Kim H, Kim S, Kim SR
… +35 more, Chae KJ, Yoo JS, Jeong J, Lee KE, Cha S, Jeong J, Sim DW, Koh YI, Kang SY, An J, Lee SE, Lee JH, Ban GY, Nam YH, Kim BK, Sohn KH, Lee YS, Park SY, Jung JW, Lee HY, Yoon SY, Shim JS, Kim MH, Ahn KM, Yang MS, Kwon JW, Kim SH, Park HK, Jang AS, Song WJ, Kim JH, Kim SH, Park HW, Choi S, Korean Severe Asthma Registry (KoSAR) Investigators
BACKGROUND: While chronic airway inflammation and remodeling are well-established features of severe asthma, the associated vascular changes remain poorly understood. OBJECTIVE: To assess severity-related changes in pulm...BACKGROUND: While chronic airway inflammation and remodeling are well-established features of severe asthma, the associated vascular changes remain poorly understood. OBJECTIVE: To assess severity-related changes in pulmonary vascular remodeling and their associations with clinical features and computed tomography (CT)-based airway functional measures among patients with asthma. METHODS: Full inspiratory and normal expiratory CT scans from 159 healthy subjects, 53 patients with non-severe asthma, and 159 patients with severe asthma were analyzed after 3:1:3 propensity score matching. Total pulmonary blood vessel volume during inspiration and expiration (TBV and TBV), vascular compressibility between inspiration and expiration (TBV), and the expiratory small-vessel fraction were quantified. Associations with clinical variables and CT-derived indices-air trapping percentage (AirT%), and parenchymal deformation (Jacobian)-were assessed using multivariable regression. RESULTS: TBV decreased stepwise from healthy subjects to those with non-severe and severe asthma (p < 0.05). In multivariable regression analyses with additional adjustment for the Jacobian and AirT%, higher TBV was significantly associated with worse lung function (lower FEV % predicted, β = -0.40; lower FEV/FVC, β = -0.26) and higher cumulative steroid corticosteroid dose (β = 0.13, all p < 0.05). Lower TBV remained independently associated with higher blood eosinophil count (β = -0.37, p < 0.05). CONCLUSION: TBV decreases with increasing asthma severity and remains independently associated with type 2 inflammation and possibly with clinical burden after accounting for lung mechanics. These findings suggest that CT-based expiratory vascular metrics capture intrinsic vascular alterations beyond mechanical factors and may add value for asthma phenotyping and disease monitoring.
BACKGROUND: Cross-linking of IgE to its high-affinity receptor FcεRI on mast cells initiates intracellular signaling that drives the pathogenesis of allergic disorders, including asthma, allergic rhinitis, and atopic der...BACKGROUND: Cross-linking of IgE to its high-affinity receptor FcεRI on mast cells initiates intracellular signaling that drives the pathogenesis of allergic disorders, including asthma, allergic rhinitis, and atopic dermatitis. Precise regulation of mast cell signaling is essential for immune homeostasis and controlling allergic inflammation. METHODS: We examined SMURF2 expression in mast cells from allergic rhinitis patients, PBMCs and induced sputum from acute asthma patients, and IgE-activated mast cells. The function of SMURF2 was assessed in vitro and in mast cell-specific Smurf2-deficient mice subjected to IgE-mediated anaphylaxis and OVA-induced allergic airway disease. Molecular mechanisms were defined by co-immunoprecipitation and ubiquitination assays. RESULTS: SMURF2 was markedly upregulated in patient samples and stimulated mast cells. SMURF2 positively regulated IgE-dependent mast cell activation in vitro. Mast cell-specific Smurf2 deficiency attenuated passive systemic anaphylaxis and OVA-induced allergic airway disease. Mechanistically, SMURF2 interacted with NEDD4L and promoted its K27-linked ubiquitination and proteasomal degradation, thereby enhancing Syk-mediated FcεRI signaling. CONCLUSION: SMURF2 is a critical positive regulator of mast cell activation and allergic responses by targeting NEDD4L for degradation to amplify Syk signaling. SMURF2 represents a potential diagnostic marker and therapeutic target for allergic diseases.
