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Ontogeny of Early Life Immunity
Abstract
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.
... Neonatal immunization occurs in a backdrop of distinct early life immunity. Recent reviews have highlighted that both cellular and soluble aspects of the immune system are distinct at birth (9,10). Neonatal immunity must not only defend the newborn against a potential onslaught of potential pathogens, but also mediate the acquisition of a colonizing microbiome over the first hours and days of life. ...
... The distinct composition of human newborn cord blood plasma includes soluble mediators such as maternal Abs, high levels of immunosuppressive adenosine, and low levels of complement, important for triggering adaptive immune responses (11). Accordingly, modeling age-specific immunity in vitro should take into account distinct composition of age-specific autologous plasma, rather than, for example, fetal bovine serum (9). Distinct cellular immunity in the newborn includes reduced Th1 but robust anti-inflammatory IL-10 responses of antigen-presenting cells to stimulation by PRR agonists, high frequency of naïve-and regulatory-T cells and CD71+ erythroid precursors that may limit, for example, responses to pertussis immunization (10,12,13). ...
... Accordingly, many vaccine formulations fail or are less effective in vulnerable subpopulations such as the very young or elderly. In this context, human in vitro platforms that model age-specific vaccineinduced innate and adaptive immune responses as benchmarked to licensed vaccines offer the possibility of accelerating and derisking vaccine development (9,88). Indeed age-specific human in vitro platforms such as newborn whole blood assays, dendritic cell arrays, and microphysiologic tissue constructs (89) have been successfully used to define novel biomarkers of vaccine adjuvanticity (90) and identify TLR7/8 agonists as adjuvants active in early life (63). ...
Infections take their greatest toll in early life necessitating robust approaches to protect the very young. Here, we review the rationale, current state, and future research directions for one such approach: neonatal immunization. Challenges to neonatal immunization include natural concern about safety as well as a distinct neonatal immune system that is generally polarized against Th1 responses to many stimuli such that some vaccines that are effective in adults are not in newborns. Nevertheless, neonatal immunization could result in high-population penetration as birth is a reliable point of healthcare contact, and offers an opportunity for early protection of the young, including preterm newborns who are deficient in maternal antibodies. Despite distinct immunity and reduced responses to some vaccines, several vaccines have proven safe and effective at birth. While some vaccines such as polysaccharide vaccines have little effectiveness at birth, hepatitis B vaccine can prime at birth and requires multiple doses to achieve protection, whereas the live-attenuated Bacille Calmette-Guérin (BCG), may offer single shot protection, potentially in part via heterologous ("non-specific") beneficial effects. Additional vaccines have been studied at birth including those directed against pertussis, pneumococcus, Haemophilus influenza type B and rotavirus providing important lessons. Current areas of research in neonatal vaccinology include characterization of early life immune ontogeny, heterogeneity in and heterologous effects of BCG vaccine formulations, applying systems biology and systems serology, in vitro platforms that model age-specific human immunity and discovery and development of novel age-specific adju-vantation systems. These approaches may inform, de-risk, and accelerate development of novel vaccines for use in early life. Key stakeholders, including the general public, should be engaged in assessing the opportunities and challenges inherent to neonatal immunization.
... A recent study has shown that the immune status of healthy individuals is continuous rather than discrete, meaning that individuals of the same age may differ in their physiological age in terms of immunity. This high inter-individual variability emphasizes the need for quantitative evaluation of immune status to study the gradual changes occurring in the immune system [5,[8][9][10][11][12][13][14][15][16][17][18]. Currently, clinicians generally assess the immune status of patients based on the presence of basic diseases such as diabetes, malignant tumors, and chronic renal failure. ...
... Random forest (RF) is an algorithm that integrates multiple decision trees through ensemble learning, so that it has better generalization ability [33]. For a certain input (11) Table 2 Steps of EM algorithm EM algorithm: ...
Background
With the COVID-19 outbreak, an increasing number of individuals are concerned about their health, particularly their immune status. However, as of now, there is no available algorithm that effectively assesses the immune status of normal, healthy individuals. In response to this, a new score-based method is proposed that utilizes complete blood cell counts (CBC) to provide early warning of disease risks, such as COVID-19.
Methods
First, data on immune-related CBC measurements from 16,715 healthy individuals were collected. Then, a three-platform model was developed to normalize the data, and a Gaussian mixture model was optimized with expectation maximization (EM-GMM) to cluster the immune status of healthy individuals. Based on the results, Random Forest (RF), Light Gradient Boosting Machine (LightGBM) and Extreme Gradient Boosting (XGBoost) were used to determine the correlation of each CBC index with the immune status. Consequently, a weighted sum model was constructed to calculate a continuous immunity score, enabling the evaluation of immune status.
Results
The results demonstrated a significant negative correlation between the immunity score and the age of healthy individuals, thereby validating the effectiveness of the proposed method. In addition, a nonlinear polynomial regression model was developed to depict this trend. By comparing an individual’s immune status with the reference value corresponding to their age, their immune status can be evaluated.
Conclusion
In summary, this study has established a novel model for evaluating the immune status of healthy individuals, providing a good approach for early detection of abnormal immune status in healthy individuals. It is helpful in early warning of the risk of infectious diseases and of significant importance.
... Newborns have a distinct immune system, characterized by reduced inflammation and Th polarizing innate immunity and a bias towards Th2/ Th17 responses 3,5,6 , while elder individuals (>65 years of age) demonstrate immunosenescence, an age-related decline in general immune function, with a decrease in naïve T cell production and an increase in memory T cells in tissues 7,8 , resulting in a decreased ability to mount an effective immune response to new pathogens. Newborns are generally more dependent on their innate immune system for protection against infections 9 . CXCL8mediated enhanced IFNγ expression in γδ T cells might be the important producers of effector cytokines in newborns, which are rare in adults 6 . ...
Vaccination reduces morbidity and mortality due to infections, but efficacy may be limited due to distinct immunogenicity at the extremes of age. This raises the possibility of employing adjuvants to enhance immunogenicity and protection. Early IFNγ production is a hallmark of effective vaccine immunogenicity in adults serving as a biomarker that may predict effective adjuvanticity. We utilized mass cytometry (CyTOF) to dissect the source of adjuvant-induced cytokine production in human blood mononuclear cells (BMCs) from newborns (~39-week-gestation), adults (~18-63 years old) and elders (>65 years of age) after stimulation with pattern recognition receptors agonist (PRRa) adjuvants. Dimensionality reduction analysis of CyTOF data mapped the BMC compartment, elucidated age-specific immune responses and profiled PRR-mediated activation of monocytes and DCs upon adjuvant stimulation. Furthermore, we demonstrated PRRa adjuvants mediated innate IFNγ induction and mapped NK cells as the key source of TLR7/8 agonist (TLR7/8a) specific innate IFNγ responses. Hierarchical clustering analysis revealed age and TLR7/8a-specific accumulation of innate IFNγ producing γδ T cells. Our study demonstrates the application of mass cytometry and cutting-edge computational approaches to characterize immune responses across immunologically distinct age groups and may inform identification of the bespoke adjuvantation systems tailored to enhance immunity in distinct vulnerable populations.
... Neonatal sepsis is a serious infectious disease in the neonatal care unit that has a significant impact on the survival rate of newborns [26]. In the neonatal period, the infant's immune system develops very slowly, is relatively naive, has low immune ability [68], and is extremely susceptible to pathogens. The onset of neonatal sepsis is rapid and once infection occurs, it is extremely challenging to manage [69]. ...
Objective
The purpose of this study is to investigate the relationship between single nucleotide polymorphisms of inflammatory cytokines and neonatal sepsis through meta-analysis.
Methods
We collected research literature on the correlation between inflammatory cytokine polymorphisms and neonatal sepsis published before August 2023 through computer searches of databases such as PubMed, Embase, etc. The Stata 14.0 software was utilized for Meta-analysis. To assess heterogeneity, the chi-squared Q-test and I² statistics were used. The Egger and Begg tests were conducted to determine the possibility of publication bias.
Results
After reviewing 1129 articles, 29 relevant articles involving 3348 cases and 5183 controls were included in the study. The meta-analysis conducted on IL-1βrs1143643 polymorphism revealed significant findings: the T allele genotype has a lower risk of neonatal sepsis(P = 0.000, OR = 0.224, 95% CI: 0.168–0.299), while the TC and TT genotypes showed an increased risk(TC: P = 0.000,OR = 4.251, 95% CI: 2.226–8.119; TT: P = 0.019,OR = 2.020, 95% CI: 1.122–3.639). Similarly, newborns with the IL-6-174 CC genotype had a significantly higher risk of sepsis(P = 0.000,OR = 1.591, 95% CI: 1.154–2.194), while those with the IL-8-rs4073 TT (P = 0.003,OR = 0.467, 95% CI: 0.280–0.777)and TT + AA(P = 0.003,OR = 0.497, 95% CI: 0.315–0.785) genotypes had a significantly lower risk of sepsis. For the IL-10-1082 gene, newborns with the AA genotype(P = 0.002,OR = 1.702, 95% CI: 1.218–2.377), as well as those with the AA + GA genotype(P = 0.016,OR = 1.731, 95% CI: 1.108–2.705), had a significantly higher risk of sepsis. Lastly, newborns carrying the TNF-α–308 A allele (P = 0.016,OR = 1.257, 95% CI: 1.044–1.513)or the AA genotype(P = 0.009,OR = 1.913, 95% CI: 1.179–3.10) have a significantly increased risk of sepsis. Notwithstanding, additional studies must be included for validation. Applying these cytokines in clinical practice and integrating them into auxiliary examinations facilitates the early detection of susceptible populations for neonatal sepsis, thereby providing a new diagnostic and therapeutic approach for neonatal sepsis.
... Discussion: Our analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality. KEYWORDS biomarker, transcriptomic, infant sepsis, sepsis severity, blood, immune deconvolution Introduction Sepsis affects over 19 million patients annually, with global mortality rates at around 25-30% (1)(2)(3). Although palliative care and anti-microbial treatment have markedly improved sepsis management, mortality rates remains high due to disease heterogeneity, highly variable host characteristics, including cardiovascular and immunological comorbidities, and shortcomings in methods for early detection and diagnosis (4,5). ...
Introduction
Sepsis remains a major cause of mortality and morbidity in infants. In recent years, several gene marker strategies for the early identification of sepsis have been proposed but only a few have been independently validated for adult cohorts and applicability to infant sepsis remains unclear. Biomarkers to assess disease severity and risks of shock also represent an important unmet need.
Methods
To elucidate characteristics driving sepsis in infants, we assembled a multi-transcriptomic dataset from public microarray datasets originating from five independent studies pertaining to bacterial sepsis in infant < 6-months of age (total n=335). We utilized a COmbat co-normalization strategy to enable comparative evaluation across multiple studies while preserving the relationship between cases and controls.
Results
We found good concordance with only two out of seven of the published adult sepsis gene signatures (accuracy > 80%), highlighting the narrow utility of adult-derived signatures for infant diagnosis. Pseudotime analysis of individual subjects’ gene expression profiles showed a continuum of molecular changes forming tight clusters concurrent with disease progression between healthy controls and septic shock cases. In depth gene expression analyses between bacteremia, septic shock, and healthy controls characterized lymphocyte activity, hemostatic processes, and heightened innate immunity during the molecular transition toward a state of shock.
Discussion
Our analysis revealed the presence of multiple significant transcriptomic perturbations that occur during the progression to septic shock in infants that are characterized by late-stage induction of clotting factors, in parallel with a heightened innate immune response and a suppression of adaptive cell functionality.
... Limitations of the study Neonatal sepsis is characterized by an early dominant hyperinflammatory state and a transition to an anti-inflammatory immune state with sepsis-induced immunosuppression (Dowling and Levy, 2014). In this study, the transcriptomic profiles are mostly from late time points in the sepsis period, 3-5 days after the diagnosis of LOS, which may explain the heterogeneity of CD83 expression in the preterm and term neonates with early-onset sepsis, observed in the independent study population. ...
Preterm infants are at high risk of developing neonatal sepsis. γδ T cells are thought to be an important set of effector cells in neonates. Here, γδ T cells were investigated in a longitudinal cohort of preterm neonates using next-generation sequencing, flow cytometry, and functional assays. During the first year of life, the Vγ9Vδ2 T cell subset showed dynamic phenotypic changes and elevated levels of fetal-derived Vγ9Vδ2 T cells were evident in infants with sepsis. Single-cell transcriptomics identified HLA-DRhiCD83+ γδ T cells in neonatal sepsis, which expressed genes related to antigen presentation. In vitro assays showed that CD83 was expressed on activated Vγ9Vδ2 T cells in preterm and term neonates, but not in adults. In contrast, activation of adult Vγ9Vδ2 T cells enhanced CD86 expression, which was presumably the key receptor to induce CD4 T cell proliferation. Together, we provide a map of the maturation of γδ T cells after preterm birth and highlight their phenotypic diversity in infections.
... Легкие новорожденного ребенка имеют ряд структурно-функциональных особенностей, делающих их более уязвимыми к инфекционной агрессии. Среди них следует отметить сниженный мукоцилиарный клиренс, относительно меньшее количество альвеолярных макрофагов, незрелость иммунной системы [5][6][7]. При этом врожденный иммунитет, как системный, так и локализованный на слизистых оболочках дыхательных путей и паренхиме легких, является незрелым, а адаптивный иммунитет, представленный в основном в форме IgG, полученных от матери, недостаточно состоятелен. Он постепенно формируется постнатально в процессе колонизации ребенка естественной микрофлорой. ...
