On March 7, 2025, the US Food and Drug Administration (FDA) approved the first biosimilar to omalizumab (omalizumab-igec, Omlyclo; Celltrion). This is the first biosimilar approved for a biologic with an indication for t...On March 7, 2025, the US Food and Drug Administration (FDA) approved the first biosimilar to omalizumab (omalizumab-igec, Omlyclo; Celltrion). This is the first biosimilar approved for a biologic with an indication for the treatment of allergic diseases and/or asthma. Recent FDA announcements focus on accelerating biosimilar development and lowering costs by streamlining the approval process. On October 29, 2025, the FDA issued draft guidance proposing to no longer routinely require comparative clinical efficacy studies for biosimilarity, supporting the goal of reducing development time and cost. This review discusses FDA regulation of biologics and biosimilars, the recent approval of the first omalizumab biosimilar, and the evolving regulatory landscape for biosimilars to decrease the costs of their development while ensuring their efficacy and safety. The approval of biosimilars for treating allergic diseases and asthma is expected to significantly improve accessibility and affordability of these therapies, providing health care providers and patients with confidence in high-quality, cost-effective treatment options for patients with severe and refractory asthma and allergic conditions.
BACKGROUND: IL-23-driven IL-17 production by γδ17 and T17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. However, the intracellular mechanisms linking IL-23 signaling to effector cytoki...BACKGROUND: IL-23-driven IL-17 production by γδ17 and T17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. However, the intracellular mechanisms linking IL-23 signaling to effector cytokine production remain incompletely defined, limiting the development of therapeutics targeting pathways downstream of IL-23. OBJECTIVES: We elucidated signaling mechanisms connecting IL-23 stimulation to IL-17 production and identified pharmacologic inhibitors of type 3 immune responses. METHODS: We developed an in vitro model using a γδ17 T-cell line to study IL-23 responses and performed a drug-repurposing screen of US Food and Drug Administration-approved compounds. Hits were validated in primary cells. The in vivo efficacy of candidate inhibitors was evaluated in the imiquimod-induced model of skin inflammation via intraperitoneal, oral, and topical administration. Mechanistic studies assessed IL-23-dependent activation of mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 and the role of Src family kinases. RESULTS: Src/Abl kinase inhibitor dasatinib was identified as potent suppressor of IL-23-induced IL-17A production. In vivo, dasatinib treatment reduced epidermal thickening, immune cell infiltration, and the accumulation of IL-17-producing T cells in inflamed skin. Dasatinib inhibited IL-23-dependent activation of mTORC1 and mTORC2. Loss-of-function experiments revealed the Src kinase Blk (B lymphoid kinase) as a critical mediator of IL-23-induced mTORC1 activation and IL-17A production in γδ17 T cells. CONCLUSIONS: These findings define a novel IL-23-Src-mTOR signaling axis in type 3 immunity and identify Src kinase networks as promising therapeutic targets in IL-23/IL-17-driven inflammation.
van Heusden NS, Cuijpers I, Meijer N
… +11 more, Pieren D, Markovska A, Gabay C, Girard C, Koné-Paut I, Vastert B, Hamann D, Jans J, Van Nieuwenhove E, Frenkel J, Boes M
BACKGROUND: Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic def...BACKGROUND: Mevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to a lowering of the threshold for pyrin inflammasome activation. OBJECTIVE: A cellular model of MKD was established to discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and IFN-γ signaling. METHODS: Using CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harboring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses after stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived peripheral blood mononuclear cells were performed to validate in vitro findings. RESULTS: MVK THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVK THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD peripheral blood mononuclear cells hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and natural killer cells were characterized by enhanced IL-18-driven IFN-γ production. Elevated IFN-γ and IL-18 binding protein levels in MKD plasma as well as transcriptomic data of MKD peripheral blood mononuclear cells further confirmed the presence of an IFN-γ signature in MKD. CONCLUSION: A pyrin inflammasome-driven IL-18/IFN-γ axis is a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
