bims-reprim 2021-09-19 papers

bims-reprim

Biomed News

on Reproductive immunology

Issue of 2021–09–19
seventeen papers selected by
Iva Filipovic, Karolinska Institutet

Role of Decidual Natural Killer Cells in Human Pregnancy and Related Pregnancy Complications.
BCG-trained innate immunity leads to fetal growth restriction by altering immune cell profile in the mouse developing placenta.
A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages.
Changes in serum cytokines throughout pregnancy in women with polycystic ovary syndrome.
Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy.
The abnormal expression of Tim-3 is involved in the regulation of myeloid-derived suppressor cells and its correlation with preeclampsia.
Maternal B cell signaling orchestrates fetal development in mice.
Antibiotic Intervention Affects Maternal Immunity During Gestation in Mice.
Decidual Inflammation Drives Chemokine-Mediated Immune Infiltration Contributing to Term Labor.
The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II.
Chlamydia evasion of neutrophil host defense results in NLRP3 dependent myeloid-mediated sterile inflammation through the purinergic P2X7 receptor.
Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth.
Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis.
The roles of polymorphonuclear myeloid-derived suppressor cells in endometriosis.
Parity associates with chromosomal damage in uterine leiomyomas.
Menstrual changes after covid-19 vaccination.
Western diet shifts immune cell balance.

Front Immunol. 2021 ;12 728291

Role of Decidual Natural Killer Cells in Human Pregnancy and Related Pregnancy Complications.

Xiuhong Zhang, Haiming Wei.

  Pregnancy is a unique type of immunological process. Healthy pregnancy is associated with a series of inflammatory events: implantation (inflammation), gestation (anti-inflammation), and parturition (inflammation). As the most abundant leukocytes during pregnancy, natural killer (NK) cells are recruited and activated by ovarian hormones and have pivotal roles throughout pregnancy. During the first trimester, NK cells represent up to 50-70% of decidua lymphocytes. Differently from peripheral-blood NK cells, decidual natural killer (dNK) cells are poorly cytolytic, and they release cytokines/chemokines that induce trophoblast invasion, tissue remodeling, embryonic development, and placentation. NK cells can also shift to a cytotoxic identity and carry out immune defense if infected in utero by pathogens. At late gestation, premature activation of NK cells can lead to a breakdown of tolerance of the maternal-fetal interface and, subsequently, can result in preterm birth. This review is focused on the role of dNK cells in normal pregnancy and pathological pregnancy, including preeclampsia, recurrent spontaneous abortion, endometriosis, and recurrent implantation failure. dNK cells could be targets for the treatment of pregnancy complications.

Keywords:  anti-inflammation; decidual natural killer cells; human pregnancy; immune tolerance; inflammation; maternal-fetal interface; pregnancy complications

DOI:  https://doi.org/10.3389/fimmu.2021.728291
J Leukoc Biol. 2021 Sep 17.

BCG-trained innate immunity leads to fetal growth restriction by altering immune cell profile in the mouse developing placenta.

Yipu Dang, Camille Souchet, Fabiana Moresi, Mohamed Jeljeli, Bruno Raquillet, Carole Nicco, Sandrine Chouzenoux, Isabelle Lagoutte, Louis Marcellin, Frederic Batteux, Ludivine Doridot.

  Trained immunity is a new concept illustrating that innate immune cells are able to undergo a long-term metabolic and epigenetic reprogramming after infection or vaccination, thus displaying either a pro- or an anti-inflammatory phenotype during a sequential unrelated challenge. Innate immune cells such as natural killer (NK) cells and macrophages constitute a large part of the decidual leukocyte population at the maternal-fetal interface, playing an important role in placental development and as such in fetal growth and development. In this study, we hypothesized that training the innate immune cells before pregnancy could have an impact on pregnancy. To test this hypothesis, we used CBA/J x DBA/2 mouse model to investigate pregnancy outcomes and leukocyte population at the maternal-fetal interface. Although we were not able to show a beneficial effect of LPS-tolerogenic training on fetal resorption, Bacillus Calmette-Guérin (BCG) training, known to prime innate immune cells to be proinflammatory, led to fetal growth restriction, without aggravating the fetal resorption rate. We also found that BCG training led to less NK cells and macrophages at the maternal-fetal interface at the early stage of placentation (E9.5), associated with a down-regulation of Ccr3 and Lif mRNA expression. This induced altered leucocyte population profile can be an explanation for the subsequent fetal growth restriction. These data suggest that preconceptional infections-induced trained immunity could influence pregnancy outcomes.

