Helena Thulin, Ladan Mansouri, Maria Altman, Simon Kebede Merid, Joachim Lundahl, Caroline Nilsson, Jesper Säfholm
Background: Noninvasive biomarkers for diagnosing and monitoring eosinophilic esophagitis (EoE) are currently lacking. This study evaluates 20 biomarkers in serum and saliva, aiming to assess their diagnostic potential in pediatric EoE patients and healthy individuals.
Methods: Blood and saliva from children undergoing upper endoscopy were analyzed for biomarkers, including absolute eosinophil count (AEC), eosinophil-derived neurotoxin (EDN), total and specific IgG4-antibodies (sIgG4), specific IgE-antibodies (sIgE) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE). Some patients participated twice, forming a longitudinal cohort. The ability to use the biomarkers to predict the EoE diagnosis was evaluated.
Results: Analysis from 105 children divided into active EoE, remission, and healthy, revealed elevated levels of serum biomarkers (AEC, EDN, 15(S)-HETE, sIgG4, and sIgE) in active EoE compared to healthy individuals. A combination of biomarkers (AEC, EDN, sIgE to egg white and wheat) and symptoms showed an AUC of 0.92 in distinguishing between the three groups. We further showed that optimal cutoff values for these biomarkers could discriminate between active EoE and healthy with a sensitivity of 88% and a specificity of 100% in distinguishing EoE (active and in remission) from healthy. Longitudinally, levels of EDN, sIgG4 to Bos d 4, Bos d 5, Bos d 8, gliadin, and birch, and sIgE to milk decreased in patients progressing from active EoE to remission (p <.05).
Conclusions: This study identified novel biomarkers associated with EoE and proposes a panel, together with symptoms, for effective discrimination between active EoE, EoE in remission, and healthy individuals. The findings may contribute to a less invasive diagnostic method and may be a potential surveillance tool for pediatric EoE patients.
背景:目前尚缺乏诊断和监测嗜酸性粒细胞食管炎(EoE)的无创生物标志物。本研究评估了血清和唾液中的 20 种生物标志物,旨在评估它们对小儿嗜酸性食管炎患者和健康人的诊断潜力:分析了接受上内镜检查的儿童的血液和唾液中的生物标志物,包括嗜酸性粒细胞绝对计数(AEC)、嗜酸性粒细胞衍生神经毒素(EDN)、总抗体和特异性IgG4-抗体(sIgG4)、特异性IgE-抗体(sIgE)和15-羟基二十碳四烯酸(15(S)-HETE)。一些患者参与了两次,形成了一个纵向队列。结果:结果:对分为活动性咽喉炎、缓解期和健康期的 105 名儿童进行的分析表明,活动性咽喉炎患者的血清生物标志物(AEC、EDN、15(S)-HETE、sIgG4 和 sIgE)水平高于健康人。生物标志物(AEC、EDN、蛋白和小麦 sIgE)与症状的组合显示,区分三组的 AUC 为 0.92。我们进一步发现,这些生物标志物的最佳临界值可区分活动性咽喉炎和健康咽喉炎,在区分咽喉炎(活动性和缓解期)和健康咽喉炎方面,灵敏度为 88%,特异度为 100%。纵向来看,从活动性咽喉炎发展到缓解期的患者,EDN水平、对Bos d 4、Bos d 5、Bos d 8、麦胶蛋白和桦木的sIgG4水平以及对牛奶的sIgE水平均有所下降(p 结论:该研究发现了一种新的生物标志物,可用于区分活动性咽喉炎和健康咽喉炎,其灵敏度为88%,特异性为100%:这项研究确定了与咽喉炎相关的新型生物标志物,并提出了一个与症状相结合的面板,可有效区分活动性咽喉炎、缓解期咽喉炎和健康人。这些发现可能有助于开发一种侵入性较小的诊断方法,并可能成为儿科咽喉炎患者的潜在监测工具。
{"title":"Biomarkers for a less invasive strategy to predict children with eosinophilic esophagitis.","authors":"Helena Thulin, Ladan Mansouri, Maria Altman, Simon Kebede Merid, Joachim Lundahl, Caroline Nilsson, Jesper Säfholm","doi":"10.1111/all.16275","DOIUrl":"https://doi.org/10.1111/all.16275","url":null,"abstract":"<p><strong>Background: </strong>Noninvasive biomarkers for diagnosing and monitoring eosinophilic esophagitis (EoE) are currently lacking. This study evaluates 20 biomarkers in serum and saliva, aiming to assess their diagnostic potential in pediatric EoE patients and healthy individuals.</p><p><strong>Methods: </strong>Blood and saliva from children undergoing upper endoscopy were analyzed for biomarkers, including absolute eosinophil count (AEC), eosinophil-derived neurotoxin (EDN), total and specific IgG<sub>4</sub>-antibodies (sIgG<sub>4</sub>), specific IgE-antibodies (sIgE) and 15-hydroxyeicosatetraenoic acid (15(S)-HETE). Some patients participated twice, forming a longitudinal cohort. The ability to use the biomarkers to predict the EoE diagnosis was evaluated.</p><p><strong>Results: </strong>Analysis from 105 children divided into active EoE, remission, and healthy, revealed elevated levels of serum biomarkers (AEC, EDN, 15(S)-HETE, sIgG<sub>4</sub>, and sIgE) in active EoE compared to healthy individuals. A combination of biomarkers (AEC, EDN, sIgE to egg white and wheat) and symptoms showed an AUC of 0.92 in distinguishing between the three groups. We further showed that optimal cutoff values for these biomarkers could discriminate between active EoE and healthy with a sensitivity of 88% and a specificity of 100% in distinguishing EoE (active and in remission) from healthy. Longitudinally, levels of EDN, sIgG<sub>4</sub> to Bos d 4, Bos d 5, Bos d 8, gliadin, and birch, and sIgE to milk decreased in patients progressing from active EoE to remission (p <.05).</p><p><strong>Conclusions: </strong>This study identified novel biomarkers associated with EoE and proposes a panel, together with symptoms, for effective discrimination between active EoE, EoE in remission, and healthy individuals. The findings may contribute to a less invasive diagnostic method and may be a potential surveillance tool for pediatric EoE patients.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141998927","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":"Type 2 memory B cells: The repository of allergic memory?","authors":"Jesse Mulder, Alexandra R Dvorscek, Zhoujie Ding","doi":"10.1111/all.16278","DOIUrl":"https://doi.org/10.1111/all.16278","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986953","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}
