BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear. OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task For...BACKGROUND: The benefits and harms of using macrolides for asthma remain unclear. OBJECTIVE: As part of upcoming Academy of Allergy, Asthma and Immunology/American College of Allergy, Asthma and Immunology Joint Task Force on Practice Parameters guidelines addressing severe asthma, we systematically reviewed the efficacy and safety of macrolides for asthma. METHODS: We systematically searched MEDLINE, Embase, and CENTRAL to April 12, 2025, for randomized trials comparing macrolides with placebo or standard care for asthma. Paired reviewers independently screened records and extracted data. Individual patient-level data in random effects analysis of covariance models addressed asthma control and asthma-related quality of life. Random effects meta-analyses addressed severe exacerbations and harms. We used the Grading of Recommendations Assessment, Development and Evaluation approach to evaluate certainty of evidence. Our study protocol is registered in PROSPERO (CRD42023408677). RESULTS: Our meta-analysis comprised 19 trials enrolling 1825 participants. Compared with placebo, macrolides improve asthma control (6-item Asthma Control Questionnaire; score range 0-6, lower better; between-group mean difference: -0.23 [95% CI -0.32 to -0.13]; 40.6% vs 21.6% improving by minimally important difference of 0.5 point; high certainty), likely reduce severe exacerbations (incidence rate ratio: 0.75 [95% CI 0.57 to 0.98]; rate difference: 0.26 fewer events per patient-year [95% CI 0.45 to 0.02 fewer events]; moderate certainty), and likely modestly improve quality of life (Asthma Quality of Life Questionnaire; score range 1-7, higher better; mean difference: 0.11 [95% CI -0.06 to 0.29]; 47.6% vs 42.4% improving by minimally important difference of 0.5 points; moderate certainty) with little to no effect on serious adverse events and mortality (high certainty). Relative effects were similar among patients with type 2 high inflammation versus type 2 low inflammation asthma. CONCLUSIONS: Macrolides likely reduce severe exacerbations and improve asthma control and quality of life with little to no difference in serious harms among patients with type 2 high inflammation or type 2 low inflammation asthma.
Al-Musa A, Platt C, Elkins M
… +9 more, Novak T, Woods B, Bourdine A, Magin L, Craiglow BG, Newhams MM, Kong M, Randolph A, Chou J
J Allergy Clin Immunol
· 2026 Jun · PMID 41654261
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BACKGROUND: Inborn errors of immunity are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized un...BACKGROUND: Inborn errors of immunity are classically identified in infants and young children with severe or recurrent infections. However, hypomorphic variants with a partial loss of function can remain unrecognized until later in life and may underlie clinically significant susceptibility to infections in previously healthy individuals. OBJECTIVE: We sought to investigate how 3 novel heterozygous variants in dedicator of cytokinesis 2 (DOCK2) contribute to impaired antiviral immunity, extending the understanding of DOCK2 deficiency beyond an autosomal-recessive disease. METHODS: After identifying the first DOCK2 variant, we screened 1109 exomes from 3 cohorts of patients with a history of at least 1 severe respiratory, blood-borne, or soft-tissue infection. We assessed the biologic impact of each variant via functional and transcriptional assays of the patients' primary PBMCs and in cell-based overexpression systems. RESULTS: Six individuals from 3 unrelated families, aged 3 months to 50 years, carried 1 of 3 heterozygous variants in DOCK2 and experienced severe infections with human papilloma virus, respiratory syncytial virus, or severe acute respiratory syndrome coronavirus 2. All variants reside within the DOCK2 domain that binds and stabilizes ELMO1. Each variant reduced DOCK2 protein expression, ELMO1 binding, and DOCK2 function, as shown by diminished Rac1 activation and selective defects in Toll-like receptor signaling. Weekly IFN-α therapy led to complete resolution of refractory warts in 1 patient, highlighting a potential therapeutic approach for DOCK2-associated immunodeficiency. CONCLUSIONS: These findings expand the spectrum of DOCK2-related disease by showing that heterozygous pathogenic variants disrupting DOCK2-ELMO1 interactions impair protein stability and antiviral immunity, revealing a previously unrecognized inborn error of immunity affecting otherwise healthy individuals.
