Innate Lymphoid Cells in the Maternal and Fetal Compartments

Pregnancy success is orchestrated by the complex balance between the maternal and fetal immune systems. Herein, we summarize the potential role of innate lymphoid cells (ILCs) in the maternal and fetal compartments. We reviewed published literature describing different ILC subsets [ILC1s, ILC2s, ILC3s, and lymphoid tissue inducer (LTi) cells] in the uterus, decidua, fetal tissues [liver, secondary lymphoid organs (SLO), intestine, and lung] and amniotic cavity. ILC1s, ILC2s, and ILC3s are present in the murine uterus prior to and during pregnancy but have only been detected in the non-pregnant endometrium in humans. Specifically, ILC2s reside in the murine uterus from mid-pregnancy to term, ILC1s increase throughout gestation, and ILC3s remain constant. Yet, LTi cells have only been detected in the non-pregnant murine uterus. In the human decidua, ILC1s, ILC3s, and LTi-like cells are more abundant during early gestation, whereas ILC2s increase at the end of pregnancy. Decidual ILC1s were also detected during mid-gestation in mice. Interestingly, functional decidual ILC2s and ILC3s increased in women who underwent spontaneous preterm labor, indicating the involvement of such cells in this pregnancy complication. Fetal ILCs exist in the liver, SLO, intestine, lung, and amniotic cavity. The fetal liver is thought to be the source of ILC progenitors since the differentiation of these cells from hematopoietic stem cells occurs at this site, and mature ILC subsets can be found in this compartment as well. The interaction between LTi cells and specialized stromal cells is important during the formation of SLO. Mature ILCs are found at the mucosal surfaces of the lung and intestine, from where they can extravasate into the amniotic cavity. Amniotic fluid ILCs express high levels of RORγt, CD161, and CD103, hallmarks of ILC3s. Such cells are more abundant in the second trimester than later in gestation. Although amniotic fluid ILC3s produce IL-17A and TNFα, indicating their functionality, their numbers in patients with intra-amniotic infection/inflammation remain unchanged compared to those without this pregnancy complication. Collectively, these findings suggest that maternal (uterine and decidual) ILCs play central roles in both the initiation and maintenance of pregnancy, and fetal ILCs participate in the development of immunity

Are B cells altered in the decidua of women with preterm or term labor?

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/1/aji13102_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/149277/2/aji13102.pd

RNA Sequencing Reveals Diverse Functions of Amniotic Fluid Neutrophils and Monocytes/Macrophages in Intra-Amniotic Infection

Intra-amniotic infection, the invasion of microbes into the amniotic cavity resulting in inflammation, is a clinical condition that can lead to adverse pregnancy outcomes for the mother and fetus as well as severe long-term neonatal morbidities. Despite much research focused on the consequences of intra-amniotic infection, there remains little knowledge about the innate immune cells that respond to invading microbes. We performed RNA-seq of sorted amniotic fluid neutrophils and monocytes/macrophages from women with intra-amniotic infection to determine the transcriptomic differences between these innate immune cells. Further, we sought to identify specific transcriptomic pathways that were significantly altered by the maternal or fetal origin of amniotic fluid neutrophils and monocytes/macrophages, the presence of a severe fetal inflammatory response, and pregnancy outcome (i.e., preterm or term delivery). We show that significant transcriptomic differences exist between amniotic fluid neutrophils and monocytes/macrophages from women with intra-amniotic infection, indicating the distinct roles these cells play. The transcriptome of amniotic fluid immune cells varies based on their maternal or fetal origin, and the significant transcriptomic differences between fetal and maternal monocytes/macrophages imply that those of fetal origin exhibit impaired functions. Notably, transcriptomic changes in amniotic fluid monocytes/macrophages suggest that these immune cells collaborate with neutrophils in the trafficking of fetal leukocytes throughout the umbilical cord (i.e., funisitis). Finally, amniotic fluid neutrophils and monocytes/macrophages from preterm deliveries display enhanced transcriptional activity compared to those from term deliveries, highlighting the protective role of these cells during this vulnerable period. Collectively, these findings demonstrate the underlying complexity of local innate immune responses in women with intra-amniotic infection and provide new insights into the functions of neutrophils and monocytes/macrophages in the amniotic cavity. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements

Incidence and outcomes of uterine rupture among women with prior caesarean section: WHO Multicountry Survey on Maternal and Newborn Health

