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Peripheral CD4+CD25+FOXP3+Tregs Cell Distribution in Women With and Without a History of Recurrent Pregnancy Loss in Relation to ACE rs4646994 (I/D) Polymorphism 外周血CD4+CD25+FOXP3+Tregs细胞分布与ACE rs4646994 (I/D)多态性的关系
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-11 DOI: 10.1111/aji.70174
Nargis Fatima, Rashmi Bhuwalka, Sufaya Jameel, Aatika Ejaz, Rajeshwari Bonu, Praveen Jahan

Problem

Recurrent pregnancy loss (RPL) a reproductive concern affects 1%–5% of couples worldwide and 50% of the cases are idiopathic. Pregnancy, a dynamic state of inflammation is influenced by diverse physiological factors. A multifunctional angiotensin converting enzyme (ACE) has direct effect on inflammation, oxidative stress, and fibrinolytic balance through Angiotensin-II. By blocking the NF-κB1 transcription factor complex, ACE inhibitors stimulate regulatory T-cells (Tregs). Based on this, we postulated that ACE functional polymorphism(s) may influence the Tregs in RPL.

Aim

To assess the association of rs4646994 (I/D) polymorphism with circulating Tregs in south Indian pregnant women with (RPL) and without (nRPL) the history of RPL.

Methods of Study

Genomic DNA and peripheral blood mononuclear cells (PBMC's) from nRPL(60) and RPL(77) pregnant women were isolated and subjected to PCR for rs4646994 genotyping and flow cytometry for enumeration of Tregs, respectively.

Results

We observed significantly diminished circulating Tregs (p < 0.0001) in RPL over the nRPL and lack of association of rs4646994 polymorphism with RPL. However, consistently lower Tregs irrespective of the genotypes within RPL group (p > 0.05) and significant elevation in percentage of Tregs in nRPL pregnant women with II (p = 0.003) and ID (0.007) genotypes when compared to their respective counterparts in RPL group was noted.

Conclusion

This is first study to explore the association between ACE genotypes and distribution of Tregs in RPL. Understanding the relation may help resolve to certain extent the heterogeneity existing in idiopathic RPL for the better management. The limitation of the study is small sample size and lack of information on serum ACE levels.

问题:复发性妊娠丢失(RPL)是一种生殖问题,影响全世界1%-5%的夫妇,50%的病例是特发性的。妊娠期,炎症处于动态状态,受多种生理因素的影响。一种多功能血管紧张素转换酶(ACE)通过血管紧张素- ii直接影响炎症、氧化应激和纤溶平衡。通过阻断NF-κB1转录因子复合物,ACE抑制剂刺激调节性t细胞(Tregs)。基于此,我们推测ACE功能多态性可能影响RPL的treg。目的:评估rs4646994 (I/D)多态性与印度南部有和无RPL病史孕妇循环Tregs的关系。研究方法:分离nRPL(60例)和RPL(77例)孕妇的基因组DNA和外周血单个核细胞(PBMC’s),分别采用PCR进行rs4646994基因分型和流式细胞术进行Tregs计数。结果:我们观察到与RPL组相比,II (p = 0.003)和ID(0.007)基因型nRPL孕妇的循环Tregs显著减少(p 0.05), Tregs百分比显著升高。结论:本研究首次探讨了ACE基因型与RPL中Tregs分布的关系。了解这种关系可以在一定程度上解决特发性RPL存在的异质性,从而更好地进行治疗。该研究的局限性是样本量小,缺乏血清ACE水平的信息。
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引用次数: 0
Distinct Suppression of Prednisone on Endometrial Immune Cells in Women With Reproductive Failure 强的松对生殖衰竭妇女子宫内膜免疫细胞的明显抑制
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-07 DOI: 10.1111/aji.70151
Lu Chen, Xiaoyan Chen, Qianhan Xu, Joshua Jing Xi Li, Wen-Jui Yang, Hanbin Wu, Chi Chiu Wang, Xiaodan Fan, Jie Ji, Jacqueline Pui Wah Chung, Mingqing Li, Tin Chiu Li, Tao Zhang

Research Question

For women with reproductive failure, prednisone is widely used but remains controversial as a therapy for improving clinical outcomes. This study aimed to investigate the impact of prednisone on various endometrial immune cells.

