Poisot T, Murat de Montaï Q, Grolleau C
… +19 more, Roux C, Bergerat D, Delmotte A, Merandet M, Schiavon V, Battistella M, Saussine A, Bozonnat A, Battesti G, Mahévas T, Charvet E, Jachiet M, Paugoy H, Serror K, Boccara D, Tamoutounour S, Aguilar L, Le Buanec H, Bouaziz JD
BACKGROUND: A precise etiologic diagnosis of seasonal allergic rhinitis (SAR) is essential for tailored prescription of its only curative treatment, allergen immunotherapy. This is a challenging task in temperate climate...BACKGROUND: A precise etiologic diagnosis of seasonal allergic rhinitis (SAR) is essential for tailored prescription of its only curative treatment, allergen immunotherapy. This is a challenging task in temperate climates, where most patients are polysensitized to multiple pollen with overlapping seasons. OBJECTIVE: The study aimed to develop a modular, flexible, and validated clinical decision support system (CDSS) generated with artificial intelligence for etiologic diagnosis of SAR. METHODS: Within the @IT-2020 project, we developed a CDSS for SAR etiologic diagnosis, automated through machine learning (ML). The CDSS includes 3 progressive modules: (a) clinical history and SPT, (b) plus molecular sIgE, (c) plus electronic/environmental diary. Three raters performed ML training, by identifying culprit pollen in 100 SAR patients (Rome, Italy) using guidelines and a Delphi-like process. RESULTS: Best-performing ML models for each diagnostic module realibly replicated expert diagnosis (area under the receiver operating characteristics curve >95%). Their validity was confirmed by: (A) contextual adaptability, with performance linked to patient complexity; (B) interpretability, as clinical features and sensitization patterns contrtibuted to predictions (SHAP analysis); (C) geographical generalizability, with consistent performance in 92 patients from Tirana (Albania); (D) temporal generalizability, maintaining high performance with reduced monitoring (45 days); (E) AIT prescription adaptability, reproducing gold-standard prescriptions; and (F) human-plus capability, ouperforming 24 physicians in a diagnostic challenge. CONCLUSION: In this proof-of-concept study, an ML-based modular CDSS reliably replicated raters' diagnosis and AIT prescription in SAR. Further studies should confirm replication and prospectively asses CDSS role in enabling SAR personalized treatment and improving disease control.
BACKGROUND: The type 2 inflammation-blocking agent dupilumab has gained traction as an effective treatment of multiple atopic diseases. New-onset autoimmune manifestations have been infrequently reported in dupilumab-tre...BACKGROUND: The type 2 inflammation-blocking agent dupilumab has gained traction as an effective treatment of multiple atopic diseases. New-onset autoimmune manifestations have been infrequently reported in dupilumab-treated atopic patients, primarily among adults. Autoimmune outcomes in atopic children on dupilumab are less clear. OBJECTIVE: We aimed to determine if dupilumab treatment of atopic children is associated with increased autoimmune or autoinflammatory disease diagnosis risk. METHODS: Using a multi-institutional electronic health record database composed of 10 PEDSnet academic health systems, we performed a retrospective cohort study of children aged 6-17 with atopy (ie, moderate-to-severe atopic dermatitis and/or persistent asthma, as defined by diagnosis codes and prescriptions) with or without (n = 4,189 and n = 4,195 in inverse-probability-of-treatment-weighted cohorts, respectively) dupilumab prescription between October 1, 2018, and November 29, 2023. Poisson regression estimated autoimmune disease incidence rates and rate differences, and Cox proportional hazards models estimated relative associations between dupilumab exposure and disease diagnosis. RESULTS: Among atopic children, the adjusted incidence rate difference (dupilumab-treated minus untreated) for any autoimmune disease was 2.47 (95% confidence interval, 0.82, 4.30) per 1,000 person-years, driven primarily by cutaneous autoimmune diseases (rate difference, 2.20 [95% confidence interval 0.77, 3.70] per 1,000 person-years). The rates of any or cutaneous autoimmune disease within 4 years of dupilumab treatment were 1.45-fold and 1.57-fold higher, respectively, in treated compared with untreated atopic children. CONCLUSION: We detected a modest association between dupilumab and cutaneous autoimmune disease diagnosis in atopic children. These findings help address knowledge gaps about clinical outcomes in atopic children treated with this biologic.
