Peter N. Le Souëf

Relationship between helminthic infection and IgE response in atopic and nonatopic children in a tropical environment

BACKGROUND Although IgE antibody is clearly involved in allergic reactions to environmental allergens, this immunoglobulin is an important component of host-protective immune responses against the helminthic parasites that are endemic in the majority of the world population. However, these infections not only stimulate the production of antiparasite IgE antibody but can nonspecifically induce polyclonal IgE synthesis that results in highly elevated total serum IgE levels. Such polyclonal stimulation can diminish specific IgE antibody responses and cause saturation of mast cell Fc epsilon receptors, thus inhibiting allergic reactivity. This may represent a mechanism of immune evasion by the parasite. OBJECTIVE Because an atopic disposition is generally recognized to be associated with elevated IgE synthesis against environmental allergens, the aim of this study was to evaluate the influence of atopy on the antiparasite response. To this end, we examined two groups of Venezuelan children in whom the intestinal helminth Ascaris lumbricoides is endemic but that differ greatly in their level of atopy. One group was from an island population (Coche Island) that has a very strong atopic background and in which the prevalence of allergic disease is extremely high. The other was a group of nonatopic children belonging to a mainland population (Barrio Los Erasos) that is of comparable socioeconomic level and has an exposure to helminthic infection similar to that of the island group but a relatively low expression of allergic diseases. RESULTS Although the living conditions and the prevalence of Ascaris infection of the two groups were comparable, the intensity of the parasitic infection was considerably higher in the nonatopic mainland children (geometric mean values of eggs per gram of feces: Barrio Los Erasos, 7621; Coche Island, 1435; p < 0.001). In addition, their total serum IgE levels were significantly more elevated than in the atopic island group (geometric mean: Barrio Los Erasos, 2172; Coche Island, 941 IU/ml; p < 0.001). In contrast, the specific anti-Ascaris response was much stronger in the atopic children (geometric mean: Barrio Los Erasos, 0.30; Coche Island, 0.91 PRU/ml; p < 0.001), which resulted in the ratio of specific to total IgE being nine times higher than in the nonatopic mainland subjects. These differences were maintained even when the children were matched on the basis of infection intensity, thus indicating that the atopic children have an intrinsic propensity to favor specific over polyclonal IgE responses to the parasite. CONCLUSIONS The children with a strong atopic background demonstrated IgE responses concordant with an enhanced protective response against helminthic parasites and had significantly lower intensities of infection than their nonatopic counterparts. These observations support the concept that the atopic state has conferred a selective evolutionary advantage that could compensate for its involvement in allergic disease.

TLR4 Polymorphisms Mediate Impaired Responses to Respiratory Syncytial Virus and Lipopolysaccharide

Severe bronchiolitis following respiratory syncytial virus (RSV) infection occurs in only a small subset of infected infants and the basis for variations in disease severity is not understood. Innate immune responses to RSV are mediated by TLR-4, and the 299Gly and 399Ile alleles of the TLR4 gene have been linked epidemiologically with increased severity of RSV disease in children. We hypothesized that cellular immune responses to RSV mediated by these variant forms of the receptor are defective relative to responses mediated via the common form of the receptor. Human bronchial epithelial cells were transfected with TLR4 constructs encoding the common TLR4 gene sequence (299Asp/399Thr), or the 299Gly or 399Ile alleles, and cytokine responses to in vitro RSV challenge were analyzed in the different transfected cells. Follow-up studies compared RSV-induced responses in PBMC from children expressing these same TLR4 genotypes. Human bronchial epithelial expressing 299Gly or 399Ile displayed normal levels of intracellular TLR4 but failed to efficiently translocate the receptor to the cell surface. This was associated with reduced NF-κB signaling post-TLR4 engagement, reduced production of IFNs, IL-8, IL-10, IL-12p35, IL-18, and CCL8, and the absence of acute-phase TNF-α. These findings were mirrored by blunted PBMC responses to RSV in children expressing the same TLR4 variants. Compromised first-line defense against RSV at the airway-epithelial surface of children expressing these TLR4 variants may thus confer increased susceptibility to severe infections with this virus.

