BACKGROUND: Chronic rhinosinusitis with nasal polyps involves mixed type 2-type 3 inflammation, associated with disease severity and treatment resistance, yet mechanisms remain unclear. OBJECTIVE: We sought to investigat...BACKGROUND: Chronic rhinosinusitis with nasal polyps involves mixed type 2-type 3 inflammation, associated with disease severity and treatment resistance, yet mechanisms remain unclear. OBJECTIVE: We sought to investigate the role of IL-2 and its interaction with type 3 inducers (TNF-α, IL-1β, and IL-23) in driving mixed type 2-type 3 inflammation. METHODS: IL-2 and receptor expression in nasal polyps was analyzed using tissue homogenates and public RNA-sequencing data. Dispersed nasal polyp cells were treated with IL-2/type 3 inducers, with cytokine production, proliferation, and gene expression analyzed via immunoassays, flow cytometry, and RNA sequencing. IL-2 receptor/Janus kinase (JAK) blockade studies were conducted. Furthermore, CD4 and CD8 T cells were magnetically isolated from nasal polyps to evaluate their response to cytokine stimulation. RESULTS: IL-2 levels were increased in chronic rhinosinusitis with nasal polyps, particularly in type 3-dominant and mixed type 2-type 3 subgroups, and correlated with type 3 cytokines. RNA sequencing supported upregulated IL-2 receptors and their coexpression with type 3 genes. IL-2 synergized with type 3 inducers to enhance both type 2 and type 3 cytokine production in dispersed nasal polyp cells. Direct functional evidence from isolated CD4 and CD8 T cells confirmed this synergy, with CD8 T cells emerging as a novel source of IL-13. Flow cytometry further supported these findings, showing synergistic cytokine production across diverse cell populations, including T-cell subsets and natural killer cells. Memory T cells mediated T-cell receptor-independent cytokine production. Transcriptomic analysis identified activated type 3, type 2, and JAK-signal transducer and activator of transcription signaling pathways. IL-2 receptor blockade, particularly JAK inhibition, attenuated IL-2/type 3 inducer-mediated synergistic inflammation. CONCLUSIONS: A novel mechanism was identified whereby IL-2 synergizes with proinflammatory type 3 inducers to amplify mixed type 2-type 3 inflammation via innate-like T-cell activation, and targeted JAK inhibition was validated as a potential therapy.
BACKGROUND: The relationships between allergic diseases (AD) and IgE levels are complex. OBJECTIVE: We sought to identify genes associated with AD and IgE having close proximity in the interactome and to elucidate the as...BACKGROUND: The relationships between allergic diseases (AD) and IgE levels are complex. OBJECTIVE: We sought to identify genes associated with AD and IgE having close proximity in the interactome and to elucidate the associated biological mechanisms. METHODS: We integrated a comprehensive interactome with data from genome-wide (GWAS) and epigenome-wide (EWAS) association studies of AD and IgE levels, respectively. We used the SigMod algorithm to identify gene modules enriched in AD- and IgE-associated signals. We performed a connectivity analysis of these two modules to characterize direct cross-trait connections. Finally, we conducted an in-depth functional analysis of the directly-connected AD and IgE genes. RESULTS: We identified gene modules that were significantly associated with AD and IgE, respectively (P < 10). The connectivity analysis revealed that 139 AD- and IgE-associated genes had direct cross-trait connections in the interactome. Combinations of these genes were enriched (false discovery rate < 0.05) in pathways notably involved in type 2 and non-type 2 immune responses. These results were corroborated by cell-specific enrichment of gene expression. Of the 139 genes, 55% (77 genes) had not previously been associated with AD and/or IgE. These genes are implicated in biological processes including host defense against pathogens, ubiquitination, gene expression regulation, inflammation, and neuroimmune interactions. The 139 genes are enriched in drug targets (P = 7.7 × 10). CONCLUSIONS: This study sheds light on the biological mechanisms influenced by AD and IgE genes that are directly linked in the interactome. It emphasizes the role of IgE in both allergic and antiviral responses. This study also identifies new genes for further investigation.