BACKGROUND: Joint hypermobility (JH) and autonomic symptoms commonly coexist and are associated with gastrointestinal symptoms and poor quality of life. Gastric and duodenal mast cells (MCs) may be increased in these pat...BACKGROUND: Joint hypermobility (JH) and autonomic symptoms commonly coexist and are associated with gastrointestinal symptoms and poor quality of life. Gastric and duodenal mast cells (MCs) may be increased in these patients; however, their relevance to eosinophilic esophagitis (EoE) is unclear. OBJECTIVE: We aimed to understand the relationship between autonomic symptoms and JH in EoE with symptoms, QOL, and MCs. METHODS: Eighty EoE patients undergoing esophagogastroduodenoscopy at Lurie Children's Hospital (January 2021 to March 2024) were prospectively enrolled. Patients/caregivers completed validated surveys assessing EoE symptoms (Pediatric Eosinophilic Esophagitis Symptom Score [PEESS], QOL, and autonomic symptoms (Composite Autonomic Symptom Score 31 [COMPASS-31]). JH was determined using a published survey and Beighton score. Tryptase immunohistochemistry was quantified in gastric and duodenal biopsy samples. COMPASS-31 was compared by disease activity and hypermobility and with a published control cohort. Associations with PEESS, Pediatric Quality of Life Inventory (PedsQL), and MCs were assessed. Linear regression evaluated COMPASS-31 predictors. RESULTS: COMPASS-31 was higher in EoE patients than controls (P < .001) and active EoE compared to remission (P = .02). COMPASS-31 correlated positively with PEESS scores, particularly gastroesophageal reflux, nausea/vomiting, and pain domains, and inversely with QOL. 26% of EoE patients were hypermobile and had higher COMPASS-31 (P = .003). Disease activity (P < .01) and hypermobility (P < .01) independently predicted COMPASS-31. Neither gastric or duodenal MC density was associated with COMPASS-31 or hypermobility. CONCLUSION: In EoE patients, autonomic symptoms are increased with active disease and hypermobility, underscoring the need for clinician screening to inform management. Gastric and duodenal MC density was not associated with autonomic symptoms or hypermobility, limiting the utility of quantification.
Bieber T, Bochner BS, Boyce JA
… +11 more, Kabashima K, Barrett N, Holloway JW, Izuhara K, Jenmalm M, Kraft M, Sagi-Eisenberg R, Sehmi R, Wenzel SE, Vercelli D, Collegium Internationale Allergologicum
Xie S, Yuan X, Liu L
… +6 more, Wu M, Gu W, Zhang H, Xie Z, Jiang W, Gao P
J Allergy Clin Immunol
· 2026 Jun · PMID 42269941
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BACKGROUND: Epithelial remodeling, particularly squamous metaplasia (SM), is a common but understudied epithelial alteration in refractory allergic rhinitis (AR). Its molecular drivers and contribution to steroid resista...BACKGROUND: Epithelial remodeling, particularly squamous metaplasia (SM), is a common but understudied epithelial alteration in refractory allergic rhinitis (AR). Its molecular drivers and contribution to steroid resistance remain unclear. OBJECTIVE: We sought to define the epithelial keratinization program underlying SM in AR and determine its role in glucocorticoid resistance. METHODS: Nasal mucosa tissues from patients with refractory AR with or without SM were assessed by immunostaining and transcriptomic profiling. Small proline-rich protein 2A (SPRR2A)-deficient mice were used to determine the role of SPRR2A in epithelial keratinization and steroid responsiveness. Primary nasal epithelial cells were stimulated with IL-17A or cystatin A (CSTA) to evaluate SPRR2A-dependent keratinization and steroid resistance. Serum SPRR2A and CSTA levels were quantified in patients with AR stratified by steroid responsiveness. RESULTS: Transcriptomic analysis identified SPRR2A as a leading epithelial marker associated with SM in AR. SPRR2A-associated keratin remodeling, including upregulation of KRT6A and KRT13, represented a defining molecular signature of SM. Glucocorticoid receptor β, a key mediator of steroid resistance, was markedly increased and colocalized with KRT6A and KRT13 in SM tissues. IL-17A induced a robust SPRR2A-keratin remodeling module, generating a steroid-resistant epithelial state. Genetic deletion of Sprr2a abolished IL-17A-driven keratinization, prevented SM, and restored steroid responsiveness. Mechanistically, CSTA emerged as a SPRR2A-dependent effector that promoted squamous differentiation and epithelial GRβ induction. Csta-treated primary cultures recapitulated SM and conferred steroid resistance. Clinically, elevated serum SPRR2A and CSTA levels distinguished patients with steroid-resistant AR from those with steroid-responsive AR. CONCLUSIONS: SPRR2A promotes epithelial SM and steroid resistance through CSTA, identifying the SPRR2A-CSTA axis as a potential therapeutic target and biomarker pathway in refractory AR.
