Responses In Early Life Research Articles

Attenuation of Respiratory Syncytial Virus–Induced and RIG-I–Dependent Type I IFN Responses in Human Neonates and Very Young Children

Newborn infants, including those born at term without congenital disorders, are at high risk of severe disease from respiratory syncytial virus (RSV) infection. Indeed, our current local surveillance data demonstrate that approximately half of children hospitalized with RSV were ≤3 mo old, and 74% were born at term. Informed by this clinical epidemiology, we investigated antiviral innate immune responses in early life, with the goal of identifying immunological factors underlying the susceptibility of infants and young children to severe viral lower respiratory tract infections. We compared RSV-induced innate cytokine production in blood mononuclear cells from neonates, young children aged 12-59 mo, and healthy adults. RSV-induced IFN-α production was primarily mediated by plasmacytoid dendritic cells (pDCs), and was significantly lower in term infants and young children < 5 y of age than in adults (p < 0.01). RSV-induced IFN-α production in human pDCs proceeded independently of endosomal TLRs, and human pDCs from healthy adult donors produced IFN-α in a retinoic acid-inducible gene I protein (RIG-I)-dependent manner. Of interest, young age and premature birth were independently associated with attenuated RIG-I-dependent IFN-α responses (p < 0.01). In contrast to IFN-α production, proinflammatory IL-6 responses to RSV were mediated by monocytes, appeared less dependent on RIG-I, and were significantly impaired only among preterm infants, not in term infants and young children. Our results suggest that human pDCs are less functional in early life, which may contribute to the increased susceptibility of infants and young children to severe RSV disease.

Role of cellular immunity in cow's milk allergy: pathogenesis, tolerance induction, and beyond.

Food allergy is an aberrant immune-mediated reaction against harmless food substances, such as cow's milk proteins. Due to its very early introduction, cow's milk allergy is one of the earliest and most common food allergies. For this reason cow's milk allergy can be recognized as one of the first indications of an aberrant inflammatory response in early life. Classically, cow's milk allergy, as is true for most other allergies as well, is primarily associated with abnormal humoral immune responses, that is, elevation of specific immunoglobulin E levels. There is growing evidence indicating that cellular components of both innate and adaptive immunity play significant roles during the pathogenesis of cow's milk allergy. This is true for the initiation of the allergic phenotype (stimulation and skewing towards sensitization), development and outgrowth of the allergic disease. This review discusses findings pertaining to roles of cellular immunity in allergic inflammation, and tolerance induction against cow's milk proteins. In addition, a possible interaction between immune mechanisms underlying cow's milk allergy and other types of inflammation (infections and noncommunicable diseases) is discussed.

Neonatal antibody responses are attenuated by interferon-γ produced by NK and T cells during RSV infection

Respiratory syncytial virus (RSV) infects most children in the first year of life and is a major single cause of hospitalization in infants and young children. There is no effective vaccine, and antibody generated by primary neonatal infection is poorly protective against reinfection even with antigenically homologous viral strains. Studying the immunological basis of these observations in neonatal mice, we found that antibody responses to infection were low and unaffected by CD4 depletion, in contrast with adult mice, which had stronger CD4-dependent antibody responses. Natural killer cell depletion or codepletion of CD4(+) and CD8(+) cells during neonatal RSV infection caused a striking increase in anti-RSV antibody titer. These cells are major sources of the cytokine IFN-γ, and blocking IFN-γ also enhanced RSV-specific antibody responses in neonates. In addition, infection with a recombinant RSV engineered to produce IFN-γ reduced antibody titer, confirming that IFN-γ plays a pivotal role in inhibition of antibody responses after neonatal infection. These unexpected findings show that the induction of a strong cellular immune response may limit antibody responses in early life and that vaccines that induce IFN-γ-secreting cells might, in some situations, be less protective than those that do not.

