Emma Björk, Pernilla Israelsson, Olga Nagaeva, Lucia Mincheva-Nilsson, Ulrika Ottander
Problem: NK-cell dysfunction in endometriosis is suggested to contribute to the survival of ectopic endometrial tissue. However, the underlying causes of this impairment remain unclear. NK cells are divided into: CD56+bright, which produce high amounts of cytokines but have low or no cytotoxic ability, and CD56+dim, which are mainly cytotoxic. CD56+bright NK cells, constitutively present in human endometrium (eNK cells), represent only 0-2% of NK cells in PBMC, where CD56+dim cells dominate.
Method of study: NK-cell subpopulations and NKG2D receptor expression in PBMC were analyzed by flow cytometry in two cohorts of untreated and treated endometriosis patients and healthy age-matched controls.
Results: Elevated numbers of CD56+bright cells were observed in 8 of 21 untreated endometriosis patients compared to controls. These numbers were normalized following surgery and hormonal treatment. The NKG2D receptor expression was reduced in untreated patients compared to controls and treated patients.
Conclusions: The significantly increased proportion of peripheral CD56+bright NK/eNK cells may result from migration of these cells from ectopic endometrial tissue. The downregulation of NKG2D receptor expression in PBMCs may be mediated by immunosuppressive endometriotic exosomes, as previously reported by us. Taken together, our results suggest that: (1) the impaired NK cell cytotoxicity in untreated endometriosis patients may be due both to an influx of CD56+bright/eNK cells and exosome-induced NKG2D receptor downregulation; and (2) elevated numbers of peripheral CD56+bright NK cells could be considered as a potential diagnostic marker for endometriosis.
{"title":"Enhanced CD56 Expression and Increased Number of CD56<sup>+bright</sup> Cells in the Peripheral Blood of Untreated Endometriosis Patients.","authors":"Emma Björk, Pernilla Israelsson, Olga Nagaeva, Lucia Mincheva-Nilsson, Ulrika Ottander","doi":"10.1111/aji.70214","DOIUrl":"10.1111/aji.70214","url":null,"abstract":"<p><strong>Problem: </strong>NK-cell dysfunction in endometriosis is suggested to contribute to the survival of ectopic endometrial tissue. However, the underlying causes of this impairment remain unclear. NK cells are divided into: CD56<sup>+bright</sup>, which produce high amounts of cytokines but have low or no cytotoxic ability, and CD56<sup>+dim</sup>, which are mainly cytotoxic. CD56<sup>+bright</sup> NK cells, constitutively present in human endometrium (eNK cells), represent only 0-2% of NK cells in PBMC, where CD56<sup>+dim</sup> cells dominate.</p><p><strong>Method of study: </strong>NK-cell subpopulations and NKG2D receptor expression in PBMC were analyzed by flow cytometry in two cohorts of untreated and treated endometriosis patients and healthy age-matched controls.</p><p><strong>Results: </strong>Elevated numbers of CD56<sup>+bright</sup> cells were observed in 8 of 21 untreated endometriosis patients compared to controls. These numbers were normalized following surgery and hormonal treatment. The NKG2D receptor expression was reduced in untreated patients compared to controls and treated patients.</p><p><strong>Conclusions: </strong>The significantly increased proportion of peripheral CD56<sup>+bright </sup>NK/eNK cells may result from migration of these cells from ectopic endometrial tissue. The downregulation of NKG2D receptor expression in PBMCs may be mediated by immunosuppressive endometriotic exosomes, as previously reported by us. Taken together, our results suggest that: (1) the impaired NK cell cytotoxicity in untreated endometriosis patients may be due both to an influx of CD56<sup>+bright</sup>/eNK cells and exosome-induced NKG2D receptor downregulation; and (2) elevated numbers of peripheral CD56<sup>+bright</sup> NK cells could be considered as a potential diagnostic marker for endometriosis.</p>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 2","pages":"e70214"},"PeriodicalIF":2.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12873557/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146117637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Ziyi Song, Fang Fang, Yunxia Gong, Yuke Hou, Wenqiong Wang, Chun Li, Xuewu Zhang, Qun Lu
Problem: Recurrent implantation failure (RIF) remains a significant challenge in reproductive medicine, with immune dysfunction being a key contributing factor to implantation failure. However, data on the effectiveness of immunomodulatory therapy in RIF patients remain limited. This study aimed to assess the impact of immunomodulatory therapy on pregnancy outcomes in women with RIF undergoing in Vitro fertilization-embryo transfer (IVF-ET).
