Ontogeny Of Immune System Research Articles

Expected impact of immunomodulatory agents during pregnancy: A newborn's perspective.

The neonatal immune ontogeny begins during pregnancy to ensure that the neonate is well-suited for perinatal life. It prioritizes Th2/M2 and regulatory responses over Th/M1 activity to avoid excessive inflammatory responses and to ensure immune tolerance and homeostasis. Newborns also present increased Th17/Th22 responses providing effective anti-fungal immunity and mucosal protection. Intrauterine exposure to immune modulatory drugs with the placental transfer may influence the natural course of the fetal immune development. The vertical transfer of both biological therapy and small molecules begins during the first trimester through neonatal Fc receptor or placental diffusion, respectively, reaching its maximum transfer potential during the third trimester of pregnancy. Most of the biological therapy have a prolonged half-life in newborn's blood, being detectable in infants up to 12 months after birth (usually 6-9 months). The use of immunomodulators during pregnancy is gaining global interest. Current evidence mainly reports birth-related outcomes without exhaustive analysis of the on-target side effect on the perinatal immune system ontogeny, the infection risk, or the immune dysregulation. The present review will focus on: (1) the main characteristics of the perinatal immune system to understand its specific features and vulnerabilities to immune modulation; (2) the mechanisms of placental transfer of immunomodulators; and (3) the immune changes reported to date in newborns exposed to immunomodulators with emphasis on the current concerns and gaps in knowledge.

Validating Urinary Neopterin as a Biomarker of Immune Response in Captive and Wild Capuchin Monkeys.

Non-invasive health monitoring is advantageous for wild and captive primate populations because it reduces the need for traditional invasive techniques (i.e., anesthetization) that can be stressful and potentially harmful for individuals. The biomarker neopterin is an emerging tool in primatology to measure immune activation and immunosenescence, however, most neopterin studies have focused on catarrhine species with little comparative work examining neopterin and health in platyrrhines. To address this gap, we validated a commercially available enzyme-linked immunosorbent assay (ELISA) to measure urinary neopterin in two types of capuchin monkeys, a wild population of white-faced capuchins (Cebus imitator) and a socially housed captive colony of tufted capuchins (Sapajus apella). We analytically validated methods for measuring urinary neopterin in two capuchin populations and demonstrated that two commonly-used methods to control for urine concentration—creatinine and specific gravity (SG)—produced highly concordant results. We also biologically validated these methods by examining variation in neopterin levels based on environment (captive and wild) and age, and changes in levels associated with immune-response. We found that neopterin increased after immune perturbation (rabies vaccine booster), varied by environmental condition, and mirrored expected trends in immune system ontogeny. Our results improve understanding of the innate immune system in platyrrhine species and suggest neopterin may be useful for non-invasive health monitoring in both captive and wild primates.

Neonatal Immune System Ontogeny: The Role of Maternal Microbiota and Associated Factors. How Might the Non-Human Primate Model Enlighten the Path?

Interactions between the immune system and the microbiome play a crucial role on the human health. These interactions start in the prenatal period and are critical for the maturation of the immune system in newborns and infants. Several factors influence the composition of the infant’s microbiota and subsequently the development of the immune system. They include maternal infection, antibiotic treatment, environmental exposure, mode of delivery, breastfeeding, and food introduction. In this review, we focus on the ontogeny of the immune system and its association to microbial colonization from conception to food diversification. In this context, we give an overview of the mother–fetus interactions during pregnancy, the impact of the time of birth and the mode of delivery, the neonate gastrointestinal colonization and the role of breastfeeding, weaning, and food diversification. We further review the impact of the vaccination on the infant’s microbiota and the reciprocal case. Finally, we discuss several potential therapeutic interventions that might help to improve the newborn and infant’s health and their responses to vaccination. Throughout the review, we underline the main scientific questions that are left to be answered and how the non-human primate model could help enlighten the path.

Gut Microbial-Derived Metabolomics of Asthma.