Keywords:  BCG; LPS; fetal weight; innate immune memory; maternal-fetal interface; pregnancy

DOI:  https://doi.org/10.1002/JLB.4A0720-458RR
Front Immunol. 2021 ;12 711231

A History of Endometriosis Is Associated With Decreased Peripheral NK Cytotoxicity and Increased Infiltration of Uterine CD68+ Macrophages.

Linlin Wang, Longfei Li, Yuye Li, Chunyu Huang, Ruochun Lian, Tonghua Wu, Jingwen Ma, Yan Zhang, Yanxiang Cheng, Lianghui Diao, Yong Zeng.

  Women with endometriosis may have a defective immune system. However, evidence of the immune responses of endometriosis patients with a history of endometriosis surgery is lacking, and the association between the location of endometriosis lesions and immune responses is unclear. This retrospective study included 117 females with reproductive failure and a history of endometriosis and 200 females with reproductive failure but without endometriosis to analyze their endometrial and peripheral immune responses. The results show that endometriosis was associated with decreased peripheral natural killer (NK) cytotoxicity and increased uterine macrophages. Peripheral NK cytotoxicity at effector-to-target ratios of 25:1 and 50:1 was significantly reduced in women with a history of endometriosis from that of the control group (26.6% versus 33.3% and 36.1% versus 43.3%, respectively, both P < 0.001). Furthermore, after further division of patients into three subgroups according to the location of endometriosis lesions, we observed that NK cytotoxicity in the endometriosis subgroups, especially the mixed endometriosis group, was strongly decreased from that of the controls (P = 0.001). The endometrial CD68+ macrophage proportion in the mixed endometriosis subgroup was higher than that in the control group (2.8% versus 2.1%, P = 0.043). In addition, the baseline estradiol (E2) level was weakly correlated with the percentage of endometrial macrophages (r = 0.251, P = 0.009), indicating a potential association among the endocrine system, endometrial immune environment, and endometriosis. This study indicated that peripheral NK cytotoxicity and endometrial immune cell profiles could be useful for diagnosing and treating endometriosis and endometriosis-related reproductive diseases.

Keywords:  endometriosis; estradiol; peripheral natural killer cytotoxicity; reproductive failure; uterine macrophages

DOI:  https://doi.org/10.3389/fimmu.2021.711231
J Clin Endocrinol Metab. 2021 Sep 16. pii: dgab684. [Epub ahead of print]

Changes in serum cytokines throughout pregnancy in women with polycystic ovary syndrome.

Live Marie T Stokkeland, Guro F Giskeødegård, Mariell Ryssdal, Anders Hagen Jarmund, Bjørg Steinkjer, Torfinn Støve Madssen, Signe N Stafne, Solhild Stridsklev, Tone S Løvvik, Ann-Charlotte Iversen, Eszter Vanky.

   CONTEXT: Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with low-grade inflammation and increased incidence of pregnancy complications, but its influence on the maternal immune system in pregnancy is unknown. Longitudinal serum cytokine profiling is a sensitive measure of the complex immunological dynamics of pregnancy.
OBJECTIVE: Determine the immunological dynamics of serum cytokines throughout pregnancy in women with PCOS and compare it to pregnancy in women without PCOS.
DESIGN AND SETTING: A post hoc analysis of longitudinal serum samples from two randomized, placebo-controlled multicenter studies of pregnant women with PCOS and two studies of pregnant women without PCOS.
PARTICIPANTS: Pregnant women with PCOS (n = 358) and without PCOS (n = 258, controls) provided 1752 serum samples from four time points in pregnancy (weeks 10, 19, 32, 36).
MAIN OUTCOME MEASURES: Maternal serum levels of 22 cytokines and C-reactive protein (CRP) at four time points in pregnancy.
RESULTS: Women with PCOS showed marked immunological changes in serum cytokines throughout pregnancy. Compared to controls, women with PCOS showed higher levels of 17 cytokines and CRP at week 10 of pregnancy and a distinct cytokine development throughout pregnancy. The immunological dynamics in women with PCOS was significantly affected by maternal BMI, smoking and fetal sex.
CONCLUSION: Pregnancy in women with PCOS was associated with a strong early mobilization of inflammatory and other serum cytokines persisting throughout pregnancy, indicating a more activated immune status. These findings provide a novel basis for further study of PCOS and pregnancy complications.

