Journal of Allergy and Clinical Immunology

BackgroundImmunoglobulin E (IgE) plays a fundamental role in the pathogenesis of allergic disease, including asthma. The IgE-producing plasma cells (PCs) are thought to persist indefinitely, providing a sustained source of allergen-specific IgE. Although these cells can accumulate in the bone marrow (BM), after prolonged allergen exposure, their frequency remains remarkably low, and the mechanisms that regulate their migration are poorly understood. ObjectiveTo investigate the chemokine receptor profile and the migration potential of the human IgE-producing cells. MethodsTonsil B cells were stimulated with IL-4 and anti-CD40 to induce class switching to IgE and IgG1. The chemokine receptor profile of IgE+ and IgG1+ switched cells was determined using flow cytometry and migration towards relevant chemokines was quantified using transwell chemotaxis assays. Chemokine expression was also validated by re-analysis of a published single cell RNA sequencing (scRNAseq) dataset of PCs isolated from nasal polyps (NP) of patients with allergic fungal rhinosinusitis. ResultsIgE PCs exhibit significantly reduced expression of the BM-homing chemokine receptor CXCR4 and impaired migration towards its ligand, CXCL12. While IgE+ PCs can upregulate CCR10 and respond to its ligand, CCL28, this behaviour is similar to IgG1+ PCs. Strikingly, however, IgE PCs selectively upregulate CCR2 and migrate robustly towards its ligand CCL2. Re-analysis of NP scRNAseq data confirmed that IgE PCs express significantly higher levels of CCR2 compared with PCs of all other isotypes. ConclusionsThese findings identify CCR2 as a key regulator of IgE PC migration and provide insights into their homing preferences that may shape the nature of the IgE responses.

To the editorO_ST_ABSBackgroundC_ST_ABSAnaphylaxis is an acute and potentially life-threatening hypersensitivity reaction often involving the cardiovascular system. Circulating microRNAs (miRNAs/miR), including those carried by extracellular vesicles (EVs), are emerging biomarkers that display regulatory functions in allergy. This study aims to investigate the role of miR-29a in anaphylaxis. MethodsMiR-29a (3p and 5p) levels were assessed by qPCR from acute and baseline samples of serum and EVs from 70 patients with food- and drug-mediated anaphylaxis. EVs purification was confirmed by Western blot, electron microscopy, and NanoSight. MiR-29a-3p target genes were studied in silico using systems biology analysis (SBA). Moreover, miR-29a levels were evaluated in vitro in endothelial cells (ECs) exposed to anaphylactic mediators. Additionally, a panel of endothelial glycocalyx (eGCX)-associated mRNA was analyzed after transfection with a miR-29a-3p inhibitor. ResultsPatients with food-induced anaphylaxis exhibited reduced miR-29a-3p levels in both serum and EVs during the acute reaction. In contrast, miR-29a-5p levels were decreased in serum but not in EVs. No significant modulation of either miRNA was observed in drug-induced anaphylaxis. SBA of miR-29a-3p identified molecular pathways, biological processes and functional networks associated with eGCX remodelling. Intracellular levels of miR-29a-3p were modulated in vitro in ECs following exposure to anaphylactic mediators. Inhibition of miR-29a-3p significantly reduced ESM1 expression. ConclusionsThe miR-29a-3p levels are decreased in serum and EVs from patients with acute food-induced anaphylaxis, suggesting its potential as a promising biomarker. Moreover, a role for miR-29a-3p in eGCX integrity under anaphylactic conditions was demonstrated, potentially regulating ESM1. Key MessageMiR-29a-3p is selectively reduced in serum and extracellular vesicles during acute food-induced anaphylaxis and may regulate endothelial glycocalyx-related pathways, which supports its potential as a novel biomarker and molecular mediator of vascular involvement in anaphylactic reactions.