Specific patterns of allergic sensitization in early childhood and asthma &amp; rhinitis risk

Specific patterns of allergic sensitization as well as quantification of the in vitro IgE response in early life may provide relevant clinical insight into future rhinitis and asthma risk. To define relationships among established sensitization to particular aeroallergens, quantitative analyses of allergen-specific IgE levels, pet exposure and sensitization, and asthma and rhinitis risk. Children at high-risk for the development of asthma and allergic diseases were enrolled at birth into the Childhood Origins of ASThma (COAST) study. Allergen-specific IgE was assessed at ages 1, 3, 6, and 9years by fluoroenzyme immunoassay (Unicap(®) 100; Pharmacia Diagnostics). Current asthma and rhinitis were diagnosed at age 6 and 8years. Sensitization to dog was strongly associated with increased asthma risk (P<0.0001). Sensitization to perennial compared with seasonal allergens was more strongly associated with asthma risk, while sensitization to seasonal allergens was more closely associated with rhinitis risk. Increased levels of specific IgE to perennial allergens were associated with an increased asthma risk (P=0.05), while any detectable level of IgE to seasonal allergens was associated with increased rhinitis risk (P=0.0009). While dog and cat sensitization were both independently associated with increased asthma and rhinitis risk, dog exposure at birth was associated with a reduced risk of asthma, regardless of dog sensitization status during the first 6years of life (P=0.05). Analysing specific patterns of an individual's allergic sensitization profile reveals additional relevant associations with asthma and rhinitis risk as opposed to the information gained from characterizing an individual as 'atopic' by the presence of any demonstrable sensitization alone. Furthermore, protective mechanisms of dog exposure with regards to asthma risk appear to be unrelated to the prevention of sensitization.

Congenital infection with Trypanosoma cruzi primes cord blood Vd2 T cells to proliferate in response to isopentenyl pyrophosphate.

Event Abstract Back to Event Congenital infection with Trypanosoma cruzi primes cord blood Vδ2 T cells to proliferate in response to isopentenyl pyrophosphate. Cristina Alonso-Vega1*, Emmanuel Hermann2, Carine Truyens3, Aurélie Berthe3, Amilcar Flores1, Rudy Parrado1, Faustino Torrico1 and Yves Carlier3 1 Universidad Mayor de San Simón, IIBISMED, Facultad de Medicina, Bolivia 2 CIIL - Center for Infection and Immunity of Lille, Institut Pasteur de Lille, Team 10: Basic and Clinical Immunology of Parasitic Diseases, France 3 Faculté de Médecine, Université Libre de Bruxelles (U.L.B.), Laboratoire de Parasitologie, Belgium Trypanosoma cruzi is the protozoa agent of Chagas’ disease in South America. Our team has previously demonstrated that newborns congenitally-infected with T. cruzi develop a parasite-specific CD8 αβ T cell immune response in utero. In the present study, we have investigated whether cord blood TCRVδ2 T cells were also involved in such response, by analysing their phenotype and their capacity to proliferate in response to isopentenyl pyrophosphate (IPP) in both uninfected and congenitally-infected newborns. We found that Vδ2 T cells can be expanded following congenital infection with T. cruzi. Cord blood Vδ2 T cells from congenitally-infected newborns expressed inhibitory NK cell receptors such as NKG2A and killer inhibitory receptors. Moreover, they vigorously expand in response to IPP combined with IL-2. Altogether these results demonstrate that Vδ2 T cells can be activated in utero and that these cells can be primed to respond to phosphoantigens. In conclusion, this work demonstrates that congenital infection with T. cruzi induces significant activation of fetal γδ T cells in utero, and supports the notion that it’s possible to boost the γδ T cell immune response in early life. Acknowledgements We thank Eduardo Suarez and the staff of the maternity German Urquidi (Cochabamba, Bolivia) for the management of patients, Mary-Cruz Torrico, Miguel Guzman and Marco Antonio Solano (CUMETROP/LABIMED, U.M.S.S., Cochabamba, Bolivia) for performing the serological and parasitological diagnosis of patients.