Childhood asthma and increased airway responsiveness : a relationship that begins in infancy

RATIONALE Asthma is associated with increased airway responsiveness (AR), but the age when this relationship becomes established is not clear. The present study tested the hypothesis that the association between increased AR and asthma is established after 1 month of age. OBJECTIVES To relate AR in infancy to asthma in childhood. METHODS As part of a birth cohort study, AR was determined at 1 (early infancy), 6 (mid-infancy), and 12 months of age (late infancy). At 11 years of age (childhood), AR and the presence of asthma symptoms were determined. MEASUREMENTS AND MAIN RESULTS Of the 253 study subjects enrolled, AR was determined in 202 in early infancy, 174 in mid-infancy, 147 in late infancy, and 176 in childhood. Increased AR in late infancy, but not in early or mid-infancy, was associated with increased wheeze at 11 years of age (P = 0.016). Increased AR in infancy persisted into childhood in association with male gender, early respiratory illness, and maternal smoking and asthma. Among the 116 subjects assessed in late infancy and childhood, recent wheeze was present in 35% of children with increased AR at both ages, 13% with increased AR in childhood only, 12% for those with increased AR in late infancy only, and 0% for those who did not have increased AR at either age (P = 0.023); the proportions of children with diagnosed asthma in the corresponding groups were 27, 20, 12, and 0% (P = 0.038). CONCLUSIONS The association between increased infantile AR and childhood asthma emerges at the end of the first year of life.

Allergen-enhanced thrombomodulin (blood dendritic cell antigen 3, CD141) expression on dendritic cells is associated with a TH2-skewed immune response.

BACKGROUND Dendritic cells (DCs) are important in allergic diseases such as asthma, although little is known regarding the mechanisms by which DCs induce T(H)2-polarized responses in atopic individuals. It has been suggested that intrinsic properties of allergens can directly stimulate T(H)2 polarizing functions of DCs, but little is known of the underlying mechanisms. OBJECTIVE To identify novel genes expressed by house dust mite (HDM) allergen-exposed DCs. METHODS We screened for allergen-induced gene expression by microarray, and validated differentially expressed genes at the mRNA and protein levels. RESULTS Thrombomodulin (CD141, blood dendritic cell antigen 3) expression by microarray was higher on HDM-stimulated DCs from atopic (relative to nonatopic) individuals. These findings were confirmed at both the mRNA and protein levels in an independent group. Purified thrombomodulin(+) DCs induced a strongly T(H)2-polarized cytokine response by allergen-specific T cells compared with DCs lacking thrombomodulin. In vivo, thrombomodulin(+) circulating DCs were significantly more frequent in subjects with HDM allergy and asthma, compared with control subjects. Furthermore, thrombomodulin expression in blood leukocytes was higher in children with acute asthma than at convalescence 6 weeks later. CONCLUSION Thrombomodulin expression on DCs may be involved in the pathogenesis of atopy and asthma.

Flow limitation during tidal expiration in symptom-free infants and the subsequent development of asthma.

During a longitudinal study of lung function and airway responsiveness in a cohort of healthy infants, we identified a subgroup of symptom-free infants at the age of 1 month with flow limitation during tidal expiration. We report a 2-year follow-up of 252 infants who were first studied at 1 month of age. Maximal flow at functional residual capacity (VmaxFRC) was measured from a forced expiratory flow-volume curve by the rapid thoracic compression technique. The pattern of tidal breathing was assessed with the ratio of the time to reach maximal expiratory flow during expiration to the total expiratory time (Tme/Te ratio). Histamine inhalation challenge was used to determine the level of airway responsiveness. Compliance and resistance of the total respiratory system were measured from a passive expiration after occlusion at end inspiration. Data regarding the family history of asthma, atopy, and parental smoking were obtained by questionnaire. Flow limitation was considered present when the forced expiratory flow did not exceed tidal flow at functional residual capacity. Nineteen infants were identified with flow limitation at 5 weeks of age; all had a family history of asthma, atopy, and/or parental smoking. These 19 infants were compared with 35 infants with no family history of asthma or parental smoking and 38 gender-, history-, and age-matched control infants without flow limitation during tidal expiration. At the age of 1 month, the flow-limited group had reduced VmaxFRC, Tme/Te, and respiratory compliance and increased respiratory resistance. At 6 and 12 months of age, although no longer flow limited, these infants still had significantly reduced lung function and increased airway responsiveness. Flow limitation in early life was also significantly associated with the development of physician-diagnosed asthma by the age of 2 years (odds ratio, 7.4; 95% confidence interval, 1.4 to 35.2). Infants with abnormal lung function soon after birth may have a genetic predisposition to asthma or other airway abnormalities that predict the risk of subsequent lower respiratory tract illness.

