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Single-cell genomics studies have decoded the immune cell composition of several human prenatal organs but were limited in describing the developing immune system as a distributed network across tissues. We profiled nine prenatal tissues combining single-cell RNA sequencing, antigen-receptor sequencing, and spatial transcriptomics to reconstruct the developing human immune system. This revealed the late acquisition of immune-effector functions by myeloid and lymphoid cell subsets and the maturation of monocytes and T cells before peripheral tissue seeding. Moreover, we uncovered system-wide blood and immune cell development beyond primary hematopoietic organs, characterized human prenatal B1 cells, and shed light on the origin of unconventional T cells. Our atlas provides both valuable data resources and biological insights that will facilitate cell engineering, regenerative medicine, and disease understanding.

At the transition from intrauterine to postnatal life, drastic alterations are mirrored by changes in cellular immunity. These changes are in part immune cell intrinsic, originate in the replacement of fetal cells, or result from global regulatory mechanisms and adaptation to changes in the tissue microenvironment. Overall, longer developmental trajectories are intersected by events related to mother-infant separation, birth cues, acquisition of microbiota and metabolic factors. Perinatal alterations particularly affect immune niches, where structures with discrete functions meet, the intestinal mucosa, epidermis and lung. Accordingly, the following questions will be addressed in this review., How does the preprogrammed development supported by endogenous cues, steer innate immune cell differentiation, adaptation to tissue structures, and immunity to infection?, How does the transition at birth impact on tissue immune make-up including its topology?, How do postnatal cues guide innate immune cell differentiation and function at immunological niches?, Competing Interests: PH, KK, LH, MS, MH No competing interests declared, (© 2021, Henneke et al.)

Immunologic tolerance refers to a state of immune nonreactivity specific to particular antigens as an important issue in the field of transplantation and the management of autoimmune diseases. Tolerance conceptually originated from Owen's observation of blood cell sharing in twin calves. Owen's conceptual framework subsequently constituted the backbone of Medawar's "actively acquired tolerance" as the major tenet of modern immunology. Based upon this knowledge, the delivery of genetically distinct hematopoietic stem cells into pre-immune fetuses represented a novel and unique approach to their engraftment without the requirement of myeloablation or immunosuppression. It might also make fetal recipients commit donor alloantigens to memory of their patterns as "self" so as to create a state of donor-specific tolerance. Over the years, the effort made experimentally or clinically toward in utero marrow transplantation could not reliably yield sufficient hematopoietic chimerism for curing candidate diseases as anticipated, nor did allogeneic graft tolerance universally develop as envisaged by Medawar following in utero exposure to various forms of alloantigens from exosomes, lymphocytes or marrow cells. Enduring graft tolerance was only conditional on a state of significant hematopoietic chimerism conferred by marrow inocula. Notably, fetal exposure to ovalbumin, oncoprotein and microbial antigens did not elicit immune tolerance, but instead triggered an event of sensitization to the antigens inoculated. These fetal immunogenic events might be clinically relevant to prenatal imprinting of atopy, immune surveillance against developmental tumorigenesis, and prenatal immunization against infectious diseases. Briefly, the immunological consequences of fetal exposure to foreign antigens could be tolerogenic or immunogenic, relying upon the type or nature of antigens introduced. Thus, the classical school of "actively acquired tolerance" might oversimplify the interactions between developing fetal immune system and antigens. Such interactions might rely upon fetal macrophages, which showed up earlier than lymphocytes and were competent to phagocytose foreign antigens so as to bridge toward antigen-specific adaptive immunity later on in life. Thus, innate fetal macrophages may be the potential basis for exploring how the immunological outcome of fetal exposure to foreign antigens is determined to improve the likelihood and reliability of manipulating fetal immune system toward tolerization or immunization to antigens., Competing Interests: The author declares that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2021 Chen.)

In humans, maternal IgGs are transferred to the fetus from the second trimester of pregnancy onwards. The transplacental delivery of maternal IgG is mediated by its binding to the neonatal Fc receptor (FcRn) after endocytosis by the syncytiotrophoblast. IgGs present in the maternal milk are also transferred to the newborn through the digestive epithelium upon binding to the FcRn. Importantly, the binding of IgGs to the FcRn is also responsible for the recycling of circulating IgGs that confers them with a long half-life. Maternally delivered IgG provides passive immunity to the newborn, for instance by conferring protective anti-flu or anti-pertussis toxin IgGs. It may, however, lead to the development of autoimmune manifestations when pathological autoantibodies from the mother cross the placenta and reach the circulation of the fetus. In recent years, strategies that exploit the transplacental delivery of antigen/IgG complexes or of Fc-fused proteins have been validated in mouse models of human diseases to impose antigen-specific tolerance, particularly in the case of Fc-fused factor VIII (FVIII) domains in hemophilia A mice or pre-pro-insulin (PPI) in the case of preclinical models of type 1 diabetes (T1D). The present review summarizes the mechanisms underlying the FcRn-mediated transcytosis of IgGs, the physiopathological relevance of this phenomenon, and the repercussion for drug delivery and shaping of the immune system during its ontogeny., (Copyright © 2020 Mimoun, Delignat, Peyron, Daventure, Lecerf, Dimitrov, Kaveri, Bayry and Lacroix-Desmazes.)