Banerji A, Craig T, Sitz K
… +21 more, Li HH, Lumry W, Adatia A, Yang W, Jacobs JS, Tachdjian R, Soong W, Manning M, Wedner J, Savic S, Manson A, Valerieva A, Gunsior M, Mugundu G, Cohen T, Bernard K, VanEenwyk C, Joseph K, Best JM, Morabito C, Riedl MA
BACKGROUND: Hereditary angioedema (HAE), characterized by unpredictable, painful, recurrent swelling events (HAE attacks), poses a significant health care burden. OBJECTIVE: This phase 1b/2 trial (ALPHA-STAR) assessed th...BACKGROUND: Hereditary angioedema (HAE), characterized by unpredictable, painful, recurrent swelling events (HAE attacks), poses a significant health care burden. OBJECTIVE: This phase 1b/2 trial (ALPHA-STAR) assessed the safety, efficacy, pharmacokinetics, pharmacodynamics, and immunogenicity of navenibart, a novel long-acting monoclonal antibody targeting plasma kallikrein. METHODS: This global, dose-ranging, proof-of-concept trial assigned adults with HAE due to C1 inhibitor deficiency (HAE-C1INH) sequentially to 3 cohorts: 450 mg as a single dose on day 1 (cohort 1); 600 mg on day 1 and 300 mg on day 84 (cohort 2); or 600 mg on days 1 and 28 (cohort 3). Study assessments lasted up to 9 months (6 months after final dose). Primary end points included safety, secondary end points included clinical outcomes, and exploratory end points included quality of life. RESULTS: Twenty-nine participants received navenibart and completed the trial. There were no severe or serious treatment-emergent adverse events, and no treatment-emergent adverse events led to discontinuation. The most common treatment-emergent adverse events were headache, nasopharyngitis, and urinary tract infection. Rapid reductions in HAE attack rates (including moderate and severe attacks) versus baseline were observed in all cohorts. Overall, the mean (standard deviation) time-normalized monthly attack rate was reduced from 2.23 (1.46) at baseline to 0.31 (0.48) after treatment with navenibart. The overall mean (median) reduction in time-normalized monthly attack rate was 86.3% (95.4%) compared with baseline. Participants had improved Angioedema Quality of Life total scores, with a mean decrease ranging 21.0 to 30.3 points. CONCLUSIONS: Navenibart was well tolerated and substantially reduced HAE attacks, providing support for every-3-month and every-6-month administration of navenibart to prevent HAE attacks.
J Allergy Clin Immunol
· 2026 Jun · PMID 41791680
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BACKGROUND: Chronic rhinosinusitis (CRS) is a complex multifactorial disease characterized by persistent sinonasal inflammation of unknown etiology. A unique inflammatory signature of CRS associated with exposure to part...BACKGROUND: Chronic rhinosinusitis (CRS) is a complex multifactorial disease characterized by persistent sinonasal inflammation of unknown etiology. A unique inflammatory signature of CRS associated with exposure to particulate matter with a diameter of less than 2.5 μm (PM) has recently been identified, characterized by univariate elevations in mucus IL-2, IL-5, IL-7, IL-12/23p40, and IL-21. OBJECTIVE: We sought to validate and further define this putative endotype by a joint multivariate cytokine analysis. METHODS: Clinical and demographic data for 634 patients undergoing sinus surgery were extracted with a spatiotemporal machine learning model to estimate daily PM exposure for 12 months before surgery. Inflammatory mucus cytokines were quantified with a cytometric bead assay. Levels of IL-2, IL-5, IL-7, IL-13, IL-12/23p40, and IL-21 were log transformed, scaled, and summed to create a composite measure. Spearman correlation and regression analysis were performed to characterize the relationship between this scaled metric and estimated PM exposure. RESULTS: Estimated 12-month PM levels were positively associated with elevations in the composite cytokine score on univariate analysis (β = 1.17, P < .0001). This relationship between the IL-2, IL-5, IL-7, IL-13, IL-12/23p40, and IL-21 composite score and PM levels was persistent after adjusting for numerous potential clinical and sociodemographic confounders, including age, body mass index, history of asthma/allergic rhinitis, polyps, and income/rurality measures (β = 1.27, P < .0001). CONCLUSION: PM-associated CRS is characterized by joint multivariate elevations in mucus IL-2, IL-5, IL-7, IL-12/23p40, IL-13, and IL-21, providing key evidence for a putative mixed type 2 and 3 endotype of CRS associated with air pollution.
