RESUMO
Prenatal administration of monoclonal antibodies (mAbs) is a strategy that could be exploited to prevent viral infections during pregnancy and early life. To reach protective levels in fetuses, mAbs must be transported across the placenta, a selective barrier that actively and specifically promotes the transfer of antibodies (Abs) into the fetus through the neonatal Fc receptor (FcRn). Because FcRn also regulates Ab half-life, Fc mutations like the M428L/N434S, commonly known as LS mutations, and others have been developed to enhance binding affinity to FcRn and improve drug pharmacokinetics. We hypothesized that these FcRn-enhancing mutations could similarly affect the delivery of therapeutic Abs to the fetus. To test this hypothesis, we measured the transplacental transfer of leronlimab, an anti-CCR5 mAb, in clinical development for preventing HIV infections, using pregnant rhesus macaques to model in utero mAb transfer. We also generated a stabilized and FcRn-enhanced form of leronlimab, termed leronlimab-PLS. Leronlimab-PLS maintained higher levels within the maternal compartment while also reaching higher mAb levels in the fetus and newborn circulation. Further, a single dose of leronlimab-PLS led to complete CCR5 receptor occupancy in mothers and newborns for almost a month after birth. These findings support the optimization of FcRn interactions in mAb therapies designed for administration during pregnancy.
Assuntos
Feto , Antígenos de Histocompatibilidade Classe I , Macaca mulatta , Receptores CCR5 , Receptores Fc , Animais , Gravidez , Receptores Fc/genética , Receptores Fc/imunologia , Receptores Fc/metabolismo , Feminino , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/imunologia , Feto/imunologia , Receptores CCR5/genética , Receptores CCR5/imunologia , Animais Recém-Nascidos , Humanos , Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/genética , Infecções por HIV/imunologia , Infecções por HIV/tratamento farmacológico , Infecções por HIV/genética , Troca Materno-Fetal/imunologia , Mutação , Anticorpos Anti-HIV/imunologia , Anticorpos Anti-HIV/genética , Antagonistas dos Receptores CCR5/farmacologia , Anticorpos Monoclonais Humanizados/imunologiaRESUMO
Mother and child are immunologically interconnected by mechanisms that we are only beginning to understand. During pregnancy, multiple molecular and cellular factors of maternal origin are transferred across the placenta and influence the development and function of the fetal and newborn immune system. Altered maternal immune states arising from pregnancy-associated infections or immunizations have the potential to program offspring immune function in ways that may have long-term health consequences. In this study, we review current literature on the impact of prenatal infection and vaccination on the developing immune system, highlight knowledge gaps, and look to the horizon to envision maternal interventions that could benefit both the mother and her child.
Assuntos
Vacinação , Humanos , Gravidez , Feminino , Recém-Nascido , Placenta/imunologia , Sistema Imunitário/imunologia , Complicações Infecciosas na Gravidez/imunologia , Troca Materno-Fetal/imunologia , Mães , Criança , Feto/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologiaRESUMO
The contribution of placental immune responses to congenital Zika virus (ZIKV) syndrome remains poorly understood. Here, we leveraged a mouse model of ZIKV infection to identify mechanisms of innate immune restriction exclusively in the fetal compartment of the placenta. ZIKV principally infected mononuclear trophoblasts in the junctional zone, which was limited by mitochondrial antiviral-signaling protein (MAVS) and type I interferon (IFN) signaling mechanisms. Single nuclear RNA sequencing revealed MAVS-dependent expression of IFN-stimulated genes (ISGs) in spongiotrophoblasts but not in other placental cells that use alternate pathways to induce ISGs. ZIKV infection of Ifnar1-/- or Mavs-/- placentas was associated with greater infection of the adjacent immunocompetent decidua, and heterozygous Mavs+/- or Ifnar1+/- dams carrying immunodeficient fetuses sustained greater maternal viremia and tissue infection than dams carrying wild-type fetuses. Thus, MAVS-IFN signaling in the fetus restricts ZIKV infection in junctional zone trophoblasts, which modulates dissemination and outcome for both the fetus and the pregnant mother.