Birth cohorts in asthma and allergic diseases: Report of a NIAID/NHLBI/MeDALL joint workshop

Population-based birth cohorts on asthma and allergies increasingly provide new insights into the development and natural history of the diseases. More than 130 birth cohorts focusing on asthma and allergy have been initiated in the last 30 years. A National Institute of Allergy and Infectious Diseases; National Heart, Lung, and Blood Institute; Mechanisms of the Development of Allergy (MeDALL; Framework Programme 7 of the European Commission) joint workshop was held in Bethesda, Maryland, on September 11-12, 2012, with 3 objectives: (1) documenting the knowledge that asthma/allergy birth cohorts have provided, (2) identifying the knowledge gaps and inconsistencies, and (3) developing strategies for moving forward, including potential new study designs and the harmonization of existing asthma birth cohort data. The meeting was organized around the presentations of 5 distinct workgroups: (1) clinical phenotypes, (2) risk factors, (3) immune development of asthma and allergy, (4) pulmonary development, and (5) harmonization of existing birth cohorts. This article presents the workgroup reports and provides Web links (AsthmaBirthCohorts.niaid.nih.gov or www.medall-fp7.eu), where the reader will find tables describing the characteristics of the birth cohorts included in this report, the type of data collected at differing ages, and a selected bibliography provided by the participating birth cohorts.

In Utero Smoke Exposure and Role of Maternal and Infant Glutathione S-Transferase Genes on Airway Responsiveness and Lung Function in Infancy

RATIONALE Xenobiotics in the maternal circulation are capable of crossing the placental barrier so a reduction in the mother and fetuss detoxification ability due to genetic variation in the glutathione S-transferases (GSTs) could expose the fetus to higher levels of toxins. OBJECTIVES To investigate the interactive effects of maternal smoking during pregnancy with maternal and infant GST genotypes on airway responsiveness (AR) and lung function in infancy. METHODS GSTT1, GSTP1 and GSTM1 were genotyped in infants and mothers, in utero smoke exposure was evaluated by questionnaire, AR was assessed by histamine challenge and Vmax(FRC) was measured using the rapid thoracoabdominal compression technique. We investigated the interactive effects of maternal smoking during pregnancy with maternal and infant GST genes on AR and lung function at 1, 6, and 12 months and longitudinally throughout the first year. MEASUREMENTS AND MAIN RESULTS Infant and/or maternal GSTT1 nonnull was associated with reduced AR at 12 months and throughout the first year and increased Vmax(FRC) at 6 months. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. In infants exposed to in utero smoke, infant and/or maternal GSTT1 nonnull was associated with reduced AR at 1 month and throughout the first year and increased Vmax(FRC) throughout the first year. Maternal GSTP1 Val/Val or Ile/Val was associated with increased Vmax(FRC) at 6 months. CONCLUSIONS GST genes may be especially important during fetal development as they may modify, through proficient detoxification, the effects of in utero maternal smoke exposure on AR and lung function in infants.

β2-Adrenoceptor Polymorphisms Predict Response to β2-Agonists in Children with Acute Asthma

The aim of this study was to determine the influence of single nucleotide polymorphisms in the β2-adrenoceptor gene, on the response to inhaled β2-agonists in children with acute asthma. We hypothesised that children with polymorphisms that generate enhanced receptor downregulation in vitro, Gly16 and Gln27, would have a slower response to β2-agonist therapy during acute asthma. One hundred and forty-eight children with acute asthma were recruited and genotyped for β2Arg16Gly and β2Gln27Glu. For Gln27Glu, individuals Gln27Gln took longest to stretch out to 1, 2 and 4 hourly β2-agonists, followed by heterozygotes who were intermediate and Glu27Glu who responded most rapidly (1hourly: 2.6hr vs. 2.0 vs. 1.4, p = 0.02; 2 hourly: 10.6hr vs. 10.7 vs. 6.8, p = 0.07; 4 hourly: 29.8hr vs. 28.5 vs. 24.3, p = 0.30). The ability to prospectively identify children who respond less effectively to β 2-agonists during an acute asthma attack has the potential to allow the generation of genotype-specific treatment pathways.