Keywords:  C-reactive protein; PCOS; chemokine; cytokine; multivariate analysis; pregnancy

DOI:  https://doi.org/10.1210/clinem/dgab684
Front Immunol. 2021 ;12 689181

Role of Transforming Growth Factor-β1 in Regulating Fetal-Maternal Immune Tolerance in Normal and Pathological Pregnancy.

Dongyong Yang, Fangfang Dai, Mengqin Yuan, Yajing Zheng, Shiyi Liu, Zhimin Deng, Wei Tan, Liping Chen, Qianjie Zhang, Xiaomiao Zhao, Yanxiang Cheng.

  Transforming growth factor-β (TGF-β) is composed of three isoforms, TGF-β1, TGF-β2, and TGF-β3. TGF-β1 is a cytokine with multiple biological functions that has been studied extensively. It plays an important role in regulating the differentiation of immune cells and maintaining immune cell functions and immune homeostasis. Pregnancy is a carefully regulated process. Controlled invasion of trophoblasts, precise coordination of immune cells and cytokines, and crosstalk between trophoblasts and immune cells play vital roles in the establishment and maintenance of normal pregnancy. In this systematic review, we summarize the role of TGF-β1 in regulating fetal-maternal immune tolerance in healthy and pathological pregnancies. During healthy pregnancy, TGF-β1 induces the production of regulatory T cells (Tregs), maintains the immunosuppressive function of Tregs, mediates the balance of M1/M2 macrophages, and regulates the function of NK cells, thus participating in maintaining fetal-maternal immune tolerance. In addition, some studies have shown that TGF-β1 is dysregulated in patients with recurrent spontaneous abortion or preeclampsia. TGF-β1 may play a role in the occurrence and development of these diseases and may be a potential target for the treatment of these diseases.

Keywords:  immune tolerance; preeclampsia; pregnancy; recurrent spontaneous abortion; transforming growth factor-β1

DOI:  https://doi.org/10.3389/fimmu.2021.689181
Placenta. 2021 Aug 26. pii: S0143-4004(21)00579-8. [Epub ahead of print]114 108-114

The abnormal expression of Tim-3 is involved in the regulation of myeloid-derived suppressor cells and its correlation with preeclampsia.

Shuai Dong, Neelam Kumari Shah, Jin He, Shumei Han, Min Xie, Ying Wang, Tingting Cheng, Zitao Liu, Chang Shu.

   INTRODUCTION: Maternal immune system tolerance to the semi-allogeneic fetus is critical to a successful pregnancy. We previously reported that myeloid-derived suppressor cells (MDSC) was associated with maternal immune imbalance. T cell immunoglobulin and mucin-containing protein 3 (Tim-3)/Galectin-9 (Gal-9) pathway modulates function of various immune cells in maternal-fetal interface. However, the regulatory effects of Tim-3/Gal-9 signaling on MDSCs and its role in preeclampsia (PE) remain unclear.
METHODS: In the current study we investigated the expression of Tim-3 on MDSC in preeclampsia (PE) patients to further explore the pathogenesis of PE.
RESULTS: The proportion of Tim-3+ M-MDSC (monocytic MDSC) cells was higher in PE patients than in healthy control. Meanwhile, the protein expression of Gal-9, as the ligand of Tim-3, was increased in placenta of PE patients. M-MDSC also expressed a higher level of interferon-γ (IFN-γ) and a lower level of transforming growth factor-β (TGF-β) in PE. Furthermore, our study suggested that blocking Tim-3 could attenuate the inhibitory function of MDSC.
DISCUSSION: The abnormal expression of Tim-3 on MDSC might be involved in the pathogenesis of PE, and could be a marker to evaluate the immune function in PE.