Неонатальные пневмонии занимают значимое место в структуре заболеваемости и смертности новорожденных. Особую опасность среди них представляют врожденные пневмонии с ранней манифестацией. Успех лечения таких пациентов зависит от своевременной диагностики и дифференциальной диагностики заболевания. Традиционная рентгенологическая диагностика является «золотым стандартом». В дополнение к ней активно исследуются и внедряются в практику лабораторные маркеры пневмонии, такие как тромбоцитарные индексы, соотношение С-реактивного белка и альбумина, прокальцитонин и другие. Данные тесты также важны для контроля за эффективностью проводимого лечения. Важное место в лечении занимают вопросы ухода за пациентом и профилактики контаминации госпитальной флорой.
Neonatal pneumonias occupy a significant place in the structure of morbidity and mortality of newborns. Of particular danger among them are congenital pneumonia with early manifestation. The success of treatment of such patients depends on timely diagnosis and differential diagnosis of the disease. Traditional x-ray diagnostics is the "gold standard". In addition to it, laboratory markers of pneumonia, such as platelet indices, the ratio of C-reactive protein to albumin, procalcitonin and others, are being actively researched and put into practice. These tests are also important for monitoring the effectiveness of treatment. An important place in treatment is occupied by the issues of patient care and prevention of contamination by hospital flora.
... This harm can lead to conditions such as respiratory distress syndrome, bronchopulmonary dysplasia, brain injury, and retinopathy of prematurity (ROP), known collectively as "oxygen radical disease of neonatology" [2]. Additionally, the dynamic immune changes of infants and reduced proinflammatory responses in the first months increase their susceptibility to infection [3,4]. Recent studies link pro-inflammatory cytokines to various newborn diseases, including pulmonary issues, ROP, perinatal brain injury, and immune dysfunction [5][6][7]. ...
Newborns’ eyes and brains are prone to oxidative stress. Lutein has antioxidant properties and is the main component of macular pigment essential for protecting the retina, but has low bioavailability, thereby limiting its potential as a nutritional supplement. Oil-in-water emulsions have been used as lutein delivery systems. In particular, octenylsuccinated (OS) starch is a biopolymer-derived emulsifier safe to use in infant foods, while exhibiting superior emulsifying capacity. This study determined the effects of an OS starch-stabilized lutein emulsion on lutein bioavailability in Sprague-Dawley neonatal rats. In an acute study, 10-day-old pups received a single oral dose of free lutein or lutein emulsion, with subsequent blood sampling over 24 h to analyze pharmacokinetics. The lutein emulsion group had a 2.12- and 1.91-fold higher maximum serum lutein concentration and area under the curve, respectively, compared to the free lutein group. In two daily dosing studies, oral lutein was given from postnatal day 5 to 18. Blood and tissue lutein concentrations were measured. The results indicated that the daily intake of lutein emulsion led to a higher lutein concentration in circulation and key tissues compared to free lutein. The OS starch-stabilized emulsion could be an effective and safe lutein delivery system for newborns.
... Children under 5 years of age, especially infants under the age of 2, are at higher risk of complications (Clohisey and Baillie, 2019;Ruf and Knuf, 2014). This is thought to be due, at least in part, to lack of pre-existing immunity and a heavy reliance on CD4 type 2 responses in children as opposed to the CD4 type 1 and CD8 T cell predominant responses in adults (Cerwenka et al., 1999;Chang et al., 2011;de Kleer et al., 2016;Dowling and Levy, 2014;Duan and Thomas, 2016). While more studies are needed to fully understand the infant immune system, recent studies have provided insight into their unique immune responses. ...
Analysis of pre-existing immunity and its effects on acute infection often focus on memory responses associated with a prior infectious exposure. However, memory responses occur in the context of the overall immune state and leukocytes must interact with their microenvironment and other immune cells. Thus, it is important to also consider non-antigen-specific factors which shape the composite basal state and functional capacity of the immune system, termed here as I 0 (‘I naught’). In this review, we discuss the determinants of I 0 . Utilizing influenza virus as a model, we then consider the effect of I 0 on susceptibility to infection and disease severity. Lastly, we outline a mathematical framework and demonstrate how researchers can build and tailor models to specific needs. Understanding how diverse factors uniquely and collectively impact immune competence will provide valuable insights into mechanisms of immune variation, aid in screening for high-risk populations, and promote the development of broadly applicable prophylactic and therapeutic treatments.
... Numerous research studies have investigated the impact of age on immune regulation, revealing that young children and the elderly are more susceptible to infections compared to other age groups (Afridi, 2017;Brodin and Davis, 2017;Dowling and Levy, 2014;Simon et al., 2015). Infants' immune systems develop as they are exposed to the environment, while older individuals experience a slower immune response due to diminished immune cells, lymphopenia, and reduced diversity in receptor genes (Goronzy and Weyand, 2003;Qi et al., 2014). ...
Exercise has been shown to improve immune competence. The immune system functions to distinguish between 'self' and 'non-self' and is composed of innate and adaptive immune cells. Exercise, especially regular moderate-intensity exercise, has positive effects on the immune system, including enhanced vaccination responses, reduced inflammation, improved neutrophil activity, and longer leukocyte telomeres. Sedentary lifestyles contribute to an increased risk of diseases, while regular exercise is beneficial for immune function and overall health. The effects of exercise on the immune system depend on factors such as exercise intensity, duration, and type. Exercise-induced immune responses vary in different populations, including young and elderly individuals, with variations in the magnitude and extent of the effects. Exercise has been associated with reduced immunosenescence and improved vaccine-induced immunity. Factors such as age, sex, genetics, microbial diversity, and environmental influences also impact immune function. Understanding the complex relationship between exercise, external factors, and immune responses is important for developing tailored interventions and improving health outcomes. More research is needed to fully understand the mechanisms and implications of exercise on the immune system. The objective of the study was to assess the impact of exercise on variations of the immune system caused by various factors, providing further insights into the complex relationship between exercise and immunity.
... Infectious diseases represent the most frequent cause of death among infants and young children (10-16). Susceptibility to invasive pathogens is related to the fact that immune response in infants is generally less competent than in adults (17)(18)(19)(20)(21)(22)(23)(24)(25). Elucidating why infant immune responses to microbes and vaccines are less protective than the one observed in adults, has major implications for developing improved vaccines. ...
While the first 1,000 days of life are a critical period in child's development, limited information on the main determinants affecting this period in the Latin America and the Caribbean (LAC) region is available. Therefore, the Latin American Pediatric Infectious Diseases Society (SLIPE) held an ad hoc workshop in May 2022 with an expert panel designed to analyze the main factors impacting the development of childhood in the region during this period and the main causes of maternal infant morbimortality. The aim was to identify priorities, generate recommendations, and advise practical actions to improve this situation. Considerations were made about the challenges involved in bridging the gap that separates the region from more developed countries regarding an optimal early childhood and maternal care. Extensive discussion was conducted to reach consensus recommendations on general strategies intended to reduce maternal and infant mortality associated with infections and immune-preventable diseases during the first 1,000 days of life in LAC.
... Newborns and infants are vulnerable to infections mostly because their immune system is not as efficient as the adult immune system in controlling microbial assaults and responding to vaccines [1][2][3][4][5][6] . Incomplete understanding of the underlying mechanisms of suboptimal immune responses to vaccines during early age is an obstacle in improving pediatric vaccines 7 . ...
The inability of neonates to develop CD4 + FoxP3-CXCR5 hi PD-1 hi T follicular helper (T FH) cells contributes to their weak vaccine responses. In previous studies, we measured diminished IgG responses when IL-6 was co-injected with a pneumococcal conjugate vaccine (PCV) in neonatal mice. This is in sharp contrast to adults, where IL-6 improves vaccine responses by downregulating the expression of IL-2Rβ on T FH cells and protecting them from the inhibitory effect of IL-2. In this study, we found that splenic IL-6 levels rapidly increased in both adult and neonatal mice following immunization, but the increase in neonatal mice was significantly more than that of adult mice. Moreover, immunized neonatal T FH cells expressed significantly more IL-2 as well as its receptors, IL-2Rα and IL-2Rβ, than the adult cells. Remarkably, IL-6 co-injection with PCV vaccine further increased the production of IL-2 and the expression of its receptors by neonatal T FH cells, whereas excess IL-6 had totally opposite effect in immunized adult mice. Underscoring the role of IL-6 in activating the IL-2 mediated suppression of vaccine responses, immunization of IL-6 knockout neonates led to improved antibody responses accompanied by expanded T FH cells as well as lower levels of IL-2 and IL-2 receptors on T FH cells. Moreover, CpG containing PCV improved T FH response in neonates by suppressing the expression of IL-2 receptors on T FH cells and inhibiting IL-2 activity. These findings unveil age-specific differences in IL-6 mediated vaccine responses and highlight the need to consider age-related immunobiological attributes in designing vaccines. npj Vaccines (2023) 8:173 ; https://doi.
... During early life, the newborn relies mainly on innate immunity as maturation of adaptive immunity lags behind that of innate immunity. Intestinal innate immunity consists of two key parts: the surface of the intestinal epithelium which acts as a physical barrier, and the immune cells, which respond quickly to potential threats (12)(13)(14). IMjs are the most abundant immune cells in the intestine and the first white blood cells to appear in the developing intestine. Mjs first appear in the fetal intestine at 11-12 weeks of gestation, increase rapidly during the 12-22 weeks period, and then continue to expand at a slower pace through early childhood (15). ...
Necrotizing enterocolitis (NEC) is an inflammatory intestinal disease that profoundly affects preterm infants. Currently, the pathogenesis of NEC remains controversial, resulting in limited treatment strategies. The preterm infants are thought to be susceptible to gut inflammatory disorders because of their immature immune system. In early life, intestinal macrophages (IMφs), crucial components of innate immunity, demonstrate functional plasticity and diversity in intestinal development, resistance to pathogens, maintenance of the intestinal barrier, and regulation of gut microbiota. When the stimulations of environmental, dietary, and bacterial factors interrupt the homeostatic processes of IMφs, they will lead to intestinal disease, such as NEC. This review focuses on the IMφs related pathogenesis in NEC, discusses the multi-functional roles and relevant molecular mechanisms of IMφs in preterm infants, and explores promising therapeutic application for NEC.
... Demand-adapted production from these hematopoietic stem and progenitor cells (HSPC) is an essential feature of the hematopoietic response to systemic inflammation 4 . Each period of the lifespan (e.g., fetal, childhood, adulthood, aging) also superimposes features that modulate hematopoiesis to affect immune responses 5 , with the perinatal period posing distinct immunological challenges 6 . Maternal tolerance for the semiallogeneic fetus is essential for continued pregnancy, which can be threatened by inflammation. ...
Neonates, in contrast to adults, are highly susceptible to inflammation and infection. Here we investigate how late fetal liver (FL) mouse hematopoietic stem and progenitor cells (HSPC) respond to inflammation, testing the hypothesis that deficits in engagement of emergency myelopoiesis (EM) pathways limit neutrophil output and contribute to perinatal neutropenia. We show that despite similar molecular wiring as adults, fetal HSPCs have limited production of myeloid cells at steady state and fail to activate a classical EM transcriptional program. Moreover, we find that fetal HSPCs are capable of responding to EM-inducing inflammatory stimuli in vitro , but are restricted by maternal anti-inflammatory factors, primarily interleukin-10 (IL-10), from activating EM pathways in utero . Accordingly, we demonstrate that loss of maternal IL-10 restores EM activation in fetal HSPCs but at the cost of premature parturition. These results reveal the evolutionary trade-off inherent in maternal anti-inflammatory responses that maintain pregnancy but render the fetus unresponsive to EM activation signals and susceptible to infection.
HIGHLIGHTS
The structure of the HSPC compartment is conserved from late fetal to adult life.
Fetal HSPCs have diminished steady-state myeloid cell production compared to adult.
Fetal HSPCs are restricted from engaging in emergency myelopoiesis by maternal IL-10.
Restriction of emergency myelopoiesis may explain neutropenia in septic neonates.
ETOC BLURB
Fetal hematopoietic stem and progenitor cells are restricted from activating emergency myelopoiesis pathways by maternal IL-10, resulting in inadequate myeloid cell production in response to inflammatory challenges and contributing to neonatal neutropenia.
... The immune system of neonates of small ruminants is not efficient enough at birth and matures over time (Dowling & Levy, 2014). During the neonatal period, maternal immunity is an extraordinary mechanism to protect neonates against some infectious pathogens (Hernandez-Castellano et al., 2015). ...
Background
Small ruminant morbillivirus (SRMV) is the etiological agent of Peste des petits ruminants (PPR) disease. PPR is one of the most important viral diseases of small ruminant husbandry. In the endemic countries, vaccination is the main way to control this disease. Administering the first PPR vaccine in goat kids requires decreased maternal immunity.
Objective
The aim of this study was to determine the decreasing trend of maternal immunity against SRMV in goat kids born from vaccinated goats.
Methods
Twenty Saanen goat kids were studied in two groups including control (n = 5, receiving colostrum from unvaccinated goats) and treatment (n = 15, receiving colostrum from vaccinated goats). Virus neutralisation (VN) test was used to evaluate serum specific antibodies against SRMV in goat kids from birth to 100 days of age.