The blood and immune systems develop in parallel during early prenatal life. Waves of hematopoiesis separated in anatomical space and time give rise to circulating and tissue-resident immune cells. Previous observations have relied on animal models, which differ from humans in both their developmental timeline and exposure to microorganisms. Decoding the composition of the human immune system is now tractable using single-cell multi-omics approaches. Large-scale single-cell genomics, imaging technologies, and the Human Cell Atlas initiative have together enabled a systems-level mapping of the developing human immune system and its emergent properties. Although the precise roles of specific immune cells during development require further investigation, the system as a whole displays malleable and responsive properties according to developmental need and environmental challenge., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

There are limited data on fetal and early life development of human intestinal immunity. Using mass cytometry (CyTOF) and next-generation sequencing of B and T cell receptor (BCR and TCR) repertoires, we demonstrate complex intestinal immunity from 16 weeks' gestational age (GA). Both BCR and TCR repertoires are diverse with CDRH and CDR3β length increasing with advancing GA. The difference-from-germline, CDR insertions and/or deletions, similarly occur in utero for TCR but not BCR, suggesting earlier mucosal T than B cell maturity. Innate immunity is dominated by macrophages, dendritic cells (DCs), innate lymphoid cells (ILCs), and natural killer (NK) cells. Follicular and transitional B cells are enriched in fetuses while CD69 + IgM + B cells are abundant in infants. Both CD4 + and CD8 + T cells are abundant, capable of secreting cytokines and are phenotypically of the tissue resident memory state in utero. Our data provide the foundation for a 2nd trimester and infant intestinal immune atlas and suggest that a complex innate and adaptive immune landscape exists significantly earlier than previously reported., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The mammalian immune system is a highly complex, interactive network of cells that facilitates innate and adaptive immune responses. The neonatal immune system may be more susceptible to chemical perturbations than that of the adult. The effects of immunotoxicants during development may not be fully detected in toxicity studies performed on adult animals. Studies characterizing the ontogeny of the immune system in developing animals have shown that there are different critical windows of susceptibility to immunotoxicants. Developmental differences are evident among species compared to humans. Functional immune assays, such as the T-cell antibody dependent response assay, in rat models have been validated for use in the assessment of immunotoxicity with other assays. Recently, published studies have explored the feasibility of using additional techniques, such as in vitro studies using human whole blood cells or cell lines, mostly lacking either sensitivity or proper validation for regulatory purposes. However, some techniques may be developed further to enable translation of animal toxicity findings to human risk assessment of potential immunotoxicants. This paper summarizes the information on the developing immune system in humans versus rats and how the currently available assays might be used to contribute to the safety assessment of food contact substances., (Published by Elsevier Ltd.)

The chick immune system is a fundamental model in basic immunology. In birds, the bone marrow derived pluripotent stem cells after entering the circulation, migrate to bursa of Fabricius to benefit from a microenvironment which supports the differentiation and maturation of B lymphocytes by the help of its resident cells and tissues. Delivering sufficient functional B cells is required to maintain their peripheral population and normal peripheral humoral responses. Additionally, bursa acts as an active site for the generation of antibody diversity through gene conversion. Being consisted of 98% B lymphocytes, the organ is occupied by other cell types including T cells, macrophages, eosinophils and mast cells. Thymus, which is an epithelial organ is the main site of T cell development where positive and negative selections contribute to the development of functional and not autoreactive T cell repertoire. Bursectomy and thymectomy are surgical exercises through which the involvement of cells of specific immunity including B cells and T cells can be determined., (Copyright © 2019 Elsevier Inc. All rights reserved.)

The human fetal immune system must protect the infant against the sudden exposure to a large variety of pathogens upon birth. While it is known that the fetal immune system develops in sequential waves, relatively little is known about the composition of the innate and adaptive immune system in the tissues. Here, we applied high-dimensional mass cytometry to profile the immune system in human fetal liver, spleen, and intestine. With Hierarchical Stochastic Neighbor Embedding (HSNE) we distinguished 177 distinct immune cell clusters, including both previously identified and novel cell clusters. PCA analysis indicated substantial differences between the compositions of the immune system in the different organs. Through dual t-SNE we identified tissue-specific cell clusters, which were found both in the innate and adaptive compartment. To determine the spatial location of tissue-specific subsets we developed a 31-antibody panel to reveal both the immune compartment and surrounding stromal elements through analysis of snap-frozen tissue samples with imaging mass cytometry. Imaging mass cytometry reconstructed the tissue architecture and allowed both the characterization and determination of the location of the various immune cell clusters within the tissue context. Moreover, it further underpinned the distinctness of the immune system in the tissues. Thus, our results provide evidence for early compartmentalization of the adaptive and innate immune compartment in fetal spleen, liver, and intestine. Together, our data provide a unique and comprehensive overview of the composition and organization of the human fetal immune system in several tissues.

