BACKGROUNDMonoallelic RELA variants resulting in haploinsufficiency (HI) have been linked to recurrent mucocutaneous ulcers and enteritis. Heterozygous RELA dominant-negative (DN) variants often exhibit autoinflammatory phenotypes associated with type I interferonopathy beyond those typically associated with RELA-HI variants. The vast majority of documented cases of autosomal dominant (AD) RelA deficiency are caused by non-missense deleterious variants introducing a premature stop codon.OBJECTIVEWe sought to characterize the clinical manifestations and pathologic significance of RELA variants and to establish the boundary separating RELA-HI and RELA-DN variants to facilitate position-based estimation of the nature of RELA variants.METHODSRELA variants were characterized via a nuclear factor-κB reporter assay, immunoblotting, immunoprecipitation, and electrophoretic mobility shift assay in RELA and NFKB1 double knockout cells.RESULTSEight patients from 5 families with AD RelA deficiency were identified, and all harbored novel RELA variants. A comprehensive functional study using RELA nonsense variants identified amino acid P290 as the boundary between RELA-HI and RELA-DN variants in non-missense deleterious variants. In patients with RELA-DN variants, corticosteroid preparations were relatively ineffective, leading to increased use of biological drugs, mainly anti-TNF agents. We also identified atypical additional variants, including a missense variant and an in-frame variant, and experimentally confirmed their pathogenicity.CONCLUSIONSThe positions of non-missense deleterious variants in RELA allow the estimation of the associated functional changes, facilitating the precise diagnosis of AD RelA deficiency. Conversely, RELA missense variants require functional verification, as their impact cannot be predicted solely from their position.
{"title":"Discovering patterns in the pathologic significance of non-missense deleterious variants in RELA.","authors":"Hiroko Hayakawa,Miyuki Tsumura,Takanori Utsumi,Hiroshi Nihira,Wei-Te Lei,Ryo Ogino,Giorgia Bucciol,Tomohiro Nakano,Kiyoko Amo,Kunihiko Moriya,Seiichi Hayakawa,Yoko Mizoguchi,Shuhei Karakawa,You-Ning Lin,Han-Po Shih,Chia-Chi Lo,Sunita Janssenswillen,Sien Van Loo,Djalila Mekahli,Dusan Bogunovic,Stephanie Boisson-Dupuis,Kazushi Izawa,Cheng-Lung Ku,Takahiro Yasumi,Takaki Asano,Isabelle Meyts,Satoshi Okada","doi":"10.1016/j.jaci.2026.01.020","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.01.020","url":null,"abstract":"BACKGROUNDMonoallelic RELA variants resulting in haploinsufficiency (HI) have been linked to recurrent mucocutaneous ulcers and enteritis. Heterozygous RELA dominant-negative (DN) variants often exhibit autoinflammatory phenotypes associated with type I interferonopathy beyond those typically associated with RELA-HI variants. The vast majority of documented cases of autosomal dominant (AD) RelA deficiency are caused by non-missense deleterious variants introducing a premature stop codon.OBJECTIVEWe sought to characterize the clinical manifestations and pathologic significance of RELA variants and to establish the boundary separating RELA-HI and RELA-DN variants to facilitate position-based estimation of the nature of RELA variants.METHODSRELA variants were characterized via a nuclear factor-κB reporter assay, immunoblotting, immunoprecipitation, and electrophoretic mobility shift assay in RELA and NFKB1 double knockout cells.RESULTSEight patients from 5 families with AD RelA deficiency were identified, and all harbored novel RELA variants. A comprehensive functional study using RELA nonsense variants identified amino acid P290 as the boundary between RELA-HI and RELA-DN variants in non-missense deleterious variants. In patients with RELA-DN variants, corticosteroid preparations were relatively ineffective, leading to increased use of biological drugs, mainly anti-TNF agents. We also identified atypical additional variants, including a missense variant and an in-frame variant, and experimentally confirmed their pathogenicity.CONCLUSIONSThe positions of non-missense deleterious variants in RELA allow the estimation of the associated functional changes, facilitating the precise diagnosis of AD RelA deficiency. Conversely, RELA missense variants require functional verification, as their impact cannot be predicted solely from their position.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"56 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439525","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 : 2026-03-11DOI: 10.1016/j.jaci.2026.02.043
Anna Winberg,Kotryna Simonyté Sjödin,Magnus Öhlund,Christina E West
BACKGROUNDGut microbial composition has been proposed to influence disease onset in children with food protein induced enterocolitis syndrome (FPIES).OBJECTIVETo investigate differences in gut microbiota profiles in children with newly diagnosed FPIES and healthy controls.METHODSFecal samples were collected at FPIES diagnosis from 56 children stratified into three age groups: young infants at mean (SD) age 4.6 (0.5) months, infants at 6.5 (0.6) months and young children, at 11.7 (7.8) months. Gut microbiota profiles were analyzed using 16S rRNA gene amplicon sequencing and compared between children with FPIES and 43 age matched controls.RESULTSAge was the strongest determinant of gut microbiota composition, followed by FPIES status. ß-diversity differed significantly between children with FPIES and controls (p<0.01), primarily driven by shifts in Bacteroidota, Proteobacteria, Actinobacteriota, and Verrucomicrobiota. Children with FPIES had lower Bifidobacterium and higher abundances of Bacteroides, Haemophilus, and Veillonella. FPIES food triggers were associated with reduced Verrucomicrobiota abundance.CONCLUSIONChildren with FPIES exhibit gut microbial dysbiosis characterized by reduced Bifidobacterium and Verrucomicrobiota abundance, suggesting potential links between early-life microbiota development and disease pathogenesis.