Results
The first goat kid (n = 1) in the treatment group was seronegative at the age of 28 days. All the goat kids were seronegative at the age of 100 days. The average serum titre of the goat kids at the age of 70–100 days became negative.
Conclusions
Some goat kids became seronegative before reaching the age of receiving the first PPR vaccine. The age of 70–100 days could be a good age range to give the first dose of PPR vaccine to the goat kids, but more studies were needed on the effectiveness of this vaccine at this age range.
... The gut microbiome of an animal is influenced by many factors including diet (De Filippo et al., 2010), exposures to bacteria during post-gestational growth (Torrazza and Neu, 2011;Dowling and Levi, 2014), lifestyle (Clemente et al., 2015;Tun et al., 2017), disease status (Deng and Swanson, 2015), and host genetics (Hughes et al., 2020). Studies suggest a genetic effect on the microbiome composition (Blekhman et al., 2015;Weissbrod et al., 2018;Hughes et al., 2020;Bubier et al., 2021), and differences in gut microbiome composition among dog breeds (Hooda et al., 2012;You and Kim, 2021), although the mechanisms through which specific genes modulate microbiome composition is still unclear. ...
A group of diseases have been shown to correlate with a phenomenon called microbiome dysbiosis, where the bacterial species composition of the gut becomes abnormal. The gut microbiome of an animal is influenced by many factors including diet, exposures to bacteria during post-gestational growth, lifestyle, and disease status. Studies also show that host genetics can affect microbiome composition. We sought to test whether host genetic background is associated with gut microbiome composition in the Norwegian Lundehund dog, a highly inbred breed with an effective population size of 13 individuals. The Lundehund has a high rate of a protein-losing enteropathy in the small intestine that is often reported as Lundehund syndrome, which negatively affects longevity and life-quality. An outcrossing project with the Buhund, Norrbottenspets, and Icelandic sheepdog was recently established to reintroduce genetic diversity to the Lundehund and improve its health. To assess whether there was an association between host genetic diversity and the microbiome composition, we sampled the fecal microbiomes of 75 dogs of the parental (Lundehund), F1 (Lundehund x Buhund), and F2 (F1 x Lundehund) generations. We found significant variation in microbiome composition from the parental Lundehund generation compared to the outcross progeny. The variation observed in purebred Lundehunds corresponded to dysbiosis as seen by a highly variable microbiome composition with an elevated Firmicutes to Bacteroidetes ratio and an increase in the prevalence of Streptococcus bovis/Streptococcus equinus complex, a known pathobiont that can cause several diseases. We tracked several other environmental factors including diet, the presence of a cat in the household, living in a farm and the use of probiotics, but we did not find evidence of an effect of these on microbiome composition and alpha diversity. In conclusion, we found an association between host genetics and gut microbiome composition, which in turn may be associated with the high incidence of Lundehund syndrome in the purebred parental dogs.
... Children are characteristically born with low memory T and B cells, reflecting their naivety to the environment, and those levels progressively rise as they are exposed to new antigens and develop memory. 13,14 Exposure to respiratory viruses and bacteria and the development of memory follow the same principles: it is necessary to have been exposed to the agents to "remember" them. Therefore, low exposure secondary to pandemic non-pharmaceutical interventions generates an "immunity debt" that must be eventually "paid", as already pointed out by researchers. ...
... The adaptive and the innate components of the immune system are immature in all neonates, yet especially so in preterm infants. This immaturity is thought to be related to a lack of antigenic exposure, enhanced self-modulatory immunosuppressive mechanisms, reduced physical barriers and impaired function of most cell types [68][69][70][71][72] . Furthermore, a lower number of goblet and Paneth cells, thinner mucus, reduced levels of IgG combined with low opsonic activity, reduced Figure 1. ...
Necrotizing enterocolitis (NEC) is a devastating disease in premature infants and the leading cause of death and disability from gastrointestinal disease in this vulnerable population. Although the pathophysiology of NEC remains incompletely understood, current thinking indicates that the disease develops in response to dietary and bacterial factors in the setting of a vulnerable host. As NEC progresses, intestinal perforation can result in serious infection with the development of overwhelming sepsis. In seeking to understand the mechanisms by which bacterial signaling on the intestinal epithelium can lead to NEC, we have shown that the gram-negative bacterial receptor toll-like receptor 4 is a critical regulator of NEC development, a finding that has been confirmed by many other groups. This review article provides recent findings on the interaction of microbial signaling, the immature immune system, intestinal ischemia, and systemic inflammation in the pathogenesis of NEC and the development of sepsis. We will also review promising therapeutic approaches that show efficacy in pre-clinical studies.
... During the first months of life, protection against infectious diseases relies on the transfer of maternal immunity across the placenta (Levy et al., 2013;Dowling and Levy, 2014;Jennewein et al., 2019). In healthy pregnancy, IgG levels in the umbilical cord blood typically are enriched, reaching more than 100% of maternal IgG levels (Kohler and Farr, 1966;Palmeira et al., 2012), due to the active transfer of antibodies across the placenta. ...
Introduction: Placental transfer of maternal antibodies is essential for neonatal immunity over the first months of life. In the setting of maternal HIV infection, HIV-exposed uninfected (HEU) infants are at higher risk of developing severe infections, including active tuberculosis (TB). Given our emerging appreciation for the potential role of antibodies in the control of Mycobacterium tuberculosis (Mtb), the bacteria that causes TB, here we aimed to determine whether maternal HIV status altered the quality of Mtb-specific placental antibody transfer.
Methods: Antigen-specific antibody systems serology was performed to comprehensively characterize the Mtb-specific humoral immune response in maternal and umbilical cord blood from HIV infected and uninfected pregnant people in Uganda.
Results: Significant differences were noted in overall antibody profiles in HIV positive and negative maternal plasma, resulting in heterogeneous transfer of Mtb-specific antibodies. Altered antibody transfer in HIV infected dyads was associated with impaired binding to IgG Fc-receptors, which was directly linked to HIV viral loads and CD4 counts.
Conclusions: These results highlight the importance of maternal HIV status on antibody transfer, providing clues related to alterations in transferred maternal immunity that may render HEU infants more vulnerable to TB than their HIV-unexposed peers.
... Newborns and especially preterm infants are many times more susceptible to infection than older children and adults. This increased susceptibility to infection is due to the fact that the neonatal immune system reacts differently to infectious agents compared to the adult immune system and only matures to the functional state of the adult immune system during the first postnatal months [2][3][4]. ...
The newborn's immune system is faced with the challenge of having to learn quickly to fight off infectious agents, but tolerating the colonization of the body surfaces with commensals without reacting with an excessive inflammatory response. Myeloid-derived suppressor cells (MDSC) are innate immune cells with suppressive activity on other immune cells that regulate fetal-maternal tolerance during pregnancy and control intestinal inflammation in neonates. Until now, nothing is known about the role of MDSC in microbiome establishment. One of the transcription factors regulating MDSC homeostasis is the hypoxia-inducible factor 1α (HIF-1α). We investigated the impact of HIF-1α on MDSC accumulation and microbiome establishment during the neonatal period in a mouse model with targeted deletion of HIF-1α in myeloid cells (Hif1a loxP/loxP LysMCre+). We show that in contrast to wildtype mice, where an extensive expansion of MDSC was observed, MDSC-expansion in neonatal Hif1a loxP/loxP LysMCre+ mice was dramatically reduced both systemically and locally in the intestine. This was accompanied by an altered microbiome composition and intestinal T-cell homeostasis. Our results point towards a role of MDSC in inflammation regulation in the context of microbiome establishment and thus reveal a new aspect of the biological role of MDSC during the neonatal period. This article is protected by copyright. All rights reserved.
... The immune system during the early stages of development is of utmost importance, as it shapes immune development throughout the life course, and the early stages are also considered sensitive and of high risk due to high susceptibility to infection. 41,42 Our results showed that all three PFASs interfered with the innate immune system in early-life-stage zebrafish by increasing the numbers of macrophage and neutrophil cells and stimulating specific adaptive responses (inducing CRP, IgM, LYSO content, the expression of inflammatory factors, and the complement C3 level). The inhibition of the adaptive immune protein, ALB, and induction of GLB further suggests that chronic inflammation occurs during early-life development in fish following PFAS exposure. ...
Previous studies have reported the immunotoxicity of per- and polyfluoroalkyl substances (PFASs), but it remains a significant challenge to assess over 10,000 distinct PFASs registered in the distributed structure-searchable toxicity (DSSTox) database. We aim to reveal the mechanisms of immunotoxicity of different PFASs and hypothesize that PFAS immunotoxicity is dependent on the carbon chain length. Perfluorobutanesulfonic acid (PFBA), perfluorooctanoic acid (PFOA), and perfluorononanoic acid (PFNA) representing different carbon chain lengths (4-9) at environmentally relevant levels strongly reduced the host's antibacterial ability during the zebrafish's early-life stage. Innate and adaptive immunities were both suppressed after PFAS exposures, exhibiting a significant induction of macrophages and neutrophils and expression of immune-related genes and indicators. Interestingly, the PFAS-induced immunotoxic responses were positively correlated to the carbon chain length. Moreover, PFASs activated downstream genes of the toll-like receptor (TLR), uncovering a seminal role of TLR in PFAS immunomodulatory effects. Myeloid differentiation factor 88 (MyD88) morpholino knock-down experiments and MyD88 inhibitors alleviated the immunotoxicity of PFASs. Overall, the comparative results demonstrate differences in the immunotoxic responses of PFASs due to carbon chain length in zebrafish, providing new insights into the prediction and classification of PFASs mode of toxic action based on carbon chain length.
... Firstly, we may not presume with certainty that the immunostimulatory property of rTcMIP observed in vitro on cord blood cells and in vivo in mice will be the same in vivo in humans. Although we have attractive preliminary results in mice, neither rodent models nor adult human leukocytes accurately model human newborn and infant responses (39). Secondly, molecules similar to TcMIP are expressed by various other pathogens such as Legionella pneumophila, Neisseria meningitidis, N. gonorrhoeae and Chlamydia trachomatis (24,(40)(41)(42)(43). Like TcMIP, these MIPs act as virulence factors through their PPIase activity. ...
This work identifies the protein “macrophage infectivity potentiator” of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.
... upper respiratory or gastrointestinal tract), and the type of antigen (viral or bacterial) [78]. In contrast to the predominant Th1, CD25 + , and IFN inflammatory response in adults, children are characterized by a particularly noteworthy Th2 and Th17 immune response [79]. Th1 cell development is primarily regulated by IL-12 and IFNgamma, while Th2 cell development is largely determined by IL-4 [78]. ...
Immune responses following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children are still under investigation. Even though coronavirus disease 2019 (COVID-19) is usually mild in the pediatric population, some children exhibit severe clinical manifestations, require hospitalization, or develop the most severe condition: a multisystem inflammatory syndrome in children (MIS-C) associated with SARS-CoV-2 infection. The activated innate, humoral and T-cell-mediated immunological pathways that lead certain pediatric populations to present with MIS-C or remain asymptomatic after SARS-CoV-2 infection are yet to be established. This review focuses on the immunological aspects of MIS-C with respect to innate, humoral, and cellular immunity. In addition, presents the role of the SARS-CoV-2 Spike protein as a superantigen in the pathophysiological mechanisms, discusses the great heterogeneity among the immunological studies in the pediatric population, and highlights possible reasons why some children with a certain genetic background present with MIS-C.
... 102 In children, the lymphocyte response to SARS-CoV-2 is characterized by a lower amount of pro-inflammatory cytokines than in adults, being more skewed toward a Th2 response. 36,105 This could partly explain the higher inflammatory cascade in the adult population and the consequent higher severity of the disease. In severe and fatal cases of COVID-19, elevated innate immune cytokines were detected in peripheral blood, including IL-1, IL-6, IL-8, or C-X-C Motif Chemokine Ligand 10. 37,106,107 Pierce et al. described significant differences in cytokines of 65 children and youth (<24 years) compared with adults with SARS-CoV-2 regardless of the severity of symptoms. ...
Coronavirus disease 2019 in children presents with milder clinical manifestations than in adults. On the other hand, the presence of a wide range of inflammatory manifestations, including multisystem inflammatory syndrome in children (MIS-C), in the period after infection suggests a particular susceptibility of some children toward severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Both protective factors that prevent evolution to severe forms and risk factors for post-infectious conditions are likely to be found in age-related differences in the immune system. The prompt innate response with type I IFN production and the generation of neutralizing antibodies play a crucial role in containing the infection. The greater number of naive and regulatory cells in children helps to avoid the cytokine storm while the causes of the intense inflammatory response in MIS-C need to be elucidated. This review aims to analyze the main results of the recent literature assessing immune response to SARS-CoV-2 over the pediatric age group. We summarized such observations by dividing them into innate and acquired immunity, then reporting how altered immune responses can determine post-infectious conditions. IMPACT: The main immune markers of acute SARS-CoV-2 infection in children are summarized in this review. This paper reports a broad overview of age-related differences in the immune response to SARS-CoV-2 and emerging post-infection conditions. A summary of currently available therapies for the pediatric age group is provided.
... Immune system is found to function differently amongst different age groups. Young children and aged people are found to be more vulnerable to infectious diseases when compared with people from other age groups (Dowling and Levy 2014;Simon et al. 2015). Studies reveal that immune responses are impaired with age (Yager et al. 2008). ...