Gabapentin (GPT) has become an emerging contaminant in aquatic environments due to its wide application in medical treatment all over the world. In this study, embryos of zebrafish were exposed to gabapentin at realistically environmental concentrations, 0.1 μg/L and 10 μg/L, so as to evaluate the ecotoxicity of this emergent contaminant. The transcriptomics profiling of deep sequencing was employed to illustrate the mechanisms. The zebrafish (Danio rerio) embryo were exposed to GPT from 12 hpf to 96 hpf resulting in 136 and 750 genes differentially expressed, respectively. The results of gene ontology (GO) analysis and the Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis illustrated that a large amount of differentially expressed genes (DEGs) were involved in the antioxidant system, the immune system and the nervous system. RT-qPCR was applied to validate the results of RNA-seq, which provided direct evidence that the selected genes involved in those systems mentioned above were all down-regulated. Acetylcholinesterase (AChE), lysozyme (LZM) and the content of C-reactive protein (CRP) were decreased at the end of exposure, which is consistent with the transcriptomics results. The overall results of this study demonstrate that GPT simultaneously affects various vital functionalities of zebrafish at early developmental stage, even at environmentally relevant concentrations., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Important questions raised in (nano)ecotoxicology are whether biodistribution of nanoparticles (NPs) is affected by particle shape and to what extent local adverse responses are subsequently initiated. For nanomedicine, these same questions become important when the labeled NPs lose the labeling. In this study, we investigated the biodistribution patterns of gold nanoparticles (AuNPs) as well as immune-related local and systemic sublethal markers of exposure and behavioral assessment. Hatched zebrafish embryos were exposed to four differently shaped non-coated AuNPs with comparable sizes: nanospheres, nanorods, nano-urchins, and nano-bipyramids. Shape-dependent trafficking of the particles resulted in a different distribution of the particles over the target organs. The differences across the distribution patterns indicate that the particles behave slightly different, although they eventually reach the same target organs - yet in different ratios. Mainly local induction of the immune system was observed, whereas systemic immune responses were not clearly visible. Macrophages were found to take AuNPs from the body fluid, be transferred into the veins and transported to digestive organs for clearance. No significant behavioral toxicological responses in zebrafish embryos were observed after exposure. The trafficking of the particles in the macrophages indicates that the particles are removed via the mononuclear phagocytic system. The different ratios in which the particles are distributed over the target organs indicate that the shape influences their behavior and eventually possibly the toxicity of the particles. The observed shape-dependent biodistribution patterns might be beneficial for shape-specific targeting in nanomedicine and stress the importance of incorporating shape-features in nanosafety assessment.

Cannabinoids are the most commonly abused illicit drugs worldwide. While cannabis can be beneficial for certain heath conditions, abuse of potent synthetic cannabinoids has been on the rise. Exposure to cannabinoids is also prevalent in women of child-bearing age and pregnant women. These compounds can cross the placental barrier and directly affect the fetus. They mediate their effects primarily through G-protein coupled cannabinoid receptors, CB1 and CB2. In addition to significant neurological effects, cannabinoids can trigger robust immunomodulation by altering cytokine levels, causing apoptosis of lymphoid cells and inducing suppressor cells of the immune system. Profound effects of cannabinoids on the immune system as discussed in this review, suggest that maternal exposure during pregnancy could lead to dysregulation of innate and adaptive immune system of developing fetus and offspring potentially leading to weakening of immune defenses against infections and cancer later in life. Emerging evidence also indicates the underlying role of epigenetic mechanisms causing long-lasting impact following cannabinoid exposure in utero.

The microbiome modulates host immune function across the gastrointestinal tract, peripheral lymphoid organs, and central nervous system. In this review, we highlight emerging evidence that microbial effects on select immune phenotypes arise developmentally, where the maternal and neonatal microbiome influence immune cell ontogeny in the offspring during gestation and early postnatal life. We further discuss roles for the perinatal microbiome and early-life immunity in regulating normal neurodevelopmental processes. In addition, we examine evidence that abnormalities in microbiota-neuroimmune interactions during early life are associated with altered risk of neurological disorders in humans. Finally, we conclude by evaluating the potential implications of microbiota-immune interventions for neurological conditions. Continued progress toward dissecting mechanistic interactions between the perinatal microbiota, immune system, and nervous system might uncover fundamental insights into how developmental interactions across physiological systems inform later-life health and disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Preterm infants have immature organ functions that predispose them to gut and immune disorders. Developmental delays at preterm birth may affect various organs differently at term-corrected age. We hypothesized that gut and immune maturation in moderately preterm neonates depends more on birth and postnatal factors than on advancing postconceptional age (PCA). Using preterm pigs as models, we investigated how gut and immune parameters develop until term-corrected age and how these differ from those in term counterparts. Preterm ( n = 43, 106 days of gestation) and term pigs ( n = 41, 116 days of gestation) were delivered by caesarean section and euthanized at birth ( day 1) or postnatal day 11 (term-corrected age for preterm pigs) using identical rearing conditions. Relative to term pigs, preterm pigs had lower blood oxygenation, glucose, and cortisol levels, lower gut lactase activity, villus height, and goblet cell density, and lower blood neutrophil, helper T, and cytotoxic T cell numbers at birth. Despite slower growth in preterm pigs, most intestinal and immune parameters increased markedly after birth in both groups. However, some parameters remained negatively affected by preterm birth until postnatal day 11 (goblet cells, gut permeability, and cytotoxic T cells). The colon microbiota showed limited differences between preterm and term pigs at this time. At the same PCA, preterm 11-day-old pigs had higher blood leukocyte numbers and gut enzyme activities but lower villus height and blood cytotoxic T cell numbers relative to newborn term pigs. Birth and postnatal factors, not advancing PCA, are key determinants of gut and immune maturation in moderately preterm neonates. NEW & NOTEWORTHY Postnatally, preterm infants are often considered to reach a physiological maturation similar to that in term infants when they reach term-corrected postconceptional age (PCA). Using preterm pigs as models, we show that PCA may be a poor measure of gut and immune maturation because environmental triggers (regardless of PCA at birth) are critical. Possibly, PCA is only relevant to evaluate physiological maturation of organs that develop relatively independent of the external environment (e.g., the brain).