Design

A total of 24 women with repeated implantation failure and recurrent miscarriage underwent their first endometrial biopsy precisely 7 days after luteinizing hormone surge (LH surge +7). Prednisone was administered from the first day of the subsequent menstrual cycle, followed by the second endometrial sampling on day LH surge +7 again. The density and cell–cell clustering of CD3−CD56+CD16− NK cells, CD3−CD56+CD16+ NK cells, CD68+CD16− macrophages, CD68+CD16+ macrophages, CD3+CD56− T cells, and CD3+CD56+ NK-T cells were analyzed by multiplex staining and compared before and after prednisone treatment.

Results

Following prednisone treatment, a significant decrease in the percentage of CD3−CD56+CD16− NK cells (p < 0.001), CD68+CD16− macrophages (p = 0.007), and their clustering degree (p = 0.038) was observed. No significant changes were noted in CD3−CD56+CD16+ NK cells, CD68+CD16+ macrophages, CD3+CD56− T cells, CD3+CD56+ NK-T cells, and their cell–cell clustering.

Conclusion

Prednisone does not generally reduce all endometrial immune cells; instead, it selectively suppresses specific immune cell subtypes in women with reproductive failure.

研究问题:对于生育失败的女性,泼尼松被广泛使用,但作为一种改善临床结果的治疗方法仍存在争议。本研究旨在探讨强的松对子宫内膜各种免疫细胞的影响。设计:共有24名反复着床失败和复发性流产的妇女在黄体生成素激增(LH激增+7)后7天进行了第一次子宫内膜活检。从随后月经周期的第一天开始给药强的松,然后在黄体生成素激增+7日再次进行第二次子宫内膜取样。采用多重染色法分析强的松治疗前后CD3-CD56+CD16- NK细胞、CD3-CD56+CD16+ NK细胞、CD68+CD16-巨噬细胞、CD68+CD16+巨噬细胞、CD3+CD56- T细胞、CD3+CD56+ NK-T细胞的密度和细胞细胞聚类。结果:泼尼松治疗后,CD3-CD56+CD16- NK细胞百分比(p < 0.001)、CD68+CD16-巨噬细胞百分比(p = 0.007)及聚类程度(p = 0.038)均显著降低。CD3-CD56+CD16+ NK细胞、CD68+CD16+巨噬细胞、CD3+CD56- T细胞、CD3+CD56+ NK-T细胞及其细胞-细胞聚类无明显变化。结论:强的松并不普遍降低所有子宫内膜免疫细胞;相反,它选择性地抑制生殖失败女性的特定免疫细胞亚型。
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引用次数: 0
Elevated Aspartate Aminotransferase to Platelet Ratio Index Associated With Dyslipidaemia and Obesity in Patients With Polycystic Ovary Syndrome 多囊卵巢综合征患者血脂异常和肥胖与天冬氨酸转氨酶血小板比值指数升高相关
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-10-04 DOI: 10.1111/aji.70171
Muradiye Yildirim, Neval Cayonu Kahraman, Mesut Simsek, Onur Numan, Belgin Savran Ucok, Dilara Duygulu Bulan, Yaprak Engin-Ustun

Problem

Polycystic ovary syndrome (PCOS) and steatotic liver disease associated with metabolic dysfunction are closely related. The aspartate aminotransferase platelet ratio index (APRI), one of the non-invasive indices, has a high prognostic value in metabolic and cardiovascular abnormalities. The primary outcome of this study was to compare APRI levels in PCOS patients with different metabolic subgroups.

Method of Study

The study included women aged 20–45 years with a diagnosis of PCOS. Baseline blood samples were collected after spontaneous menstrual bleeding between days 2 and 5 of the menstrual cycle, following an overnight fast. Patients were classified as obese or non-obese, with or without hypertriglyceridemia, and with normal or abnormal fasting glucose.

Results

A total of 106 patients were included in the study. Triglyceride, low-density lipoprotein cholesterol levels and APRI scores of lean and overweight patients were significantly lower than those of obese patients. APRI was significantly lower in normotriglyceridemic PCOS patients. The APRI score was positively correlated with triglycerides and negatively correlated with sex-hormone binding globulin.

Conclusions

Current evidence-based international guidelines emphasise that PCOS is not an isolated condition but a systemic endocrine disorder that requires multidisciplinary management. Metabolic abnormalities and indicators of cardiovascular disease risk can be assessed non-invasively in women with PCOS, one of the world's most important health problems. At the same time, patients at risk can be followed more closely and carefully. Given that metabolic risks vary by phenotype and region, personalised assessment and management are essential.