Method of study: This retrospective cohort study included women with RIF between 2016 and 2019. Patients in the treatment group received hydroxychloroquine (HCQ)-based immunomodulatory therapy after immunological evaluation, while those in the control group did not receive immunomodulatory treatment. Generalized estimating equations assessed the association between HCQ-based immunomodulatory therapy and pregnancy outcomes. Additionally, patients were stratified based on autoimmune antibody status, and subgroup analyses were conducted to further evaluate treatment effects.
Results: A total of 320 patients were included in the study, with 74 receiving HCQ-based immunomodulatory therapy (treatment group) and 246 undergoing IVF-ET alone (control group). The treatment group showed higher biochemical pregnancy (49.5% vs. 31.7%, p < 0.001), clinical pregnancy (43.8% vs. 24.3%, p < 0.001), embryo implantation (30.7% vs. 17.3%, p < 0.001), and live birth rates (33.3% vs. 12.6%, p < 0.001). Multivariate regression identified HCQ-based immunomodulatory therapy as an independent predictor of biochemical pregnancy (OR = 2.049, 95% CI: 1.440-2.915, P<0.001), clinical pregnancy (OR = 2.424, 95% CI: 1.613-3.644, P<0.001), and live birth (OR = 3.555, 95% CI: 2.235-5.652, P<0.001). Stratified analysis confirmed its benefit in both autoimmune antibody positive and negative patients.
Conclusions: Real-world evidence revealed the potential role of HCQ-based immunomodulatory therapy in improving pregnancy outcomes in IVF-ET in patients with RIF.
问题：复发性着床失败（RIF）仍然是生殖医学的一个重大挑战，免疫功能障碍是着床失败的关键因素。然而，关于免疫调节治疗在RIF患者中的有效性的数据仍然有限。本研究旨在评估免疫调节治疗对接受体外受精-胚胎移植（IVF-ET）的RIF妇女妊娠结局的影响。研究方法：这项回顾性队列研究纳入了2016年至2019年期间患有RIF的女性。治疗组患者经免疫学评价后给予以羟氯喹（HCQ）为基础的免疫调节治疗，对照组不给予免疫调节治疗。广义估计方程评估了基于hcq的免疫调节治疗与妊娠结局之间的关系。此外，根据自身免疫抗体状态对患者进行分层，并进行亚组分析以进一步评估治疗效果。结果：共纳入320例患者，其中74例患者接受基于hcq的免疫调节治疗（治疗组），246例患者单独接受IVF-ET治疗（对照组）。治疗组生化妊娠（49.5% vs. 31.7%, p < 0.001）、临床妊娠（43.8% vs. 24.3%, p < 0.001）、胚胎着床（30.7% vs. 17.3%, p < 0.001）、活产率（33.3% vs. 12.6%, p < 0.001）较高。多因素回归发现基于hcq的免疫调节治疗是生化妊娠的独立预测因子（OR = 2.049, 95% CI: 1.440-2.915）。结论：真实世界的证据揭示了基于hcq的免疫调节治疗在改善RIF患者IVF-ET妊娠结局方面的潜在作用。
{"title":"Hydroxychloroquine Based Immunomodulatory Therapy Improves Pregnancy Outcomes in Women with Recurrent Implantation Failure Undergoing in Vitro Fertilization and Embryo Transfer.","authors":"Ziyi Song, Fang Fang, Yunxia Gong, Yuke Hou, Wenqiong Wang, Chun Li, Xuewu Zhang, Qun Lu","doi":"10.1111/aji.70212","DOIUrl":"https://doi.org/10.1111/aji.70212","url":null,"abstract":"<p><strong>Problem: </strong>Recurrent implantation failure (RIF) remains a significant challenge in reproductive medicine, with immune dysfunction being a key contributing factor to implantation failure. However, data on the effectiveness of immunomodulatory therapy in RIF patients remain limited. This study aimed to assess the impact of immunomodulatory therapy on pregnancy outcomes in women with RIF undergoing in Vitro fertilization-embryo transfer (IVF-ET).</p><p><strong>Method of study: </strong>This retrospective cohort study included women with RIF between 2016 and 2019. Patients in the treatment group received hydroxychloroquine (HCQ)-based immunomodulatory therapy after immunological evaluation, while those in the control group did not receive immunomodulatory treatment. Generalized estimating equations assessed the association between HCQ-based immunomodulatory therapy and pregnancy outcomes. Additionally, patients were stratified based on autoimmune antibody status, and subgroup analyses were conducted to further evaluate treatment effects.</p><p><strong>Results: </strong>A total of 320 patients were included in the study, with 74 receiving HCQ-based immunomodulatory therapy (treatment group) and 246 undergoing IVF-ET alone (control group). The treatment group showed higher biochemical pregnancy (49.5% vs. 31.7%, p < 0.001), clinical pregnancy (43.8% vs. 24.3%, p < 0.001), embryo implantation (30.7% vs. 17.3%, p < 0.001), and live birth rates (33.3% vs. 12.6%, p < 0.001). Multivariate regression identified HCQ-based immunomodulatory therapy as an independent predictor of biochemical pregnancy (OR = 2.049, 95% CI: 1.440-2.915, P<0.001), clinical pregnancy (OR = 2.424, 95% CI: 1.613-3.644, P<0.001), and live birth (OR = 3.555, 95% CI: 2.235-5.652, P<0.001). Stratified analysis confirmed its benefit in both autoimmune antibody positive and negative patients.</p><p><strong>Conclusions: </strong>Real-world evidence revealed the potential role of HCQ-based immunomodulatory therapy in improving pregnancy outcomes in IVF-ET in patients with RIF.</p>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 2","pages":"e70212"},"PeriodicalIF":2.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091708","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}