Keywords:  Gal-9; MDSC; PBMC; Preeclampsia; Tim-3

DOI:  https://doi.org/10.1016/j.placenta.2021.08.060
Development. 2021 Sep 16. pii: dev.199783. [Epub ahead of print]

Maternal B cell signaling orchestrates fetal development in mice.

Mandy Busse, Stefanie Langwisch, Kerry Tedford, Klaus-Dieter Fischer, Ana Claudia Zenclussen.

  B cell participation in early embryo/fetal development and the underlying molecular pathways have not been explored. To understand whether maternal B cell absence or impaired signaling interferes with placental and fetal growth, we paired CD19-deficient (CD19-/-) mice, females with B cell-specific MyD88 (BMyD88-/-) or IL-10 (BIL-10-/-) deficiency as well as WT and MyD88-/- controls on C57Bl/6 background with BALB/c males. Pregnancies were followed by ultrasound and Doppler measurements. Implantation number was reduced in BMyD88-/- and MyD88-/- mice. Loss of MyD88 or B cell-specific deletion of MyD88 or IL-10 resulted in decreased implantation areas at gestation days (gd)5, 8 and 10, accompanied by reduced placental thickness, diameter and areas at gd10. Uterine artery resistance was enhanced in BIL-10-/- dams at gd10. Challenge with 0.4mg LPS/kg BW at gd16 revealed that BMyD88-/-, BIL-10-/- and CD19-/- mothers delivered preterm while controls maintained their pregnancy. B cell specific MyD88 and IL-10 expression is essential for appropriate in utero development. IL-10+B cells are involved in uterine blood flow regulation during pregnancy. Finally, B cell-specific CD19, MyD88 and IL-10 expression influences susceptibility towards preterm birth.

Keywords:  B cells; MyD88; high frequency ultrasound; pre-term birth; pregnancy

DOI:  https://doi.org/10.1242/dev.199783
Front Immunol. 2021 ;12 685742

Antibiotic Intervention Affects Maternal Immunity During Gestation in Mice.

Marilen Benner, Alejandro Lopez-Rincon, Suzan Thijssen, Johan Garssen, Gerben Ferwerda, Irma Joosten, Renate G van der Molen, Astrid Hogenkamp.

   Background: Pregnancy is a portentous stage in life, during which countless events are precisely orchestrated to ensure a healthy offspring. Maternal microbial communities are thought to have a profound impact on development. Although antibiotic drugs may interfere in these processes, they constitute the most frequently prescribed medication during pregnancy to prohibit detrimental consequences of infections. Gestational antibiotic intervention is linked to preeclampsia and negative effects on neonatal immunity. Even though perturbations in the immune system of the mother can affect reproductive health, the impact of microbial manipulation on maternal immunity is still unknown.
Aim: To assess whether antibiotic treatment influences maternal immunity during pregnancy.
Methods: Pregnant mice were treated with broad-spectrum antibiotics. The maternal gut microbiome was assessed. Numerous immune parameters throughout the maternal body, including placenta and amniotic fluid were investigated and a novel machine-learning ensemble strategy was used to identify immunological parameters that allow distinction between the control and antibiotic-treated group.
Results: Antibiotic treatment reduced diversity of maternal microbiota, but litter sizes remained unaffected. Effects of antibiotic treatment on immunity reached as far as the placenta. Four immunological features were identified by recursive feature selection to contribute to the most robust classification (splenic T helper 17 cells and CD5+ B cells, CD4+ T cells in mesenteric lymph nodes and RORγT mRNA expression in placenta).
Conclusion: In the present study, antibiotic treatment was able to affect the carefully coordinated immunity during pregnancy. These findings highlight the importance of inclusion of immunological parameters when studying the effects of medication used during gestation.