问题:多囊卵巢综合征(PCOS)与脂肪变性肝病相关代谢功能障碍密切相关。天门冬氨酸转氨酶血小板比率指数(APRI)是一种无创指标,在代谢和心血管异常中具有较高的预后价值。本研究的主要结果是比较不同代谢亚组PCOS患者的APRI水平。研究方法:研究对象为年龄在20-45岁、诊断为多囊卵巢综合征的女性。在月经周期的第2天至第5天自发性月经出血后,在禁食一夜后收集基线血液样本。患者分为肥胖或非肥胖、有或没有高甘油三酯血症、空腹血糖正常或异常。结果:共纳入106例患者。瘦和超重患者的甘油三酯、低密度脂蛋白胆固醇水平和APRI评分均显著低于肥胖患者。正常甘油三酯血症PCOS患者的APRI显著降低。APRI评分与甘油三酯呈正相关,与性激素结合球蛋白呈负相关。结论:目前的循证国际指南强调多囊卵巢综合征不是一种孤立的疾病,而是一种全身性内分泌紊乱,需要多学科治疗。多囊卵巢综合征是世界上最重要的健康问题之一,可对多囊卵巢综合征妇女的代谢异常和心血管疾病风险指标进行无创评估。与此同时,可以更密切、更仔细地跟踪高危患者。鉴于代谢风险因表型和区域而异,个性化评估和管理是必不可少的。
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引用次数: 0
Correction to "Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation" 对“Circ-ADAM9敲低通过MAPK通路失活降低糖尿病小鼠胰岛素抵抗和胎盘损伤”的更正
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-30 DOI: 10.1111/aji.70169

A. Zhao, Y. Yang, Y. Yang, Z. Chi, and Y. Sun, “Circ-ADAM9 Knockdown Reduces Insulin Resistance and Placental Injury in Diabetic Mice via MAPK Pathway Inactivation,” American Journal of Reproductive Immunology 92, no. 5 (2024): e70017, https://doi.org/10.1111/aji.70017.

In published version, the institution address “The People's Hospital of Nanjing Medical University,” is incorrect. It should be “The Affiliated Huai'an No.1 People's Hospital of Nanjing Medical University”.

We apologize for this error.

赵安,杨艳,杨艳,迟志,孙艳,“Circ-ADAM9基因敲低对糖尿病小鼠胰岛素抵抗和胎盘损伤的影响,中国生殖免疫杂志,第92期。5 (2024): e70017, https://doi.org/10.1111/aji.70017.In公布版本,机构地址“南京医科大学人民医院”不正确。应该是“南京医科大学附属淮安第一人民医院”。我们为这个错误道歉。
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引用次数: 0
The Role of Cryptotanshinone Regulates HTR-8/SVneo Cells Activity Through the p53/STAT3 Pathway in Unexplained Recurrent Spontaneous Abortion 隐丹参酮通过p53/STAT3通路调控HTR-8/SVneo细胞活性在不明原因复发性自然流产中的作用
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-29 DOI: 10.1111/aji.70163
Lidan Lu, Ximei Cai, Yang Zhang, Weibo Zhao, Haiyan Ni, Liping Zhang, Peijuan Wang

Objective

This study sought to investigate the therapeutic effects and mechanisms of cryptotanshinone (CT) on unexplained recurrent spontaneous abortion (URSA).

Methods

The DBA/2 male and CBA/J female mice were caged together to construct a URSA model before treatment with high and medium-low doses of CT. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of interleukin (IL)-1 beta (β), IL-17, and IL-22 in serum in each category of mice. Hematoxylin–eosin (HE) pathology was employed to detect decidua and uterine tissues, while polymerase chain reaction (PCR) was utilized to ascertain relative expression levels of serum messenger ribonucleic acid (mRNA) of IL-17, IL-22, and IL-1β. The effects of CT on H2O2-induced HTR-8/SVneo cells were investigated using cell counting kit-8 (CCK-8) assays and cell migration assays, while flow cytometry was used for the detection of apoptosis. Network pharmacology was used to analyze the mechanism of CT in the treatment of URSA. The repair effects and underlying mechanisms of the tumor protein 53 (p53) inhibitor and signal and transducer of transcription 3 small interfering RNA (STAT3 siRNA) were evaluated using ELISA assays, CCK-8, cell migration assays, flow cytometry, immunofluorescence, and Western blot techniques.

Results

Different doses of CT exerted protective effects on the uterine tissues of URSA. Also, CT could reduce levels of IL-17, IL-22, and IL-1β and their relative mRNA content in the serum of URSA mice, as well as increase the activity and migration rate of HTR-8/SVneo cells, and reduce the rate of apoptosis. Using p53 and STAT3 as mechanistic targets, we found that the p53 inhibitor, STAT3 siRNA, and CT restored the migratory activity of HTR-8/SVneo cells, reduced their apoptotic rate, and simultaneously downregulated the expression of retinoic acid receptor-related orphan receptor γt (RORγt) and vascular endothelial growth factor (VEGF).

