Gene-based association study of rare variants in children of diverse ancestries implicates TNFRSF21 in the development of allergic asthma.

BACKGROUND: Most genetic studies of asthma and allergy have focused on common variation in individuals primarily of European ancestry. Studying the role of rare variation in quantitative phenotypes and in asthma phenotypes in populations of diverse ancestries can provide additional, important insights into the development of these traits. OBJECTIVE: We sought to examine the contribution of rare variants to different asthma- or allergy-associated quantitative traits in children with diverse ancestries and explore their role in asthma phenotypes. METHODS: We examined whole-genome sequencing data from children participants in longitudinal studies of asthma (n = 1035; parent-identified as 67% Black and 25% Hispanic) to identify rare variants (minor allele frequency < 0.01). We assigned variants to genes and tested for associations using an omnibus variant-set test between each of 24,902 genes and 8 asthma-associated quantitative traits. On combining our results with external data on predicted gene expression in humans and mouse knockout studies, we identified 3 candidate genes. A burden of rare variants in each gene and in a combined 3-gene score was tested for its associations with clinical phenotypes of asthma. Finally, published single-cell gene expression data in lower airway mucosal cells after allergen challenge were used to assess transcriptional responses to allergen. RESULTS: Rare variants in USF1 were significantly associated with blood neutrophil count (P = 2.18 × 10-7); rare variants in TNFRSF21 with total IgE (P = 6.47 × 10-6) and PIK3R6 with eosinophil count (P = 4.10 × 10-5) reached suggestive significance. These 3 findings were supported by independent data from human and mouse studies. A burden of rare variants in TNFRSF21 and in a 3-gene score was associated with allergy-related phenotypes in cohorts of children with mild and severe asthma. Furthermore, TNFRSF21 was significantly upregulated in bronchial basal epithelial cells from adults with allergic asthma but not in adults with allergies (but not asthma) after allergen challenge. CONCLUSIONS: We report novel associations between rare variants in genes and allergic and inflammatory phenotypes in children with diverse ancestries, highlighting TNFRSF21 as contributing to the development of allergic asthma.

Single-cell immunophenotyping of the fetal immune response to maternal SARS-CoV-2 infection in late gestation.

BACKGROUND: During the COVID-19 pandemic, thousands of pregnant women have been infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The implications of maternal SARS-CoV-2 infection on fetal and childhood well-being need to be characterized. We aimed to characterize the fetal immune response to maternal SARS-CoV-2 infection. METHODS: We performed single-cell RNA-sequencing and T cell receptor sequencing on cord blood mononuclear cells (CBMCs) from newborns of mothers infected with SARS-CoV-2 in the third trimester (cases) or without SARS-CoV-2 infection (controls). RESULTS: We identified widespread gene expression changes in CBMCs from cases, including upregulation of interferon-stimulated genes and major histocompatibility complex genes in CD14+ monocytes, transcriptional changes suggestive of activation of plasmacytoid dendritic cells, and activation and exhaustion of natural killer cells. Lastly, we observed fetal T cell clonal expansion in cases compared to controls. CONCLUSIONS: As none of the infants were infected with SARS-CoV-2, our results suggest that maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. IMPACT: The implications of maternal SARS-CoV-2 infection in the absence of vertical transmission on fetal and childhood well-being are poorly understood. Maternal SARS-CoV-2 infection might modulate the fetal immune system in the absence of vertical transmission. This study raises important questions about the untoward effects of maternal SARS-CoV-2 on the fetus, even in the absence of vertical transmission.

Designer covalent heterobivalent inhibitors prevent IgE-dependent responses to peanut allergen.

Allergies are a result of allergen proteins cross-linking allergen-specific IgE (sIgE) on the surface of mast cells and basophils. The diversity and complexity of allergen epitopes, and high-affinity of the sIgE-allergen interaction have impaired the development of allergen-specific inhibitors of allergic responses. This study presents a design of food allergen-specific sIgE inhibitors named covalent heterobivalent inhibitors (cHBIs) that selectively form covalent bonds to only sIgEs, thereby permanently inhibiting them. Using screening reagents termed nanoallergens, we identified two immunodominant epitopes in peanuts that were common in a population of 16 allergic patients. Two cHBIs designed to inhibit only these two epitopes completely abrogated the allergic response in 14 of the 16 patients in an in vitro assay and inhibited basophil activation in an allergic patient ex vivo analysis. The efficacy of the cHBI design has valuable clinical implications for many allergen-specific responses and more broadly for any antibody-based disease.

