Journal of Allergy and Clinical Immunology最新文献

{"title":"Anti-KIT antibody, briquilimab, induces mast cell apoptosis and depletion in non-human primates.","authors":"Song Eun Lee,Hind Bouzid,Cheryl Kwan,Ajay Sharma,Andrea R Romo,Ruiqi Huang,Iris Zhan,Christopher Banfield,Jane R Parnes,Vaughn V Smider,Mang Yu,Hye-Sook Kwon,Wendy W Pang","doi":"10.1016/j.jaci.2025.07.019","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.019","url":null,"abstract":"BACKGROUNDMast cells (MCs) play a critical role in many allergic and inflammatory reactions in healthy and disease states. Current therapeutic strategies to treat MC-mediated diseases aim to suppress MC activation by utilizing small molecule inhibitors or antibodies targeting specific signaling receptors on MCs. However, these strategies require chronic drug exposure, which have inherent limitations including increased patient burden and potential toxicity. Moreover, the redundancy between multiple signaling pathways concomitantly regulating MC activation can lead to insufficient MC suppression.OBJECTIVETo develop a novel therapeutic strategy using an aglycosylated anti-KIT monoclonal antibody, briquilimab, to deplete MCs via KIT signaling inhibition.METHODSInhibition of KIT by briquilimab was evaluated in vitro in KIT expressing cell lines and primary human MCs. Briquilimab safety, pharmacokinetics, and MC depletion were evaluated in non-human primates (NHPs).RESULTSBriquilimab potently blocks SCF ligand binding to KIT and inhibits SCF/KIT signaling and primary MC degranulation and survival, leading to MC apoptosis via PI3K/AKT pathway in vitro. Additionally, aglycosylation of briquilimab mitigates unwanted MC activation. In NHPs, single and multi-dose high, chronic exposure of briquilimab is well-tolerated with mild to moderate, but reversible adverse effects and effectively depletes various tissue MCs, such as lung, skin, and colon, in a dose-dependent manner.CONCLUSIONSBriquilimab effectively inhibits SCF/KIT signaling and induces MC apoptosis, leading to profound and durable MC depletion in NHPs, and may provide a safe and novel therapeutic option to treat MC-mediated diseases.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"37 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144769754","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Infectious and inflammatory events in 2 siblings with IRF9 deficiency under immunoglobulin replacement therapy.","authors":"Teresa Del Rosal,Ángel Morillas-Mingorance,María Bravo García-Morato,Rebeca Rodríguez-Pena,Luz Yadira Bravo-Gallego,Ana Méndez-Echevarría","doi":"10.1016/j.jaci.2025.06.033","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.06.033","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"11 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756189","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Neighborhood disadvantage and the back-to-school epidemic of viral-associated asthma exacerbations.","authors":"Darlene Bhavnani,Peter Dunphy,Sarah Chambliss,Daniel S W Katz,Emily Hall,Rebecca A Zárate,Susan Balcer Whaley,Paul J Rathouz,Elizabeth C Matsui","doi":"10.1016/j.jaci.2025.07.014","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.014","url":null,"abstract":"BACKGROUNDRates of viral-associated asthma exacerbations typically increase when children return to school after the summer holiday. The effect of neighborhood disadvantage on this back-to-school increase in viral-associated asthma exacerbations is unknown.OBJECTIVETo evaluate the effect of neighborhood disadvantage on the back-to-school increase in asthma-related emergency department (ED) visits.METHODSAdministrative health records were used to define population-based incidence rates of asthma-related ED visits by week and census tract among children aged 5-17 years. Using Bayesian regression models of incidence rates, we evaluated additive interactions between a seven-week back-to-school period (relative to a six-week summer period) and neighborhood disadvantage (e.g., social vulnerability index, SVI).RESULTSIn census tracts with low social vulnerability (SVI=2), rates of asthma-related ED visits increased by 378 (95% CrI = 358-398) per 100,000 person-years when children went back to school. Relative to the back-to-school increase in tracts with low social vulnerability, in tracts with moderate social vulnerability (SVI=5) there was an excess of 199 asthma-related ED visits per 100,000 person-years (95% CrI = 183-214). Relative to the back-to-school increase in tracts with moderate social vulnerability, in tracts with high social vulnerability (SVI=8), there was an excess of 303 (95% CrI = 268-339) asthma-related ED visits per 100,000 person-years.CONCLUSIONGreater levels of neighborhood disadvantage were associated with a greater increase in the rate of asthma-related ED visits when children returned to school. Neighborhood disadvantage may modify the back-to-school increase in asthma exacerbations by increasing the risk of upper respiratory viral infections.