外周血及蜕膜组织CD4+ CD25+调节性T细胞比例与原因不明复发性流产的关系研究

目的探讨外周血及蜕膜组织中调节性淋巴细胞的比例原因不明复发性流产(URSA)中的作用。方法根据2013年5月至2015年5月在我院就诊的URSA患者的妊娠状态将其分成4组,分别为未孕组67例,早期流产组23例;正常早孕且自愿要求人工终止妊娠的妇女组24例及正常未孕女性组66例为对照组。计划外妊娠要求URSA患者行清宫术后的新鲜蜕膜组织,采用流式细胞仪分析外周血及蜕膜组织中调节性T细胞数量及比例,最终分析4组妇女外周血及蜕膜组织中CD4+、CD25+等调节性T细胞对URSA患者的影响。结果正常早孕妇女外周血CD4+CD25 high T细胞高于正常未孕妇女及URSA流产组,组间比较差异明显(P﹤0.01);URSA未孕患者的外周血CD4+、CD25high T细胞也显著低于正常未孕女性及URSA流产组患者(P﹤0.01);URSA流产患者蜕膜组织中CD4+、CD25high T细胞数量低于正常早孕组(P﹤0.01)。结论 CD4+CD25+调节性T细胞在维持正常妊娠中扮演重要角色,原因不明复发性流产的发生可能与CD4+、CD25+调节性T细胞的数量降低有关。     

HMGB1与原因不明复发性流产的关系

目的探讨原因不明复发性流产(URSA)患者外周血中高迁移率族蛋白B1(HMGB1)的表达水平,及其对Th17/Treg平衡的影响。方法选取42例早孕期原因不明复发性流产患者为研究对象(URSA早孕组),并以32例正常早孕孕妇为正常早孕组(NP组)。采用流式细胞术(FCM)检测外周血中Th17和Treg细胞的比例;采用酶联免疫吸附实验(ELISA)检测外周血中HMGB1、RAGE、IL-17、IL-6、TGF-β及IL-10表达水平。结果 URSA早孕组外周血中Treg细胞比例低于正常早孕组(P0.05),而Th17细胞比例和Th17/Treg比值均高于正常早孕组(P0.05);URSA早孕组外周血HMGB1和RAGE表达高于正常早孕组(P0.05);与正常早孕组相比,URSA早孕组外周血IL-17、IL-6表达水平均增高(P0.05),而TGF-β、IL-10的表达水平均下降(P0.05);在相关性分析比较中,URSA早孕组外周血HMGB1表达水平与RAGE、IL-17、IL-6均呈正相关,而HMGB1表达水平与TGF-β、IL-10均呈负相关。结论 URSA外周血中HMGB1表达水平增高,HMGB1可能通过直接或间接的方式调节Th17/Treg平衡模式参与URSA的发病机制。     

稽留流产绒毛组织中Fas／FasL表达及其意义

目的探讨稽留流产的发生与Fas／FasL表达的相关性。方法采用RT—PCR法检测稽留流产患者与健康早孕人流者绒毛组织中FasL的mRNA表达水平。结果稽留流产组FasL mRNA表达水平为（0．714-0．11）,健康早孕人流组FasL mRNA的表达水平为（1．38±0．41）,P〈0．05。结论FasL表达的降低可能是导致稽留流产的原因之一。     

Tim-3/Gal-9途径参与不明原因复发性流产的分子机制研究

目的探讨不明原因复发性流产(unexplained recurrent spontaneous abortion,URSA)Tim-3/Gal-9通路的表达变化以及淋巴细胞免疫治疗(lymphocyte immunotherapy,LIT)的分子机制。方法各采集20例正常早孕及URSA患者外周血,对URSA患者进行疗程LIT治疗后采集其外周血,利用ELISA法定量检测三组外周血中Tim-3及Gal-9的表达情况。结果 URSA患者血清中Tim-3与Gal-9的表达水平高于正常早孕组(P0.05)。LIT治疗后,URSA患者血清中Tim-3与Gal-9的含量较治疗前明显下降(P0.05)。结论 Tim-3/Gal-9通路参与了URSA,经过LIT治疗上调了Gal-9的表达,加强了Tim-3/Gal-9通路对Th1免疫细胞的负性刺激作用,使URSA患者转向以Th2型免疫细胞为主的状态,从而改善妊娠结局。     