Keywords:  antibiotics - immune effect; gestation; machine learning; mouse; offspring immunity; placenta; preeclampcia; pregnancy

DOI:  https://doi.org/10.3389/fimmu.2021.685742
J Immunol. 2021 Sep 15. pii: ji2100493. [Epub ahead of print]

Decidual Inflammation Drives Chemokine-Mediated Immune Infiltration Contributing to Term Labor.

Oksana Shynlova, Adam Boros-Rausch, Tali Farine, Kristina M Adams Waldorf, Caroline Dunk, Stephen J Lye.

Infiltration of maternal peripheral leukocytes into the uterine tissues is a critical event occurring before, during, and after term labor (TL). In this article, we investigate the contribution of uterine smooth muscle (myometrium) and pregnant endometrium (decidua) to the inflammatory process during human TL. We hypothesize that labor-related physiological inflammation is orchestrated by uterine-secreted cytokines, which dually activate the uterine vascular endothelium and maternal leukocytes to promote their adhesion and infiltration into the uterus. Using Luminex and ELISA assays, we examine a full range of cytokines (45 proteins) in media conditioned by primary decidual and myometrial cells from TL and term not in labor (TNL) women. The effect of conditioned media on the activation of human uterine microvascular endothelial cells was measured by qPCR and on peripheral leukocytes by flow cytometry. Transendothelial migration of calcein-labeled primary leukocytes toward media was assessed by fluorometry. Stromal decidual cells secrete significantly higher levels of multiple cytokines compared with myometrial cells (p < 0.05) and significantly more cytokines during TL than TNL. These cytokines activate uterine microvascular endothelial cells through the upregulation of cell adhesion molecule VCAM-1 and peripheral leukocytes by upregulation of CD11b. Furthermore, multiple cytokines secreted from the TL decidua and myometrium significantly increase migration of granulocytes, monocytes, and lymphocytes compared with TNL (p < 0.05), which was blocked by a broad-spectrum chemokine inhibitor (FX125L). These data reveal the critical role for decidual- and myometrial-secreted cytokines in the activation of inflammatory pathways leading to labor. We suggest that these pathways represent targets for therapeutic intervention during preterm labor.

DOI: https://doi.org/10.4049/jimmunol.2100493
Immunohorizons. 2021 Sep 14. 5(9): 735-751

The Distinct Immune Nature of the Fetal Inflammatory Response Syndrome Type I and Type II.

Robert Para, Roberto Romero, Derek Miller, Jose Galaz, Bogdan Done, Azam Peyvandipour, Meyer Gershater, Li Tao, Kenichiro Motomura, Douglas M Ruden, Jenna Isherwood, Eunjung Jung, Tomi Kanninen, Roger Pique-Regi, Adi L Tarca, Nardhy Gomez-Lopez.

Fetal inflammatory response syndrome (FIRS) is strongly associated with neonatal morbidity and mortality and can be classified as type I or type II. Clinically, FIRS type I and type II are considered as distinct syndromes, yet the molecular underpinnings of these fetal inflammatory responses are not well understood because of their low prevalence and the difficulty of postdelivery diagnosis. In this study, we performed RNA sequencing of human cord blood samples from preterm neonates diagnosed with FIRS type I or FIRS type II. We found that FIRS type I was characterized by an upregulation of host immune responses, including neutrophil and monocyte functions, together with a proinflammatory cytokine storm and a downregulation of T cell processes. In contrast, FIRS type II comprised a mild chronic inflammatory response involving perturbation of HLA transcripts, suggestive of fetal semiallograft rejection. Integrating single-cell RNA sequencing-derived signatures with bulk transcriptomic data confirmed that FIRS type I immune responses were mainly driven by monocytes, macrophages, and neutrophils. Last, tissue- and cell-specific signatures derived from the BioGPS Gene Atlas further corroborated the role of myeloid cells originating from the bone marrow in FIRS type I. Collectively, these data provide evidence that FIRS type I and FIRS type II are driven by distinct immune mechanisms; whereas the former involves the innate limb of immunity consistent with host defense, the latter resembles a process of semiallograft rejection. These findings shed light on the fetal immune responses caused by infection or alloreactivity that can lead to deleterious consequences in neonatal life.