Schmitz EG, Paul AJ, Ghosh R
… +61 more, Saucier N, Kolicheski A, Risma SI, McDaniels KP, Liu M, Lewis KL, de Jesus AA, Alehashemi S, Fronick CC, Stein D, Dominguez D, Hiraki LT, Lee JH, Norman S, Peng CR, Ward BR, Pettiford LH, Platt A, Lawrence MG, Rocco JM, Al-Herz W, Zerbe CS, Atkinson TP, Peng XP, Allenspach EJ, Hoytema van Konijnenburg DP, Platt CD, Elkins M, Walter JE, Bleesing JJ, Klion A, Ramaswami R, Uzel G, Lionakis MS, Dissanayake D, Su HC, Cortese I, Fuss IJ, Bergerson JRE, Dropulic L, Sereti I, Lisco A, Itan Y, Milner JD, Bogunovic D, Goldbach-Mansky R, Rao VK, Delmonte OM, Notarangelo LD, Keller MD, Durkee-Shock J, Cohen JI, Similuk MN, Holland SM, Griffith M, Griffith OL, Vogel TP, Canna S, Freeman AF, Walkiewicz MA, Cooper MA
J Allergy Clin Immunol
· 2026 May · PMID 41654260
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BACKGROUND: Identifying genetic mechanisms of inborn errors of immunity (IEI) is important for diagnosis and treatment of patients, yet most patients with suspected IEI have negative genetic testing results. Genetic mosa...BACKGROUND: Identifying genetic mechanisms of inborn errors of immunity (IEI) is important for diagnosis and treatment of patients, yet most patients with suspected IEI have negative genetic testing results. Genetic mosaicism is an emerging mechanism of IEI, but it is challenging to identify. OBJECTIVE: We used a discovery-based approach to identify mosaic variants in genes relevant to immune dysregulation in patient and healthy cohorts. METHODS: We developed custom panels for high-depth sequencing of genes known or hypothesized to cause dominant immune dysregulation. Samples from 452 patients with immune dysregulation (affected) and 154 currently healthy were sequenced using 71- or 101-gene targeted panels. RESULTS: We identified mosaic variants in 9.5% of undiagnosed patients and 7.8% of healthy individuals. Using a strategy to predict pathogenicity of variants in IEI, 33% of variants identified in patients were predicted to be likely pathogenic or pathogenic, while no mosaic variants in healthy individuals were predicted to be pathogenic. Genes with mosaicism in >1 affected undiagnosed patients included FAS, STAT3, CARD11, CARD14, NRAS, TNFAIP3, NLRP3, and IKZF2. Four patients had variants in FAS with allele fractions <5% in blood but highly enriched in double-negative T cells, diagnostic for somatic FAS autoimmune lymphoproliferative syndrome. CONCLUSION: These findings establish the utility of a high-depth sequencing panel to identify mosaic variants and demonstrate that mosaicism in immune-relevant genes is present in healthy individuals.
BACKGROUND: The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. OBJECTIVE: We comprehensively characterized efferocytosis in CRS and determin...BACKGROUND: The role of efferocytosis in chronic rhinosinusitis (CRS), particularly CRS with nasal polyps (CRSwNP), remains poorly understood. OBJECTIVE: We comprehensively characterized efferocytosis in CRS and determined its association with inflammatory endotypes and clinical outcomes in CRSwNP. METHODS: Efferocytosis-related marker expression between nasal polyps and healthy nasal mucosa was detected by quantitative real-time PCR and immunohistochemistry. Public single-cell RNA sequencing profiles of CRS were reanalyzed to dissect efferocytosis at single-cell resolution. Associations between efferocytosis and tissue inflammation were evaluated by Spearman correlation. Regression models and receiver operating characteristic analyses assessed the predictive capability of efferocytosis for CRSwNP recurrence. RESULTS: Compared with controls, CRSwNP exhibited widespread efferocytosis deficiency, including "find me" signals (CX3CR1, S1PRs, P2RY2, GPR132), "eat me" signals (ITGAV, MerTK, Tim1, ADGRB1), "don't eat me" signal CD300a, postengulfment signals (ABCA1, NR1H3/2, PPARδ/γ), and bridging molecule MFGE8. Macrophages, the principal efferocytic cells, shifted from homeostatic C3 macrophages in healthy controls to efferocytosis-impaired macrophages in CRS: FCN1 subset predominated in CRS without nasal polyps; FCN1, IL-1β, and CXCL12 subsets in noneosinophilic CRSwNP; and FN1 and SPP1 subsets in eosinophilic CRSwNP. All these CRS-associated macrophages exhibited reduced proefferocytic receptors (CX3CR1, MerTK) and elevated antiphagocytic receptor SIRPA. Efferocytosis-related signals correlated with type 2-skewed markers. A 5-molecule signature (S1PR5, MerTK, MFGE8, CD300a, PPARδ) was identified as a predictive panel for CRSwNP recurrence, with a receiver operating characteristic area under the curve of 0.867. CONCLUSION: Insufficient phagocytosis and increased antiphagocytosis activity are hallmarks of efferocytosis deficiency in CRS and are associated with the severity of inflammation and the clinical outcome of CRSwNP.