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"26 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144756190","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CARMIL2 deficiency disrupts activation-induced metabolic reprogramming in T cells, and is partially rescued by glutamine supplementation.","authors":"Mona Kabha,Maya Liaks-Bohnick,Fadia Zagairy,Orna Atar,Mira Hamed,Michael Ziv,Nada Danial-Farran,Morad Khayat,Orly Ishach,Yael Dinur-Schejter,Vered Molho-Pessach,Ido Somekh,Shirly Frizinsky,Efrat Bar-Ilan,Shoshana Greenberger,NaserEddin Adeeb,Raz Somech,Polina Stepansky,Noga Ron-Harel,Eran Cohen-Barak","doi":"10.1016/j.jaci.2025.07.018","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.018","url":null,"abstract":"BACKGROUNDT-cell activation requires signaling through the T-cell receptor and costimulatory molecules, including CD28, triggering metabolic reprogramming to support growth and proliferation of the activating T -cell. CARMIL2, a scaffold protein, facilitates CD28-mediated signaling. Individuals with CARMIL2 mutations experience inborn errors of immunity, leading to T-cell dysfunction and severe infectious and inflammatory comorbidities. However, how CARMIL2 deficiency impacts T cell metabolic reprogramming remains unknown.OBJECTIVETo investigate how CARMIL2 deficiency affects activation-induced metabolic reprogramming in T-cells.METHODSCD4+ T-cells were isolated from patients with CARMIL2 deficiency and matched healthy controls (HC). Transcriptomic profile was analyzed by bulk RNA sequencing and whole-cell metabolomics by liquid chromatography-mass spectrometry (LC-MS/MS). Activation markers and signaling pathways were measured by flow cytometry. These approaches informed identification of specific amino acids for rescue experiments.RESULTSNine patients with CARMIL2 deficiency and sixteen age-and sex-matched healthy controls were recruited. RNA sequencing of CD4+ T-cells revealed decreased expression of genes associated with metabolic activity, including mTOR signaling, glycolysis, one-carbon metabolism, and glutamine metabolism. Whole cell metabolomics reinforced these results and highlighted glutamine deficiency as a potential driver of the observed metabolic phenotype. Glutamine supplementation restored NF-kB and mTOR activity, as measured by p-65 and RPS phosphorylation, respectively, and upregulated the expression of IL17A in CARMIL2-mutated CD4+ T cells.CONCLUSIONSCARMIL2 deficiency disrupts T-cell metabolic reprogramming and was partially rescued ex-vivo with glutamine supplementation. These findings highlight a potential therapeutic approach targeting metabolism to improve immune function in individuals with CARMIL2 deficiency.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"25 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747839","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Autoantibodies in patients with 22q11.2 deletion syndrome and psychosis.","authors":"Samantha Y Starkey,Kelly Maurer,Anne Bassett,Donna McDonald McGinn,Kathleen E Sullivan","doi":"10.1016/j.jaci.2025.07.013","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.013","url":null,"abstract":"BACKGROUND22q11.2 deletion syndrome occurs in roughly 1:2000 live births. It is one of the most common chromosomal conditions worldwide. It has a frequency of psychosis in adulthood of 25%, making it the most common known etiology for psychosis. Mechanisms of disease for psychosis are poorly understood, however, there are data supporting a role for inflammation. Given the altered immune system in 22q11.2 deletion syndrome, this study examined autoantibodies associated with psychosis.OBJECTIVEThe underlying hypothesis we tested was whether patients with psychosis had an immune landscape that differed from patients without psychosis. In this study, we tested whether increased autoantibodies were seen in patients with psychosis.METHODSWe utilized