Zachary T Koenig, Shruti Eswar, Sayaka Tsuda, Nathan Schuldt, Claire A Chougnet, Braxton Forde, Sandra Andorf, Tamara Tilburgs
Problem: Maternal CD4 T cells are critical coordinators of maternal-fetal immune tolerance and immunity during pregnancy. Decidual regulatory T cells (TREG) have been shown to provide essential immune suppressive functions to control allogeneic responses and inflammation. Activated CD4 memory T cells form the largest fraction of decidual T cells, yet their diversity, specificity, and functions remain largely undefined.
Method of study: Using high-dimensional flow cytometry (HDFC), computational and functional analysis to characterize decidual CD4 memory T-cell types and their functions.
Results: Two types of decidual CD4 T cells, the effector memory cells (TEM), and CD69+ PD1+ resident memory cells (TRM) with a strong capacity to respond to cord blood allo-antigens were identified. Important differences were found in their phenotypic, cytotoxic, and cytokine profiles that were dependent on fetal sex, mode of delivery, and human cytomegalovirus (HCMV) serology.
Conclusions: Thus, decidual CD4 TEM and TRM have unique immune effector functions and the ability to recognize and respond to fetal cord blood. This suggests that decidual CD4 TEM and TRM cells can recognize fetal allo-antigens and, when not adequately controlled, may contribute to placental inflammation. Further definition of decidual TEM and CD69+ PD1+ TRM immune effector functions and specificity has clinical significance to define essential drivers of healthy pregnancy and pregnancy complications.
{"title":"Decidual CD4 Effector Memory and Resident Memory T Cells Respond to Cord Blood Allo-Antigens.","authors":"Zachary T Koenig, Shruti Eswar, Sayaka Tsuda, Nathan Schuldt, Claire A Chougnet, Braxton Forde, Sandra Andorf, Tamara Tilburgs","doi":"10.1111/aji.70213","DOIUrl":"10.1111/aji.70213","url":null,"abstract":"<p><strong>Problem: </strong>Maternal CD4 T cells are critical coordinators of maternal-fetal immune tolerance and immunity during pregnancy. Decidual regulatory T cells (T<sub>REG</sub>) have been shown to provide essential immune suppressive functions to control allogeneic responses and inflammation. Activated CD4 memory T cells form the largest fraction of decidual T cells, yet their diversity, specificity, and functions remain largely undefined.</p><p><strong>Method of study: </strong>Using high-dimensional flow cytometry (HDFC), computational and functional analysis to characterize decidual CD4 memory T-cell types and their functions.</p><p><strong>Results: </strong>Two types of decidual CD4 T cells, the effector memory cells (T<sub>EM</sub>), and CD69+ PD1+ resident memory cells (T<sub>RM</sub>) with a strong capacity to respond to cord blood allo-antigens were identified. Important differences were found in their phenotypic, cytotoxic, and cytokine profiles that were dependent on fetal sex, mode of delivery, and human cytomegalovirus (HCMV) serology.</p><p><strong>Conclusions: </strong>Thus, decidual CD4 T<sub>EM</sub> and T<sub>RM</sub> have unique immune effector functions and the ability to recognize and respond to fetal cord blood. This suggests that decidual CD4 T<sub>EM</sub> and T<sub>RM</sub> cells can recognize fetal allo-antigens and, when not adequately controlled, may contribute to placental inflammation. Further definition of decidual T<sub>EM</sub> and CD69+ PD1+ T<sub>RM</sub> immune effector functions and specificity has clinical significance to define essential drivers of healthy pregnancy and pregnancy complications.</p>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 2","pages":"e70213"},"PeriodicalIF":2.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12859743/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146091679","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Although studies have suggested a link between gut microbiota and endometriosis pathophysiology, the effects of treatment for endometriosis remain unclear.