BACKGROUND: Type I interferons (IFN-I) and type II interferon (IFN-γ) contribute to the pathogenesis of inflammatory diseases, but measurement of these cytokines remains challenging in the clinical setting. OBJECTIVE: We...BACKGROUND: Type I interferons (IFN-I) and type II interferon (IFN-γ) contribute to the pathogenesis of inflammatory diseases, but measurement of these cytokines remains challenging in the clinical setting. OBJECTIVE: We aimed to develop a clinical test that rapidly captures the activity of IFN-I and IFN-γ. METHODS: We compared RNA sequencing data from healthy controls and patients with macrophage activation syndrome, multisystem inflammatory syndrome in children, and systemic lupus erythematosus to evaluate biomarkers of IFN-I and IFN-γ signaling. We utilized a flow cytometry assay to measure interferon-inducible markers. The findings were verified by a clinical laboratory that independently developed and validated this assay. RESULTS: We identified CD274 (programmed death ligand 1, or PD-L1) as a biomarker of IFN-γ signaling and confirmed CD169 (SIGLEC-1) as a readout of IFN-I activity. We utilized a flow cytometry assay to quantify CD169 and CD274 expression on monocytes and demonstrated the validity of this method for rapid screening of interferon dysregulation in patients with various inflammatory diseases including, among others, macrophage activation syndrome, hemophagocytic lymphohistiocytosis, multisystem inflammatory syndrome in children, systemic lupus erythematosus, juvenile idiopathic arthritis, and juvenile dermatomyositis. We further demonstrated the utility of this test for assessment of interferon dysregulation in monogenic inflammatory diseases and for efficacy monitoring of medications that target the interferon pathways including Janus kinase inhibitors, emapalumab, and anifrolumab. Finally, we outlined the steps of assay validation and clinical implementation, and we showed reproducible findings in a clinical laboratory. CONCLUSION: Flow cytometry analysis of CD169 and CD274 is an effective method to rapidly quantify IFN-I and IFN-γ activity in the clinical setting.
The nasal microbiome is altered in chronic rhinosinusitis (CRS), characterized by increased bacteria density and higher relative abundance of Staphylococcus aureus compared to healthy adults. This review examines determi...The nasal microbiome is altered in chronic rhinosinusitis (CRS), characterized by increased bacteria density and higher relative abundance of Staphylococcus aureus compared to healthy adults. This review examines determinants of S aureus nasal colonization, focusing on immune control and its evasion by the bacteria. CRS and asthma share pathomechanisms of chronic airway inflammation and often co-occur. In both conditions, many patients are sensitized to secreted factors of S aureus enterotoxins and serine protease-like proteins, and produce specific IgE, which influences the disease course. Therefore, we propose to incorporate S aureus-specific IgE measurements into the routine diagnostic evaluation of CRS and asthma.
