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Microbial interactions mediating colonization resistance play key roles within the human microbiome, shaping susceptibility to infection from birth. To gain insight into microbiome-mediated defenses and respiratory pathogen colonization dynamics, we sequenced and analyzed nasal (n=229) and oral (n=210) microbiomes with associated health/environmental data from our Wisconsin Infant Study Cohort at age 24-months. Participants with early-life lower respiratory tract infection (LRTI) were more likely to be formula-fed, attend daycare, and experience wheezing. Shotgun metagenomic sequencing with detection of viral and bacterial respiratory pathogens revealed nasal microbiome composition to associate with prior LRTI - namely lower alpha diversity, depletion of Prevotella, and enrichment of Moraxella catarrhalis including drug-resistant strains. Prevotella originating from healthy microbiomes had higher biosynthetic gene cluster abundance and exhibited contact-independent inhibition of M. catarrhalis, suggesting interbacterial competition impacts nasal pathogen colonization. This work advances understanding of protective host-microbial interactions occurring in airway microbiomes that alter infection susceptibility in early-life., (Copyright © 2024. Published by Elsevier Inc.)

Background: Farm exposures in early life reduce the risks for childhood allergic diseases and asthma. There is less information about how farm exposures relate to respiratory illnesses and mucosal immune development., Objective: We hypothesized that children raised in farm environments have a lower incidence of respiratory illnesses over the first 2 years of life than nonfarm children. We also analyzed whether farm exposures or respiratory illnesses were related to patterns of nasal cell gene expression., Methods: The Wisconsin Infant Study Cohort included farm (n = 156) and nonfarm (n = 155) families with children followed to age 2 years. Parents reported prenatal farm and other environmental exposures. Illness frequency and severity were assessed using illness diaries and periodic surveys. Nasopharyngeal cell gene expression in a subset of 64 children at age 2 years was compared to farm exposure and respiratory illness history., Results: Farm versus nonfarm children had nominally lower rates of respiratory illnesses (rate ratio 0.82 [95% CI, 0.69, 0.97]) with a stepwise reduction in illness rates in children exposed to 0, 1, or ≥2 animal species, but these trends were nonsignificant in a multivariable model. Farm exposures and preceding respiratory illnesses were positively related to nasal cell gene signatures for mononuclear cells and innate and antimicrobial responses., Conclusions: Maternal and infant exposure to farms and farm animals was associated with nonsignificant trends for reduced respiratory illnesses. Nasal cell gene expression in a subset of children suggests that farm exposures and respiratory illnesses in early life are associated with distinct patterns of mucosal immune expression., (Copyright © 2024 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Thymus hypoplasia due to stromal cell problems has been linked to mutations in several transcription factors, including Forkhead box N1 (FOXN1). FOXN1 supports T-cell development by regulating the formation and expansion of thymic epithelial cells (TECs). While autosomal recessive FOXN1 mutations result in a nude and severe combined immunodeficiency phenotype, the impact of single-allelic or compound heterozygous FOXN1 mutations is less well-defined., Objective: With more than 400 FOXN1 mutations reported, their impact on protein function and thymopoiesis remains unclear for most variants. We developed a systematic approach to delineate the functional impact of diverse FOXN1 variants., Methods: Selected FOXN1 variants were tested with transcriptional reporter assays and imaging studies. Thymopoiesis was assessed in mouse lines genocopying several human FOXN1 variants. Reaggregate thymus organ cultures were used to compare the thymopoietic potential of the FOXN1 variants., Results: FOXN1 variants were categorized into benign, loss- or gain-of-function, and/or dominant-negatives. Dominant negative activities mapped to frameshift variants impacting the transactivation domain. A nuclear localization signal was mapped within the DNA binding domain. Thymopoiesis analyses with mouse models and reaggregate thymus organ cultures revealed distinct consequences of particular Foxn1 variants on T-cell development., Conclusions: The potential effect of a FOXN1 variant on T-cell output from the thymus may relate to its effects on transcriptional activity, nuclear localization, and/or dominant negative functions. A combination of functional assays and thymopoiesis comparisons enabled a categorization of diverse FOXN1 variants and their potential impact on T-cell output from the thymus., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In 2014, germline signal transducer and activator of transcription (STAT) 3 gain-of-function (GOF) mutations were first described to cause a novel multisystem disease of early-onset lymphoproliferation and autoimmunity., Objective: This pivotal cohort study defines the scope, natural history, treatment, and overall survival of a large global cohort of patients with pathogenic STAT3 GOF variants., Methods: We identified 191 patients from 33 countries with 72 unique mutations. Inclusion criteria included symptoms of immune dysregulation and a biochemically confirmed germline heterozygous GOF variant in STAT3., Results: Overall survival was 88%, median age at onset of symptoms was 2.3 years, and median age at diagnosis was 12 years. Immune dysregulatory features were present in all patients: lymphoproliferation was the most common manifestation (73%); increased frequencies of double-negative (CD4-CD8-) T cells were found in 83% of patients tested. Autoimmune cytopenias were the second most common clinical manifestation (67%), followed by growth delay, enteropathy, skin disease, pulmonary disease, endocrinopathy, arthritis, autoimmune hepatitis, neurologic disease, vasculopathy, renal disease, and malignancy. Infections were reported in 72% of the cohort. A cellular and humoral immunodeficiency was observed in 37% and 51% of patients, respectively. Clinical symptoms dramatically improved in patients treated with JAK inhibitors, while a variety of other immunomodulatory treatment modalities were less efficacious. Thus far, 23 patients have undergone bone marrow transplantation, with a 62% survival rate., Conclusion: STAT3 GOF patients present with a wide array of immune-mediated disease including lymphoproliferation, autoimmune cytopenias, and multisystem autoimmunity. Patient care tends to be siloed, without a clear treatment strategy. Thus, early identification and prompt treatment implementation are lifesaving for STAT3 GOF syndrome., (Copyright © 2022 American Academy of Allergy, Asthma & Immunology. All rights reserved.)