原因不明复发性流产患者主动免疫治疗后调节性T细胞比例变化及意义

目的探讨原因不明复发性流产（URSA）主动免疫治疗后外周血CD4＋CD25＋调节性T细胞比例变化及其意义。方法反复流产3～6次的不孕患者（n=55）,采用补体依赖细胞毒实验检测封闭抗体的水平,应用患者丈夫外周血淋巴细胞为患者做皮下免疫治疗,并随访妊娠结局;用双荧光标记流式细胞分析技术检测55名原因不明复发性流产患者治疗前后外周血CD4＋CD25＋调节性T细胞水平的变化。结果55例原因不明复发性流产患者检测封闭抗体阴性后接受主动免疫治疗,其中已分娩41例,14例患者再次流产。主动免疫治疗后,原因不明复发性流产患者外周血CD4＋CD25＋调节性T细胞的比例较治疗前明显增加（P（0.05）;妊娠成功患者外周血CD4＋CD25＋调节性T细胞的比例显著多于妊娠失败者。结论主动免疫对于原因不明复发性流产患者是一种有效的治疗方法;URSA的发生与CD4＋CD25＋调节性T细胞水平降低有关。     

自然流产妇女T淋巴细胞亚群的研究

本文对有自然流产史的未孕及已孕妇女进行了外周血Ｔ淋巴细胞亚群（Ｔｌｙｍｐｈｏｃｙｔｅｓｕｂｐｏｐｕｌａｔｉｏｎ，ＴＬＳ）的检测并对其中８例做了免疫治疗，结果表明：有自然流产史的未孕组较正常未孕组细胞减少（Ｐ＜０．０５）；细胞增多（Ｐ＜０．０２），故比值明显降低（Ｐ＜０．０１）。有自然流产史早孕组较正常早孕组间细胞元明显差异，而细胞有明显差异（Ｐ＜０．０５），因此有自然流产史早孕组比值较正常早孕组明显下降（Ｐ＜０．０５）。正常早孕妇女细胞较未孕组减少（Ｐ＜０．０５），细胞无明显变化（Ｐ＞０．０５），因此早孕组比未孕组明显降低（Ｐ＜０．０５）。有自然流产史的未孕组及早孕组细胞无明显差异（Ｐ＞０．０５）。经免疫治疗受孕成功妇女，比值上升，接近于正常早孕组。从实验结果表明，细胞免疫功能失调，是引起流产的原因之一，免疫治疗可以改善自然流产妇女的细胞免疫功能，从而获得成功妊娠。     