Methods
In this prospective observational study, 27 patients with stage III/IV endometriosis and 17 healthy controls provided a total of 56 fecal samples. In endometriosis patients, gut microbiota profiles were analyzed before and after hormonal therapy or surgery to assess treatment-related changes. 16S rRNA gene sequencing was used for microbiota analysis.
Results
No differences in α- or β-diversity were observed between the endometriosis and control groups, although patients with endometriosis had high levels of Acidaminococcus, Lachnoclostridium, and Paraprevotella and low levels of Odoribacter (all p < 0.05). Among the eight patients who received hormonal therapy, no significant changes in α- and β-diversity were observed between the pre- and post-treatment samples. A comparison of samples from the same individuals showed an increase in Blautia, which is associated with mental health stability, and a decrease in Sutterella, which is involved in regulating the intestinal barrier. In an exploratory analysis of patients without recurrence after surgery (n = 4), α-diversity significantly increased (p = 0.035), with stable β-diversity. Postsurgical increases were observed in 10 genera, including six inflammation-related taxa; five (Flavonifractor, [Eubacterium]_brachy_group, Hungatella, Incertae_Sedis, and Fournierella) are associated with anti-inflammatory effects.
Conclusions
Hormonal therapy for endometriosis may help not only to control lesions but also to support mental health. Surgical treatment may alter the composition of inflammation-associated gut bacteria; however, these exploratory results from a small cohort should be interpreted with caution. Further studies with larger sample sizes are warranted.
{"title":"Gut Microbiota Changes After Hormonal or Surgical Treatment for Endometriosis","authors":"Yosuke Ono, Osamu Yoshino, Takeshi Sasayama, Masami Ito, Tatsuya Yoshihara, Kota Tanaka, Akiko Nakagomi, Satoko Sasatsu, Maki Ogi, Hikaru Tagaya, Tomohiko Fukuda, Takeshi Nagamatsu, Takuji Yamada","doi":"10.1111/aji.70211","DOIUrl":"10.1111/aji.70211","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Purpose</h3>\u0000 \u0000 <p>Although studies have suggested a link between gut microbiota and endometriosis pathophysiology, the effects of treatment for endometriosis remain unclear.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>In this prospective observational study, 27 patients with stage III/IV endometriosis and 17 healthy controls provided a total of 56 fecal samples. In endometriosis patients, gut microbiota profiles were analyzed before and after hormonal therapy or surgery to assess treatment-related changes. 16S rRNA gene sequencing was used for microbiota analysis.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>No differences in α- or β-diversity were observed between the endometriosis and control groups, although patients with endometriosis had high levels of <i>Acidaminococcus</i>, <i>Lachnoclostridium</i>, and <i>Paraprevotella</i> and low levels of <i>Odoribacter</i> (all <i>p</i> < 0.05). Among the eight patients who received hormonal therapy, no significant changes in α- and β-diversity were observed between the pre- and post-treatment samples. A comparison of samples from the same individuals showed an increase in <i>Blautia</i>, which is associated with mental health stability, and a decrease in <i>Sutterella</i>, which is involved in regulating the intestinal barrier. In an exploratory analysis of patients without recurrence after surgery (<i>n</i> = 4), α-diversity significantly increased (<i>p</i> = 0.035), with stable β-diversity. Postsurgical increases were observed in 10 genera, including six inflammation-related taxa; five (<i>Flavonifractor</i>, <i>[Eubacterium]_brachy_group</i>, <i>Hungatella</i>, <i>Incertae_Sedis</i>, and <i>Fournierella</i>) are associated with anti-inflammatory effects.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Hormonal therapy for endometriosis may help not only to control lesions but also to support mental health. Surgical treatment may alter the composition of inflammation-associated gut bacteria; however, these exploratory results from a small cohort should be interpreted with caution. Further studies with larger sample sizes are warranted.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146028099","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}
We recently reported that trophoblast stem cells (TSCs) and TSC-differentiated trophoblasts (TSC-TBs) do not respond to TNFα. This immunological property enables these cells to avoid the cytotoxic effects induced by the combination of TNFα and IFNγ. The goal of this study is to elucidate the molecular basis for the unresponsiveness of TSCs and TSC-TBs to TNFα and assess the functionality of TNFα signaling pathways in these cells.
Method
We compared the responses of TSCs and TSC-TBs to TNFα with those of mouse embryonic fibroblasts (MEFs). Genome-wide transcriptomic profiling was performed using RNA-seq data, including the TNFα signaling pathway, TNFα-induced expression of NFκB target genes, and the transcriptional changes and functional pathway enrichment associated with TSC differentiation.
