Jagadish I, Shah D, Priessnitz J
… +1 more, Chiarella SE
J Allergy Clin Immunol
· 2026 Mar · PMID 41544716
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Asthma, a chronic inflammatory airway disease affecting 25 million people in the United States, exhibits distinct sex differences in prevalence, phenotype, and treatment response. While asthma is more common in boys duri...Asthma, a chronic inflammatory airway disease affecting 25 million people in the United States, exhibits distinct sex differences in prevalence, phenotype, and treatment response. While asthma is more common in boys during childhood, adult women experience greater disease severity, likely due to hormonal and immunologic influences. Asthma biomarkers, including blood eosinophil count, fractional exhaled nitric oxide, IgE, and emerging markers, provide insight into disease phenotypes and therapeutic response. This review synthesizes current evidence on sex-specific differences in asthma biomarkers and mechanisms underlying these variations. Sex hormones play a role in immune modulation, with estrogen and progesterone promoting type 2 inflammation, and testosterone exerting suppressive effects. Boys demonstrate higher levels of blood eosinophil counts, fractional exhaled nitric oxide, total and allergen-specific IgE, and periostin, whereas postpubertal women exhibit increased IL-5, leptin, serum amyloid A, and urinary leukotriene E, along with lower adiponectin levels. In contrast, postpubertal male subjects with asthma show higher ceramide concentrations. Additional biomarkers under investigation include microRNAs, neutrophils, tryptase, exhaled breath condensate analytes, and surfactant proteins. However, evidence supporting these research-based markers is often preclinical and/or lacks sex-stratified analyses, limiting clinical translation. Incorporating validated sex-specific biomarker patterns into asthma care may enhance phenotyping and support personalized management strategies.
The role of Staphylococcus aureus in atopic dermatitis (AD) has been extensively studied. Although its role in the pathophysiology of AD was previously controversial, current evidence now shows that it is a major factor...The role of Staphylococcus aureus in atopic dermatitis (AD) has been extensively studied. Although its role in the pathophysiology of AD was previously controversial, current evidence now shows that it is a major factor promoting the disease and is responsible for significant morbidity. Its influence in AD stems from widespread exposure because S aureus is common on healthy skin and is frequently part of the normal human skin microbiome. In AD, S aureus and the closely related Staphylococcus epidermidis gain a selective growth advantage over most other members of the skin microbiome due to a complex relationship involving the skin's innate immune system, other members of the microbiome, and skin barrier properties. Disruption in the functioning of these components or changes in their interactions lead to dysbiosis, skin barrier damage, and the progression of skin disease. This review summarizes research findings on these relationships and highlights the interactions and factors that promote S aureus survival on skin and its participation in the pathogenesis of AD.
BACKGROUND: Janus kinase (JAK) 1 is a promising target for asthma treatment; it may address inflammation not controlled by inhaled corticosteroids. Londamocitinib (AZD4604) is a selective JAK1 inhibitor designed for inha...BACKGROUND: Janus kinase (JAK) 1 is a promising target for asthma treatment; it may address inflammation not controlled by inhaled corticosteroids. Londamocitinib (AZD4604) is a selective JAK1 inhibitor designed for inhaled delivery. OBJECTIVE: A 3-part randomized placebo-controlled phase 1 study (NCT04769869) was conducted in healthy volunteers (n = 85) and participants with mild asthma (n = 18) investigating safety, tolerability, pharmacokinetics, and lung and systemic target engagement of londamocitinib. METHODS: Single (0.025-6 mg) and multiple (0.4-3 mg, inhaled) doses of londamocitinib were administered to healthy volunteers and participants with mild asthma for up to 10 days. Effect on fractional exhaled nitric oxide (Feno), a type 2 inflammation marker, was assessed in participants with mild asthma with elevated Feno. RESULTS: Londamocitinib was well tolerated after single and multiple dosing. After inhalation, londamocitinib was quickly absorbed, and systemic exposure increased approximate dose proportionally. After twice-daily dosing to obtain steady state, 2- to 4-fold accumulation was observed. Approximately 50% reductions in mean Feno were seen for 1.4 and 3 mg doses of londamocitinib in participants with mild asthma after 3 days, which persisted to day 10 of dosing, versus no significant reduction with placebo. Transient, minimal suppression of systemic target engagement (IL-4-induced STAT6 phosphorylation in peripheral CD3 T cells) was seen with the 3 mg but not the 1.4 mg londamocitinib dose. CONCLUSION: Twice-daily administration of londamocitinib provides rapid and effective reduction of Feno in patients with mild asthma with elevated Feno.