BackgroundT helper 2 (Th2) lymphocytes orchestrate type-2 immunity and drive allergic diseases that disproportionately affect females. Sexual dimorphism in Th2 responses is well-documented, yet current models attribute sex differences exclusively to circulating gonadal hormones and sex chromosomes. Whether cell-intrinsic steroidogenesis, mediated by the enzyme Cyp11a1, contributes to female-biased Th2 differentiation and function remains unknown. MethodsTranscriptomes of in vitro generated Th2 cells from male and female T cell-specific Cyp11a1-knockout (Cyp11a1fl/fl;Cd4Cre) and control (Cyp11a1fl/fl) mice were compared. Differential expression, hallmark pathway analysis, transcription factor activity scoring, and functional assays were performed across sexes and genotypes. Cyp11a1-dependent differentially expressed genes were integrated with sex-stratified human Th2 transcriptomes obtained from the type-2 inflammatory skin disease atopic dermatitis. ResultsCyp11a1 deletion markedly reduced the transcriptional signature distinguishing female from male Th2 cells. Female Cyp11a1-knockout Th2 cells underwent extensive transcriptomic reprogramming converging toward the male profile, while male cells were largely unaffected. Female-specific pathway changes included reduced inflammatory signatures and enhanced cell-cycle programmes. Functionally, female Cyp11a1-deficient Th2 cells exhibited significantly increased proliferation and elevated IL-13 production; male knockout cells showed no comparable changes. These effects were developmentally stage-specific, emerging during Th2 differentiation but not in naive precursors. Cross-species analysis identified a conserved gene module shared between Cyp11a1-deficient female mouse Th2 cells and female-biased human Th2 cells in atopic dermatitis. ConclusionsCyp11a1-mediated steroidogenesis is a cell-intrinsic regulator of the female-biased Th2 transcriptional and functional state, identifying de novo steroidogenesis as a mechanism of immunological sexual dimorphism with direct relevance for female-predominant allergic disease.

Asthma is a chronic respiratory illness that causes mild to severe inflammation throughout narrowed airways. During allergic airways inflammation, autophagy prevents extensive lung tissue impairment while inducing a protective anti-pathogen response and macrophages in the lung to maintain homeostasis. Previous studies of autophagy genes and asthma have shown an association with variants in ATG5, but a comprehensive analysis of autophagy related genes and asthma has not been performed. Here we utilize summary statistic data generated from a two-stage genome-wide association study (GWAS) of asthma in the UK Biobank. We examined variants in 21 autophagy related genes and found statistically significant associations for 28 variants in two genes in the discovery dataset and nominally significant replication for 16 of these variants, all annotated to ATG4B. This is the first evidence of an association with variants in ATG4B with asthma which provides a novel potential for future drug development.

Background: The chromosome 1q31 Th2 pathway-associated interval has been linked to asthma, but its phenotype specificity and cross-ancestry architecture remain unclear. Methods: We analyzed African (AFR) and European (EU) ancestry datasets, including 9,965 asthma cases and 37,391 controls of AFR, and 6,074 cases and 116,255 controls of EU ancestry. Imputed dosage-based association analyses were performed for asthma, steroid-dependent asthma (SDA), and non-steroid-dependent asthma, followed by QC-filtered SDA remapping, leave-one-batch-out analysis, cross-ancestry comparison, and functional enrichment. Results: Strong regional association was observed only for SDA. After quality-control (QC) filtering, the SDA signal remained significant in both ancestries, with 2,280 genome-wide significant variants in AFR and 859 in EU. Cross-ancestry comparison identified 3,129 significant variants: 10 shared, 2,270 AFR-specific, and 849 EU-specific. Shared variants showed concordant effects, whereas 237 variants showed nominal heterogeneity. AFR-specific signals included PTPRC variants with larger effects in AFR. Functional enrichment suggested different biological emphases within the same interval: immune and contractile airway-wall biology in AFR, and additional neuroaxonal components in EU. Conclusions: The 1q31 interval is strongly associated with SDA in both AFR and EU populations, and its fine-scale architecture differs by ancestry. These findings highlight population-specific effects within a shared SDA susceptibility interval, with potential implications for population-informed precision medicine in steroid responsiveness and asthma management.