In this review, we discuss gut microbial-derived metabolites involved with the origins and pathophysiology of asthma, a chronic respiratory disease that is influenced by the microbiome. Although both gut and airway microbiomes may be important in asthma development, we focus here on the gut microbiome and metabolomic pathways involved in immune system ontogeny. Metabolite classes with existing evidence that microbial-derived products influence asthma risk include short chain fatty acids, polyunsaturated fatty acids and bile acids. While tryptophan metabolites and sphingolipids have known associations with asthma, additional research is needed to clarify the extent to which the microbiome contributes to the effects of these metabolites on asthma. These metabolite classes can influence immune function in one of two ways: (i) promoting growth or maturity of certain immune cell populations or (ii) influencing antigenic load by enhancing the number or species of specific bacteria. A more comprehensive understanding of how gut microbes and metabolites interact to modify asthma risk and morbidity will pave the way for targeted diagnostics and treatments.

Defining Early Life Stress as a Precursor for Autoimmune Disease.

Childhood exposure to traumatic events, termed early life stress (ELS), is now widely recognized for causing long-term negative health effects that may not manifest until adulthood. Allostatic load (AL) describes the cumulative "wear-and-tear" effects of chronic stress on the body that may adversely affect human health by accelerating other disease processes. Recent epidemiological studies have reported higher stress levels in industrialized countries and trends of increasing prevalence in autoimmune diseases during recent decades. To elucidate mechanisms of stress-related immune dysregulation, most animal studies up to now have focused on AL and stress-triggered events occurring in adults but have not explored ELS in the context of autoimmune disorders. We have identified a current gap in understanding the impact of ELS on immune system ontogeny and its potential for priming genetically susceptible individuals who are at increased risk for autoimmune diseases later in life, through mechanisms involving neuroendocrine-immune cross talk. In this review, we highlight the intersection between stress and immune function, with a focus on ELS as consequential for increased autoimmune disorder risks later in life.

The contribution of stress and its mediators to the ontopathogeny of infections: a focus on the interactions of cytokines and glucocorticoids

Presented work is a bibliographic review about participation of glucocorticoids, cytokines and other bioregulators of stress in ontogeny of immune system and in pathogeny of infections. Besides, age-related dynamics and gender differences of morbidity and mortality caused by three infectious diseases (AIDS, pulmonary tuberculosis and sepsis) were evaluated in Brazilian states of Southern region during three chronologic periods. The results obtained indicate the necessity of higher attention to subclinical role of infectious agents in the etiopathogeny of other chronic degenerative, age-related disorders.

Understanding the ontogeny of the immune system to promote immune-mediated health for life.

Understanding the ontogeny of the human immune system is a prerequisite to developing efficient and safe interventions aimed at providing long-term protection against infectious pathogens or inflammatory disorders originating early in life. The immune system of the fetus and the newborn infant had long been considered as “immature.” This insight is based on the observation that infectious diseases are often more severe or more prolonged in early life. However, studies performed in the 80s have shown that cells involved in innate immune responses develop as early as the fourth week of gestation in humans and that mature fetal T and B lymphocytes can be detected by the end of the first trimester of gestation already. More recent evidence indicates that fetal precursors are at the origin of adult tissueresident macrophages. In addition, studies of immune responses to alloantigens and pathogens in utero demonstrated that effector and regulatory responses are operational during human fetal life, further indicating that the immune system is not fundamentally immature in early life, but simply differs from immune responses observed in later life. Studies are now needed to determine the signals involved in the regulation of the functional programing of immune cells in early life and to define how these signals could be targeted to protect against infectious diseases as well as chronic inflammatory disorders. The objective of the Research Topic is to provide an overview of the current state of knowledge of the ontogeny of the immune system and of the pathogenesis of important infectious and inflammatory diseases in early life. Four themes emerged from the excellent contributions that have been assembled here.