DeBerg HA, Baloh CH, DeGottardi Q
… +9 more, Hou J, Johansson A, Newell E, Laidlaw TM, Sanda S, Shamji M, Durham S, Togias A, Kwok WW
J Allergy Clin Immunol
· 2026 Mar · PMID 41780572
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BACKGROUND: Allergen-specific CD4 T cells are a highly heterogenous population. Depletion of these cells has been proposed as essential to achieve allergen desensitization in allergen immunotherapy. OBJECTIVE: The overal...BACKGROUND: Allergen-specific CD4 T cells are a highly heterogenous population. Depletion of these cells has been proposed as essential to achieve allergen desensitization in allergen immunotherapy. OBJECTIVE: The overall aim of this study was to characterize the heterogeneity of timothy grass (Phleum pratense) allergen-specific CD4 T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous (SCIT) immunotherapy. Correlations between frequencies of these cells with Total Nasal Symptom Score and grass-specific serum immunoglobulin were also investigated. METHODS: Mass cytometry with lanthanides-tagged peptide major histocompatibility complex class II multimers and CD154 upregulation assays were used to examine changes in the frequency and phenotype of Phl p-specific CD4 T cells in longitudinal peripheral blood mononuclear cell samples from a randomized, double-blind, placebo-controlled trial of SLIT and SCIT. Supervised and unsupervised clustering was used for data analysis. RESULTS: Phenotypes of Phl p-specific T cells were highly heterogenous but could be categorized into two major metaclusters, CRTH2CD27 and CRTH2CD27, each with distinct phenotypic profiles. Weak positive correlations between Total Nasal Symptom Score and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2CD27 cells, whereas SLIT depleted CRTH2CD27 cells. CRTH2CD27 cell frequency correlated with Phl p-specific IgE and IgG, but not IgA, levels. CONCLUSION: Unsupervised clustering revealed distinct subpopulations of allergen-specific T cells that were differentially targeted and depleted by SCIT and SLIT, suggesting that SCIT and SLIT act through overlapping but distinct immunologic pathways.
Roussel L, Bernier S, Langelier M
… +15 more, Sun Y, Mak B, Li Y, Perez A, Wloski A, Angers I, Vinh LR, Beauchamp A, Boissel S, Watters AK, Rousseau S, Routy JP, Calderon V, Arias C, Vinh DC
BACKGROUND: Kaposi sarcoma (KS), driven by the DNA virus KS-associated herpesvirus (KSHV), arises in the context of T-cell immunosuppression (eg, human immunodeficiency virus infection, transplantation) or sporadically i...BACKGROUND: Kaposi sarcoma (KS), driven by the DNA virus KS-associated herpesvirus (KSHV), arises in the context of T-cell immunosuppression (eg, human immunodeficiency virus infection, transplantation) or sporadically in ostensibly immunocompetent older adults (endemic or classic KS). The mechanisms underlying KS development without exogenous immunosuppression remain unclear. Retinoic acid-inducible gene I (RIG-I), encoded by DDX58, is a canonical cytosolic sensor of RNA viruses, but its role in human immunity to DNA viruses is not well understood. OBJECTIVE: We report a patient with RIG-I deficiency and KS and define associated antiviral and host response defects. METHODS: Whole-exome sequencing was performed to identify the genetic basis of the immunodeficiency. RIG-I-dependent antiviral signaling was evaluated through functional studies using fluorescent KSHV in patient-derived lymphoblastoid cell lines and isogenic fibroblast and endothelial models. Aberrant cellular responses during KSHV infection, latency, and reactivation in the context of RIG-I deficiency were assessed through transcriptomic, proteomic, and live-cell imaging analyses. RESULTS: A homozygous nonsense DDX58 mutation (p.Q393∗) was identified in a patient with classic KS, abolishing RIG-I expression and specifically impairing responses to RIG-I agonists. Loss of RIG-I compromised type I interferon responses to both primary KSHV infection and virus reactivation, with skewing to a persistent latent viral program and dysregulating cellular pro-oncogenic pathways. CONCLUSION: This study links RIG-I deficiency to classic KS and supports its role as a candidate inborn error of innate immunity shaping KSHV pathogenesis. The findings extend RIG-I's antiviral relevance beyond RNA viruses. Additional patients will clarify the virus susceptibility spectrum.