Health has always been a matter of concern for all. Changes in behaviours related to health and climate variability have been evident in the past few years. Alterations in ambient air, water, food, and shelter due to changing climate are weakening health infrastructure. Though people in all age groups are more focussed on dietary patterns and lifestyle in general and with the increasing attention towards health-related aspects, preservation of health has become the most important concern globally. Various dimensions of health such as physical, social, psychological, and spiritual are now separately considered contributing factors to the overall maintenance of well-being. Personal, social, and environmental factors significantly impact the state of health and wellness in individuals. Additionally, biological factors such as genetics, gut microbiota, and neurotransmitters affect mental health. Dietary patterns, nutrition, physical exercises, emotional factors, personality traits, socio-environmental, and demographic conditions also play a significant role in promoting health-related behaviours and building the immune system. Creating awareness and spreading knowledge regarding the need and importance of various aspects of health and opting for sustainable developmental strategies specifically in the industrial and agricultural sectors are the need of the hour. An overall assessment and analysis of factors contributing to a healthy state can be influential in developing a multidimensional approach which can, in turn, be beneficial to the society at large to overcome challenging situations such as a pandemic and the stressors generated due to changing climate.KeywordsBehaviourClimate changeHealthImmunityWell-being
... Our study showed a specific increase in the risk of mortality due to respiratory diseases between the 50th and 150th days of life. This might have been possible due to a cumulative effect of critical negative factors during early infancy, for example, immunological immaturity and deteriorated response to infections, poor defense mechanisms, incomplete vaccination schedule, or transient iron deficiency [40][41][42][43]. There is also a possibility that some additive physiological or pathogenic mechanisms are involved in exacerbating the health issues, including an increased risk of morbidity and mortality between the second and the fourth month of age. ...
Background:
Air pollution is a major risk factor for public health worldwide, but evidence linking this environmental problem with the mortality of children in Central Europe is limited.
Objective:
To investigate the relationship between air pollution due to the emission of industry-related particulate matter and mortality due to respiratory diseases under one year of age.
Methods:
A retrospective birth cohort analysis of the dataset including 2,277,585 children from all Polish counties was conducted, and the dataset was matched with 248 deaths from respiratory diseases under one year of age. Time to death during the first 365 days of life was used as a dependent variable. Harmful emission was described as total particle pollution (TPP) from industries. The survival analysis was performed using the Cox proportional hazards model for the emission of TPP at the place of residence of the mother and child, adjusted individual characteristics, demographic factors, and socioeconomic status related to the contextual level.
Results:
Infants born in areas with extremely high emission of TPP had a significantly higher risk of mortality due to respiratory diseases: hazard ratio (HR) = 1.781 [95% confidence interval (CI): 1.175, 2.697], p = 0.006, compared with those born in areas with the lowest emission levels. This effect was persistent when significant factors were adjusted at individual and contextual levels (HR = 1.959 [95% CI: 1.058, 3.628], p = 0.032). The increased risk of mortality was marked between the 50th and 150th days of life, coinciding with the highest exposure to TPP.
Conclusions:
The emission of TPP from industries is associated with mortality due to respiratory diseases under one year of age. A considerable proportion of children's deaths could be prevented in Poland, especially in urban areas, if air pollution due to the emission of particle pollution is reduced.
... Interestingly, not only their susceptibility to infection is elevated, but also the termination of inflammation seems to be disturbed [10], leading to dysregulated and prolonged inflammation. This failure of inflammation resolution can cause organ damage and may contribute to the development of post-inflammatory diseases such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL), thereby significantly influencing long-term outcome [11,12]. ...
Term and especially preterm neonates are much more susceptible to serious bacterial infections than adults. But not only the susceptibility to infection is increased in neonates, but also their risk for developing post-inflammatory diseases such as bronchopulmonary dysplasia (BPD) and periventricular leukomalacia (PVL). This may be due to an impaired ability to terminate inflammation. In the study presented here, we aimed to investigate the proliferative response and the expression of immune-checkpoint molecules (ICM) and activation markers on neonatal T-cells in comparison to adult T-cells with the hypothesis that an increased activation of neonatal T-cells may contribute to the failure of inflammation resolution observed in neonates. We show that neonatal CD4 ⁺ and CD8 ⁺ T-cells show an increased proliferative capacity and an increased expression of activation markers compared to adult T-cells upon stimulation with OKT3 as well as a decreased expression of ICM, especially PD-L1 on their surface. This decreased expression of PD-L1 by neonatal T-cells was also observed after stimulation with GBS, but not after stimulation with E. coli , the two most important pathogens in neonatal sepsis. Expression of the T-cell receptor CD3 and the co-stimulatory molecule CD28 did not differ between adult and neonatal T-cells upon bacterial stimulation. Decreased expression of ICM upon T-cell activation may be a reason for the increased risk of neonates to develop post-inflammatory diseases.
Many respiratory infections are selectively injurious to infants, yet the etiology of age-associated susceptibility is unknown. One such bacterial pathogen is Bordetella pertussis. In adult mice, innate interferon-gamma (IFN-γ) is produced by natural killer (NK) cells and restricts infection to the respiratory tract. In contrast, infant pertussis resembles disease in NK cell- and IFN-γ -deficient adult mice that suffer disseminated lethal infection. We hypothesized that infants exhibit age-associated deficits in NK cell frequency, maturation, and responsiveness to B. pertussis, associated with low IFN-γ levels. To delineate mechanisms behind age-dependent susceptibility, we compared infant and adult mouse models of infection. Infection in infant mice resulted in impaired upregulation of IFN-γ and substantial bacterial dissemination. B. pertussis-infected infant mice displayed fewer pulmonary NK cells than adult mice. Furthermore, the NK cells in the infant mouse lungs had an immature phenotype, and the infant lung showed no upregulation of the IFN-γ-inducing cytokine IL-12p70. Adoptive transfer of adult NK cells into infants, or treatment with exogenous IFN-γ, significantly reduced bacterial dissemination. These data indicate that the lack of NK cell-produced IFN-γ significantly contributes to infant fulminant pertussis and could be the basis for other pathogen-induced, age-dependent respiratory diseases.
Emerging clinical and preclinical data have demonstrated that the pathophysiology of arterial ischemic stroke in the adult, neonates, and children share similar mechanisms that regulate brain damage but also have distinct molecular signatures and involved cellular pathways due to the maturational stage of the central nervous system and the immune system at the time of the insult. In this review, we discuss similarities and differences identified thus far in rodent models of 2 different diseases—neonatal (perinatal) and childhood arterial ischemic stroke. In particular, we review acquired knowledge of the role of resident and peripheral immune populations in modulating outcomes in models of perinatal and childhood arterial ischemic stroke and the most recent and relevant findings in relation to the immune-neurovascular crosstalk, and how the influence of inflammatory mediators is dependent on specific brain maturation stages. Finally, we discuss the current state of treatments geared toward age-appropriate therapies that signal via the immune-neurovascular interaction and consider sex differences to achieve successful translation.
Neonatal pnömoni, başta bakteriler olmak üzere çeşitli mikroorganizmaların neden olduğu, yüksek mortalite ve morbidite potansiyeli olan ciddi bir solunum yolu enfeksiyon hastalığıdır. Neonatal pnömoni, özellikle gelişmekte olan ülkeler için önemli bir sağlık sorunu olmaya devam etmekte olup, Dünyada her yıl 1 yaşından küçük 152.000-490.000 bebeğin pnömoniden öldüğü bildirilmektedir. %1-35 arasında insidansa sahip olan neonatal pnömoni, term bebekler için %1, preterm bebekler için ise %10 sıklığında görülmektedir. İnsidans; gebelik yaşı, entübasyon durumu, yenidoğan bakım düzeyi ve standardı, ırk ve sosyoekonomik duruma göre değişiklik göstermektedir. Pnömoniye bağlı ölüm oranı genellikle gebelik yaşı ve doğum ağırlığı ile ters orantılıdır. Neonatal pnömoniler başlangıç zamanına göre “Konjenital ve Erken Başlangıçlı Pnömoni” ile “Geç Başlangıçlı Pnömoni” olarak sınıflandırılmakta olup, maternal, perinatal ve mekanik ventilasyon gibi pek çok risk faktörü bulunmaktadır. Neonatal pnömonide klinik belirtiler spesifik olmayıp, semptomlar arasında çeşitli derecelerde solunum sıkıntısı, şüpheli görünen trakeal aspiratlar, öksürük, apne, unstabil vücut sıcaklığı, yetersiz beslenme, abdominal distansiyon ve letarji yer almaktadır. Bu doğrultuda pediatri hemşireleri, pnömoni tanısı bulunan yenidoğanların hemşirelik bakımında çoğunlukla destekleyici bakım uygulamakla birlikte, bebeğin solunum durumu ve oksijenasyonunu, sıvı durumunu ve sepsis riskini rutin olarak izlemesi ve değerlendirmesi gerekmektedir.
Infants necessitate vaccinations to prevent life-threatening infections. Our understanding of the infant immune responses to routine vaccines remains limited. We analyzed two cohorts of 2-month-old infants before vaccination, one week, and one-month post-vaccination. We report remarkable heterogeneity but limited antibody responses to the different antigens. Whole-blood transcriptome analysis in an initial cohort showed marked overexpression of interferon-stimulated genes (ISGs) and to a lesser extent of inflammation-genes at day 7, which normalized one month post-vaccination. Single-cell RNA sequencing in peripheral blood mononuclear cells from a second cohort identified at baseline a predominantly naive immune landscape including ISG hi cells. On day 7, increased expression of interferon-, inflammation-, and cytotoxicity-related genes were observed in most immune cells, that reverted one month post-vaccination, when a CD8+ ISG hi and cytotoxic cluster and B cells expanded. Antibody responses were associated with baseline frequencies of plasma cells, B-cells, and monocytes, and induction of ISGs at day 7.
Adjuvants can enhance vaccine immunogenicity, but their mechanism of action is often incompletely understood, hampering rapid applicability for pandemic vaccines. Herein, we characterized the cellular and molecular activity of adjuvant formulations available for pre-clinical evaluation, including several developed for global open access. We applied four complementary human in vitro platforms to assess individual and combined adjuvants in unformulated, oil-in-water, and liposomal delivery platforms. Liposomal co-formulation of MPLA and QS-21 was most potent in promoting dendritic cell maturation, selective production of Th1-polarizing cytokines, and activation of SARS-CoV-2 Spike-specific CD4 ⁺ and CD8 ⁺ T cells in a co-culture assay. Select formulations also significantly enhanced Spike antigen-specific humoral immunity in vivo. This study confirms the utility of the cumulative use of human in vitro tools to predict adjuvanticity potential. Thus, human in vitro modeling may advance public health by accelerating the development of affordable and scalable adjuvants for vaccines tailored to vulnerable populations.
Recent evidence suggests that the timing of introduction, types, and amounts of complementary foods/allergenic foods may influence the risk of allergic disease. However, the evidence has not been updated and comprehensively synthesized. The Cochrane Library, EMBASE, Web of Science, and PubMed databases were searched from the inception of each database up to 31 May 2023 (articles prior to 2000 were excluded manually). Statistical analyses were performed using RevMan 5. The GRADE approach was followed to rate the certainty of evidence. Compared with >6 mo, early introduction of eggs (≤6 mo of age) might reduce the risk of food allergies in preschoolers aged <6 y (odds ratio [OR], 0.65; 95% confidence interval [CI], 0.53, 0.81), but had no effect on asthma or atopic dermatitis (AD). Consumption of fish at 6–12 mo might reduce the risk of asthma in children (aged 5–17 y) compared with late introduction after 12 mo (OR, 0.61; 95% CI: 0.52, 0.72). Introduction of allergenic foods for ≤6 mo of age, compared with >6 mos, was a protective factor for the future risk (children aged ≤10 y) of AD (OR, 0.93; 95% CI: 0.89, 0.97). Probiotic intervention for infants at high risk of allergic disease significantly reduced the risk of food allergy at ages 0–3 y (OR, 0.72; 95% CI: 0.56, 0.94), asthma at 6–12 y (OR, 0.61; 95% CI: 0.41, 0.90), and AD at aged <6 y (3–6 y: OR, 0.70; 95% CI: 0.52, 0.94; 0–3 y: OR, 0.73; 95% CI: 0.59, 0.91). Early introduction of complementary foods or the high-dose vitamin D supplementation in infancy was not associated with the risk of developing food allergies, asthma, or AD during childhood. Early introduction to potential allergen foods for normal infants or probiotics for infants at high risk of allergies may protect against development of allergic disease. This study was registered at PROSPERO as CRD42022379264.
Interferons (IFN) are an assemblage of signaling proteins made and released by various host cells in response to stimuli, including viruses. Respiratory syncytial virus (RSV), influenza virus, and SARS-CoV-2 are major causes of respiratory disease that induce or antagonize IFN responses depending on various factors. In this review, the role and function of type I, II, and III IFN responses to respiratory virus infections are considered. In addition, the role of the viral proteins in modifying anti-viral immunity is noted, as are the specific IFN responses that underly the correlates of immunity and protection from disease.