Background: Whether children and people with asthma and allergic diseases are at increased risk for severe acute respiratory syndrome virus 2 (SARS-CoV-2) infection is unknown., Objective: Our aims were to determine the incidence of SARS-CoV-2 infection in households with children and to also determine whether self-reported asthma and/or other allergic diseases are associated with infection and household transmission., Methods: For 6 months, biweekly nasal swabs and weekly surveys were conducted within 1394 households (N = 4142 participants) to identify incident SARS-CoV-2 infections from May 2020 to February 2021, which was the pandemic period largely before a vaccine and before the emergence of SARS-CoV-2 variants. Participant and household infection and household transmission probabilities were calculated by using time-to-event analyses, and factors associated with infection and transmission risk were determined by using regression analyses., Results: In all, 147 households (261 participants) tested positive for SARS-CoV-2. The household SARS-CoV-2 infection probability was 25.8%; the participant infection probability was similar for children (14.0% [95% CI = 8.0%-19.6%]), teenagers (12.1% [95% CI = 8.2%-15.9%]), and adults (14.0% [95% CI = 9.5%-18.4%]). Infections were symptomatic in 24.5% of children, 41.2% of teenagers, and 62.5% of adults. Self-reported doctor-diagnosed asthma was not a risk factor for infection (adjusted hazard ratio [aHR] = 1.04 [95% CI = 0.73-1.46]), nor was upper respiratory allergy or eczema. Self-reported doctor-diagnosed food allergy was associated with lower infection risk (aHR = 0.50 [95% CI = 0.32-0.81]); higher body mass index was associated with increased infection risk (aHR per 10-point increase = 1.09 [95% CI = 1.03-1.15]). The household secondary attack rate was 57.7%. Asthma was not associated with household transmission, but transmission was lower in households with food allergy (adjusted odds ratio = 0.43 [95% CI = 0.19-0.96]; P = .04)., Conclusion: Asthma does not increase the risk of SARS-CoV-2 infection. Food allergy is associated with lower infection risk, whereas body mass index is associated with increased infection risk. Understanding how these factors modify infection risk may offer new avenues for preventing infection., (Copyright © 2022. Published by Elsevier Inc.)