Informing and inspiring

This second issue of Neurology® Neuroimmunology & Neuroinflammation incorporates examples of the types of reports that incarnate our mission: to inform and inspire the community of neuroinflammation and neuroimmunology researchers. Tran et al.1 report a phase I trial of LINGO antibodies, inaugurating clinical development of remyelination therapy for multiple sclerosis (MS), and the attainment of this goal is discussed by Brugarolas and Popko,2 authorities on the relevant basic science. Radke et al.3 describe 2 adult patients with a histologic variant of dermatomyositis, 1 in whom formation of secondary lymphoid-like structures is observed. Lymphoneogenesis is a poorly understood feature of chronic inflammatory disorders, but it could potentially be unraveled by applying knowledge of immune system ontogeny. Mir et al.4 report evidence for chronic oxidative stress in the tissues of patients with progressive MS. Oxidative stress is a prominent topic of speculation in discussions of the pathogenesis of MS progression, so it's doubly rewarding to have tangible evidence for this process coming from living patients. Furthermore, this observation may provide a foundation for monitoring hoped-for treatment trials for this obdurate condition. Li et al.5 describe how to monitor macular edema in a patient with MS receiving fingolimod, thereby enabling the continuation of a therapeutic modality considered by the treating physicians to be useful for this clinical circumstance. A novel presentation of neurotransmitter receptor antibody–mediated neurologic disease comes from Zuliani et al.6: adult patients with new-onset epilepsy were found to harbor glycine receptor antibodies. Zhang et al.7 describe an unprecedented case of paraneoplastic cerebellar disease and voltage-gated calcium channel antibodies in an individual with a neuroendocrine (Merkel cell) cancer. Prüss and coworkers8 report a case which suggests another potential mechanism for inducing NMDA receptor antibody–mediated encephalitis. This contribution adds insight into a mysterious, tantalizing condition.

Plasticity for axolotl lens regeneration is associated with age-related changes in gene expression.

Mexican axolotls lose potential for lens regeneration 2 weeks after hatching. We used microarrays to identify differently expressed genes before and after this critical time, using RNA isolated from iris. Over 3700 genes were identified as differentially expressed in response to lentectomy between young (7 days post‐hatching) and old (3 months post‐hatching) axolotl larvae. Strikingly, many of the genes were only expressed in the early or late iris. Genes that were highly expressed in young iris significantly enriched electron transport chain, transcription, metabolism, and cell cycle gene ontologies, all of which are associated with lens regeneration. In contrast, genes associated with cellular differentiation and tissue maturation were uniquely expressed in old iris. Many of these expression differences strongly suggest that young and old iris samples were collected before and after the spleen became developmentally competent to produce and secrete cells with humoral and innate immunity functions. Our study establishes the axolotl as a powerful model to investigate age‐related cellular differentiation and immune system ontogeny within the context of tissue regeneration.

Maturation of Toll-like receptor 1–4 responsiveness during early life

BackgroundToll-like receptors (TLRs) are part of the highly conserved components of the innate immune system, and have been investigated extensively; however, little is known about TLR function during early postnatal life, a critical period for immune maturation. AimsIn order to achieve a more complete understanding of the ontogeny of immune system during the first years of life, our study investigated age-matched TLR1–4 responsiveness at several time points up to the age of two years. Study designMononuclear cells were isolated from cord blood (n=150) and peripheral blood from infants at 6 (n=68), 12 (n=75), and 24 (n=74)months of age, and from 50 adults. Cells were stimulated with Toll-like receptor ligands (TLR1–4) and phytohemagglutinin (PHA). Stimulated cells were assessed for their production of the cytokines tumor necrosis factor alpha (TNF-α) and interleukin-6 (IL-6), and for TLR4 gene expression. ResultsOur results suggested that cord response of IL-6 and TNF-α was not affected by allergic background. In addition, neonatal mononuclear cell had enhanced IL-6 production upon TLR1, 2, and 4 stimulations as compared to those of young children and adults. Nevertheless, after 6months of age, the level remained comparable throughout the first two years of life. While TNF-α response to all TLR stimulations remained fairly similar during early life. This cytokine pattern closely paralleled our findings for TLR4 mRNA expression, and longitudinal cytokine changes within the same individual. ConclusionsOur findings provided additional information to the understanding of immune development during early life, and offered stronger evidence of neonatal innate immunity being capable of responding adequately to TLR stimulation.

