核细胞（PBMC）经滋养细胞抗原刺激产生各细胞因子的水平,探讨Th1/Th2细胞因子与URSA的相关性。1资料与方法1．1研究对象选取1998年10月~2000年3月在山东医科大学附属医院妇产科门诊就诊的URS…     

Th1／Th2型细胞因子与妊娠高血压综合征

主要由Th1细胞分泌促进细胞免疫的Th1型细胞因子和主要由Th2细胞分泌促进体液免疫的Th2型细胞因子在妊娠时期母胎间细胞因子网络平衡的调控中有重要作用，就Th1/Th2型细胞因子在妊娠高血压综合征中的作用与机制做了大量的研究，发现存在着两种因子的失衡。     

Th1/rh2型细胞因子与妊娠高血压综合征

主要由Th1细胞分泌促进细胞免疫的Th1型细胞因子和主要由Th2细胞分泌促进体液免疫的Th2型细胞因子在妊娠时期母胎间细胞因子网络平衡的调控中有重要作用。近年，就Th1／Th2型细胞因子在妊娠高血压综合征中的作用与机制做了大量的研究，发现存在着两种因子的失衡。     

Th1/rh2型细胞因子与妊娠高血压综合征

主要由Th1细胞分泌促进细胞免疫的Th1型细胞因子和主要由Th2细胞分泌促进体液免疫的Th2型细胞因子在妊娠时期母胎间细胞因子网络平衡的调控中有重要作用。近年，就Th1／Th2型细胞因子在妊娠高血压综合征中的作用与机制做了大量的研究，发现存在着两种因子的失衡。     

Th1／Th2细胞与妇科肿瘤

机体的免疫状态与肿瘤的发生、发展关系密切。近年Th1/Th2细胞在免疫学研究中取得了令人瞩目的进展。通过追溯Th1/Th2概念的由来、分析Th1/Th2漂移的意义，阐述了Th1/Th2细胞功能失衡与卵巢癌、子宫内膜癌、宫颈肿瘤、妊娠滋养细胞疾病、子宫内膜异位症的关系，并对肿瘤免疫治疗进行了初步的探讨。为妇科肿瘤诊治提供了新的思路。     

泰山磐石散对复发性流产小鼠母胎界面Th1/Th2细胞因子及妊娠预后的影响

目的:观察泰山磐石散对复发性流产小鼠母胎界面Th1/Th2细胞因子及妊娠预后的影响,为泰山磐石散临床应用提供新的实验依据。方法:采用经典造模方式DBA/2小鼠与CBA/J杂交,获得复发性流产小鼠模型,随机将与DBA/2小鼠合笼的60只CBA/J妊娠小鼠分为模型组、中药低剂量组、中药中剂量组、中药高剂量组和阳性对照组;与BALB/C合笼的10只CBA/J孕鼠作为正常妊娠模型。于妊娠14 d后处死孕鼠,观察小鼠胎盘丢失情况,并提取培养胎界母细胞,24 h后收集细胞上清液,酶联免疫吸附测定(ELISA)法检测上清液中肿瘤坏死因子α(TNF-α)、γ干扰素(IFN-γ)、白细胞介素4(IL-4)和IL-10含量。结果:经泰山磐石散治疗后,与模型组比较,复发性流产小鼠胎盘丢失率明显改善,母胎界面细胞上清液中Th1型细胞因子IFN-γ明显降低,Th2型细胞因子IL-4、IL-10明显升高,Th1/Th2免疫调节失衡明显改善,以中药高剂量组改善最为明显。结论:泰山磐石散能改善复发性流产小鼠胎盘丢失情况,其具体机制可能是通过调节Th1/Th2免疫调节平衡实现。     