{"title":"LOSS OF SYMBIOTIC GUT BACTERIA IN CHILDREN AT DIAGNOSIS OF FOOD PROTEIN INDUCED ENTEROCOLITIS SYNDROME.","authors":"Anna Winberg,Kotryna Simonyté Sjödin,Magnus Öhlund,Christina E West","doi":"10.1016/j.jaci.2026.02.043","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.043","url":null,"abstract":"BACKGROUNDGut microbial composition has been proposed to influence disease onset in children with food protein induced enterocolitis syndrome (FPIES).OBJECTIVETo investigate differences in gut microbiota profiles in children with newly diagnosed FPIES and healthy controls.METHODSFecal samples were collected at FPIES diagnosis from 56 children stratified into three age groups: young infants at mean (SD) age 4.6 (0.5) months, infants at 6.5 (0.6) months and young children, at 11.7 (7.8) months. Gut microbiota profiles were analyzed using 16S rRNA gene amplicon sequencing and compared between children with FPIES and 43 age matched controls.RESULTSAge was the strongest determinant of gut microbiota composition, followed by FPIES status. ß-diversity differed significantly between children with FPIES and controls (p<0.01), primarily driven by shifts in Bacteroidota, Proteobacteria, Actinobacteriota, and Verrucomicrobiota. Children with FPIES had lower Bifidobacterium and higher abundances of Bacteroides, Haemophilus, and Veillonella. FPIES food triggers were associated with reduced Verrucomicrobiota abundance.CONCLUSIONChildren with FPIES exhibit gut microbial dysbiosis characterized by reduced Bifidobacterium and Verrucomicrobiota abundance, suggesting potential links between early-life microbiota development and disease pathogenesis.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"57 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447008","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 : 2026-03-11DOI: 10.1016/j.jaci.2026.03.002
Anat Yaskolka Meir,Yijun Li,Zhaozhong Zhu,Janice A Espinola,Xiumei Hong,Carlos A Camargo,Xiaobin Wang,Kohei Hasegawa,Liming Liang
BACKGROUNDEarly life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high immunoglobulin E (IgE) beyond what is captured by observed IgE levels.OBJECTIVETo establish and examine the residual effect of an epigenetic-total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population.METHODSWe used data from the 35th Multicenter Airway Research Collaboration (MARC-35; n=560), 43rd Multicenter Airway Research Collaboration (MARC-43; n=177), and the Boston Birth Cohort (BBC; n=80). DNA methylation (Illumina EPIC array) was measured in blood during infancy (MARC-35, MARC-43) and in cord blood at birth (BBC). Total IgE was assessed in blood at infancy, recurrent wheezing at age 3 years, and asthma at age 6 years for all cohorts.RESULTSMARC-35 data were used to train and evaluate a DNAm-IgE score (R=0.502 vs. total IgE). MARC-43 and BBC data were used to validate the score (R=0.309 and R=0.132). In meta-analyses of the three cohorts, 1-SD of DNAm-IgE score residuals (DNAm-IgE score regressed on total IgE) was associated with recurrent wheezing (OR=1.33 [1.11,1.60], Pheterogeneity=0.92), while 1-SD total IgE was associated with asthma (OR=1.45 [1.19,1.76], Pheterogeneity=0.29; All models adjusted for sex, race/ethnicity, and birth weight).CONCLUSIONEarly-life epigenetic patterns related to total IgE may contribute to subsequent respiratory morbidity beyond measured IgE levels. The DNAm-IgE score and its residual component should be viewed as exploratory tools that require further validation and mechanistic study.
