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CD22 and LYN mediate t-mOVA-induced B cell suppression a, Extensive N-linked glycosylation of t-mOVA. Equal volumes of pooled plasma (n = 3 mice per group (E16.5–E18.5)) were subjected to anti-OVA immunoprecipitation, deglycosylation by PNGase F digestion as indicated, then anti-OVA immunoblotting. c-OVA was analysed in parallel. b, t-mOVA sialylation. OVA from various sources was subjected to anti-OVA immunoprecipitation, sialidase digestion as indicated, then lectin blotting. Plasma came from n = 3–4 pooled xB6 pregnant WT, xmOVA pregnant WT (both E15.5–E17.5) or non-pregnant Act-mOVA (mOVA⁺) transgenic females; skin came from non-pregnant mOVA⁺ transgenic females. Each lectin blot was stripped and re-probed with anti-OVA antibodies. A nonspecific (NS) species and the sialidase itself was detected on the lectin blots. c, α(2,6)-Sia prevalence on mOVA from various tissues of Act-mOVA mice. OVA was immunoprecipitated from tissue homogenates or plasma (as in b) and subjected to SNA-I blotting, then anti-OVA immunoblotting. Blots in a–c are each representative of two to three experiments, each with independent biological replicates. For gel source data, see Supplementary Fig. 1. d–f, Representative flow plots (f), frequencies of total (d) or GL7⁺CD95⁺ GC phenotype (e) OVA-specific B cells 6 days after vaccination as described in Fig. 2c–e. WT data are from Fig. 2c, d. The flow plots show OVA-Tet⁺ B cells gated from a fixed number of total B cells across all groups. Adjusted P values were determined by ordinary one-way ANOVA with Sidak’s multiple comparisons test as described in Fig. 1. Bars show mean ± s.d. Lyn–/– and Cd22–/– data were accumulated over 14 and 11 independent experiments, respectively, and all mice are displayed. g, B cell responses to presumptive endogenous trophoblast antigens. For pregnant mice, splenic B cells were analysed on E18.5 and combine data from n = 5–9 xB6 mice and n = 5 xmOVA mice per group. Adjusted P values were determined by ordinary one-way ANOVA with Sidak’s multiple comparisons test. Bars show mean ± s.d. Source data
Source publication
Discrimination of self from non-self is fundamental to a wide range of immunological processes¹. During pregnancy, the mother does not recognize the placenta as immunologically foreign because antigens expressed by trophoblasts, the placental cells that interface with the maternal immune system, do not activate maternal T cells². Currently, these a...
Citations
... We find two distinct clusters of B cells ( Figure 1C), which have been found to play increasingly complex roles in pregnancy and fetomaternal tolerance (75,76). The first cluster we find is enriched for pan-B cell genes CD79A, CD79B, and CD22, as well as several other genes that overlap with mature, inexperienced B cells found in the liver (50). ...
Introduction
Prior to pregnancy, hormonal changes lead to cellular adaptations in the endometrium allowing for embryo implantation. Critical for successful pregnancy establishment, innate immune cells constitute a significant proportion of uterine cells prior to arrival of the embryo and throughout the first trimester in humans and animal models. Abnormal uterine immune cell function during implantation is believed to play a role in multiple adverse pregnancy outcomes. Current work in humans has focused on uterine immune cells present after pregnancy establishment, and limited in vitro models exist to explore unique functions of these cells.
Methods
With single-cell RNA-sequencing (scRNAseq), we comprehensively compared the human uterine immune landscape of the endometrium during the window of implantation and the decidua during the first trimester of pregnancy.
Results
We uncovered global and cell-type-specific gene signatures for each timepoint. Immune cells in the endometrium prior to implantation expressed genes associated with immune metabolism, division, and activation. In contrast, we observed widespread interferon signaling during the first trimester of pregnancy. We also provide evidence of specific inflammatory pathways enriched in pre- and post-implantation macrophages and natural killer (NK) cells in the uterine lining. Using our novel implantation-on-a-chip (IOC) to model human implantation ex vivo, we demonstrate for the first time that uterine macrophages strongly promote invasion of extravillous trophoblasts (EVTs), a process essential for pregnancy establishment. Pre- and post-implantation uterine macrophages promoted EVT invasion to a similar degree as pre- and post-implantation NK cells on the IOC.