Tu W, Wu M, Wan R
… +14 more, Alphonse M, Gu W, Ghosh B, Lin J, Zhang Y, Chen J, Hu X, Shen Y, Xie S, Liu L, Sidhaye V, Jia H, Wan M, Gao P
J Allergy Clin Immunol
· 2026 Jun · PMID 41633491
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BACKGROUND: Ras homolog family member A (RhoA) activation in alveolar type 2 cells has been implicated in regulating allergen-induced allergic airway inflammation; however, its role in large airway, particularly Club cel...BACKGROUND: Ras homolog family member A (RhoA) activation in alveolar type 2 cells has been implicated in regulating allergen-induced allergic airway inflammation; however, its role in large airway, particularly Club cells, remains unclear. OBJECTIVE: We sought to determine the function of RhoA in Club cells during allergic airway inflammation. METHODS: A Club cell-specific RhoA knockout mouse model (RhoA) was generated, and allergic airway inflammation was assessed. Air-liquid interface cultures were used to evaluate epithelial barrier integrity. Multidimensional flow cytometry, bulk RNA sequencing, and single-cell RNA sequencing were used to characterize immune responses and delineate downstream pathways. RESULTS: RhoA deletion in Club cells significantly attenuated allergic airway inflammation. Air-liquid interface cultures derived from RhoA epithelium exhibited increased transepithelial electrical resistance, decreased permeability, and reduced cytokine and chemokine (CCL24, TSLP, and IL-33) production. Multidimensional flow cytometry revealed that interstitial macrophages (IMs) were the most profoundly affected immune population. Bulk RNA-sequencing pinpointed IL-13 and Ccl24 as key mediators downstream of Club cell RhoA signaling. Single-cell RNA sequencing confirmed allergen-induced expansion of IMs with high expression of the C1q gene family, which was markedly reduced in RhoA lungs. Integrated bulk and single-cell RNA-sequencing data revealed Ccl24 as one of the most significantly downregulated genes in IMs from RhoA lungs. Immunofluorescence colocalization further demonstrated reduced C1qa IMs and Ccl24C1qa IM subsets. Functionally, recombinant CCL24 disrupted epithelial barrier integrity, whereas CCL24 neutralization significantly ameliorated airway inflammation. CONCLUSIONS: These findings suggest that RhoA activation in Club cells plays a pivotal role in orchestrating allergic airway inflammation by impairing epithelial barrier function and altering macrophage dynamics.
Kelly MS, Huang CY, Kim M
… +9 more, Haghnazari D, Baig A, Sun Y, Lenneman BR, Tisza MJ, Cunningham A, Gold D, Phipatanakul W, Lai PS
J Allergy Clin Immunol
· 2026 Feb · PMID 41633490
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BACKGROUND: Respiratory viral infections are common and can trigger asthma exacerbations in children. The roles of the nasal microbiome and phageome (viruses that infect microbes) are not well understood. OBJECTIVE: We s...BACKGROUND: Respiratory viral infections are common and can trigger asthma exacerbations in children. The roles of the nasal microbiome and phageome (viruses that infect microbes) are not well understood. OBJECTIVE: We sought to characterize the epidemiology of respiratory viral infections and the interplay between the nasal microbiome, phageome, and viral infections in school-age children with asthma. METHODS: We performed metagenomic sequencing and quantitative RT-PCR detection of respiratory viruses on 375 nasal samples from 227 school-age children with asthma collected routinely 3 times over a year. Surveys on parent-reported cold and asthma symptoms were administered routinely every 2 months. We evaluated multikingdom changes to the nasal microbiome during infection. A sparse partial least-squares discriminant analysis model identified microbial signatures associated with prospective viral infection risk. RESULTS: Respiratory viruses were identified in 124 (33%) samples, with rhinovirus being the most prevalent. Cold and asthma symptoms within the previous 14 days had a sensitivity of 79% and 59%, respectively, for quantitative RT-PCR-confirmed infection. Respiratory viral infection increased asthma symptoms and was accompanied by loss of nasal bacterial diversity and a reproducible bloom of pathobionts with no change in the mycobiome or phageome. A baseline bacteriome-dominated profile was protective (adjusted odds ratio, 0.41 [95% CI, 0.25-0.67]; P < .001), whereas phageome profiles increased risk (adjusted odds ratio, 3.74 [95% CI, 1.85-7.55]; P < .001) of viral infection. Specific phages inversely correlated with Staphylococcus epidermidis abundance, the most protective commensal against infection risk. CONCLUSIONS: The nasal microbiome and phageome exert opposing influences on respiratory viral infection risk, highlighting their potential roles in modulating susceptibility to viral infections.