Conclusion

The mechanism by which CT regulated the activity of HTR-8/SVneo cells involved the inhibition of p-p53, with STAT3, RORγt, and VEGF functioning as downstream targets of the p53 pathway.

目的:探讨隐丹参酮(CT)治疗不明原因复发性自然流产(URSA)的疗效及机制。方法:在高、中、低剂量CT治疗前,将DBA/2雄性小鼠与CBA/J雌性小鼠笼合,建立URSA模型。采用酶联免疫吸附法(ELISA)检测各组小鼠血清中白细胞介素(IL)-1 β (β)、IL-17和IL-22的水平。采用苏木精-伊红(HE)病理检测蜕膜和子宫组织,采用聚合酶链反应(PCR)检测血清信使核糖核酸(mRNA)中IL-17、IL-22和IL-1β的相对表达水平。采用细胞计数试剂盒-8 (CCK-8)法和细胞迁移法观察CT对h2o2诱导HTR-8/SVneo细胞的影响,流式细胞术检测细胞凋亡情况。采用网络药理学方法分析CT治疗URSA的机制。使用ELISA、CCK-8、细胞迁移、流式细胞术、免疫荧光和Western blot技术评估肿瘤蛋白53 (p53)抑制剂和转录小干扰RNA (STAT3 siRNA)的修复作用和潜在机制。结果:不同剂量CT对URSA子宫组织均有保护作用。CT可降低URSA小鼠血清中IL-17、IL-22、IL-1β水平及其相对mRNA含量,提高HTR-8/SVneo细胞活性和迁移率,降低凋亡率。以p53和STAT3为机制靶点,我们发现p53抑制剂、STAT3 siRNA和CT可恢复HTR-8/SVneo细胞的迁移活性,降低其凋亡率,同时下调视黄酸受体相关孤儿受体γt (RORγt)和血管内皮生长因子(VEGF)的表达。结论:CT调节HTR-8/SVneo细胞活性的机制与抑制p-p53有关,STAT3、RORγt和VEGF是p53通路的下游靶点。
{"title":"The Role of Cryptotanshinone Regulates HTR-8/SVneo Cells Activity Through the p53/STAT3 Pathway in Unexplained Recurrent Spontaneous Abortion","authors":"Lidan Lu,&nbsp;Ximei Cai,&nbsp;Yang Zhang,&nbsp;Weibo Zhao,&nbsp;Haiyan Ni,&nbsp;Liping Zhang,&nbsp;Peijuan Wang","doi":"10.1111/aji.70163","DOIUrl":"10.1111/aji.70163","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>This study sought to investigate the therapeutic effects and mechanisms of cryptotanshinone (CT) on unexplained recurrent spontaneous abortion (URSA).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>The DBA/2 male and CBA/J female mice were caged together to construct a URSA model before treatment with high and medium-low doses of CT. Enzyme-linked immunosorbent assay (ELISA) was used to detect levels of interleukin (IL)-1 beta (β), IL-17, and IL-22 in serum in each category of mice. Hematoxylin–eosin (HE) pathology was employed to detect decidua and uterine tissues, while polymerase chain reaction (PCR) was utilized to ascertain relative expression levels of serum messenger ribonucleic acid (mRNA) of IL-17, IL-22, and IL-1β. The effects of CT on H<sub>2</sub>O<sub>2</sub>-induced HTR-8/SVneo cells were investigated using cell counting kit-8 (CCK-8) assays and cell migration assays, while flow cytometry was used for the detection of apoptosis. Network pharmacology was used to analyze the mechanism of CT in the treatment of URSA. The repair effects and underlying mechanisms of the tumor protein 53 (p53) inhibitor and signal and transducer of transcription 3 small interfering RNA (STAT3 siRNA) were evaluated using ELISA assays, CCK-8, cell migration assays, flow cytometry, immunofluorescence, and Western blot techniques.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Different doses of CT exerted protective effects on the uterine tissues of URSA. Also, CT could reduce levels of IL-17, IL-22, and IL-1β and their relative mRNA content in the serum of URSA mice, as well as increase the activity and migration rate of HTR-8/SVneo cells, and reduce the rate of apoptosis. Using p53 and STAT3 as mechanistic targets, we found that the p53 inhibitor, STAT3 siRNA, and CT restored the migratory activity of HTR-8/SVneo cells, reduced their apoptotic rate, and simultaneously downregulated the expression of retinoic acid receptor-related orphan receptor γt (RORγt) and vascular endothelial growth factor (VEGF).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>The mechanism by which CT regulated the activity of HTR-8/SVneo cells involved the inhibition of p-p53, with STAT3, RORγt, and VEGF functioning as downstream targets of the p53 pathway.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 4","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145184527","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A Randomised Controlled Trial on the Treatment of Recurrent Implantation Failure Women Who Failed Egg Donation Cycles Using Low-Dose GM-CSF 低剂量GM-CSF治疗卵子捐赠周期失败的复发性植入失败妇女的随机对照试验
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-18 DOI: 10.1111/aji.70162
Fabio Scarpellini, Marco Sbracia, Daniela Marconi, Alice Fracassi, Katya Santi, Eugenio Desole

