Pub Date : 2024-10-16DOI: 10.1016/j.jaci.2024.10.002
Katla Kristjansdottir,Guðmundur L Norddahl,Erna V Ivarsdottir,Gisli H Halldorsson,Gudmundur Einarsson,Kristbjörg Bjarnadóttir,Gudrun Rutsdottir,Asgeir O Arnthorsson,Christian Erikstrup,Steinunn Gudmundsdottir,Kristbjorg Gunnarsdottir,María I Gunnbjornsdottir,Bjarni V Halldorsson,Hilma Holm,Dora Ludviksdottir,Bjorn R Ludviksson,Søren Brunak,Mie Topholm Bruun,Christina Mikkelsen,Susan Mikkelsen,Bitten Aagaard Jensen,Erik Sørensen,Simon Francis Thomsen,Henrik Ullum,Isleifur Olafsson,Pall T Onundarson,Sisse Rye Ostrowski,Saedis Saevarsdottir,Olof Sigurdardottir,Bardur Sigurgeirsson,Audunn S Snaebjarnarson,Gardar Sveinbjornsson,Gudny E Thorlacius,Gudmar Thorleifsson,Vinicius Tragante,Brynjar Vidarsson,Celeste Porsbjerg,Unnur S Bjornsdottir,Patrick Sulem,Daniel F Gudbjartsson,Pall Melsted,Ole Bv Pedersen,Ingileif Jonsdóttir,Thorunn A Olafsdottir,Kari Stefansson
BACKGROUNDSignal Transducer and Activator of Transcription 6 (STAT6) is central to Type 2 (T2) inflammation and common non-coding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment.OBJECTIVETo test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture.METHODSWe tested association of p.L406P with plasma protein levels, white blood cell counts and the risk of asthma and allergic phenotypes. We tested significant associations in other cohorts using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4+ T-cell responses from carriers and non-carriers of the variant.RESULTSp.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2 high asthma. We showed that p.L406P led to lower IL-4-induced activation in luciferase reporter assays and lower levels of STAT6 in CD4+ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype upon IL-4 treatment of CD4+ T cells; the effect was consistent with a weaker IL-4 response in carriers than non-carriers of p.L406P.CONCLUSIONSWe report a partial loss-of-function variant in STAT6, resulting in dampened IL-4 responses and protection from T2 high asthma, implicating STAT6 as an attractive therapeutic target.
{"title":"A partial loss-of-function variant in STAT6 protects against T2 asthma.","authors":"Katla Kristjansdottir,Guðmundur L Norddahl,Erna V Ivarsdottir,Gisli H Halldorsson,Gudmundur Einarsson,Kristbjörg Bjarnadóttir,Gudrun Rutsdottir,Asgeir O Arnthorsson,Christian Erikstrup,Steinunn Gudmundsdottir,Kristbjorg Gunnarsdottir,María I Gunnbjornsdottir,Bjarni V Halldorsson,Hilma Holm,Dora Ludviksdottir,Bjorn R Ludviksson,Søren Brunak,Mie Topholm Bruun,Christina Mikkelsen,Susan Mikkelsen,Bitten Aagaard Jensen,Erik Sørensen,Simon Francis Thomsen,Henrik Ullum,Isleifur Olafsson,Pall T Onundarson,Sisse Rye Ostrowski,Saedis Saevarsdottir,Olof Sigurdardottir,Bardur Sigurgeirsson,Audunn S Snaebjarnarson,Gardar Sveinbjornsson,Gudny E Thorlacius,Gudmar Thorleifsson,Vinicius Tragante,Brynjar Vidarsson,Celeste Porsbjerg,Unnur S Bjornsdottir,Patrick Sulem,Daniel F Gudbjartsson,Pall Melsted,Ole Bv Pedersen,Ingileif Jonsdóttir,Thorunn A Olafsdottir,Kari Stefansson","doi":"10.1016/j.jaci.2024.10.002","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.002","url":null,"abstract":"BACKGROUNDSignal Transducer and Activator of Transcription 6 (STAT6) is central to Type 2 (T2) inflammation and common non-coding variants at the STAT6 locus associate with various T2 inflammatory traits, including diseases, and its pathway is widely targeted in asthma treatment.OBJECTIVETo test the association of a rare missense variant in STAT6, p.L406P, with T2 inflammatory traits, including the risk of asthma and allergic diseases, and to characterize its functional consequences in cell culture.METHODSWe tested association of p.L406P with plasma protein levels, white blood cell counts and the risk of asthma and allergic phenotypes. We tested significant associations in other cohorts using a burden test. The effects of p.L406P on STAT6 protein function were examined in cell lines and by comparing CD4+ T-cell responses from carriers and non-carriers of the variant.RESULTSp.L406P associated with reduced plasma levels of STAT6 and IgE as well as with lower eosinophil and basophil counts in blood. It also protected against asthma, mostly driven by severe T2 high asthma. We showed that p.L406P led to lower IL-4-induced activation in luciferase reporter assays and lower levels of STAT6 in CD4+ T cells. We identified multiple genes with expression that was affected by the p.L406P genotype upon IL-4 treatment of CD4+ T cells; the effect was consistent with a weaker IL-4 response in carriers than non-carriers of p.L406P.CONCLUSIONSWe report a partial loss-of-function variant in STAT6, resulting in dampened IL-4 responses and protection from T2 high asthma, implicating STAT6 as an attractive therapeutic target.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":14.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451420","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 : 2024-10-16DOI: 10.1016/j.jaci.2024.10.004