淋巴细胞的KIR2DL4基因表达在反复性胚胎停育主动免疫治疗前后的研究

目的检测复发性胚胎停育患者淋巴细胞主动免疫前后KIR2D1,4基因的表达的变化,探讨反复性胚胎停育免疫学原因。方法选择2011年6月至2012年6月就诊的2次以上早孕胚胎停育的患者,根据以往有无人工流产和／或者分娩史分为无妊娠史（无人工流产及分娩史）组30例;有妊娠史（有人工流产史及分娩史）组55例;对照组为正常无妊娠史的未孕妇女30例。对研究者进行淋巴细胞主动免疫治疗4个周期后,采用荧光实时定量PCR技术检测治疗前后患者的淋巴细胞的KIR2DL4基因的表达。随访研究者妊娠结局。结果（1）两组胚胎停育组治疗前ⅪR2DL4基因表达无妊娠史组为（43．55±12．71×103／m1）、有妊娠史组为（21．48±9．43×103／m1）,分别与对照组（55．35±12．68×103／m1）比较,差异有统计学意义（P〈0．05）;两组胚胎停育组经淋巴细胞主动免疫治疗后KIR2DL4基因的表达分别为（56．76±10．90×103／ml、67．89±11．39×103／m1）与对照组治疗后（70．84±13．47×103／m1）比较,差异无统计学意义（P〉0．05）。两组胚胎停育组免疫治疗前后比较KIR2DL4基因比较差异有统计学意义（P〈0．05）。（2）免疫治疗前有妊娠史胚胎停育组l（IR2DL4基因的表达（21．48±9．43×103／m1）,与无妊娠史胚胎停育组KIR2DL4基因表达（43．55±12．71×103／m1）比较,差异有统计学意义（P〈0．05）,主动免疫治疗后差异无统计学意义（P〉0．05）。（3）随访结果：两组胚胎停育组免疫治疗结束后,每组妊娠患者中,胚胎停育率分别为21．74％,18．75％;对照组胚胎停育率为20％。胚胎停育率比较差异无统计学意义（P〉0．05）。结论淋巴细胞KIR2DL4基因的表达数量异常与反复性胚胎停育有关。     

白血病抑制因子在正常早孕、稽留流产蜕膜绒毛中表达的初步临床研究

目的探讨白血病抑制因子（LIF）在正常早孕、稽留流产蜕膜绒毛组织中的表达,及其与稽留流产发生的关系。方法采用免疫组化技术-链霉菌抗生物素蛋白-过氧化酶连接（SP）法对白血病抑制因子（UF）在2组妇女绒毛蜕膜组织中的表达进行组织学定位和表达强弱度分析。通过病理图像分析仪对图片进行观察,并运用所附分析系统软件测量各组平均光密度值（IOD）。采用放射免疫法检测正常早孕妇女（正常早孕组,20例）、稽留流产患者（稽留流产组,25例）血清人绒毛膜促性腺激素（β—hCG）及孕酮（P）水平。结果（1）孕酮及hCG水平在2组孕妇间的比较：正常早孕组孕妇血清中孕酮、hCG水平分别为（37．5±15．2）ng／mL、（9005,8±2134．9）mIU／L,稽留流产组孕妇分别为（19．1±11．6）ng／mL、（3120．3±1213．2）mIU／L,两组孕妇血清孕酮、hCC水平比较,有显著性（P〈0．01）;（2）LIF平均相对含量在2组孕妇蜕膜、绒毛组织中的比较：正常早孕组孕妇分别为0．38±0．15,0．36±0．11;稽留流产组孕妇分别为0．20±0．17,0．18±0．13。正常早孕组与稽留流产组比较,差异有显著性（P〈0．05）。结论LIF在稽留流产蜕膜绒毛组织中的表达量降低,可能是导致hCG及孕酮分泌下降,最终造成稽留流产的原因之一。     

原因不明复发性流产患者外周血单核细胞上Tim-3和PD-1的表达及意义

目的探讨原因不明复发性流产(unexplained recurrent spontaneous abortion,URSA)和先兆流产患者外周血单核细胞上PD-1和Tim-3的表达及其细胞因子的分泌情况,为先兆流产和URSA发病机制研究提供理论依据。方法随机选取29例健康早孕妇女作为正常早孕组(A组),37例仅有少量阴道出血的早孕妇女为先兆流产组(B组),22例URSA早孕患者为URSA组(C组);应用密度梯度离心法分离外周血单个核细胞,然后采用流式细胞分析技术检测3组孕妇外周血中CD14+单核细胞上Tim-3、PD-1的表达水平;ELISA法检测外周血中IL-4、IL-12、IFN-γ的含量。结果与正常早孕组相比,先兆流产组和URSA组外周血单核细胞上Tim-3、PD-1表达降低,外周血IL-4表达降低,URSA组低于先兆流产组(P0.05);IFN-γ、IL-12表达增高,URSA组高于先兆流产组(P0.05);相关性分析提示先兆流产组及URSA组外周血单核细胞上Tim-3与PD-1之间呈正相关;Tim-3、PD-1与IL-12呈负相关,IL-12与IL-4呈负相关,与IFN-γ呈正相关。结论外周血单核细胞上Tim-3、PD-1可能通过调节IL-12产生间接调节Th1/Th2平衡参与先兆流产和URSA的发生。     