Forkgen J, Masle-Farquhar E, Fontaine Y
… +17 more, Russell A, Ji S, Peters TJ, Qiao Z, Geaghan M, Jackson KJL, Hammond JM, Deveson IW, David C, Lemberg DA, Gupta N, Fuentes-Bolanos N, Mustjoki S, Hwa V, Tangye SG, Gray PE, Siggs OM
BACKGROUND: Mosaic genetic variation has been implicated in the pathogenesis of both malignant and nonmalignant immunologic diseases. OBJECTIVE: We sought to investigate a unique case of postnatal acquisition of a gain-o...BACKGROUND: Mosaic genetic variation has been implicated in the pathogenesis of both malignant and nonmalignant immunologic diseases. OBJECTIVE: We sought to investigate a unique case of postnatal acquisition of a gain-of-function (GoF) KRAS variant, with an additional GoF STAT5B variant, in an 18-year-old woman with inflammatory bowel disease, splenomegaly, thrombocytopenia, bronchiectasis, monocytosis, and eosinophilia. METHODS: Diagnostic panel, whole-genome, and targeted amplicon sequencing were performed on longitudinal blood and tissue samples to reveal germline and mosaic variants and their allele frequencies across different cell populations. Short- and long-read single-cell RNA sequencing and flow cytometry were used to measure the effect of variants on RNA, protein, and leukocyte cell state. RESULTS: Both mosaic variants were present across multiple leukocyte subsets and historical blood and tissue samples, with the emergence of both variants coinciding with the clinical presentation. Both variants were expressed in a unique population of monocytes, associated with dysregulated cytokine signaling and the presence of a distinct population of highly granular CD24 leukocytes. CONCLUSIONS: Taken together with the clinical presentation, these findings led to a diagnosis of combined Ras-associated autoimmune leukoproliferative disorder and nonclonal STAT5B GoF disease. To our knowledge, this is the first reported combination of 2 distinct acquired errors of immunity causing a mixed clinical phenotype, and this highlights the importance of considering acquired monogenic diseases within a broader genomic context.
de Brito JM, de Souza Xavier Costa N, Ferreira DS
… +7 more, Vergani KP, de Carvalho-Pinto RM, da Silva-Filho LVRF, Athanazio RA, Rodrigues JC, Mauad T, Eller MCN
BACKGROUND: Endobronchial biopsy studies have deepened our understanding of airway inflammation and remodeling in severe asthma, but direct comparisons between pediatric and adult populations remain scarce. OBJECTIVE: We...BACKGROUND: Endobronchial biopsy studies have deepened our understanding of airway inflammation and remodeling in severe asthma, but direct comparisons between pediatric and adult populations remain scarce. OBJECTIVE: We compared the histopathologic and clinical characteristics of children and adults with severe uncontrolled asthma. METHODS: Demographic, clinical, and laboratory data, lung function, fractional exhaled nitric oxide, and endobronchial biopsy samples were evaluated from 13 children and 36 adults with severe uncontrolled asthma. RESULTS: The pediatric group had a higher proportion of boys, while girls predominated in adults. Children exhibited better lung function than adults (median percentage predicted forced expiratory volume in 1 second 82% vs 55%). In contrast, inflammatory cell densities were significantly higher in children across multiple airway compartments: elevated levels of eosinophils, chymase-positive mast cells, and CD8 T cells in the intraepithelial layer; neutrophils, tryptase-positive mast cells, and chymase-positive mast cells in the airway smooth muscle layer; and eosinophils, tryptase-positive mast cells, and chymase-positive mast cells in the submucosal layer. In contrast, CD4 T-cell density in the submucosal layer was higher in adults. Structural parameters, including basement membrane and epithelial thickness, collagen deposition, and airway smooth muscle/total tissue area, were similar between groups. CONCLUSION: Children with severe asthma exhibit greater airway inflammation yet maintain better lung function compared to adults with similar structural remodeling. These findings highlight a potential therapeutical window in the pediatric population, emphasizing the need for age-tailored management approaches in severe asthma.