Mingce Zhang,Remy R Cron,Niansheng Chu,Junior Nguyen,Scott M Gordon,Esraa M Eloseily,T Prescott Atkinson,Peter Weiser,Mark R Walter,Portia A Kreiger,Scott W Canna,Edward M Behrens,Randy Q Cron
BACKGROUNDCytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.OBJECTIVEWe explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.METHODSDOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.RESULTSBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.CONCLUSIONMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.
{"title":"Role of DOCK8 in Cytokine Storm Syndromes.","authors":"Mingce Zhang,Remy R Cron,Niansheng Chu,Junior Nguyen,Scott M Gordon,Esraa M Eloseily,T Prescott Atkinson,Peter Weiser,Mark R Walter,Portia A Kreiger,Scott W Canna,Edward M Behrens,Randy Q Cron","doi":"10.1016/j.jaci.2024.10.004","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.10.004","url":null,"abstract":"BACKGROUNDCytokine storm syndromes (CSS), including hemophagocytic lymphohistiocytosis (HLH), are increasingly recognized as hyperinflammatory states leading to multi-organ failure and death. Familial HLH (FHL) in infancy results from homozygous genetic defects in perforin-mediated cytolysis by CD8 T-lymphocytes and natural killer (NK) cells. Later onset CSS are frequently associated with heterozygous defects in FHL genes, but genetic etiologies for most are unknown. We identified rare DOCK8 variants in CSS patients.OBJECTIVEWe explore the role of CSS patient-derived DOCK8 mutations on cytolytic activity in NK cells. We further study effects of DOCK8 deficiency in murine models of CSS.METHODSDOCK8 cDNA from 2 unrelated CSS patients with different missense mutations were introduced into human NK-92 NK cells by foamy virus transduction. NK cell degranulation (CD107a), cytolytic activity against K562 target cells, and interferon-gamma (IFNγ) production were explored by flow cytometry. A third CSS patient DOCK8 mRNA splice acceptor site variant was explored by exon trapping. Dock8-/- mice were assessed for features of CSS (weight loss, splenomegaly, hepatic inflammation, cytopenias, and IFNγ levels) upon challenge with lymphocytic choriomeningitis virus (LCMV) and excess IL-18.RESULTSBoth patient DOCK8 missense mutations decreased cytolytic function in NK cells in a partial dominant-negative fashion in vitro. The patient DOCK8 splice variant disrupted mRNA splicing in vitro. LCMV infection promoted CSS in Dock8-/- mice and interacted with excess IL-18 limiting T-cell numbers while promoting CD8 T-cell hyperactivation.CONCLUSIONMutations in DOCK8 may contribute to CSS-like hyperinflammatory states by altering cytolytic function in a threshold model of disease.","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":14.2,"publicationDate":"2024-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142451422","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}
This review explores the transformative impact of omics technologies on allergy and asthma research in recent years, focusing on advancements in high-throughput technologies related to genomics and transcriptomics. In particular, the rapid spread of single-cell RNA sequencing has markedly advanced our understanding of the molecular pathology of allergic diseases. Furthermore, high-throughput genome sequencing has accelerated the discovery of monogenic disorders that were previously overlooked as ordinary intractable allergic diseases. We also introduce microbiomics, proteomics, lipidomics, and metabolomics, which are quickly growing areas of research interest, although many of their current findings remain inconclusive as solid evidence. By integrating these omics data, we will gain deeper insights into disease mechanisms, leading to the development of precision medicine approaches that promise to enhance treatment outcomes.