Brooksby JJ, Kobayashi T, Iijima K
… +4 more, Jheng MJ, Masuda MY, Lama JK, Kita H
J Allergy Clin Immunol
· 2026 Jul · PMID 41780570
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BACKGROUND: Group 2 innate lymphoid cells (ILC2s) and CD4 T2 cells are the cores of type 2 immunity in the lungs and play central roles in the pathology of asthma. ILC2s rapidly produce innate type 2 cytokines in respons...BACKGROUND: Group 2 innate lymphoid cells (ILC2s) and CD4 T2 cells are the cores of type 2 immunity in the lungs and play central roles in the pathology of asthma. ILC2s rapidly produce innate type 2 cytokines in response to environmental allergens, whereas T2 cells provide adaptive antigen-specific immune memory. However, little is known regarding the interaction between the innate and adaptive arms of type 2 immunity. OBJECTIVE: We investigated the roles of ILC2s in establishing adaptive antigen-specific immunity in a mouse model of human asthma. METHODS: ILC2-deficient mice were intranasally sensitized to ovalbumin (OVA) using Alternaria extract as an adjuvant. Innate and adaptive responses were assessed by flow cytometry and by intranasal OVA recall challenge. The underlying mechanisms were investigated using gene-deficient mice, in vivo antibody neutralization, adoptive transfer of ILC2s, and in vitro culture systems. RESULTS: Exposure of naive mice to the fungal allergen Alternaria increased the number of lung dendritic cells (DCs), activated migratory DCs, and promoted DC production of the T2-recruiting chemokines CCL17 and CCL22; these responses were significantly suppressed in ILC2-deficient mice. Consequently, ILC2-deficient mice failed to develop T2-type tissue-resident memory CD4 T cells in the lungs and antigen-induced type 2 airway inflammation, which were restored by adoptive transfer of lung ILC2s. Granulocyte-macrophage colony-stimulating factor produced by ILC2s was indispensable in promoting these DC responses and development of lung tissue-resident memory T cells. CONCLUSION: ILC2s license lung DCs via granulocyte-macrophage colony-stimulating factor to prime and recruit T2 cells, establishing antigen-specific T-cell immune memory in the lungs.
BACKGROUND: Eosinophilic esophagitis (EoE) is a progressive fibrostenotic disease. Although proton pump inhibitors (PPIs) are a first-line EoE treatment due to their anti-inflammatory effects, their effects on remodeling...BACKGROUND: Eosinophilic esophagitis (EoE) is a progressive fibrostenotic disease. Although proton pump inhibitors (PPIs) are a first-line EoE treatment due to their anti-inflammatory effects, their effects on remodeling/fibrosis-likely driven in part by TGF-β-remain uncertain. OBJECTIVES: To elucidate remodeling/fibrosis effects, this study evaluated whether PPIs impact the esophageal transcriptome of PPI-responsive EoE and counteract TGF-β‒induced fibrotic responses in human primary esophageal fibroblasts (HEFs). METHODS: Prospectively collected paired esophageal biopsies from patients with EoE pre‒/post‒PPI treatment were analyzed by RNA sequencing (RNA-seq). Histologic responsiveness to PPIs was defined as responders (<15 eosinophils/high-power field, n = 10) or nonresponders (≥15 eosinophils/high-power field, n = 9). The ability of PPIs (esomeprazole, omeprazole) to attenuate in vitro, TGF-β‒mediated remodeling/fibrosis in HEFs was analyzed by quantitative PCR, RNA-seq, Western blotting, immunofluorescence, cell migration assays, and reactive oxygen species measurements. RESULTS: In PPI responders, we identified 746 differentially expressed genes pre‒/post‒PPI treatment (≥2-fold change, P < .05), particularly those enriched in remodeling/fibrosis. In HEFs, TGF-β increased collagen I and α-smooth muscle actin expression via SMAD2/3 phosphorylation; however, PPIs attenuated these responses. RNA-seq revealed that PPIs reversed approximately 30% of TGF-β‒induced changes overlapping with fibrotic responses; 78 genes were concordantly modulated between patient biopsies and HEFs. Functional assays further confirmed that PPIs reduced TGF-β-induced collagen deposition, fibroblast motility, and reactive oxygen species production. CONCLUSIONS: PPIs modulate remodeling-/fibrosis-related gene expression in patients with EoE and inhibit TGF-β‒induced profibrotic responses in HEFs, supporting antifibrotic potential that may help limit fibrostenotic progression in EoE.