Asthma is the most common chronic respiratory disease of childhood and is strongly associated with genetic variants at the 17q21 locus that increase expression of ORMDL3, a negative regulator of serine palmitoyl-CoA transferase (SPT), the rate-limiting enzyme in de novo sphingolipid synthesis. Reduced sphingolipid production has been linked to airway hyperreactivity, a key physiological feature of asthma, but the mechanisms connecting altered sphingolipid metabolism to airway dysfunction remain unclear. We examined whether sphingolipid metabolites regulate airway smooth muscle reactivity. Circulating sphingolipids were quantified in children with asthma carrying 17q21 risk alleles and in mice with reduced SPT activity. Functional airway responses were assessed in precision-cut lung slices exposed to sphingosine-1-phosphate (S1P), sphinganine-1-phosphate (Sa1P), and S1P receptor antagonists. Homozygous carriers of the rs7216389 risk allele and SPT-deficient mice displayed an increased S1P-to-Sa1P ratio. In functional assays, Sa1P opposed S1P-induced airway contraction, and increasing Sa1P availability reduced airway hyperresponsiveness. These findings identify the S1P/Sa1P axis as a metabolic rheostat regulating airway smooth muscle tone and suggest that targeting sphingolipid metabolism may offer a therapeutic strategy to mitigate intrinsic airway hyperreactivity in asthma. One sentence summaryAn imbalance between sphingosine-1-phosphate and sphinganine-1-phosphate links the asthma risk locus 17q21 to airway hyperreactivity and reveals sphingolipid metabolism as a potential therapeutic target.

Type 2 high asthma is driven by coordinated GATA3 dependent programs in CD4+ T cells and group 2 innate lymphoid cells (ILC2). Although biologics targeting IL4, IL5, or IL13 benefit subsets of patients, many remain symptomatic, suggesting that upstream regulatory mechanisms may sustain type 2 inflammation. We investigated whether HuR (ELAVL1), an RNA-binding protein that stabilizes GATA3 and Th2 cytokines mRNA, regulates type 2 inflammatory programs in allergic asthma. Using a house dust mite (HDM) model in vivo, HuR inhibition with the small molecule KH3 reduced lung inflammation, suppressed Th2 cytokine expression, accelerated Gata3 mRNA decay in lung CD4+ T cells, and attenuated airway hyperresponsiveness toward control levels. In ex vivo activated human lung CD4+ T cells, KH3 accelerated GATA3 mRNA decay with minimal effects on RORC or TBX21 and selectively reduced Th2 cytokine secretion, while IL10 and IL2 were unchanged. Similarly, ILC2s isolated from peripheral blood mononuclear cells (PBMCs) of type 2 high asthmatic donors showed reduced GATA3 mRNA stability and diminished Th2 cytokine production following KH3 treatment. Single-cell transcriptomic analysis of bronchoalveolar lavage fluid after allergen challenge demonstrated co-enrichment of ELAVL1 and GATA3 within Th2 clusters in human airways. Together, these findings identify HuR as a post-transcriptional regulator of GATA3 driven type 2 inflammation in allergic asthma.

BackgroundExtreme-phenotype comparisons allowed the discovery of novel asthma genetic risk loci. However, this approach remains unexplored in epigenome-wide association studies (EWAS). We aimed to identify bulk and cell-specific methylation markers of asthma with severe exacerbations across diverse ancestry groups. MethodsWe conducted a meta-EWAS of 739,543 CpGs in whole blood among 1,192 African American and Latino pediatric populations, comparing non-asthmatics and asthma exacerbators. Genome-wide CpGs were followed up for replication in a meta-analysis across 1,516 ethnically diverse participants and in a cross-tissue evaluation of 393 nasal samples. We conducted differentially methylated region (DMRs), cell-type-deconvoluted, and quantitative trait loci analyses (whole-genome sequencing n=1,668; RNA-seq n=1,209). We examined enrichment in traits, pathways, and druggable genes, and analyzed DNAm predictors of plasma proteins and aging. ResultsDNAm at 505 CpGs and 119 DMRs in whole blood were associated with asthma exacerbations (p<9x10-8, {lambda}=1.05). We replicated 25 CpGs in blood cells, cross-validated 7 in nasal samples, and detected 42 cell-specific DNAm markers mainly driven by T cells. DNAm at 134 CpGs was associated with gene expression in whole blood, including 118 associations with T-cell receptor genes, and 446 CpGs were regulated by [&ge;]1 genetic variant. We found enrichment for previous associations with environmental exposures, immune disorders, immune and inflammatory pathways, and druggable genes by developmental drugs. 21 methylation-predicted plasma proteins, involved in host defense, and one lung aging clock were associated with asthma exacerbations. ConclusionsThe first meta-EWAS of extreme asthma phenotypes identified hundreds of novel DNAm markers, suggesting novel methylation biomarkers and candidate drugs for asthma and supporting the role of T cells.