Wang Y, Zhang Y, Dudley C
… +14 more, Fitzgerald K, Carson AS, Kapita CM, Rana D, Kluckman K, Bortner D, Cowley DO, Travis CR, Vorobiov J, Choudhary S, Kepley CL, Commins SP, Smith SA, Iweala OI
J Allergy Clin Immunol
· 2026 Apr · PMID 41534718
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BACKGROUND: In alpha-gal syndrome (AGS), IgE antibodies form against the glycan galactose-α-1,3-galactose (alpha-gal) in mammal products rather than food proteins. Alpha-gal glycolipids and glycoproteins activate human b...BACKGROUND: In alpha-gal syndrome (AGS), IgE antibodies form against the glycan galactose-α-1,3-galactose (alpha-gal) in mammal products rather than food proteins. Alpha-gal glycolipids and glycoproteins activate human basophils sensitized with AGS plasma in an IgE-dependent fashion. However, it is unknown whether alpha-gal specific IgE (sIgE), independent of other blood proteins, is sufficient for mediating basophil and mast cell activation. OBJECTIVE: We sought to determine whether alpha-gal antigens could activate passively sensitized rat basophilic leukemia (RBL) SX-38 cells, which express human IgE receptors and are commonly used to model allergen/IgE-mediated mast cell activation in food protein allergy. METHODS: Using the clustered regularly interspaced short palindromic repeats technology, we created a novel, alpha-gal-deficient RBL cell line, alpha-gal knockout RBL SX-38, passively sensitizing cells with sera from AGS donors or with novel alpha-gal sIgE clones, and then stimulated with alpha-gal glycoproteins. To assess effector cell activation, we measured cell surface expression of activation marker CD63 by flow cytometry and mediator release through β-hexosaminidase release assays. RESULTS: After alpha-gal antigen stimulation, the percentage of CD63 alpha-gal knockout RBL SX-38 cells sensitized with AGS sera increased 3-fold compared with cells sensitized with control serum. Select human AGS IgE clones facilitated alpha-gal antigen-dependent and antigen-independent CD63 upregulation. Cells sensitized with pooled AGS sera released β-hexosaminidase in an alpha-gal-independent fashion. We saw no β-hexosaminidase release above background in cells sensitized with alpha-gal sIgE clones. CONCLUSIONS: Certain alpha-gal-specific human IgE clones may partially activate allergic effector cells independent of antigen, potentially lowering thresholds for subsequent alpha-gal-induced or antigen-independent allergic effector cell degranulation. This may affect duration and severity of allergic symptoms in patients with AGS.