Caesarean section (CS) is increasing globally, and women with prior CS are at higher risk of uterine rupture in subsequent pregnancies. However, little is known about the incidence, risk factors, and outcomes of uterine rupture in women with prior CS, especially in developing countries. To investigate this, we conducted a secondary analysis of the World Health Organization Multicountry Survey on Maternal and Newborn Health, which included data on delivery from 359 facilities in 29 countries. The incidence of uterine rupture among women with at least one prior CS was 0.5% (170/37,366), ranging from 0.2% in high-Human Development Index (HDI) countries to 1.0% in low-HDI countries. Factors significantly associated with uterine rupture included giving birth in medium-or low-HDI countries (adjusted odds ratio [AOR] 2.0 and 3.88, respectively), lower maternal educational level (<= 6 years) (AOR 1.71), spontaneous onset of labour (AOR 1.62), and gestational age at birth < 37 weeks (AOR 3.52). Women with uterine rupture had significantly higher risk of maternal death (AOR 4.45) and perinatal death (AOR 33.34). Women with prior CS, especially in resource-limited settings, are facing higher risk of uterine rupture and subsequent adverse outcomes. Further studies are needed for prevention/management strategies in these settings.UNDP/UNFPA/UNICEF/WHO/World Bank Special Programme of Research, Development and Research Training in Human Reproduction (HRP)World Health Organization (WHO)United States Agency for International Development (USAID)Ministry of Health, Labour and Welfare of JapanGynuity Health ProjectsJapan Agency for Medical Research and Development, AMEDNatl Res Inst Child Hlth & Dev, Dept Allergy & Clin Immunol, Tokyo, JapanUniv Tsukuba, Dept Global Hlth Nursing, Fac Med, Tsukuba, Ibaraki, JapanNatl Ctr Child Hlth & Dev, Dept Educ Clin Res, Tokyo, JapanSt Lukes Int Univ, Grad Sch Nursing Sci, Global Hlth Nursing, Tokyo, JapanWHO, UNDP UNFPA UNICEF WHO World Bank Special Programm, Dept Reprod Hlth & Res, Geneva, SwitzerlandUniv Fed Sao Paulo, Evidence Based Healthcare Postgrad Programme, Dept Internal Med, Sao Paulo, BrazilMinist Hlth, Family Hlth Bur, Maternal & Child Morbid & Mortal Unit, Colombo, Sri LankaSora No Mori Clin, Yaese, Okinawa, JapanFortis Mem Res Inst, Obstet & Gynecol, Gurgaon, IndiaNatl Ctr Dis Prevent & Control, Dept Hlth, Manila, PhilippinesKochi Univ, Kochi Med Sch, Dept Pediat, Kochi, JapanUniv Abdou Moumouni Niamey, Niamey, NigerAmer Univ Beirut, Beirut, LebanonUniv Nairobi, Obstet & Gynaecol, Sch Med, Nairobi, KenyaUniv Sao Paulo, Ribeirao Preto Med Sch, Dept Social Med, Sao Paulo, BrazilNatl Ctr Child Hlth & Dev, Dept Hlth Policy, Tokyo, JapanUniv Fed Sao Paulo, Evidence Based Healthcare Postgrad Programme, Dept Internal Med, Sao Paulo, BrazilWeb of Scienc

Induction of human regulatory innate lymphoid cells from group 2 innate lymphoid cells by retinoic acid

BACKGROUND: Group 2 innate lymphoid cells (ILC2s) play critical roles in induction and exacerbation of allergic airway inflammation. Thus, clarification of the mechanisms that underlie the regulation of ILC2 activation has received significant attention. Although ILCs are divided into three major subsets that mirror helper effector T-cell subsets, counterpart subsets of regulatory T (Treg) cells have not been well characterized. OBJECTIVE: We sought to determine the factors that induce regulatory ILCs (ILCregs). METHODS: IL-10+ ILCregs induced from ILC2s by retinoic acid (RA) were analyzed using RNA-sequencing and flow cytometry. ILCregs were evaluated in human nasal tissues from healthy individuals and patients with chronic rhinosinusitis with nasal polyp (CRSwNP), and in lung tissues from house dust mite (HDM)- or saline-treated mice. RESULTS: RA induced IL-10 secretion by human ILC2s, but not type-2 cytokines. IL-10+ ILCregs, converted from ILC2s by RA stimulation, expressed a Treg-like signature with the expression of IL-10, CTLA-4 and CD25, with down regulated effector type 2-related markers such as CRTH-2 and ST2, and suppressed activation of CD4+ T cells and ILC2s. ILCregs were rarely detected in human nasal tissue from healthy individuals or lung tissues from saline-treated mice, but were increased in nasal tissues from patients with CRSwNP and in lung tissues from HDM-treated mice. Enzymes for RA synthesis were up-regulated in airway epithelial cells during type-2 inflammation in vivo and by IL-13 in vitro. CONCLUSION: We have identified a unique immune regulatory and anti-inflammatory pathway by which RA converts ILC2s to ILCregs. Interactions between airway epithelial cells and ILC2s play an important roles in the generation of ILCregs