the UT Southwestern autoantibody array to measure levels of autoantibodies in patients and controls. Analyses used a two-tailed Student's t test with Benjamini-Hochberg correction for false discovery rate.RESULTSIn general, patients had lower levels of autoantibodies than controls for both children and adults. The adult patients with psychosis, however, had significantly higher autoantibodies than adult patients without psychosis. Eight of ten patients with psychosis had autoantibodies to ssDNA more than 2 standard deviations higher than the controls. This was not accompanied by clear clinical autoimmunity.CONCLUSIONPatients with 22q11.2 deletion syndrome and psychosis appear to have different immunologic characteristics than patients who carry the deletion but do not have psychosis. Autoantibody levels were overall significantly higher in patients with psychosis. This finding may define a high risk group within the 22q11.2 deletion syndrome population.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"27 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747841","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Hidden Splice Variants in Inborn Errors of Immunity: Uncovering Diagnoses and Therapeutic Targets.","authors":"Sebastian Ochoa,Andrew J Oler,Ivan K Chinn,Michail S Lionakis","doi":"10.1016/j.jaci.2025.07.017","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.017","url":null,"abstract":"Advancements in high-throughput DNA sequencing have drastically accelerated the discovery of novel genetic disorders, transforming the field of clinical immunology. Over 500 monogenic inborn errors of immunity (IEI) have been identified thus far, yet 60-90% of patients who present clinically with an IEI lack a genetic diagnosis. Recent genome sequencing data in large patient cohorts indicates that deep intronic and synonymous splice variants contribute significantly to undiagnosed cases. While genome sequencing (GS) detects most variants missed by exome sequencing and targeted gene panels, bioinformatic pipelines for non-coding and synonymous splice variant analysis remain underdeveloped, limiting its diagnostic yield. This review examines the landscape of splice variants \"hiding\" outside intron-exon junctions in patients with IEI and provides a practical diagnostic approach for the clinical immunologist. We explore how advances in genome sequencing, artificial intelligence and RNA sequencing (RNA-seq) are improving the detection of disease-causing splice variants and discuss the potential of splice-modulating antisense oligonucleotides as personalized treatments for IEI. While integrating advanced sequencing technologies, bioinformatics, and targeted therapies into clinical practice remains challenging, these efforts represent critical steps toward precision and personalized medicine for patients with IEI and other rare genetic diseases.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"112 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747836","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The state of the academic medical center in allergy/immunology: Work Group Report of the AAAAI A/I Division Directors Committee.","authors":"Carla M Davis,Cem Akin,Sami L Bahna,Karen S Hsu Blatman,Tara Carr,Christopher Chang,Hey J Chong,Christina E Ciaccio,Benjamin P Davis,Olajumoke Fadugba,Ramsay L Fuleihan,Mitchell H Grayson,Sudhir Gupta,Jonathan A Hemler,Rajesh Kumar,Mahboobeh Mahdavinia,Rachel L Miller,Michael R Nelson,Anna H Nowak-Wegrzyn,Pavadee Poowuttikul,Julia W Tripple,Brian P Vickery,Tao Zheng","doi":"10.1016/j.jaci.2025.05.013","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.05.013","url":null,"abstract":"The field of allergy and immunology (A/I) has transformed modern medicine with the development of diagnostic and therapeutic advances in all areas of health. This Work Group Report from the Division Directors Committee of the American Academy of Allergy, Asthma & Immunology describes the current state of 5 mission areas (clinical, educational, research, equity, and advocacy) within the A/I divisions/subdivisions of academic medical centers (AMCs) in the United States. The current states of the clinical and educational mission areas in AMCs in A/I are strong, with an increasing prevalence of atopic/immunologic disorders and novel therapeutics, solid trainee interest, and tremendous potential for research, equity, and advocacy efforts. The interest in the field of A/I has outpaced the creation of new positions, leading to an increase in unmatched applicants yearly. Weaknesses and threats include decreasing federal research and educational funding, changing health care insurance policies, the dynamic legislative environment, and the negative impact of the business focus in academic institutions. The future of A/I will depend on the preservation of a strong academic foundation with improved recruitment to academic positions, increased training positions, and greater incentives for development of career opportunities in research and education, utilizing artificial intelligence tools and strong advocacy strategies.