Development of ocular vestibular‐evoked myogenic potentials in small children

This study investigated the development of otolithic-ocular reflex in small children (<3 years old) via the ocular vestibular-evoked myogenic potential (oVEMP) test. Prospective study. Twenty full-term newborns (group A), 15 children aged 1 to 3 years (group B), and 15 children aged 4 to 13 years (group C) were enrolled in this study. All children underwent auditory brainstem response testing or audiometry, and the oVEMP test. All subjects had normal hearing. Typical biphasic oVEMP waveforms were not observed in the 20 newborns, but were present in six (40%) of 15 children aged 1 to 3 years and all (100%) children aged 4 to 13 years, exhibiting a significant difference. In group B, except for the nine children aged 12 to 24 months, the remaining six children, aged 25 to 47 months, had clear oVEMPs, with the mean nI latency and nI-pI amplitude resembling those in children aged 4 to 13 years, indicating that the otolithic-ocular reflex is mature in children aged >2 years. Despite the well-developed caloric and cervical VEMP responses in early life, oVEMPs are not present in newborns, but are present in children aged >2 years who can walk with a gait resembling an adult. Maturation of the otolithic-ocular reflex is important to balance control, which is necessary in small children for independent gait.

The Adjuvant LT-K63 Can Restore Delayed Maturation of Follicular Dendritic Cells and Poor Persistence of Both Protein- and Polysaccharide-Specific Antibody-Secreting Cells in Neonatal Mice

Ab responses in early life are low and short-lived; therefore, induction of protective immunity requires repeated vaccinations. One of the major limitations in early-life immunity is delayed maturation of follicular dendritic cells (FDCs), which play a central role in mediating the germinal center (GC) reaction leading to production of Ab-secreting cells (AbSCs). We assessed whether a nontoxic mutant of Escherichia coli heat-labile enterotoxin (LT-K63) and CpG1826 as model adjuvants could accelerate FDC maturation and immune response in neonatal mice, using a pneumococcal polysaccharide of serotype 1 conjugated to tetanus toxoid (Pnc1-TT) as a model vaccine. In neonatal NMRI mice, a single dose of Pnc1-TT coadministered with LT-K63 enhanced Pnc1-TT-induced GC reaction. In contrast, CpG1826 had no effect. Accordingly, LT-K63, but not CpG1826, accelerated the maturation of FDC networks, detected by FDC-M2(+) staining, characteristic for adult-like FDCs. This coincided with migration of MOMA-1(+) macrophages into the GCs that can enhance GC reaction and B cell activation. The FDC-M2(+) FDC networks colocalized with enhanced expression of TNF-α, which is critical for the maintenance of mature FDCs and is poorly expressed in neonates. The accelerated maturation of FDC networks correlated with increased frequency and prolonged persistence of polysaccharide- and protein-specific IgG(+) AbSCs in spleen and bone marrow. Our data show for the first time, to our knowledge, that an adjuvant (LT-K63) can overcome delayed maturation of FDCs in neonates, enhance the GC reaction, and prolong the persistence of vaccine-specific AbSCs in the BM. These properties are attractive for parenteral vaccination in early life.

Neonatal antigen-presenting cells are functionally more quiescent in children born under traditional compared with modern environmental conditions

One explanation for the high burden of allergic and autoimmune diseases in industrialized countries is inappropriate immune development under modern environmental conditions. There is increasing evidence that the process of immune deviation already begins in utero, but the underlying immunologic mechanisms are not clear. We sought to identify differences in the function of neonatal antigen-presenting cells (APCs) in children born in settings that are more traditional versus those of modern societies. Cord blood mononuclear cells were collected from newborns from Papua New Guinea (PNG; traditional) and Australia (modern) and compared for differences in APCs and T-cell phenotype and function. Australian cord naive T cells (CD4(+)CD25(-)CD127(+) cells) showed an enhanced and more rapid proliferative response in an autologous, APC-dependent culture system, a result of differences in neonatal APCs rather than T-cell function. This included an increased capacity to process antigen and to upregulate activation markers after stimulation. In contrast, resting PNG APCs exhibited higher baseline levels of activation and inhibitory markers and were less responsive or nonresponsive to stimulation in vitro. This study supports the hypothesis that prenatal environments can influence the developing immune system in utero. Children born under modern environmental conditions exhibit increased APC reactivity at birth compared with children born under traditional environmental conditions. The functionally more quiescent nature of PNG neonatal APCs might protect against the development of harmful inflammatory responses in early life.