Trimarchi MP, Namjou-Khales B, Ben-Baruch Morgenstern N
… +15 more, Rochman M, Chen X, Osswald GA, Besse JA, Shook MS, Caldwell JM, Lape M, Shoda T, Weirauch MT, Ruffner MA, Constantine GM, Martin LJ, Kottyan LC, Rothenberg ME, Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR) Investigators
J Allergy Clin Immunol
· 2026 Mar · PMID 41865802
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BACKGROUND: Eosinophilic esophagitis (EoE) is an atopic disease driven in part by genetic susceptibility, but single-trait genome-wide association study (GWAS) has identified a limited number of genome-wide significant r...BACKGROUND: Eosinophilic esophagitis (EoE) is an atopic disease driven in part by genetic susceptibility, but single-trait genome-wide association study (GWAS) has identified a limited number of genome-wide significant risk loci. OBJECTIVE: We sought to expand discovery of EoE genetic risk loci by leveraging shared genetic architecture with other atopic diseases and to develop a polygenic risk score (PRS) for EoE. METHODS: We performed a GWAS of 1,757 individuals with EoE and 14,467 population controls. We then applied multitrait analysis of GWAS (MTAG), integrating EoE with other atopic disease GWAS (UK Biobank; >450,000 subjects). Functional analyses were used to nominate candidate EoE risk genes. PRS models derived from MTAG were compared to PRS derived from the EoE-only GWAS. An interactive tool (EGIDExpress; https://egidexpress. RESEARCH: cchmc.org/GWAS/) was developed to enable dataset queries and visualization. RESULTS: The EoE-only GWAS identified 11 independent risk variants across 8 loci (P < 5 × 10), including 3 novel loci. MTAG identified 33 independent EoE risk variants across 24 loci, including 14 novel loci. Functional studies nominated 90 candidate EoE risk genes, including genes implicating mechanisms beyond type 2 immunity. A PRS derived from MTAG outperformed a PRS derived from the EoE-only GWAS (OR 11.57 [95% confidence interval, 6.90-19.40] for top vs bottom decile). CONCLUSION: Leveraging shared atopic disease genetics via MTAG substantially expands the landscape of EoE risk loci and improves EoE polygenic risk prediction, underscoring shared genetic mechanisms across atopic diseases. We further provide a public resource (EGIDExpress; https://egidexpress. RESEARCH: cchmc.org/GWAS/) to advance the field.
BACKGROUND: Nemolizumab reduces pruritus and skin lesions in patients with atopic dermatitis (AD), yet some patients develop cutaneous adverse events (CAEs) with increased serum thymus- and activation-regulated chemokine...BACKGROUND: Nemolizumab reduces pruritus and skin lesions in patients with atopic dermatitis (AD), yet some patients develop cutaneous adverse events (CAEs) with increased serum thymus- and activation-regulated chemokine (TARC); mechanisms are unclear. OBJECTIVE: We sought to define systemic changes and the mechanism underlying TARC elevation after IL-31 receptor A (IL-31RA) blockade. METHODS: Serum proteomics (Olink), MC903 models with or without anti-IL-31RA, single-cell RNA sequencing of AD skin with in situ validation, functional assays using human dendritic cells (DCs), and human dorsal root ganglion analyses with ligand-receptor inference were integrated. RESULTS: In patients with CAEs, TARC levels increased and correlated with type 2 markers. In mice, IL-31RA blockade increased serum and dermal TARC without broad transcriptomic shifts. A Ccl17-T2A-GFP reporter localized TARC to dermal DCs, enriched in type 2 conventional DCs. In patients, CCL17 localized to LAMP3CD1c mature DCs in situ. Analyses supported calcitonin gene-related peptide (CGRP) signaling via the calcitonin receptor-like (CALCRL) signaling from IL-31RA/oncostatin M receptor-positive nociceptors to mature DCs; CGRP reduced DC maturation and TARC in vitro. CONCLUSION: Findings support an IL-31-dependent CGRP-CALCRL neuroimmune brake that restrains DC maturation and TARC. IL-31RA blockade disinhibits this circuit, linking antipruritic therapy to DC-driven chemokine programs and offering a rationale for stronger TARC responses in patients than in the MC903 model. Monitoring TARC and neuroimmune context may aid management of nemolizumab-treated patients with AD.
