BACKGROUNDKaposi 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.OBJECTIVEWe report a patient with RIG-I deficiency and KS and define associated antiviral and host response defects.METHODSWhole-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.RESULTSA 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.CONCLUSIONThis 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.
{"title":"Human retinoic acid-inducible gene I deficiency is associated with susceptibility to classic Kaposi sarcoma.","authors":"Lucie Roussel,Stéphane Bernier,Mélanie Langelier,Yichun Sun,Benjamin Mak,Yongbiao Li,Anna Perez,Alexi Wloski,Isabelle Angers,Lily-Rose Vinh,Annie Beauchamp,Sarah Boissel,A Kevin Watters,Simon Rousseau,Jean-Pierre Routy,Virginie Calderon,Carolina Arias,Donald C Vinh","doi":"10.1016/j.jaci.2026.02.027","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.027","url":null,"abstract":"BACKGROUNDKaposi 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.OBJECTIVEWe report a patient with RIG-I deficiency and KS and define associated antiviral and host response defects.METHODSWhole-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.RESULTSA 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.CONCLUSIONThis 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.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"91 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147351036","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}
Pub Date : 2026-03-02DOI: 10.1016/j.jaci.2026.02.026
Hannah A DeBerg,Carolyn H Baloh,Quinn DeGottardi,Jue Hou,Alexandra Johansson,Evan Newell,Tanya M Laidlaw,Srinath Sanda,Mohamed Shamji,Stephen Durham,Alkis Togias,William W Kwok
BACKGROUNDAllergen-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.OBJECTIVEThe overall aim of this study was to characterize the heterogeneity of Timothy grass (Phleum pratense, Phl p) allergen-specific CD4+ T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous immunotherapy (SCIT). Correlations between frequencies of these cells with Total Nasal Symptom Score (TNSS) and grass-specific serum immunoglobulin were also investigated.METHODSMass cytometry with lanthanides-tagged pMHCII 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.RESULTSPhenotypes of Phl p-specific T cells were highly heterogenous but can be categorized into two major meta-clusters: CRTH2HiCD27Lo and CRTH2LoCD27Hi , each with distinct phenotypic profiles. Weak positive correlations between TNSS and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2HiCD27Lo cells whereas SLIT depleted CRTH2LoCD27Hi cells. CRTH2HiCD27Lo cell frequency correlated with Phl p-specific IgE and IgG4, but not IgA levels.CONCLUSIONUnsupervised 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 immunological pathways.
{"title":"Differential effects of subcutaneous and sublingual immunotherapy on Timothy grass-specific Th2 CD4+ T cell subsets.","authors":"Hannah A DeBerg,Carolyn H Baloh,Quinn DeGottardi,Jue Hou,Alexandra Johansson,Evan Newell,Tanya M Laidlaw,Srinath Sanda,Mohamed Shamji,Stephen Durham,Alkis Togias,William W Kwok","doi":"10.1016/j.jaci.2026.02.026","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.026","url":null,"abstract":"BACKGROUNDAllergen-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.OBJECTIVEThe overall aim of this study was to characterize the heterogeneity of Timothy grass (Phleum pratense, Phl p) allergen-specific CD4+ T cells and determine how the frequency and phenotype of these cells change in response to sublingual (SLIT) and subcutaneous immunotherapy (SCIT). Correlations between frequencies of these cells with Total Nasal Symptom Score (TNSS) and grass-specific serum immunoglobulin were also investigated.METHODSMass cytometry with lanthanides-tagged pMHCII 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.RESULTSPhenotypes of Phl p-specific T cells were highly heterogenous but can be categorized into two major meta-clusters: CRTH2HiCD27Lo and CRTH2LoCD27Hi , each with distinct phenotypic profiles. Weak positive correlations between TNSS and frequencies of T cells within both subsets were observed. SCIT preferentially depleted CRTH2HiCD27Lo cells whereas SLIT depleted CRTH2LoCD27Hi cells. CRTH2HiCD27Lo cell frequency correlated with Phl p-specific IgE and IgG4, but not IgA levels.CONCLUSIONUnsupervised 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 immunological pathways.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"15 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350741","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}
Pub Date : 2026-03-02DOI: 10.1016/j.jaci.2026.02.028
Jared J Brooksby,Takao Kobayashi,Koji Iijima,Min-Jhen Jheng,Mia Y Masuda,Jyoti K Lama,Hirohito Kita
BACKGROUNDGroup 2 innate lymphoid cells (ILC2s) and CD4+ TH2 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 TH2 cells provide adaptive antigen-specific immune memory. However, little is known regarding the interaction between the innate and adaptive arms of type 2 immunity.OBJECTIVEWe investigated the roles of ILC2s in establishing adaptive antigen-specific immunity in a mouse model of human asthma.METHODSILC2-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.RESULTSExposure 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 TH2-recruiting chemokines CCL17 and CCL22; these responses were significantly suppressed in ILC2-deficient mice. Consequently, ILC2-deficient mice failed to develop TH2-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.CONCLUSIONILC2s license lung DCs via granulocyte-macrophage colony-stimulating factor to prime and recruit TH2 cells, establishing antigen-specific T-cell immune memory in the lungs.