BACKGROUND: Allergic asthma pathogenesis encompasses systemic immune, metabolic, and epithelial barrier dysfunction; however, minimally invasive tools to longitudinally explore these processes remain limited. OBJECTIVE:...BACKGROUND: Allergic asthma pathogenesis encompasses systemic immune, metabolic, and epithelial barrier dysfunction; however, minimally invasive tools to longitudinally explore these processes remain limited. OBJECTIVE: We evaluated the potential of minimally invasive skin tape strips to capture age-specific immune, metabolic, and epithelial barrier dysregulation in children, adolescents, and adults with allergic asthma and their association with asthma-related outcomes. METHODS: We collected tape strips from healthy-appearing skin of patients with moderate or severe allergic asthma and age-matched controls. RNA sequencing and differential gene expression analyses were performed to identify unique and common asthma-associated immune and barrier genes across age groups. Gene set variation analyses, pathway enrichment, correlation with clinical outcomes, and biomarker classification using receiver operating characteristic analysis were conducted. RESULTS: Children demonstrated the greatest transcriptomic dysregulation, including robust downregulation of barrier-related genes (FLG, CDH19, JAM2), upregulation of oxidative phosphorylation genes (NDUFS4, COX15), and T1 immune skewing. Adolescents exhibited attenuated barrier and immune changes compared to children and adults, suggestive of a transitional state. Adults with severe asthma showed dominant type 2/type 17 skewing, metabolic suppression, and fewer barrier alterations compared to children. Several differentially expressed genes correlated with asthma outcomes: ENG and MUC4 with small airway resistance in children, and inflammatory coding genes (CD1C, IL3RA, CCL17) with annual exacerbation rates in adults. The two-gene classifiers HOXA5-KDM6B and PCGF1-SLC39A2 accurately distinguished asthmatic subjects from controls (area under the curve = 1.0), with olfactory receptors and immune-related genes uniquely classifying adolescent asthma patients. CONCLUSIONS: Skin tape strips identify age-specific immune, epithelial barrier, and metabolic signatures in allergic asthma, offering a minimally invasive tool to explore disease mechanisms.
BACKGROUND: Asthma and recurrent wheeze in the first years of life represent a heterogeneous and poorly understood syndrome with a need to understand to what extent phenotypes reflect distinct underlying mechanisms. OBJE...BACKGROUND: Asthma and recurrent wheeze in the first years of life represent a heterogeneous and poorly understood syndrome with a need to understand to what extent phenotypes reflect distinct underlying mechanisms. OBJECTIVE: We sought to investigate whether specific genetic asthma mechanisms, represented by genetic risk loci, were associated with specific disease courses and asthma phenotypes. METHODS: Known childhood asthma risk loci (GSDMB, CDHR3, FUT2, ABO, HLA-DQA1, IL33, IL1RL1, IL13, and TSLP) were analyzed in relation to redeemed prescriptions for asthma and allergy medication from birth to age 15 years in more than 23,000 children from the iPSYCH (Integrative Psychiatric Research) study. Gene variants were studied separately and as combined scores on the basis of putative similar mechanisms. Association with atopic and nonatopic asthma phenotypes was examined in more than 6000 children from the COPSAC (Copenhagen Prospective Study on Asthma in Childhood), BAMSE (Children, Allergy, Milieu, Stockholm, Epidemiology), and CHILD (Canadian Healthy Infant Longitudinal Development) birth cohorts. RESULTS: GSDMB and CDHR3 were the strongest risk loci for asthma prescriptions in the first years of life, with effects continuing into school age, although with attenuating effect size. CDHR3 was characterized by associations present already in the first year of life and a strong interaction with GSDMB genotype. Suspected T2-related loci were characterized by a slightly later onset around age 2 to 3 years, with increasing or stable effect size till age 15 years and increased risk of allergic rhinitis. GSDMB and CDHR3 were associated with early transient disease, whereas most other loci were associated with both persistent and late-onset disease and with both atopic and nonatopic asthma. CONCLUSIONS: Risk loci of early childhood asthma seem to involve different disease mechanisms as illustrated by their specific age-related effects. However, risk loci generally showed associations across classical age- and atopy-related phenotypes, suggesting that specific asthma mechanisms are not well captured by classical phenotyping.