Testicular macrophages (TM) comprise the largest immune cell population in the mammalian testis. They are characterized by a subdued proinflammatory response upon adequate stimulation, and a polarization toward the immunoregulatory and immunotolerant M2 phenotype. This enables them to play a relevant role in supporting the archetypical functions of the testis, namely spermatogenesis and steroidogenesis. During infection, the characteristic blunted immune response of TM reflects the need for a delicate balance between a sufficiently strong reaction to counteract invading pathogens, and the prevention of excessive proinflammatory cytokine levels with the potential to disturb or destroy spermatogenesis. Local microenvironmental factors that determine the special phenotype of TM have just begun to be unraveled, and are discussed in this review., (©2018 Society for Leukocyte Biology.)

Introduction: Relapse of inflammatory bowel disease (IBD) during conception and pregnancy has been associated with a negative pregnancy outcome. Therefore, it is advised to maintain drugs in order to prevent relapse. The effect of drugs, which cross the placenta, on children who have been exposed during pregnancy will be discussed in this review. Areas covered: A literature search was performed using the following search terms: inflammatory bowel disease, pregnancy, infant, antitumor necrosis factor alpha, infliximab, adalimumab, golimumab, certolizumab, anti-integrins, vedolizumab, anti-interleukin (IL)-12/23 ustekinumab, placenta, vaccination. Other studies were identified by using references from articles identified through our original literature search. The occurrence of unfavorable pregnancy outcome and congenital malformations does not seem to be increased after exposure to anti-TNFα, but the effects on the developing immune system are largely unknown. For anti-integrins and anti IL-12/23, the numbers of exposed pregnancies are too small to draw any conclusions. Expert commentary: Follow-up of the developing immune system in children exposed to these drugs seems warranted, preferably in a prospective study design.

Recent lineage tracing analyses have significantly improved our understanding of immune system development and highlighted the importance of the different hematopoietic waves. The current challenge is to understand whether these waves interact and whether this affects the function of the immune system. Here we report a molecular pathway regulating the immune response and involving the communication between embryonic and larval hematopoietic waves in Drosophila . Down-regulating the transcription factor Gcm specific to embryonic hematopoiesis enhances the larval phenotypes induced by over-expressing the pro-inflammatory Jak/Stat pathway or by wasp infestation. Gcm works by modulating the transduction of the Upd cytokines to the site of larval hematopoiesis and hence the response to chronic (Jak/Stat over-expression) and acute (wasp infestation) immune challenges. Thus, homeostatic interactions control the function of the immune system in physiology and pathology. Our data also indicate that a transiently expressed developmental pathway has a long-lasting effect on the immune response., Competing Interests: WB, PC, CD, VD, RS, YY, AG No competing interests declared, (© 2018, Bazzi et al.)

Fighting external pathogens requires an ever-changing immune system that relies on tight regulation of gene expression. Transcriptional control is the first step to build efficient responses while preventing immunodeficiencies and autoimmunity. Post-transcriptional regulation of RNA editing, location, stability, and translation are the other key steps for final gene expression, and they are all controlled by RNA-binding proteins (RBPs). Nowadays we have a deep understanding of how transcription factors control the immune system but recent evidences suggest that post-transcriptional regulation by RBPs is equally important for both development and activation of immune responses. Here, we review current knowledge about how post-transcriptional control by RBPs shapes our immune system and discuss the perspective of RBPs being the key players of a hidden immune cell epitranscriptome.

X-chromosome inactivation (XCI) occurs during the gestation period to compensate for the dosage of X-linked genes in female mammals. Xist RNA is a long noncoding RNA with a global epigenetic function and is indispensable for XCI from the initiation to establishment and maintenance phases. The X chromosome contains over 1,000 genes that are essential for proper development, especially that of the brain, immune system, metabolism and reproductive functions. We found that exposure to bisphenol A or folate deficiency during the fetal period changes the expressions of Xist, Tsix (the antisense repressor of Xist), and many X chromosome linked genes widely in newborn mice. This finding suggests that this X-chromosome mediated effect is considered one of the mechanisms of various problems encountered in the fetal environment. The Developmental Origins of Health and Disease (DOHaD) hypothesis states that nutrition and other environmental stimuli during critical periods affect developmental pathways with epigenetics and induce metabolism and chronic disease susceptibility. The XCI process has some similarities to this hypothesis and it may become one of the approaches to reveal the DOHaD mechanisms.

Immune-based childhood diseases and conditions, including allergic diseases and asthma, recurrent otitis media, pediatric celiac disease, and type 1 diabetes have been on the rise over the past decades. As a result, the use of developmental immunotoxicity (DIT) testing to identify potential environmental risk factors contributing to these and other diseases has become a priority for scientists across sectors. This chapter serves to provide insight into the scientific basis for DIT and determining the necessity of DIT testing and offers recommendations for DIT testing parameters to optimize sensitivity, power, and concordance among DIT assays.

Through its role as gatekeeper and filter to the external world, the microbiome affects developmental programming of physiological systems including the immune system. In turn, the immune system must tolerate, personalize, and prune the microbiome. Immune and host barrier status in early life significantly effects everything from embryo viability and pregnancy duration to the likelihood of misregulated inflammation, and risk of noncommunicable diseases (NCDs). Since the programming of and interactions among the microbiome, the host defense barrier, and the immune system can affect inflammation-driven health risks across the lifespan, a systems biology-type understanding of these three biological components may be useful. Here, I consider the potential utility of focusing on programming of a newly-defined systems biology unit termed the "microimmunosome.", (Copyright © 2016 Elsevier Inc. All rights reserved.)