BACKGROUND: The soluble alpha chain of FcεRI (sFcεRI) is released during receptor cross-linking on mast cells (MCs) and serves as an acceptor site for circulating IgE. Recent data suggest that sFcεRI counteracts MC activ...BACKGROUND: The soluble alpha chain of FcεRI (sFcεRI) is released during receptor cross-linking on mast cells (MCs) and serves as an acceptor site for circulating IgE. Recent data suggest that sFcεRI counteracts MC activation in allergic patients. OBJECTIVES: We measured the levels of sFcεRI and its effect in cutaneous mastocytosis and systemic mastocytosis (SM). METHODS: sFcεRI levels were quantified by ELISA in 114 patients with mastocytosis, including cutaneous mastocytosis (n = 12), indolent SM (n = 67), smoldering SM (n = 5), SM with associated hematologic neoplasm (n = 17), aggressive SM (n = 9), and MC leukemia (n = 4). We measured sFcεRI levels at diagnosis and during follow-up and established correlations with the SM variant, prognostic parameters, and survival. Moreover, we assessed sFcεRI effects on proliferation of neoplastic MCs and IgE-dependent activation and histamine release in basophils obtained from SM patients. RESULTS: Compared to healthy controls, sFcεRI levels were within normal range in most patients with cutaneous mastocytosis and indolent SM, whereas in most patients with advanced SM, especially those with aggressive SM, increased sFcεRI levels were detected. Moreover, we found that a clearly elevated sFcεRI level in SM correlates with poor survival and a lower risk of vascular instability. sFcεRI levels did not correlate with serum tryptase levels, total IgE levels, or the presence of hereditary α-tryptasemia. In in vitro experiments, sFcεRI suppressed anti-IgE-induced CD63 expression and histamine release in basophils and growth of neoplastic MCs. CONCLUSION: sFcεRI is often elevated in patients with advanced SM and acts as negative regulator of growth and activation of neoplastic MCs.
Maier L, Sun Y, Kronberg J
… +68 more, Abner E, Estonian Biobank Research Team, Coley K, Marenholz I, Weiss S, Foraita R, Karramass T, Mykkänen J, Hernandez-Pacheco N, Wang CA, Kitaba NT, Pechlivanis S, Bouzigon E, Tingskov Pedersen CE, Schoos AM, Curtin JA, Kress S, Hernangomez-Laderas A, Foppiano F, Ashley S, Batini C, Bryant L, Homuth G, Gieger C, Gilles S, Lyytikäinen LP, Rovio S, Pahkala K, Vernet R, Valenta R, Llop S, Torrent M, Böck A, Tang MLK, Schmidt-Weber CB, Metspalu A, Esko T, Sprikkelman AB, John C, Lee YA, Beyer K, Völzke H, Pigeot I, Traidl-Hoffmann C, Duijts L, Lu H, Raitakari OT, Lehtimäki T, Kähönen M, Thio CHL, Melén E, Pennell CE, Holloway JW, von Mutius E, Siroux V, Bønnelykke K, Custovic A, Simpson A, Schikowski T, Bilbao JR, Schaub B, Peters R, Kersten ETG, Vonk JM, Thiering E, Peters A, Koppelman GH, Standl M
BACKGROUND: Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been...BACKGROUND: Food allergy (FA) arises from a complex interplay between an individual's genetic predisposition and environmental factors, and its prevalence is increasing. Genome-wide association studies to date have been hindered by small sample sizes and varying FA definitions. OBJECTIVE: We sought to identify novel FA risk loci by conducting a genome-wide association study meta-analysis in children and adults by using a multiphenotype approach to ensure a good trade-off between sufficient sample size and valid FA definitions. METHODS: Analyses were conducted separately in children and adults on the basis of the following FA phenotypes: self-report, doctor diagnosis, food-specific sensitization, and doctor diagnosis plus food-specific sensitization. A meta-analysis was performed of genome-wide association studies from up to 16 cohorts of people of European ancestry including 229,426 adults and 14,234 children. Models were adjusted for sex, age, principal components, and, if applicable, further study-specific confounders. Sensitivity models were additionally adjusted for hay fever. Replication was conducted in additional external cohorts and a validation in oral food challenge-defined FA cases. RESULTS: Thirty-seven single nucleotide polymorphisms met suggestive significance (P < 1 × 10), with two reaching genome-wide significance: rs116936231 (FGL1) in adult doctor-diagnosed FA plus food-specific sensitization phenotype (stable after additional hay fever adjustment) and rs8022829 (AKAP6-NPAS3), which was significant only in the hay fever-adjusted model in adults. However, neither variant was validated. Further, we identified 3 single nucleotide polymorphisms previously reported for FA and atopic disease. CONCLUSION: This study identified 37 single nucleotide polymorphisms suggestively associated with FA and demonstrated genetic differences across phenotypes. It highlights the need for a unified FA definition and sheds light on FA's shared genetic architecture with allergies.