Conclusions
This work provides a foundation for further investigation of the individual roles of uterine immune cell subtypes present prior to embryo implantation and during early pregnancy, which will be critical for our understanding of pregnancy complications associated with abnormal trophoblast invasion and placentation.
... Generally, Breg cells are recognized for their ability to curtail the proliferation of cytotoxic T cells and other pro-inflammatory lymphocytes by generating cytokines such as IL-10, IL-35, and TGF-b (87,88). Notably, aside from their role in T cell suppression, these cells have been identified as one subtype of antigen-presenting cells (APCs), raising questions about their unique capacity to tolerate trophoblast antigens during the crucial stage of embryo implantation (89). Furthermore, a study observed higher CD19(+) CD24(hi) CD27(+) Breg cell frequency in peripheral blood of normal pregnancy onsets but not in spontaneous abortions by flow cytometry, indicating its partition in gestation maintenance in early pregnancy (90), and a meaningful research provide evidence that Breg cell suppression to trophoblast antigens to establish fetal-maternal tolerance in mice was mediated by glycan through CD22-LYN inhibitory signaling (89). ...
... Notably, aside from their role in T cell suppression, these cells have been identified as one subtype of antigen-presenting cells (APCs), raising questions about their unique capacity to tolerate trophoblast antigens during the crucial stage of embryo implantation (89). Furthermore, a study observed higher CD19(+) CD24(hi) CD27(+) Breg cell frequency in peripheral blood of normal pregnancy onsets but not in spontaneous abortions by flow cytometry, indicating its partition in gestation maintenance in early pregnancy (90), and a meaningful research provide evidence that Breg cell suppression to trophoblast antigens to establish fetal-maternal tolerance in mice was mediated by glycan through CD22-LYN inhibitory signaling (89). In summary, B cells contribute to maintaining the IME of maternal-fetal immune balance through antibody production, secretion of immune regulatory molecules, interaction with immune cells, and regulation of surface molecules. ...
Female fertility decline is an accumulative consequence caused by complex factors, among them, the disruption of the immune profile in female reproduction stands out as a crucial contributor. Presently, the effects of immune microenvironment (IME) on the female reproductive process have attracted increasing attentions for their dynamic but precisive roles. Immunocytes including macrophages, dendritic cells, T cells, B cells and neutrophils, with diverse subpopulations as well as high plasticity functioned dynamically in the process of female reproduction through indirect intercellular communication via specific cytokine release transduced by molecular signal networks or direct cell-cell contact to maintain the stability of the reproductive process have been unveiled. The immune profile of female reproduction in each stage has also been meticulously unveiled. Especially, the application of single-cell sequencing (scRNA-seq) technology in this process reveals the distribution map of immune cells, which gives a novel insight for the homeostasis of IME and provides a research direction for better exploring the role of immune cells in female reproduction. Here, we provide an all-encompassing overview of the latest advancements in immune modulation within the context of the female reproductive process. Our approach involves structuring our summary in accordance with the physiological sequence encompassing gonadogenesis, folliculogenesis within the ovaries, ovulation through the fallopian tubes, and the subsequent stages of embryo implantation and development within the uterus. Our overarching objective is to construct a comprehensive portrayal of the immune microenvironment (IME), thereby accentuating the pivotal role played by immune cells in governing the intricate female reproductive journey. Additionally, we emphasize the pressing need for heightened attention directed towards strategies that focus on immune interventions within the female reproductive process, with the ultimate aim of enhancing female fertility.
... Thus, B-cell suppression is associated with the loss of cognate CD4 T cells. Trophoblast antigen glycans likely modulate CD22-Siglec interactions via the recruitment of endogenous sialylated proteins [34]. The CD22 protein is a member of the immunoglobulin superfamily and is homologous to three cell adhesion proteins: carcinoembryonic antigen, myelin-associated glycoprotein, and neural cell adhesion molecule [35]. ...