In utero exposure to EPFR-containing PM inhibits pulmonary Th1 maturation and enhances adult asthma development in mice (57.15)

Abstract Environmentally persistent free radicals (EPFRs), with half-lives on the order of weeks have been detected in association with airborne particulate matter (PM) and early exposure to environmental hazards, such as PM, has been associated with an increased incidence of asthma in childhood. We hypothesized that in utero exposure to EPFR-containing PM disrupts immune development resulting in aberrant immune responses and enhancing susceptibility to asthma. To test this hypothesis, we exposed pregnant mice to ultrafine particles containing persistent free radicals (EPFR-UFP) and determined postnatal immune development and response to allergen sensitization and challenge. Intrauterine exposure to EPFR-UFP inhibited pulmonary T helper (Th1/Th2/Th17) and T regulatory (Treg) responses in early life (&amp;lt;1 week of age). Th2 and Treg responses recovered to normal levels; whereas Th1 responses remained attenuated at 6 weeks of age. In the asthma model, intrauterine EPFR-UFP-exposed mice exhibited higher airway hyperresponsiveness and pulmonary eosinophilia. In addition, levels of IL-4 and IL-5 (Th2 cytokines) in the bronchoalveolar lavage fluid of these mice were significantly higher than that of non-exposed mice that were sensitized and challenged with ovalbumin. Our data suggest that in utero exposure to EPFR-UFP enhances adult asthma development in mice, which might be related to the inhibition of pulmonary Th1 maturation.

Programming of the lung by early-life infection.

Many important human diseases, such as asthma, have their developmental origins in early life. Respiratory infections in particular may alter the course of asthma and may either protect against or promote the development of this disease. It is likely that the nature of the effects depends on the type and age of infection and is determined by the impact of infection on the immune and respiratory systems. Immunity in early life is plastic and can be moulded by antigen encounter, which may enhance or reinforce the asthmatic phenotype of early life, or induce protective responses. Chlamydial respiratory infections have specific effects and may increase asthma severity in early life by promoting systemic interleukin 13 responses and causing permanent changes in lung structure. Respiratory viral infections, such as those of respiratory syncytial virus and rhinovirus, promote pro-asthmatic responses in early life that contribute to the induction of asthma. By contrast, probiotics or infection or exposure to certain bacteria, such as Streptococcus pneumoniae, may have protective effects in asthma by increasing the numbers and activity of regulatory T cells. Here, we review the impact of infections on the developmental origins of asthma. Understanding these effects may lead to new therapeutic approaches for asthma that either target deleterious infections or utilize beneficial ones.

Gene expression profiles in rat mesenteric lymph nodes upon supplementation with Conjugated Linoleic Acid during gestation and suckling

BackgroundDiet plays a role on the development of the immune system, and polyunsaturated fatty acids can modulate the expression of a variety of genes. Human milk contains conjugated linoleic acid (CLA), a fatty acid that seems to contribute to immune development. Indeed, recent studies carried out in our group in suckling animals have shown that the immune function is enhanced after feeding them with an 80:20 isomer mix composed of c9,t11 and t10,c12 CLA. However, little work has been done on the effects of CLA on gene expression, and even less regarding immune system development in early life.ResultsThe expression profile of mesenteric lymph nodes from animals supplemented with CLA during gestation and suckling through dam's milk (Group A) or by oral gavage (Group B), supplemented just during suckling (Group C) and control animals (Group D) was determined with the aid of the specific GeneChip® Rat Genome 230 2.0 (Affymettrix). Bioinformatics analyses were performed using the GeneSpring GX software package v10.0.2 and lead to the identification of 89 genes differentially expressed in all three dietary approaches. Generation of a biological association network evidenced several genes, such as connective tissue growth factor (Ctgf), tissue inhibitor of metalloproteinase 1 (Timp1), galanin (Gal), synaptotagmin 1 (Syt1), growth factor receptor bound protein 2 (Grb2), actin gamma 2 (Actg2) and smooth muscle alpha actin (Acta2), as highly interconnected nodes of the resulting network. Gene underexpression was confirmed by Real-Time RT-PCR.ConclusionsCtgf, Timp1, Gal and Syt1, among others, are genes modulated by CLA supplementation that may have a role on mucosal immune responses in early life.