免疫治疗不明原因反复自然流产患者群体反应抗体、TGF-β和nTreg表达变化的研究

目的:探讨不明原因反复自然流产(URSA)患者经免疫治疗后其血清群体反应抗体(PRA)、转化生长因子β(TGF-β)和外周血单个核细胞(PBMC)中转录调节因子3(FOXP3)阳性的天然调节性T细胞(n Treg,CD4+CD25+FOXP3+)表达的变化及临床意义。方法:应用酶联免疫及流式分析方法,分别检测正常妊娠组及URSA患者免疫治疗后未孕组和妊娠组血清PRA、TGF-β含量及外周血单个核细胞n Treg表达率。结果:RSA患者经免疫治疗后未孕组血清PRA、TGF-β中位数较免疫治疗后妊娠组中位数降低(27.5%、107.7 pg/L vs 68.75%、189.9 pg/L,P0.01);未孕组n Treg表达率中位数也较妊娠组低(5.05%vs 8.05%,P0.01)。结论:URSA患者经免疫治疗后其血清PRA的产生及TGF-β含量增加和n Treg的诱导性升高是RSA患者经免疫治疗后成功妊娠的重要因素,PRA、TGF-β及n Treg的检测对RSA患者的免疫治疗方案的确定和疗效判断有重要的临床意义。     

Natural killer cell functional activity suppression by intravenous immunoglobulin, intralipid and soluble human leukocyte antigen-G

PROBLEM: The purpose of this study was to compare the ability of intravenous immunoglobulin (IVIg), intralipid and soluble human leukocyte antigen (sHLA)-G to suppress natural killer (NK) cell cytotoxicity in an in vitro assay. METHOD OF STUDY: Blood samples taken from 275 women experiencing reproductive failure were analyzed for NK cytotoxicity and the suppression of NK cytotoxicity by IVIg 4 and 2 mg/mL (n = 275), intralipid 18 and 9 mg/mL (n = 275) and sHLA-G 70 and 35 ng/mL (n = 50) using immunofluorescent labeled K562 cells as targets and flow cytometry. RESULTS: Natural killer cytotoxicity was suppressed in all samples. Among patients with normal NK cell activity, IVIg suppressed NK cytotoxicity by 44.9 +/- 8.1%, intralipid suppressed NK killing by 45.2 +/- 8.3% and sHLA-G suppressed by 49.0 +/- 9.2%. When specimens with abnormal NK activity were observed for suppression of cytotoxicity, IVIg suppressed by 38.9 +/- 5.4%, intralipid suppressed by 39.8 +/- 6.2% and sHLA-G suppressed by 39.9 +/- 5.0%. CONCLUSION: Intravenous immunoglobulin, intralipid and sHLA-G suppressed NK cell cytotoxicity with equal efficacy in an in vitro assay.     

Lymphocyte Immunotherapy (LI) Increases Serum Levels of Progesterone Induced Blocking Factor (PIBF)

PROBLEM: To determine if allogenic stimulation from leukocyte immunization (LI) can increase the production of an immunomodulatory protein called progesterone induced blocking factor (PIBF) by CD8+ T-lymphocytes. METHOD: The study group consisted of 35 women, 29 who failed to conceive after repeated embryo transfers (ETs) and six with recurrent spontaneous abortion (RSA). The women underwent LI using the male partner's blood as the source of leukocytes. Progesterone induced blocking factor was measured pre- and post-LI with an immunocytochemistry method using a PIBF-specific polyclonal antibody. RESULTS: The mean percentage of lymphocytes expressing PIBF, as well as the percentage of cases whose PIBF level increased to 1% or more, was significantly higher post-LI. Similarly post-LI, there was a significantly lower percentage of zero PIBF levels. CONCLUSIONS: Leukocyte immunization causes an increase in PIBF in many cases. Possibly the improved pregnancy outcome in immunized patients with RSA or previous failure to conceive with in vitro fertilization may be partially or possibly completely explained by its stimulatory effect on PIBF.     