... Glycosylation is of the utmost importance in non-immune self-recognition in the placenta and the subsequent prevention of immunemediated pregnancy complications that may lead to pathological placental structure and function, as seen in ASD pregnancies. Glycans are also involved in the regulation of the antigen immune response to autoimmunity [34]. A study by Ziganshina et al. explored the specificity of immune tolerance in preeclampsia. ...
Autism Spectrum Disorder (ASD) is a synaptic disorder with a GABA/glutamate imbalance in the perineuronal nets and structural abnormalities such as increased dendritic spines and decreased long distance connections. Specific pregnancy disorders significantly increase the risk for an ASD phenotype such as preeclampsia, preterm birth, hypoxia phenomena, and spontaneous miscarriages. They are associated with defects in the glycosylation-immune placental processes implicated in neurogenesis. Some glycans epitopes expressed in the placenta, and specifically in the extra-villous trophoblast also have predominant functions in dendritic process and synapse function. Among these, the most important are CD57 or HNK1, CD22, CD24, CD33 and CD45. They modulate the innate immune cells at the maternal–fetal interface and they promote foeto-maternal tolerance. There are many glycan-based pathways of immunosuppression. N-glycosylation pathway dysregulation has been found to be associated with autoimmune-like phenotypes and maternal-autoantibody-related (MAR) autism have been found to be associated with central, systemic and peripheric autoimmune processes. Essential molecular pathways associated with the glycan-epitopes expression have been found to be specifically dysregulated in ASD, notably the Slit/Robo, Wnt, and mTOR/RAGE signaling pathways. These modifications have important effects on major transcriptional pathways with important genetic expression consequences. These modifications lead to defects in neuronal progenitors and in the nervous system’s implementation specifically, with further molecular defects in the GABA/glutamate system. Glycosylation placental processes are crucial effectors for proper maternofetal immunity and endocrine/paracrine pathways formation. Glycans/ galectins expression regulate immunity and neurulation processes with a direct link with gene expression. These need to be clearly elucidated in ASD pathophysiology.
... Here, we provide a hypothesis that in adipose tissue, especially in tissue near the maternal-fetal interface such as PmAT, adipocytes could act as a sensor that is capable of responding to biological changes during pregnancy and triggering downstream responses, including shutting down communication toward B cells, to induce B-cell tolerance and sequentially resulting in a paradigm shift of immunological tolerance to adipose tissue. Therefore, given the critical contribution of B cells to the development of tissue-specific maternal-fetal tolerance, B-cell suppression may benefit the prevention of immune-mediated pregnancy complications, such as low-level inflammation, weight gain, coagulation disorder, and tumor immune evasion, as we mentioned in the results of pathway analysis (25). In addition to PmAT, all adipocyte tissue located near the placenta could also participate in the establishment of the maternal-fetal tolerance network. ...
... 61,62 Sialylated glycans on fetal antigens have also been implicated to suppress maternal B cells via CD22-LYN inhibitory signaling. 63 Crosstalk between decidual NK cells and decidual CD14+ cells produce the enzyme IDO (indoleamine 2,3-dioxygenase) which catalyzes tryptophan, essential for T cell proliferation, into catabolites such as L-kynurenine that can inhibit immune cell function. 64,65 Additionally, in a typical pregnancy, there is a shift from a Th1 to a Th2-dominant environment. ...
... Successful implantation and healthy pregnancy are associated with the local immune recognition of the trophoblast during gestation; however, functions of the maternal immune system that play a role in reproductive success remain controversial in humans [1]. It is through B cell tolerance against fetal antigens and placental cells that females do not identify the placenta as immune heterogeneous in mice and humans [2]. Domestic ruminant conceptus secretes interferon-tau (IFNT) to modulate the gene expression of the innate immune system, and progesterone can also be associated with a changing maternal immune function during pregnancy [3]. ...