DOI: https://doi.org/10.4049/immunohorizons.2100047
Nat Commun. 2021 Sep 15. 12(1): 5454

Chlamydia evasion of neutrophil host defense results in NLRP3 dependent myeloid-mediated sterile inflammation through the purinergic P2X7 receptor.

Chunfu Yang, Lei Lei, John W Marshall Collins, Michael Briones, Li Ma, Gail L Sturdevant, Hua Su, Anuj K Kashyap, David Dorward, Kevin W Bock, Ian N Moore, Christine Bonner, Chih-Yu Chen, Craig A Martens, Stacy Ricklefs, Masahiro Yamamoto, Kiyoshi Takeda, Yoichiro Iwakura, Grant McClarty, Harlan D Caldwell.

Chlamydia trachomatis infection causes severe inflammatory disease resulting in blindness and infertility. The pathophysiology of these diseases remains elusive but myeloid cell-associated inflammation has been implicated. Here we show NLRP3 inflammasome activation is essential for driving a macrophage-associated endometritis resulting in infertility by using a female mouse genital tract chlamydial infection model. We find the chlamydial parasitophorous vacuole protein CT135 triggers NLRP3 inflammasome activation via TLR2/MyD88 signaling as a pathogenic strategy to evade neutrophil host defense. Paradoxically, a consequence of CT135 mediated neutrophil killing results in a submucosal macrophage-associated endometritis driven by ATP/P2X7R induced NLRP3 inflammasome activation. Importantly, macrophage-associated immunopathology occurs independent of macrophage infection. We show chlamydial infection of neutrophils and epithelial cells produce elevated levels of extracellular ATP. We propose this source of ATP serves as a DAMP to activate submucosal macrophage NLRP3 inflammasome that drive damaging immunopathology. These findings offer a paradigm of sterile inflammation in infectious disease pathogenesis.

DOI: https://doi.org/10.1038/s41467-021-25749-3
JAMA Netw Open. 2021 Sep 01. 4(9): e2125308

Association Between Human Papillomavirus Infection Among Pregnant Women and Preterm Birth.

HERITAGE Study Group

Importance: Preterm birth remains a leading cause of perinatal mortality and lifelong morbidity worldwide. The cause of most preterm births is unknown, although several infectious processes have been implicated.
Objective: To assess whether human papillomavirus (HPV) infection, a frequent infection among women of childbearing age, is associated with preterm birth.
Design, Setting, and Participants: The prospective HERITAGE cohort study was conducted at 3 academic hospitals in Montreal, Québec, Canada, among 899 pregnant women recruited between November 8, 2010, and October 16, 2016. Follow-up was completed on June 15, 2017. Statistical analysis was conducted from February 6, 2020, to January 21, 2021.
Exposures: Vaginal HPV DNA detection in the first and third trimesters of pregnancy and placental HPV infection.
Main Outcomes and Measures: The main outcome was preterm birth (defined as a live birth or stillbirth between 20 weeks and 0 days and 36 weeks and 6 days of gestation). The association between HPV DNA detection and preterm birth was measured using logistic regression. Odds ratios (ORs) and 95% CIs were adjusted by inverse probability of treatment weights of the propensity score.
Results: The study included 899 women (mean [SD] age, 31.3 [4.6] years [range, 19-47 years]) with singleton pregnancies. A total of 378 women (42.0%) had HPV DNA detected in vaginal samples collected during the first trimester, and it was detected in 91 of 819 placentas (11.1%) at delivery. Fifty-five participants experienced preterm birth (38 spontaneous and 17 medically indicated). Persistent vaginal HPV-16/18 detection was significantly associated with all preterm births (adjusted OR [aOR], 3.72; 95% CI, 1.47-9.39) and spontaneous preterm births (aOR, 3.32; 95% CI, 1.13-9.80), as was placental HPV infection (all preterm births: aOR, 2.53; 95% CI, 1.06-6.03; spontaneous preterm births: aOR, 2.92; 95% CI, 1.09-7.81). Results were similar when restricting the analysis to participants without a history of cervical intraepithelial neoplasia treatment.
Conclusions and Relevance: The study's results suggest that persistent HPV-16/18 infection is associated with an increased risk of preterm birth, independent of cervical treatment. Future studies should investigate the association of HPV vaccination and vaccination programs with the risk of preterm birth.