Mixed granulocytic asthma (MGA) is a severe Th2-low endotype, characterized by high Th17/neutrophilic burden and exacerbated airway remodeling. Both features confer resistance to inhaled corticosteroids, and typical asthma treatments. Thus, MGA is an enormous public health burden. Gaps in knowledge include how Th17 cells induce pathological tissue remodeling, and how Th17 differentiation occurs in response to allergens. We generated a Th2-low murine model of asthma that recapitulates major features of human MGA namely, heightened airway reactivity to methacholine, Th17/neutrophilic inflammation, airway remodeling, and resistance to corticosteroid treatment. Two specific biomarkers enriched in human MGA, the TNF superfamily member 14 (aka LIGHT), and the mitochondrial oxidative phosphorylation (OXPHOS) pathway, are upregulated in this model. We show OXPHOS promotes the metabolic reprograming of Th17 cells, to produce LIGHT that controls airway remodeling. Mechanistically, OXPHOS regulates ROR{gamma}t expression and the subsequent transcriptional network to program survival and differentiation of Th17 cells, whereas LIGHT drives airway remodeling by activating the MMP9-dependent TGF{beta} pathway. Additionally, OXPHOS+Th17 cells promote the expression of osteopontin necessary for fibroblast activation. LIGHT antagonistic blockade reduces airway remodeling, whereas OXPHOS chemical inhibition reduces Th17 cells and neutrophilia. Importantly, the dual blockade of LIGHT and OXPHOS reverses all features of MGA and reciprocally increase the numbers of Treg cells. Thus, the dual blockade of LIGHT and OXPHOS constitutes a promising target for clinical interventions in human MGA, possibly extending to other Th17-driven fibrotic diseases.

Immunoglobulin E (IgE) drives allergic disease, yet what restrains the persistence of IgE production remains poorly understood. Mouse studies suggest that BCR-induced apoptosis limits the survival of IgE-producing plasma cells (PCs). Whether this mechanism applies to human IgE PCs is unclear. Using a human IgE class-switching system, we show that BCR crosslinking preferentially kills IgE PCs compared to IgG1+ PCs. However, this selective sensitivity is not explained by surface BCR levels or proximal BCR signaling as suggested in mice. Instead, elevated PTEN expression in IgE PCs constrains PI3K/Akt pro-survival signaling and lowers the apoptotic threshold by upregulating BIM, while JNK signaling sustains PTEN expression and amplifies their apoptotic sensitivity. CRISPR/Cas9 targeting of PTEN or BIM, or JNK inhibition protects IgE PCs from BCR-mediated killing. Therapeutic anti-IgE antibodies, including omalizumab and extracellular membrane-proximal domain (EMPD)-targeting antibodies, exploit this sensitivity to selectively eliminate IgE PCs and suppress IgE production, providing a mechanistic rationale for depleting IgE PCs in allergic disease. SummaryRamadani et al. identify a JNK/PTEN/BIM signaling axis that intrinsically limits human IgE plasma cell survival and drives their preferential sensitivity to BCR-induced apoptosis. This mechanism is distinct from that established in mice and has direct implications for anti-IgE therapeutic strategies.