Validity of Calculating Continuous Relative Phase during Cycling from Measures Taken with Skin-Mounted Electro-Goniometers.

The aim of this study was to assess the validity of electro-goniometers as a tool for recording continuous relative phase data at two joint couplings during cycling tasks at a range of cadences. Seven participants (4 male, 3 female, age: 29 ± 7 years, height: 1.76 ± 0.10 m, mass: 71.97 ± 11.57 kg) performed exercise bouts of 30 s at four prescribed cadences (60, 80, 100, 120 rev·min-1) on a stationary ergometer (Wattbike, Nottingham, UK). Measures were synchronously recorded by bi-axial electro-goniometers (Biometrics, UK) and a 12-camera motion-capture system (Qualisys, Gothenburg, Sweden), with both systems sampling at 500 Hz. Sagittal plane joint angle and joint angular velocity were recorded at the hip, knee and ankle and analysed for ten complete pedal revolutions per participant per condition. Data were interpolated to 100 time points and used to calculate mean continuous relative phase (CRP) per pedal revolution at two intra-limb couplings: (i) knee flexion/extension-ankle plantarflexion/dorsiflexion (KA) and (ii) hip flexion/extension-knee flexion/extension (HK). At the KA coupling, significant differences in mean CRP were found between measurement systems at 120 rev·min-1 (p = 0.006). At the HK coupling, significant differences in mean CRP were found between measurement systems at 80 rev·min-1 (p = 0.043) and 100 rev·min-1 (p = 0.028). ICC values for most comparisons were below 0.5, suggesting poor levels of agreement between systems. Significant differences in mean CRP per pedal revolution and poor levels of agreement between systems suggests that electro-goniometers are not a suitable alternative to motion-capture systems when attempting to record CRP during cycling.

Peanut protein acts as a TH2 adjuvant by inducing RALDH2 in human antigen-presenting cells.

BACKGROUND: Peanut is a potent inducer of proallergenic TH2 responses in susceptible individuals. Antigen-presenting cells (APCs) including dendritic cells and monocytes instruct naive T cells to differentiate into various effector cells, determining immune responses such as allergy and tolerance. OBJECTIVE: We sought to detect peanut protein (PN)-induced changes in gene expression in human myeloid dendritic cells (mDCs) and monocytes, identify signaling receptors that mediate these changes, and assess how PN-induced genes in mDCs impact their ability to promote T-cell differentiation. METHODS: mDCs, monocytes, and naive CD4+ T cells were isolated from blood bank donors and peanut-allergic patients. APCs were incubated with PN and other stimulants, and gene expression was measured using microarray and RT quantitative PCR. To assess T-cell differentiation, mDCs were cocultured with naive TH cells. RESULTS: PN induced a unique gene expression profile in mDCs, including the gene that encodes retinaldehyde dehydrogenase 2 (RALDH2), a rate-limiting enzyme in the retinoic acid (RA)-producing pathway. Stimulation of mDCs with PN also induced a 7-fold increase in the enzymatic activity of RALDH2. Blocking antibodies against Toll-like receptor (TLR)1/TLR2, as well as small interfering RNA targeting TLR1/TLR2, reduced the expression of RALDH2 in PN-stimulated APCs by 70%. Naive TH cells cocultured with PN-stimulated mDCs showed an RA-dependent 4-fold increase in production of IL-5 and expression of integrin α4ß7. CONCLUSIONS: PN induces RALDH2 in human APCs by signaling through the TLR1/TLR2 heterodimer. This leads to production of RA, which acts on TH cells to induce IL-5 and gut-homing integrin. RALDH2 induction by PN in APCs and RA-promoted TH2 differentiation could be an important factor determining allergic responses to peanut.

Injuries in youth football and the relationship to player maturation: An analysis of time-loss injuries during four seasons in an English elite male football academy.