{"title":"Infancy IgE Methylation Score and Childhood Wheezing and Asthma; a Multi-Cohort Study.","authors":"Anat Yaskolka Meir,Yijun Li,Zhaozhong Zhu,Janice A Espinola,Xiumei Hong,Carlos A Camargo,Xiaobin Wang,Kohei Hasegawa,Liming Liang","doi":"10.1016/j.jaci.2026.03.002","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.03.002","url":null,"abstract":"BACKGROUNDEarly life epigenetic programming may mediate gene-environment interactions underlying recurrent wheezing and asthma. Multi-CpG methylation scores can summarize the epigenetic potential for high immunoglobulin E (IgE) beyond what is captured by observed IgE levels.OBJECTIVETo establish and examine the residual effect of an epigenetic-total IgE (DNAm-IgE) score on respiratory morbidity in a pediatric population.METHODSWe used data from the 35th Multicenter Airway Research Collaboration (MARC-35; n=560), 43rd Multicenter Airway Research Collaboration (MARC-43; n=177), and the Boston Birth Cohort (BBC; n=80). DNA methylation (Illumina EPIC array) was measured in blood during infancy (MARC-35, MARC-43) and in cord blood at birth (BBC). Total IgE was assessed in blood at infancy, recurrent wheezing at age 3 years, and asthma at age 6 years for all cohorts.RESULTSMARC-35 data were used to train and evaluate a DNAm-IgE score (R=0.502 vs. total IgE). MARC-43 and BBC data were used to validate the score (R=0.309 and R=0.132). In meta-analyses of the three cohorts, 1-SD of DNAm-IgE score residuals (DNAm-IgE score regressed on total IgE) was associated with recurrent wheezing (OR=1.33 [1.11,1.60], Pheterogeneity=0.92), while 1-SD total IgE was associated with asthma (OR=1.45 [1.19,1.76], Pheterogeneity=0.29; All models adjusted for sex, race/ethnicity, and birth weight).CONCLUSIONEarly-life epigenetic patterns related to total IgE may contribute to subsequent respiratory morbidity beyond measured IgE levels. The DNAm-IgE score and its residual component should be viewed as exploratory tools that require further validation and mechanistic study.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"16 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447010","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 : 2026-03-11DOI: 10.1016/j.jaci.2026.03.003
Yitao Gong,Ionut Atanasoai,Premkumar Siddhuraj,Anna-Karin Johnsson,Yueling Peng,Mamdoh Al-Ameri,Erik Sachs,Kasra Vali,Mikael Adner,Jesper Säfholm,Jonas S Erjefält,Gunnar P Nilsson,Elin Rönnberg
BACKGROUNDExpression of CD25, the IL-2 receptor alpha-chain, on human mast cells is primarily associated with aberrant mast cells in clonal mast cell disorders. However, the regulation of CD25 expression in normal, mature tissue-resident mast cells remains poorly understood.OBJECTIVEIL-33 is a key modulator of immune responses, including in lung inflammatory conditions. As mast cells are prominent IL-33 receptor expressing cells, we investigated the effect of IL-33 on CD25 expression in purified human lung mast cells.METHODSPurified human lung mast cells were stimulated with IL-33 and the transcriptional responses were measured by RNA sequencing. The expression of the IL-2 receptor subunits CD25 (IL2RA), CD122 (IL2RB), and CD132 (IL2RG) was quantified by RT-qPCR and flow cytometry. IL2RA expression was further examined in publicly available single-cell RNA-seq datasets, and in situ CD25 protein expression on human lung mast cells was assessed in human lung tissue using immunofluorescence staining.RESULTSIL-33 robustly induced the expression of CD25 and CD132 in HLMCs, without a corresponding upregulation of CD122, resulting in absent IL-2-mediated signaling despite enhanced IL-2 binding via CD25. Single-cell RNA sequencing data identified IL2RA+ mast cells as a distinct subpopulation with enriched IL-33 response signatures and upregulation of genes linked to immune signaling and inflammatory pathways. CD25+ HLMCs were also detected in situ, displaying substantial heterogeneity in expression levels and spatial distribution.CONCLUSIONSCD25 expression in HLMCs is upregulated by IL-33 and dynamically regulated in human lung tissues.