Th1/Th2细胞与妇科肿瘤

机体的免疫状态与肿瘤的发生、发展关系密切。近年Th1／Th2细胞在免疫学研究中取得了令人瞩目的进展。通过追溯Th1／Th2概念的由来、分析Th1／Th2漂移的意义，阐述了Th1／Th2细胞功能失衡与卵巢癌、子宫内膜癌、宫颈肿瘤、妊娠滋养细胞疾病、子宫内膜异位症的关系，并对肿瘤免疫治疗进行了初步的探讨。为妇科肿瘤诊治提供了新的思路。     

CD4＋T细胞在原因不明复发性流产中的研究进展

正常妊娠有赖于母体对胚胎半同种抗原的免疫耐受,一旦免疫耐受失衡,将导致免疫排斥、免疫攻击从而导致自然流产,原因不明复发性流产被认为与母胎免疫耐受失衡有关.CD4＋T在同种异体急性排斥反应中发挥重要作用,根据所分泌的细胞因子不同,CD4＋T 细胞分为Th1、Th2、调节性T细胞（Treg）及新近发现的Th17细胞.早期研究发现母体外周血、母胎界面CD4＋T细胞增高与复发性流产密切相关.随免疫耐受机制研究的不断深入,母胎免疫耐受的研究历经Th1/Th2平衡到Treg的免疫负调控作用,再到Th17/Treg平衡.综述CD4＋T细胞在原因不明复发性流产中的研究进展.     

Th1／Th2细胞因子与反复自然流产的关系研究

Th1/Th2两类细胞因子可以调节人体的免疫反应,它们在母体的妊娠免疫反应中也有重要作用。正常的母体妊娠免疫反应是以Th2型细胞因子为主,而在反复自然流产患者中是以Th1型细胞因子为主,因此,可以通过Th1型细胞因子向Th2型细胞因子逆转来治疗反复自然流产。     

正常妊娠和子痫前期患者外周血树突细胞亚群的变化

目的:探讨树突细胞(DCs)及其亚群在正常妊娠和子痫前期患者间的变化,及与Th1/Th2型反应的关系。方法:选取正常妊娠孕妇25例、子痫前期患者17例和正常未孕妇女15例,用流式细胞术检测3组外周血树突细胞及其髓样(MDC)和淋巴样(PDC)亚群,比较其数量和比值在妊娠前后及子痫前期患者的变化,并与Th1/Th2型细胞因子的含量比较。结果:与正常妊娠早期和晚期相比,妊娠中期MDC和PDC数量减少,MDC/PDC比值升高,妊娠早、晚期相比无显著差异。与正常晚期妊娠妇女比较,子痫前期患者PDC数量减少,MDC数量改变不明显,MDC/PDC比值升高,两组相比差异显著。与正常晚期妊娠妇女相比较,子痫前期患者Th1型细胞因子IL-2含量增加,IFN-γ无显著差异,Th2型细胞因子IL-10减少,IL-2/IL-10、IFN-γ/IL-10比值升高。结论:DCs在正常妊娠的不同阶段其数量和亚群发生变化,子痫前期患者出现PDC减少和MDC/PDC比值升高现象,并与Th1/Th2型细胞因子的变化趋势一致。     

VEGF、JAK2/STAT3信号通路与妇科疾病的关系

信号传导与转录激活因子3(STAT3)作为STATS家族成员之一,在很多组织中发挥重要功能,是细胞生长过程中的主要调节者。Janus激酶2(JAK2)为胞内蛋白酪氨酸激酶,参与造血和免疫等系统的信号转导,在多种细胞因子的信号传导中起重要作用。血管内皮生长因子(VEGF)是一种糖蛋白,是内皮细胞的特异性丝裂原,可特异性地作用于血管内皮细胞,增加新生血管形成,使血管通透性增加。STAT3作为JAK2重要的底物,在细胞因子的信号转导中起着关键性的作用,JAK2/STAT3信号转导途径的调控在维持人体正常免疫中起着重要作用。VEGF、JAK2/STAT3信号通路在妇科肿瘤、子宫内膜异位症等疾病中调控靶基因的表达,促进新生血管的形成,直接参与疾病的发生发展过程。综述VEGF、JAK2/STAT3信号通路在妇科疾病的研究进展。     

Maternal circulating interferon-gamma and interleukin-6 as biomarkers of Th1/Th2 immune status throughout pregnancy.