Montero-Hernández JE, Vibhushan S, Bratti M
… +9 more, Bex-Coudrat J, Gómez-Secundino O, Danglot L, Galli T, Sepulveda FE, Charles N, González-Espinosa C, Benhamou M, Blank U
BACKGROUND: IgE/allergen-activated murine mast cells (MCs) release potent granule-stored mediators by degranulation and secrete newly synthesized chemokines to locally recruit inflammatory cells. Whereas the fusion and t...BACKGROUND: IgE/allergen-activated murine mast cells (MCs) release potent granule-stored mediators by degranulation and secrete newly synthesized chemokines to locally recruit inflammatory cells. Whereas the fusion and trafficking steps during degranulation have been extensively studied, chemokine vesicular trafficking remains poorly understood. OBJECTIVE: We explored the trafficking of C-C motif chemokine ligand 2 (CCL2) in IgE-activated MCs and in a murine model of passive cutaneous anaphylaxis (PCA). METHODS: Bone marrow-derived and peritoneal cell-derived MCs from wild-type and newly established CCL2-enhanced green fluorescent protein knock-in mice were sensitized with anti-DNP (2,4-dinitrophenol) IgE and activated with DNP-human serum albumin antigen. Using time-course experiments, fluorescence-activated cell sorting, ELISA, and confocal and fluorescence microscopy analyses, the CCL2 vesicular trafficking in and secretion from MCs were analyzed. In vivo experiments were conducted to analyze CCL2 secretion during PCA. RESULTS: Cultured MCs released CCL2 in a biphasic manner, exocytosing vesicular prestored chemokine followed by secretion of neosynthesized protein that partly trafficked through vesicular-associated membrane protein (VAMP) 3- and VAMP7-positive vesicular carriers. CCL2 trafficking in soluble antigen-activated CCL2-enhanced green fluorescent protein knock-in MCs followed a complex pattern-polarized, multidirectional, or pseudopodia targeted-regulated by the interplay between the actin and microtubule cytoskeletons. Secreted CCL2 interacted with proteoglycans released during degranulation. On polarized activation by immobilized antigen, prestored CCL2 was secreted at the degranulatory interface, whereas neosynthesized CCL2 trafficked away from it. During PCA, CCL2 rapidly appeared lining blood vessels after MC degranulation and was locally released in the surrounding tissue. CONCLUSION: Our study reveals the complex dynamics of chemokine secretion and trafficking driving local inflammation during MC-driven allergic responses.
Miranda-Katz MR, Gern JE, Bochkov YA
… +1 more, Wilson JL
J Allergy Clin Immunol
· 2026 Apr · PMID 41581615
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Rhinoviruses (RVs) are the most common respiratory pathogens and a significant cause of asthma exacerbations and wheezing illnesses in children. In addition, RV wheezing illnesses during the preschool years strongly pred...Rhinoviruses (RVs) are the most common respiratory pathogens and a significant cause of asthma exacerbations and wheezing illnesses in children. In addition, RV wheezing illnesses during the preschool years strongly predict asthma development. This review includes updates on RV epidemiology and virus diversity, highlighting species-specific differences and antigenic variability that present significant challenges for vaccine design. Host responses to RV involve canonical antiviral responses originating in airway epithelial cells, followed by activation of adaptive immunity. In patients with asthma and allergic disease, type 2 inflammation, genetic susceptibility, and epithelial remodeling impair these antiviral defenses. These factors, combined with airway dysbiosis, can exacerbate airway injury and lead to more severe illnesses. RV infection disrupts epithelial barrier integrity, promotes pathobiont growth, and induces factors that can drive structural changes associated with airway obstruction and chronic asthma. Therapeutic strategies, including direct antivirals and interferons, show promise but remain limited by adverse effects and modest efficacy, while extreme virus diversity remains an obstacle to vaccine development. Advances in understanding how host factors, such as type 2 inflammation, increase susceptibility to RV infection and illness identify alternative approaches to reducing RV morbidity in high-risk children with allergic diseases and asthma.