Results
The data provide a comprehensive view of TNFα-induced NFκB activation and the subsequent induction of NFκB target genes with diverse functions. In MEFs, TNFα upregulates or downregulates the transcription of numerous NFκB target genes, but it has little to no effect on gene expression in TSCs and TSC-TBs. Nevertheless, many NFκB target genes essential for shared or cell type-specific functions are expressed in TSCs and TSC-TBs and are regulated in a cell type-specific manner.
Conclusions
The results provide the molecular basis for the lack of TNFα-induced inflammatory responses in TSCs and TSC-TBs. They also suggest that TSCs and TSC-TBs have evolved mechanisms to avoid the cytotoxic effects associated with TNFα-induced inflammation response, while still permitting the expression of other NFκB target genes essential for their cellular functions.
{"title":"Mouse Trophoblast Stem Cells Are Deficient in TNFα-Activated NFκB Signaling Pathway and Inflammatory Response","authors":"Yeseul Bae, Marwah Walid Ali Alzara, Yan-Lin Guo","doi":"10.1111/aji.70208","DOIUrl":"10.1111/aji.70208","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>We recently reported that trophoblast stem cells (TSCs) and TSC-differentiated trophoblasts (TSC-TBs) do not respond to TNFα. This immunological property enables these cells to avoid the cytotoxic effects induced by the combination of TNFα and IFNγ. The goal of this study is to elucidate the molecular basis for the unresponsiveness of TSCs and TSC-TBs to TNFα and assess the functionality of TNFα signaling pathways in these cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method</h3>\u0000 \u0000 <p>We compared the responses of TSCs and TSC-TBs to TNFα with those of mouse embryonic fibroblasts (MEFs). Genome-wide transcriptomic profiling was performed using RNA-seq data, including the TNFα signaling pathway, TNFα-induced expression of NFκB target genes, and the transcriptional changes and functional pathway enrichment associated with TSC differentiation.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>The data provide a comprehensive view of TNFα-induced NFκB activation and the subsequent induction of NFκB target genes with diverse functions. In MEFs, TNFα upregulates or downregulates the transcription of numerous NFκB target genes, but it has little to no effect on gene expression in TSCs and TSC-TBs. Nevertheless, many NFκB target genes essential for shared or cell type-specific functions are expressed in TSCs and TSC-TBs and are regulated in a cell type-specific manner.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>The results provide the molecular basis for the lack of TNFα-induced inflammatory responses in TSCs and TSC-TBs. They also suggest that TSCs and TSC-TBs have evolved mechanisms to avoid the cytotoxic effects associated with TNFα-induced inflammation response, while still permitting the expression of other NFκB target genes essential for their cellular functions.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146008473","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}
Shubhangi Jha, Suresh Singh Yadav, Rohina Aggarwal, Rohini R. Nair
<div> <section> <h3> Background</h3> <p>Pregnancy requires maternal immune tolerance of the semi-allogeneic fetus without compromising host defense. Myeloid-derived suppressor cells (MDSCs) have emerged as key regulators of maternal fetal tolerance, but their role in early miscarriage (EM), recurrent pregnancy loss (RPL), and recurrent implantation failure (RIF) remains incompletely defined.</p> </section> <section> <h3> Objective</h3> <p>To systematically evaluate the role of MDSCs in EM, RPL, and RIF and assess their potential as biomarkers and therapeutic targets in implantation failure and pregnancy loss.</p> </section> <section> <h3> Methodology</h3> <p>A systematic review in accordance with PRISMA guidelines. Searches were conducted in Google Scholar up to April 13, 2025, using the terms “Myeloid Derived Suppressor Cells,” “in vitro fertilization,” “early miscarriage,” “pregnancy loss,” and “implantation failure.” Studies were eligible if they quantified MDSCs in peripheral blood or endometrial samples of women with EM, RPL, or RIF and animal-only studies. Reviews, abstracts, and inaccessible full texts were excluded.</p> </section> <section> <h3> Results</h3> <p>Of 70 records identified, 11 met inclusion criteria (seven human, five murine, one has included human samples and murine models). In human studies, reduced granulocytic MDSCs (G-MDSCs) were strongly associated with EM and RPL, correlating with low estradiol/progesterone, impaired STAT3 signaling, and a Th1-dominant cytokine milieu. Findings in RIF were heterogeneous: some reported decreased polymorphonuclear MDSCs with functional impairment, while others observed elevated monocytic MDSCs (M-MDSCs) with diminished suppressive capacity, suggesting dysfunctional or compensatory expansion. Placental enrichment of G-MDSCs demonstrated their tolerogenic role in situ, promoting Treg induction and macrophage polarization. Murine models confirmed it as the cause since MDSC depletion abolished pregnancy, while progesterone-STAT3-ROS signaling supported their expansion and suppressive function. Adoptive MDSC transfer partially rescued fetal resorption in abortion-prone models.</p> </section> <section> <h3> Conclusions</h3> <p>MDSCs are central to maternal fetal tolerance, and their dysregulation contributes to EM, RPL, and RIF. Human and animal data support their potential as predictive biomarkers and therapeutic targets in implantation failure. Standardization of MDSC phenotyping and mechanistic studies of subset-specific functions are warranted to advance clinical translation.</p> </