Dimitrova D, Bosticardo M, Delmonte OM
… +33 more, Kenney H, An A, Pala F, Magro G, Myint-Hpu K, Kang E, Santangeli E, Angelova A, Vujkovic-Cvijin I, Schwarz B, Campos J, Chai A, Cusmano A, Flomerfelt FA, Hyder MA, Mangusan R, Rechache K, Sabina R, Telford W, Kong HH, Nagao K, Agharahimi A, Bergerson JRE, Freeman AF, Holland SM, Ale H, El-Marsafy A, Pasic S, Verbsky J, Walter J, Kanakry CG, Notarangelo LD, Kanakry JA
BACKGROUND: Partial recombinase activating gene deficiency (pRD) leads to combined immunodeficiency with immune dysregulation. It can be cured by allogeneic hematopoietic cell transplantation (HCT), but optimal referral...BACKGROUND: Partial recombinase activating gene deficiency (pRD) leads to combined immunodeficiency with immune dysregulation. It can be cured by allogeneic hematopoietic cell transplantation (HCT), but optimal referral criteria and approaches remain to be defined. OBJECTIVE: Our study evaluated low-toxicity approaches to HCT for pRD. METHODS: Thirteen children and adults with pRD received radiation-free, predominantly reduced-intensity conditioning (pentostatin/cyclophosphamide/busulfan) HCT with posttransplantation cyclophosphamide-based graft-versus-host disease (GVHD) prophylaxis at median (range) age 20 (4-46) years. RESULTS: With median 2.6 years' follow-up, overall survival for the entire cohort was estimated at 92% and 83% at 1 and 2 years and 100% and 90% for reduced-intensity conditioning recipients (n = 12), with 2 deaths attributed to sepsis. Reversal of clinical manifestations was associated with immune reconstitution, with minimal de novo autoimmunity, 15% 1-year cumulative incidence of grade III-IV acute GVHD, and no chronic GVHD. Vα7.2-positive T-cell proportion increased rapidly after HCT, while mucosa-associated invariant T-cell reconstitution lagged. Dysreactive CD19CD21 and 9G4 B cells decreased after HCT, along with clinically relevant autoantibodies. However, baseline elevated anti-type I interferon antibodies, potentially predisposing to severe viral infections, decreased slowly, although neutralizing activity was reduced at last follow-up. Outcomes did not differ by donor carrier status or HLA matching. Bronchiectasis exacerbations incurred rehospitalizations in long-term follow-up of patients who entered HCT with irreversible lung disease. CONCLUSION: Reduced-intensity conditioning HCT with posttransplantation cyclophosphamide-based GVHD prophylaxis is safe and effectively reverses immune dysfunction in patients with pRD.
BACKGROUND: Concomitant exposure to IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 augments antigen-induced contractions of isolated human small bronchi through enhanced mast cell reactivity. OBJECTIVE: We sought...BACKGROUND: Concomitant exposure to IL-33, thymic stromal lymphopoietin (TSLP), and IL-25 augments antigen-induced contractions of isolated human small bronchi through enhanced mast cell reactivity. OBJECTIVE: We sought to test the individual contribution of alarmins in antigen-induced airway hyperresponsiveness and hyperosmolarity-induced responses evoked by mannitol, a surrogate model of exercise-induced bronchoconstriction. METHODS: Intact segments of small airways, isolated from fresh human lung tissue, were incubated with IL-33, TSLP, IL-25, or buffer control for 48 hours. Contractile responses to anti-IgE or mannitol were then assessed using myograph systems. Mast cell degranulation and mediator release were analyzed both from the bronchial segments and from isolated primary human lung mast cells as well as from the human mast cell line LAD2 (Laboratory of Allergic Diseases 2). RESULTS: IL-33 increased contractile force (E) to anti-IgE and hyperosmolar mannitol by 62% and 78%, respectively. IL-33 also doubled antigen-IgE-induced prostaglandin D release from bronchial segments as well as enhanced degranulation, cysteinyl leukotriene, and prostaglandin D release from isolated human lung mast cells stimulated by anti-IgE or mannitol. In contrast, TSLP and IL-25 had no effect on contraction, degranulation, or mediator release in response to either stimulus. CONCLUSIONS: IL-33, but not TSLP or IL-25, enhances bronchoconstriction in human small bronchi by amplifying mast cell activation and mediator release in response to both antigen and hyperosmolar challenge.
BACKGROUND: Since the coronavirus disease 2019 pandemic, local immune responses in the nasal mucosa have become an area of growing research interest. In this context, studies using noninvasive nasal brushing (NB) samples...BACKGROUND: Since the coronavirus disease 2019 pandemic, local immune responses in the nasal mucosa have become an area of growing research interest. In this context, studies using noninvasive nasal brushing (NB) samples have increased markedly. However, it remains unclear whether NB samples accurately reflect the immune landscape of the nasal tissue (NT). OBJECTIVE: A study was conducted to directly compare the cellular composition and immune cell responses of NB and NT samples. METHODS: Paired NB and NT samples were collected from the same anatomic site. The frequency, phenotype, and effector functions of epithelial and immune cells were analyzed by single-cell RNA sequencing and flow cytometry. RESULTS: NB samples contained a significantly higher proportion of epithelial cells than NT samples, while fibroblasts, endothelial cells, and B cells were significantly less abundant. Within the epithelial compartment, NB showed an enrichment of ciliated and secretory cells, whereas basal cells were less frequent and glandular basal/secretory cells were rarely detected. Additionally, CD103 tissue-resident memory T cells and CD56 natural killer cells were more abundant in NB samples than in NT samples. Functional analyses revealed distinct T-cell effector profiles between the two sample types. Notably, severe acute respiratory syndrome coronavirus 2-specific T cells were significantly less frequent in NB samples than in NT. CONCLUSIONS: NB is well suited for sampling cells located near the epithelial surface but captures fewer cells from deeper mucosal layers. Additionally, NB samples display distinct T-cell effector profiles and virus-specific T-cell frequencies compared with NT. These findings highlight the importance of selecting sampling methods that align with the specific objectives of a study.