{"title":"Group 2 Innate Lymphoid Cells Program Pulmonary Adaptive Immunity via GM-CSF.","authors":"Jared J Brooksby,Takao Kobayashi,Koji Iijima,Min-Jhen Jheng,Mia Y Masuda,Jyoti K Lama,Hirohito Kita","doi":"10.1016/j.jaci.2026.02.028","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.028","url":null,"abstract":"BACKGROUNDGroup 2 innate lymphoid cells (ILC2s) and CD4+ TH2 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 TH2 cells provide adaptive antigen-specific immune memory. However, little is known regarding the interaction between the innate and adaptive arms of type 2 immunity.OBJECTIVEWe investigated the roles of ILC2s in establishing adaptive antigen-specific immunity in a mouse model of human asthma.METHODSILC2-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.RESULTSExposure 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 TH2-recruiting chemokines CCL17 and CCL22; these responses were significantly suppressed in ILC2-deficient mice. Consequently, ILC2-deficient mice failed to develop TH2-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.CONCLUSIONILC2s license lung DCs via granulocyte-macrophage colony-stimulating factor to prime and recruit TH2 cells, establishing antigen-specific T-cell immune memory in the lungs.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"15 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147350704","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}
Pub Date : 2026-03-01Epub Date: 2025-11-26DOI: 10.1016/j.jaci.2025.09.032
David Friedmann PhD , Kathryn J. Payne PhD , Victoria Cousin MSc , Geoffroy Andrieux PhD , Ke Meng MMed , Alexandra Emilia Schlaak MD , Susanne Unger PhD , Adam Klocperk MD, PhD , Christoph Geier MD , Katja Gräwe MTA , Jens Pfeiffer MD , Till F. Jakob MD , Oliver Hausmann MD , Peter Anhut MD , Michelle Shabani MD , Konrad Kurowski MD , Manuel Rogg MD , Konrad Aumann MD , Maximilian Seidl MD , Jan Provaznik MD , Klaus Warnatz MD
Background
Patients with common variable immunodeficiency (CVID) suffer from hypogammaglobulinemia linked to an inadequate differentiation of long-lived humoral immunity and an impaired germinal center (GC) response in most cases.
Objective
We sought to further characterize the transcriptome and phenotype of T follicular helper (TFH) cells of patients with complicated CVID (CVIDc) as key players in the GC reaction.
Methods
Sorted TFH cells from CVIDc lymph nodes and non-CVID immunocompetent tonsils were analyzed by bulk RNA sequencing. Altered protein expression was verified by comparison with non-CVID tonsils and lymph nodes using cytometry by time-of-flight analysis. Tissue localization of cells was determined by multifluorescence imaging.
Results
Transcriptome analysis of sorted TFH cells revealed an enrichment of cytotoxicity-associated gene sets in patients with CVIDc. Extended immune phenotyping identified different cytotoxic CD4 memory populations expressing T-bet, EOMES (eomesodermin), class I–restricted T-cell–associated molecule, perforin, and granzymes. One cluster coexpressing markers of TFH differentiation C-X-C chemokine receptor type 5, inducible costimulator, and programmed cell death protein 1 was expanded in CVIDc lymph nodes. Histologic sections confirmed the increase in Granzyme-B+EOMES+CD4 cells within GCs of patients’ lymph nodes. Only few of these cells circulate in peripheral blood.