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal , Decídua , Feto , Interferon Tipo I , Placenta , Receptor de Interferon alfa e beta , Transdução de Sinais , Trofoblastos , Infecção por Zika virus , Zika virus , Feminino , Animais , Gravidez , Interferon Tipo I/metabolismo , Interferon Tipo I/imunologia , Transdução de Sinais/imunologia , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/genética , Placenta/imunologia , Placenta/virologia , Placenta/metabolismo , Infecção por Zika virus/imunologia , Infecção por Zika virus/virologia , Zika virus/imunologia , Zika virus/fisiologia , Camundongos , Decídua/imunologia , Decídua/virologia , Decídua/metabolismo , Feto/imunologia , Feto/virologia , Trofoblastos/imunologia , Trofoblastos/virologia , Trofoblastos/metabolismo , Receptor de Interferon alfa e beta/genética , Receptor de Interferon alfa e beta/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , Imunidade Inata , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/virologia , Modelos Animais de DoençasRESUMO
In utero gene editing (IUGE) is a potential treatment for inherited diseases that cause pathology before or soon after birth. Preexisting immunity to adeno-associated virus (AAV) vectors and Cas9 endonuclease may limit postnatal gene editing. The tolerogenic fetal immune system minimizes a fetal immune barrier to IUGE. However, the ability of maternal immunity to limit fetal gene editing remains a question. We investigated whether preexisting maternal immunity to AAV or Cas9 impairs IUGE. Using a combination of fluorescent reporter mice and a murine model of a metabolic liver disease, we demonstrated that maternal anti-AAV IgG antibodies were efficiently transferred from dam to fetus and impaired IUGE in a maternal titer-dependent fashion. By contrast, maternal cellular immunity was inefficiently transferred to the fetus, and neither maternal cellular nor humoral immunity to Cas9 impaired IUGE. Using human umbilical cord and maternal blood samples collected from mid- to late-gestation pregnancies, we demonstrated that maternal-fetal transmission of anti-AAV IgG was inefficient in midgestation compared with term, suggesting that the maternal immune barrier to clinical IUGE would be less relevant at midgestation. These findings support immunologic advantages for IUGE and inform maternal preprocedural testing protocols and exclusion criteria for future clinical trials.
Assuntos
Dependovirus , Edição de Genes , Animais , Feminino , Dependovirus/genética , Dependovirus/imunologia , Camundongos , Gravidez , Humanos , Imunoglobulina G/imunologia , Imunoglobulina G/genética , Imunoglobulina G/sangue , Proteína 9 Associada à CRISPR/genética , Proteína 9 Associada à CRISPR/imunologia , Vetores Genéticos/imunologia , Troca Materno-Fetal/imunologia , Troca Materno-Fetal/genética , Anticorpos Antivirais/imunologia , Anticorpos Antivirais/sangue , Sistemas CRISPR-Cas , Feto/imunologia , Imunidade Materno-Adquirida/imunologiaRESUMO
Porcine reproductive and respiratory syndrome (PRRS) is one of the costliest diseases to pork producers worldwide. We tested samples from the pregnant gilt model (PGM) to better understand the fetal response to in-utero PRRS virus (PRRSV) infection. Our goal was to identify critical tissues and genes associated with fetal resilience or susceptibility. Pregnant gilts (N=22) were infected with PRRSV on day 86 of gestation. At 21 days post maternal infection, the gilts and fetuses were euthanized, and fetal tissues collected. Fetuses were characterized for PRRS viral load in fetal serum and thymus, and preservation status (viable or meconium stained: VIA or MEC). Fetuses (N=10 per group) were compared: uninfected (UNIF; <1â¯log/µL PRRSV RNA), resilient (HV_VIA, >5â¯log virus/µL but viable), and susceptible (HV_MEC, >5â¯log virus/µL with MEC). Gene expression in fetal heart, kidney, and liver was investigated using NanoString transcriptomics. Gene categories investigated were hypothesized to be involved in fetal response to PRRSV infection: renin- angiotensin-aldosterone, inflammatory, transporter and metabolic systems. Following PRRSV infection, CCL5 increased expression in heart and kidney, and ACE2 decreased expression in kidney, each associated with fetal PRRS susceptibility. Liver revealed the most significant differential gene expression: CXCL10 decreased and IL10 increased indicative of immune suppression. Increased liver gene expression indicated potential associations with fetal PRRS susceptibility on several systems including blood pressure regulation (AGTR1), energy metabolism (SLC16A1 and SLC16A7), tissue specific responses (KL) and growth modulation (TGFB1). Overall, analyses of non-lymphoid tissues provided clues to mechanisms of fetal compromise following maternal PRRSV infection.