Problem

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a cytokine promoting leukocyte proliferation and trophoblast growth. Recurrent implantation failure (RIF) is the repeated failure to reach pregnancy in IVF cycles. In this randomized controlled trial, the use of low dose of GM-CSF in the treatment of RIF in egg donation cycles was tested.

Methods of Study

A randomized controlled trial was conducted on women with RIF after egg donation cycles. The inclusion criteria were age between 30 and 49 years old: at least three previous transfers failed with good quality blastocysts in egg donation cycles: no uterine defects. The patients were randomly subdivided into two groups: one treated with subcutaneous GM-CSF 0.3microg/kg/day from the day before embryo transfer to the b-hCG day. Since RIF patients may be at risk for miscarriage, this treatment was continued until the eighth week of gestation to avoid possible early miscarriage. The control group was treated with a subcutaneous saline solution infusion in the same way as the study group. Primary outcomes were the clinical pregnancy rate and live-birth rate.

Results

Epidemiological data of the two groups did not show statistically significant differences. The clinical pregnancy rate in the GM-CSF group was 73.5% (39/53), while in control group it was 34.6% (18/52) (p < 0.0001), the live-birth rate was 67.9% (36/53) and 28.8% (15/52), respectively (p < 0.0001).

Conclusion

The clinical use of GM-CSF in women who experienced implantation failure may be a useful treatment in a selected group of patients. The model of women with RIF after egg donation, at the light of our results, may be considered a valid model to study this clinical entity.

Trial Registration

ClinicalTrials.gov identifier: NCT01715974.

问题:粒细胞-巨噬细胞集落刺激因子(GM-CSF)是一种促进白细胞增殖和滋养细胞生长的细胞因子。复发性着床失败(RIF)是指在体外受精周期中反复未能达到妊娠。在这个随机对照试验中,测试了在卵子捐赠周期中使用低剂量的GM-CSF治疗RIF。研究方法:对卵子捐赠周期后的RIF妇女进行随机对照试验。纳入标准为年龄在30 - 49岁之间:在捐卵周期中至少有三次移植失败且囊胚质量良好;无子宫缺陷。将患者随机分为两组:一组从胚胎移植前一天开始至b-hCG日,皮下注射GM-CSF 0.3微克/千克/天。由于RIF患者可能有流产的风险,这种治疗一直持续到妊娠第八周,以避免可能的早期流产。对照组采用与研究组相同的方法皮下输注生理盐水。主要结局为临床妊娠率和活产率。结果:两组患者流行病学资料差异无统计学意义。GM-CSF组临床妊娠率为73.5%(39/53),对照组为34.6%(18/52)。(p)结论:临床应用GM-CSF治疗植入失败的妇女可能是一种有效的治疗方法。根据我们的结果,捐赠卵子后患有RIF的妇女模型可能被认为是研究这一临床实体的有效模型。试验注册:ClinicalTrials.gov标识符:NCT01715974。
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引用次数: 0
Aberrant Expression of Gonadotropin-Releasing Hormone Receptor in Human Mast Cells Enhances the Recruitments of Trophoblasts and NK Cells 促性腺激素释放激素受体在人肥大细胞中的异常表达促进滋养细胞和NK细胞的募集。
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-18 DOI: 10.1111/aji.70168
Takashi Matsuzaki, Hiroaki Hamaguchi, Ken R. Ito, Ryota Nakagawa, Hiroya Nakamura, Hiroaki Ito, Chiyuki Ueshima, Akihiko Yoshizawa, Hironori Haga, Tatsuki R. Kataoka

Problem

Gonadotropin-releasing hormone (GnRH), primarily known for its hypothalamic role in regulating gonadotropin secretion, is also expressed in extra-hypothalamic tissues, including trophoblasts at implantation sites. We investigated the association between trophoblasts and mast cells, demonstrating their role in producing leukemia inhibitory factor (LIF) and matrix metalloproteinase-9 (MMP-9). Therefore, we hypothesized an additional interaction between trophoblasts and mast cells mediated by GnRH.