Plasma soluble human leukocyte antigen G levels in asthmatic children

BACKGROUND: Human leukocyte antigen G (HLA-G) is a nonclassical major histocompatibility complex class I gene. HLA-G stimulates Th2 cytokine secretion by peripheral blood mononuclear cells. The role of soluble HLA-G (sHLA-G) in bronchial asthma is incompletely understood and the plasma level of sHLA-G in asthmatic children has not been investigated. OBJECTIVE: It was the aim of this study to investigate the plasma level of sHLA-G in asthmatic children. METHODS: Asthmatic (n = 53) and healthy children (n = 16) were included in the study. Levels of sHLA-G were determined in plasma using ELISA. Spirometry, total immunoglobulin E and eosinophil counts were obtained and skin testing done with a battery of 25 antigens with appropriate positive and negative controls. RESULTS: No significant difference was observed in the plasma level of sHLA-G between the asthmatic and healthy children (p > 0.05). When we compared atopic asthmatics with healthy controls, we found significantly higher levels of sHLA-G in atopic asthmatics (p < 0.05). There was a significant difference in the peripheral blood eosinophil counts and total immunoglobulin E levels among the groups (p < 0.001). CONCLUSION: Our study shows that plasma sHLA-G levels do not differ between asthmatic children and healthy controls. However, higher plasma levels of sHLA-G in atopic asthmatics may suggest a role for sHLA-G in atopy. Further investigations are required to better define the mechanism of the production and the role of sHLA-G molecules observed in patients with asthma.     

Immunology: The effect of serum follicular phase luteinizing hormone concentrations in habitual abortion: correlation with results of paternal leukocyte immunization

A prospective study was carried out on 153 couples with recurrentabortions who desired pregnancy. The object was to determinethe incidence of raised luteinizing hormone (LH) levels; tocompare the outcome of further pregnancies in habitually abortingwomen with and without raised circulating LH concentrations;and to assess whether the efficacy of paternal leukocyte immunizationis affected in the presence of raised LH concentrations. Ofthe 153 women with recurrent abortions (>3) included in thisstudy, 56 (36.6%) had follicular phase serum LH concentrations>10 mIU/ml. Of the 103 pregnancies that were followed prospectively,65 (63.1%) resulted in a birth of a live infant. There was nosignificant relationship between the pregnancy outcome and LHconcentrations. Women who underwent immunization with paternalleukocytes had significantly more live births (75.8%) than thosewho were not immunized (43.6%). However, the live birth ratewas lower after paternal leukocyte immunization in the presenceof raised LH concentrations or a raised LH/follicle stimulatinghormone (FSH) ratio.     

Effect of leukocyte therapy on tumor necrosis factor-alpha and interferon-gamma production in patients with recurrent spontaneous abortion

PROBLEM: Considering the deleterious role of T helper1 (Th1) cells in pregnancy outcome, a successful treatment for recurrent spontaneous abortion (RSA) should be able to make a significant shift away from Th1 responses. Although paternal leukocyte immunization has been used for treatment of RSA for years, because of methodological differences there is no consensus on the mechanism of action and effectiveness of this method. METHOD OF STUDY: Twenty-five Iranian non-pregnant women with RSA and 16 non-pregnant control women with at least two successful pregnancies were included in this study. All cases were followed up after leukocyte therapy for pregnancy outcome. Mononuclear cells from women were co-cultured with the husband's mononuclear cells before and after immunotherapy. The levels of tumor necrosis factor-alpha (TNF-alpha) and interferon-gamma (IFN-gamma) were checked on culture supernatant by enzyme-linked immunosorbent assay method. RESULTS: The mean concentration of TNF-alpha was significantly higher in patients compared with that in normal controls (P=0.0001). After immunotherapy, the TNF-alpha level was only significantly decreased in women with successful outcome (P=0.0001). Immunotherapy also induced a significant reduction in the IFN-gamma level (P=0.009). CONCLUSION: The results of this investigation confirm the role of TNF-alpha in RSA and propose the assessment of TNF-alpha production as a valuable prognostic parameter for the prediction of abortion after leukocyte therapy.     