Assuntos
Resistência à Doença , Feto , Síndrome Respiratória e Reprodutiva Suína , Transcriptoma , Síndrome Respiratória e Reprodutiva Suína/imunologia , Vírus da Síndrome Respiratória e Reprodutiva Suína/imunologia , Resistência à Doença/genética , Resistência à Doença/imunologia , Gravidez , Animais , Suínos , Feminino , Feto/imunologia , Feto/virologia , Regulação da Expressão Gênica/imunologia , Miocárdio/imunologia , Fígado/imunologia , Suscetibilidade a Doenças/imunologia , Complicações Infecciosas na Gravidez/imunologia , Complicações Infecciosas na Gravidez/veterinária , Rim/imunologiaRESUMO
Introduction: Maternal intervillous monocytes (MIMs) and fetal Hofbauer cells (HBCs) are myeloid-derived immune cells at the maternal-fetal interface. Maternal reproductive history is associated with differential risk of pregnancy complications. The molecular phenotypes and roles of these distinct monocyte/macrophage populations and the influence of gravidity on these phenotypes has not been systematically investigated. Methods: Here, we used RNA sequencing to study the transcriptional profiles of MIMs and HBCs in normal term pregnancies. Results: Our analyses revealed distinct transcriptomes of MIMs and HBCs. Genes involved in differentiation and cell organization pathways were more highly expressed in MIMs vs. HBCs. In contrast, HBCs had higher expression of genes involved in inflammatory responses and cell surface receptor signaling. Maternal gravidity influenced monocyte programming, as expression of pro-inflammatory molecules was significantly higher in MIMs from multigravidae compared to primigravidae. In HBCs, multigravidae displayed enrichment of gene pathways involved in cell-cell signaling and differentiation. Discussion: Our results demonstrated that MIMs and HBCs have highly divergent transcriptional signatures, reflecting their distinct origins, locations, functions, and roles in inflammatory responses. Furthermore, maternal gravidity influences the gene signatures of MIMs and HBCs, potentially modulating the interplay between tolerance and trained immunity. The phenomenon of reproductive immune memory may play a novel role in the differential susceptibility of primigravidae to pregnancy complications.
Assuntos
Macrófagos , Placenta , Transcriptoma , Feminino , Gravidez , Humanos , Macrófagos/imunologia , Macrófagos/metabolismo , Placenta/imunologia , Placenta/metabolismo , Perfilação da Expressão Gênica , Feto/imunologia , Adulto , Monócitos/imunologia , Monócitos/metabolismoRESUMO
Maternal obesity and over/undernutrition can have a long-lasting impact on offspring health during critical periods in the first 1000 days of life. Children born to mothers with obesity have reduced immune responses to stimuli which increase susceptibility to infections. Recently, maternal western-style diets (WSDs), high in fat and simple sugars, have been associated with skewing neonatal immune cell development, and recent evidence suggests that dysregulation of innate immunity in early life has long-term consequences on metabolic diseases and behavioral disorders in later life. Several factors contribute to abnormal innate immune tolerance or trained immunity, including changes in gut microbiota, metabolites, and epigenetic modifications. Critical knowledge gaps remain regarding the mechanisms whereby these factors impact fetal and postnatal immune cell development, especially in precursor stem cells in bone marrow and fetal liver. Components of the maternal microbiota that are transferred from mothers consuming a WSD to their offspring are understudied and identifying cause and effect on neonatal innate and adaptive immune development needs to be refined. Tools including single-cell RNA-sequencing, epigenetic analysis, and spatial location of specific immune cells in liver and bone marrow are critical for understanding immune system programming. Considering the vital role immune function plays in offspring health, it will be important to understand how maternal diets can control developmental programming of innate and adaptive immunity.