Ghosh R, Fazal Z, Oler AJ
… +33 more, Tokita MJ, Lewis KL, Paul AJ, Schmitz EG, Saucier N, Yan J, Kamen M, Seifert BA, NIAID Centralized Sequencing Program,, Klion AD, Khoury P, Delmonte OM, Notarangelo LD, Freeman AF, Zerbe CS, Uzel G, Metcalfe DD, Komarow HD, Carter MC, McDermott DH, Murphy PM, Olivier KN, Fuss I, Strober W, Rao VK, Bergerson JRE, Almeida de Jesus A, Goldbach-Mansky R, Al-Herz W, Holland SM, Cooper MA, Similuk MN, Walkiewicz MA
J Allergy Clin Immunol
· 2026 May · PMID 41724404
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BACKGROUND: Mosaic variants represent a significant but underrecognized contributor to human disease such as cancer and immune diseases. Despite advances in genetic diagnostics, mosaic variant detection remains challengi...BACKGROUND: Mosaic variants represent a significant but underrecognized contributor to human disease such as cancer and immune diseases. Despite advances in genetic diagnostics, mosaic variant detection remains challenging as a result of low variant allele fractions, tissue specificity, and clinical heterogeneity. OBJECTIVE: We investigated the prevalence, diagnostic impact, and clinical relevance of mosaic variants in participants with immune disorders. METHODS: Exome sequencing of blood and/or saliva was performed in 2655 participants, including 2064 affected participants. Mosaic variants were detected using two algorithms, LoFreq2 and Mutect2. A subset of the detected variants was orthogonally validated. Clinical data were retrospectively analyzed to assess the clinical significance of these variants. RESULTS: Mosaic variants associated with immune disorders contributed to a molecular diagnosis in 29 (1.4%) of 2064 affected participants. Notably, 9 (31%) of 29 of diagnostic variants were missed by standard germline analysis as a result of low variant allele fractions. Clinically relevant parental mosaicism was ascertained in two families. Enrichment of mosaic variants was observed in clonal hematopoiesis-related genes driven by older age and GATA2 deficiency, with prognostic implications for hematologic disorders. Finally, chemotherapy drug resistance variants in NRAS, KRAS, and IDH2 were identified, demonstrating the potential for mosaic variant detection to inform treatment strategies. CONCLUSION: Mosaic variants contribute significantly to the molecular diagnosis and prognosis of immune and hematologic disorders and are missed by typical germline variant-calling workflow.
BACKGROUND: Staphylococcal superantigen-specific IgE (SAg-IgE) correlates with disease severity in patients with type 2 (T2) chronic rhinosinusitis with nasal polyps (CRSwNP). Although Staphylococcus aureus is recognized...BACKGROUND: Staphylococcal superantigen-specific IgE (SAg-IgE) correlates with disease severity in patients with type 2 (T2) chronic rhinosinusitis with nasal polyps (CRSwNP). Although Staphylococcus aureus is recognized as a primary source of SAgs, SAg-IgE is detected even in patients with culture-negative S aureus. OBJECTIVE: We sought to identify the source of SAgs in SAg-IgE-positive patients with T2 CRSwNP with culture-negative S aureus. METHODS: Metagenomic sequencing was conducted in patients with T2 CRSwNP with repeatedly negative S aureus cultures, stratified by SAg-IgE status. We screened clinical isolates for SAg genes and evaluated SAg functionality by measuring SAg-specific T-cell receptor repertoire expansion and T2 inflammatory responses in an ex vivo infection model. RESULTS: The SAg-IgE-positive group showed significantly higher abundances of S epidermidis, S aureus, Lysinibacillus xylanilyticus, and S capitis compared with the SAg-IgE-negative group. Interestingly, in all participants in whom S aureus was detected, S capitis was also present, albeit at low abundance. Redundancy analysis demonstrated clustering of the Staphylococcus genus, SAg-IgE, and IL-5, supporting a potential link between the Staphylococcus genus and SAg-driven immune responses. Notably, a clinical S capitis isolate carried SEA (staphylococcal enterotoxin A) and SEC genes and secreted functional SAgs, which triggered the clonal expansion of SEA/SEC-specific T-cell receptors and exacerbated the T2 inflammatory response via IL-33 induction. CONCLUSIONS: Metagenomic sequencing reveals that S capitis, beyond S aureus, produces functional SAg to drive T2 response in SAg-IgE-positive patients with CRSwNP when conventional cultures fail to detect S aureus. Independent of culturable bacterial load, tissue SAg-IgE positivity reliably indicates bacterial colonization and SAg exposure in CRSwNP.