Elevation of plasma soluble human leukocyte antigen-G in patients with chronic hepatitis C virus infection

The subversion of immune responses that hepatitis C virus (HCV) uses to escape immune surveillance and to establish persistent infection has been poorly understood. The immune-suppressive molecule human leukocyte antigen-G (HLA-G) has been supposed to play important roles in viral infection. In the current study, HCV genotype was analyzed in 67 chronic HCV-infected (CHC) patients. Plasma soluble sHLA-G (including sHLA-G1 and HLA-G5), interleukin-10 (IL-10), and interferon-γ (IFN-γ) levels were determined in these CHC patients and in healthy subjects by enzyme-linked immunosorbent assay, and the sHLA-G isoforms present in plasma were determined by Western blot. Data showed that HCV 1b was the predominant genotype, with a prevalence of 64.2%. sHLA-G was dramatically increased in CHC patients (median: 85.54 U/ml, range: 19.40-204.07) over that in normal controls (median: 9.13 U/ml, range: 5.07-69.56) (p < 0.001). Western blotting revealed that plasma sHLA-G was derived from sHLA-G1 and HLA-G5. IL-10 and IFN-γ levels were also significant higher in CHC patients than in normal controls (median: 16.3 pg/ml vs 1.8 pg/ml, p < 0.001, and 1025.3 pg/ml vs 858.3 pg/ml, p = 0.03, respectively). No significant association was observed for the HCV genotype and viral RNA load with the levels of sHLA-G, IL-10, and IFN-γ in CHC patients. These results indicate that elevation of sHLA-G expression in HCV patients was independent of viral genotype and viral RNA load. Given its immunotolerant property, an increase in sHLA-G may play a role in the persistency of HCV infection.     

Embryonic soluble HLA-G as a marker of developmental potential in embryos

BACKGROUND: In human reproduction, embryo implantation is complex and poorly understood. At present, no single markers are used in routine treatment to assay biochemical functions of the human embryo. Soluble human leukocyte antigen-G (sHLA-G) could be considered a possible marker of embryo developmental potential. It is localized primarily on the extravillous trophoblast, making this antigen a potential mediator of immune interaction at the maternal-fetal interface during gestation. METHODS: Soluble-HLA-G levels were evaluated by an enzyme-linked immunosorbent assay (ELISA) employing monoclonal antibody MEM-G9. It was evaluated in 318 media of single embryo cultures. We correlated the presence of sHLA-G with embryo morphology and the pregnancy obtained in that treatment cycle. RESULTS: No correlation was found between embryo morphology and sHLA-G levels. Pregnancy was observed only when the medium of at least one transferred embryo contained sHLA-G. In 26 out of 66 patients, none of the obtained embryos showed any detectable sHLA-G molecules and no pregnancy occurred. CONCLUSIONS: From our results, we propose sHLA-G as a potential marker of embryo development: the sHLA-G ELISA can be a useful biochemical assay in addition to embryo morphology in embryo selection for transfer in IVF treatment if there are other embryos with the same morphology.     