The immune system of preterm infants is immature, placing them at increased risk for serious immune-related complications. Human milk provides a variety of immune protective and immune maturation factors that are beneficial to the preterm infant's poorly developed immune system. The most studied immune components in human milk include antimicrobial proteins, maternal leukocytes, immunoglobulins, cytokines and chemokines, oligosaccharides, gangliosides, nucleotides, and long-chain polyunsaturated fatty acids. There is growing evidence that these components contribute to the lower incidence of immune-related conditions in the preterm infant. Therefore, provision of these components in human milk, donor milk, or formula may provide immunologic benefits., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Zebrafish has been used for over a decade to study the mechanisms of a wide variety of inflammatory disorders and infections, with models ranging from bacterial, viral, to fungal pathogens. Zebrafish has been especially relevant to study the differentiation, specialization, and polarization of the two main innate immune cell types, the macrophages and the neutrophils. The optical accessibility and the early appearance of myeloid cells that can be tracked with fluorescent labels in zebrafish embryos and the ability to use genetics to selectively ablate or expand immune cell populations have permitted studying the interaction between infection, development, and metabolism. Additionally, zebrafish embryos are readily colonized by a commensal flora, which facilitated studies that emphasize the requirement for immune training by the natural microbiota to properly respond to pathogens. The remarkable conservation of core mechanisms required for the recognition of microbial and danger signals and for the activation of the immune defenses illustrates the high potential of the zebrafish model for biomedical research. This review will highlight recent insight that the developing zebrafish has contributed to our understanding of host responses to invading microbes and the involvement of the microbiome in several physiological processes. These studies are providing a mechanistic basis for developing novel therapeutic approaches to control infectious diseases., (© 2017 Elsevier Inc. All rights reserved.)

TYRO3, AXL and MERTK comprise the TAM family of receptor protein tyrosine kinases. Activated by their ligands, protein S (PROS1) and growth-arrest-specific 6 (GAS6), they mediate numerous cellular functions throughout development and adulthood. Expressed by a myriad of cell types and tissues, they have been implicated in homeostatic regulation of the immune, nervous, vascular, bone and reproductive systems. The loss-of-function of TAM signaling in adult tissues culminates in the destruction of tissue homeostasis and diseased states, while TAM gain-of-function in various tumors promotes cancer phenotypes. Combinatorial ligand-receptor interactions may elicit different molecular and cellular responses. Many of the TAM regulatory functions are essentially developmental, taking place both during embryogenesis and postnatally. This review highlights current knowledge on the role of TAM receptors and their ligands during these developmental processes in the immune, nervous, vascular and reproductive systems.

Hemocytes play vital roles in the immune response. Despite progress in the characterization of molluscan hemocytes and immune cells, including their cellular receptors and signal transduction pathways, the processes that lead to their differentiation in bivalve larvae remain unknown. Furthermore, the molecular mechanisms of that decide hemocyte stem cell fate and self-renewal during development remain poorly characterized. Similar to adult mollusks, the larvae are filter feeders and are highly susceptible to pathogens and biotoxins; therefore, it is important to understand the development and function of their immune system. This review summarizes the current data on the appearance of elements of the immune system in bivalve larvae. I have discussed why the immune cells emerge before the circular blood vessel system, which differentiates at the late stages of development. I also discuss how molluscan hemocytes are involved in the development of disseminated neoplasia., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Environmental factors clearly influence the pathogenesis of Type 1 diabetes, an autoimmune disease. We have studied gut microbiota as important environmental agents that could affect the initiation or progression of type 1 diabetes especially in the prenatal period. We used neomycin, targeting mainly Gram negative or vancomycin, targeting mainly Gram positive bacteria, to treat pregnant NOD mothers and to study autoimmune diabetes development in their offspring. Neomycin-treated offspring were protected from diabetes, while vancomycin-treated offspring had accelerated diabetes development, and both antibiotics caused distinctly different shifts in gut microbiota composition compared with the offspring from untreated control mice. Our study demonstrated that neomycin treatment of pregnant mothers leads to generation of immune-tolerogenic antigen-presenting cells (APCs) in the offspring and these APCs had reduced specific autoantigen-presenting function both in vitro and in vivo. Moreover, the protection from diabetes mediated by tolerogenic APCs was vertically transmissible to the second generation. In contrast, more diabetogenic inflammatory T cells were found in the lymphoid organs of the offspring from the vancomycin-treated pregnant mothers. This change however was not transmitted to the second generation. Our results suggested that prenatal exposure to antibiotic influenced gut bacterial composition at the earliest time point in life and is critical for consequent education of the immune system. As different bacteria can induce different immune responses, understanding these differences and how to generate self-tolerogenic APCs could be important for developing new therapy for type 1 diabetes., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

The pathway to generate T cells from hematopoietic stem cells guides progenitors through a succession of fate choices while balancing differentiation progression against proliferation, stage to stage. Many elements of the regulatory system that controls this process are known, but the requirement for multiple, functionally distinct transcription factors needs clarification in terms of gene network architecture. Here, we compare the features of the T-cell specification system with the rule sets underlying two other influential types of gene network models: first, the combinatorial, hierarchical regulatory systems that generate the orderly, synchronized increases in complexity in most invertebrate embryos; second, the dueling 'master regulator' systems that are commonly used to explain bistability in microbial systems and in many fate choices in terminal differentiation. The T-cell specification process shares certain features with each of these prevalent models but differs from both of them in central respects. The T-cell system is highly combinatorial but also highly dose-sensitive in its use of crucial regulatory factors. The roles of these factors are not always T-lineage-specific, but they balance and modulate each other's activities long before any mutually exclusive silencing occurs. T-cell specification may provide a new hybrid model for gene networks in vertebrate developmental systems., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