Method of Study

Immunohistochemical analysis was conducted to investigate GnRH receptor (GnRHR) expressing mast cell in endometrial and tubal tissues from both pregnant and non-pregnant conditions (2005–2018). We established a human mast cell line LAD2 with forced expression of GnRHR expression (GnRHR-expressing LAD2) via lentiviral transfection method. The cells were stimulated with or without leuprorelin (1 µM) and transcriptomic analysis and cell migration assays were conducted.

Results

GnRHR is expressed in decidual mast cells during uterine pregnancy and in mast cells adjacent to or embedded in trophoblasts of tubal pregnancy. Notably, GnRHR expression was also observed in endometrial mast cells in non-pregnancy conditions. The levels of transcripts encoding LIF, MMP-9, and a natural killer (NK) cell attractant C-X-C motif chemokine ligand 16 (CXCL16) were significantly upregulated in GnRHR-expressing LAD2 than in control cells. In addition, culture supernatants from GnRHR-expressing LAD2 cells enhanced the migration of the trophoblast cell line HTR-8/SVneo and the NK cell line NK-92 MI.

Conclusions

These findings suggest that GnRHR expression in mast cells promotes their supportive role in pregnancy establishment by increasing the LIF, MMP-9, and CXCL16 productions, recruiting trophoblasts and NK cells.

问题:促性腺激素释放激素(GnRH)主要在下丘脑调节促性腺激素分泌,也在下丘脑外组织表达,包括着床部位的滋养细胞。我们研究了滋养细胞和肥大细胞之间的关系,证明了它们在产生白血病抑制因子(LIF)和基质金属蛋白酶-9 (MMP-9)中的作用。因此,我们假设滋养层细胞和肥大细胞之间有GnRH介导的额外相互作用。研究方法:采用免疫组化方法研究2005-2018年妊娠和非妊娠患者子宫内膜和输卵管组织肥大细胞中GnRH受体(GnRHR)表达情况。我们通过慢病毒转染法建立了强制表达GnRHR的人肥大细胞系LAD2(表达GnRHR的LAD2)。用leuprorelin(1µM)或不加leuprorelin刺激细胞,进行转录组学分析和细胞迁移实验。结果:GnRHR在子宫妊娠期间的肥大细胞中表达,在输卵管妊娠滋养细胞附近或包埋的肥大细胞中表达。值得注意的是,在非妊娠条件下,子宫内膜肥大细胞中也观察到GnRHR的表达。在表达gnrhr的LAD2细胞中,编码LIF、MMP-9和自然杀伤(NK)细胞引诱剂C-X-C基序趋化因子配体16 (CXCL16)的转录本水平显著高于对照细胞。此外,表达GnRHR的LAD2细胞培养上清液增强了滋养细胞HTR-8/SVneo和NK细胞NK-92 mi的迁移。结论:这些发现表明,肥大细胞中表达GnRHR通过增加LIF、MMP-9和CXCL16的产生,募集滋养细胞和NK细胞,促进了它们在妊娠建立中的支持作用。
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引用次数: 0
Revealing the Complexity of Immunobiological Shifts From Non-Pregnant to Pregnant State 揭示从未怀孕到怀孕状态的免疫生物学转变的复杂性。
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-18 DOI: 10.1111/aji.70166
Chelsea A. DeBolt, Haocheng Yu, Valerie Riis, Liqhwa Ncube, Amir Horowitz, Michal A. Elovitz

Problem

Significant immunological shifts, systemically and at the maternal–fetal interface, are required for successful pregnancy. As immune perturbations are emerging as pivotal drivers of adverse maternal health, elucidating how normal pregnancy alters maternal systemic immunity is imperative.

Methods

From our prospectively enrolled cohort of Black women, peripheral blood samples were collected pre-pregnancy (V1) and in the second trimester (16–24 weeks, V2). Among those who became pregnant, 23 had available samples from both time points. RNA was extracted and subjected to bulk RNA sequencing, followed by differential gene expression analyses, immune cell-type deconvolution, and pathway enrichment analyses. Participants were stratified by pre-pregnancy obesity (body mass index ≥ 30 kg/m2) to examine its impact on pregnancy-induced immune changes.