Conclusions
Our study reports for the first time that the type 1 polarization in lymph nodes of patients with CVIDc is associated with an expansion of a distinct cytotoxic CD4 TFH-cell cluster within GCs, which is only poorly reflected in peripheral blood. Because a detrimental role of these cells has been implied in the context of autoimmunity and chronic infection, further investigations are required to explore their role in the GC failure and immune dysregulation in patients with CVID.
{"title":"Expansion of a distinct cytotoxic CD4 TFH-cell cluster in lymph nodes of patients with complicated common variable immunodeficiency","authors":"David Friedmann PhD , Kathryn J. Payne PhD , Victoria Cousin MSc , Geoffroy Andrieux PhD , Ke Meng MMed , Alexandra Emilia Schlaak MD , Susanne Unger PhD , Adam Klocperk MD, PhD , Christoph Geier MD , Katja Gräwe MTA , Jens Pfeiffer MD , Till F. Jakob MD , Oliver Hausmann MD , Peter Anhut MD , Michelle Shabani MD , Konrad Kurowski MD , Manuel Rogg MD , Konrad Aumann MD , Maximilian Seidl MD , Jan Provaznik MD , Klaus Warnatz MD","doi":"10.1016/j.jaci.2025.09.032","DOIUrl":"10.1016/j.jaci.2025.09.032","url":null,"abstract":"<div><h3>Background</h3><div>Patients with common variable immunodeficiency (CVID) suffer from hypogammaglobulinemia linked to an inadequate differentiation of long-lived humoral immunity and an impaired germinal center (GC) response in most cases.</div></div><div><h3>Objective</h3><div>We sought to further characterize the transcriptome and phenotype of T follicular helper (T<sub>FH</sub>) cells of patients with complicated CVID (CVIDc) as key players in the GC reaction.</div></div><div><h3>Methods</h3><div>Sorted T<sub>FH</sub> cells from CVIDc lymph nodes and non-CVID immunocompetent tonsils were analyzed by bulk RNA sequencing. Altered protein expression was verified by comparison with non-CVID tonsils and lymph nodes using cytometry by time-of-flight analysis. Tissue localization of cells was determined by multifluorescence imaging.</div></div><div><h3>Results</h3><div>Transcriptome analysis of sorted T<sub>FH</sub> cells revealed an enrichment of cytotoxicity-associated gene sets in patients with CVIDc. Extended immune phenotyping identified different cytotoxic CD4 memory populations expressing T-bet, EOMES (eomesodermin), class I–restricted T-cell–associated molecule, perforin, and granzymes. One cluster coexpressing markers of T<sub>FH</sub> differentiation C-X-C chemokine receptor type 5, inducible costimulator, and programmed cell death protein 1 was expanded in CVIDc lymph nodes. Histologic sections confirmed the increase in Granzyme-B<sup>+</sup>EOMES<sup>+</sup>CD4 cells within GCs of patients’ lymph nodes. Only few of these cells circulate in peripheral blood.</div></div><div><h3>Conclusions</h3><div>Our study reports for the first time that the type 1 polarization in lymph nodes of patients with CVIDc is associated with an expansion of a distinct cytotoxic CD4 T<sub>FH</sub>-cell cluster within GCs, which is only poorly reflected in peripheral blood. Because a detrimental role of these cells has been implied in the context of autoimmunity and chronic infection, further investigations are required to explore their role in the GC failure and immune dysregulation in patients with CVID.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 754-766"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145609480","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":"AGEP and GPP share immune mechanisms but have different clinical courses","authors":"Siew-Eng Choon FRCP , Hervé Bachelez MD , Chuang-Wei Wang PhD , Wen-Hung Chung MD, PhD","doi":"10.1016/j.jaci.2025.10.019","DOIUrl":"10.1016/j.jaci.2025.10.019","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Page 779"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145777267","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}
Pub Date : 2026-03-01Epub Date: 2025-12-29DOI: 10.1016/j.jaci.2025.11.012
Kelsey R. van Straalen MD, PhD , Johann E. Gudjonsson MD, PhD
{"title":"Hidradenitis suppurativa: Why dose escalation often fails and what biology tells us about next steps","authors":"Kelsey R. van Straalen MD, PhD , Johann E. Gudjonsson MD, PhD","doi":"10.1016/j.jaci.2025.11.012","DOIUrl":"10.1016/j.jaci.2025.11.012","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 776-778"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145856446","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}
Pub Date : 2026-03-01Epub Date: 2026-01-14DOI: 10.1016/j.jaci.2025.12.1010
Ishitha Jagadish MD , Divya Shah MD , Jennifer Priessnitz MD , Sergio E. Chiarella MD