{"title":"Omics in allergy and asthma.","authors":"Hirohisa Saito, Masato Tamari, Kenichiro Motomura, Masashi Ikutani, Susumu Nakae, Kenji Matsumoto, Hideaki Morita","doi":"10.1016/j.jaci.2024.09.023","DOIUrl":"10.1016/j.jaci.2024.09.023","url":null,"abstract":"<p><p>This review explores the transformative impact of omics technologies on allergy and asthma research in recent years, focusing on advancements in high-throughput technologies related to genomics and transcriptomics. In particular, the rapid spread of single-cell RNA sequencing has markedly advanced our understanding of the molecular pathology of allergic diseases. Furthermore, high-throughput genome sequencing has accelerated the discovery of monogenic disorders that were previously overlooked as ordinary intractable allergic diseases. We also introduce microbiomics, proteomics, lipidomics, and metabolomics, which are quickly growing areas of research interest, although many of their current findings remain inconclusive as solid evidence. By integrating these omics data, we will gain deeper insights into disease mechanisms, leading to the development of precision medicine approaches that promise to enhance treatment outcomes.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142390675","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 : 2024-10-09DOI: 10.1016/j.jaci.2024.10.001
Donata Vercelli
{"title":"IL-4 and dendritic cells in atopic dermatitis: Old dogs learn new tricks.","authors":"Donata Vercelli","doi":"10.1016/j.jaci.2024.10.001","DOIUrl":"10.1016/j.jaci.2024.10.001","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400313","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 : 2024-10-09DOI: 10.1016/j.jaci.2024.09.025
Sunny Palumbo, Joseph Irish, Nirushan Narendran, Debra A Stern, Sophia Volpe, Christopher H Le, Rebekah Starks, Anthony Bosco, Fernando D Martinez, Eugene H Chang
Background: Acute exacerbations of chronic rhinosinusitis (AECRS) are commonly triggered by rhinovirus (RV) infections with secondary bacterial infections. Risk factors for AECRS are not well understood.
Objective: We sought to determine whether carriers of the minor allele rs6967330 (AA/AG) in the cadherin-related family member 3 (CDHR3) gene have an increased risk for RV infections in AECRS in vivo and identify CDHR3 genotype-dependent host responses to RV infection in differentiated nasal airway-liquid interface (ALI) cultures ex vivo.
Methods: We performed a prospective year-long study of adult subjects with chronic rhinosinusitis by the rs6967330 genotype (AA/AG, n = 16; GG, n = 38). We contacted subjects every 2 weeks, and if they reported AECRS, then clinical data were collected. ALI cultures of adults with chronic rhinosinusitis (AG/AA, n = 19; GG, n = 19) were challenged with RV-A and RV-C. We measured viral copy numbers at 4 and 48 hours postinfection and RNA transcriptomes and cytokines at 48 hours postinfection.
Results: Subjects with the minor allele had significantly higher rates of RV and bacterial infections than those with the major allele. ALI minor allele cultures had higher viral copy numbers of RV-A and RV-C after 48 hours compared with the major allele. Differentially expressed genes and pathways identified an upregulation of IL-10 and IL-4/IL-13 pathways and a significant downregulation of Toll-like receptor pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all differentially expressed genes suggested that allergic rhinitis had an additive effect on this response.