Results

Pathway analyses revealed innate immune activation and increased neutrophil-driven inflammation during pregnancy. Significant increase in neutrophils and monocytes occurred during pregnancy, whereas naïve CD8+ T-cell and B-cell subsets were significantly decreased. Pre-pregnancy obesity amplified these changes, further increasing innate populations (gamma delta T cells, neutrophils) and decreasing adaptive populations (CD8 naïve T cells, B memory cells).

Conclusion

From individuals with uncomplicated pregnancies, we demonstrate dramatic immunological changes when transitioning from a non-pregnant to pregnant state. Intricate immune modulation, including changes in inflammatory mechanisms and immune cell dynamics were observed. Pre-pregnancy obesity enhances these inflammatory shifts, providing insights into potential mechanisms driving adverse pregnancy outcomes in obese women. Future studies investigating how these immunological shifts are required for optimal maternal health and/or may promote increased vulnerability to adverse pregnancy outcomes will create new opportunities to improve maternal outcomes.

问题:成功怀孕需要全身和母胎界面的显著免疫变化。由于免疫紊乱正在成为孕产妇健康不良的关键驱动因素,阐明正常妊娠如何改变孕产妇全身免疫是必要的。方法:从前瞻性纳入的黑人妇女队列中,收集妊娠前(V1)和妊娠中期(16-24周,V2)的外周血样本。在怀孕的人中,有23人有两个时间点的可用样本。提取RNA并进行大量RNA测序,随后进行差异基因表达分析、免疫细胞型反褶积和途径富集分析。根据孕前肥胖(体重指数≥30 kg/m2)对参与者进行分层,以检查其对妊娠引起的免疫变化的影响。结果:途径分析显示妊娠期先天免疫激活和中性粒细胞驱动的炎症增加。怀孕期间中性粒细胞和单核细胞显著增加,而naïve CD8+ t细胞和b细胞亚群显著减少。孕前肥胖放大了这些变化,进一步增加了先天种群(γ δ T细胞、中性粒细胞),减少了适应性种群(CD8 naïve T细胞、B记忆细胞)。结论:从个体无并发症妊娠,我们证明了戏剧性的免疫变化,从非怀孕过渡到怀孕状态。观察到复杂的免疫调节,包括炎症机制和免疫细胞动力学的变化。孕前肥胖增强了这些炎症转变,为肥胖妇女不良妊娠结局的潜在机制提供了见解。未来研究如何需要这些免疫变化来实现最佳的孕产妇健康和/或可能增加对不良妊娠结果的脆弱性,将为改善孕产妇结局创造新的机会。
{"title":"Revealing the Complexity of Immunobiological Shifts From Non-Pregnant to Pregnant State","authors":"Chelsea A. DeBolt,&nbsp;Haocheng Yu,&nbsp;Valerie Riis,&nbsp;Liqhwa Ncube,&nbsp;Amir Horowitz,&nbsp;Michal A. Elovitz","doi":"10.1111/aji.70166","DOIUrl":"10.1111/aji.70166","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Significant immunological shifts, systemically and at the maternal–fetal interface, are required for successful pregnancy. As immune perturbations are emerging as pivotal drivers of adverse maternal health, elucidating how normal pregnancy alters maternal systemic immunity is imperative.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>From our prospectively enrolled cohort of Black women, peripheral blood samples were collected pre-pregnancy (V1) and in the second trimester (16–24 weeks, V2). Among those who became pregnant, 23 had available samples from both time points. RNA was extracted and subjected to bulk RNA sequencing, followed by differential gene expression analyses, immune cell-type deconvolution, and pathway enrichment analyses. Participants were stratified by pre-pregnancy obesity (body mass index ≥ 30 kg/m<sup>2</sup>) to examine its impact on pregnancy-induced immune changes.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Pathway analyses revealed innate immune activation and increased neutrophil-driven inflammation during pregnancy. Significant increase in neutrophils and monocytes occurred during pregnancy, whereas naïve CD8+ T-cell and B-cell subsets were significantly decreased. Pre-pregnancy obesity amplified these changes, further increasing innate populations (gamma delta T cells, neutrophils) and decreasing adaptive populations (CD8 naïve T cells, B memory cells).</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>From individuals with uncomplicated pregnancies, we demonstrate dramatic immunological changes when transitioning from a non-pregnant to pregnant state. Intricate immune modulation, including changes in inflammatory mechanisms and immune cell dynamics were observed. Pre-pregnancy obesity enhances these inflammatory shifts, providing insights into potential mechanisms driving adverse pregnancy outcomes in obese women. Future studies investigating how these immunological shifts are required for optimal maternal health and/or may promote increased vulnerability to adverse pregnancy outcomes will create new opportunities to improve maternal outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"94 3","pages":""},"PeriodicalIF":2.4,"publicationDate":"2025-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145079116","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Comment on “Deciphering the Molecular Crosstalk of Endoplasmic Reticulum Stress and Immune Infiltration in Endometriosis” 《解读子宫内膜异位症内质网应激与免疫浸润的分子串扰》述评
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-15 DOI: 10.1111/aji.70158
Saraswati Sah, Renu Sah
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引用次数: 0
Endothelial Activation and Stress Index as a Novel Prognostic Marker in Intrahepatic Cholestasis of Pregnancy: A Case–Control Study 内皮细胞激活和应激指数作为妊娠肝内胆汁淤积的一种新的预后指标:一项病例对照研究
IF 2.4 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-09-15 DOI: 10.1111/aji.70167
Dilara Duygulu Bulan, Ruken Dayanan, Merve Ayas Özkan, Zeynep Şeyhanlı, Gülşan Karabay, Ali Turhan Çağlar