DOI: https://doi.org/10.1001/jamanetworkopen.2021.25308
Front Immunol. 2021 ;12 722489

Preterm Birth Is Associated With Immune Dysregulation Which Persists in Infants Exposed to Histologic Chorioamnionitis.

Gemma Sullivan, Paola Galdi, Nis Borbye-Lorenzen, David Q Stoye, Gillian J Lamb, Margaret J Evans, Kristin Skogstrand, Siddharthan Chandran, James P Boardman.

   Introduction: Preterm infants are at increased risk of exposure to histologic chorioamnionitis (HCA) when compared to term-born controls, and this is associated with several neonatal morbidities involving brain, lungs and gut. Preterm infants could benefit from immunomodulatory therapies in the perinatal period, but development of rational treatment strategies requires improved characterization of the perinatal response to HCA. We had two objectives: The first, to characterize the umbilical cord blood immune profile in preterm infants compared to term-born controls; the second, to investigate the postnatal immune response in preterm infants exposed to HCA versus those who were not.
Population: For objective one 59 term infants [mean gestational age (GA) 39+4 (37+3 to 42+0)] and 55 preterm infants [mean GA29+0(23+3 to 32+0)] with umbilical cord samples available were included; for objective two we studied 96 preterm infants [mean GA29+1(23+2 to 32+0)] for whom placental histology and postnatal blood samples were available.
Methods: Placental histopathology was used to identify reaction patterns indicative of HCA, and a customized immunoassay of 24 inflammatory markers and trophic proteins selected to reflect the perinatal immune response was performed on umbilical cord blood in term and preterm participants and postnatal day 5 blood in the preterm group.
Results: The umbilical cord blood immune profile classified gestational age category with 86% accuracy (95% CI 0.78-0.92), p-value=1.242x10-14. Pro-inflammatory proteins IL-6, MCP-1 and CRP were elevated in the cord blood of preterm infants whilst BDNF, C3, C9, IL-18, MMP-9 and RANTES were decreased, compared to infants born at term. In preterm infants, exposure to HCA was associated with elevations in 8 immune proteins on postnatal day 5 (BDNF, C3, C5a, C9, IL-8, MCP-1, MIP-1β and MMP-9) when compared to preterm infants who were not exposed.
Conclusion: Preterm birth is associated with a distinct immune profile in umbilical cord blood and preterm infants exposed to HCA with evidence of a fetal inflammatory response have specific alterations in immune function that are apparent on day 5 of postnatal life.

Keywords:  complement; cytokine; fetal inflammatory response; histologic chorioamnionitis; immunity; inflammation; interleukin; preterm birth

DOI:  https://doi.org/10.3389/fimmu.2021.722489
J Reprod Immunol. 2021 Sep 04. pii: S0165-0378(21)00101-7. [Epub ahead of print]148 103371

The roles of polymorphonuclear myeloid-derived suppressor cells in endometriosis.

Erina Satake, Kaori Koga, Masashi Takamura, Gentaro Izumi, Mohammed Elsherbini, Ayumi Taguchi, Tomoko Makabe, Arisa Takeuchi, Miyuki Harada, Tetsuya Hirata, Yasushi Hirota, Osamu Wada-Hiraike, Yutaka Osuga.