Krueger JG, Cutcutache I, Lebwohl M
… +14 more, Gudjonsson JE, Pinter A, Langley RG, Merola J, Tada Y, Skelton A, Rastrick J, Ferecskó AS, Page M, Davies O, López Pinto JM, Warham R, Shaw S, Warren RB
BACKGROUND: Bimekizumab (BKZ), an IL-17A and IL-17F inhibitor, has demonstrated a rapid and high level of complete skin clearance in patients with psoriasis and complete normalization of the transcriptional signature of...BACKGROUND: Bimekizumab (BKZ), an IL-17A and IL-17F inhibitor, has demonstrated a rapid and high level of complete skin clearance in patients with psoriasis and complete normalization of the transcriptional signature of lesional skin after 8 weeks. OBJECTIVE: We sought to assess the durability of initial clinical response to BKZ for up to 4 years and investigate molecular mechanisms leading to the observed response. METHODS: Clinical data were pooled from 3 1-year phase 3 feeder studies (BE VIVID, BE READY, and BE SURE) and their 3-year open-label extension (BE BRIGHT). Transcriptomic analyses were conducted on 3 independent single-cell RNA-sequencing data sets from lesional psoriasis biopsies and bulk RNA-sequencing data from a phase 2a study. RESULTS: Among patients who achieved complete skin clearance after 16 weeks, continued to receive double-blind BKZ treatment, and entered BE BRIGHT, 73.0% achieved this response at the end of year 4 (N = 503; modified nonresponder imputation). Single-cell transcriptomic analyses revealed a group of tissue-resident memory T (T) cells in lesional skin expressing IL17A and/or IL17F that are minimally present in healthy skin, postulated to constitute a pathogenic T-cell subset. Prosurvival factors expressed in T cells in lesional skin were identified, with IL7R shown to be more highly expressed in IL17F than in IL17A T cells. Reversal of expression of these prosurvival factors, alongside a general T gene signature, was demonstrated in bulk transcriptomic analyses after 8 weeks of treatment (2 BKZ doses). CONCLUSIONS: The strong durability and high response level observed with BKZ may be associated with normalization of pathogenic T cells.
Hayashi H, Nagai J, Lai J
… +12 more, Zaleski K, Feng C, Hastings M, Nishida A, Tani Y, Lin J, Sasaki M, Alhallak K, Marshall SA, Liu T, Balestrieri B, Boyce JA
J Allergy Clin Immunol
· 2026 Jun · PMID 41577142
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BACKGROUND: Platelets amplify lung type 2 inflammation (T2I), but the underlying mechanisms remain incompletely understood. OBJECTIVE: We elucidated the platelet-driven T2I mechanisms, particularly the role of platelet-d...BACKGROUND: Platelets amplify lung type 2 inflammation (T2I), but the underlying mechanisms remain incompletely understood. OBJECTIVE: We elucidated the platelet-driven T2I mechanisms, particularly the role of platelet-derived leukotriene C (LTC). METHODS: We assessed lung T2I to Alternaria alternata extract in vivo using mice with targeted deletions of Ltc4s in platelets, macrophages (Macs), or mast cells (MCs); Il33 in Macs, hematopoietic cells, or alveolar type 2 (AT2) cells; and cysteinyl leukotriene receptors. Exogenous administration of LTC and IL-33 in naïve mice complemented the genetic models. Sex- and age-matched mice were randomly assigned, and histopathologic evaluations were performed under blinded conditions. RESULTS: Platelets promoted IL-33 expression in perivascular Macs and induced transcellular LTC synthesis. Although platelet Ltc4s was not needed to induce IL-33 Macs, it promoted both IL-33 AT2 cell and group 2 innate lymphoid cell expansions in a sex-biased manner. Platelet depletion abrogated A alternata-induced increases in IL-33 and AT2 cell expansion. Platelet-adherent Macs expressed higher IL-33 than no-adherent counterparts. Platelet-specific Ltc4s deletion reduced eosinophil, group 2 innate lymphoid cell, and AT2 cell expansion in female animals in a delayed manner. Mac-specific Il33 deletion eliminated platelet-driven IL-33 increases and attenuated AT2 cell expansion selectively in female animals. Exogenous LTC and IL-33 synergistically induced IL-33 Macs and expanded AT2 cells. CONCLUSION: Adherent platelets rapidly upregulate IL-33-expressing Macs, and platelet-derived LTC sustains IL-33-driven expansion of AT2 cells and group 2 innate lymphoid cells, driving sex-biased amplification of T2I. This platelet-Mac axis may contribute to sex differences in type 2 inflammatory airway diseases such as asthma.