The thymus is an essential component of maternal immune systems that play key roles in recognizing the placenta as immunologically foreign. The inhibitor of the NF-κB (IκB) family has essential effects on the NF-κB pathway; however, it is unclear whether early pregnancy modulates the expression of the IκB family in the thymus. In this study, maternal thymuses were sampled on day 16 of nonpregnancy and different gestation stages in the ovine, and the expression of IκB proteins was analyzed. The data showed that B cell leukemia-3 and IκBβ increased; however, IκBα, IκBε, and IKKγ deceased during gestation. Furthermore, there was an increase in IκBNS and IκBζ expression values on day 13 of pregnancy; however, this decreased on day 25 of gestation. In summary, the expression of the IκB family was modulated in the thymus during early gestation, suggesting that the maternal thymus can be associated with maternal immunologic tolerance and pregnancy establishment in ewes.
... During normal pregnancy, the body undergoes many hormonal, immune, and metabolic changes [11][12][13][14]. Obesityassociated metabolic inflammation is driven by factors ranging from increased body fat in early pregnancy to decreased *Address correspondence to this author at the Department of Endocrinology and Metabolism, The Affiliated Hospital of Southwest Medical University, Luzhou, China; E-mail: wanqin360@swmu.edu.cn ...
Aims:
This cross-sectional study aimed to analyze the relationship between live birth and the prevalence of obesity in Chinese women over 40 years of age.
Methods:
From April to November 2011, the Endocrinology Branch of the Chinese Medical Association conducted the REACTION project, a national, multicenter, cross-sectional study of Chinese adults aged 40 years and older. Demographic and medical data were collected through validated questionnaires and equipment. Anthropometric indicators, blood pressure, and biochemical data were measured by professional medical personnel. Data were analyzed using descriptive statistics and logistic analysis. Multivariate regression models were used to analyze obesity-related risk factors.
Results:
The prevalence of obesity among women increased gradually from 3.8% to 6.0% with an increasing number of live births. Women with two live births had the highest prevalence of overweight at 34.3%. Overall, the obesity and overweight rates were slightly higher in premenopausal women than in postmenopausal women. Univariate regression analysis showed that the risk of obesity in women increased with an increasing number of live births. In addition, multivariate regression analysis showed that the risk of obesity increased with an increasing number of live births in women with systolic blood pressure (SBP) < 121 mmHg or current smoking (P<0.05).
Conclusion:
The risk of obesity increases with the number of live births in Chinese women over 40 years of age with SBP <121 mmHg or current smoking. Our findings may facilitate the development of interventions to prevent obesity in this population.
... In humans, multiple additional mechanisms shore up tolerance to placental alloantigens, including T-cell inactivation through indoleamine 2,3-dioxygenases (IDO)-dependent tryptophan deprivation, secretion of immunosuppressive mediators [such as glycodelin A (PAEP), prostaglandin E2 (PGE2), TGFβ and galectin 1], entrapment of antigen-presenting immune cells at the maternal-fetal interface, and the absence of HLA class I and II allotypes on non-invading trophoblasts (reviewed by Moffett and Shreeve, 2022). Further, in both humans and mice, trophoblast antigens are decorated with immunosuppressive glycans, which suppress a systematic immune response when shed into the maternal circulation (Rizzuto et al., 2022) Decidualisation Haemochorial placentation coincided with the inflammatory reprogramming of endometrial stromal cells into progesteronedependent decidual cells (Lynch et al., 2015;Erkenbrack et al., 2018;Chavan et al., 2021), a process that involves massive changes in gene expression under the control of novel TE-derived regulatory elements that confer responsiveness to steroid hormones . Decidual cells are defined by their epithelioid morphology, resistance to oxidative and metabolic stress signals and Box 2. Chromosome instability in pre-implantation human embryos Aneuploidy, the gain or loss of entire chromosomes compared with the typical 46-chromosome complement, is the primary cause of embryonic loss and fetal demise. ...
Embryo implantation in humans is interstitial, meaning the entire conceptus embeds in the endometrium before the placental trophoblast invades beyond the uterine mucosa into the underlying inner myometrium. Once implanted, embryo survival pivots on the transformation of the endometrium into an anti-inflammatory placental bed, termed decidua, under homeostatic control of uterine natural killer cells. Here, we examine the evolutionary context of embryo implantation and elaborate on uterine remodelling before and after conception in humans. We also discuss the interactions between the embryo and the decidualising endometrium that regulate interstitial implantation and determine embryo fitness. Together, this Review highlights the precarious but adaptable nature of the implantation process.