Assuntos
Dieta Ocidental , Desenvolvimento Fetal , Efeitos Tardios da Exposição Pré-Natal , Humanos , Feminino , Gravidez , Dieta Ocidental/efeitos adversos , Animais , Desenvolvimento Fetal/imunologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Sistema Imunitário/imunologia , Sistema Imunitário/metabolismo , Epigênese Genética , Microbioma Gastrointestinal/imunologia , Imunidade Inata , Fenômenos Fisiológicos da Nutrição Materna , Feto/imunologiaRESUMO
OBJECTIVE: To investigate the situation of women's dietary quality during pregnancy and explore the correlations between maternal dietary index and fetal immune function. METHODS: From September 2010 to February 2011, pregnant women who had routine physical examination in Yuexiu District and Baiyun District Maternal and Child Health Hospital of Guangzhou were recruited as study objects to use 3-day 24-hour dietary review to investigate diet during pregnancy, and general demographic information of pregnant women was collected through questionnaire, and the neonatal umbilical cord blood was collected during delivery. Laboratory detection of immunological indicators included IgG, IgA, IgM, IFN-γ and IL-6. The quality of diet during pregnancy was evaluated by diet quality index for pregnancy(DQI-P), dietary balance index for pregnancy(DBI-P) and alternate Medierranean diet score(aMED). Spearman correlation analysis and multiple linear regression analysis were used to explore the correlations between dietary quality during pregnancy and fetal immune function. RESULTS: The mean score of total DQI-P score of the study subjects was 55.8±10.0, and the mean score of overall food diversity and protein food source diversity was as high as 12.0±2.4 and 4.8±0.7. The mean score of nutrient energy ratio and fatty acid energy ratio was only 0.3±1.0 and 0.4±1.0, indicating that the population had good dietary diversity during pregnancy, but the dietary adequacy, suitability and balance were poor. The total score of DBI-P score was-19.2±9.4. The positive end score was 4.6±2.9, only 7.2% of the subjects had a high degree of dietary intake during pregnancy. The negative end score was 23.9±7.9, indicating the status of moderate dietary intake. Dietary quality was 28.5±7.1. Only 0.6% of the study population had a balanced dietary situation, and more than 67.9% of pregnant women had high intake imbalance. The mean total score of aMED score was 4.9±1.3, and the proportion of the food intake of beans and nuts was less than the median population was 62.5% and 79.1%, respectively, indicating that the food intake of beans and nuts was insufficient in this population. After adjusting for confounding factors such as maternal age, parity, parity, prepregnancy BMI, weight gain during pregnancy, and mode of delivery, multiple linear regression analysis showed DQI-P during pregnancy and negatively with IL-6(ß=0.143, ß=-0.155, P<0.05). DBI-P was negatively associated with IL-6(ß=-0.177, P<0.01) and aMED and IFN-γ(ß=-0.161, P<0.01). CONCLUSION: The dietary quality of women in late pregnancy in Guangzhou is low, the dietary structure is unbalanced. Higher dietary quality during pregnancy can promote the development of fetal immune system and improve fetal immune function.
Assuntos
Dieta , Humanos , Feminino , Gravidez , China , Adulto , Feto/imunologia , Inquéritos e Questionários , Sangue Fetal/imunologia , Sangue Fetal/química , Fenômenos Fisiológicos da Nutrição Materna , Inquéritos sobre Dietas , Interleucina-6/sangueRESUMO
BACKGROUND AND AIM: Autoimmunity refers to the presence of autoantibodies and autoreactive lymphocytes against the structural molecules of an individual's cells or tissues, known as self-antigens or autoantigens. It might exist in the absence of autoimmune disease. However, how autoimmunity develops remains a mystery, despite the discovery of autoantibodies in human cord blood. METHODS: Murine fetuses on day 14 of gestation were subjected to intraperitoneal injection of murine thyroid peroxidase (TPO) peptides or collagen type II (CII) at graded doses via transuterine approach. Postnatally, the recipients were examined for autoantibodies by ELISA and autoreactive lymphocytes by in vitro incorporation of tritium and for the development of autoimmune thyroiditis or arthritis. RESULTS: At one month of age, the recipients did not secrete significant levels of anti-TPO or CII IgG2a in sera until a dose of 0.5 µg TPO or 5.0 µg CII was injected in utero. Serum anti-TPO or CII IgG2a persisted for at least two to four months postnatally. In recipients with elevated autoantibodies, their lymphocytes also showed proliferative responses specifically to TPO or CII. However, the development of autoantibodies and autoreactive lymphocytes was not associated with inflammatory cell infiltration of thyroid glands or paw joints even though anti-TPO or CII IgG2a was enhanced by postnatal TPO or CII challenge. CONCLUSION: Fetal exposure to free autoantigens could be immunogenic, shedding new light on the in utero origin of autoantibodies and autoreactive lymphocytes. The development of autoimmunity requires a threshold intensity of autoantigen exposure in the fetus.