Background: Few studies have examined longitudinal asthma incidence rates (IRs) from a public health surveillance perspective., Objective: Our aim was to calculate descriptive asthma IRs in children over time with consideration for demographics and parental asthma history., Methods: Data from 9 US birth cohorts were pooled into 1 population covering the period from 1980 to 2017. The outcome was earliest parental report of a doctor diagnosis of asthma. IRs per 1,000 person-years were calculated., Results: The racial/ethnic backgrounds of the 6,283 children studied were as follows: 55% European American (EA), 25.5% African American (AA), 9.5% Mexican-Hispanic American (MA) and 8.5% Caribbean-Hispanic American (CA). The average follow-up was 10.4 years (SD = 8.5 years; median = 8.4 years), totaling 65,291 person-years, with 1789 asthma diagnoses yielding a crude IR of 27.5 per 1,000 person-years (95% CI = 26.3-28.8). Age-specific rates were highest among children aged 0 to 4 years, notably from 1995 to 1999, with a decline in EA and MA children in 2000 to 2004 followed by a decline in AA and CA children in 2010 to 2014. Parental asthma history was associated with statistically significantly increased rates. IRs were similar and higher in AA and CA children versus lower but similar in EA and MA children. The differential rates by sex from birth through adolescence principally resulted from a decline in rates among males but relatively stable rates among females., Conclusions: US childhood asthma IRs varied dramatically by age, sex, parental asthma history, race/ethnicity, and calendar year. Higher rates in the 0- to 4-year-olds group, particularly among AA/CA males with a parental history of asthma, as well as changes in rates over time and by demographic factors, suggest that asthma is driven by complex interactions between genetic susceptibility and variation in time-dependent environmental and social factors., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Wheeze and allergic sensitization are the strongest early-life predictors of childhood asthma development; the molecular origins of these early-life phenotypes are poorly understood., Objectives: We sought to identify metabolites associated with early-life wheeze, allergic sensitization, and childhood asthma., Methods: We conducted a nested case-control study using Environmental influences on Child Health Outcomes Program cohorts for discovery and independent replication. Wheeze and allergic sensitization were defined by number of wheeze episodes and positive specific IgE at age 1 year, respectively. Asthma was defined as physician diagnosis of asthma at age 5 or 6 years. We used untargeted metabolomics, controlling for observed and latent confounding factors, to assess associations between the plasma metabolome and early-life wheeze, allergy, and childhood asthma., Results: Eighteen plasma metabolites were associated with first-year wheeze in the discovery cohort (n = 338). Z,Z unconjugated bilirubin (UCB) and its related metabolites exhibited a dose-response relationship with wheeze frequency; UCB levels were 13% (β = 0.87; 95% CI, 0.74-1.02) and 22% (β = 0.78; 95% CI, 0.68-0.91) lower in children with 1 to 3 and 4+ wheeze episodes compared with those who never wheezed, respectively. UCB levels were also associated with childhood asthma (β = 0.82; 95% CI, 0.68-0.98). Similar trends were observed in 2 independent cohorts. UCB was significantly negatively correlated with eicosanoid- and oxidative stress-related metabolites. There were no significant associations between metabolites and allergic sensitization., Conclusions: We identified a novel inverse, dose-dependent association between UCB and recurrent wheeze and childhood asthma. Inflammatory lipid mediators and oxidative stress byproducts inversely correlated with UCB, suggesting that UCB modulates pathways critical to the development of early-life recurrent wheeze and childhood asthma., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Farm exposures may reduce the risk of atopic dermatitis (AD) in children, but this is controversial and US data are limited., Objective: This study was conducted to identify patterns of farm exposure in Wisconsin family farms that modify AD incidence and prevalence in early childhood., Methods: Environmental exposures, health history, and clinical outcomes were prospectively recorded for 111 farm families and 129 non-farm families enrolled in the Wisconsin Infant Study Cohort birth cohort study. Exposures from the prenatal and early postnatal (2-month) visits were evaluated together with parental report of AD diagnosis by a health care provider through age 24 months. Latent class analysis was performed with prenatal and early postnatal farm-exposure variables to assign farm children to 3 classes., Results: Overall, children of farm families had reduced AD incidence (P = .03). Within farm families, exposures including poultry (3% vs 28%; P = .003), pig (4% vs 25%; P = .04), feed grain (13% vs 34%; P = .02), and number of animal species were inversely associated with AD incidence. Among the latent class groups, children in families with diverse or more intense farm exposures (classes A and B) had reduced AD incidence, whereas low-exposure (class C) infants had AD incidence similar to that in nonfarm children., Conclusions: Infants in Wisconsin farm families had reduced AD incidence, and patterns of farm exposures further defined AD risk. These findings suggest that exposure to diverse farm animals, feed, and bedding during the prenatal period and in early infancy reduce the risk of early-onset AD, a phenotype associated with multiple other atopic diseases., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