Gut microbiota, probiotics, and vitamin D: Interrelated exposures influencing allergy, asthma, and obesity?

Current evidence supports a role for gut colonization in promoting and maintaining a balanced immune response in early life. An altered or less diverse gut microbiota composition has been associated with atopic diseases, obesity, or both. Moreover, certain gut microbial strains have been shown to inhibit or attenuate immune responses associated with chronic inflammation in experimental models. However, there has been no fully adequate longitudinal study of the relation between the neonatal gut microbiota and the development of allergic diseases (eg, atopic asthma) and obesity. The emergence of promising experimental studies has led to several clinical trials of probiotics (live bacteria given orally that allow for intestinal colonization) in human subjects. Probiotic trials thus far have failed to show a consistent preventive or therapeutic effect on asthma or obesity. Previous trials of probiotics have been limited by small sample size, short duration of follow-up, or lack of state-of-the art analyses of the gut microbiota. Finally, there is emerging evidence that the vitamin D pathway might be important in gut homeostasis and in signaling between the microbiota and the host. Given the complexity of the gut micriobiota, additional research is needed before we can confidently establish whether its manipulation in early life can prevent or treat asthma, obesity, or both.

Mucosal and systemic anti-GAG immunity induced by neonatal immunization with HIV LAMP/gag DNA vaccine in mice

Vaccines capable of inducing mucosal immunity in early postnatal life until adulthood, protecting early sexual initiation, should be considered as strategies to vaccination against HIV. The HIV-1 GAG protein as a chimera with the lysosome-associated membrane protein (LAMP/gag), encoded by a DNA vaccine, is targeted to the endosomal/lysosomal compartment that contains class II MHC molecules and has been shown to be immunogenic in adult mice. Assuming that one such strategy could help to overcome the immunological immaturity in the early postnatal period, we have evaluated the systemic and mucosal immunogenicity of LAMP/gag immunization in neonatal mice. Intranasal immunization with LAMP/gag vaccine induced higher levels of sIgA and IgG anti-GAG antibodies in intestinal washes than did the gag vaccine. The combination of ID injections and the IN protocol with the chimeric vaccine promoted the increase of Ab levels in sera. Both vaccines induced splenic IFN-γ− secreting cells against GAG peptide pools, as well as in vivo cytotoxic T lymphocyte (CTL) function, and increased the percentage of CD8+ T cells to the immunodominant class I peptide in gut and spleen. However, only the chimeric vaccine was able to enhance Th1/Th2 cytokine secretion in response to class II GAG peptide and to enhance IL-4-secreting cells against GAG peptides and p24 protein stimuli. Long-lasting humoral and cellular responses were detected until adult age, following neonatal immunization with the chimeric vaccine. The LAMP/gag vaccination was able to induce potent GAG-specific T and B cell immune responses in early life which are essential to elicit sustained and long-lasting mucosal and systemic humoral response.

The Origins of Asthma and Chronic Obstructive Pulmonary Disease in Early Life

Results from birth cohort and cross-sectional studies of young children with wheezing have uncovered strong associations between both lung function and immune responses in early life and the subsequent development of persistent wheezing and chronic airway obstruction up to mid-adulthood. It is now apparent that the pattern of bronchial hyperresponsiveness, deficits in lung function, and structural airway remodeling that are characteristic of asthma may be already established during the preschool years in most patients. Interactions between acute viral infections, especially those due to rhinovirus and respiratory syncytial virus, and exposure to perennial aeroallergens may induce persistent alterations in immune responses and airway function in susceptible subjects. Similarly, deficits in airway function present shortly after birth predict airflow limitation in early adult life, which in turn is a strong predisposing factor for chronic obstructive pulmonary disease. The fact that these alterations are more likely to occur during early life and even in utero than later during childhood suggests that there a developmental window of susceptibility during which exposures can disrupt normal growth trajectories. Novel strategies for primary prevention of chronic respiratory diseases will be based on the identification of the genetic and environmental factors that interactively cause these disruptions.