{"title":"Role of Myeloid-Derived Suppressor Cells as a Potential Biomarker in Implanation Failure: A Systematic Review","authors":"Shubhangi Jha, Suresh Singh Yadav, Rohina Aggarwal, Rohini R. Nair","doi":"10.1111/aji.70203","DOIUrl":"10.1111/aji.70203","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Pregnancy requires maternal immune tolerance of the semi-allogeneic fetus without compromising host defense. Myeloid-derived suppressor cells (MDSCs) have emerged as key regulators of maternal fetal tolerance, but their role in early miscarriage (EM), recurrent pregnancy loss (RPL), and recurrent implantation failure (RIF) remains incompletely defined.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Objective</h3>\u0000 \u0000 <p>To systematically evaluate the role of MDSCs in EM, RPL, and RIF and assess their potential as biomarkers and therapeutic targets in implantation failure and pregnancy loss.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methodology</h3>\u0000 \u0000 <p>A systematic review in accordance with PRISMA guidelines. Searches were conducted in Google Scholar up to April 13, 2025, using the terms “Myeloid Derived Suppressor Cells,” “in vitro fertilization,” “early miscarriage,” “pregnancy loss,” and “implantation failure.” Studies were eligible if they quantified MDSCs in peripheral blood or endometrial samples of women with EM, RPL, or RIF and animal-only studies. Reviews, abstracts, and inaccessible full texts were excluded.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Of 70 records identified, 11 met inclusion criteria (seven human, five murine, one has included human samples and murine models). In human studies, reduced granulocytic MDSCs (G-MDSCs) were strongly associated with EM and RPL, correlating with low estradiol/progesterone, impaired STAT3 signaling, and a Th1-dominant cytokine milieu. Findings in RIF were heterogeneous: some reported decreased polymorphonuclear MDSCs with functional impairment, while others observed elevated monocytic MDSCs (M-MDSCs) with diminished suppressive capacity, suggesting dysfunctional or compensatory expansion. Placental enrichment of G-MDSCs demonstrated their tolerogenic role in situ, promoting Treg induction and macrophage polarization. Murine models confirmed it as the cause since MDSC depletion abolished pregnancy, while progesterone-STAT3-ROS signaling supported their expansion and suppressive function. Adoptive MDSC transfer partially rescued fetal resorption in abortion-prone models.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>MDSCs are central to maternal fetal tolerance, and their dysregulation contributes to EM, RPL, and RIF. Human and animal data support their potential as predictive biomarkers and therapeutic targets in implantation failure. Standardization of MDSC phenotyping and mechanistic studies of subset-specific functions are warranted to advance clinical translation.</p>\u0000 </","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145996984","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}
{"title":"Testosterone-Induced Pyroptotic Death of Ovarian Granulosa Cells in PCOS Might Involve Both GSDMD and GSDME, the Latter Possibly Enabling a Crosstalk Between Apoptosis and Pyroptosis","authors":"Caglar Berkel","doi":"10.1111/aji.70207","DOIUrl":"10.1111/aji.70207","url":null,"abstract":"","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997077","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}
The use of low-dose cyclosporine A (CsA) has been shown to increase live birth rates in cases of unexplained recurrent spontaneous abortions, without causing significant side effects for the pregnant woman or fetus. The primary aim of this study was to evaluate the effect of CsA on immune system indicators and pregnancy success in adverse pregnancies.
Methods
Data were collected from patients diagnosed with adverse pregnancies caused by immune-related abnormalities at the Department of Rheumatology and Immunology in a tertiary hospital in Shenzhen, China, between September 2023 and October 2024. Information collected included patient details, cytokine levels, lymphocyte subpopulations, blocking antibody changes, and CsA blood concentration during medication. This helped determine the effective blood concentration range of CsA for these patients, aimed at enhancing the drug's safety and effectiveness.