Yuan X, Xie S, Liu L
… +7 more, Jia J, Gu W, Zeng Y, Zhang H, Jiang W, Xie Z, Gao P
J Allergy Clin Immunol
· 2026 Jun · PMID 41759749
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BACKGROUND: Epithelial remodeling, especially basal cell hyperplasia (BCH), is a hallmark of allergic rhinitis (AR), yet the upstream drivers and their related mechanisms remain incompletely understood. OBJECTIVE: We sou...BACKGROUND: Epithelial remodeling, especially basal cell hyperplasia (BCH), is a hallmark of allergic rhinitis (AR), yet the upstream drivers and their related mechanisms remain incompletely understood. OBJECTIVE: We sought to investigate the role of complement C3 induction and downstream C3a-C3a receptor (C3aR) signaling in epithelial remodeling and macrophage-mediated inflammation in AR. METHODS: Transcriptome sequencing was conducted on nasal mucosa from patients with AR and healthy control subjects. Epithelial remodeling was evaluated in patients, an AR mouse model, and an air-liquid interface culture of mouse nasal epithelial cells. C3-deficient (C3) mice and a C3aR antagonist were used to assess the impact of C3/C3a-C3aR signaling on epithelial remodeling, BCH, macrophage activation, and metabolic reprogramming. Fatty acid oxidation (FAO) and PCCB were targeted to define their functional contributions to macrophage activation. RESULTS: Nasal mucosa from patients with AR exhibited increased epithelial remodeling, particularly BCH. Transcriptome sequencing identified C3 as the most upregulated complement-related gene in AR mucosa, with expression positively correlating with disease severity, epithelial remodeling, and BCH. C3 mice and C3aR antagonist treatment attenuated AR-associated epithelial remodeling, BCH, and type 2 inflammation. Mechanistically, C3a-C3aR signaling promoted a CD206 macrophage phenotype and induced a lipid metabolic program enriched for lipid uptake, FAO, and lipid biosynthesis. Inhibition of FAO or PCCB knockdown attenuated C3a-C3aR signaling-driven macrophage activation that contributes to epithelial remodeling via TGF-β1. CONCLUSIONS: These findings suggest that C3/C3a-C3aR signaling drives epithelial remodeling in AR by promoting macrophage lipid metabolic reprogramming.
BACKGROUND: Epithelial remodeling is a key pathologic feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). Among the various remodeling patterns, squamous metaplasia remains an underrecognized comp...BACKGROUND: Epithelial remodeling is a key pathologic feature of eosinophilic chronic rhinosinusitis with nasal polyps (eCRSwNP). Among the various remodeling patterns, squamous metaplasia remains an underrecognized component in eCRSwNP. OBJECTIVE: This study aimed to systematically assess the prevalence of squamous metaplasia in eCRSwNP and explore its potential mechanisms. METHODS: A total of 844 chronic rhinosinusitis with nasal polyps specimens were histologically reviewed to assess the prevalence of squamous metaplasia and compare rates between eCRSwNP and noneosinophilic (neCRSwNP) subtypes. RNA sequencing was used to profile related gene expression in controls, neCRSwNP, and eCRSwNP tissues, with reverse transcription quantitative PCR and immunofluorescence validation in an independent cohort. Nasal epithelial cells were cultured in an air-liquid interface (ALI) system, stimulated with IL-4/IL-13 and dupilumab to evaluate morphologic and molecular changes. RESULTS: Of the 844 chronic rhinosinusitis with nasal polyps samples, 132 (15.6%) showed squamous metaplasia, with higher prevalence in eCRSwNP (25.7%) compared to neCRSwNP (7.5%). Transcriptomic analysis revealed significantly elevated expression scores of keratinocyte differentiation-related genes in eCRSwNP, with KRT6A and KRT13 markedly upregulated. Cohort validation confirmed increased mRNA and protein levels of KRT6A, KRT13, filaggrin, p63, and Ki-67 in eCRSwNP, predominantly localized to the epithelium. In vitro, IL-4/IL-13 exposure induced squamous alterations in ALI cultures, characterized by increased expression of squamous differentiation markers and reduction in ciliated and secretory cell markers. These pathologic changes were attenuated by dupilumab treatment. CONCLUSION: Squamous metaplasia is a common but underappreciated epithelial remodeling feature in eCRSwNP. IL-4/IL-13 drive this pathologic shift, whereas dupilumab attenuates these changes, suggesting a role in preserving epithelial homeostasis beyond inflammation control.