Interleukin-10/Interleukin-5 Responses at Birth Predict Risk for Respiratory Infections in Children with Atopic Family History

Respiratory infections in early life are associated with risk for wheezing bronchiolitis, especially in children at high risk of atopy. The underlying mechanisms are unknown, but are suspected to involve imbalance(s) in host defense responses against pathogens stemming from functional immaturity of the immune system in this age group. To assess the contribution of eosinophil-trophic IL-5, and the potent antiinflammatory cytokine IL-10, to risk for infection in early life. We prospectively monitored a cohort of 198 high-risk children to age 5 years, recording every acute respiratory infection episode and classifying them by severity. We measured cord blood T-cell capacity to produce IL-10 and IL-5, and related these functions to subsequent infection history. IL-10 and IL-5 were associated, respectively, with resistance versus susceptibility to infections. The greatest contrasting effects of these two cytokines were seen when they were considered in combination by generating IL-10/IL-5 response ratios for each subject. The low IL-10/high IL-5 T-cell response phenotype was strongly associated with susceptibility to all grades of acute respiratory infection, relative to the more resistant high IL-10/low IL-5 phenotype. Excessive production of IL-5 by T cells at birth is associated with heightened risk for subsequent severe respiratory infections, and this risk is attenuated by concomitant IL-10 production. The underlying mechanisms may involve IL-10-mediated feedback inhibition of IL-5-dependent eosinophil-induced inflammation, which is a common feature of host antiviral responses in early life.

The Challenges of Vaccine Responses in Early Life: Selected Examples

One of the major challenges in vaccinology is the development of products that are able to induce protective immunity in the early life period. There are clear differences between adult and neonatal immune responses in both mice and humans with respect to both humoral and cell-mediated immunity. As a rule, neonates respond poorly to T-independent polysaccharide antigens and make lower and less persistent antibody responses to T-dependent protein antigens. Nevertheless, B-cell priming in neonates may lead to the generation of memory B cells. Similarly, neonatal cell-mediated immune responses are of lower potency than those generated in adults, and a key factor underlying this phenomenon may be a less effective interaction between antigen and neonatal dendritic cells. In addition to immunological immaturity in the neonate, the presence of inhibitory concentrations of maternally derived antibody imposes a further barrier to effective early life vaccination. Novel vaccination strategies including early priming and subsequent boosting are most likely to counteract these effects and provide protection from exposure to infectious disease in early life.

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Although cells expressing insulin are detected early in human fetal development, islets isolated from fetal pancreases show poor insulin secretory responses to glucose, which may be the result of deficient glucose sensing. We have used dual and triple immunolabelling of human fetal and adult pancreas sections to investigate the presence of proteins that participate in glucose sensing in the pancreatic beta cell, namely glucose transporter 1 (GLUT 1, also known as SLC2A1), glucose transporter 2 (GLUT2, also known as SLC2A2), glucokinase (GCK) and inwardly rectifying K+ channel (KIR6.2, also known as KCNJ11) and sulphonylurea receptor 1 (SUR1, also known as ABCC8) subunits of ATP-sensitive K+ channels (K+(ATP) channels). Pancreases obtained with ethical approval from human fetuses from 11 to 36 weeks of gestation, from infants and from adults were formalin-fixed and embedded in paraffin. Sections were labelled with antibodies to proteins of interest. Co-production of antigens was examined by dual and triple immunolabelling. GLUT2 and K+(ATP) channel labelling was detected in the 11-week pancreas, but largely within the pancreatic epithelium, whereas no labelling for GLUT1 was observed. From 15 weeks, GLUT1, GCK and K+(ATP) channel labelling was detected in an increasing proportion of insulin-positive cells and epithelial labelling with K+(ATP) channel antibodies diminished. GLUT2 was seen in the majority of beta cells only after 7 months of age. The results demonstrate that only a subpopulation of beta cells in the human fetal pancreas produce all key elements of the glucose-sensing apparatus, which may contribute to poor secretory responses in early life.