Asthma, a chronic inflammatory airway disease affecting 25 million people in the United States, exhibits distinct sex differences in prevalence, phenotype, and treatment response. While asthma is more common in boys during childhood, adult women experience greater disease severity, likely due to hormonal and immunologic influences. Asthma biomarkers, including blood eosinophil count, fractional exhaled nitric oxide, IgE, and emerging markers, provide insight into disease phenotypes and therapeutic response. This review synthesizes current evidence on sex-specific differences in asthma biomarkers and mechanisms underlying these variations. Sex hormones play a role in immune modulation, with estrogen and progesterone promoting type 2 inflammation, and testosterone exerting suppressive effects. Boys demonstrate higher levels of blood eosinophil counts, fractional exhaled nitric oxide, total and allergen-specific IgE, and periostin, whereas postpubertal women exhibit increased IL-5, leptin, serum amyloid A, and urinary leukotriene E4, along with lower adiponectin levels. In contrast, postpubertal male subjects with asthma show higher ceramide concentrations. Additional biomarkers under investigation include microRNAs, neutrophils, tryptase, exhaled breath condensate analytes, and surfactant proteins. However, evidence supporting these research-based markers is often preclinical and/or lacks sex-stratified analyses, limiting clinical translation. Incorporating validated sex-specific biomarker patterns into asthma care may enhance phenotyping and support personalized management strategies.
{"title":"Sex-based hormonal influences on asthma biomarkers","authors":"Ishitha Jagadish MD , Divya Shah MD , Jennifer Priessnitz MD , Sergio E. Chiarella MD","doi":"10.1016/j.jaci.2025.12.1010","DOIUrl":"10.1016/j.jaci.2025.12.1010","url":null,"abstract":"<div><div>Asthma, a chronic inflammatory airway disease affecting 25 million people in the United States, exhibits distinct sex differences in prevalence, phenotype, and treatment response. While asthma is more common in boys during childhood, adult women experience greater disease severity, likely due to hormonal and immunologic influences. Asthma biomarkers, including blood eosinophil count, fractional exhaled nitric oxide, IgE, and emerging markers, provide insight into disease phenotypes and therapeutic response. This review synthesizes current evidence on sex-specific differences in asthma biomarkers and mechanisms underlying these variations. Sex hormones play a role in immune modulation, with estrogen and progesterone promoting type 2 inflammation, and testosterone exerting suppressive effects. Boys demonstrate higher levels of blood eosinophil counts, fractional exhaled nitric oxide, total and allergen-specific IgE, and periostin, whereas postpubertal women exhibit increased IL-5, leptin, serum amyloid A, and urinary leukotriene E<sub>4</sub>, along with lower adiponectin levels. In contrast, postpubertal male subjects with asthma show higher ceramide concentrations. Additional biomarkers under investigation include microRNAs, neutrophils, tryptase, exhaled breath condensate analytes, and surfactant proteins. However, evidence supporting these research-based markers is often preclinical and/or lacks sex-stratified analyses, limiting clinical translation. Incorporating validated sex-specific biomarker patterns into asthma care may enhance phenotyping and support personalized management strategies.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 558-574"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145986532","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}
Pub Date : 2026-03-01Epub Date: 2026-02-28DOI: 10.1016/S0091-6749(26)00041-2
{"title":"Brief Overview of This Month's JACI","authors":"","doi":"10.1016/S0091-6749(26)00041-2","DOIUrl":"10.1016/S0091-6749(26)00041-2","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Page A4"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147334786","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}
Pub Date : 2026-03-01Epub Date: 2025-11-14DOI: 10.1016/j.jaci.2025.10.033
Delfien J.A. Bogaert MD, PhD , Christina H. Wolfsberger MD , Andishe Attarbaschi MD , Jonathan Gathmann , Klaus Warnatz MD , Gabriele Mueller , Anna Mukhina MD , Stephan Rusch DiplInf
Background
Inborn errors of immunity (IEI), or primary immune disorders (PIDs), predispose individuals to infections, autoimmunity, inflammation, allergy, and malignancy. Malignancies are a major cause of morbidity and mortality in patients with IEI/PIDs, with poorer outcomes compared with the general population.