Psoriasis is a chronic immune-mediated inflammatory skin disease characterized by excessive keratinocyte proliferation, immune cell infiltration and dysregulated inflammatory signaling. Despite the availability of biologic therapies targeting inflammatory cytokines, many patients experience incomplete responses or relapse, highlighting the need to better understand molecular regulators of cutaneous inflammation. CD109 is a glycosylphosphatidylinositol (GPI)-anchored protein previously identified by our lab as a co-receptor and negative regulator of Transforming Growth Factor-{beta} (TGF-{beta}) signaling that inhibits fibrotic responses. Emerging evidence suggests that CD109 also modulates immune and inflammatory pathways. In this study, we investigated whether epidermal CD109 overexpression influences cutaneous inflammatory responses. Transgenic (TG) mice overexpressing CD109 under the keratin-14 (K14) promoter were used to restrict transgene expression to the epidermis. TG and wild-type (WT) littermates were subjected to lipopolysaccharide (LPS)-induced skin inflammation. CD109 TG mice exhibited significantly reduced immune cell recruitment, including macrophages and neutrophils, along with decreased expression of the pro-inflammatory mediators IL-1 and MCP-1/CCL2 compared with WT mice. Transcriptomic analysis of primary keratinocytes revealed downregulation of multiple inflammatory signaling pathways in CD109-overexpressing cells, including TNF-/NF-{kappa}B, IL-2/STAT5, IFN-{gamma}, IFN-, and IL-6/JAK/STAT3 pathways. Together, these findings demonstrate that epidermal CD109 overexpression attenuates cutaneous inflammatory responses by suppressing key inflammatory signaling networks and limiting immune cell recruitment, suggesting that CD109 may represent an important regulator of inflammatory signaling in the skin and a potential target for inflammatory skin diseases such as psoriasis.

Autophagy has been implicated in several lung diseases, either protecting tissues or driving pathology. Hypersensitivity pneumonitis (HP) is a complex inflammatory lung disease, and autophagy is heavily involved in regulating inflammation. The role of autophagy in HP remains unclear. The aim of our study was to understand the role of autophagy in HP pathogenesis. GFP-LC3 transgenic mice were exposed intranasally to Saccharopolyspora rectivirgula (SR) to induce HP and follow autophagy activation in the lung. Then, we take advantage of our Atg4b-deficient mouse model to assess how autophagy disruption impacts lung inflammation in response to SR antigen challenge. Increased autophagy activation was observed in epithelial and inflammatory cells after SR antigen exposure in GFP-LC3 transgenic lungs. GFP-LC3 puncta colocalized with ATG4B and ATG5 in epithelial and inflammatory cells after antigen exposure. Autophagy impairment limits the inflammatory response after SR antigen exposure in the lungs from the Atg4b-deficient mice when compared to WT mice. To evaluate whether lipopolysaccharide (LPS) exacerbates the inflammatory response in the Atg4b-deficient, a SR+LPS combined treatment was developed and we discovered that LPS aggravates the SR-induced HP in WT but not in Atg4b-deficient mice. Reduced HP severity in Atg4b-deficient mice was associated with decreased expression of NFkB, CCL1, CCL25, CXCL1, TNFR1, IL-13, and IL-17A, diminished CD4+ T cell recruitment and expansion, reduced M2-like macrophages, and decreased granuloma and iBALT development. Our findings highlight autophagy as a critical driver in HP pathogenesis and as a potetial target for novel theraphy development.

miR-378a-3p has been reported to be upregulated in the lesional skin of patients with atopic dermatitis (AD); however, its function in AD remains unclear. Here, we demonstrate that miR-378a-3p expression is induced by IL-4 and live Staphylococcus aureus (S. aureus) in normal human epidermal keratinocytes (NHEKs) cultured in proliferative conditions or in a 3D epidermal culture model. Transcriptomic profiling and gene set enrichment analysis of miR-378a-3p-transfected NHEKs revealed positive enrichment of inflammatory response pathways alongside downregulation of genes associated with epidermal development. More specifically, miR-378a-3p enhanced expression of multiple NF-{kappa}B-dependent inflammatory mediators, accompanied by increased phosphorylation of p65, indicating activation of canonical NF-{kappa}B pathway. Notably, miR-378a-3p concomitantly reduced the expression of several NF-{kappa}B family members and upstream adaptor molecules, supporting a model in which miR-378a-3p promotes canonical NF-{kappa}B activity through coordinated modulation of multiple components within the NF-{kappa}B regulatory network. In NHEKs exposed to live S. aureus, miR-378a-3p significantly increased the secretion of IL-1{beta}, IL-1Ra, and IL-8, indicating that miR-378a-3p may amplify innate immune responses triggered by S. aureus colonization in AD. Collectively, these findings identify miR-378a-3p as a positive regulator of keratinocyte inflammatory responses that may contribute to AD exacerbation, particularly in the context of S. aureus colonization.