Cellular immune responses in the pathophysiology of preeclampsia

Preeclampsia, defined as new- onset hypertension accompanied by proteinuria occurring at 20 weeks of gestation or later, is a leading cause of perinatal morbidity and mortality worldwide. The pathophysiology of this major multi- systemic syndrome includes defective deep placentation, oxidative stress, endothelial dysfunction, the presence of an anti- angiogenic state, and intravascular inflammation, among others. In this review, we provide a comprehensive overview of the cellular immune responses involved in the pathogenesis of preeclampsia. Specifically, we summarize the role of innate and adaptive immune cells in the maternal circulation, reproductive tissues, and at the maternal- fetal interface of women affected by this pregnancy complication. The major cellular subsets involved in the pathogenesis of preeclampsia are regulatory T cells, effector T cells, NK cells, monocytes, macrophages, and neutrophils. We also summarize the literature on those immune cells that have been less characterized in this clinical condition, such as γδ T cells, invariant natural killer T cells, dendritic cells, mast cells, and B cells. Moreover, we discuss in vivo studies utilizing a variety of animal models of preeclampsia to further support the role of immune cells in this disease. Finally, we highlight the existing gaps in knowledge of the immunobiology of preeclampsia that require further investigation. The goal of this review is to promote translational research leading to clinically relevant strategies that can improve adverse perinatal outcomes resulting from the obstetrical syndrome of preeclampsia.Graphical AbstractInnate and adaptive immune cell responses in women with preeclampsiaPeer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/171226/1/jlb10901_am.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/171226/2/jlb10901.pd

The optimal age for epicutaneous sensitization following tape-stripping in BALB/c mice

Background: Direct contact of food proteins with eczematous lesions is thought to be the main cause of epicutaneous sensitization. To further investigate the development and pathogenesis of food allergy in vivo, a good mouse model of epicutaneous sensitization is needed. However, a fundamental problem in that regard is that the optimal age for epicutaneous sensitization of mice is unknown. In this study, we attempted to elucidate that optimal age. Methods: Dorsal skin of wild-type BALB/c female mice (1, 3, 8 and 24 weeks old) was shaved, depilated and tape-stripped. A Finn chamber containing a 20-μl-aliquot of 20-mg/ml (OVA) was applied to the tape-stripped skin on 3 consecutive days/week, for 3 weeks. The body temperature was measured after intraperitoneal OVA challenge. Serum OVA-specific IgE titers and OVA-induced cytokine production by spleen cells were measured by ELISA. Dendritic cells (DCs) that migrated to the draining lymph nodes were quantified by FITC-labeled OVA and flow cytometry. The mRNA expression levels in the dorsal skin were measured by qPCR. Results: A significant age-dependent body temperature decline was observed after OVA challenge. The serum OVA-specific IgE titer, OVA-induced cytokine production (i.e., IL-4, IL-5 and IL-13) by spleen cells, and number of FITC-OVA-engulfing DCs increased with age. In addition, mRNA for IL-33, but not TSLP or IL-25, was significantly induced in the skin by tape-stripping and increased with age. Conclusions: Twenty-four-week-old mice showed the greatest DC migration, Th2 polarization, IgE production and body temperature decline. Skin-derived IL-33 is likely to play key roles in those changes. Keywords: Epicutaneous sensitization, Food allergy, IL-33, Mouse model, Tape strippin

Clarithromycin prevents preterm birth and neonatal mortality by dampening alarmin-induced maternal–fetal inflammation in mice

Abstract Background One of every four preterm neonates is born to a woman with sterile intra-amniotic inflammation (inflammatory process induced by alarmins); yet, this clinical condition still lacks treatment. Herein, we utilized an established murine model of sterile intra-amniotic inflammation induced by the alarmin high-mobility group box-1 (HMGB1) to evaluate whether treatment with clarithromycin prevents preterm birth and adverse neonatal outcomes by dampening maternal and fetal inflammatory responses. Methods Pregnant mice were intra-amniotically injected with HMGB1 under ultrasound guidance and treated with clarithromycin or vehicle control, and pregnancy and neonatal outcomes were recorded (n = 15 dams each). Additionally, amniotic fluid, placenta, uterine decidua, cervix, and fetal tissues were collected prior to preterm birth for determination of the inflammatory status (n = 7–8 dams each). Results Clarithromycin extended the gestational length, reduced the rate of preterm birth, and improved neonatal mortality induced by HMGB1. Clarithromycin prevented preterm birth by interfering with the common cascade of parturition as evidenced by dysregulated expression of contractility-associated proteins and inflammatory mediators in the intra-uterine tissues. Notably, clarithromycin improved neonatal survival by dampening inflammation in the placenta as well as in the fetal lung, intestine, liver, and spleen. Conclusions Clarithromycin prevents preterm birth and improves neonatal survival in an animal model of sterile intra-amniotic inflammation, demonstrating the potential utility of this macrolide for treating women with this clinical condition, which currently lacks a therapeutic intervention.http://deepblue.lib.umich.edu/bitstream/2027.42/173661/1/12884_2022_Article_4764.pd