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"1 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144747840","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Heterozygous loss of MAP4K1 causes immune dysregulation by amplifying T cell responses.","authors":"Kaustio Meri,Szymanska Monika,Li Weiwei,Braathen Ragnhild,Tessa M Campbell,Frida L Haugen,Dahal-Koirala Shiva,Silventoinen Kristiina,Nurmi Katariina,Dinius Matas,Nowlan Kirsten,Hetemäki Iivo,Chen Pu,Mamia Katariina,Seppänen Mikko,Grönholm Juha,Kekäläinen Eliisa,Emma M Haapaniemi,Aalto Kristiina,Martelius Timi,Bryceson Yenan,Kari K Eklund,Saarela Janna","doi":"10.1016/j.jaci.2025.07.010","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.010","url":null,"abstract":"BACKGROUNDMAP4K1 encodes Hematopoietic Progenitor Kinase 1 (HPK1), a serine/threonine kinase that negatively regulates T cell receptor (TCR) signaling via phosphorylation of the adaptor proteins SLP-76 and Gads. While common MAP4K1 variants have been implicated in polygenic immune-mediated diseases, the impact of rare germline variants on human immunity remains undefined.OBJECTIVETo investigate the immunological and functional consequences of HPK1 deficiency in individuals with suspected Inborn Errors of Immunity (IEI).METHODSWe performed genomic linkage analysis and exome sequencing to identify disease-associated variants in IEI patients. Immunophenotyping, RNA-sequencing and functional assays were conducted on patient-derived lymphocytes, complemented by CRISPR-Cas9-mediated MAP4K1 disruption and correction in primary T cells.RESULTSHeterozygous MAP4K1 loss-of-function variants were identified in two kindreds presenting with diverse immune dysregulatory symptoms, including recurrent fevers, inflammatory arthritis, EBV-related complications, and nephritis. These variants led to reduced HPK1 protein levels and SLP-76Ser376 phosphorylation. While lymphocyte development was largely preserved, T cells from HPK1-deficient individuals displayed hyperresponsiveness to TCR stimulation, characterized by elevated secretion of proinflammatory cytokines, particularly interferon-γ (IFN-γ) and tumor necrosis factor (TNF). CRISPR-mediated knockout recapitulated, and variant-correction partially reversed this phenotype. Transcriptomic profiling of stimulated CD4+ T cells further revealed upregulation of immune signaling pathways-including NF-κB, JAK/STAT, and AP-1-as well as increased expression of multiple T cell cytokines, consistent with enhanced TCR signaling and T cell responses in HPK1-deficient individuals.CONCLUSIONHPK1 deficiency, caused by heterozygous loss of MAP4K1, is a novel monogenic cause of immune dysregulation. Increased T cell activation and pro-inflammatory cytokine production are implicated in disease pathogenesis.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"11 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144719909","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Cockroach immunotherapy modulates dominant T cell responses independent of allergen extract content.","authors":"Ricardo da Silva Antunes, Aaron Sutherland, Adam Abawi, April Frazier, Anna Pomés, Jill Glesner, Jay E Slater, Samuel T Mindaye, Kate Cho, Grace Zhou, Marie V Ozanne, Agustin Calatroni, Cynthia M Visness, Matthew C Altman, Robert A Wood, George T O'Connor, Jacqueline A Pongracic, Gurjit K Khurana Hershey, Carolyn M Kercsmar, Rebecca S Gruchalla, Michelle Gill, Daniel Searing, Andrew H Liu, Edward Zoratti, Meyer Kattan, Paula J Busse, Will Sheehan, Leonard B Bacharier, Stephen J Teach, Lisa M Wheatley, Alkis Togias, William W Busse, Daniel J Jackson, Alessandro Sette","doi":"10.1016/j.jaci.2025.07.011","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.07.011","url":null,"abstract":"<p><strong>Background: </strong>T cell responses to the individual components of allergen extracts have not been fully elucidated in subcutaneous allergen immunotherapy (SCIT). Specifically, it is unknown whether T cell responses to immunodominant allergens are more or less sensitive to modulation, and whether allergen abundance in the immunotherapy extract influences T cell response modulation.