Conclusions: The rs6967330 minor allele is associated with increased RV-A and RV-C replication, downregulation of Toll-like receptor-mediated responses, and increased type-2 and cytokine and chemokine responses during RV infection.
{"title":"The rs6967330 minor allele in CDHR3 is a significant risk factor for severe acute exacerbations in chronic rhinosinusitis.","authors":"Sunny Palumbo, Joseph Irish, Nirushan Narendran, Debra A Stern, Sophia Volpe, Christopher H Le, Rebekah Starks, Anthony Bosco, Fernando D Martinez, Eugene H Chang","doi":"10.1016/j.jaci.2024.09.025","DOIUrl":"10.1016/j.jaci.2024.09.025","url":null,"abstract":"<p><strong>Background: </strong>Acute exacerbations of chronic rhinosinusitis (AECRS) are commonly triggered by rhinovirus (RV) infections with secondary bacterial infections. Risk factors for AECRS are not well understood.</p><p><strong>Objective: </strong>We sought to determine whether carriers of the minor allele rs6967330 (AA/AG) in the cadherin-related family member 3 (CDHR3) gene have an increased risk for RV infections in AECRS in vivo and identify CDHR3 genotype-dependent host responses to RV infection in differentiated nasal airway-liquid interface (ALI) cultures ex vivo.</p><p><strong>Methods: </strong>We performed a prospective year-long study of adult subjects with chronic rhinosinusitis by the rs6967330 genotype (AA/AG, n = 16; GG, n = 38). We contacted subjects every 2 weeks, and if they reported AECRS, then clinical data were collected. ALI cultures of adults with chronic rhinosinusitis (AG/AA, n = 19; GG, n = 19) were challenged with RV-A and RV-C. We measured viral copy numbers at 4 and 48 hours postinfection and RNA transcriptomes and cytokines at 48 hours postinfection.</p><p><strong>Results: </strong>Subjects with the minor allele had significantly higher rates of RV and bacterial infections than those with the major allele. ALI minor allele cultures had higher viral copy numbers of RV-A and RV-C after 48 hours compared with the major allele. Differentially expressed genes and pathways identified an upregulation of IL-10 and IL-4/IL-13 pathways and a significant downregulation of Toll-like receptor pathways in the minor allele cultures after RV-A and RV-C infection. Unsupervised hierarchical analysis of all differentially expressed genes suggested that allergic rhinitis had an additive effect on this response.</p><p><strong>Conclusions: </strong>The rs6967330 minor allele is associated with increased RV-A and RV-C replication, downregulation of Toll-like receptor-mediated responses, and increased type-2 and cytokine and chemokine responses during RV infection.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400314","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 : 2024-10-08DOI: 10.1016/j.jaci.2024.09.024
Daniel Lozano-Ojalvo, Xin Chen, Wajiha Kazmi, David Menchén-Martínez, Leticia Pérez-Rodríguez, Weslley Fernandes-Braga, Scott Tyler, Keith Benkov, Nanci Pittman, Joanne Lai, Hugh A Sampson, Maria Curotto de Lafaille, David Dunkin, M Cecilia Berin
Background: IgE-mediated food allergy and eosinophilic esophagitis (EoE) are diseases commonly triggered by milk. Milk-responsive CD4+ T cells producing type 2 cytokines are present in both diseases, yet the clinical manifestation of disease in milk allergy (MA) and EoE are distinct.
Objective: To identify CD4+ T cell differences between EoE and MA that may be responsible for distinct disease manifestations.
Methods: The total and milk-specific CD4+ T cell phenotype of children with milk allergy (MA), EoE (active or in remission) and controls was measured using spectral flow cytometry of peripheral blood (all groups) or esophageal biopsies (EoE and control).