Post-transplant increase in soluble human leukocyte antigen-G associated with non-severe cardiac allograft vasculopathy

Cardiac allograft vasculopathy (CAV) is the single most important long-term limitation to heart transplantation. This study aimed to assess the value of monitoring soluble human leukocyte antigen-G (sHLA-G) during the first year post-transplantation to predict the severity of CAV, in 21 out of 77 heart recipients assessed by intravascular ultrasound (IVUS). Serum sHLA-G concentration increased after transplant in recipients free of severe CAV, but decreased in recipients suffering from severe CAV, significant differences between these two groups were found 6 to 12 months post-transplantation. The optimal value of the change in post-transplant sHLA-G for identifying severe CAV was ?0.062%, which maximized sensitivity (80%) and specificity (100%). Importantly, increases in post-transplant sHLA-G were inversely associated with severe CAV, but directly associated with human cytomegalovirus reactivation. In addition, recipients presenting non-severe CAV or an increased sHLA-G post-transplantation, showed higher numbers of CD8⁺CD28⁻ T cells and a down-modulation of CD28 on CD4⁺ lymphocytes, which typically identifies CD8⁺ regulatory T cells and anergic/tolerogenic T helper cells, respectively. In conclusion, quantification of sHLA-G might offer a complementary non-invasive method for identifying recipients at risk of more severe CAV and who might benefit from earlier preventive therapies, although these results need to be confirmed in larger series.     

Placental abruption is associated with decreased maternal plasma levels of soluble HLA-G

During pregnancy the fetus represents a semi-allograft. Both membrane-bound and soluble forms of the nonclassic human leukocyte antigen (HLA)-G protect the fetus from maternal immune attack. To assess the relevance of soluble HLA-G (sHLA-G) levels in the maternal circulation for the occurrence of characteristic pregnancy disorders, we analyzed sHLA-G plasma levels of women with normal and pathological pregnancies. Compared to normal pregnancy, significantly increased sHLA-G levels were detected in women delivered preterm because of intrauterine activation (uncontrollable labor, rupture of fetal membranes, cervical insufficiency) and women with Hemolysis, Elevated Liver enzymes, Low Platelet count (HELLP) syndrome. Contrary to these disorders, the sHLA-G levels in women with placental abruption were more than three times lower than in normal pregnancy (p < 0.0001). Nonparametric discriminant analysis showed that women with sHLA-G levels below 9.95 ng/mL had a relative risk of 7.12 for the development of placental abruption during further course of pregnancy. These results suggest that the occurrence of pregnancy-associated diseases is strongly influenced by maternal sHLA-G plasma levels.     

Human leukocyte antigen (HLA)-G during pregnancy part I: Correlations between maternal soluble HLA-G at midterm,at term,and umbilical cord blood soluble HLA-G at term

Human leukocyte antigen (HLA)-G is a class Ib molecule with restricted tissue distribution expressed on trophoblast cells and has been proposed to have immunomodulatory functions during pregnancy. Soluble HLA-G1 (sHLA-G1) can be generated by the shedding of membrane-bound HLA-G molecules; however, three soluble isoforms also exist (HLA-G5 to -G6). During pregnancy, it is unknown whether there is a correlation between sHLA-G levels in maternal and fetal blood. In 246 pregnancies, we have measured the levels of sHLA-G1/-G5 in maternal blood plasma samples from gestational week 20 (GW20) and at term, as well as in umbilical cord blood samples. Soluble HLA-G levels declined by 38.4% in maternal blood from GW20 to term, and sHLA-G levels were significantly lower in maternal blood at term than in GW20 (P < 0.001). At term, the sHLA-G levels were significantly higher in maternal blood than in umbilical blood (P < 0.001). HLA-G levels in maternal blood in GW20 and at term, and in maternal blood at term and umbilical cord blood, were correlated (P < 0.001 and P < 0.01, respectively). This is the first large study simultaneously measuring sHLA-G in both maternal and umbilical cord blood. The finding that sHLA-G levels are significantly lower in fetal compared with maternal blood at term documents for the first time that sHLA-G is not freely transferred over the placental barrier. Soluble HLA-G levels in maternal and fetal blood were found to be correlated, which may be due to shared genetic factors of importance for production of sHLA-G in the mother and child, or it may support the theory that sHLA-G in the pregnant woman and the fetus is partly derived from a “shared organ”, the placenta.