A better insight into injuries in elite-youth football may inform prevention strategies. The purpose of this prospective cohort study was to investigate the frequency, incidence, and pattern of time-loss injuries in an elite male football academy, exploring injuries in relation to age and maturation status. Across four consecutive playing seasons, playing exposure and injuries to all academy players (U'9 to U'21) were recorded by club medical staff. Maturation status at the time of injury was also calculated for players competing in U'13 to U'16 aged squads. Time-loss injury occurrence and maturation status at time of injury were the main outcome measures. A total of 603 time-loss injuries were recorded, from 190 different players. Playing exposure was 229 317 hours resulting in an overall injury rate of 2.4 p/1000 h, ranging from 0.7 p/1000 h (U'11) to 4.8 p/1000 h (U'21). Most injuries were traumatic in mechanism (73%). The most common injury location was the thigh (23%), and the most common injury type was muscle injury (29%) combining to provide the most common injury diagnosis; thigh muscle injury (17%). In U'13-U'16 players, a higher number of injuries to early-maturing players were observed in U'13-U'14 players, while more injuries to U'15-U'16 players occurred when classed as "on-time" in maturity status. Maturation status did not statistically relate to injury pattern; however, knee bone (not-fracture) injuries peaked in U'13 players while hip/groin muscle injuries peaked in U'15 players.

The effect of approach velocity on pelvis and kick leg angular momentum conversion strategies during football instep kicking.

During football instep kicking, whole-body deceleration during the final stride has been associated with greater kick leg angular momentum and enhanced foot and ball velocities, but the influence of approach velocity on these mechanisms is unknown. This study assessed how approach velocity affects momentum conversion strategies of experienced players performing fast and accurate kicks. Eleven semi-professional footballers performed instep kicks from self-selected (3.34 ± 0.43 m/s), fast (3.71 ± 0.33 m/s) and slow (2.77 ± 0.32 m/s) approaches. Kicking motions and ground reaction forces under the support leg were captured using 3D motion analysis (1000 Hz). The players responded to perturbations in approach velocity by using the support leg to regulate whole-body deceleration and create ideal conditions for co-ordinated pelvic and kick leg momentums during the downswing. Further, the pelvis was key for generating transverse momentum at the kick leg, but the participants displayed distinctly different pelvis transverse rotation strategies. Identification of these inter-individual strategies may provide a basis for technical and strength training practices to be tailored for individual players. Future research might investigate if training practices that expose footballers to varying approach velocities of between 2.5 and 4.0 m/s promotes development of movement strategies that are robust to perturbations in approach conditions.

Expansion of the CD4+ effector T-cell repertoire characterizes peanut-allergic patients with heightened clinical sensitivity.

BACKGROUND: Individuals with peanut allergy range in clinical sensitivity: some can consume grams of peanut before experiencing any symptoms, whereas others suffer systemic reactions to 10 mg or less. Current diagnostic testing only partially predicts this clinical heterogeneity. OBJECTIVE: We sought to identify characteristics of the peanut-specific CD4+ T-cell response in peanut-allergic patients that correlate with high clinical sensitivity. METHODS: We studied the T-cell receptor ß-chain (TCRß) usage and phenotypes of peanut-activated, CD154+ CD4+ memory T cells using fluorescence-activated cell sorting, TCRß sequencing, and RNA-Seq, in reactive and hyporeactive patients who were stratified by clinical sensitivity. RESULTS: TCRß analysis of the CD154+ and CD154- fractions revealed more than 6000 complementarity determining region 3 sequences and motifs that were significantly enriched in the activated cells and 17% of the sequences were shared between peanut-allergic individuals, suggesting strong convergent selection of peanut-specific clones. These clones were more numerous among the reactive patients, and this expansion was identified within effector, but not regulatory T-cell populations. The transcriptional profile of CD154+ T cells in the reactive group skewed toward a polarized TH2 effector phenotype, and expression of TH2 cytokines strongly correlated with peanut-specific IgE levels. There were, however, also non-TH2-related differences in phenotype. Furthermore, the ratio of peanut-specific clones in the effector versus regulatory T-cell compartment, which distinguished the clinical groups, was independent of specific IgE concentration. CONCLUSIONS: Expansion of the peanut-specific effector T-cell repertoire is correlated with clinical sensitivity, and this observation may be useful to inform our assessment of disease phenotype and to monitor disease longitudinally.

Early decrease in basophil sensitivity to Ara h 2 precedes sustained unresponsiveness after peanut oral immunotherapy.