BACKGROUND: Few studies have investigated the association between breast-feeding and asthma and allergy up to adulthood. OBJECTIVE: We examined the development of asthma and IgE sensitization up to young adulthood in rel...BACKGROUND: Few studies have investigated the association between breast-feeding and asthma and allergy up to adulthood. OBJECTIVE: We examined the development of asthma and IgE sensitization up to young adulthood in relation to duration of exclusive breast-feeding in a longitudinal cohort. METHODS: The 3,919 participants in the study population were from a Swedish birth cohort with questionnaire data on breast-feeding at age 1 year. Asthma was based on questionnaire data up to age 24 years. Blood sampling for IgE analyses was performed at 4, 8, 16, and 24 years. Longitudinal analyses were performed with generalized estimating equations. RESULTS: Exclusive breast-feeding for ≥4 months was associated with overall reduced odds of prevalent asthma up to age 24 years (adjusted odds ratio [OR] = 0.75; 95% confidence interval [CI], 0.64-0.87). Age-specific analyses showed a statistically significant inverse association with asthma up to age 12 years, but not thereafter. Analyzing asthma phenotypes over time resulted in a borderline significant inverse association with early transient asthma and a significant inverse association with persistent asthma (OR = 0.64; 95% CI, 0.48-0.84). However, there was no association with late-onset asthma. Breast-feeding was overall also inversely associated with IgE sensitization (OR = 0.82; 95% CI, 0.70-0.96). Exclusion of children with early symptoms of wheeze and/or eczema during breast-feeding (n = 486) strengthened the associations for both asthma and sensitization. CONCLUSIONS: Exclusive breast-feeding for ≥4 months was inversely associated with asthma, in particular with disease onset during the first 12 years of life, as well as IgE sensitization up to young adulthood.
BACKGROUND: Studies of twins, parents, and families have demonstrated a strong heritable role in allergy and food allergy in particular (60%-80%). However, genetic loci identified in previous genome-wide association stud...BACKGROUND: Studies of twins, parents, and families have demonstrated a strong heritable role in allergy and food allergy in particular (60%-80%). However, genetic loci identified in previous genome-wide association studies focused on common variants, have not withstood validation, are not located inside protein coding exons, do not explain familial allergy, or have a low effect size. OBJECTIVE: We sought to apply forward genetics of families and exome sequencing to identify the frequency of Mendelian gene mutations for food allergy with emphasis on rare coding high-risk variants. METHODS: To enrich the probability of detecting Mendelian genetic variants, we included probands who had at least 2 food allergies confirmed by a food allergist. Family history of eczema, asthma, or food allergy was preferred but not required. Exome sequencing and analysis of DNA samples from probands, siblings, and parents was conducted to detect inheritance and enrichment of specific genes. RESULTS: Of 28 full trio families and 28 singletons, we found that 39.3% probands (n = 22/56) had a loss-of-function (LoF) mutation in FLG, a gene known to cause food allergy. We further found genes suspected of causing Mendelian food allergy: SMAD3 LoF mutation (n = 1) and dominant inheritance of LoF mutations in IFIH1 (MDA5) (n = 3 independent probands). FLG LoF mutations were significantly enriched in our non-Hispanic White cohort compared with 1100 non-Hispanic White controls (P = 4.28 × 10; odds ratio 3.38 [95% CI 1.72-6.67]). Notably, exome sequencing improved detection of FLG LoF mutations by 58% compared with previously used FLG genotyping methods, especially for people of non-European ancestry. Furthermore, we found FLG LoF variants in most subjects of African (55%, 5/9) ancestry with food allergy, but this observation could be limited by low sample size. CONCLUSIONS: A Mendelian cause for food allergy may be present in 39.3% of patients with multiple food allergies. Expanded genomic studies of ethnically diverse groups and validation cohorts are warranted to uncover the variety of LoF variants from FLG present and confirm a potential role for MDA5.
The development of targeted mAbs has transformed the treatment of moderate-to-severe asthma. The main clinical trial outcomes have focused on exacerbation reduction and lung function improvement. In the past few years, t...The development of targeted mAbs has transformed the treatment of moderate-to-severe asthma. The main clinical trial outcomes have focused on exacerbation reduction and lung function improvement. In the past few years, there have been many high-quality studies examining pathophysiologic effects of the biologic therapies, giving insight into their downstream impacts. Clinical remission is a growing area of interest, and many studies highlight the utility as well as the limitations of commonly available biomarkers to predict treatment response. This review synthesizes the results of recent clinical trials and related topics focusing on relevant updates to the literature since 2024, highlighting new indications for use, predictors of response, safety data, real-world comparative effectiveness, remission, and mechanistic advances.