The Role of Age and Exposure to Plasmodium falciparum in the Rate of Acquisition of Naturally Acquired Immunity: A Randomized Controlled Trial

Background The rate of acquisition of naturally acquired immunity (NAI) against malaria predominantly depends on transmission intensity and age, although disentangling the effects of these is difficult. We used chemoprophylaxis to selectively control exposure to P. falciparum during different periods in infancy and explore the effect of age in the build-up of NAI, measured as risk of clinical malaria. Methods and Findings A three-arm double-blind randomized placebo-controlled trial was conducted in 349 infants born to Mozambican HIV-negative women. The late exposure group (LEG) received monthly Sulfadoxine-Pyrimethamine (SP) plus Artesunate (AS) from 2.5–4.5 months of age and monthly placebo from 5.5–9.5 months; the early exposure group (EEG) received placebo from 2.5–4.5 months and SP+AS from 5.5–9.5 months; and the control group (CG) received placebo from 2.5–9.5 months. Active and passive case detection (PCD) were conducted from birth to 10.5 and 24 months respectively. The primary endpoint was time to first or only episode of malaria in the second year detected by PCD. The incidence of malaria during the second year was of 0.50, 0.51 and 0.35 episodes/PYAR in the LEG, EEG and CG respectively (p = 0.379 for the adjusted comparison of the 3 groups). The hazard ratio of the adjusted comparison between the LEG and the CG was 1.38 (0.83–2.28, p = 0.642) and that between the EEG and the CG was 1.35 (0.81–2.24, p = 0.743). Conclusions After considerably interfering with exposure during the first year of life, there was a trend towards a higher risk of malaria in the second year in children who had received chemoprophylaxis, but there was no significant rebound. No evidence was found that the age of first exposure to malaria affects the rate of acquisition of NAI. Thus, the timing of administration of antimalarial interventions like malaria vaccines during infancy does not appear to be a critical determinant. Trial Registration ClinicalTrials.gov NCT00231452

Toll-like receptor 7 and 8 polymorphisms: associations with functional effects and cellular and antibody responses to measles virus and vaccine

Successful defence against viral pathogens requires the rapid recognition of virus-specific “danger signals” and the activation of both innate and adaptive immunity. Toll-like receptors (TLR) 7 and 8 play a critical role in the elimination of viruses by recognising the common viral component, single stranded (ss)RNA. Measles virus, an ssRNA virus, continues to cause serious morbidity and mortality worldwide despite available measles vaccines. TLR7 and TLR8 genetic variation may cause functional alterations that result in impaired responses to measles. In a population of 12-month-old Australian infants, receptor protein expression was examined to assess the functionality of TLR7 and TLR8 polymorphisms, and the effects of these polymorphisms on cellular and antibody responses after the first measles vaccine dose were investigated. TLR7 Leu11Gln showed associations with TNF-α responses after ligand (imiquimod) stimulation in males only (P = 0.040), and non-responders were more likely to be Gln males (P = 0.044). TNF-α non-responders after imiquimod also had higher percentages of TLR8 -4284TT (69.6%) (P = 0.001) and TLR8 -558CC (69.6%) (P = 0.002) in females. Receptor protein expression after imiquimod or measles stimulation was not significantly altered compared with baseline, nor was it affected by genotype. None of the TLR7 or TLR8 polymorphisms studied were associated with measles-specific cytokine levels or with measles IgG levels. In conclusion, we report gender-specific associations with TLR7 and TLR8 polymorphisms and TNF-α cellular responses to its ligand. However, we found no evidence of any functional effects of TLR7 or TLR8 polymorphisms on receptor expression, measles-specific cellular responses or measles vaccine antibody responses.