BACKGROUND: Type 2 (T2)-low asthma is defined by low levels of T2 inflammation and is associated with resistance to inhaled corticosteroids. Its molecular mechanisms are mostly unknown, and treatment options are limited....BACKGROUND: Type 2 (T2)-low asthma is defined by low levels of T2 inflammation and is associated with resistance to inhaled corticosteroids. Its molecular mechanisms are mostly unknown, and treatment options are limited. We previously showed that nasal brush transcriptomes differ between asthma and controls, reflecting disease-relevant biology. OBJECTIVE: We explored nasal gene expression related to T2-low asthma in the ATLANTIS cohort. METHODS: We compared nasal brush RNA sequencing data between 82 T2-low and 63 T2-high asthma patients and 57 controls. T2-low asthma was defined as blood eosinophil counts < 0.15 × 10/L and Feno < 25 ppb and T2-high as blood eosinophil counts > 0.3 × 10/L and Feno > 25 ppb. Weighted gene coexpression network analysis (WGCNA) was applied to identify gene modules associated with T2-low asthma. The BAMSE and U-BIOPRED cohorts were used for replication analyses. RESULTS: Although differentially expressed genes were found in patients with T2-high asthma across all 3 cohorts, no differentially expressed genes were observed in individuals with T2-low disease compared to controls in ATLANTIS, nor consistently across other cohorts. Our assessment of molecular heterogeneity could not attribute this result to greater intersample variability within the T2-low group. WGCNA in ATLANTIS identified "black" and "purple" gene modules linked to T2-low asthma, with genes enriched in T-cell immunity and ribosomal RNA biology pathways, respectively. The "black" module was replicated in U-BIOPRED and showed the same direction in BAMSE. CONCLUSION: T2-high asthma shows a distinct nasal gene expression signature compared to healthy controls, while patients with T2-low asthma exhibit no consistent changes. Future studies should explore T-cell immunity in T2-low asthma and integrate lower airway multiomics data.
Miyachi H, Shibata R, Javornik Cregeen SJ
… +7 more, Surathu A, Sijaric M, Espinola JA, Sullivan AF, Mansbach JM, Camargo CA, Zhu Z
J Allergy Clin Immunol
· 2026 Apr · PMID 41485494
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BACKGROUND: The gut microbiome is thought to influence risk of childhood allergic diseases; however, the data on species-level links to childhood asthma and lung function are limited, and the role of host genetics in the...BACKGROUND: The gut microbiome is thought to influence risk of childhood allergic diseases; however, the data on species-level links to childhood asthma and lung function are limited, and the role of host genetics in the gut-lung axis remains unclear. METHODS: In a multicenter cross-sectional study of children with a history of bronchiolitis from the 35th Multicenter Airway Research Collaboration, we performed shotgun metagenomic profiling of stool samples obtained at age 6 years and examined associations of the gut microbiome with asthma prevalence and lung function. We also calculated polygenic risk scores (PRSs) of asthma and lung function to investigate the interaction between host genetics and the gut microbiome in relation to these traits. RESULTS: In the 300 children included for this study, 3 bacterial species (ie, Bacteroides vulgatus, Eisenbergiella massiliensis, and Butyricimonas virosa) were differentially associated with FEV value and 4 bacterial species were differentially associated with ratio of FEV value to forced vital capacity (FVC) (eg, Bifidobacterium longum) (false discovery rate [FDR] according to the R package MaAsLin < 0.25). Furthermore, host genetics-gut microbiome interaction analysis showed association of B vulgatus (FDR = 0.037) and Bacteroides uniformis (FDR = 0.037) with FEV/FVC ratio among children with a high FEV/FVC ratio PRS. Additionally, Ruminococcus bromii (FDR = 0.067) and Alistipes indistinctus (FDR = 0.13) were suggested to have protective associations with asthma, specifically in children with a high asthma PRS, indicating that host genetics can modulate the effect of the gut microbiome on these respiratory outcomes. CONCLUSION: By applying the metagenomic approach to a multicenter cohort of children with a history of bronchiolitis during infancy, this study suggests potential interplay of host genetics with the gut microbiome, as well as their integrated relationship with childhood asthma and lung function.