BACKGROUND: Mechanisms that restrict class switch recombination (CSR) to IgE may limit the subsequent production of IgE antibodies in allergic diseases. A role for B-cell receptor (BCR) signaling in IgE regulation was re...BACKGROUND: Mechanisms that restrict class switch recombination (CSR) to IgE may limit the subsequent production of IgE antibodies in allergic diseases. A role for B-cell receptor (BCR) signaling in IgE regulation was revealed in mice and in cultured B cells with altered BCR signaling. While prior work has focused on BCR signaling in IgE-switched cells, BCR signaling also reportedly inhibits CSR. OBJECTIVE: We sought to determine whether BCR signaling selectively inhibits IgE CSR. METHODS: We assessed whether BCR signaling strength affected IgE responses in immunized mice. For mechanistic evaluation, primary mouse or human B cells were induced to switch to IgE in cell culture and were perturbed with antibodies or cognate antigen to ligate the BCR, pharmacologic inhibitors of signaling proteins, and/or additional cytokines. Primary readouts were flow cytometry and RNA analysis. RESULTS: In immunized mice, BCR signaling strength inversely correlated with the relative frequencies of IgE-switched germinal center B cells and plasma cells. In mouse B-cell cultures, BCR signaling selectively inhibited IgE CSR in a manner dependent on ligand concentration, affinity, and avidity. This inhibition required Syk, whereas blockade of the PI3K subunit p110δ increased IgE cell frequencies independently of BCR ligation. The cytokines IL-21 or TGF-β1, in combination with BCR ligation, cooperatively inhibited IgE CSR. Similar results were observed in cultures of human tonsillar B cells. CONCLUSION: IgE CSR is uniquely susceptible to inhibition by BCR signaling in mouse and human B cells, with important implications for the regulation and pathogenesis of allergic disease.
Rochman Y, Melamed JR, Klingler AM
… +11 more, Kotliar M, Rochman M, Caldwell JM, Felton JM, Osswald GA, Muscat-Rivera J, Kegel M, Barski A, Lewkowich IP, Weissman D, Rothenberg ME
BACKGROUND: Immune tolerance in allergic diseases is associated with attenuation of T2 responses by shifting of antigen-specific immunity toward T1 and regulatory T-cell pathways, but current strategies incompletely indu...BACKGROUND: Immune tolerance in allergic diseases is associated with attenuation of T2 responses by shifting of antigen-specific immunity toward T1 and regulatory T-cell pathways, but current strategies incompletely induce durable regulatory immunity. OBJECTIVE: We determined whether combining an allergen-encoded messenger RNA (mRNA) lipid nanoparticle (LNP) vaccine with inhibition of the mechanistic target of rapamycin (mTOR) enhances regulatory T-cell responses. METHODS: Mice were immunized with an allergen-encoded mRNA-LNP vaccine alone or in combination with an mTOR inhibitor, followed by induction of a preclinical model of allergic asthma. Antigen-specific T-cell responses, eosinophil activation, airway hyperresponsiveness, mucus production, and markers of cytotoxicity were assessed. RESULTS: Immunization with allergen-encoded mRNA-LNP elicited T1-associated and cytotoxic CD8 T responses that counterbalanced T2 immunity. Coadministration with an mTOR inhibitor shifted this profile by promoting generation of functional regulatory T cells and attenuating IFN-γ production and CD8 T-cell responses. This combinatorial strategy preserved the antiallergic effects of mRNA-LNP immunization, reduced eosinophil activation markers, and limited vaccine-associated cytotoxicity. CONCLUSION: The ability of an mTOR inhibitor to profoundly modify mRNA-LNP therapy by inducing regulatory T cells presents a potential strategy to enhance regulatory immunity in the treatment of allergy and other inflammatory diseases.