Objective: This study aims to evaluate the clinical applicability and prognostic value of the endothelial activation and stress index (EASIX) in patients with intrahepatic cholestasis of pregnancy (ICP). By investigating the potential of the EASIX score to predict perinatal complications and the clinical course of ICP, we seek to contribute to the improved management and prognosis of ICP patients.

Methods: This retrospective cohort study aimed to investigate the prognostic value of the EASIX in patients diagnosed with ICP at Ankara Etlik City Hospital between January 2023 and January 2025. A total of 121 ICP patients and 133 control patients were included. The EASIX score was calculated using lactate dehydrogenase, creatinine and thrombocyte levels. The relationship between EASIX and perinatal complications, including preterm birth and neonatal distress, was assessed.

Results: The EASIX score was significantly higher in the ICP group compared to controls (p < 0.001), with severe ICP showing the highest EASIX scores (p = 0.019). Cut-off analysis indicated that an EASIX score > 0.64 had a sensitivity of 75% and specificity of 64% for severity prediction (AUC = 0.767, p < 0.001), while a score > 0.69 had a sensitivity of 62% and specificity of 61% for predicting composite adverse perinatal outcomes (AUC = 0.711, p < 0.001).

Conclusion: This study demonstrates that the EASIX score may serve as an important prognostic tool in predicting disease severity and neonatal outcomes in ICP. Given the limited availability of bile acid measurements in some clinics, the EASIX score provides a practical and accessible alternative for clinical use. This study evaluates the prognostic value of the endothelial activation and stress index (EASIX) in intrahepatic cholestasis of pregnancy, highlighting its potential to predict disease severity and neonatal outcomes, offering a practical tool for clinical use.

目的:探讨内皮活化与应激指数(EASIX)在妊娠肝内胆汁淤积症(ICP)患者中的临床适用性及预后价值。通过研究EASIX评分预测围产儿并发症和ICP临床病程的潜力,我们试图为改善ICP患者的管理和预后做出贡献。方法:本回顾性队列研究旨在探讨EASIX对2023年1月至2025年1月在安卡拉埃特利克市医院诊断为ICP患者的预后价值。共纳入121例ICP患者和133例对照患者。EASIX评分采用乳酸脱氢酶、肌酐和血小板水平计算。评估EASIX与围产期并发症(包括早产和新生儿窘迫)之间的关系。结果:ICP组的EASIX评分明显高于对照组(p < 0.001),其中重度ICP的EASIX评分最高(p = 0.019)。截止分析显示,EASIX评分为>; 0.64时预测严重程度的敏感性为75%,特异性为64% (AUC = 0.767, p < 0.001),而评分为>; 0.69时预测围产期综合不良结局的敏感性为62%,特异性为61% (AUC = 0.711, p < 0.001)。结论:本研究表明EASIX评分可作为预测ICP疾病严重程度和新生儿结局的重要预后工具。鉴于胆汁酸测量在一些诊所的可用性有限,EASIX评分为临床使用提供了一个实用和可访问的替代方案。本研究评估了内皮细胞激活和应激指数(EASIX)在妊娠肝内胆汁淤积中的预后价值,强调了其预测疾病严重程度和新生儿结局的潜力,为临床应用提供了实用工具。
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引用次数: 0
期刊
American Journal of Reproductive Immunology
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