Assuntos
Autoanticorpos , Autoantígenos , Autoimunidade , Feto , Iodeto Peroxidase , Animais , Autoantígenos/imunologia , Autoimunidade/imunologia , Feminino , Camundongos , Autoanticorpos/imunologia , Autoanticorpos/sangue , Iodeto Peroxidase/imunologia , Gravidez , Feto/imunologia , Colágeno Tipo II/imunologia , Imunoglobulina G/imunologia , Imunoglobulina G/sangue , Linfócitos/imunologia , Tireoidite Autoimune/imunologiaRESUMO
Rodent models of maternal immune activation (MIA) are increasingly used as experimental tools in preclinical research of immune-mediated neurodevelopmental disorders and mental illnesses. Using a viral-like MIA model that is based on prenatal poly(I:C) exposure in mice, we have recently identified the existence of subgroups of MIA-exposed offspring that show dissociable behavioral, transcriptional, brain network and inflammatory profiles even under conditions of genetic homogeneity and identical MIA. Here, we tested the hypothesis that the intrauterine positions of fetuses, which are known to shape individual variability in litter-bearing mammals through variations in fetal hormone exposure, may contribute to the variable outcomes of MIA in mice. MIA was induced by maternal administration of poly(I:C) on gestation day 12 in C57BL/6N mice. Determining intrauterine positions using delivery by Cesarean section (C-section), we found that MIA-exposed offspring developing between female fetuses only (0M-MIA offspring) displayed significant deficits in sociability and sensorimotor gating at adult age, whereas MIA-exposed offspring developing between one or two males in utero (1/2M-MIA offspring) did not show the same deficits. These intrauterine position effects similarly emerged in male and female offspring. Furthermore, while MIA elevated fetal brain levels of pro- and anti-inflammatory cytokines independently of the precise intrauterine position and sex of adjacent fetuses during the acute phase, fetal brain levels of TNF-α remained elevated in 0M-MIA but not 1/2M-MIA offspring until the post-acute phase in late gestation. As expected, 1/2M offspring generally showed higher testosterone levels in the fetal brain during late gestation as compared to 0M offspring, confirming the transfer of testosterone from male fetuses to adjacent male or female fetuses. Taken together, our findings identify a novel source of within-litter variability contributing to heterogeneous outcomes of short- and long-term effects in a mouse model of MIA. In broader context, our findings highlight that individual differences in fetal exposure to hormonal and inflammatory signals may be a perinatal factor that shapes risk and resilience to MIA.
Assuntos
Encéfalo , Modelos Animais de Doenças , Camundongos Endogâmicos C57BL , Poli I-C , Efeitos Tardios da Exposição Pré-Natal , Animais , Feminino , Gravidez , Camundongos , Masculino , Poli I-C/farmacologia , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Encéfalo/metabolismo , Encéfalo/imunologia , Citocinas/metabolismo , Transtornos do Neurodesenvolvimento/imunologia , Comportamento Animal/fisiologia , Feto/imunologia , Feto/metabolismo , Útero/metabolismo , Útero/imunologiaRESUMO
The fetal development of organs and functions is vulnerable to perturbation by maternal inflammation which may increase susceptibility to disorders after birth. Because it is not well understood how the placenta and fetus respond to acute lung- inflammation, we characterize the response to maternal pulmonary lipopolysaccharide exposure across 24 h in maternal and fetal organs using multi-omics, imaging and integrative analyses. Unlike maternal organs, which mount strong inflammatory immune responses, the placenta upregulates immuno-modulatory genes, in particular the IL-6 signaling suppressor Socs3. Similarly, we observe no immune response in the fetal liver, which instead displays metabolic changes, including increases in lipids containing docosahexaenoic acid, crucial for fetal brain development. The maternal liver and plasma display similar metabolic alterations, potentially increasing bioavailability of docosahexaenoic acid for the mother and fetus. Thus, our integrated temporal analysis shows that systemic inflammation in the mother leads to a metabolic perturbation in the fetus.