AIM: T cells may be classified as T helper type 1 (Th1) cells, which synthesize cytokines inducing cellular immunity, or T helper type 2 (Th2), which synthesize cytokines inducing humoral immunity. According to the Th1/Th2 paradigm, it has been postulated that successful pregnancy induces an immune Th2 bias, but it is not yet clear how Th1 and Th2 systems vary simultaneously throughout the pregnancy. METHODS: Using maternal circulating interferon-gamma (IFN-gamma) and interleukin-6 (IL-6) as biomarkers of Th1 and Th2 cytokines, respectively, we examined the variation of circulating Th1/Th2 ratio in 35 healthy pregnant women from 10 to 40 weeks of pregnancy. RESULTS: With increasing gestational age, maternal circulating levels of IFN-gamma decrease, whereas those of IL-6 increase. The IFN-gamma/IL-6 ratio switches around the 19th week of pregnancy. CONCLUSIONS: Our results suggest that maternal systemic IFN-gamma and IL-6 concentrations may be biomarkers of Th1/Th2 immune status during pregnancy. Moreover, our findings showed that contrary to the Th1/Th2 paradigm, the Th1 bias may be prevailing at the beginning of pregnancy, balanced in the middle of pregnancy and supplanted by the Th2 bias at the end of pregnancy.     

The influence of paternal lymphocyte immunization on the balance of Th1/Th2 type reactivity in women with unexplained recurrent spontaneous abortion

OBJECTIVES: Paternal lymphocyte immunization has been proposed as an efficient treatment for unexplained recurrent spontaneous abortion (RSA), however precise mechanism that underlie the benefits of this immunotherapy are still unclear. It was proposed that successful pregnancy is reminiscent of T helper 2 (Th2)--dominant situation but unsuccessful pregnancy is a Th1-type situation. The aim of the study was the evaluation of influence of paternal lymphocyte immunization on the balance of Th1/Th2--type reactivity in women with unexplained recurrent spontaneous abortion. MATERIAL AND METHODS: 8 patients with a history of 3 or more consecutive primary spontaneous abortions of unknown etiology and no positive autoimmune factors were selected for the study. Immunization with paternal lymphocytes, obtained from 100 ml of peripheral blood, was performed twice prior conception with a 4-week interval. The following immunological parameters were studied: peripheral blood T lymphocyte subpopulations (CD3, CD4, CD8) and secretion of the Th1-type cytokines (IL-2, IFN-gamma), Th2-type cytokines (IL-6) and TGF-beta 1 by phytohaemaglutinin-stimulated peripheral blood lymphocytes. Evaluation of immunity parameters were performed before and 2 weeks after immunotherapy. RESULTS: It was found that paternal lymphocytes immunization significantly increase the percentage of CD4 T lymphocytes (37.11 +/- 7.65 vs. 41.38 +/- 5.57, p = 0.007). Immunotherapy also leads to a significant enhancement in Th2-type cytokines (IL-6) secretion (22,677 +/- 17,907 mg/ml vs. 44,550 +/- 15,907 mg/ml, p = 0.008) and a significant decreasing in Th1-type cytokines (IL-2) secretion (6.50 +/- 5.98 mg/ml vs. 0.00 +/- 0.00 mg/ml, p = 0.0179). CONCLUSIONS: The data of the present studies suggest that paternal lymphocytes immunization modulate of immunity in women with unexplained recurrent spontaneous abortion. Our studies indicate a shift in the balance fo cytokine profiles away from Th1-type reactivity to a Th2-type reactivity after immunotherapy.     