{"title":"Expression of CD25 in Human Lung Mast Cells and its Regulation by IL-33.","authors":"Yitao Gong,Ionut Atanasoai,Premkumar Siddhuraj,Anna-Karin Johnsson,Yueling Peng,Mamdoh Al-Ameri,Erik Sachs,Kasra Vali,Mikael Adner,Jesper Säfholm,Jonas S Erjefält,Gunnar P Nilsson,Elin Rönnberg","doi":"10.1016/j.jaci.2026.03.003","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.03.003","url":null,"abstract":"BACKGROUNDExpression of CD25, the IL-2 receptor alpha-chain, on human mast cells is primarily associated with aberrant mast cells in clonal mast cell disorders. However, the regulation of CD25 expression in normal, mature tissue-resident mast cells remains poorly understood.OBJECTIVEIL-33 is a key modulator of immune responses, including in lung inflammatory conditions. As mast cells are prominent IL-33 receptor expressing cells, we investigated the effect of IL-33 on CD25 expression in purified human lung mast cells.METHODSPurified human lung mast cells were stimulated with IL-33 and the transcriptional responses were measured by RNA sequencing. The expression of the IL-2 receptor subunits CD25 (IL2RA), CD122 (IL2RB), and CD132 (IL2RG) was quantified by RT-qPCR and flow cytometry. IL2RA expression was further examined in publicly available single-cell RNA-seq datasets, and in situ CD25 protein expression on human lung mast cells was assessed in human lung tissue using immunofluorescence staining.RESULTSIL-33 robustly induced the expression of CD25 and CD132 in HLMCs, without a corresponding upregulation of CD122, resulting in absent IL-2-mediated signaling despite enhanced IL-2 binding via CD25. Single-cell RNA sequencing data identified IL2RA+ mast cells as a distinct subpopulation with enriched IL-33 response signatures and upregulation of genes linked to immune signaling and inflammatory pathways. CD25+ HLMCs were also detected in situ, displaying substantial heterogeneity in expression levels and spatial distribution.CONCLUSIONSCD25 expression in HLMCs is upregulated by IL-33 and dynamically regulated in human lung tissues.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"19 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147447007","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 : 2026-03-10DOI: 10.1016/j.jaci.2026.02.041
Sabiha Khan,Thomas M Herndon,Anjeni Keswani,Katherine Clarridge,Dipak S Pisal,Ping Ji,Jessica Kim,Martin Klein,Stacy Chin,Chandrahas Sahajwalla,Kelly D Stone
On March 7, 2025, the FDA approved the first biosimilar to omalizumab (omalizumab-igec, OMLYCLO; Celltrion, Inc.). This is the first biosimilar approved for a biologic with an indication for the treatment of allergic diseases and/or asthma. Recent FDA announcements focus on accelerating biosimilar development and lowering costs by streamlining the approval process. On October 29, 2025, the FDA issued draft guidance proposing to no longer routinely require comparative clinical efficacy studies for biosimilarity, supporting the goal of reducing development time and cost. This review discusses FDA regulation of biologics and biosimilars, the recent approval of the first omalizumab biosimilar, and the evolving regulatory landscape for biosimilars to decrease the costs of development while ensuring the efficacy and safety of biosimilars. The approval of biosimilars for allergic diseases and asthma treatment is expected to significantly improve accessibility and affordability of these therapies, providing healthcare providers and patients with confidence in high-quality, cost-effective treatment options for patients with severe and refractory asthma and allergic conditions.