Immune reconstitution refers to the recovery of different immune cells post stem cell transplant (SCT). It is important for immune system to reconstitute following SCT because impaired or delayed immune system is associated with increased risk of infections, autoimmune manifestations, graft-versus-host disease (GVHD) and increased risk of relapse of hematological malignancies. For a transplant physician It is important to understand the mechanisms involved in the T cell recovery after SCT as these T cells are involved both in favorable (fighting infection and mediating GVL effect) and unfavorable (GVHD, autoimmunity) effects of transplant. T cell recovery post SCT is depends upon combined effect of the multiple factors. Following SCT, the thymus is subjected to damage by the conditioning regimens, corticosteroids, and post transplant immunosuppressive agents, leading to its impaired function. The methods to induce immunologic tolerance to a foreign antigen are based on the same principles that are involved in the tolerance to self-antigens. Immunosuppressive agents are used to suppress autoreactive, allo-aggressive, or hyper-inflammatory T cells. To regain the capability of responding to millions of environmental antigens post SCT the T cell compartment has to diversify enormously for which both thymic-dependent and thymic-independent pathways are needed. Immune reconstitution can be measured by monitoring the activity of cells of innate and adaptive immunity. Aging affects both T cells and B cells. This chapter highlights the basic questions which a transplant physician faces regarding the mechanisms behind the immune reconstitution after SCT. A thorough knowledge of T and B cell development is necessary to understand the principles of immune reconstitution.
Microbial experience fundamentally shapes immunity, particularly during the perinatal period when the immune system is underdeveloped, and novel microbial encounters are common. Most animal models are raised in specific pathogen-free (SPF) conditions with relatively uniform microbial communities. How SPF housing conditions alter early-life immune development relative to natural microbial exposure (NME) has not been thoroughly investigated. In this article, we compare immune development in SPF-raised mice with mice born from immunologically experienced mothers in microbially diverse environments. NME induced broad immune cell expansion, including naive cells, suggesting mechanisms besides activation-induced proliferation contribute to the increase in immune cell numbers. We found NME conditions also expanded immune cell progenitor cell populations in the bone marrow, suggesting microbial experience enhances immune development at the earliest stages of immune cell differentiation. Multiple immune functions characteristically impaired in infants were also enhanced by NME, including T cell memory and Th1 polarization, B cell class switching and Ab production, proinflammatory cytokine expression, and bacterial clearance after Listeria monocytogenes challenge. Collectively, our studies reveal numerous impairments in immune development in SPF conditions relative to natural immune development.
Background:
The long-term immunologic effects of antiretroviral therapy (ART) in children with perinatally-acquired HIV (PHIV) have not been fully elucidated. Here, we investigated how the timing of ART initiation affects the long-term immune profile of children living with PHIV by measuring immunomodulatory plasma cytokines, chemokines, and adenosine deaminases (ADAs).
Methods:
40 PHIV participants initiated ART during infancy. 39 participant samples were available; 30 initiated ART ≤6 months (early-ART treatment); 9 initiated ART >6 months and <2 years (late-ART treatment). We compared plasma cytokine and chemokine concentrations and ADA enzymatic activities between early-ART and late-ART treatment 12.5 years later and measured correlation with clinical covariates.
Results:
Plasma concentrations of 10 cytokines and chemokines (IFNγ, IL-12p70, IL-13, IL-17A, IL-IRA, IL-5, IL-6, and IL-9 as well as CCL7, CXCL10), ADA1, and ADA total were significantly higher in late-ART compared to early-ART treatment. Furthermore, ADA1 was significantly positively correlated with IFNγ, IL-17A, and IL-12p70. Meanwhile, total ADA was positively correlated with IFNγ, IL-13, IL-17A, IL-1RA, IL-6, and IL-12p70 as well as CCL7.
Conclusions:
Elevation of several pro-inflammatory plasma analytes in late-ART despite 12.5 years of virologic suppression compared to early-ART treatment suggests that early treatment dampens the long-term plasma inflammatory profile in PHIV participants.
Impact:
This study examines differences in the plasma cytokine, chemokine, and ADA profiles 12.5 years after treatment between early (≤6months) and late (>6 months and <2 years) antiretroviral therapy (ART) treatment initiation in a cohort of European and UK study participants living with PHIV. Several cytokines and chemokines (e.g., IFNγ, IL-12p70, IL-6, and CXCL10) as well as ADA-1 are elevated in late-ART treatment in comparison to early-ART treatment. Our results suggest that effective ART treatment initiated within 6 months of life in PHIV participants dampens a long-term inflammatory plasma profile as compared to late-ART treatment.
We set out to gain insight into peripheral blood B and T cell repertoires from 120 infants of the LoewenKIDS birth cohort to investigate potential determinants of early life respiratory infections. Low antigen-dependent somatic hypermutation of B cell repertoires, as well as low T and B cell repertoire clonality, high diversity, and high richness especially in public T cell clonotypes reflected the immunological naivety at 12 months of age when high thymic and bone marrow output are associated with relatively few prior antigen encounters. Infants with inadequately low T cell repertoire diversity or high clonality showed higher numbers of acute respiratory infections over the first 4 years of life. No correlation of T or B cell repertoire metrics with other parameters such as sex, birth mode, older siblings, pets, the onset of daycare, or duration of breast feeding was noted. Together, this study supports that—regardless of T cell functionality—the breadth of the T cell repertoire is associated with the number of acute respiratory infections in the first 4 years of life. Moreover, this study provides a valuable resource of millions of T and B cell receptor sequences from infants with available metadata for researchers in the field.
Few studies have addressed the impact of maternal mild/asymptomatic SARS-CoV-2 infection on the developing neonatal immune system. In this study, we analyzed umbilical cord blood and placental chorionic villi from newborns of unvaccinated mothers with mild/asymptomatic SARS-CoV-2 infection during pregnancy using flow cytometry, single-cell transcriptomics, and functional assays. Despite the lack of vertical transmission, levels of inflammatory mediators were altered in cord blood. Maternal infection was also associated with increased memory T, B cells, and non-classical monocytes as well as increased activation. However, ex vivo responses to stimulation were attenuated. Finally, within the placental villi, we report an expansion of fetal Hofbauer cells and infiltrating maternal macrophages and rewiring towards a heightened inflammatory state. In contrast to cord blood monocytes, placental myeloid cells were primed for heightened antiviral responses. Taken together, this study highlights dysregulated fetal immune cell responses in response to mild maternal SARS-CoV-2 infection during pregnancy.
Microbial experience fundamentally shapes immunity, particularly during the perinatal period when the immune system is underdeveloped, and novel microbial encounters are common. Most animal models are raised in specific pathogen-free (SPF) conditions with relatively uniform microbial communities. How SPF housing conditions alter early-life immune development relative to natural microbial exposure (NME) has not been thoroughly investigated. In this article, we compare immune development in SPF-raised mice with mice born from immunologically experienced mothers in microbially diverse environments. NME induced broad immune cell expansion, including naive cells, suggesting mechanisms besides activation-induced proliferation contribute to the increase in immune cell numbers. We found NME conditions also expanded immune cell progenitor cell populations in the bone marrow, suggesting microbial experience enhances immune development at the earliest stages of immune cell differentiation. Multiple immune functions characteristically impaired in infants were also enhanced by NME, including T cell memory and Th1 polarization, B cell class switching and Ab production, proinflammatory cytokine expression, and bacterial clearance after Listeria monocytogenes challenge. Collectively, our studies reveal numerous impairments in immune development in SPF conditions relative to natural immune development.
Individuals differ in the nature of the immune responses they produce, affecting disease susceptibility and ultimately health and fitness. These differences have been hypothesised to have an origin in events experienced early in life that then affect trajectories of immune development and responsiveness. Here, we investigate how early life immune expression profiles influence life history outcomes in a natural population of field voles, Microtus agrestis, in which we are able to monitor variation between and within individuals through time by repeat sampling of individually marked animals. We analysed the co-expression of 20 immune genes in early life to create a correlation network consisting of three main clusters, one of which (containing Gata3, Il10 and Il17) was associated with later life reproductive success and susceptibility to chronic bacterial (Bartonella) infection. More detailed analyses supported associations between early life expression of Il17 and reproductive success later in life, and of Il10 expression early in life and later infection with Bartonella. We also found significant association between an Il17 genotype and the early life expression of Il10. Our results demonstrate that immune expression profiles can be manifested during early life with effects that persist through adulthood and that shape the variability among individuals in susceptibility to infection and fitness widely seen in natural populations.
Transplacental transfer of maternal antibodies provides the fetus and newborn with passive protection against infectious diseases. While the role of the highly conserved neonatal Fc receptor (FcRn) in transfer of IgG in mammals is undisputed, recent reports have suggested that a second receptor may contribute to transport in humans. We report poor transfer efficiency of plant-expressed recombinant HIV-specific antibodies, including engineered variants with high FcRn affinity, following subcutaneous infusion into rhesus macaques close to parturition. Unexpectedly, unlike those derived from mammalian tissue culture, plant-derived antibodies were essentially unable to cross macaque placentas. This defect was associated with poor Fcγ receptor binding and altered Fc glycans and was not recapitulated in mice. These results suggest that maternal-fetal transfer of IgG across the three-layer primate placenta may require a second receptor and suggest a means of providing maternal antibody treatments during pregnancy while avoiding fetal harm.
IMPORTANCE This study compared the ability of several human HIV envelope-directed monoclonal antibodies produced in plants with the same antibodies produced in mammalian cells for their ability to cross monkey and mouse placentas. We found that the two types of antibodies have comparable transfer efficiencies in mice, but they are differentially transferred across macaque placentas, consistent with a two-receptor IgG transport model in primates. Importantly, plant-produced monoclonal antibodies have excellent binding characteristics for human FcRn receptors, permitting desirable pharmacokinetics in humans. The lack of efficient transfer across the primate placenta suggests that therapeutic plant-based antibody treatments against autoimmune diseases and cancer could be provided to the mother while avoiding transfer and preventing harm to the fetus.
Measles, mumps and rubella (MMR) are contagious infectious diseases that can be prevented by immunization. However, MMR infections can occur in previously immunized individuals. The vaccine response is, among other factors, influenced by the combined effects of many genes. This systematic review investigates the genetic influence on measles, mumps and rubella antibody responses after childhood vaccination. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta‐Analyses (PRISMA), systematic literature searches were conducted in the medical databases PubMed, EMBASE and PsycINFO. Search strings were adjusted for each database. Citations were included if they measured and compared the immune response with immunogenetics after vaccination with a vaccine containing one or more of the following components: measles, mumps and/or rubella, MMR. The measure of vaccine response studied was antibodies after vaccination. Forty‐eight articles were included in the final analysis. The results suggest that genetic determinants, including host genes, and single nucleotide polymorphisms in immune‐related genes influence the MMR antibody responses after vaccination. Specifically, replicated associations were found between HLA, CD46, RARB, IRF9, EIF2AK2, cytokine genes and MMR vaccine‐induced humoral immune responses. This knowledge can be useful in understanding and predicting immune responses and may have implications for future vaccine strategies.
The impact of nutritional status during fetal life on the overall health of adults has been recognized; however, dietary effects on the developing immune system are largely unknown. Development of secondary lymphoid organs occurs during embryogenesis and is considered to be developmentally programmed. Secondary lymphoid organ formation depends on a subset of type 3 innate lymphoid cells (ILC3) named lymphoid tissue inducer (LTi) cells. Here we show that mouse fetal ILC3s are controlled by cell-autonomous retinoic acid (RA) signalling in utero, which pre-sets the immune fitness in adulthood. We found that embryonic lymphoid organs contain ILC progenitors that differentiate locally into mature LTi cells. Local LTi cell differentiation was controlled by maternal retinoid intake and fetal RA signalling acting in a haematopoietic cell-autonomous manner. RA controlled LTi cell maturation upstream of the transcription factor RORγt. Accordingly, enforced expression of Rorgt restored maturation of LTi cells with impaired RA signalling, whereas RA receptors directly regulated the Rorgt locus. Finally, we established that maternal levels of dietary retinoids control the size of secondary lymphoid organs and the efficiency of immune responses in the adult offspring. Our results reveal a molecular link between maternal nutrients and the formation of immune structures required for resistance to infection in the offspring.
To evaluate mononuclear cell expression and function of the cytosolic nucleotide-binding oligomerization domain-containing receptors, NOD1 and NOD2, in very preterm and full-term infants.
NOD1 and NOD2 gene and protein expression in very preterm infants, term infants and healthy adult, cord and peripheral blood mononuclear cells (C/PBMC) were quantified using qPCR and flow cytometry. Cytokine responses of purified infant and adult monocytes to NOD1- and NOD2-specific agonists were assessed using a multiplex immunoassay (Bioplex).
NOD1 and NOD2 were expressed by a range of infant and adult mononuclear cell types, including T- and B-cells, with highest expression in classical (CD14(++) CD16(-) ) and intermediate (CD14(++) CD16(+) ) monocytes. NOD1 and NOD2 expression levels by monocytes from very preterm infant were similar to those in term infants or adults. Monocyte production of TNFα, IL-6 and IL-1β, induced by activation of NOD1 and NOD2, was similar between very preterm infants, term infants and adults.
Monocyte expression and function of NOD1 and NOD2 in very preterm infants are intact and comparable/equivalent to term infants and adults. Functional deficiencies in monocyte NOD signalling pathways are unlikely to contribute to the increased susceptibility to bacterial sepsis in preterm infants. This article is protected by copyright. All rights reserved.
Memory T cells constitute the most abundant lymphocyte population in the body for the majority of a person's lifetime; however, our understanding of memory T cell generation, function and maintenance mainly derives from mouse studies, which cannot recapitulate the exposure to multiple pathogens that occurs over many decades in humans. In this Review, we discuss studies focused on human memory T cells that reveal key properties of these cells, including subset heterogeneity and diverse tissue residence in multiple mucosal and lymphoid tissue sites. We also review how the function and the adaptability of human memory T cells depend on spatial and temporal compartmentalization.