</p><p><strong>Objective: </strong>To fill these gaps, we evaluated CD4+ T cell reactivity specific to each of the main cockroach (CR) allergens in the double-blinded, placebo controlled, multi-center CRITICAL SCIT trial.</p><p><strong>Methods: </strong>Participants (8-17 years) with mild to moderate, well controlled asthma, received 12-month dosing of CR SCIT (n=20) or placebo (n=26). Peripheral blood mononuclear cells (PBMC) were isolated prior to, and after 12 months of therapy. CD4+ T cell responses at baseline and after treatment were assessed using overlapping peptide pools derived from 11 well-defined CR allergens and intracellular cytokine staining for IL-4, IFNγ and IL-10 production. T cell responses were evaluated for magnitude, cytokine polarization, allergen immunodominance and correlation with allergen content in the CR SCIT extract.</p><p><strong>Results: </strong>SCIT modulation was more prominent in participants with the strongest and most Th2 polarized responses. Down-modulation was observed against Bla g 5 and Bla g 9, the most dominantly recognized allergens in the population study. Furthermore, effective modulation was observed independent of allergen content in the CR SCIT extract.</p><p><strong>Conclusion: </strong>Our results suggest that immunodominant responses are effectively modulated by SCIT, and this effect is independent of allergen abundance in the extract utilized for SCIT.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":" ","pages":""},"PeriodicalIF":11.4,"publicationDate":"2025-07-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144717870","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Genetic Risk for Adult Obstructive Lung Function and Its Early-Life Associations.","authors":"Casper-Emil T Pedersen,Anders Eliasen,Kasper Fischer-Rasmussen,Yang Luo,Frederikke Skov,Astrid Sevelsted,Jonathan Thorsen,Jens-Ulrik Stæhr Jensen,Jørgen Vestbo,Thomas Werge,Andreanne Morin,Carole Ober,Morten A Rasmussen,George Davey Smith,Jakob Stokholm,Bo Chawes,Klaus Bønnelykke","doi":"10.1016/j.jaci.2025.06.035","DOIUrl":"https://doi.org/10.1016/j.jaci.2025.06.035","url":null,"abstract":"BACKGROUNDChronic obstructive pulmonary disease (COPD) may partly originate in early life under influence from prenatal or early postnatal risk factors, including genetic predisposition.OBJECTIVEWe investigated to which extent the genetic predisposition to adult obstructive lung function manifests already at birth and throughout childhood in terms of impaired lung function, bronchial responsiveness and asthma-related symptoms.METHODSWe constructed a polygenic risk score (PRS) for adult obstructive lung function (FEV1/FVC) and associated it with neonatal and childhood lung function, bronchial responsiveness, asthma, and respiratory tract infections in the COPSAC birth cohorts, and with hospitalization for wheeze, asthma, and infections in 114,283 unrelated individuals from the IPSYCH cohort.RESULTSThe FEV1/FVC PRS was associated with obstructive lung function shortly after birth (e.g., neonatal FEV0.5/FVC (β: -0.20 [-0.31;-0.09], P < 0.0003)), with continued progression into adolescence. A higher PRS was also linked to an increased risk of severe wheeze/asthma episodes (OR 1.24 [1.19;1.29], P = 1.6∙10-26) and lower respiratory tract infections (OR 1.09 [1.06-1.12], P = 3.5∙10-8) requiring hospitalization, which was evident a few months after birth. In COPSAC2000, there was no evidence of asthma exacerbations mediating the association between FEV1/FVC PRS and lung function by age 18 years.CONCLUSIONGenetic predisposition to obstructive lung function was evident shortly after birth in terms of impaired neonatal lung function and increased susceptibility to severe wheeze, asthma, and lower respiratory tract infections. This indicates prenatal life and early childhood as a window of opportunity for improving lung health in adulthood.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"55 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2025-07-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144701341","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}