Background: The determinants of immunoglobulin E (IgE) remain poorly understood in older adults, a population with an increasing burden of chronic diseases. Identifying IgE's determinants may improve its clinical interpretation in the evaluation of allergic and IgE-related conditions. Objective: To investigate age, sex, smoking, alcohol, body mass index (BMI), corticosteroid use, and season as potential determinants of total IgE (tIgE) and inhaled allergen-specific IgE (sIgE). Methods: Using Rotterdam Study data, we investigated the determinants of tIgE and sIgE using multivariable linear regression. Longitudinal changes and the effects of corticosteroids were assessed with linear mixed models. Results: We included 8769 participants, of which 478 had repeated IgE measurements. Age showed a U-shaped relationship with tIgE and L-shaped relationship with sIgE (both p<0.001). Women had lower tIgE (OR [95%CI]: 0.69 [0.65-0.74]), whereas current smokers (1.34 [1.23-1.46]), higher BMI (1.01 [1.01-1.02]), topical corticosteroid users (1.27 [1.07-1.50]) and inhaled corticosteroid users (1.93 [1.64-2.26]) showed higher tIgE. Women (0.96 [0.92-1.00]), former smokers (0.87 [0.83-0.91]) and current smokers (0.72 [0.68-0.76]) had lower sIgE, whereas topical corticosteroid users (1.20 [1.07-1.35]) and inhaled corticosteroid users (1.20 [1.07-1.35]) showed higher sIgE. Over time, tIgE and sIgE decreased (p<0.001) but did not significantly change after corticosteroid use. Conclusion: We identified age, sex, smoking, BMI, season and topical and inhaled corticosteroids as determinants of tIgE and sIgE. Incorporating these determinants may improve IgE's clinical interpretation for the diagnosis and management of allergic and IgE-related conditions. Future research should investigate how these determinants shape IgE's relationship with chronic diseases in aging populations.

DNA methylation is a stable epigenetic mark that critically influences the phenotype of immune cells. Identifying differentially methylated regions within immune cell lineages supports their phenotypic and functional characterization, leading to a better understanding of lineage-specific transcriptional regulation. Here, we performed a genome-wide methylation analysis of human innate lymphoid cells (ILCs), which allowed us to define specific epigenetic marker regions for ILC1, ILC2, and ILC3. These regions were associated with genes that have well-described functions in ILCs, such as TBX21 in ILC1, GATA3 and MAF in ILC2, RORC and IL23R in ILC3, but were also found in genetic loci that have not been previously associated with ILCs. In-depth analysis of ILC2-related marker regions within the HPGDS and NRROS gene loci confirmed their critical role in transcriptional regulation and suggested a novel role for NRROS in ILC2. Genome-wide methylation analysis of ILC2, derived from the blood of juvenile donors with atopy or asthma led to the identification of several disease-specific epigenetic regions associated with genes such as GIMAP4 and PTGS2. Together, our study not only provides novel epigenetic marker regions in human ILCs and confirms the functional role of ILC2-related markers, but also identifies promising markers for studying allergies in humans.