BACKGROUND: Only some patients with peanut allergy undergoing oral immunotherapy (OIT) achieve sustained clinical response. Basophil activation could provide a functional surrogate of efficacy. OBJECTIVE: We hypothesized that changes in basophil sensitivity and area under the curve (AUC) to the immunodominant allergen Ara h 2 correlate with clinical responses to OIT. METHODS: Children with peanut allergy aged 7 to 13 years were enrolled in a single-center, open-label peanut OIT trial. Levels of specific immunoglobulins were measured throughout OIT. Peripheral blood from multiple time points was stimulated in vitro with peanut allergens for flow cytometric assessment of the percentage of CD63hi activated basophils. RESULTS: Twenty-two of 30 subjects were successfully treated with OIT; after avoidance, 9 achieved sustained unresponsiveness (SU), and 13 had transient desensitization (TD). Basophil sensitivity, measured by using the dose that induces 50% of the maximal basophil response, to Ara h 2 stimulation decreased from baseline in subjects with SU (after OIT, P = .0041; after avoidance, P = .0011). At 3 months of OIT, basophil sensitivity in subjects with SU decreased from baseline compared with that in subjects with TD (median, 18-fold vs 3-fold; P = .01), with a receiver operating characteristic of 0.84 and optimal fold change of 4.9. Basophil AUC to Ara h 2 was suppressed after OIT equally in subjects with SU and those with TD (P = .4). After avoidance, basophil AUC rebounded in subjects with TD but not those with SU (P < .001). Passively sensitized basophils suppressed with postavoidance SU plasma had a lower AUC than TD plasma (6.4% vs 38.9%, P = .03). CONCLUSIONS: Early decreases in basophil sensitivity to Ara h 2 correlate with SU. Basophil AUC rebounds after avoidance in subjects with TD. Therefore, different aspects of basophil activation might be useful for monitoring of OIT efficacy.

Agent-based models of malaria transmission: a systematic review.

BACKGROUND: Much of the extensive research regarding transmission of malaria is underpinned by mathematical modelling. Compartmental models, which focus on interactions and transitions between population strata, have been a mainstay of such modelling for more than a century. However, modellers are increasingly adopting agent-based approaches, which model hosts, vectors and/or their interactions on an individual level. One reason for the increasing popularity of such models is their potential to provide enhanced realism by allowing system-level behaviours to emerge as a consequence of accumulated individual-level interactions, as occurs in real populations. METHODS: A systematic review of 90 articles published between 1998 and May 2018 was performed, characterizing agent-based models (ABMs) relevant to malaria transmission. The review provides an overview of approaches used to date, determines the advantages of these approaches, and proposes ideas for progressing the field. RESULTS: The rationale for ABM use over other modelling approaches centres around three points: the need to accurately represent increased stochasticity in low-transmission settings; the benefits of high-resolution spatial simulations; and heterogeneities in drug and vaccine efficacies due to individual patient characteristics. The success of these approaches provides avenues for further exploration of agent-based techniques for modelling malaria transmission. Potential extensions include varying elimination strategies across spatial landscapes, extending the size of spatial models, incorporating human movement dynamics, and developing increasingly comprehensive parameter estimation and optimization techniques. CONCLUSION: Collectively, the literature covers an extensive array of topics, including the full spectrum of transmission and intervention regimes. Bringing these elements together under a common framework may enhance knowledge of, and guide policies towards, malaria elimination. However, because of the diversity of available models, endorsing a standardized approach to ABM implementation may not be possible. Instead it is recommended that model frameworks be contextually appropriate and sufficiently described. One key recommendation is to develop enhanced parameter estimation and optimization techniques. Extensions of current techniques will provide the robust results required to enhance current elimination efforts.

Support leg action can contribute to maximal instep soccer kick performance: an intervention study.

This investigation assessed whether a Technique Refinement Intervention designed to produce pronounced vertical hip displacement during the kicking stride could improve maximal instep kick performance. Nine skilled players (age 23.7 ± 3.8 years, height 1.82 ± 0.06 m, body mass 78.5 ± 6.1 kg, experience 14.7 ± 3.8 years; mean ± SD) performed 10 kicking trials prior to (NORM) and following the intervention (INT). Ground reaction force (1000 Hz) and three-dimensional motion analysis (250 Hz) data were used to calculate lower limb kinetic and kinematic variables. Paired t-tests and statistical parametric mapping examined differences between the two kicking techniques across the entire kicking motion. Peak ball velocities (26.3 ± 2.1 m · s-1 vs 25.1 ± 1.5 m · s-1) and vertical displacements of the kicking leg hip joint centre (0.041 ± 0.012 m vs 0.028 ± 0.011 m) were significantly larger (P < 0.025) when performed following INT. Further, various significant changes in support and kicking leg dynamics contributed to a significantly faster kicking knee extension angular velocity through ball contact following INT (70-100% of total kicking motion, P < 0.003). Maximal instep kick performance was enhanced following INT, and the mechanisms presented are indicative of greater passive power flow to the kicking limb during the kicking stride.