BACKGROUND: Type I interferon-mediated diseases present diagnostic challenges due to heterogeneous clinical manifestations and limitations of current molecular diagnostics, such as the type I interferon score (IS). OBJEC...BACKGROUND: Type I interferon-mediated diseases present diagnostic challenges due to heterogeneous clinical manifestations and limitations of current molecular diagnostics, such as the type I interferon score (IS). OBJECTIVES: We sought to evaluate SIGLEC-1 expression on monocytes as a practical biomarker for type I interferon activation. METHODS: We conducted a combined retrospective (n = 47) and prospective (n = 62) study of patients with suspected interferon-mediated diseases. SIGLEC-1 expression was quantified by flow cytometry as mean fluorescence intensity (MFI) and percentage of SIGLEC-1 monocytes. Analytical robustness was assessed in 52 paired samples comparing whole blood versus PBMCs and 2 cytometers (BD Fortessa vs BD Lyric). Fold-change normalization was evaluated to reduce interinstrument variability. RESULTS: In the retrospective cohort, SIGLEC-1 MFI and percentage of SIGLEC-1 monocytes strongly correlated with the type I IS (R = 0.76; P < .0001), with excellent diagnostic accuracy (area under the curve [AUC] = 0.99 and 0.98). In 11 patients with paired samples (high and low IS), SIGLEC-1 decreased in parallel with the IS. In the prospective cohort, optimized MFI and percentage cutoffs (2307 and 40.65) perfectly discriminated patients with interferonopathies from those with alternative diagnoses (AUC = 1.0). Analytical validation showed that although absolute values differed between PBMCs and whole blood, correlations were strong (R > 0.97) and diagnostic classification was maintained. Similarly, Lyric values were lower than Fortessa but remained highly correlated (R > 0.93) with stable classification. Fold-change normalization (cutoffs: 4.7 for MFI; 12 for %) minimized platform variability while preserving 100% sensitivity and specificity. CONCLUSIONS: Flow-cytometric SIGLEC-1 is a robust, cost-effective, and reproducible surrogate of type I IS, supporting its implementation for diagnosis, patient stratification, and longitudinal monitoring.
BACKGROUND: Type 1-mediated chronic inflammatory skin diseases affect skin, hair, nails, and mucosa and dramatically impact patients' quality of life. The 2 most prominent examples are lichen planus (LP) and cutaneous lu...BACKGROUND: Type 1-mediated chronic inflammatory skin diseases affect skin, hair, nails, and mucosa and dramatically impact patients' quality of life. The 2 most prominent examples are lichen planus (LP) and cutaneous lupus erythematosus (CLE). Various cell death pathways are activated in both diseases, including apoptosis and necroptosis. RIPK1 is a key regulator of programmed cell death and thus represents a potential new target for treatment of these diseases. OBJECTIVE: We sought to determine the impact of RIPK1 on cell death and inflammation in LP and CLE. METHODS: RNA sequencing of inflammatory skin diseases (n = 179) assessed cell death, hypothermia, and inflammatory markers affected by eclitasertib, a novel RIPK1 inhibitor, in human cells, murine TNF-α-induced systemic inflammatory response syndrome model, reconstructed human epidermis, and ex vivo skin biopsy culture. RESULTS: Markers of apoptosis (CASPASE8) and necroptosis (RIPK3, MLKL) are upregulated in LP and CLE. Eclitasertib restored body temperature when orally administered 15 minutes after TNF-α injection in the murine systemic inflammatory response syndrome model. RIPK1 inhibition prevented keratinocyte cell death; normalized epidermal architecture; and decreased release of IL-1α, IL-1β, TNF-α, and CCL20 in reconstructed human epidermis on stimulation with LP and CLE T-cell supernatant. Ex vivo culture of LP and CLE biopsy specimens with eclitasertib reduced expression of disease-specific genes and downregulated pathways associated with inflammation. CONCLUSIONS: Inhibition of RIPK1 targets 2 major pathogenic events in LP and CLE: epidermal cell death and type 1-mediated skin inflammation.