BACKGROUND: Asthma is the most common chronic respiratory disease in children, with known sex differences in prevalence and severity that shift after puberty. Total IgE, a marker of type 2-high asthma, also differs by se...BACKGROUND: Asthma is the most common chronic respiratory disease in children, with known sex differences in prevalence and severity that shift after puberty. Total IgE, a marker of type 2-high asthma, also differs by sex and age and may contribute to these disparities. METHODS: We tested whether nasal epithelial gene expression differs by sex and interacts with total IgE in ways that may inform asthma pathogenesis in a transcriptome-wide association study in nasal epithelial samples from participants in two cohorts: EVA-PR (including 398 Puerto Rican youths aged 12-20 years) and PIAMA (including 303 Dutch adolescents aged 16 years). RESULTS: Differential expression analysis by sex identified 406 genes at a false discovery rate-adjusted P value of <.05, with 225 upregulated and 181 downregulated in female compared to male subjects. Top differentially expressed genes included hormone- and immune-related genes such as THRB, IL17REL, and CD207. Among these, 6 genes (MNDA, IFIT1, IFIT2, SLC22A17, JAG2, and MT3) showed significant sex-by-total IgE interaction effects on expression. Pathway enrichment analyses revealed that female subjects had activation of eukaryotic translation pathways (eg, EIF2 signaling), while male subjects showed activation of immune-related pathways (eg, interferon signaling). Additionally, 19 pathways were enriched in the sex-by-IgE interaction model, including TREM1 and cytokine storm signaling. CONCLUSIONS: Our findings provide new insights into sex-specific regulation of gene expression in airway epithelium and its interaction with total IgE, helping to explain observed sex differences in asthma. This underscores the need to consider sex as a biological variable in asthma research and points to potential targets for precision medicine approaches.
Koskimäki F, Ruokamo-Korva K, Ahokas O
… +8 more, Liinamaa J, Reis K, Reigo A, FinnGen, Estonian Biobank Research Team, Palta P, Kettunen J, Karjalainen MK, Saarela V
BACKGROUND: Despite the high prevalence of allergic conjunctivitis, the genetic factors contributing to it have not been characterized in detail. OBJECTIVE: We sought to characterize genetic factors associated with aller...BACKGROUND: Despite the high prevalence of allergic conjunctivitis, the genetic factors contributing to it have not been characterized in detail. OBJECTIVE: We sought to characterize genetic factors associated with allergic conjunctivitis both in relation to and independent of systemic atopic or allergic conditions. METHODS: We performed a genome-wide association study meta-analysis using data from FinnGen, Estonian Biobank, and UK Biobank cohorts. A total of 45,734 cases with allergic conjunctivitis and 1,084,159 controls were included. We conducted a phenome-wide association study and pathway and enrichment analyses, and assessed genetic correlations with other phenotypes. RESULTS: Genome-wide significant (P < 5 × 10) associations were identified for allergic conjunctivitis at 34 loci, many of which had not been reported to associate with allergic conjunctivitis before. Many of the associated loci included genes involved in immunology and allergy-related conditions, for example, ID2 and TSLP. Several loci were also associated with other allergic health conditions, such as asthma, allergic rhinitis, and eczema. Three loci (EIF2AK2, RANBP2, and NFAT5) had no previous association with allergy-related phenotypes. We detected that allergic conjunctivitis is associated with pathways related to neuroinflammation, immune responses, and cytokine signaling. We detected an enrichment of genes associated with immune-related biological processes such as cytokine production. Allergic conjunctivitis was genetically correlated with 27 phenotypes. CONCLUSIONS: We identified 34 allergic conjunctivitis-associated loci, most of which were involved in immunology and allergy-related conditions. Our findings underline the central role of inflammation-related genes in genetic predisposition to allergic conjunctivitis and advance the overall understanding of its genetic background.