Susceptibility to infection as well as response to vaccination varies among populations. To date, the underlying mechanisms responsible for these clinical observations have not been fully delineated. Because innate immunity instructs adaptive immunity, we hypothesized that differences between populations in innate immune responses may represent a mechanistic link to variation in susceptibility to infection or response to vaccination.
Determine whether differences in innate immune responses exist among infants from different continents of the world.
We determined the innate cytokine response following pattern recognition receptor (PRR) stimulation of whole blood from 2-year-old infants across 4 continents (Africa, North America, South America, and Europe).
We found that despite the many possible genetic and environmental exposure differences in infants across 4 continents, innate cytokine responses were similar for infants from North America, South America, and Europe. However, cells from South African infants secreted significantly lower levels of cytokines than did cells from infants from the 3 other sites, and did so following stimulation of extracellular and endosomal but not cytosolic PRRs.
Substantial differences in innate cytokine responses to PRR stimulation exist among different populations of infants that could not have been predicted. Delineating the underlying mechanism(s) for these differences will not only aid in improving vaccine-mediated protection but possibly also provide clues for the susceptibility to infection in different regions of the world.
Newborn infants are highly susceptible to infection. This defect in host defence has generally been ascribed to the immaturity of neonatal immune cells; however, the degree of hyporesponsiveness is highly variable and depends on the stimulation conditions. These discordant responses illustrate the need for a more unified explanation for why immunity is compromised in neonates. Here we show that physiologically enriched CD71(+) erythroid cells in neonatal mice and human cord blood have distinctive immunosuppressive properties. The production of innate immune protective cytokines by adult cells is diminished after transfer to neonatal mice or after co-culture with neonatal splenocytes. Neonatal CD71(+) cells express the enzyme arginase-2, and arginase activity is essential for the immunosuppressive properties of these cells because molecular inhibition of this enzyme or supplementation with l-arginine overrides immunosuppression. In addition, the ablation of CD71(+) cells in neonatal mice, or the decline in number of these cells as postnatal development progresses parallels the loss of suppression, and restored resistance to the perinatal pathogens Listeria monocytogenes and Escherichia coli. However, CD71(+) cell-mediated susceptibility to infection is counterbalanced by CD71(+) cell-mediated protection against aberrant immune cell activation in the intestine, where colonization with commensal microorganisms occurs swiftly after parturition. Conversely, circumventing such colonization by using antimicrobials or gnotobiotic germ-free mice overrides these protective benefits. Thus, CD71(+) cells quench the excessive inflammation induced by abrupt colonization with commensal microorganisms after parturition. This finding challenges the idea that the susceptibility of neonates to infection reflects immune-cell-intrinsic defects and instead highlights processes that are developmentally more essential and inadvertently mitigate innate immune protection. We anticipate that these results will spark renewed investigation into the need for immunosuppression in neonates, as well as improved strategies for augmenting host defence in this vulnerable population.
Neonates suffer more severely and die more often than adults from a wide range of infections [1]. Although quantitative differences between neonatal and adult immune capacity are known, the molecular basis for the transition of immunologic function from fetal to postnatal life has remained a mystery. However, over the past decade, there has been an explosion of knowledge on immunity of the newborn and its importance to early host response to infection. Recent advances in developmental immunology now allow us to better understand the mechanisms underlying the susceptibility of neonates to many bacterial and viral infections [2, 3]. In addition, neonatal intestinal microbial ecology is now appreciated to play a role in host defenses and in the pathogenesis of neonatal necrotizing enterocolitis (NEC) [4]. In this special issue, we have collected reviews and papers to provide insight in immunologic adaptation of the neonate to its new environment and the consequences of this transition to newborn host defense mechanisms to bacterial and viral infection.
Plain pneumococcal polysaccharide (PPS) booster administered during second year of life has been shown to cause hyporesponsiveness. We assessed the effects of PPS booster on splenic memory B cell responses and persistence of PPS-specific long-lived plasma cells in the bone marrow (BM).
Neonatal mice were primed subcutanously (s.c.) or intranasally (i.n.) with pneumococcal conjugate (Pnc1-TT) and the adjuvant LT-K63, and boosted with PPS+LT-K63 or saline 1, 2 or 3 times with 16 day intervals. Seven days after each booster, spleens were removed, germinal centers (GC), IgM(+), IgG(+) follicles and PPS-specific antibody secreting cells (AbSC) in spleen and BM enumerated.
PPS booster s.c., but not i.n., compromised the Pnc1-TT-induced PPS-specific Abs by abrogating the Pnc1-TT-induced GC reaction and depleting PPS-specific AbSCs in spleen and limiting their homing to the BM. There was no difference in the frequency of PPS-specific AbSCs in spleen and BM between mice that received 1, 2 or 3 PPS boosters s.c.. Repeated PPS+LT-K63 booster i.n. reduced the frequency of PPS-specific IgG(+) AbSCs in BM.
PPS booster-induced hyporesponsiveness is caused by abrogation of conjugate-induced GC reaction and depletion of PPS-specific IgG(+) AbSCs resulting in no homing of new PPS-specific long-lived plasma cells to the BM or survival. These results should be taken into account in design of vaccination schedules where polysaccharides are being considered.
Background:
Deficiencies in phagocytosis may contribute to the increased susceptibility of infants to early life infections. Data on phagocytosis of the major neonatal pathogens Staphylococcus epidermidis (SE), Staphylococcus aureus (SA), and Escherichia coli (EC) by preterm infant leukocytes are inconsistent.
Methods:
Cord and <24-h peripheral blood were collected from very preterm (<30.1 wks gestational age (GA)) and term (37-42 wks GA) infants. Monocyte and neutrophil phagocytosis of pHrodo-labeled SE, SA, and EC were analyzed using a small-volume flow cytometry assay, with simultaneous characterization of surface activation marker expression.
Results:
Preterm infants had lower proportions of monocytes and neutrophils capable of phagocytosis than term infants, but preterm infant phagocytes had higher phagocytic capacity. Phagocytosis was strongly correlated between cord and <24-h peripheral blood. Supplementation with exogenous complement significantly increased phagocytosis of EC but not of SE or SA. Monocyte human leukocyte antigen (HLA)-DR expression was lower in preterm infants but did not correlate with phagocytosis.
Conclusion:
There is no defect in phagocytosis by monocytes and neutrophils from preterm compared with term infants, although preterm infants possess fewer phagocytes, possibly contributing to susceptibility to bacterial infection. Further investigation into the development of postnatal phagocytic competence is warranted.
The human fetal immune system is naturally exposed to maternal allogeneic cells, maternal antibodies, and pathogens. As such, it is faced with a considerable challenge with respect to the balance between immune reactivity and tolerance. Here, we show that fetal natural killer (NK) cells differentiate early in utero and are highly responsive to cytokines and antibody-mediated stimulation but respond poorly to HLA class I-negative target cells. Strikingly, expression of killer-cell immunoglobulin-like receptors (KIRs) did not educate fetal NK cells but rendered them hyporesponsive to target cells lacking HLA class I. In addition, fetal NK cells were highly susceptible to TGF-β-mediated suppression, and blocking of TGF-β signaling enhanced fetal NK cell responses to target cells. Our data demonstrate that KIR-mediated hyporesponsiveness and TGF-β-mediated suppression are major factors determining human fetal NK cell hyporesponsiveness to HLA class I-negative target cells and provide a potential mechanism for fetal-maternal tolerance in utero. Finally, our results provide a basis for understanding the role of fetal NK cells in pregnancy complications in which NK cells could be involved, for example, during in utero infections and anti-RhD-induced fetal anemia.
Extracellular adenosine, a key regulator of physiology and immune cell function that is found at elevated levels in neonatal blood, is generated by phosphohydrolysis of adenine nucleotides released from cells and catabolized by deamination to inosine. Generation of adenosine monophosphate (AMP) in blood is driven by cell-associated enzymes, whereas conversion of AMP to adenosine is largely mediated by soluble enzymes. The identities of the enzymes responsible for these activities in whole blood of neonates have been defined in this study and contrasted to adult blood. We demonstrate that soluble 5'-nucleotidase (5'-NT) and alkaline phosphatase (AP) mediate conversion of AMP to adenosine, whereas soluble adenosine deaminase (ADA) catabolizes adenosine to inosine. Newborn blood plasma demonstrates substantially higher adenosine-generating 5'-NT and AP activity and lower adenosine-metabolizing ADA activity than adult plasma. In addition to a role in soluble purine metabolism, abundant AP expressed on the surface of circulating neonatal neutrophils is the dominant AMPase on these cells. Plasma samples from infant observational cohorts reveal a relative plasma ADA deficiency at birth, followed by a gradual maturation of plasma ADA through infancy. The robust adenosine-generating capacity of neonates appears functionally relevant because supplementation with AMP inhibited whereas selective pharmacologic inhibition of 5'-NT enhanced Toll-like receptor-mediated TNF-α production in neonatal whole blood. Overall, we have characterized previously unrecognized age-dependent expression patterns of plasma purine-metabolizing enzymes that result in elevated plasma concentrations of anti-inflammatory adenosine in newborns. Targeted manipulation of purine-metabolizing enzymes may benefit this vulnerable population.
Two-day-old (P2), but not 9-day-old (P9), rat pups are susceptible to systemic infection following gastrointestinal colonization
by Escherichia coli K1. Age dependency reflects the capacity of colonizing K1 to translocate from gastrointestinal (GI) tract to blood. A complex
GI microbiota developed by P2, showed little variation over P2 to P9, and did not prevent stable K1 colonization. Substantial
developmental expression was observed over P2 to P9, including upregulation of genes encoding components of the small intestinal
(α-defensins Defa24 and Defa-rs1) and colonic (trefoil factor Tff2) mucus barrier. K1 colonization modulated expression of
these peptides: developmental expression of Tff2 was dysregulated in P2 tissues and was accompanied by a decrease in mucin
Muc2. Conversely, α-defensin genes were upregulated in P9 tissues. We propose that incomplete development of the mucus barrier
during early neonatal life and the capacity of colonizing K1 to interfere with mucus barrier maturation provide opportunities
for neuropathogen translocation into the bloodstream.
The intestinal tract is engaged in a relationship with a dense and complex microbial ecosystem, the microbiota. The establishment of this symbiosis is essential for host physiology, metabolism, and immune homeostasis. Because newborns are essentially sterile, the first exposure to microorganisms and environmental endotoxins during the neonatal period is followed by a crucial sequence of active events leading to immune tolerance and homeostasis. Contact with potent immunostimulatory molecules starts immediately at birth, and the discrimination between commensal bacteria and invading pathogens is essential to avoid an inappropriate immune stimulation and/or host infection. The dysregulation of these tight interactions between host and microbiota can be responsible for important health disorders, including inflammation and sepsis. This review summarizes the molecular events leading to the establishment of postnatal immune tolerance and how pathogens can avoid host immunity and induce neonatal infections and sepsis.
The human innate immune response to pathogens is not fully effective and mature until well into childhood, as exemplified
by various responses to Toll-like receptor (TLR) agonists in newborns compared to adults. To better understand the mechanistic
basis for this age-related difference in innate immunity, we compared tumor necrosis factor alpha (TNF-α) production by monocytes
from cord blood (CB) and adult blood (AB) in response to LAM (lipoarabinomannan from Mycobacterium tuberculosis, a TLR2 ligand) and LPS (lipopolysaccharide from Escherichia coli, a TLR4 ligand). LPS or LAM-induced TNF-α production was 5 to 18 times higher in AB than in CB monocytes, whereas interleukin-1α
(IL-1α) stimulated similar levels of TNF-α in both groups, suggesting that decreased responses to LPS or LAM in CB are unlikely
to be due to differences in the MyD88-dependent signaling pathway. This impaired signaling was attributable, in part, to lower
functional TLR4 expression, especially on CD14+ CD16+ monocytes, which are the primary cell subset for LPS-induced TNF-α production. Importantly, the frequency of CD14+ CD16+ monocytes in CB was 2.5-fold lower than in AB (P < 0.01). CB from Kenyan newborns sensitized to parasite antigens in utero had more CD14+ CD16+ monocytes (P = 0.02) and produced higher levels of TNF-α in response to LPS (P = 0.004) than CB from unsensitized Kenyan or North American newborns. Thus, a reduced CD14+ CD16+ activated/differentiated monocyte subset and a correspondingly lower level of functional TLR4 on monocytes contributes to
the relatively low TNF-α response to LPS observed in immunologically naive newborns compared to the response in adults.
Background:
Newborns display distinct immune responses that contribute to susceptibility to infection and reduced vaccine responses. Toll-like receptor (TLR) agonists may serve as vaccine adjuvants, when given individually or in combination, but responses of neonatal leukocytes to many TLR agonists are diminished. TLR8 agonists are more effective than other TLR agonists in activating human neonatal leukocytes in vitro, but little is known about whether different TLR8 agonists may distinctly activate neonatal leukocytes. We characterized the in vitro immuno-stimulatory activities of a novel benzazepine TLR8 agonist, VTX-294, in comparison to imidazoquinolines that activate TLR8 (R-848; (TLR7/8) CL075; (TLR8/7)), with respect to activation of human newborn and adult leukocytes. Effects of VTX-294 and R-848 in combination with monophosphoryl lipid A (MPLA; TLR4) were also assessed.