Results: Circulating milk-responsive T cells could be identified in active (A)-EoE and MA. An increased frequency of Th2A cells was also noted in MA and EoE. In circulating T cells, type 2 cytokine production was elevated in MA, but not EoE. Within the milk-responsive Tfh subset, a dichotomy of phenotype was noted: Tfh13 cells predominated in MA, while IL-10-producing Tfh cells predominated in EoE. In the esophagus, CD4+ T cells were constitutively activated and expressed not only type 2 cytokines, but also IL-10 and IL-21 in A-EoE. There was production of IgG4 from CD38+ plasma cells in close proximity to CD4+ T cells. In vitro activation studies demonstrated that IL-10 and IL-21 elicited strong IgG4 responses in B lymphocytes, while IL-4 and IL-13 promoted IgE production.
Conclusion: Our studies demonstrate a dichotomy of Tfh responses that may be the basis for the different clinical manifestations to milk in EoE and MA.
背景:IgE介导的食物过敏和嗜酸性粒细胞食管炎(EoE)是由牛奶引发的常见疾病。这两种疾病中都存在产生 2 型细胞因子的牛奶反应性 CD4+ T 细胞,但牛奶过敏(MA)和嗜酸性粒细胞性食管炎的临床表现却截然不同:目的:确定牛奶过敏和肠易激综合征的 CD4+ T 细胞差异可能是导致不同疾病表现的原因:方法:使用光谱流式细胞术测量外周血(所有组别)或食管活检组织(EoE 和对照组)中牛奶过敏(MA)、EoE(活动期或缓解期)和对照组儿童的总 CD4+ T 细胞表型和牛奶特异性 CD4+ T 细胞表型:结果:在活动性(A)-EoE 和 MA 中可发现循环牛奶反应性 T 细胞。在 MA 和 EoE 中,Th2A 细胞的频率也有所增加。在循环 T 细胞中,2 型细胞因子的产生在 MA 中升高,但在 EoE 中没有升高。在牛奶反应性 Tfh 亚群中,发现了表型的二分法:在 MA 中以 Tfh13 细胞为主,而在 EoE 中则以产生 IL-10 的 Tfh 细胞为主。在食管中,CD4+ T 细胞被持续激活,不仅表达 2 型细胞因子,而且在急性食管炎中还表达 IL-10 和 IL-21。CD38+ 浆细胞在靠近 CD4+ T 细胞处产生 IgG4。体外活化研究表明,IL-10 和 IL-21 在 B 淋巴细胞中引起强烈的 IgG4 反应,而 IL-4 和 IL-13 则促进 IgE 的产生:我们的研究证明了Tfh反应的二分法,这可能是EoE和MA患者对牛奶的不同临床表现的基础。
{"title":"Differential Tfh cell phenotypes distinguish IgE-mediated milk allergy from eosinophilic esophagitis in children.","authors":"Daniel Lozano-Ojalvo, Xin Chen, Wajiha Kazmi, David Menchén-Martínez, Leticia Pérez-Rodríguez, Weslley Fernandes-Braga, Scott Tyler, Keith Benkov, Nanci Pittman, Joanne Lai, Hugh A Sampson, Maria Curotto de Lafaille, David Dunkin, M Cecilia Berin","doi":"10.1016/j.jaci.2024.09.024","DOIUrl":"https://doi.org/10.1016/j.jaci.2024.09.024","url":null,"abstract":"<p><strong>Background: </strong>IgE-mediated food allergy and eosinophilic esophagitis (EoE) are diseases commonly triggered by milk. Milk-responsive CD4<sup>+</sup> T cells producing type 2 cytokines are present in both diseases, yet the clinical manifestation of disease in milk allergy (MA) and EoE are distinct.</p><p><strong>Objective: </strong>To identify CD4<sup>+</sup> T cell differences between EoE and MA that may be responsible for distinct disease manifestations.</p><p><strong>Methods: </strong>The total and milk-specific CD4<sup>+</sup> T cell phenotype of children with milk allergy (MA), EoE (active or in remission) and controls was measured using spectral flow cytometry of peripheral blood (all groups) or esophageal biopsies (EoE and control).</p><p><strong>Results: </strong>Circulating milk-responsive T cells could be identified in active (A)-EoE and MA. An increased frequency of Th2A cells was also noted in MA and EoE. In circulating T cells, type 2 cytokine production was elevated in MA, but not EoE. Within the milk-responsive Tfh subset, a dichotomy of phenotype was noted: Tfh13 cells predominated in MA, while IL-10-producing Tfh cells predominated in EoE. In the esophagus, CD4<sup>+</sup> T cells were constitutively activated and expressed not only type 2 cytokines, but also IL-10 and IL-21 in A-EoE. There was production of IgG4 from CD38<sup>+</sup> plasma cells in close proximity to CD4<sup>+</sup> T cells. In vitro activation studies demonstrated that IL-10 and IL-21 elicited strong IgG4 responses in B lymphocytes, while IL-4 and IL-13 promoted IgE production.</p><p><strong>Conclusion: </strong>Our studies demonstrate a dichotomy of Tfh responses that may be the basis for the different clinical manifestations to milk in EoE and MA.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142400312","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 : 2024-10-04DOI: 10.1016/j.jaci.2024.09.020