Assuntos
Feto , Lipopolissacarídeos , Fígado , Pulmão , Placenta , Feminino , Gravidez , Placenta/metabolismo , Placenta/imunologia , Animais , Feto/imunologia , Feto/metabolismo , Pulmão/imunologia , Pulmão/metabolismo , Fígado/metabolismo , Fígado/imunologia , Ácidos Docosa-Hexaenoicos/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/metabolismo , Proteína 3 Supressora da Sinalização de Citocinas/genética , Camundongos , Inflamação/imunologia , Inflamação/metabolismo , Camundongos Endogâmicos C57BL , Adaptação Fisiológica/imunologia , Desenvolvimento Fetal/imunologia , Troca Materno-Fetal/imunologia , Interleucina-6/metabolismo , Interleucina-6/imunologiaRESUMO
Pregnancy is a remarkable event where the semi-allogeneic fetus develops in the mother's uterus, despite genetic and immunological differences. The antigen handling and processing at the maternal-fetal interface during pregnancy appear to be crucial for the adaptation of the maternal immune system and for tolerance to the developing fetus and placenta. Maternal antigen-presenting cells (APCs), such as macrophages (Mφs) and dendritic cells (DCs), are present at the maternal-fetal interface throughout pregnancy and are believed to play a crucial role in this process. Despite numerous studies focusing on the significance of Mφs, there is limited knowledge regarding the contribution of DCs in fetomaternal tolerance during pregnancy, making it a relatively new and growing field of research. This review focuses on how the behavior of DCs at the maternal-fetal interface adapts to pregnancy's unique demands. Moreover, it discusses how DCs interact with other cells in the decidual leukocyte network to regulate uterine and placental homeostasis and the local maternal immune responses to the fetus. The review particularly examines the different cell lineages of DCs with specific surface markers, which have not been critically reviewed in previous publications. Additionally, it emphasizes the impact that even minor disruptions in DC functions can have on pregnancy-related complications and proposes further research into the potential therapeutic benefits of targeting DCs to manage these complications.
Assuntos
Células Dendríticas , Tolerância Imunológica , Troca Materno-Fetal , Placenta , Humanos , Gravidez , Células Dendríticas/imunologia , Feminino , Troca Materno-Fetal/imunologia , Placenta/imunologia , Feto/imunologia , Animais , Macrófagos/imunologia , Complicações na Gravidez/imunologiaRESUMO
ABSTRACT: Normal pregnancy is a contradictory and complicated physiological process. Although the fetus carries the human leukocyte antigen (HLA) inherited from the paternal line, it does not cause maternal immune rejection. As the only exception to immunological principles, maternal-fetal immune tolerance has been a reproductive immunology focus. In early pregnancy, fetal extravillous trophoblast cells (EVTs) invade decidual tissues and come into direct contact with maternal decidual immune cells (DICs) and decidual stromal cells (DSCs) to establish a sophisticated maternal-fetal crosstalk. This study reviews previous research results and focuses on the establishment and maintenance mechanism of maternal-fetal tolerance based on maternal-fetal crosstalk. Insights into maternal-fetal tolerance will not only improve understanding of normal pregnancy but will also contribute to novel therapeutic strategies for recurrent spontaneous abortion, pre-eclampsia, and premature birth.