The thymus is a primary lymphoid tissue that supports the generation of αβT cells. In this review, we describe the processes that give rise to the thymus medulla, a site that nurtures self-tolerant T-cell generation following positive selection events that take place in the cortex. To summarize the developmental pathways that generate medullary thymic epithelial cells (mTEC) from their immature progenitors, we describe work on both the initial emergence of the medulla during embryogenesis, and the maintenance of the medulla during postnatal stages. We also investigate the varying roles that receptors belonging to the tumor necrosis factor receptor superfamily have on thymus medulla development and formation, and highlight the impact that T-cell development has on thymus medulla formation. Finally, we examine the evidence that the thymic medulla plays an important role during the intrathymic generation of distinct αβT-cell subtypes. Collectively, these studies provide new insight into the development and functional importance of medullary microenvironments during self-tolerant T-cell production in the thymus., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Exposure to environmental contaminants can produce profound effects on the immune system. Many classes of xenobiotics can significantly suppress or enhance immune responsiveness depending on the levels (i.e., dose) and context (i.e., timing, route) of exposure. Although defining the effects that toxicants can have on the immune system is a valuable component to improving public health, environmental immunology has greatly enhanced our understanding of how the immune system functions and has provided innovative avenues to explore new immunotherapies. This Brief Review focuses on three examples of how immunotoxicology has benefitted the field of immunology, presenting information on the aryl hydrocarbon receptor signaling pathway, the immunomodulatory effects of nanomaterials, and the impact of xenobiotic exposure on the developing immune system. Collectively, contributions from immunotoxicology have significantly enhanced public health and spurred seminal advances in both basic and applied immunology., (Copyright © 2016 by The American Association of Immunologists, Inc.)

Background . The neonatal immune system is not fully developed at birth; newborns have adequate lymphocytes counts but these cells lack function. Objective . To assess the activity of T-cells and the influence of the main perinatal factors in very preterm infants (birth weight < 1500 g). Design . Blood samples from 59 preterm infants (21/59 were dizygotic twins) were collected at birth and at 30 days of life to measure CD4+ T-cell activity using the ImmuKnow™ assay. Fifteen healthy adults were included as a control group. Results . CD4+ T-cell activity was lower in VLBW infants compared with adults ( p < 0.001). Twins showed lower immune activity compared to singletons ( p = 0.005). Infants born vaginally showed higher CD4+ T-cell activity compared to those born by C-section ( p = 0.031); infants born after prolonged Premature Rupture of Membranes (pPROM) showed higher CD4+ T-cell activity at birth ( p = 0.002) compared to infants born without pPROM. Low CD4+ T-cell activity at birth is associated with necrotizing enterocolitis (NEC) in the first week of life ( p = 0.049). Conclusions . Preterm infants show a lack in CD4+ T-cell activity at birth. Perinatal factors such as intrauterine inflammation, mode of delivery, and zygosity can influence the adaptive immune activation capacity at birth and can contribute to exposing these infants to serious complications such as NEC., Competing Interests: All the authors declare that they have no conflict of interests in connection with this paper.

The physiology of NGF is extremely complex, and although the study of this neurotrophin began more than 60 years ago, it is far from being concluded. NGF, its precursor molecule pro-NGF, and their different receptor systems (i.e., TrkA, p75NTR, and sortilin) have key roles in the development and adult physiology of both the nervous and immune systems. Although the NGF receptor system and the pathways activated are similar for all types of cells sensitive to NGF, the effects exerted during embryonic differentiation and in committed mature cells are strikingly different and sometimes opposite. Bearing in mind the pleiotropic effects of NGF, alterations in its expression and synthesis, as well as variations in the types of receptor available and in their respective levels of expression, may have profound effects and play multiple roles in the development and progression of several diseases. In recent years, the use of NGF or of inhibitors of its receptors has been prospected as a therapeutic tool in a variety of neurological diseases and injuries. In this review, we outline the different roles played by the NGF system in various moments of nervous and immune system differentiation and physiology, from embryonic development to aging. The data collected over the past decades indicate that NGF activities are highly integrated among systems and are necessary for the maintenance of homeostasis. Further, more integrated and multidisciplinary studies should take into consideration these multiple and interactive aspects of NGF physiology in order to design new therapeutic strategies based on the manipulation of NGF and its intracellular pathways.