Outcome
The study included a total of 661 participants, among whom 279 achieved successful pregnancies after CsA treatment (A clinically confirmed pregnancy is considered a successful pregnancy). The CD3+, CD4+, and CD8+ blocking antibody efficiency levels were significantly increased after CsA administration (P < 0.001, p = 0.003, p = 0.017), and the former two changes were strongly correlated with pregnancy success (p = 0.002, P < 0.001). The receiver operating characteristic (ROC) curve revealed that increases in CD3+, CD4+ blocking antibodies were strong predictors of successful pregnancy outcomes. Cytokine levels, including IL-2, IL-4, IL-6, IL-10, IL-17, IFN-γ, and TNF-α, decreased significantly after treatment (P < 0.01). Ratios such as IL-2/IL-10 and IFN-γ/IL-10 also showed significant reductions (P < 0.001), while the IFN-γ/IL-4 and TNF-α/IL-4 ratios increased significantly (P < 0.001). The majority of patients had blood CsA concentrations between 10–70 ng/mL.
Conclusion
These findings suggest that CsA can effectively regulate immune markers and restore immune balance, reducing the impact of immune-related adverse pregnancy outcomes.
目的：使用低剂量环孢素A （CsA）已被证明可增加原因不明的复发性自然流产病例的活产率，而不会对孕妇或胎儿造成明显的副作用。本研究的主要目的是评估CsA对不良妊娠免疫系统指标和妊娠成功率的影响。方法：收集2023年9月至2024年10月在中国深圳某三级医院风湿病免疫科诊断为免疫相关异常导致的不良妊娠患者的数据。收集的信息包括患者详细信息、细胞因子水平、淋巴细胞亚群、阻断抗体变化和用药期间CsA血药浓度。这有助于确定这些患者CsA的有效血药浓度范围，旨在提高药物的安全性和有效性。结果：本研究共纳入661例受试者，其中279例经CsA治疗后妊娠成功（临床证实妊娠为成功妊娠）。CsA给药后CD3+、CD4+、CD8+阻断抗体水平均显著升高（P < 0.001, P = 0.003, P = 0.017），且CD3+、CD4+和CD8+阻断抗体水平与妊娠成功率密切相关（P = 0.002, P < 0.001）。受试者工作特征（ROC）曲线显示，CD3+、CD4+阻断抗体的升高是成功妊娠结局的有力预测因子。治疗后细胞因子IL-2、IL-4、IL-6、IL-10、IL-17、IFN-γ、TNF-α水平均显著降低（P < 0.01）。IL-2/IL-10和IFN-γ/IL-10比值也显著降低（P < 0.001）， IFN-γ/IL-4和TNF-α/IL-4比值显著升高（P < 0.001）。大多数患者血CsA浓度在10-70 ng/mL之间。结论：CsA可有效调节免疫标志物，恢复免疫平衡，降低免疫相关不良妊娠结局的影响。
{"title":"The Effect of Oral Cyclosporine A on Immune Indicators and Pregnancy Outcomes in Patients With Adverse Pregnancies: A Retrospective Study","authors":"Maojiao Wang, Zhongchao Fu, Rangeng Shi, Peng Zhang, Shiqi Lin, Jiang Liu, Chenli Ye, Weiling Cao, Xiaogui Cheng","doi":"10.1111/aji.70210","DOIUrl":"10.1111/aji.70210","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Aim</h3>\u0000 \u0000 <p>The use of low-dose cyclosporine A (CsA) has been shown to increase live birth rates in cases of unexplained recurrent spontaneous abortions, without causing significant side effects for the pregnant woman or fetus. The primary aim of this study was to evaluate the effect of CsA on immune system indicators and pregnancy success in adverse pregnancies.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>Data were collected from patients diagnosed with adverse pregnancies caused by immune-related abnormalities at the Department of Rheumatology and Immunology in a tertiary hospital in Shenzhen, China, between September 2023 and October 2024. Information collected included patient details, cytokine levels, lymphocyte subpopulations, blocking antibody changes, and CsA blood concentration during medication. This helped determine the effective blood concentration range of CsA for these patients, aimed at enhancing the drug's safety and effectiveness.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Outcome</h3>\u0000 \u0000 <p>The study included a total of 661 participants, among whom 279 achieved successful pregnancies after CsA treatment (A clinically confirmed pregnancy is considered a successful pregnancy). The CD3+, CD4+, and CD8+ blocking antibody efficiency levels were significantly increased after CsA administration (<i>P</i> < 0.001, <i>p</i> = 0.003, <i>p</i> = 0.017), and the former two changes were strongly correlated with pregnancy success (<i>p</i> = 0.002, <i>P</i> < 0.001). The receiver operating characteristic (ROC) curve revealed that increases in CD3+, CD4+ blocking antibodies were strong predictors of successful pregnancy outcomes. Cytokine levels, including IL-2, IL-4, IL-6, IL-10, IL-17, IFN-<i>γ</i>, and TNF-<i>α</i>, decreased significantly after treatment (<i>P</i> < 0.01). Ratios such as IL-2/IL-10 and IFN-<i>γ</i>/IL-10 also showed significant reductions (<i>P</i> < 0.001), while the IFN-<i>γ</i>/IL-4 and TNF-<i>α</i>/IL-4 ratios increased significantly (<i>P</i> < 0.001). The majority of patients had blood CsA concentrations between 10–70 ng/mL.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>These findings suggest that CsA can effectively regulate immune markers and restore immune balance, reducing the impact of immune-related adverse pregnancy outcomes.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145997052","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}