Metz M, Mitha E, Leflein J
… +10 more, Talreja N, Gotua M, Krasowska D, Peter J, Anderson J, Young D, Heath-Chiozzi M, Paradise E, Greenberg S, Bernstein JA
BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by wheals and/or angioedema without identifiable triggers. Mast cells play a pathogenic role in disease, but more evidence is needed to support their role...BACKGROUND: Chronic spontaneous urticaria (CSU) is characterized by wheals and/or angioedema without identifiable triggers. Mast cells play a pathogenic role in disease, but more evidence is needed to support their role in driving clinical manifestations. OBJECTIVE: We assessed the efficacy and safety of various dose regimens of barzolvolimab, a mast cell-depleting anti-KIT antibody, in patients with CSU. METHODS: Adults with antihistamine-refractory CSU (urticaria activity score over 7 days [UAS7] ≥ 16) in a phase 2 double-blind placebo-controlled trial were randomized 1:1:1:1 to receive barzolvolimab 75 mg every 4 weeks (n = 53); 150 mg every 4 weeks (n = 52); 300 mg every 8 weeks (n = 51); or placebo (n = 51). The primary end point was UAS7 change from baseline to week 12. RESULTS: There was significant improvement in mean (95% confidence interval) change from baseline to week 12 in UAS7 in barzolvolimab-treated patients compared to patients who received placebo (75 mg every 4 weeks: -6.60 [-10.71, -2.49] P = .0017; 150 mg every 4 weeks: -12.55 [-16.56, -8.55] P < .0001; 300 mg every 8 weeks: -13.41 [-17.47, -9.34] P < .0001). Clinical improvement was rapid and marked, with 22.9%, 51.1%, and 37.5% (75 mg, 150 mg, and 300 mg, respectively) of barzolvolimab-treated patients who experienced complete response (UAS7 = 0) versus 6.4% for placebo at 12 weeks. The disease of patients with and without prior omalizumab treatment responded similarly. All doses of barzolvolimab were well tolerated, with urticaria and hair color change as the most common adverse events in barzolvolimab-treated patients. CONCLUSION: This study provides evidence for the essential role of mast cells in the signs and symptoms of CSU. Barzolvolimab is a promising treatment for CSU. TRIAL REGISTRATION INFORMATION: ClinicalTrials.gov NCT05368285.
Hu BD, He H, Bose S
… +14 more, Gour D, Nandymazumdar M, Zhou J, Golla A, Del Duca E, Beaziz J, Avallone G, Zhao W, Pfeifer H, DeGrange M, Taliercio M, Pasumarthi A, Estrada Y, Guttman-Yassky E
BACKGROUND: Alopecia areata (AA) is an autoimmune hair loss disorder characterized by follicular destruction. While bulk transcriptomic studies have identified contributory inflammatory axes, specific cell pathways remai...BACKGROUND: Alopecia areata (AA) is an autoimmune hair loss disorder characterized by follicular destruction. While bulk transcriptomic studies have identified contributory inflammatory axes, specific cell pathways remain underexplored. OBJECTIVE: We characterized the single-cell transcriptomic landscape underpinning AA scalp compared to healthy controls. METHODS: We performed single-cell RNA sequencing on lesional (LS) and nonlesional scalp biopsy samples from 13 patients with moderate-to-severe AA (5 with alopecia totalis/universalis) and 11 healthy controls. RESULTS: Overall, we profiled 41,067 high-quality cells. LS AA samples demonstrated robust T1 activation and cytotoxicity, with upregulated IFNG, GZMH/K, and XCL1/2. Concurrently, T2 skewing (IL13, IL13RA1, IL4R) and TNFRSF4/OX40 elevations in LS CD4 and regulatory T-cells were also observed. IL15, JAK2/3, and STAT1 levels were increased in distinct LS dendritic cell subsets, with JAK/STAT genes also upregulated in fibroblasts and keratinocytes. Fibroblasts and smooth muscle cells exhibited enriched proinflammatory and profibrotic markers (CXCL9, CCL26, POSTN, COL5A3, COL6A6). LS keratinocytes further demonstrated downregulated hair keratins and increased interferon signaling. AA endothelial cells showed increased angiogenic and interferon signatures. Compared to patchy AA and controls, alopecia totalis/universalis demonstrated higher expression of multiple cytotoxic, T1, T2, and JAK/STAT markers in immune cells, and proliferative and inflammatory signatures in nonimmune cells. CONCLUSION: This comprehensive high-resolution single-cell map uncovers potential communication networks between immune and nonimmune cell populations in AA scalp, possibly disrupting immune privilege at the hair follicle and driving disease progression and/or severity.
BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic, recurrent inflammatory dermatosis characterized by sterile pustules on the palms and/or soles, and its pathogenesis remains incompletely understood. OBJECTIVE: We s...BACKGROUND: Palmoplantar pustulosis (PPP) is a chronic, recurrent inflammatory dermatosis characterized by sterile pustules on the palms and/or soles, and its pathogenesis remains incompletely understood. OBJECTIVE: We sought to investigate the immune landscape underlying PPP progression using a multiomics approach. METHODS: We conducted single-cell RNA sequencing on pustular and nonpustular sole lesions from patients with PPP. Key findings were further validated at the tissue level using high-resolution spatial transcriptomics (ST). RESULTS: We identified elevated JAK-STAT signaling in keratinocytes and fibroblasts, accompanied by a stepwise increase in myeloid dendritic cells and T17 cells from healthy control to nonpustular and pustular lesions. Cell-cell interaction analysis revealed CCL19-CCR7 interactions between fibroblastic reticular cell-like fibroblasts and LAMP3 migratory dendritic cells, and CCL22/CCL17-CCR4 interactions between dendritic cells and CD4 T cells, including T17 populations. ST analysis confirmed these interactions in situ and identified a lymphoid-like immune niche within the CCL19 upper dermis. Additionally, the pustule and surrounding keratinocytes were identified as major sources of CXCL1/6/8-ACKR1 signaling, facilitating neutrophil recruitment through interactions with endothelial cells. Together, these coordinated cell-cell interactions support an amplifying immune network that drives the formation of a spatially organized, dense immune niche during PPP progression. Finally, transcriptome-guided drug effect prediction identified JAK and phosphodiesterase-4 inhibitors as potential multitarget therapeutic candidates. CONCLUSIONS: Collectively, our findings provide a comprehensive view of the immune dynamics in PPP and offer insights into effective treatment strategies.
Nanishi M, Reyna ME, Pajdakovska M
… +21 more, Breton VL, Bédard MA, Duan Q, George E, Khan MKA, Chowdhury B, Sharma BT, Dai R, Metwali N, Perry SS, Simons E, Turvey SE, Mandhane P, Becker A, Azad MB, Sears MR, Lou W, Moraes TJ, Brook JR, Thorne PS, Subbarao P
BACKGROUND: Childhood asthma is characterized by altered lung function and airway inflammation that is thought to result from complex gene-environment interactions, especially with allergens. However, previous studies ha...BACKGROUND: Childhood asthma is characterized by altered lung function and airway inflammation that is thought to result from complex gene-environment interactions, especially with allergens. However, previous studies have shown inconsistent associations between allergen exposure and asthma. OBJECTIVES: We aimed to examine the longitudinal relationship between indoor allergen exposure during infancy with subsequent asthma and spirometry and the potential effect modification by genetic factors. METHODS: Data from a subcohort of the CHILD (Canadian Healthy Infant Longitudinal Development) study with analyzed dust samples (including Canis familiaris 1 [dog], Felinus domesticus 1 [cat], and endotoxin) and physician-diagnosed asthma or spirometry data were used to examine the relationships between allergen levels in dust analytes at age 3 months and asthma and, separately, spirometry data at age 5 years, including potential effect modification by genetic factors obtained by using lung function polygenic scores (PGSs). RESULTS: Of 1050 children with dust samples, 6.6% developed asthma by age 5 years. In an adjusted multivariable model, higher Can f 1 level significantly decreased the risk of asthma (odds ratio = 0.52 [95% CI = 0.25-0.98]). Independently, children exposed to high levels of Can f 1 had significantly higher FEVz scores (β = 0.23 [95% CI = 0.06-0.40]), regardless of asthma status. In the gene-environment analyses, there were significant effects of gene-environment interactions in the relationship between Can f 1 and PGS on lung function, independent of asthma status. CONCLUSIONS: In a general population birth cohort, early-life exposure to high levels of Can f 1 was associated with improved lung function and protection against asthma at age 5 years. Furthermore, exposure to high levels of Can f 1 may modulate lung function in individuals with low PGSs.