{"title":"Food and Drug Administration Regulation of Biosimilar Products- Improving Affordability of Biologics for Patients with Asthma and Allergic Diseases.","authors":"Sabiha Khan,Thomas M Herndon,Anjeni Keswani,Katherine Clarridge,Dipak S Pisal,Ping Ji,Jessica Kim,Martin Klein,Stacy Chin,Chandrahas Sahajwalla,Kelly D Stone","doi":"10.1016/j.jaci.2026.02.041","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.041","url":null,"abstract":"On March 7, 2025, the FDA approved the first biosimilar to omalizumab (omalizumab-igec, OMLYCLO; Celltrion, Inc.). This is the first biosimilar approved for a biologic with an indication for the treatment of allergic diseases and/or asthma. Recent FDA announcements focus on accelerating biosimilar development and lowering costs by streamlining the approval process. On October 29, 2025, the FDA issued draft guidance proposing to no longer routinely require comparative clinical efficacy studies for biosimilarity, supporting the goal of reducing development time and cost. This review discusses FDA regulation of biologics and biosimilars, the recent approval of the first omalizumab biosimilar, and the evolving regulatory landscape for biosimilars to decrease the costs of development while ensuring the efficacy and safety of biosimilars. The approval of biosimilars for allergic diseases and asthma treatment is expected to significantly improve accessibility and affordability of these therapies, providing healthcare providers and patients with confidence in high-quality, cost-effective treatment options for patients with severe and refractory asthma and allergic conditions.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"18 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439232","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 : 2026-03-10DOI: 10.1016/j.jaci.2026.02.042
Immaculeta Osuji,Nives Zimmermann
{"title":"IRF1 is a master regulator of type 1 eosinophils.","authors":"Immaculeta Osuji,Nives Zimmermann","doi":"10.1016/j.jaci.2026.02.042","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.042","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"11 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147439558","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 : 2026-03-09DOI: 10.1016/j.jaci.2026.02.037
Niels S van Heusden,Isa Cuijpers,Nils Meijer,Daan Pieren,Angela Markovska,Cem Gabay,Charlotte Girard,Isabelle Koné-Paut,Bas Vastert,Dörte Hamann,Judith Jans,Erika Van Nieuwenhove,Joost Frenkel,Marianne Boes
BACKGROUNDMevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK-gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to lowering of the threshold for pyrin inflammasome activation.OBJECTIVETo establish a cellular model of MKD and discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and interferon-gamma (IFNγ) signaling.METHODSUsing CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harbouring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses following stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived PBMCs were performed to validate in vitro findings.RESULTSMVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD PBMCs hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and NK cells were characterized by enhanced IL-18-driven IFNγ production. Elevated IFNγ and IL-18BP levels in MKD plasma, and transcriptomic data of MKD PBMCs, further confirmed the presence of an IFNγ signature in MKD.CONCLUSIONOur findings identify a pyrin-inflammasome driven IL-18/IFNγ axis as a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.
{"title":"Pyrin Inflammasome Activation Triggers an IL-18-Driven IFNγ Response in Mevalonate Kinase Deficiency.","authors":"Niels S van Heusden,Isa Cuijpers,Nils Meijer,Daan Pieren,Angela Markovska,Cem Gabay,Charlotte Girard,Isabelle Koné-Paut,Bas Vastert,Dörte Hamann,Judith Jans,Erika Van Nieuwenhove,Joost Frenkel,Marianne Boes","doi":"10.1016/j.jaci.2026.02.037","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.037","url":null,"abstract":"BACKGROUNDMevalonate kinase deficiency (MKD) is a rare monogenic autoinflammatory disorder characterized by recurrent fever episodes driven by dysregulated IL-1β secretion. Mutations in the MVK-gene cause enzymatic defects resulting in a shortage of geranylgeranyl pyrophosphate, leading to lowering of the threshold for pyrin inflammasome activation.OBJECTIVETo establish a cellular model of MKD and discover novel inflammatory pathways contributing to disease pathogenesis, with a focus on IL-18 and interferon-gamma (IFNγ) signaling.METHODSUsing CRISPR/Cas9 gene editing, we generated a THP1 monocyte cell line harbouring homozygous MVK I268T mutations, a pathogenic variant observed in patients with MKD. Functional assays were conducted to assess inflammasome activation and cytokine responses following stimulation with the pyrin agonist etiocholanolone. Experiments using MKD patient-derived PBMCs were performed to validate in vitro findings.RESULTSMVKI268T/I268T THP1 cells exhibited impaired isoprenoid biosynthesis, consistent with the metabolic defect observed in MKD. Activation of the pyrin inflammasome in MVKI268T/I268T THP1 cells induced robust secretion of IL-1β and IL-18, which was attenuated by supplementation with geranylgeranyl pyrophosphate. MKD PBMCs hypersecreted IL-18 in response to pyrin inflammasome activation, reflected by elevated IL-18 levels in plasma of MKD patients. Specifically, MKD T and NK cells were characterized by enhanced IL-18-driven IFNγ production. Elevated IFNγ and IL-18BP levels in MKD plasma, and transcriptomic data of MKD PBMCs, further confirmed the presence of an IFNγ signature in MKD.CONCLUSIONOur findings identify a pyrin-inflammasome driven IL-18/IFNγ axis as a key signaling module of MKD-associated inflammation. This pathway may represent a novel target for therapeutic intervention in MKD.