BACKGROUND: The National Institutes of Health initiated the Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program with the objective of implementing adaptive design strategies to test multiple n...BACKGROUND: The National Institutes of Health initiated the Precision Medicine in Severe and/or Exacerbation Prone Asthma (PrecISE) program with the objective of implementing adaptive design strategies to test multiple new treatments in biomarker-identified patient subsets. OBJECTIVE: The PrecISE study sought to recruit a cohort of patients with severe asthma for a biomarker-stratified adaptive trial of 5 different interventions. METHODS: Patients aged 12 years and older with a clinical diagnosis of asthma who were adhering to a stable medical regimen consisting of at least medium-dose inhaled corticosteroids and a second controller were enrolled if their diagnosis could be confirmed by bronchodilator responsiveness on spirometry or airway hyperreactivity to methacholine. Protocol adaptations over the course of the study to biomarker sampling and enrichment, interventions studied, the statistical analysis plan, and sample size are described. The baseline characteristics of the cohort were analyzed. RESULTS: A total of 358 participants were randomized. The 4 predictive biomarkers used for intervention randomization assignments were blood eosinophil count (median = 180; interquartile range (IQR) = 100-290 cells/mL), fractional exhaled nitric oxide measurement (median = 18; IQR = 11-27 ppb); plasma IL-6 level (median = 2.5; IQR = 1.6-3.6 pg/mL), and ADH5 risk genotype (present in 253 participants [71%]). Blood eosinophil counts weakly correlated with fractional exhaled nitric oxide measures (Rs = 0.13; P = .02) and IL-6 levels (Rs = 0.17; P = .002); otherwise, these biomarkers were independent from each other. Specific intervention results will be reported separately. CONCLUSION: The PrecISE adaptive study design with multiperiod crossovers is an efficient and novel way to study multiple interventions simultaneously in a heterogeneous disease such as asthma.
He T, Wang J, Carpio Tumba M
… +133 more, Wang S, Luo Y, Chen J, Li G, Shu Z, Zhang S, Stone DL, Huang Y, Lv Q, Xiong W, Wang J, Yu Z, Cuff CV, Kairis E, Kethri A, Towheed A, Goyette K, Karri U, Wang J, Liu C, Romeo T, Alsina L, Rosenberg DL, Clemente D, López-Robledillo JC, Rong Z, Zhao X, Jiang L, Aldave-Becerra JC, Muñoz-Urribarri AB, Oommen PT, Campbell-Stokes P, Zhu M, Liu P, Guo L, Xu Y, Yu Z, Tong H, Qiu X, Zhang Y, Chen H, Zhang C, Ou J, Liu C, Liu J, Shen Y, Cao J, Zhang X, Yang K, Bao Y, Li Z, Cao J, Duan Y, Liu F, Shi B, Sun M, Ma L, Chen Y, Yang W, Han X, Ma S, Luo J, Gu W, Yu G, Shi W, Zhao R, Sun L, Li W, An Y, Tang X, Zhao X, Han T, Ma J, Li Y, Piao Y, Sun F, Zhang D, Yin M, Zheng S, Li T, Niu H, Lin L, Mei S, Zhou F, Yang S, Li D, Yan M, Zeng H, Zeng P, Zheng W, Li X, Li X, Liu Y, Huang L, Yu H, Fan Z, Shen M, Lu M, Fang Z, Rimland CA, Song H, Peterson LW, Yousuf Al-Nesf MA, Aqel S, Mudawi DS, Raje N, Slowik V, Harris JG, Snyder B, Scheffler-Mendoza S, Yamazaki-Nakashimada MA, Cooper MA, Lau YL, Cetin Gedik K, Wang W, Ying W, Hou J, Zhou Q, Sun B, Sun J, Wang X, Ombrello AK, Huang Y, Wu HL, Sun L, Mao H, Yu X, Liu Z, Aksentijevich I, Kastner DL, Schwartz DM, Yang J, Zhou Q
J Allergy Clin Immunol
· 2026 Jun · PMID 41692116