The effects of barbell load on countermovement vertical jump power and net impulse.

The aim of this study was to examine the effects of barbell load on countermovement vertical jump (CMJ) power and net impulse within a theoretically valid framework, cognisant of the underpinning force, temporal, and spatial components. A total of 24 resistance-trained rugby union athletes (average ± SD: age: 23.1 ± 3.4 years; height: 1.83 ± 0.05 m; body mass (BM): 91.3 ± 10.5 kg) performed maximal CMJ under 5 experimental conditions in a randomised, counterbalanced order: unloaded, and with additional loads of 25%, 50%, 75%, and 100% of BM. Peak power and average power were maximised during the unloaded condition, both decreasing significantly (P < 0.05) as load increased. Net impulse was maximised with 75% of BM, which was significantly greater (P < 0.05) than the unloaded and 100% of BM conditions. Net mean force and mean velocity were maximised during the unloaded condition and decreased significantly (P < 0.05) as load increased, whereas phase duration increased significantly (P < 0.05) as load increased. As such, the interaction between barbell load and the underpinning force, time, and displacement components should be considered by strength and conditioning coaches when prescribing barbell loads.

Discovery and evaluation of a novel monocyclic series of CXCR2 antagonists.

Antagonism of the chemokine receptor CXCR2 has been proposed as a strategy for the treatment of inflammatory diseases such as arthritis, chronic obstructive pulmonary disease and asthma. Earlier series of bicyclic CXCR2 antagonists discovered at AstraZeneca were shown to have low solubility and poor oral bioavailability. In this Letter we describe the design, synthesis and characterisation of a new series of monocyclic CXCR2 antagonists with improved solubility and good pharmacokinetic profiles.

Effects of exercise therapy on muscular strength in firefighters with back pain.

[Purpose] The purpose of this study was to determine how an exercise program focusing on muscular strength could aid firefighters with chronic lower back pain. [Subjects] The research subjects were randomly assigned to two groups, the experimental group (n=8) and the control (n=8). [Methods] The experimental group performed two types of exercise programs four times per week for 8 weeks under supervision. Tests were performed before and after the 8 weeks of exercise in accordance with the Korea Occupational Safety and Health Agency's program. [Results] At the end of the 8 weeks of the rehabilitation program, abdominal muscular strength were significantly increased in the experimental group, and this indicates that the exercise therapy was effective for improvement of muscular strength. [Conclusion] We found that exercise therapy is an effective intervention that can reduce the pain of patients with chronic lower back pain. The firefighters with chronic lower back pain who participated in this study exhibited enhanced lower back muscular strength and obtained some additional benefits. They need regular exercise.

Genetic and phenotypic characterization of a hybrid zone between polyandrous Northern and Wattled Jacanas in Western Panama.

BACKGROUND: Hybridization provides a unique perspective into the ecological, genetic and behavioral context of speciation. Hybridization is common in birds, but has not yet been reported among bird species with a simultaneously polyandrous mating system; a mating system where a single female defends a harem of males who provide nearly all parental care. Unlike simple polyandry, polyandrous mating is extremely rare in birds, with only 1% of bird species employing this mating system. Although it is classically held that females are "choosy" in avian hybrid systems, nearly-exclusive male parental care raises the possibility that female selection against heterospecific matings might be reduced compared to birds with other mating systems. RESULTS: We describe a narrow hybrid zone in southwestern Panama between two polyandrous freshwater waders: Northern Jacana, Jacana spinosa and Wattled Jacana, J. jacana. We document coincident cline centers for three phenotypic traits, mtDNA, and one of two autosomal introns. Cline widths for these six markers varied from seven to 142 km, with mtDNA being the narrowest, and five of the six markers having widths less than 100 km. Cline tails were asymmetrical, with greater introgression of J. jacana traits extending westward into the range of J. spinosa. Likewise, within the hybrid zone, the average hybrid index of phenotypic hybrids was significantly biased towards J. spinosa. Species distribution models indicate that the hybrid zone is located at the edge of a roughly 100 km wide overlap where habitat is predicted to be suitable for both species, with more westerly areas suitable only for spinosa and eastward habitats suitable only for J. jacana. CONCLUSION: The two species of New World jacanas maintain a narrow, and persistent hybrid zone in western Panama. The hybrid zone may be maintained by the behavioral dominance of J. spinosa counterbalanced by unsuitable habitat for J. spinosa east of the contact zone. Although the two parental species are relatively young, mitochondrial cline width was extremely narrow. This result suggests strong selection against maternally-inherited markers, which may indicate either mitonuclear incompatibilities and/or female choice against heterospecific matings typical of avian hybrid systems, despite jacana sex role reversal.