Assuntos
Tolerância Imunológica , Humanos , Gravidez , Feminino , Tolerância Imunológica/imunologia , Troca Materno-Fetal/imunologia , Decídua/imunologia , Trofoblastos/imunologia , Feto/imunologiaRESUMO
Skin, the largest organ of body, is a highly immunogenic tissue with a diverse collection of immune cells. Highly polymorphic human leukocyte antigen (HLA) molecules have a central role in coordinating immune responses as recognition molecules. Nevertheless, HLA gene expression patterns among diverse cell types within a specific organ, like the skin, have yet to be thoroughly investigated, with stromal cells attracting much less attention than immune cells. To illustrate HLA expression profiles across different cell types in the skin, we performed single-cell RNA sequencing (scRNA-seq) analyses on skin datasets, covering adult and fetal skin, and hair follicles as the skin appendages. We revealed the variation in HLA expression between different skin populations by examining normal adult skin datasets. Moreover, we evaluated the potential immunogenicity of multiple skin populations based on the expression of classical HLA class I genes, which were well represented in all cell types. Furthermore, we generated scRNA-seq data of developing skin from fetuses of 15 post conception weeks (PCW), 17 PCW, and 22 PCW, delineating the dynamic expression of HLA genes with cell type-dependent variation among various cell types during development. Notably, the pseudotime trajectory analysis unraveled the significant variance in HLA genes during the evolution of vascular endothelial cells. Moreover, we uncovered the immune-privileged properties of hair follicles at single-cell resolution. Our study presents a comprehensive single-cell transcriptomic landscape of HLA genes in the skin, which provides new insights into variation in HLA molecules and offers a clue for allogeneic skin transplantation.
Assuntos
Perfilação da Expressão Gênica , Antígenos HLA , Análise de Célula Única , Pele , Transcriptoma , Humanos , Pele/imunologia , Pele/metabolismo , Antígenos HLA/genética , Antígenos HLA/imunologia , Folículo Piloso/imunologia , Folículo Piloso/metabolismo , Feto/imunologia , Adulto , Privilégio ImunológicoRESUMO
Proper development of mucosal immunity is critical for human health. Over the past decade, it has become evident that in humans, this process begins in utero. However, there are limited data on the unique features and functions of fetal mucosal immune cells. To address this gap, we integrated several single-cell ribonucleic acid sequencing datasets of the human small intestine (SI) to create an SI transcriptional atlas throughout the human life span, ranging from the first trimester to adulthood, with a focus on immune cells. Fetal SI displayed a complex immune landscape comprising innate and adaptive immune cells that exhibited distinct transcriptional programs from postnatal samples, especially compared with pediatric and adult samples. We identified shifts in myeloid populations across gestation and progression of memory T-cell states throughout the human lifespan. In particular, there was a marked shift of memory T cells from those with stem-like properties in the fetal samples to fully differentiated cells with a high expression of activation and effector function genes in adult samples, with neonatal samples containing both features. Finally, we demonstrate that the SI developmental atlas can be used to elucidate improper trajectories linked to mucosal diseases by implicating developmental abnormalities underlying necrotizing enterocolitis, a severe intestinal complication of prematurity. Collectively, our data provide valuable resources and important insights into intestinal immunity that will facilitate regenerative medicine and disease understanding.
Assuntos
Feto , Intestino Delgado , Análise de Célula Única , Humanos , Intestino Delgado/imunologia , Intestino Delgado/metabolismo , Feto/imunologia , Adulto , Criança , Células T de Memória/imunologia , Células T de Memória/metabolismo , Adolescente , Feminino , Pré-Escolar , Imunidade nas Mucosas , Lactente , Recém-Nascido , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Transcriptoma , Enterocolite Necrosante/imunologia , Enterocolite Necrosante/genética , Imunidade Inata , Imunidade Adaptativa , Perfilação da Expressão Gênica , Gravidez , Diferenciação Celular , Memória ImunológicaRESUMO
Shifting pools of antigen can influence pregnancy-induced immune tolerance.