... In common with mouse, human and other species, all cat trophoblast subsets are richly endowed with sialic acid, both α2-3-linked (MAA) and α2-6linked (SNA-1). In mice, sialylated chain termini on the trophoblast cell surface are important for the establishment and maintenance of tolerance to rejection by maternal B-cells [28]. ...
Introduction:
Placental glycosylation has been examined on eight feline placentae ranging from approximately 15 to 60 days post-conception as little is known about changes in glycan distribution in this species.
Methods:
Specimens were resin embedded and lectin histochemistry was applied to semi-thin sections using a panel of 24 lectins and an avidin-biotin revealing system.
Results:
Abundant tri-tetraantennary complex N-glycan and α-galactosyl residues found in the syncytium in early pregnancy were greatly reduced in mid-pregnancy, though retained at the invasion front in the syncytium (N-glycan) or cytotrophoblast layer (αGal). Some other glycans were also uniquely present in invading cells. Abundant polylactosamine was found in the infolding basal lamina of syncytiotrophoblast and the apical villous cytotrophoblast membrane. Syncytial secretory granules often clustered near the apical membrane abutting maternal vessels. Decidual cells selectively expressed β-galactosyl residues throughout pregnancy and highly branched N-glycan levels increased over time.
Discussion:
Glycan distribution changes significantly over pregnancy, probably relating to the development of transport and invasive properties of trophoblast which in the endotheliochorial placenta reaches the level of the maternal vessels. Highly branched complex N-glycans, often associated with invasive cells, N-Acetylgalactosamine and terminal α-galactosyl residues are present at the invasion front abutting the junctional zone of the endometrium. Abundant polylactosamine on the syncytiotrophoblast basal lamina may reflect the presence of specialised adhesive interactions, while clustering of glycosylated granules apically is probably associated with secretion and absorption of material via maternal vasculature. It is suggested that lamellar and invasive cytotrophoblast represent distinct differentiation pathways. 246 words.
... Sialic acid acetylation also reduces the activity of human neuraminidases 44 , which may fine-tune antibody half-life and optimize embryogenesis, as forced expression of sialic-acid-deacetylating enzymes in mice is associated with tissue-specific developmental defects 45 . Suppressed expansion of maternal B cells with fetal specificity by CD22 during murine pregnancy 46 , and the increased expression of placental SIAE during human pregnancy complications such as pre-eclampsia 25 , together suggest that modulation of sialic acid acetylation promotes fetal tolerance. Acetylated sialic acid is also the target for several viral attachment proteins 20 , and SIAE upregulation during pregnancy may therefore decrease infection susceptibility. ...
Adaptive immune components are thought to exert non-overlapping roles in antimicrobial host defence, with antibodies targeting pathogens in the extracellular environment and T cells eliminating infection inside cells1,2. Reliance on antibodies for vertically transferred immunity from mothers to babies may explain neonatal susceptibility to intracellular infections3,4. Here we show that pregnancy-induced post-translational antibody modification enables protection against the prototypical intracellular pathogen Listeria monocytogenes. Infection susceptibility was reversed in neonatal mice born to preconceptually primed mothers possessing L. monocytogenes-specific IgG or after passive transfer of antibodies from primed pregnant, but not virgin, mice. Although maternal B cells were essential for producing IgGs that mediate vertically transferred protection, they were dispensable for antibody acquisition of protective function, which instead required sialic acid acetyl esterase⁵ to deacetylate terminal sialic acid residues on IgG variable-region N-linked glycans. Deacetylated L. monocytogenes-specific IgG protected neonates through the sialic acid receptor CD226,7, which suppressed IL-10 production by B cells leading to antibody-mediated protection. Consideration of the maternal–fetal dyad as a joined immunological unit reveals protective roles for antibodies against intracellular infection and fine-tuned adaptations to enhance host defence during pregnancy and early life.