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"33 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393743","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 : 2026-03-09DOI: 10.1016/j.jaci.2026.02.036
M J Valle-Pastor,I Cayuela,J S Yebra,L Senach-Rasilla,G Pastor-Fernández,A Oliva,J Traba,M N Navarro
BACKGROUNDIL-23-driven IL-17 production by γδ17 and Th17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. However, the intracellular mechanisms linking IL-23 signalling to effector cytokine production remain incompletely defined, limiting the development of therapeutics targeting pathways downstream of IL-23.OBJECTIVESTo elucidate signalling mechanisms connecting IL-23 stimulation to IL-17 production and to identify pharmacologic inhibitors of type 3 immune responses.METHODSWe developed an in vitro model using a γδ17 T-cell line to study IL-23 responses and performed a drug-repurposing screen of FDA-approved compounds. Hits were validated in primary cells. The in vivo efficacy of candidate inhibitors was evaluated in the Imiquimod-induced model of skin inflammation using intraperitoneal, oral and topical administration. Mechanistic studies assessed IL-23-dependent activation of mTORC1 and mTORC2 and the role of Src family kinases.RESULTSSrc/Abl kinase inhibitor Dasatinib was identified as potent suppressor of IL-23-induced IL-17A production. In vivo, Dasatinib treatment reduced epidermal thickening, immune cell infiltration, and the accumulation of IL-17-producing T cells in inflamed skin. Dasatinib inhibited IL-23-dependent activation of mTORC1 and mTORC2. Loss-of-function experiments revealed the Src kinase Blk as a critical mediator of IL-23-induced mTORC1 activation and IL-17A production in γδ17 T cells.CONCLUSIONSThese findings define a novel IL-23-Src-mTOR signalling axis in type 3 immunity and identify Src kinase networks as promising therapeutic targets in IL-23/IL-17-driven inflammation.
{"title":"\"Drug screening identifies the Src/Abl inhibitor Dasatinib as suppressor of IL-23 signalling in skin inflammation\".","authors":"M J Valle-Pastor,I Cayuela,J S Yebra,L Senach-Rasilla,G Pastor-Fernández,A Oliva,J Traba,M N Navarro","doi":"10.1016/j.jaci.2026.02.036","DOIUrl":"https://doi.org/10.1016/j.jaci.2026.02.036","url":null,"abstract":"BACKGROUNDIL-23-driven IL-17 production by γδ17 and Th17 cells is central to the pathogenesis of psoriasis and other autoimmune disorders. However, the intracellular mechanisms linking IL-23 signalling to effector cytokine production remain incompletely defined, limiting the development of therapeutics targeting pathways downstream of IL-23.OBJECTIVESTo elucidate signalling mechanisms connecting IL-23 stimulation to IL-17 production and to identify pharmacologic inhibitors of type 3 immune responses.METHODSWe developed an in vitro model using a γδ17 T-cell line to study IL-23 responses and performed a drug-repurposing screen of FDA-approved compounds. Hits were validated in primary cells. The in vivo efficacy of candidate inhibitors was evaluated in the Imiquimod-induced model of skin inflammation using intraperitoneal, oral and topical administration. Mechanistic studies assessed IL-23-dependent activation of mTORC1 and mTORC2 and the role of Src family kinases.RESULTSSrc/Abl kinase inhibitor Dasatinib was identified as potent suppressor of IL-23-induced IL-17A production. In vivo, Dasatinib treatment reduced epidermal thickening, immune cell infiltration, and the accumulation of IL-17-producing T cells in inflamed skin. Dasatinib inhibited IL-23-dependent activation of mTORC1 and mTORC2. Loss-of-function experiments revealed the Src kinase Blk as a critical mediator of IL-23-induced mTORC1 activation and IL-17A production in γδ17 T cells.CONCLUSIONSThese findings define a novel IL-23-Src-mTOR signalling axis in type 3 immunity and identify Src kinase networks as promising therapeutic targets in IL-23/IL-17-driven inflammation.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"1 1","pages":""},"PeriodicalIF":14.2,"publicationDate":"2026-03-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147393744","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 : 2026-03-05DOI: 10.1016/j.jaci.2026.02.033
Daniel H. Lofgren, Christina Dorismond, Rory J. Lubner, Katherine N. Cahill, Justin H. Turner, Rakesh K. Chandra, Mason R. Krysinski, Ping Li, Naweed I. Chowdhury
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