Objective
We sought to determine the frequency and types of malignancies in patients with IEI/PIDs and to assess clinical management approaches across Europe.
Methods
Descriptive analyses were performed on malignancy data within each IEI category. In addition, a European Society for Immunodeficiencies Registry survey (05/2022-03/2024) collected data on management strategies and challenges.
Results
Of 19,959 patients with IEI/PIDs, 1783 (8.9%) developed malignancies, of whom 27.1% presented malignancy as first manifestation of IEI/PIDs. A total of 1210 malignancies were specified; B-cell non-Hodgkin lymphoma was most common (24.2%). Detailed malignancy-IEI/PID association maps are provided. Predominantly antibody deficiencies accounted for 59.1% of malignancy cases, with a higher median age at first malignancy (43.6 years) compared with other IEI/PID categories, for example, combined immunodeficiencies with syndromic or associated features (11.7 years). Survey findings revealed that oncological treatment was modified because of IEI/PIDs in 21.5% of cases, with assumed negative impacts of IEI/PIDs on complications and outcomes (in 27.4% and 30.7%, respectively). IEI/PIDs influenced transplant decisions in 16.5% of cases. Management practices such as interdisciplinary decision finding and guideline availability were recorded.
Conclusions
This study provides comprehensive epidemiological data on malignancies in IEI/PIDs, highlighting the need for tailored screening and management. Survey results emphasize the real-world challenges and support the development of IEI/PID-specific oncological surveillance guidelines and treatment strategies.
{"title":"Epidemiology and management of malignancies in patients with inborn errors of immunity—An ESID registry study of 19,959 patients","authors":"Delfien J.A. Bogaert MD, PhD , Christina H. Wolfsberger MD , Andishe Attarbaschi MD , Jonathan Gathmann , Klaus Warnatz MD , Gabriele Mueller , Anna Mukhina MD , Stephan Rusch DiplInf","doi":"10.1016/j.jaci.2025.10.033","DOIUrl":"10.1016/j.jaci.2025.10.033","url":null,"abstract":"<div><h3>Background</h3><div>Inborn errors of immunity (IEI), or primary immune disorders (PIDs), predispose individuals to infections, autoimmunity, inflammation, allergy, and malignancy. Malignancies are a major cause of morbidity and mortality in patients with IEI/PIDs, with poorer outcomes compared with the general population.</div></div><div><h3>Objective</h3><div>We sought to determine the frequency and types of malignancies in patients with IEI/PIDs and to assess clinical management approaches across Europe.</div></div><div><h3>Methods</h3><div>Descriptive analyses were performed on malignancy data within each IEI category. In addition, a European Society for Immunodeficiencies Registry survey (05/2022-03/2024) collected data on management strategies and challenges.</div></div><div><h3>Results</h3><div>Of 19,959 patients with IEI/PIDs, 1783 (8.9%) developed malignancies, of whom 27.1% presented malignancy as first manifestation of IEI/PIDs. A total of 1210 malignancies were specified; B-cell non-Hodgkin lymphoma was most common (24.2%). Detailed malignancy-IEI/PID association maps are provided. Predominantly antibody deficiencies accounted for 59.1% of malignancy cases, with a higher median age at first malignancy (43.6 years) compared with other IEI/PID categories, for example, combined immunodeficiencies with syndromic or associated features (11.7 years). Survey findings revealed that oncological treatment was modified because of IEI/PIDs in 21.5% of cases, with assumed negative impacts of IEI/PIDs on complications and outcomes (in 27.4% and 30.7%, respectively). IEI/PIDs influenced transplant decisions in 16.5% of cases. Management practices such as interdisciplinary decision finding and guideline availability were recorded.</div></div><div><h3>Conclusions</h3><div>This study provides comprehensive epidemiological data on malignancies in IEI/PIDs, highlighting the need for tailored screening and management. Survey results emphasize the real-world challenges and support the development of IEI/PID-specific oncological surveillance guidelines and treatment strategies.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"157 3","pages":"Pages 739-753"},"PeriodicalIF":11.2,"publicationDate":"2026-03-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145534636","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}
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