Multiplanar lumbar, pelvis and kick leg sequencing during soccer instep kicking from different approach angles.

Multiplanar kinematic and kinetic sequencing from different approach angles can highlight how soccer players perform fast and accurate kicks. This study therefore aimed to a) determine multiplanar torso, pelvis and kick leg sequencing during instep kicks and b) highlight the effect of different approach angles on these sequencing patterns. Twenty male soccer players (mass 77.9 ± 6.5 kg, height 1.71 ± 0.09 m, age 23.2 ± 3.7 years) performed kicks from self-selected (∼30-45°), straight (0°) and wide (67.5°) approaches and multiplanar lumbo-pelvic, hip and knee angular velocities, moments and powers were derived from 3D motion analysis. The results suggest tension arc release between the upper and lower body functions as a two-stage mechanism. The first phase of arc release was characterised by increases in concentric hip flexion and transverse lumbo-pelvic velocities towards the ball. The second phase was characterised by increasing concentric lumbo-pelvic flexion and knee extension work to angularly accelerate the kicking knee towards foot-to-ball contact. Further, alterations in kinematic and kinetic sequencing helped maintain performance (ball and foot velocities at ball contact) and accuracy at approach angles other than self-selected. These findings can help coaches and practitioners design effective training practices.

Insights into breast health issues in women's rugby.

World RugbyTM supports dedicated women's welfare, injury surveillance and medical/technical interventions, yet breast health has received limited attention. This article aims to provide insights into breast health issues in rugby, including breast impacts and injuries. We discuss how breast anatomy and position may be problematic in rugby. Breast volume relates to body size, which may be increasing in women's rugby, suggesting increased breast surface area and mass, potentially increasing injury risk. Breast health issues in rugby have been reported previously, with 58% of contact footballers (including rugby) experiencing breast injuries. There are damaging effects related to these breast health issues, with breast impacts often causing pain and swelling. Breast impacts may lead to haematomas, cysts and fat necrosis which can calcify over time making them difficult to distinguish from breast carcinoma, causing further investigation and anxiety. In sport, poor bra fit and insufficient support are associated with pain, skin strain and performance decrements. This article reports the potential implications of these breast health issues on performance in rugby. Recent breast-related projects supported by rugby communities may address recommendations identified in the literature for robust breast injury classifications, updated injury surveillance systems and prospective data collection on breast injury prevalence, severity and impact in rugby. These data should inform breast injury care pathways and intervention research, including evidence-based bra design. Understanding the implications of breast impacts on tissue properties, health and wellbeing is vital. Finally, data should inform rugby-specific breast education, raising awareness of this aspect of athlete health.

Metabolomics of IgE-Mediated Food Allergy and Oral Immunotherapy Outcomes based on Metabolomic Profiling.