A major diagnostic intervention in the consideration of many patients suspected to have primary immunodeficiency diseases (PIDDs) is the application and interpretation of vaccination. Specifically, the antibody response to antigenic challenge with vaccines can provide substantive insight into the status of human immune function. There are numerous vaccines that are commonly used in healthy individuals, as well as others that are available for specialized applications. Both can potentially be used to facilitate consideration of PIDD. However, the application of vaccines and interpretation of antibody responses in this context are complex. These rely on consideration of numerous existing specific studies, interpolation of data from healthy populations, current diagnostic guidelines, and expert subspecialist practice. This document represents an attempt of a working group of the American Academy of Allergy, Asthma & Immunology to provide further guidance and synthesis in this use of vaccination for diagnostic purposes in consideration of PIDD, as well as to identify key areas for further research., (Copyright © 2012 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.)

Background: There is evidence that CD4(+)CD25(high) T-regulatory cells are important for establishing tolerance to allergens, but information in children is limited., Objective: To test the hypothesis that greater numbers and function of CD4(+)CD25(high) T cells are associated with a reduced risk of childhood allergies and wheezing., Methods: A cohort of 151 six-year-old children from atopic families was analyzed for peripheral blood CD4(+)CD25(high) and CD4(+)CD25(int) T cells by flow cytometry and for clinical and immunologic correlates of atopy. The associations between these variables were assessed by regression analysis., Results: Factors positively associated with % CD4(+)CD25(high)/CD4 T cells were male sex, number of positive allergen-specific IgE tests, total IgE, season, and 1-month average total pollen count preceding blood draw. The percentage of CD4(+)CD25(high)/total CD4 T cells did not correlate with induced cytokine production, and correlated negatively with suppressive capacity of CD4(+)CD25(+) T cells (r = -0.45; P = .034). The percentage of CD4(+)CD25(int)/CD4 T cells was 54% higher in pollen-sensitized children compared with nonsensitized children in spring (P = .023 for interaction), and correlated positively with IL-5, IL-10, and IL-13 (P < or = .001 for all)., Conclusion: Our findings suggest that blood CD4(+)CD25(high) cells are a mixture of activated and regulatory T cells, and that these cells could be seasonally regulated by environmental factors such as pollen exposure., Clinical Implications: Seasonal increases in CD4CD25(high) expression in children with allergy may represent systemic immune activation caused by pollen exposures.

As a chronic inflammatory disease, much of the research related to asthma has been focused on proinflammatory mechanisms. Recently, advances have been made in defining mechanisms that control inflammation and induce immune tolerance to specific antigens. Subsets of CD4(+) cells known as T regulatory cells play an important role in directing these processes, and recent experiments have begun to define crucial molecular and signaling pathways. There is a growing body of evidence describing the function of T regulatory cells in the development, disease activity, and treatment responses related to asthma and other atopic diseases. Collectively, this new information suggests that a greater understanding of these pathways might lead to new therapeutic targets for asthma and other diseases of chronic airway inflammation.

Background: T(H)2 cells play a critical role in the pathogenesis of asthma, but the precise immunologic mechanisms that inhibit T(H)2 cell function in vivo are not well understood., Objective: The purpose of our studies was to determine whether T cells producing IL-10 regulate the development of asthma., Methods: We used gene therapy to generate ovalbumin-specific CD4 T-helper cells to express IL-10, and we examined their capacity to regulate allergen-induced airway hyperreactivity., Results: We demonstrated that the CD4 T-helper cells engineered to express IL-10 abolished airway hyperreactivity and airway eosinophilia in BALB/c mice sensitized and challenged with ovalbumin and in SCID mice reconstituted with ovalbumin-specific T(H)2 effector cells. The inhibitory effect of the IL-10-secreting T-helper cells was accompanied by the presence of increased quantities of IL-10 in the bronchoalveolar lavage fluid, was antigen-specific, and was reversed by neutralization of IL-10. Moreover, neutralization of IL-10 by administration of anti-IL-10 mAb in mice sensitized and challenged with ovalbumin seriously exacerbated airway hyperreactivity and airway inflammation., Conclusion: Our results demonstrate that T cells secreting IL-10 in the respiratory mucosa can indeed regulate T(H)2-induced airway hyperreactivity and inflammation, and they strongly suggest that IL-10 plays an important inhibitory role in allergic asthma.