Methods:
TLR agonist specificity was assessed using TLR-transfected HEK293 cells expressing a NF-κB reporter gene. TLR agonist-induced cytokine production was measured in human newborn cord and adult peripheral blood using ELISA and multiplex assays. Newborn and adult monocytes were differentiated into monocyte-derived dendritic cells (MoDCs) and TLR agonist-induced activation assessed by cytokine production (ELISA) and co-stimulatory molecule expression (flow cytometry).
Results:
VTX-294 was ≈ 100x more active on TLR8- than TLR7-transfected HEK cells (EC50, ≈ 50 nM vs. ≈ 5700 nM). VTX-294-induced TNF and IL-1β production were comparable in newborn cord and adult peripheral blood, while VTX-294 was 1 log more potent in inducing TNF and IL-1β production than MPLA, R848 or CL075. Combination of VTX-294 and MPLA induced greater blood TNF and IL-1β responses than combination of R-848 and MPLA. VTX-294 also potently induced expression of cytokines and co-stimulatory molecules HLA-DR and CD86 in human newborn MoDCs.
Conclusions:
VTX-294 is a novel ultra-potent TLR8 agonist that activates newborn and adult leukocytes and is a candidate vaccine adjuvant in both early life and adulthood.
Microbial infections are a major cause of infant mortality worldwide as a result of impaired immune defenses in this population. The nature of this work was to further understand the mechanistic limitations of the neonatal and infant immune response. Interleukin (IL)-27 is a heterodimeric cytokine of the IL-12 family that is produced primarily by antigen presenting cells and is immunosuppressive toward a variety of immune cell types. Here we show that IL-27 gene expression is elevated in cord blood-derived macrophages relative to macrophages originating from healthy adults. We also evaluated the duration in which elevated IL-27 gene expression may impact immune responses in mice. Age-dependent analysis of IL-27 gene expression indicated that levels of IL-27 remain significantly elevated throughout infancy and then declined in adult mice. Flow cytometric analysis of intracellular cytokine-stained splenocytes further confirmed these results. IL-27 may be induced during pregnancy to contribute to the immunosuppressive environment at the fetal-maternal interface since we demonstrate dose-responsive gene expression to progesterone in macrophages. Neutralization of IL-27 in neonatal macrophages improved the ability of these cells to limit bacterial replication. Moreover, neutralization of IL-27 during incubation with the Mycobacterium bovis BCG vaccine augmented the level of interferon (IFN)-γ elicited from allogeneic CD4+ T lymphocytes. This suggests that blocking IL-27 during vaccination and infection may improve immune responses in newborn and infant populations. Furthermore, mice will be a suitable model system to further address these possibilities. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
Approximately 826,000 children, mostly young infants, die annually from invasive pneumococcal disease. A 6-10-14-week schedule of pneumococcal conjugate vaccine (PCV) is efficacious but neonatal PCV may provide earlier protection and better coverage. We conducted an open randomized controlled trial in Papua New Guinea to compare safety, immunogenicity and priming for memory of 7-valent PCV (PCV7) given in a 0-1-2-month (neonatal) schedule with that of the routine 1-2-3-month (infant) schedule.
We randomized 318 infants at birth to receive PCV7 in the neonatal or infant schedule or no PCV7. All infants received 23-valent pneumococcal polysaccharide vaccine (PPV) at age 9 months. Serotype-specific serum IgG for PCV7 (VT) serotypes and non-VT serotypes 2, 5 and 7F were measured at birth and 2, 3, 4, 9, 10 and 18 months of age. Primary outcomes were geometric mean concentrations (GMCs) and proportions with concentration ≥0.35 µg/ml of VT serotype-specific pneumococcal IgG at age 2 months and one month post-PPV.
We enrolled 101, 105 and 106 infants, respectively, into neonatal, infant and control groups. Despite high background levels of maternally derived antibody, both PCV7 groups had higher GMCs than controls at age 2 months for serotypes 4 (p<0.001) and 9V (p<0.05) and at age 3 months for all VTs except 6B. GMCs for serotypes 4, 9V, 18C and 19F were significantly higher (p<0.001) at age 2 months in the neonatal (one month post-dose2 PCV7) than in the infant group (one month post-dose1 PCV7). PPV induced significantly higher VT antibody responses in PCV7-primed than unprimed infants, with neonatal and infant groups equivalent. High VT and non-VT antibody concentrations generally persisted to age 18 months.
PCV7 is well-tolerated and immunogenic in PNG neonates and young infants and induces immunologic memory to PPV booster at age 9 months with antibody levels maintained to age 18 months.
ClinicalTrials.gov NCT00219401NCT00219401.
Compared with older children and adults, human neonates have reduced and delayed CD4 T cell immunity to certain pathogens, but the mechanisms for these developmental differences in immune function remain poorly understood. We investigated the hypothesis that impaired human neonatal CD4 T cell immunity was due to reduced signaling by naive CD4 T cells following engagement of the αβ-TCR/CD3 complex and CD28. Surprisingly, calcium flux following engagement of CD3 was significantly higher in neonatal naive CD4 T cells from umbilical cord blood (CB) compared with naive CD4 T cells from adult peripheral blood. Enhanced calcium flux was also observed in adult CD4 recent thymic emigrants. Neonatal naive CD4 T cells also had higher activation-induced Erk phosphorylation. The microRNA miR-181a, which enhances activation-induced calcium flux in murine thymocytes, was expressed at significantly higher levels in CB naive CD4 T cells compared with adult cells. Overexpression of miR-181a in adult naive CD4 T cells increased activation-induced calcium flux, implying that the increased miR-181a levels of CB naive CD4 T cells contributed to their enhanced signaling. In contrast, AP-1-dependent transcription, which is downstream of Erk and required for full T cell activation, was decreased in CB naive CD4 T cells compared with adult cells. Thus, CB naive CD4 T cells have enhanced activation-dependent calcium flux, indicative of the retention of a thymocyte-like phenotype. Enhanced calcium signaling and Erk phosphorylation are decoupled from downstream AP-1-dependent transcription, which is reduced and likely contributes to limitations of human fetal and neonatal CD4 T cell immunity.
Functionality and morphology of pDCs of preterm newborns, with emphasis on TLR9 triggered IFN-α production.
Bacterial and viral infections cause high rates of morbidity and mortality in premature newborns. In the setting of viral infection, pDCs play a key role as strong producers of IFN-α upon TLR9 activation. We analyzed pDC frequency, phenotype, morphology, and function in CB of preterm and term newborns in comparison with adults. Whereas all age groups show similar pDC numbers, BDCA-2, CD123, and TLR9 levels, the expression of BDCA-4 and capacity to produce IFN-α upon TLR9 challenge were decreased significantly in preterm neonates. Furthermore, we show by means of electron microscopy that pDCs from preterm newborns exhibit a distinct, “immature” morphology. Taken together, these findings suggest decreased functionality of pDCs in the premature newborn. The reduced capacity to produce IFN-α is likely to render such infants more susceptible to viral infections.
A cornerstone of modern biomedical research is the use of mouse models to explore basic pathophysiological mechanisms, evaluate new therapeutic approaches, and make go or no-go decisions to carry new drug candidates forward into clinical trials. Systematic studies evaluating how well murine models mimic human inflammatory diseases are nonexistent. Here, we show that, although acute inflammatory stresses from different etiologies result in highly similar genomic responses in humans, the responses in corresponding mouse models correlate poorly with the human conditions and also, one another. Among genes changed significantly in humans, the murine orthologs are close to random in matching their human counterparts (e.g., R(2) between 0.0 and 0.1). In addition to improvements in the current animal model systems, our study supports higher priority for translational medical research to focus on the more complex human conditions rather than relying on mouse models to study human inflammatory diseases.
Neonates are highly susceptible to infectious diseases and defective antiviral pDC immune responses have been proposed to contribute to this phenomenon. Isolated cord blood pDCs innately responded to a variety of TLR7 and TLR9 dependent viruses, including influenza A virus (IAV), human immunodeficiency virus (HIV) or herpes-simplex virus (HSV) by efficiently producing IFN-α, TNF-α as well as chemokines. Interestingly, following activation by CpGA, but not viruses, cord pDCs tend to survive less efficiently. We found that a hallmark of pDCs in neonates is an extended CD2+pDCs compartment compared to adult pDCs without affecting the antiviral IFN-α response. Within CD2+pDCs, we identified a subpopulation expressing CD5 and responsible for IL-12p40 production, however this population is significantly decreased in cord blood compared to adult blood. Therefore, neonatal pDCs clearly display variation in phenotype and subset composition, but without major consequences for their antiviral responses.
A vaccine that would protect young infants against measles could facilitate elimination efforts and decrease morbidity and mortality in developing countries. However, immaturity of the immune system is an important obstacle to the development of such a vaccine. In this study, DNA vaccines expressing the measles virus (MeV) hemagglutinin (H) protein or H and fusion (F) proteins, previously shown to protect juvenile macaques, were used to immunize groups of 4 newborn rhesus macaques. Monkeys were inoculated intradermally with 200 μg of each DNA at birth and at 10 months of age. As controls, 2 newborn macaques were similarly vaccinated with DNA encoding the influenza virus H5 and 4 received one dose of the current live attenuated MeV vaccine (LAV) intramuscularly. All monkeys were monitored for development of MeV-specific neutralizing and binding IgG antibody and cytotoxic T lymphocyte (CTL) responses. These responses were poor in comparison with the responses induced by LAV. At 18 months of age all monkeys were challenged intratracheally with a wild type strain of MeV. Monkeys that received the DNA vaccine encoding H and F, but not H alone, were primed for a MeV-specific CD8(+) CTL response, but not for production of antibody. LAV-vaccinated monkeys were protected from rash and viremia while DNA-vaccinated monkeys developed rashes similar to control monkeys, but had 10-fold lower levels of viremia. We conclude that vaccination of infant macaques with DNA encoding MeV H and F provided only partial protection from MeV infection.
Leukocyte recruitment is ontogenetically regulated during fetal life, with strongly impaired adhesiveness of fetal leukocytes and endothelial cells, during early fetal development.
Attenuation of the immune response contributes to the high rate of neonatal infections, particularly in premature infants. Whereas our knowledge of innate immune functions in mature neonates is growing, little is known about the ontogeny of neutrophil recruitment. We investigated neutrophils and ECs in the course of gestation with respect to rolling and adhesive functions. With the use of microflow chambers, we demonstrate that the neutrophilˈs ability to roll and adhere directly correlates with gestational age. These adhesion-related abilities are very rare in extremely premature infants (<30 weeks of gestation), which may correlate with our observation of markedly reduced expression of PSGL-1 and Mac-1 on neutrophils in preterm infants. In parallel, the capacity of HUVECs to mediate neutrophil adhesion under flow increases with gestational age. In addition, HUVECs from extremely premature infants exerting the lowest ability to recruit adult neutrophils show a diminished up-regulation of E-selectin and ICAM-1. Finally, by following neutrophil function postnatally, we show that maturation of PMN recruitment proceeds equivalently during extra- and intrauterine development. Thus, PMN recruitment and EC adhesion-related functions are ontogenetically regulated in the fetus, which might contribute significantly to the high risk of life-threatening infections in premature infants.
Infants in Papua New Guinea (PNG) are at a high risk of invasive pneumococcal disease, and a substantial burden of this falls on children less than six months old. PNG is planning to introduce a pneumococcal conjugate vaccine for infants in the near future, but to make the maximum impact neonatal immunization will have to be considered. To provide evidence on safety and immunogenicity for neonatal and early infant immunization, we undertook an open randomized controlled trial of 7-valent pneumococcal conjugate vaccine (7vPCV). 318 children received 7vPCV at ages 0, 1 and 2 months or at 1, 2 and 3 months or not at all. All children received 23-valent pneumococcal polysaccharide vaccine at age 9 months. This was a large and complex trial: village reporters visited participants weekly during the first year and fortnightly for a further 6 months and nurses monitored self-reported morbidity and collected many thousands of biological samples. The study team was remarkably successful in achieving the study aims, with 18-month follow-up completed on 77% of enrolled children and over 80% of scheduled samples collected. While the results of the trial will be reported elsewhere, this paper discusses the design of the study and dissects out some of the main reasons for its successful completion. Strong community engagement was an essential factor in success and the principles of equitable partnership and service provision led to a strong research partnership. A two-stage consent process, comprising primary assent followed by later informed consent, led to a high drop-out before initial enrolment, but an outstanding retention of those enrolled in the study. We conclude that factors such as strong community participation, reciprocity and a good relationship between the study team and participants are just as important as the technical elements of laboratory testing and data handling in ensuring the success of a vaccine trial in PNG.
IL-21, a member of the IL-2 cytokine family, is mainly produced by activated CD4+ T cells and controls the activity of immune and also non-immune cells. As a pleiotropic cytokine, IL-21 acts on both innate
and adaptive immune responses, suggesting that IL-21 may be a master regulator of the T-cell-dependent adaptive immune response.
Although IL-21 is described as mostly promoting inflammation, evidence also suggests inhibitory effects of IL-21. However,
its role, particularly in the human neonatal immune system, has not been detailed so far. Here, we assessed the effect of
IL-21 in the specific context of the neonatal immune response and delineated differences between the human newborn and adult
immune response. In umbilical cord blood, we demonstrated that IL-21 polarized naive CD4+ T cells into Th1 cells, producing IL-10, a key negative regulator during certain infections and autoimmunity. Furthermore, IL-21 stimulation
increased IFNγ secretion and inhibited the development of Th2 and Th17 cells and molecules associated with their function. Thus, in neonates, known to show limitations in establishing Th1 responses, IL-21 played a clear role in supporting Th1 responses in vitro, while appearing irrelevant for the adult immune response. Overall, we demonstrated the capability of IL-21 to induce the
immunosuppressive cytokine IL-10 and outlined its potential to compensate the restricted Th1 response in human newborns and consequently to reduce the susceptibility for infectious diseases in the first period of
life.