{"title":"Comment on: “Study on the Effects of Doxycycline Treatment on Endometrial Microbiota and Pregnancy Outcomes in Chronic Endometritis”: Beyond Composition: The Potential Role of Microbial Load in CE Pathophysiology","authors":"Yinglan Ma, Qun Zhou, Huilin Yang","doi":"10.1111/aji.70204","DOIUrl":"10.1111/aji.70204","url":null,"abstract":"","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145964984","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}
Abigail C. Fischer, Hanah M. Georges, Deidre M. Jones, Lawrence W. Chamley, Vikki M. Abrahams
Problem
Obstetric antiphospholipid syndrome (APS) is characterized by the presence of circulating anti-phospholipid antibodies (aPL), which disrupt early placentation and contribute to adverse pregnancy outcomes including pregnancy loss and preterm birth. aPL, specifically those targeting beta 2 glycoprotein 1 (β2GPI), interact with placental trophoblast cells and induce inflammation, disrupt angiogenic factor production, and reduce cell migration. In addition, aPL have been shown to promote a state of oxidative stress in trophoblast cells and in APS patients. This study aimed to investigate if the antioxidant, nicotinamide riboside (NR), could mitigate the negative effects of aPL on trophoblast cells.
Method of Study
The human first-trimester trophoblast cell line, Sw.71, was treated with or without aPL in the presence or absence of NR. Trophoblast supernatants were measured by ELISA for pro-inflammatory cytokines/chemokines and angiogenic factors. Cell migration was measured using a two-chamber colorimetric assay. ROS production was measured using a fluorescence assay.
Results
NR blocked aPL-induced trophoblast inflammation and ROS production, and reversed the effects of aPL on trophoblast angiogenic factor production. However, NR was unable to rescue aPL-induced trophoblast migratory dysfunction.
Conclusion
NR mitigated some, but not all, aPL-induced trophoblast dysfunction. This provides new insight into the role of antioxidant therapies on aPL-induced pregnancy complications, and a possible new avenue of managing obstetric APS to explore further.
{"title":"Nicotinamide Riboside Mitigates Antiphospholipid Antibody-Induced Dysfunction in Human Trophoblast Cells","authors":"Abigail C. Fischer, Hanah M. Georges, Deidre M. Jones, Lawrence W. Chamley, Vikki M. Abrahams","doi":"10.1111/aji.70205","DOIUrl":"10.1111/aji.70205","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Problem</h3>\u0000 \u0000 <p>Obstetric antiphospholipid syndrome (APS) is characterized by the presence of circulating anti-phospholipid antibodies (aPL), which disrupt early placentation and contribute to adverse pregnancy outcomes including pregnancy loss and preterm birth. aPL, specifically those targeting beta 2 glycoprotein 1 (β<sub>2</sub>GPI), interact with placental trophoblast cells and induce inflammation, disrupt angiogenic factor production, and reduce cell migration. In addition, aPL have been shown to promote a state of oxidative stress in trophoblast cells and in APS patients. This study aimed to investigate if the antioxidant, nicotinamide riboside (NR), could mitigate the negative effects of aPL on trophoblast cells.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Method of Study</h3>\u0000 \u0000 <p>The human first-trimester trophoblast cell line, Sw.71, was treated with or without aPL in the presence or absence of NR. Trophoblast supernatants were measured by ELISA for pro-inflammatory cytokines/chemokines and angiogenic factors. Cell migration was measured using a two-chamber colorimetric assay. ROS production was measured using a fluorescence assay.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>NR blocked aPL-induced trophoblast inflammation and ROS production, and reversed the effects of aPL on trophoblast angiogenic factor production. However, NR was unable to rescue aPL-induced trophoblast migratory dysfunction.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusion</h3>\u0000 \u0000 <p>NR mitigated some, but not all, aPL-induced trophoblast dysfunction. This provides new insight into the role of antioxidant therapies on aPL-induced pregnancy complications, and a possible new avenue of managing obstetric APS to explore further.</p>\u0000 </section>\u0000 </div>","PeriodicalId":7665,"journal":{"name":"American Journal of Reproductive Immunology","volume":"95 1","pages":""},"PeriodicalIF":2.4,"publicationDate":"2026-01-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145958375","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}
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