Steininger HM, McCauley KE, Braga GE
… +24 more, Morin A, Lee KE, Visness CM, Fadrosh DW, Dapas M, O'Connor GT, Bacharier LB, Rivera-Spoljaric K, Kattan M, Lemanske RF, Zoratti EM, Martinez FD, Gold DR, Hartert TV, Johnson CC, Miller RL, Seroogy CM, Wood RA, Togias A, Jackson DJ, Gern JE, Ober C, Lynch SV, CADRE Investigators
BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic w...BACKGROUND: Single-nucleotide polymorphisms (SNPs) in the chromosome 17q12-q21 region and, independently, early-life nasal microbiota dominated by Moraxella, Streptococcus, or Haemophilus (MSH) increase risk of chronic wheeze and asthma development. OBJECTIVE: We sought to determine whether 17q12-q21 risk SNPs and nasal microbiota interact to modulate childhood wheeze risk. METHODS: Nasal wash samples from 12-month-old infants in 2 birth cohorts, COAST (Childhood Origins of Asthma; n = 180) and URECA (Urban Environment and Childhood Asthma; n = 139), underwent 16S ribosomal RNA variable region 4 sequencing. Nasal microbiota dominated by MSH or Corynebacterium, Dolosigranulum, Staphylococcus, or Bacillus (CDSB) were assessed. Paired blood was genotyped for 9 17q12-q21 risk SNPs. Logistic regression tested interactions between 17q12-q21 SNPs and MSH or CDSB on wheeze risk in the first 3 years of life. A549 lung epithelial cells, CRISPR-edited to encode the rs7216389 risk genotype (rs7216389) were compared to the heterozygous (rs7216389) line using bulk RNA sequencing. RESULTS: SNPs, particularly those in the ORMDL3 (rs8076131; odds ratio [OR]: 1.72; 95% CI: 1.09-2.71; P = .031) and GSDMB (rs2305480; OR: 1.72; 95% CI: 1.09-2.71; P = 0.042; and rs7216389; OR: 1.73; 95% CI: 1.09-2.70; P = .047) genes, interact with MSH microbiota to increase early-life wheeze risk (false discovery rate P = .016 for all), while interactions with CDSB reduce risk. A549 airway epithelial cells homozygous for rs7216389 exhibited decreased expression of genes involved in antimicrobial responses and neutrophil recruitment and evidence increased microbial adherence compared with the heterozygous cell line. CONCLUSION: Airway microbiota interact with SNPs at the 17q12-q21 locus in genes involved in sphingolipid metabolism and intracellular antimicrobial responses, to modulate wheeze risk.
BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency marked by impaired antibody production and infection susceptibility, with about half the patients developing noninfectious complications....BACKGROUND: Common variable immunodeficiency (CVID) is a primary immunodeficiency marked by impaired antibody production and infection susceptibility, with about half the patients developing noninfectious complications. B-cell activating factor (BAFF) elevation and genetic variants in a BAFF receptor (BAFF-R), transmembrane activator and CAML interactor (TACI), frequently occur in CVID. Although these findings associate with autoimmune and lymphoproliferative complications, pathogenic mechanisms remain incompletely defined. OBJECTIVE: We sought to explore how coexistent changes in BAFF, its receptors, and B-cell subsets may shape CVID. METHODS: Plasma protein measurement, spectral flow cytometry, and single-cell RNA sequencing were performed. RESULTS: CVID with autoimmune cytopenia and lymphoid hyperplasia had elevated plasma BAFF:TACI ratio and increased transitional and activated naive B cells. Activated naive B cells from patients with CVID had increased mRNA of genes downstream of BAFF-R that promote B-cell survival. Also, on these expanded subsets, BAFF-R surface protein decreased, consistent with negative feedback, whereas autoreactive B-cell receptor (BCR) VH4-34 clonality increased. CONCLUSIONS: Spectral flow cytometry, paired BCR-sequencing RNA-seq, and measurement of BAFF and related proteins in plasma found CVID with autoimmune and lymphoproliferative complications to be marked by coexistent BAFF and B-cell subset dysregulation. This included increased plasma BAFF, BAFF:TACI ratio, and transitional and activated naive B cells with reduced BAFF-R expression and BCR repertoire diversity. The expanded activated naive B-cell subset in CVID had increased expression of BAFF-R-driven genes that subvert B-cell tolerance as well as increased autoreactive VH4-34 clonality. Convergence of BAFF, its receptors, and B-cell subset dysregulation should be further explored in CVID.
Aging exerts broad effects on human physiology, leading to reduced organ function and increased susceptibility to chronic diseases. Cutaneous aging provides a visible and accessible model of systemic aging, driven by bot...Aging exerts broad effects on human physiology, leading to reduced organ function and increased susceptibility to chronic diseases. Cutaneous aging provides a visible and accessible model of systemic aging, driven by both intrinsic biological processes and extrinsic environmental factors, leading to progressive structural and functional deterioration of the skin. A key hallmark of aging is cellular senescence, which links molecular damage and inflammation through the senescence-associated secretory phenotype, altering matrix composition, impairing epidermal renewal, and promoting chronic inflammation. In parallel, inflammaging, a low-grade, persistent inflammatory state, sustains immune activation and hinders regeneration, accelerating cutaneous deterioration. In advanced stages, skin aging is characterized by marked atrophy and manifests clinically as chronic cutaneous fragility, impaired wound healing, and diminished immunosurveillance, ultimately increasing susceptibility to infection and injury. Thus, targeting skin aging now extends beyond a merely aesthetic pursuit, addressing tissue homeostasis, counteracting cumulative molecular damage, and preserving the equilibrium between regeneration and inflammation. This review summarizes recent advances in the understanding of skin aging, focusing on its mechanistic drivers, phenotypic expression, and evolving treatment approaches. It also explores the bidirectional crosstalk between skin and systemic inflammation, highlighting key knowledge gaps and future directions for clinical and translational research.