Antigen-dependent T lymphocytes (TcRβ +) are primarily differentiated in the thymus rather than in other lymphoid tissues in sea bass ( Dicentrarchus labrax, L.)

All jawed vertebrates share lymphocyte receptors that allow the recognition of pathogens and the discrimination between self and non-self antigens. The T cell transmembrane receptor (TcR) has a central role in the maturation and function of T lymphocytes in vertebrates via an important role in positive selection of the variable region of TcR αβ/γδ chains. In this study, the TcRβ transcript expression and TcRβ + cell distribution during the ontogeny of the immune system of sea bass ( Dicentrarchus labrax, L.) were analysed. RT-PCR analysis of larvae during early development demonstrated that the β chain transcript is expressed by 19 days post-fertilisation (p.f.). RNA probes specific for the β chain were synthesised and used for in situ hybridisation experiments on 30 day p.f. to 180 day old juvenile larvae. A parallel immunohistochemical study was performed using the anti-T cell monoclonal antibody DLT15 developed in our laboratory [Scapigliati et al., Fish Shellfish Immunol 1996; 6:383–401]. The first thymus anlage was detectable at 32–33 days p.f. (Corresponding to about 27 days post-hatch). DLT15 + cells were detected at day 35 p.f. in the thymus whereas TcRβ + cells were recognisable at day 38 p.f. in the thymus and at day 41 p.f. in the gut. TcRβ + cells were observed in capillaries from 41 to 80 days p.f. At day 46 p.f., TcRβ + cells were identified in the head kidney and were detected in the spleen 4 days later. The present results demonstrate that TcRβ + cells can be differentiated first in the thymus and then in other organs/tissues, suggesting potential TcRβ + cell colonisation from the thymus to the middle gut. Once the epithelial architecture of the thymus is completed with the formation of the cortical-medullary border (around 70–75 days p.f.), DLT15 + cells or TcRβ + cells are confined mainly to the cortex and cortical-medullary border. In particular, a large influx of TcRβ + cells was observed at the cortical-medullary border from 72 to 90 days p.f., suggesting a role in positive selection for this thymic region during the ontogeny of the fish immune system. This study provides novel information about the primary differentiation and distribution of TcRβ + cells in sea bass larvae and juveniles.

De l’utilité des animaux domestiques pour la recherche en immunologie

RÉSUMÉLes recherches en immunologie des animaux domestiques fournissent des données complémentaires à celles menées chez la souris, du fait des « opportunités » qu’offrent ces espèces. Certaines d’entre elles font l’objet de cette communication: approche chirurgicale du fonctionnement in vivo des organes lymphoïdes, interventions in utero pour l’étude de l’ontogénèse du système immunitaire, pertinence de l’étude physiopathologique des infections sur espèces cibles.

Ontogeny of the immune system of fish

Information on the ontogeny of the fish immune system is largely restricted to a few species of teleosts (e.g., rainbow trout, catfish, zebrafish, sea bass) and has previously focused on morphological features. However, basic questions including the identification of the first lympho-hematopoietic sites, the origin of T- and B-lymphocytes and the acquisition of full immunological capacities remain to be resolved. We review these three main topics with special emphasis on recent results obtained from the zebrafish, a new experimental model particularly suitable for study of the ontogeny of the immune system because of its rapid development and easy manipulation. This species also provides an easy way of creating mutations that can be detected by various types of screens. In some teleosts (i.e., angelfish) the first blood cells are formed in the yolk sac. In others, such as zebrafish, the first hematopoietic site is an intraembryonic locus, the intermediate cell mass (ICM), whereas in both killifish and rainbow trout the first blood cells appear for a short time in the yolk sac but later the ICM becomes the main hematopoietic area. Erythrocytes and macrophages are the first blood cells to be identified in zebrafish embryos. They occur in the ICM, the duct of Cuvier and the peripheral circulation. Between 24 and 30 hour post-fertilization (hpf) at a temperature of 28 °C a few myeloblasts and myelocytes appear between the yolk sac and the body walls, and the ventral region of the tail of 1–2 day-old zebrafish also contains developing blood cells. The thymus, kidney and spleen are the major lymphoid organs of teleosts. The thymus is the first organ to become lymphoid, although earlier the kidney can contain hematopoietic precursors but not lymphocytes. In freshwater, but not in marine, teleosts the spleen is the last organ to acquire that condition. We and other authors have demonstrated an early expression of Rag-1 in the zebrafish thymus that correlates well with the morphological identification of lymphoid cells. On the other hand, the origins and time of appearance of B lymphocytes in teleosts are a matter of discussion and recent results are summarized here. The functioning rather than the mere morphological evidence of lymphocytes determines when the full immunocompetence in fish is attained. Information on the histogenesis of fish lymphoid organs can also be obtained by analysing zebrafish mutants with defects in the development of immune progenitors and/or in the maturation of non-lymphoid stromal elements of the lymphoid organs. The main characteristics of some of these mutants will also be described.