Background: The immunometabolic mechanisms underlying variable responses to oral immunotherapy (OIT) in patients with IgE-mediated food allergy are unknown. Objective: To identify novel pathways associated with tolerance in food allergy, we used metabolomic profiling to find pathways important for food allergy in multi-ethnic cohorts and responses to OIT. Methods: Untargeted plasma metabolomics data were generated from the VDAART healthy infant cohort (N=384), a Costa Rican cohort of children with asthma (N=1040), and a peanut OIT trial (N=20) evaluating sustained unresponsiveness (SU, protection that lasts after therapy) versus transient desensitization (TD, protection that ends immediately afterwards). Generalized linear regression modeling and pathway enrichment analysis identified metabolites associated with food allergy and OIT outcomes. Results: Compared with unaffected children, those with food allergy were more likely to have metabolomic profiles with altered histidines and increased bile acids. Eicosanoids (e.g., arachidonic acid derivatives) (q=2.4×10 -20 ) and linoleic acid derivatives (q=3.8×10 -5 ) pathways decreased over time on OIT. Comparing SU versus TD revealed differing concentrations of bile acids (q=4.1×10 -8 ), eicosanoids (q=7.9×10 -7 ), and histidine pathways (q=0.015). In particular, the bile acid lithocholate (4.97[1.93,16.14], p=0.0027), the eicosanoid leukotriene B4 (3.21[1.38,8.38], p=0.01), and the histidine metabolite urocanic acid (22.13[3.98,194.67], p=0.0015) were higher in SU. Conclusions: We observed distinct profiles of bile acids, histidines, and eicosanoids that vary among patients with food allergy, over time on OIT and between SU and TD. Participants with SU had higher levels of metabolites such as lithocholate and urocanic acid, which have immunomodulatory roles in key T-cell subsets, suggesting potential mechanisms of tolerance in immunotherapy. Key Messages: - Compared with unaffected controls, children with food allergy demonstrated higher levels of bile acids and distinct histidine/urocanic acid profiles, suggesting a potential role of these metabolites in food allergy. - In participants receiving oral immunotherapy for food allergy, those who were able to maintain tolerance-even after stopping therapyhad lower overall levels of bile acid and histidine metabolites, with the exception of lithocholic acid and urocanic acid, two metabolites that have roles in T cell differentiation that may increase the likelihood of remission in immunotherapy. Capsule summary: This is the first study of plasma metabolomic profiles of responses to OIT in individuals with IgE-mediated food allergy. Identification of immunomodulatory metabolites in allergic tolerance may help identify mechanisms of tolerance and guide future therapeutic development.

Airway basal stem cells are necessary for the maintenance of functional intraepithelial airway macrophages.

Adult stem cells play a crucial role in tissue homeostasis and repair through multiple mechanisms. In addition to being able to replace aged or damaged cells, stem cells provide signals that contribute to the maintenance and function of neighboring cells. In the lung, airway basal stem cells also produce cytokines and chemokines in response to inhaled irritants, allergens, and pathogens, which affect specific immune cell populations and shape the nature of the immune response. However, direct cell-to-cell signaling through contact between airway basal stem cells and immune cells has not been demonstrated. Recently, a unique population of intraepithelial airway macrophages (IAMs) has been identified in the murine trachea. Here, we demonstrate that IAMs require Notch signaling from airway basal stem cells for maintenance of their differentiated state and function. Furthermore, we demonstrate that Notch signaling between airway basal stem cells and IAMs is required for antigen-induced allergic inflammation only in the trachea where the basal stem cells are located whereas allergic responses in distal lung tissues are preserved consistent with a local circuit linking stem cells to proximate immune cells. Finally, we demonstrate that IAM-like cells are present in human conducting airways and that these cells display Notch activation, mirroring their murine counterparts. Since diverse lung stem cells have recently been identified and localized to specific anatomic niches along the proximodistal axis of the respiratory tree, we hypothesize that the direct functional coupling of local stem cell-mediated regeneration and immune responses permits a compartmentalized inflammatory response.

Single-cell transcriptomic analyses reveal distinct immune cell contributions to epithelial barrier dysfunction in checkpoint inhibitor colitis.

Immune checkpoint inhibitor (ICI) therapy has revolutionized oncology, but treatments are limited by immune-related adverse events, including checkpoint inhibitor colitis (irColitis). Little is understood about the pathogenic mechanisms driving irColitis, which does not readily occur in model organisms, such as mice. To define molecular drivers of irColitis, we used single-cell multi-omics to profile approximately 300,000 cells from the colon mucosa and blood of 13 patients with cancer who developed irColitis (nine on anti-PD-1 or anti-CTLA-4 monotherapy and four on dual ICI therapy; most patients had skin or lung cancer), eight controls on ICI therapy and eight healthy controls. Patients with irColitis showed expanded mucosal Tregs, ITGAEHi CD8 tissue-resident memory T cells expressing CXCL13 and Th17 gene programs and recirculating ITGB2Hi CD8 T cells. Cytotoxic GNLYHi CD4 T cells, recirculating ITGB2Hi CD8 T cells and endothelial cells expressing hypoxia gene programs were further expanded in colitis associated with anti-PD-1/CTLA-4 therapy compared to anti-PD-1 therapy. Luminal epithelial cells in patients with irColitis expressed PCSK9, PD-L1 and interferon-induced signatures associated with apoptosis, increased cell turnover and malabsorption. Together, these data suggest roles for circulating T cells and epithelial-immune crosstalk critical to PD-1/CTLA-4-dependent tolerance and barrier function and identify potential therapeutic targets for irColitis.