The Practice Parameter for Inborn Errors of Immunity was revised in 2025 and published recently. We reviewed the most significant changes of this update regarding the previous parameter update in 2015. In contrast to pre...The Practice Parameter for Inborn Errors of Immunity was revised in 2025 and published recently. We reviewed the most significant changes of this update regarding the previous parameter update in 2015. In contrast to previous revisions focused on individual genetic entities, this update was written with a new structure of recommendations divided into 2 parts: diagnosis and management. The diagnosis part includes discussions of newborn screening for severe combined immunodeficiency, genetic testing, and surveillance of comorbidities, in addition to reviewing clinically available testing for immunologic diagnosis. The management part includes recommendations for immunoglobulin replacement, antibiotic prophylaxis, hematopoietic stem cell transplantation, precision medicine, and quality-of-life assessment.
BACKGROUND: Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in genome-wide association studies but are often limited by a single-cel...BACKGROUND: Transcriptome-wide association studies (TWAS) identify genetically regulated expression (GReX) components and can pinpoint causal genes in genome-wide association studies but are often limited by a single-cell context. OBJECTIVE: We hypothesized that modeling GReX across multiple conditions could enhance power to identify causal genes for complex inflammatory diseases. METHODS: We conducted TWAS on 400 transcriptomes under 8 proinflammatory cytokine stimulations in keratinocytes, modeling GReX for 18,599 genes against genome-wide association studies from 7 inflammatory skin diseases: atopic dermatitis, psoriasis, acne, alopecia areata, systemic sclerosis, systemic lupus erythematosus, and vitiligo. RESULTS: Our TWAS identified 274 loci from the 7 diseases that harbor a single significant TWAS gene association. We nominated causal genes and their associated proinflammatory cytokine stimuli, including ERAP2 for psoriasis with IL-17A + TNF-α stimulation; WNT10A for acne with IFN-γ stimulation; and RAET1L, MAP3K11, and ITGAM for alopecia areata, acne, and systemic lupus erythematosus, respectively, with TNF stimulation. Notably, our TWAS-identified genes showed overwhelming evidence of colocalization with genome-wide association study signals (P = 1.03 × 10), and our method successfully captured >85% of all genes with colocalizing expression quantitative trait loci. Single-cell-resolution spatial profiling further demonstrated the modulation of TWAS signals in keratinocytes by close proximity to TNF/IL-17-expressing cells in psoriatic skin. CONCLUSION: Modeling gene expression across relevant cellular states substantially improves the power and resolution of TWAS.
BACKGROUND: Inborn errors of immunity (IEI) associated with gain-of-function (GOF) in the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathways (JAK-STAT GOF IEI) are rare disorders characte...BACKGROUND: Inborn errors of immunity (IEI) associated with gain-of-function (GOF) in the Janus kinase (JAK)/Signal Transducer and Activator of Transcription (STAT) pathways (JAK-STAT GOF IEI) are rare disorders characterized by immune dysregulation, autoimmunity, malignancy and increased infection susceptibility. To date, no JAK inhibitors (JAKi) are licensed for these conditions, but they are frequently prescribed off-label, even though high-quality evidence and treatment guidelines remain limited. OBJECTIVE: To develop evidence- and consensus-based recommendations for JAKi treatment in JAK-STAT GOF IEI across all age groups based on a systematic literature review and expert consensus. METHODS: An international expert group conducted a systematic literature review and developed recommendations on JAKi treatment in JAK-STAT GOF IEI using a modified Delphi approach. Recommendations were developed based on published evidence, data from an international retrospective cohort study, and patient representative input. These statements were then tested for consensus in a two round Delphi survey procedure in a larger, interdisciplinary expert panel. RESULTS: Consensus- and evidence-based guidance is presented across five thematic areas: (I) JAKi indications/contraindications, (II) pre-treatment assessment, (III) pharmacology/dosing, (IV) monitoring, and (V) use in the context of hematopoietic stem cell transplantation. A total of 51 statements were established and contextualized with the available evidence. CONCLUSION: This consensus provides structured guidance for clinicians managing JAK-STAT GOF IEI with JAKi. While prospective trials will further refine these strategies, this guidance represents the current international standard of care, reflecting the synthesis of clinical experience and the best available evidence.