Assuntos
Quimerismo , Feto , Tolerância Imunológica , Troca Materno-Fetal , Criança , Feminino , Humanos , Gravidez , Troca Materno-Fetal/imunologia , Antígenos/imunologia , Feto/citologia , Feto/imunologiaRESUMO
Pregnancy confers partner-specific protection against complications in future pregnancy that parallel persistence of fetal microchimeric cells (FMcs) in mothers after parturition. We show that preexisting FMcs become displaced by new FMcs during pregnancy and that FMc tonic stimulation is essential for expansion of protective fetal-specific forkhead box P3 (FOXP3)-positive regulatory T cells (Treg cells). Maternal microchimeric cells and accumulation of Treg cells with noninherited maternal antigen (NIMA) specificity are similarly overturned in daughters after pregnancy, highlighting a fixed microchimeric cell niche. Whereas NIMA-specific tolerance is functionally erased by pregnancy, partner-specific resiliency against pregnancy complications persists in mothers despite paternity changes in intervening pregnancy. Persistent fetal tolerance reflects FOXP3 expression plasticity, which allows mothers to more durably remember their babies, whereas daughters forget their mothers with new pregnancy-imprinted immunological memories.
Assuntos
Quimerismo , Feto , Tolerância Imunológica , Memória Imunológica , Troca Materno-Fetal , Gravidez , Animais , Feminino , Camundongos , Gravidez/imunologia , Antígenos/imunologia , Plasticidade Celular , Feto/citologia , Feto/imunologia , Fatores de Transcrição Forkhead/imunologia , Troca Materno-Fetal/imunologia , Camundongos Endogâmicos C57BL , Linfócitos T Reguladores/imunologiaAssuntos
Transfusão Feto-Materna , Doença Enxerto-Hospedeiro , Complicações na Gravidez , Humanos , Feto/imunologia , Doença Enxerto-Hospedeiro/imunologia , Transplante de Células-Tronco Hematopoéticas , Feminino , Gravidez , Complicações na Gravidez/imunologia , Transfusão Feto-Materna/complicações , Transfusão Feto-Materna/imunologiaRESUMO
BACKGROUND: Anti-s is a rare alloantibody, and the reported cases of hemolytic disease of the fetus and newborn (HDFN) caused by anti-s are limited to non-Asian populations. METHODS: Here, we report the case of a Chinese woman with a history of multiple pregnancies who developed an alloantibody with anti-s specificity. RESULTS: Her newborn developed HDFN caused by anti-s but the clinical symptoms were not serious. After supportive treatment and bilirubin light phototherapy, the baby was discharged with a good prognosis. CONCLUSIONS: This is the first reported case of anti-s-induced HDFN in a Chinese patient, highlighting the need for further research in the Asian population.
Assuntos
Antígenos de Grupos Sanguíneos , População do Leste Asiático , Eritroblastose Fetal , Isoanticorpos , Feminino , Humanos , Recém-Nascido , Gravidez , Eritroblastose Fetal/diagnóstico , Eritroblastose Fetal/etiologia , Eritroblastose Fetal/imunologia , Eritroblastose Fetal/terapia , Feto/imunologia , Hemólise/imunologia , Isoanticorpos/imunologia , Antígenos de Grupos Sanguíneos/imunologia , FototerapiaRESUMO
Whether the human fetus and the prenatal intrauterine environment (amniotic fluid and placenta) are stably colonized by microbial communities in a healthy pregnancy remains a subject of debate. Here we evaluate recent studies that characterized microbial populations in human fetuses from the perspectives of reproductive biology, microbial ecology, bioinformatics, immunology, clinical microbiology and gnotobiology, and assess possible mechanisms by which the fetus might interact with microorganisms. Our analysis indicates that the detected microbial signals are likely the result of contamination during the clinical procedures to obtain fetal samples or during DNA extraction and DNA sequencing. Furthermore, the existence of live and replicating microbial populations in healthy fetal tissues is not compatible with fundamental concepts of immunology, clinical microbiology and the derivation of germ-free mammals. These conclusions are important to our understanding of human immune development and illustrate common pitfalls in the microbial analyses of many other low-biomass environments. The pursuit of a fetal microbiome serves as a cautionary example of the challenges of sequence-based microbiome studies when biomass is low or absent, and emphasizes the need for a trans-disciplinary approach that goes beyond contamination controls by also incorporating biological, ecological and mechanistic concepts.