Simran Samra, Jenna R E Bergerson, Alexandra F Freeman, Stuart E Turvey
The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling cascade is an evolutionarily conserved signal transduction pathway that regulates many vital cellular processes, including immune function and hematopoiesis. Human genetic variants that disrupt JAK-STAT signaling are being found to cause a rapidly increasing number of diseases, including both germline-encoded inborn errors of immunity (IEI) and acquired somatic variants, causing a so-called phenocopy of the IEI. Multiple genetic mechanisms are responsible for this growing group of JAK-STAT diseases including loss-of-function, gain-of-function, and dominant negative effects. In this review, we discuss the clinical presentation and pathogenesis of all currently described JAK-STAT defects, as well as provide an overview of the guiding principles to consider in diagnosing and treating these conditions.
{"title":"JAK-STAT signaling pathway, immunodeficiency, inflammation, immune dysregulation, and inborn errors of immunity.","authors":"Simran Samra, Jenna R E Bergerson, Alexandra F Freeman, Stuart E Turvey","doi":"10.1016/j.jaci.2024.09.020","DOIUrl":"10.1016/j.jaci.2024.09.020","url":null,"abstract":"<p><p>The Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling cascade is an evolutionarily conserved signal transduction pathway that regulates many vital cellular processes, including immune function and hematopoiesis. Human genetic variants that disrupt JAK-STAT signaling are being found to cause a rapidly increasing number of diseases, including both germline-encoded inborn errors of immunity (IEI) and acquired somatic variants, causing a so-called phenocopy of the IEI. Multiple genetic mechanisms are responsible for this growing group of JAK-STAT diseases including loss-of-function, gain-of-function, and dominant negative effects. In this review, we discuss the clinical presentation and pathogenesis of all currently described JAK-STAT defects, as well as provide an overview of the guiding principles to consider in diagnosing and treating these conditions.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142380907","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 : 2024-10-03DOI: 10.1016/j.jaci.2024.09.022
Roger D Peng, Sarah E Chambliss
{"title":"Opportunities for using artificial intelligence in air pollution and health research.","authors":"Roger D Peng, Sarah E Chambliss","doi":"10.1016/j.jaci.2024.09.022","DOIUrl":"10.1016/j.jaci.2024.09.022","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377929","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 : 2024-10-03DOI: 10.1016/j.jaci.2024.09.019
Chuan-Yen Sun, Yohannes Tesfaigzi, Gin-Yi Lee, Yi-Hsuan Chen, Scott T Weiss, Kevin Sheng-Kai Ma
Background: Previous randomized controlled trials had established the efficacy of dupilumab among patients with chronic obstructive pulmonary disease (COPD) treated with triple therapy over 52 weeks of follow-up.
Objective: This population-based cohort study aimed to explore the long-term clinical effectiveness of dupilumab in COPD patients.
Methods: This population-based cohort study included U.S. patients with COPD between April 2017 and August 2024. Patients initiating dupilumab and therapies that incorporated long-acting β2-agonists (LABA) inhalers were included. Patients with asthma or lung cancer were excluded. The risk of outcomes after the initiation of dupilumab versus LABA-containing therapies was measured. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org.