BackgroundRecent guidelines differ in how fractional exhaled nitric oxide (FeNO) is used to diagnose school-age asthma, either as one of several tests with a cut-off at 25 ppb or as a single rule-in test at 35 ppb. Evidence on its diagnostic performance and clinical utility in subgroups remain limited. MethodsWe analysed data from 1,979 school-age children in the Swiss Paediatric Airway Cohort referred for suspected asthma. We investigated FeNO performance with diagnosis by paediatric pulmonologists as reference standard using receiver operating characteristics curves, selected cut-offs and simulated predictive values across different prevalence. Subgroup analyses considered allergic sensitisation with allergic rhinitis and current inhaled corticosteroid (ICS) use. ResultsIn the overall cohort (asthma diagnosis 70%), FeNO showed poor discrimination for asthma (AUC 0.66; 95% CI 0.64-0.68) with an optimal cut-off at 22 ppb. At 25 and 35 ppb, sensitivity was low (43%, 95% CI 40-46; 31%, 95% CI 29-34) and specificity moderate to high (84%, 95% CI 77-84; 90%, 95% CI 87-92). Positive predictive value at 35 ppb was 88% and was 57% when simulated at a prevalence of 30%. FeNO had no diagnostic value in non-sensitised children and lower performance in sensitised children with allergic rhinitis than in those without (AUC 0.59 vs 0.68). Current ICS use did not influence performance. ConclusionFeNO has limited diagnostic performance as a stand-alone test for school-age asthma, and underlying asthma prevalence and allergic characteristics should be considered in the interpretation.

BackgroundGastroesophageal reflux disease (GERD) is highly prevalent in systemic sclerosis (SSc) and frequently persists despite proton pump inhibitor (PPI) therapy. However, the mechanisms underlying PPI-refractory GERD in SSc remain incompletely understood. MethodsWe conducted a singlel7lcentre, retrospective study of adults with SSc who underwent ambulatory pH-multichannel intraluminal impedance (pH/MII) monitoring while receiving twicel7ldaily PPI therapy (2021-2025). Esophageal motility (highl7lresolution manometry, HREM) and gastric emptying scintigraphy were integrated to examine associations between gastro-esophageal dysmotility and reflux phenotypes. ResultsThirty patients were included, of whom 67% had PPI-refractory reflux symptoms and 33% were undergoing pre-lung transplantation evaluation. Refractory GERD was present in 29/30 patients (97%) based on Lyon 2.0 classification, with conclusive evidence in 53% and borderline evidence in 43%. Esophageal dysmotility was identified in 80%, most commonly absent contractility (67%), and was associated with impaired reflux clearance, reflected by longer acid clearance times (2.20 [1.15-3.75] vs 1.15 [0.43-1.90] min) and prolonged reflux episode duration (16.60 [4.38-40.63] vs 1.95 [0.53-20.43] min). Gastric dysmotility was identified in 60.7% and was associated with an increased reflux episode burden (51.00 [30.00-81.50] vs 25.00 [21.00-54.00] episodes/24h). ConclusionsPPIl7lrefractory GERD is nearly universal in this SSc cohort and reflects heterogeneous, quantifiable abnormalities across the foregut, including impaired esophageal clearance and increased reflux burden related to gastric retention. These findings support integrated physiologic evaluation to define reflux mechanisms, inform risk stratification (including lung transplantation), and guide targeted, mechanism-based therapies beyond acid suppression.

PurposeWe evaluated healthcare resource utilization (HCRU) and costs in patients with eosinophilic granulomatosis with polyangiitis (EGPA). MethodsPatients with newly diagnosed EGPA (2017-2021), [&ge;]12 months pre-diagnosis health plan enrollment, and [&ge;]1 inpatient or [&ge;]2 outpatient claims with an EGPA diagnosis were included. Follow-up was from EGPA diagnosis until disenrollment or database end. HCRU and health insurer payment costs during follow-up were compared with those for matched cohorts of general insured patients without EGPA (comparison A) and without EGPA but with severe uncontrolled asthma (SUA; comparison B). ResultsIn comparison A, all-cause HCRU was higher in the EGPA cohort (n = 213) versus matched patients (n = 779) for all clinical encounters/pharmacy claim types; annualized, mean total all-cause costs were 16-fold higher ($117,563/patient) versus matched patients ($7,520/patient). In comparison B, all-cause HCRU was higher for the EGPA cohort (n = 182) versus the matched SUA cohort (n = 640) for all clinical encounters/pharmacy claim types, with 5-fold higher mean total all-cause costs ($118,127/patient vs $22,286/patient). In both EGPA cohorts, HCRU and associated costs increased between the baseline and follow-up periods. ConclusionsThese findings highlight the need for more effective treatments to reduce the clinical and economic burden of EGPA.