BACKGROUND: Expression of CD25, the IL-2 receptor alpha chain, on human mast cells is primarily associated with aberrant mast cells in clonal mast cell disorders. However, the regulation of CD25 expression in normal, mat...BACKGROUND: Expression of CD25, the IL-2 receptor alpha chain, on human mast cells is primarily associated with aberrant mast cells in clonal mast cell disorders. However, the regulation of CD25 expression in normal, mature tissue-resident mast cells remains poorly understood. OBJECTIVE: IL-33 is a key modulator of immune responses, including in lung inflammatory conditions. Because mast cells are prominent IL-33 receptor-expressing cells, we investigated the effect of IL-33 on CD25 expression in purified human lung mast cells (HLMCs). METHODS: Purified HLMCs were stimulated with IL-33 and the transcriptional responses measured by RNA sequencing. The expression of the IL-2 receptor subunits CD25 (IL2RA), CD122 (IL2RB), and CD132 (IL2RG) was quantified by real-time quantitative PCR and flow cytometry. IL2RA expression was further examined in publicly available single-cell RNA sequencing datasets, and in situ CD25 protein expression on HLMCs was assessed in human lung tissue by immunofluorescence staining. RESULTS: IL-33 robustly induced the expression of CD25 and CD132 in HLMCs without a corresponding upregulation of CD122, resulting in absent IL-2-mediated signaling despite enhanced IL-2 binding via CD25. Single-cell RNA sequencing data identified IL2RA mast cells as a distinct subpopulation with enriched IL-33 response signatures and upregulation of genes linked to immune signaling and inflammatory pathways. CD25-positive HLMCs were also detected in situ, displaying substantial heterogeneity in expression levels and spatial distribution. CONCLUSIONS: CD25 expression in HLMCs is upregulated by IL-33 and is dynamically regulated in human lung tissues.
Yaskolka Meir A, Li Y, Zhu Z
… +6 more, Espinola JA, Hong X, Camargo CA, Wang X, Hasegawa K, Liang L
J Allergy Clin Immunol
· 2026 Jul · PMID 41825598
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BACKGROUND: Early-life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high IgE beyond wh...BACKGROUND: Early-life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high IgE beyond what is captured by observed IgE levels. OBJECTIVE: We sought to establish and examine the residual effect of an epigenetic total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population. METHODS: We used data from the 35th Multicenter Airway Research Collaboration (MARC-35; n = 560), the 43rd Multicenter Airway Research Collaboration (MARC-43; n = 177), and the Boston Birth Cohort (BBC; n = 80). DNA methylation (Illumina EPIC array) was measured in blood during infancy (MARC-35, MARC-43) and in cord blood at birth (BBC). Total IgE was assessed in blood at infancy, recurrent wheezing at age 3 years, and asthma at age 6 years for all cohorts. RESULTS: MARC-35 data were used to train and evaluate a DNAm-IgE score (R = 0.502 vs total IgE). MARC-43 and BBC data were used to validate the score (R = 0.309 and R = 0.132). In meta-analyses of the 3 cohorts, 1 standard deviation of DNAm-IgE score residuals (DNAm-IgE score regressed on total IgE) was associated with recurrent wheezing (OR = 1.33 [95% confidence interval, 1.11, 1.60], P = .92), while 1 standard deviation of total IgE was associated with asthma (OR = 1.45 [95% confidence interval, 1.19, 1.76], P = .29). All models were adjusted for sex, race/ethnicity, and birth weight. CONCLUSION: Early-life epigenetic patterns related to total IgE may contribute to subsequent respiratory morbidity beyond measured IgE levels. The DNAm-IgE score and its residual component should be viewed as exploratory tools that require further validation and mechanistic study.