The first year of life represents a time of marked susceptibility to infections; this is particularly true for regions in sub-Saharan Africa. As innate immunity directs the adaptive immune response, the observed increased risk for infection as well as a suboptimal response to vaccination in early life may be due to less effective innate immune function. In this study, we followed a longitudinal cohort of infants born and raised in South Africa over the first year of life, employing the most comprehensive analysis of innate immune response to stimulation published to date. Our findings reveal rapid changes in innate immune development over the first year of life. This is the first report depicting dramatic differences in innate immune ontogeny between different populations in the world, with important implications for global vaccination strategies.
Pregnancy is an intricately orchestrated process where immune effector cells with fetal specificity are selectively silenced. This requires the sustained expansion of immune-suppressive maternal FOXP3(+) regulatory T cells (T(reg) cells), because even transient partial ablation triggers fetal-specific effector T-cell activation and pregnancy loss. In turn, many idiopathic pregnancy complications proposed to originate from disrupted fetal tolerance are associated with blunted maternal T(reg) expansion. Importantly, however, the antigen specificity and cellular origin of maternal T(reg) cells that accumulate during gestation remain incompletely defined. Here we show that pregnancy selectively stimulates the accumulation of maternal FOXP3(+) CD4 cells with fetal specificity using tetramer-based enrichment that allows the identification of rare endogenous T cells. Interestingly, after delivery, fetal-specific T(reg) cells persist at elevated levels, maintain tolerance to pre-existing fetal antigen, and rapidly re-accumulate during subsequent pregnancy. The accelerated expansion of T(reg) cells during secondary pregnancy was driven almost exclusively by proliferation of fetal-specific FOXP3(+) cells retained from prior pregnancy, whereas induced FOXP3 expression and proliferation of pre-existing FOXP3(+) cells each contribute to T(reg) expansion during primary pregnancy. Furthermore, fetal resorption in secondary compared with primary pregnancy becomes more resilient to partial maternal FOXP3(+) cell ablation. Thus, pregnancy imprints FOXP3(+) CD4 cells that sustain protective regulatory memory to fetal antigen. We anticipate that these findings will spark further investigation on maternal regulatory T-cell specificity that unlocks new strategies for improving pregnancy outcomes and novel approaches for therapeutically exploiting T(reg) cell memory.
Adaptive features of innate immunity, recently described as "trained immunity," have been documented in plants, invertebrate animals, and mice, but not yet in humans. Here we show that bacille Calmette-Guérin (BCG) vaccination in healthy volunteers led not only to a four- to sevenfold increase in the production of IFN-γ, but also to a twofold enhanced release of monocyte-derived cytokines, such as TNF and IL-1β, in response to unrelated bacterial and fungal pathogens. The enhanced function of circulating monocytes persisted for at least 3 mo after vaccination and was accompanied by increased expression of activation markers such as CD11b and Toll-like receptor 4. These training effects were induced through the NOD2 receptor and mediated by increased histone 3 lysine 4 trimethylation. In experimental studies, BCG vaccination induced T- and B-lymphocyte-independent protection of severe combined immunodeficiency SCID mice from disseminated candidiasis (100% survival in BCG-vaccinated mice vs. 30% in control mice). In conclusion, BCG induces trained immunity and nonspecific protection from infections through epigenetic reprogramming of innate immune cells.
The microbiota plays a fundamental role on the induction, training, and function of the host immune system. In return, the immune system has largely evolved as a means to maintain the symbiotic relationship of the host with these highly diverse and evolving microbes. When operating optimally, this immune system-microbiota alliance allows the induction of protective responses to pathogens and the maintenance of regulatory pathways involved in the maintenance of tolerance to innocuous antigens. However, in high-income countries, overuse of antibiotics, changes in diet, and elimination of constitutive partners, such as nematodes, may have selected for a microbiota that lack the resilience and diversity required to establish balanced immune responses. This phenomenon is proposed to account for some of the dramatic rise in autoimmune and inflammatory disorders in parts of the world where our symbiotic relationship with the microbiota has been the most affected.
It has been widely recognised that the phylogenetic distance between laboratory animals and humans limits the former's predictive value for immunogenicity testing of biopharmaceuticals, nanostructure-based drug delivery and adjuvant systems. 2D in vitro assays have been established in conventional culture plates with little success so far. Here, we detail the status of various 3D approaches to emulate innate immunity in non-lymphoid organs and adaptive immune response in human professional lymphoid immune organs in vitro. We stress the tight relationship between the necessarily changing architecture of professional lymphoid organs at rest and when activated by pathogens, and match it with the immunity identified in vitro. Recommendations for further improvements of lymphoid tissue architecture relevant to the development of a sustainable adaptive immune response in vitro are summarized. At the end, we sketch a forecast of translational innovations in the field to model systemic innate and adaptive immunity in vitro.
The gut microbiome plays an important role in regulation of metabolic processes, including digestion, absorption, and synthesis of bioactive molecules that signal physiological host mechanisms. Changes in the human gut microbiome are associated with type 2 diabetes and insulin resistance. Water-soluble dietary fibres like inulin and beta-glucan are fermented in the colon, and beta-glucan increases viscosity. Blueberries improve insulin sensitivity through an antioxidant effect. A cobiotic, consisting of purified inulin, sugar-free blueberry pomace extract, and an oat preparation of purified beta-glucan was developed for twice a day (bid) consumption as a smoothie drink to repair the gastrointestinal dysbiosis in type 2 diabetes. A 30-year-old man presented with new onset type 2 diabetes and a fasting glucose (FBS) of 375 mg/dl. Metformin 500 mg bid was initiated and increased to 1 g bid after 1 week. During the first 9 days of metformin treatment, he developed diarrhoea, but his FBS only dropped to 325 mg/dl. The cobiotic bid was added on the 9th day of metformin treatment, and after 2 days, his FBS dropped to 175 mg/dl. After 8 weeks on metformin and the cobiotic, his blood sugar was 100 mg/dl and he lost 5.5 kg. His stools became soft and formed on the cobiotic, reverted to diarrhoea when off of it for 2 days, and returned to normal on resuming the cobiotic formulation. Metformin is a safe, effective and inexpensive generic medication favouring weight loss, recommended as initial treatment of type 2 diabetes by the American Diabetes Association. However, a 20% incidence of diarrhoea limits its tolerability. A safe food supplement that can increase the efficacy of metformin and its tolerability, as occurred in this case report, would have significant positive public health consequences. A controlled clinical trial of the cobiotic with metformin is planned.
Neutrophils have traditionally been thought of as simple foot soldiers of the innate immune system with a restricted set of pro-inflammatory functions. More recently, it has become apparent that neutrophils are, in fact, complex cells capable of a vast array of specialized functions. Although neutrophils are undoubtedly major effectors of acute inflammation, several lines of evidence indicate that they also contribute to chronic inflammatory conditions and adaptive immune responses. Here, we discuss the key features of the life of a neutrophil, from its release from bone marrow to its death. We discuss the possible existence of different neutrophil subsets and their putative anti-inflammatory roles. We focus on how neutrophils are recruited to infected or injured tissues and describe differences in neutrophil recruitment between different tissues. Finally, we explain the mechanisms that are used by neutrophils to promote protective or pathological immune responses at different sites.
Infection of germ-free isolator piglets with swine influenza (S-FLU) that generates dsRNA during replication causes elevation of immunoglobulins in serum and bronchoalveolar lavage, a very weak response to trinitrophenyl conjugates but an immune response to S-FLU. The increased immunoglobulin levels result mainly from the polyclonal activation of B cells during the infection, but model antigen exposure may contribute. The 10-fold increase in local and serum IgG accompanies a 10-fold decrease in the transcription of IgG3 in the tracheal-bronchial lymph nodes and in the ileal Peyer's patches. Infection results in class switch recombination to downstream Cγ genes, which diversify their repertoire; both features are diagnostic of adaptive immunity. Meanwhile the repertoires of IgM and IgG3 remain undiversified suggesting that they encode innate, natural antibodies. Whereas IgG3 may play an initial protective role, antibodies encoded by downstream Cγ genes with diversified repertoires are predicted to be most important in long-term protection against S-FLU.
Natural killer (NK) cells are effector cells of the innate immune system and are important in the control of viral infection. Their relevance is reflected by the multiple mechanisms evolved by viruses to evade NK cell-mediated immune responses. Over recent years, our understanding of the interplay between NK cell immunity and viral pathogenesis has improved significantly. Here, we review the role of NK cells in the control of four important viral infections in humans: cytomegalovirus, influenza virus, HIV-1, and hepatitis C virus. Expected final online publication date for the Annual Review of Immunology Volume 31 is March 19, 2013. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
Innate lymphoid cells (ILCs) are newly identified members of the lymphoid lineage that have emerging roles in mediating immune responses and in regulating tissue homeostasis and inflammation. Here, we review the developmental relationships between the various ILC lineages that have been identified to date and summarize their functions in protective immunity to infection and their pathological roles in allergic and autoimmune diseases.
The development of vaccines for infants and young children requires the use of animal models at various stages of preclinical development. Animal models are being used to assess the quantity and quality of the immune response, onset and duration of the response, induction of systemic versus local immunity, protection against challenge infection for the assessment of vaccine efficacy, as well as safety and toxicity of the vaccine formulation itself. A variety of animal models are available, each with its own specific advantages and disadvantages. Here, we review the most common animal models for preclinical vaccine development for human infants.
Plasma is a rich mixture of immune regulatory factors that shape immune cell function. This immunomodulatory role of plasma is especially important in neonates. To maintain in utero feto-maternal tolerance and to allow for microbial colonization after birth, the neonatal immune system is biased against pro-inflammatory responses while favoring immune suppression. Therefore, the neonatal period provides a unique opportunity to study the physiologic mechanisms regulating the immune system. Several recent studies in neonates have identified plasma factors that play a key role in immune regulation. Insight into immune regulation by neonatal and adult plasma may have clinical implications, because plasma is easily accessible, affordable, and widely available. Herein, we review plasma-mediated immune regulation, with specific focus on neonatal plasma. We discuss how immune suppression is a key function of plasma and provide a systematic overview of the published literature regarding plasma-derived immune suppressive proteins, lipids, purines, and sugars. Finally, we outline how immune regulation by these factors, which are particularly abundant in neonatal plasma, may eventually be used to treat immune-mediated diseases, such as autoimmune, allergic, and inflammatory diseases.
Follicular Th (T(FH)) cells have emerged as a new Th subset providing help to B cells and supporting their differentiation into long-lived plasma cells or memory B cells. Their differentiation had not yet been investigated following neonatal immunization, which elicits delayed and limited germinal center (GC) responses. We demonstrate that neonatal immunization induces CXCR5(high)PD-1(high) CD4(+) T(FH) cells that exhibit T(FH) features (including Batf, Bcl6, c-Maf, ICOS, and IL-21 expression) and are able to migrate into the GCs. However, neonatal T(FH) cells fail to expand and to acquire a full-blown GC T(FH) phenotype, as reflected by a higher ratio of GC T(FH)/non-GC CD4(+) T cells in immunized adults than neonates (3.8 × 10(-3) versus 2.2 × 10(-3), p = 0.01). Following the adoptive transfer of naive adult OT-II CD4(+) T cells, OT-II T(FH) cells expand in the vaccine-draining lymph nodes of immunized adult but not infant recipients, whereas naive 2-wk-old CD4(+) OT-II cells failed to expand in adult hosts, reflecting the influence of both environmental and T cell-intrinsic factors. Postponing immunization to later in life increases the number of T(FH) cells in a stepwise manner, in direct correlation with the numbers of GC B cells and plasma cells elicited. Remarkably, adjuvantation with CpG oligonucleotides markedly increased GC T(FH) and GC B cell neonatal responses, up to adult levels. To our knowledge, this is the first demonstration that the T(FH) cell development limits early life GC responses and that adjuvants/delivery systems supporting T(FH) differentiation may restore adultlike early life GC B cell responses.
Given the "inborn" nature of the innate immune system, it is surprising to find that innate immune function does in fact change with age. Similar patterns of distinct Toll-like-receptor-mediated immune responses come to light when one contrasts innate immune development at the beginning of life with that toward the end of life. Importantly, these developmental patterns of innate cytokine responses correlate with clinical patterns of susceptibility to disease: A heightened risk of suffering from excessive inflammation is often detected in prematurely born infants, disappears over the first few months of life, and reappears toward the end of life. In addition, risk periods for particular infections in early life reemerge in older adults. The near-mirror-image patterns that emerge in contrasts of early versus late innate immune ontogeny emphasize changes in host-environment interactions as the underlying molecular and teleologic drivers.
Subunit vaccine formulations often include adjuvants that primarily stimulate innate immune cells. While young infants represent the major target population for vaccination, effective immunization in this age group remains a challenge. Many parameters of innate immune responses differ quantitatively and qualitatively from newborns to infants and adults, revealing a highly regulated developmental program. Herein, we discuss the potential implications of innate immune ontogeny for the activity of adjuvants contained in licensed infant vaccines, as well as future directions for rational design of adjuvanted vaccines for this age group.