The reproductive and developmental toxicity of ixekizumab, a selective inhibitor of interleukin-17A (IL-17A), was assessed in the following studies in cynomolgus monkeys: fertility (3-month dosing), embryo-fetal development (EFD; dosing from gestation day (GD) 20 through 139), and pre-postnatal development (PPND; dosing from GD 20 through parturition). Because IL-17A has functional roles in innate and humoral immunity, immune system modulation was evaluated in the EFD and PPND studies; immunological evaluations in infants comprised peripheral blood immunophenotyping, Natural Killer cell cytolytic activity, and T-cell-dependent antibody (IgG and IgM) primary and secondary responses to antigen challenge. Ixekizumab exposure was sustained during the dosing periods in most adult monkeys. Fetal exposure at Cesarean section (GD 140-142; EFD study) was 18-25% of maternal exposure and ixekizumab was present in infants for up to 29 weeks postpartum. There were no adverse effects attributed to ixekizumab in any study. Importantly, immune system development and maturation were unaffected., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Our understanding of how equine immunoglobulin genes are organized has increased significantly in recent years. For equine heavy chains, 52 IGHV, 40 IGHD, 8 IGHJ and 11 IGHC are present. Seven of these IGHCs are gamma chain genes. Sequence diversity is increasing between fetal, neonatal, foal and adult age. The kappa light chain contains 60 IGKV, 5 IGKJ and 1 IGKC, whereas there are 144 IGLV, 7 IGLJ, and 7 IGLC for the lambda light chain, which is expressed predominantly in horses. Significant transcriptional differences for IGLV and IGLC are identified in different breeds. Allotypic and allelic variants are observed for IGLC1, IGLC5, and IGLC6/7, and two IGLV pseudogenes are also transcribed. During age development, a decrease in IGLVs is noted, although nucleotide diversity and significant differences in gene usage increased. The following paper suggests a standardization of the existing nomenclature of immunoglobulin genes., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Atopic diseases are a major public health problem worldwide, and several factors are thought to contribute to this rapid increase. The observed association between mode of delivery and risk of atopy in childhood has had a great deal of interest during the past few decades. In fact, even during delivery, exposure to antigens can index immune system in newborn, which induces the release of biologically active molecules, which are polarizing immune responses toward the T-helper 2 atopic profile. However, to date, studies on the relationship between mode of delivery and atopy have produced conflicting findings. The aim of this review was to summarize what is known about the relationship between mode of delivery and risk of atopic diseases in children. A literature search of electronic databases was undertaken for the major studies published from 1994 to today. The databases searched were PubMed, EMBASE, Medline, and Cochrane Library. The following key words were used: mode of delivery, cesarean section, vaginal delivery, atopy, and atopic diseases.

Population-based pregnancy cohorts recruiting women before or at the moment of childbirth allow a longitudinal follow-up on children's health later in life. Important findings arising from pregnancy cohorts are discussed in the present review. These insights have led to revised guidelines on how to minimize disease risks in children, e.g., in the context of chronic immune diseases including allergies and asthma. Moreover, insights from pregnancy cohorts also unveiled a collateral effect of pregnancy on maternal immunity, mirrored by an ameliorated course of certain autoimmune diseases, but also an increased risk of infection with influenza A virus. Future pregnancy cohort studies are still required to close gaps in knowledge on how parameters involved in the developmental origin of health or poor immunity observed in children later in life are operational. We discuss here features that should be covered by future pregnancy cohort studies. Expected insights from such studies will then lay the foundation for biomarker discovery and offer opportunities for interventions to ameliorate adverse immune responses in humans., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

While critical for normal development, the exact timing of establishment of the intestinal microbiome is unknown. For example, although preterm labor and birth have been associated with bacterial colonization of the amniotic cavity and fetal membranes for many years, the prevailing dogma of a sterile intrauterine environment during normal term pregnancies has been challenged more recently. While found to be a key contributor of evolution in the animal kingdom, maternal transmission of commensal bacteria may also constitute a critical process during healthy pregnancies in humans with yet unclear developmental importance. Metagenomic sequencing has elucidated a rich placental microbiome in normal term pregnancies likely providing important metabolic and immune contributions to the growing fetus. Conversely, an altered microbial composition during pregnancy may produce aberrant metabolites impairing fetal brain development and life-long neurological outcomes. Here we review the current understanding of microbial colonization at the feto-maternal interface and explain how normal gut colonization drives a balanced neonatal mucosal immune system, while dysbiosis contributes to aberrant immune function early in life and beyond. We discuss how maternal genetics, diet, medications, and probiotics inform the fetal microbiome in preparation for perinatal and postnatal bacterial colonization.

Evidence from research in humans and animals suggest that ingesting alcohol during pregnancy can disrupt the fetal immune system and result in an increased risk of infections and disease in newborns that may persist throughout life. Alcohol may have indirect effects on the immune system by increasing the risk of premature birth, which itself is a risk factor for immune-related problems. Animal studies suggest that alcohol exposure directly disrupts the developing immune system. A comprehensive knowledge of the mechanisms underlying alcohol's effects on the developing immune system only will become clear once researchers establish improved methods for identifying newborns exposed to alcohol in utero.

Tissue homeostasis requires a complete repertoire of functional macrophages in peripheral tissues. Recent evidence indicates that many resident tissue macrophages are seeded during embryonic development and persist through adulthood as a consequence of localized proliferation. Mononuclear phagocytes are also produced during adult hematopoiesis; these cells are then recruited to sites throughout the body, where they function in tissue repair and remodeling, resolution of inflammation, maintenance of homeostasis, and disease progression. The focus of this review is on mononuclear phagocytes that comprise the nonresident monocyte/macrophage populations in the body. Key features of monocyte differentiation are presented, focusing primarily on the developmental hierarchy that is established through this process, the markers used to identify discrete cell populations, and novel, functional attributes of these cells. These features are then explored in the context of the tumor microenvironment, where mononuclear phagocytes exhibit extensive plasticity in phenotype and function., (© 2014 Society for Leukocyte Biology.)