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BACKGROUND: Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis,...BACKGROUND: Haploinsufficiency of A20 (HA20) is an immune dysregulation disorder caused by loss-of-function TNFAIP3 mutations. This international multicenter study aimed to delineate its clinical spectrum, genetic basis, and natural history. METHODS: A cross-sectional retrospective analysis was conducted in HA20 patients with pathogenic or likely pathogenic TNFAIP3 variants. Clinical, laboratory, and treatment data were assessed. Clustering analysis was applied to evaluate clinical features and disease phenotypes. Patients were stratified by age (<16 years vs ≥16 years), country of origin (China vs United States), and sex. RESULTS: A total of 185 patients from 41 clinics across 7 countries were included (median age at onset, 3.3 years). Common clinical features were mucocutaneous involvement (80.5%), recurrent fever (63.3%), gastrointestinal symptoms (58.6%), cytopenia (56.6%), arthritis/arthralgia (46.7%), and recurrent infections (35.5%). Compared with adults and patients from the US cohort, intestinal ulcers were significantly more frequent in children and patients from the Chinese cohort (P = .002 and P < .0001, respectively), whereas uveitis was less common in these groups (P = .001 and P < .0001, respectively). Hierarchical clustering of clinical disease phenotypes based on Pearson distance identified two major clusters, an autoinflammation-predominant phenotype and an autoimmune-predominant phenotype. The autoinflammation-predominant phenotype was more common in children and patients from the Chinese cohort (P = .033 and .003, respectively). A total of 89 pathogenic TNFAIP3 mutations were identified, including 46 novel variants. Large deletions were associated with neurologic disease and developmental delay (P = .0054 and .0245, respectively); however, there were no clear associations between disruptions of specific functional A20 domains and age at onset or phenotype. Therapeutically, TNF and IL-1 inhibitors were effective in most patients, with thalidomide and JAK inhibitors provided in refractory cases; 51.5% had obtained minimal disease activity at most recent follow-up. CONCLUSIONS: HA20 is a common dominantly inherited immune dysregulation disorder with phenotypic heterogeneity and potential age-dependent evolution. This large international cohort highlights diagnostic and therapeutic strategies to advance evaluation and management of HA20.
Hereditary angioedema (HAE) is a genetic disorder caused by either deficiency of C1 esterase inhibitor (85% of cases) or normal to high levels of nonfunctional C1 esterase inhibitor. Both defects lead to dysregulation of...Hereditary angioedema (HAE) is a genetic disorder caused by either deficiency of C1 esterase inhibitor (85% of cases) or normal to high levels of nonfunctional C1 esterase inhibitor. Both defects lead to dysregulation of the kallikrein pathway, unregulated bradykinin production, and episodic swelling involving the skin, abdomen, and, in up to 50% of patients, the airway sometime during their life-span. A newer phenotype, HAE with normal C1 inhibitor (HAE type III), has also been recognized, although its mechanisms remain incompletely defined and diagnosis is largely based on consensus algorithms. Chronic spontaneous urticaria (CSU) is a mast cell-mediated inflammatory skin disorder characterized by transient pruritic wheals; angioedema occurs in up to 40% of patients and may be the only manifestation in 10-20%. HAE and CSU are mechanistically distinct, and misdiagnosis may lead to inappropriate treatment and worse outcomes. This review summarizes recent advances in the pathophysiology of HAE and CSU and how these insights have driven the development of targeted therapies. Emerging precision medicine approaches and greater emphasis on shared decision-making are reshaping management and hold promise for improving clinical outcomes and quality of life in HAE and CSU.