Expression of penaeidin antimicrobial peptides in early larval stages of the shrimp Penaeus vannamei

Penaeidins are a family of antimicrobial peptides constitutively produced and stored in the hemocytes of penaeid shrimps. We have determined the expression and the localization of penaeidins in the first early larval stages (Nauplius V, Zoea I, II, III and Mysis II) and in post-larvae (1 and 8) of the shrimp Penaeus vannamei. Using in situ hybridization and immunohistochemical analyses, we localized penaeidin transcripts and peptides in a few hemocytes of larvae from Mysis II stage. However, RT-PCR analyses showed that penaeidin mRNAs are already present in the early stage of Nauplius V. In addition, penaeidin expression could not be detected in other cells than hemocytes. Our observations highlight the potential involvement of penaeidins during larval development and the ontogeny of immune system through hemocytes during this period of life, where shrimps are particularly susceptible to infectious diseases.

The ontogeny of the gut mucosal immune system and the susceptibility to infections in infants of developing countries.

In this review we summarize data on the human gut mucosa associated lymphatic tissues as part of the common mucosal immune system. Its embryonal-fetal and post-natal ontogeny becomes severely distorted and compromised by mal-/undernutrition which is so prevalent in developing countries. Pathogenetic interdependencies exist between maternal-fetal undernutrition, the ontogeny of the immune system, constant antigenic stimulation of the mucosal immune system post-natally, and the 14 million deaths annually from infections in children below the age of 5 years in developing countries. A detailed knowledge of these interdependencies is required for effective prevention and treatment in an attempt to reduce the high morbidity and mortality rates of children in developing countries.

Total parenteral nutrition in germfree colostrum‐deprived neonatal miniature piglets: a unique model to study the ontogeny of the immune system

In order to investigate the regulatory role of the immune system on gastrointestinal macromolecular permeability in neonates, and ontogeny of the neonatal immune system, we have developed a total parenteral nutrition (TPN) program capable of maintaining immunologically "virgin" germfree (GF) neonatal piglets. GF colostrum-deprived piglets obtained by aseptic hysterectomy 3-5 days prior to term were denied any oral feeding and maintained on central venous hyperalimentation in the GF isolators. GF piglets were anesthetized and 20-gauge silicone tubing was inserted into the external jugular vein and advanced to the level of right auricle of the heart. The distal end of the cannula was subcutaneously tunneled out between the shoulders and attached to a light jacket, tether, and swivel assembly that allowed the piglet to move freely inside the cage in a germfree unit. The TPN formula provided 60 Cal/kg/day for the first day and gradually increased up to 165 Cal/kg/day for day-7 and older piglets. The GF piglets were maintained on the TPN formula for 21 days and weight gain of the GF-TPN piglets averaged 23 g/day. The hematologic and serum biochemical parameters of GF-TPN piglets were within the normal range of gnotobiotic animals of their age group. The serum levels of total protein and albumin in the GF-TPN piglets were significantly less than those of colostrum-fed piglets, who absorbed a large quantity of the colostral macromolecules through their gastrointestinal tract into the blood stream.(ABSTRACT TRUNCATED AT 250 WORDS)