Results: A total of 1,521 dupilumab initiators and 1,521 propensity score-matched patients receiving LABA-based therapies were included. Dupilumab recipients were associated with lower all-cause mortality (HR:0.53, 95% CI:0.43-0.65), emergency visits (HR:0.78, 95% CI:0.69-0.89), and acute exacerbation (AE) rates (HR:0.59, 95% CI:0.53-0.65). Dupilumab was also associated with reductions in the requirement of short-acting β2-agonists (HR:0.48, 95% CI:0.43-0.52), short-acting muscarinic antagonists (HR:0.43, 95% CI:0.37-0.49) for symptoms control. Additionally, dupilumab decreased subsequent pneumonia (HR:0.65, 95% CI:0.50-0.86), and COPD-relevant comorbidities including new-onset heart failure (HR:0.69, 95% CI:0.53-0.90) and new-onset anxiety (HR:0.70, 95% CI:0.53-0.93).
Conclusions: Dupilumab was associated with a lower rate of mortality, emergency visits, reduced risk of AEs, respiratory symptoms, and respiratory infections in COPD patients. More studies are required to validate the effectiveness of dupilumab among patients with COPD across various severities.
{"title":"Clinical Effectiveness and Safety of Dupilumab in Chronic Obstructive Pulmonary Disease Patients: A 7-Year Population-based Cohort Study.","authors":"Chuan-Yen Sun, Yohannes Tesfaigzi, Gin-Yi Lee, Yi-Hsuan Chen, Scott T Weiss, Kevin Sheng-Kai Ma","doi":"10.1016/j.jaci.2024.09.019","DOIUrl":"10.1016/j.jaci.2024.09.019","url":null,"abstract":"<p><strong>Background: </strong>Previous randomized controlled trials had established the efficacy of dupilumab among patients with chronic obstructive pulmonary disease (COPD) treated with triple therapy over 52 weeks of follow-up.</p><p><strong>Objective: </strong>This population-based cohort study aimed to explore the long-term clinical effectiveness of dupilumab in COPD patients.</p><p><strong>Methods: </strong>This population-based cohort study included U.S. patients with COPD between April 2017 and August 2024. Patients initiating dupilumab and therapies that incorporated long-acting β2-agonists (LABA) inhalers were included. Patients with asthma or lung cancer were excluded. The risk of outcomes after the initiation of dupilumab versus LABA-containing therapies was measured. For detailed Methods, please see the Methods section in this article's Online Repository at www.jacionline.org.</p><p><strong>Results: </strong>A total of 1,521 dupilumab initiators and 1,521 propensity score-matched patients receiving LABA-based therapies were included. Dupilumab recipients were associated with lower all-cause mortality (HR:0.53, 95% CI:0.43-0.65), emergency visits (HR:0.78, 95% CI:0.69-0.89), and acute exacerbation (AE) rates (HR:0.59, 95% CI:0.53-0.65). Dupilumab was also associated with reductions in the requirement of short-acting β2-agonists (HR:0.48, 95% CI:0.43-0.52), short-acting muscarinic antagonists (HR:0.43, 95% CI:0.37-0.49) for symptoms control. Additionally, dupilumab decreased subsequent pneumonia (HR:0.65, 95% CI:0.50-0.86), and COPD-relevant comorbidities including new-onset heart failure (HR:0.69, 95% CI:0.53-0.90) and new-onset anxiety (HR:0.70, 95% CI:0.53-0.93).</p><p><strong>Conclusions: </strong>Dupilumab was associated with a lower rate of mortality, emergency visits, reduced risk of AEs, respiratory symptoms, and respiratory infections in COPD patients. More studies are required to validate the effectiveness of dupilumab among patients with COPD across various severities.</p>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142377928","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 : 2024-10-02DOI: 10.1016/j.jaci.2024.09.021
Lily Li, Kimberly G Blumenthal
{"title":"Role of anti-IgE in immediate drug allergy.","authors":"Lily Li, Kimberly G Blumenthal","doi":"10.1016/j.jaci.2024.09.021","DOIUrl":"10.1016/j.jaci.2024.09.021","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":null,"pages":null},"PeriodicalIF":11.4,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142375420","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}