BACKGROUND: Gut microbial composition has been proposed to influence disease onset in children with food protein-induced enterocolitis syndrome (FPIES). OBJECTIVE: We sought to investigate differences in gut microbiota p...BACKGROUND: Gut microbial composition has been proposed to influence disease onset in children with food protein-induced enterocolitis syndrome (FPIES). OBJECTIVE: We sought to investigate differences in gut microbiota profiles in children with newly diagnosed FPIES and healthy control subjects. METHODS: Fecal samples were collected at FPIES diagnosis from 56 children stratified into 3 age groups: mean (SD) age 4.6 (0.5) months, 6.5 (0.6) months, and 11.7 (7.8) months. Gut microbiota profiles were analyzed using 16S ribosomal RNA gene amplicon sequencing and compared between children with FPIES and 43 age-matched control subjects. RESULTS: Age was the strongest determinant of gut microbiota composition, followed by FPIES status. β-diversity differed significantly between children with FPIES and control subjects (P < .01), primarily driven by shifts in Bacteroidota, Proteobacteria, Actinobacteriota, and Verrucomicrobiota. Children with FPIES had lower Bifidobacterium and higher abundances of Bacteroides, Haemophilus, and Veillonella. FPIES food triggers were associated with reduced Verrucomicrobiota abundance. CONCLUSIONS: Children with FPIES exhibit gut microbial dysbiosis characterized by reduced Bifidobacterium and Verrucomicrobiota abundance, suggesting potential links between early-life microbiota development and disease pathogenesis.
Hayakawa H, Tsumura M, Utsumi T
… +24 more, Nihira H, Lei WT, Ogino R, Bucciol G, Nakano T, Amo K, Moriya K, Hayakawa S, Mizoguchi Y, Karakawa S, Lin YN, Shih HP, Lo CC, Janssenswillen S, Van Loo S, Mekahli D, Bogunovic D, Boisson-Dupuis S, Izawa K, Ku CL, Yasumi T, Asano T, Meyts I, Okada S
BACKGROUND: Monoallelic RELA variants resulting in haploinsufficiency (HI) have been linked to recurrent mucocutaneous ulcers and enteritis. Heterozygous RELA dominant-negative (DN) variants often exhibit autoinflammator...BACKGROUND: Monoallelic RELA variants resulting in haploinsufficiency (HI) have been linked to recurrent mucocutaneous ulcers and enteritis. Heterozygous RELA dominant-negative (DN) variants often exhibit autoinflammatory phenotypes associated with type I interferonopathy beyond those typically associated with RELA-HI variants. The vast majority of documented cases of autosomal dominant (AD) RelA deficiency are caused by non-missense deleterious variants introducing a premature stop codon. OBJECTIVE: We sought to characterize the clinical manifestations and pathologic significance of RELA variants and to establish the boundary separating RELA-HI and RELA-DN variants to facilitate position-based estimation of the nature of RELA variants. METHODS: RELA variants were characterized via a nuclear factor-κB reporter assay, immunoblotting, immunoprecipitation, and electrophoretic mobility shift assay in RELA and NFKB1 double knockout cells. RESULTS: Eight patients from 5 families with AD RelA deficiency were identified, and all harbored novel RELA variants. A comprehensive functional study using RELA nonsense variants identified amino acid P290 as the boundary between RELA-HI and RELA-DN variants in non-missense deleterious variants. In patients with RELA-DN variants, corticosteroid preparations were relatively ineffective, leading to increased use of biological drugs, mainly anti-TNF agents. We also identified atypical additional variants, including a missense variant and an in-frame variant, and experimentally confirmed their pathogenicity. CONCLUSIONS: The positions of non-missense deleterious variants in RELA allow the estimation of the associated functional changes, facilitating the precise diagnosis of AD RelA deficiency. Conversely, RELA missense variants require functional verification, as their impact cannot be predicted solely from their position.