BackgroundEpidemiological studies have consistently documented an inverse association between atopic dermatitis (AD) and glioblastoma (GBM), yet the immunogenetic mechanisms underlying this paradox remain elusive. We hypothesized that distinct immune subsets driven by shared genetic variants exhibiting antagonistic pleiotropy may explain this relationship. ObjectiveTo dissect the immunogenetic basis underlying the inverse association between AD and GBM by integrating single-cell transcriptomics and clustered Mendelian randomization, and to identify shared immune subsets and genetic variants exhibiting antagonistic pleiotropy that may explain this epidemiological paradox. MethodsWe integrated single-cell RNA sequencing (scRNA-seq) of publicly available datasets from AD skin (GSE153760) and GBM tumors (GSE256490) with genome-wide association study (GWAS) summary statistics. Disease-specific immune cell subsets were identified, and pathway enrichment was conducted on marker genes. Clustered Mendelian randomization (MR-Clust) was applied to detect heterogeneous causal effects, followed by drug target enrichment analysis using the DGIdb database. ResultsscRNA-seq revealed that Th2A cells were the predominant pathogenic subset in AD lesions, whereas S100A9+HLA-low suppressive monocytes were enriched in the GBM microenvironment. Both subsets shared enrichment in the NF-{kappa}B and Fc{varepsilon}RI signaling pathways, revealing a common immunological framework linking peripheral Type 2 inflammation to central nervous system immunosuppression. MR-Clust identified a distinct genetic cluster (Cluster 2) comprising 32 genes (e.g., IL4R, JAK1, SYK, FCER1G) significantly overexpressed in these cell types. This cluster exhibited antagonistic pleiotropy: it was directionally associated with reduced AD risk (OR = 0.930, 95% CI 0.846-1.023, p = 0.137) but a non-significant risk trend for GBM (OR = 1.447, 95% CI 0.737-2.841, p = 0.283). Drug target analysis indicated that Cluster 2 genes are primary targets of approved AD therapies, including dupilumab (IL4R) and JAK inhibitors (JAK1). ConclusionOur integrative analysis uncovers an immune-genetic axis linking Th2A cells in AD to suppressive monocytes in GBM, providing a mechanistic basis for their inverse comorbidity. These findings highlight a potential therapeutic paradox, underscoring the need for pharmacovigilance regarding long-term cancer risk in AD patients receiving targeted immunomodulators.

Sarcoidosis is a multisystem disorder that primarily affects the lungs and is characterizedby granulomatous inflammation. However, much of the underlying disease mechanisms remain poorly understood. Extracellular vesicles (EVs) are small membrane-bound particles released by all cells and carry various cargos including metabolites. They are involved in intercellular communication that can be dysregulated in diseases.This study characterizes the metabolic cargo of EVs isolated from bronchoalveolar lavage fluid (BALF), using liquid chromatography-mass spectrometry (LC-MS)-based metabolomic analysis, in patients with sarcoidosis (n=37), compared to healthy controls (n=10). Additionally, the sarcoidosis signature was compared to another pulmonary disorder, anti-synthetase syndrome (ASyS, n=10). Arachidonic acid (AA) results were verified by ELISA. A total of 1202 metabolites were detected, with 111 annotated ones further analyzed. EVs from sarcoidosis patients showed distinct metabolomic profiles compared to both ASyS patients and healthy controls, with 38 annotated metabolites differentially expressed in any of the groups. In both annotated and non-annotated data, sarcoidosis patients clustered separately from ASyS patients and healthy individuals. Furthermore, sarcoidosis patients clustered in 3 subgroups, whereof one was similar to ASyS patients and one stood out as showing higher cell counts in BALF. Higher AA levels were found in sarcoidosis patient EVs by LC-MS, and AA results were verified by ELISA. Our data show that BALF EV metabolites are disease-dependent and support the notion thatsarcoidosis patients should be further subgrouped for better diagnosis and treatment.