MicroRNAs (miRNAs) play an important role in the regulation of many fundamental biological processes in eukaryotes; however, miRNAs associated with immune functions in the common carp have not been reported. In this study, a small-RNA cDNA library was constructed from the spleen of the common carp. A total of 10,603,456 high-quality clean reads, representing 293,603 unique sequences, were obtained from the small-cDNA library using the Solexa sequencing. By the bioinformatic analysis, 194 conserved miRNAs and 12 novel miRNAs were identified in the carp spleen. The abundant miRNAs principally belong to 30 miRNA gene families such as let-7, mir-10, mir-15, mir-30, and so on. The conservation analysis showed that 23 families were present both in protostomes and deuterostomes, 46 families were conserved only in vertebrates, and 5 families (mir-430, mir-722, mir-724, mir-734, and mir-738) were identified only in fish species. Furthermore, GO enrichment analysis and KEGG pathway analysis suggested that miRNAs expressed in the spleen of common carp are involved in immune system development, lymphoid organ development, lymphocyte activation, immune response, B cell receptor signaling pathway, T cell receptor signaling pathway, Fc gamma R-mediated phagocytosis, Toll-like receptor signaling pathway, and so on. This study described the miRNA transcriptome in spleen tissue for the first time in the common carp. The results expand the number of known common carp miRNAs and provides a meaningful framework to understand the common carp immune system and defense mechanisms., (© 2014 Wiley Periodicals, Inc.)

The human immune system comprises cellular and molecular components designed to coordinately prevent infection while avoiding potentially harmful inflammation and autoimmunity. Immunity varies with age, reflecting unique age-dependent challenges including fetal gestation, the neonatal phase, and infancy. Here, we review novel mechanistic insights into early life immunity, with an emphasis on emerging models of human immune ontogeny, which may inform age-specific translational development of novel anti-infectives, immunomodulators, and vaccines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Sturgeon aquaculture has increased considerably worldwide but little is known about their immunological development and competence in early life stages. Culture of larvae is one of the most critical stages in intensive sturgeon farming, often associated with high mortality rates. The objective of this study was to characterize the developmental morphology (light and transmission electron microscopy, LM and TEM) of the meningeal myeloid tissue, spleen and thymus in Atlantic sturgeon (Acipenser oxyrinchus oxyrinchus) from hatching until 5 months old (2895°C·day (dd)). The spleen was first visible on 541 dd larvae LM sections and the other two immune organs in 768 dd samples (approximately 400 and 600 dd after onset of feeding). Generally, younger fish had significantly higher percentages of undifferentiated cells (meningeal myeloid tissue and spleen) and effective adaptive immune competence would not be expected in these fish on the onset of feeding, but further functional immune assessment is needed., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The current review focuses on pre- and post-natal development of intestinal immunoglobulin A (IgA) production in pig. IgA production is influenced by intrinsic genetic factors in the foetus as well as extrinsic environmental factors during the post-natal period. At birth, piglets are exposed to new antigens through maternal colostrums/milk as well as exogenous microbiota. This exposure to new antigens is critical for the proper development of the gut mucosal immune system and is characterized mainly by the establishment of IgA response. A second critical period for neonatal intestinal immune system development occurs at weaning time when the gut environment is exposed to new dietary antigens. Neonate needs to establish oral tolerance and in the absence of protective milk need to fight potential new pathogens. To improve knowledge about the immune response in the neonates, it is important to identify intrinsic and extrinsic factors which influence the intestinal immune system development and to elucidate their mechanism of action., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The intra-uterine environment provides the first regulatory connection for the developing fetus and shapes its physiological responses in preparation for postnatal life. Psychological stress acts as a programming determinant by setting functional parameters to abnormal levels, thus inducing postnatal maladaptation. The effects of prenatal maternal stress (PNMS) on the developing immune system have been documented mostly through animal studies, but inconsistent results and methodological differences have hampered the complete understanding of these findings. As the immune system follows a similar ontogenic pattern in all mammals, a translational framework based on the developmental windows of vulnerability proposed by immunotoxicology studies was created to integrate these findings. The objective of this review is to examine the available literature on PNMS and immune function in the offspring through the above framework and gain a better understanding of these results by elucidating the moderating influence of the stressor type, timing and duration, and the offspring species, sex and age at assessment. The evaluation of the literature through this framework showed that the effects of PNMS are parameter specific: the moderating effects of timing in gestation were relevant for lymphocyte population numbers, Natural Killer cell function and mitogen-induced proliferation. The presence of an important and directional sexual dimorphism was evident and the influence of the type or duration of PNMS paralleled that of stress in non-pregnant animals. In conclusion, PNMS is a relevant factor in the programming of immune function. Its consequences may be related to disorders with an important immune component such as allergies.

Maternal microchimerism, which occurs naturally during gestation in hemochorial placental mammals upon transplacental migration of maternal cells into the fetus, is suggested to significantly influence the fetal immune system. In our previous publication, we explored the sensitivity of quantitative polymerase chain reaction and flow cytometry to detect cellular microchimerism. With that purpose, we created mixed cells suspensions in vitro containing reciprocal frequencies of wild type cells and cells positive for enhanced green fluorescent protein or CD45.1(+), respectively. Here, we now introduce the H-2 complex, which defines the major histocompatibility complex in mice and is homologous to HLA in human, as an additional target to detect maternal microchimerism among fetal haploidentical cells. We envision that this advanced approach to detect maternal microchimeric cells by flow cytometry facilitates the pursuit of phenotypic, gene expression and functional analysis of microchimeric cells in future studies.