   OBJECTIVES: This study aimed to determine the systemic and local proportions, focal localization, and characteristics of polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs) in endometriosis.
STUDY DESIGN: Peripheral blood and peritoneal fluid were obtained from patients with a benign gynecologic condition (controls) or endometriosis. PMN-MDSCs were defined as CD33+HLA-DRlow/-CD14-CD15+ and monocytic (M)-MDSCs were defined as CD33+HLA-DRlow/-CD14+CD15-, and were identified using flowcytometry. Ovarian endometriotic tissues were obtained, and the expression of lectin-type oxidized low density lipoprotein receptor-1 (LOX1) as a marker of PMN-MDSCs, arginine 1 (Arg1), and matrix metalloproteinase 9 (MMP9) were detected using immunohistochemistry. Anti-Ly6G antibody was administered to endometriosis model mice, and the number and weight of the lesions were measured, and cell proliferations and apoptosis in the lesions were analyzed using Ki67 immunohistochemistry and TUNEL assay.
RESULTS: In the peripheral blood, the proportion of PMN-MDSCs was significantly higher in endometriosis (3.20 vs 1.63 %, p < 0.05), but the proportion of M-MDSCs did not differ between the groups. In the peritoneal fluid, the proportion of PMN-MDSCs was significantly higher in endometriosis (7.82 × 10-1% vs 6.48 × 10-2%, p < 0.05), whereas the proportion of M-MDSCs did not differ between the groups. PMN-MDSCs were detected in the stromal cell layer of the endometriotic cyst wall. Double staining for LOX1 and Arg1, and LOX1 and MMP9 was confirmed. Administration of Ly6G antibody did not change the number or weight of endometriosis lesions, but significantly decreased Ki67-positive cells and increased TUNEL-positive cells in the lesions.
CONCLUSIONS: PMN-MDSCs may contribute to the pathogenesis of endometriosis via Arg1 and MMP9 expression.

Keywords:  Arginine 1 (Arg1); Endometriosis; Low density lipoprotein receptor-1 (LOX1); Matrix metalloproteinase 9 (MMP9); Polymorphonuclear myeloid-derived suppressor cells (PMN-MDSC)

DOI:  https://doi.org/10.1016/j.jri.2021.103371
Nat Commun. 2021 Sep 14. 12(1): 5448

Parity associates with chromosomal damage in uterine leiomyomas.

Heli Kuisma, Simona Bramante, Kristiina Rajamäki, Lauri J Sipilä, Eevi Kaasinen, Jaana Kaukomaa, Kimmo Palin, Netta Mäkinen, Jari Sjöberg, Nanna Sarvilinna, Jussi Taipale, Liisa Kauppi, Manuela Tumiati, Antti Hassinen, Janne Pitkäniemi, Jyrki Jalkanen, Sanna Heikkinen, Annukka Pasanen, Oskari Heikinheimo, Ralf Bützow, Niko Välimäki, Lauri A Aaltonen.

Mechanical forces in a constrained cellular environment were recently established as a facilitator of chromosomal damage. Whether this could contribute to tumorigenesis is not known. Uterine leiomyomas are common neoplasms that display relatively few chromosomal aberrations. We hypothesized that if mechanical forces contribute to chromosomal damage, signs of this could be seen in uterine leiomyomas from parous women. We examined the karyotypes of 1946 tumors, and found a striking overrepresentation of chromosomal damage associated with parity. We then subjected myometrial cells to physiological forces similar to those encountered during pregnancy, and found this to cause DNA breaks and a DNA repair response. While mechanical forces acting in constrained cellular environments may thus contribute to neoplastic degeneration, and genesis of uterine leiomyoma, further studies are needed to prove possible causality of the observed association. No evidence for progression to malignancy was found.

DOI: https://doi.org/10.1038/s41467-021-25806-x
BMJ. 2021 Sep 15. 374 n2211

Menstrual changes after covid-19 vaccination.

Victoria Male.

DOI: https://doi.org/10.1136/bmj.n2211
Elife. 2021 09 13. pii: e72787. [Epub ahead of print]10

Western diet shifts immune cell balance.

Christina M Bergey.

  The immune cells of macaques fed a Western-like diet adopt a pro-inflammatory profile.

Keywords:  behavior; diet; epidemiology; evolutionary mismatch; global health; immunology; inflammation; macaca fascicularis; monocyte

DOI:  https://doi.org/10.7554/eLife.72787