The advantage of mucosal immunization for polysaccharide‐specific memory responses in early life

The aim of vaccination is to rapidly elicit protective immunity and generate memory for sustained protection. We studied the induction and persistence of polysaccharide (PS)-specific memory in neonatal and infant mice primed with pneumococcal conjugate (Pnc1-TT) by assessing the response to native pneumococcal PS (PPS-1), the kinetics of the PPS-1-specific IgG response to a second Pnc1-TT dose and affinity maturation. A subcutaneous (s.c.) Pnc1-TT booster induced a rapid increase in PPS-1-specific IgG, indicating efficient priming for memory by a single dose of Pnc1-TT already at 1 week of age. High levels were maintained for >12 weeks. However, a PPS-1 booster induced no response in neonatal or infant mice. The adjuvant LT-K63 significantly enhanced the IgG response and affinity to Pnc1-TT by both the s.c. and the intranasal (i.n.) route in all age groups. In neonatal and infant mice, PPS-1 and LT-K63 induced a booster response only when given i.n. following either s.c. or i.n. priming with Pnc1-TT and LT-K63. In contrast, PPS-1 with or without LT-K63 administered s.c. compromised the ongoing PPS-1-specific response elicited in neonatal mice by either s.c. or i.n. priming with Pnc1-TT and LT-K63. These results demonstrate the advantage of the mucosal route for elicitation of PS-specific memory responses in early life.

Evidence that negative feedback between antibody concentration and affinity regulates humoral response consolidation to a non-infectious antigen in infants

The dynamics of human antigen-specific immunoglobulin (Ig) responses in early life are not well characterized. We have previously observed an inverse relationship between allergen-specific Ig concentration and allergen-Ig-binding affinity in allergen-sensitive atopic adults, suggesting a possible feedback relationship between these variables. We prospectively studied children (6 months to 6 years) with and without atopic sensitization to the Der p 1major allergen. Experimental results showed the following trends. (1) In both study groups, there was little change with age in average Der p 1-specific Ig (IgG1 or IgE) concentrations or allergen-Ig-binding affinities, and concentrations and affinities were independent. (2) Among individuals, however, there was a negative correlation between Ig concentration changes and affinity changes with age. (3) The rate of increase with age of the non-atopic Der p 1–IgG1 total binding capacity (Ig concentration × Ig affinity) paralleled that for the atopic Der p 1–IgE total binding capacity, and there was a comparable ‘consolidation’ of responses with age reflected by a narrowing of the variance of total binding capacity values. Except for the Ig classes involved, development of a humoral response to a non-infectious allergen is similarly regulated in atopic and non-atopic children, with Ig total binding capacity as the key regulatory variable. These results also suggest that there is a time-dependent feedback relationship between Ig concentrations and affinities that establishes an optimal Ig total binding capacity for a given environmental ‘antigen load’. A theoretical model is proposed to account for this relationship.

Influence of complement C3 amount on IgG responses in early life: immunization with C3b-conjugated antigen increases murine neonatal antibody responses

Complement component C3, which plays an important role in both the innate and adaptative immune response, is present at low level in human infants. We show here that: (i) serum C3 amount is weak also in infant mice, (ii) these young animals fail to upregulate C3 to adult levels following tetanus toxoid immunization, (iii) neonatal macrophages have a limited capacity to synthesize C3 upon LPS exposure, (iv) conjugation of antigen to C3b significantly enhances antibody response elicited in 1-week-old mice—although it does not increase primary IgG response in adult mice. Altogether, this identifies C3 as one of the factors limiting early life antibody response and emphasizes the potential interest of immunization strategies overcoming this limitation.