Th1/Th2 cytokines balance--yin and yang of reproductive immunology

For years conception of Th2 overbalance during pregnancy has been a paradigm for immunology of reproduction, while Th1 activity has been presented as unwanted component. Studies concerning Th1/Th2 balance in physiological and complicated pregnancy have been reviewed. Th1 activity during early peri-implantation period, premature and term labour not only accompanies but even predominates over Th2 activity. Th1 activity plays important role in promotion of Th2 response, regulation of placentation process, defense against infections and initiation of delivery. Together with Th2 activity it is necessary component of immunological reactions during pregnancy, both activities being inseparable like yin and yang. So paradigm of "Th1-Th2 cooperation" is much closer to reality than "Th2 phenomenon".     

The role of cytokines at the fetomaternal interface]

Various mechanisms are necessary for regulating the survival of the semiallogenic embryo in the maternal organism. In addition to the lack of classical MHC class I and II antigens at the trophoblast the cytokines play an important role at the fetomaternal interface. Different cytokines regulate the immunological processes with an emphasis on the Th1/Th2 balance. In contrast to the peripheral blood there is a certain composition of immune competent cells at the fetomaternal interface. There are many different interactions between the endocrine and immunological system. Hormones modulate the secretion of certain cytokines and vice versa. In reproductive medicine it is of specific interest to evaluate these functions for treating problems during the early pregnancy.     

Th1/Th2细胞平衡及NK细胞对胚胎种植的影响

目的:通过研究反复种植失败(RIF)患者与首次移植妊娠成功患者种植窗口期外周血中Th1、Th2型细胞因子及自然杀伤(NK)细胞的表达差异,探讨Th1/Th2细胞平衡及NK细胞对胚胎种植的影响及调节机制.方法:选取2020年3月至2020年9月于山东大学齐鲁医院不孕不育诊疗中心就诊的35例RIF患者(RIF组)和首次行体...     

Th1型/Th2型细胞因子对人孕早期蜕膜的免疫调节作用

目的 :研究Th1型 /Th2型细胞因子对人孕早期蜕膜细胞活性及TGFβ1和PRL分泌的影响。方法 :蜕膜细胞活性采用MTT法进行检测 ,蜕膜组织分泌TGFβ1和PRL的活性分别采用ELISA法和RIA进行分析测定。结果 :Th1型细胞因子IFNγ低浓度时 ( 1～ 10ng/ml)对蜕膜细胞活性及PRL分泌有促进作用 (P <0 .0 5 ) ,高浓度时 ( 10 0～ 10 0 0ng/ml)则有抑制作用 (P <0 .0 1) ;IFNγ在一定剂量范围内 ( 10～ 10 0 0ng/ml)还可抑制TGFβ1的分泌 (P <0 .0 1)。而Th2型细胞因子IL 4在一定浓度范围内 ( 1～ 10ng/ml)可明显促进蜕膜的分泌活性 (P <0 .0 1)。结论 :Th1型 /Th2型细胞因子可能是通过影响蜕膜细胞活性及TGFβ1和PRL分泌而在早期妊娠中起重要的免疫调节作用     

Changes in plasma soluble CD26 and CD30 during pregnancy: markers of Th1/Th2 balance?

The theory that the Th1 and Th2 cell ratio shifts towards Th2 dominance during pregnancy may improve fetal survival has gained support from recent studies. Also, the variation in the Th1/Th2 cell ratio is reportedly associated with intrauterine growth retardation and preeclampsia. On the basis of these findings, the analysis of the Th1/Th2 balance may be useful in predicting severe complications during pregnancy. However, simple methods for the analysis of Th1/Th2 balance are presently not available. Recently, it has been reported that regulation of CD26 cell surface expression correlates with the production of Th1-like cytokines. On the other hand, previous studies proposed that the sCD30 molecule is an activation marker useful for evaluation of a Th2 immune response. It is, therefore, possible that the analysis of the Th1/Th2 balance during pregnancy by measuring plasma sCD26 and sCD30 simultaneously is a simple and useful method. We herein demonstrate that combined analysis of sCD26 and sCD30 is a potent surrogate tool to evaluate the Th1/Th2 balance during pregnancy.