<p>Regulatory T cells (Tregs) hold a pivotal role in orchestrating immune homeostasis through their ability to modulate the activity of T helper cell subsets, but are impaired in many autoimmune and chronic inflammatory diseases including psoriasis (PsO) and atopic dermatitis (AD).<span><sup>1, 2</sup></span> Interleukin-2 (IL-2) plays a role in controlling the proliferation and survival of Tregs,<span><sup>3</sup></span> with low-dose IL-2 shown to partially rescue Treg function and provide clinical benefit in autoimmune diseases.<span><sup>4</sup></span> Low-dose IL-2, however, has limited therapeutic practicality, including a narrow therapeutic window and short half-life, thereby requiring more frequent dosing that could, in turn, result in conventional CD4 and CD8 T cell (Tcon) induction.</p><p>The patent application<span><sup>5</sup></span> described herein provides therapeutically advantageous formulations, doses, and dosing regimens for rezpegaldesleukin (REZPEG), an IL-2 receptor (IL-2R) pathway agonist designed to stimulate the expansion and function of Tregs. REZPEG incorporates the approved recombinant human IL-2 (rhIL-2) aldesleukin sequence, which has been conjugated with stable, covalently attached polyethylene glycol (PEG) moieties (Figure 1). The result is a drug candidate having an extended half-life as well as a selectivity for Treg stimulation over Tcons compared with rhIL-2.<span><sup>5, 6</sup></span> The formulations, doses, and dosing regimens described in this patent include a range of fixed unit doses and regimens for induction and maintenance dosing. The objectives of these being to achieve effective autoimmune and chronic inflammatory disease management, increased patient compliance, convenience, and tolerability while also minimizing the risk of off-target Tcon stimulation.</p><p>In two randomized, double-blind, placebo-controlled Phase 1b trials in patients with AD or PsO, REZPEG was safe and well-tolerated, demonstrating consistent pharmacokinetics (PK) and clinical efficacy, meeting the primary, secondary, and exploratory objectives in both trials (NCT04081350 and NCT04119557). Notably, AD patients receiving 24 μg/kg REZPEG every 2 weeks (q2w) demonstrated an 83% improvement in Eczema Area and Severity Index (EASI) score after 12 weeks of treatment. EASI improvement of ≥75% (EASI-75) and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) responses were maintained for 36 weeks after the end of the treatment period in 71% and 80% of patients responding to treatment at week 12, respectively. These clinical improvements were accompanied by sustained increases in CD25<sup>bright</sup> Tregs over the 12-week treatment period.</p><p>We set about designing an IL-2-based biologic that could be used as a potential therapeutic to drive the proliferation and activation of Tregs over Tcons. We rejected a traditional drug discovery screening approach focused on in vitro ligand binding on our belief that it w
JZ 和 CF 是 Nektar Therapeutics 公司的员工和股东。
{"title":"Recent patents in allergy and immunology: The interleukin-2 receptor pathway agonist rezpegaldesleukin (REZPEG) for the rescue of regulatory T cells in chronic inflammatory and autoimmune diseases","authors":"Christie Fanton, Jonathan Zalevsky","doi":"10.1111/all.16271","DOIUrl":"10.1111/all.16271","url":null,"abstract":"<p>Regulatory T cells (Tregs) hold a pivotal role in orchestrating immune homeostasis through their ability to modulate the activity of T helper cell subsets, but are impaired in many autoimmune and chronic inflammatory diseases including psoriasis (PsO) and atopic dermatitis (AD).<span><sup>1, 2</sup></span> Interleukin-2 (IL-2) plays a role in controlling the proliferation and survival of Tregs,<span><sup>3</sup></span> with low-dose IL-2 shown to partially rescue Treg function and provide clinical benefit in autoimmune diseases.<span><sup>4</sup></span> Low-dose IL-2, however, has limited therapeutic practicality, including a narrow therapeutic window and short half-life, thereby requiring more frequent dosing that could, in turn, result in conventional CD4 and CD8 T cell (Tcon) induction.</p><p>The patent application<span><sup>5</sup></span> described herein provides therapeutically advantageous formulations, doses, and dosing regimens for rezpegaldesleukin (REZPEG), an IL-2 receptor (IL-2R) pathway agonist designed to stimulate the expansion and function of Tregs. REZPEG incorporates the approved recombinant human IL-2 (rhIL-2) aldesleukin sequence, which has been conjugated with stable, covalently attached polyethylene glycol (PEG) moieties (Figure 1). The result is a drug candidate having an extended half-life as well as a selectivity for Treg stimulation over Tcons compared with rhIL-2.<span><sup>5, 6</sup></span> The formulations, doses, and dosing regimens described in this patent include a range of fixed unit doses and regimens for induction and maintenance dosing. The objectives of these being to achieve effective autoimmune and chronic inflammatory disease management, increased patient compliance, convenience, and tolerability while also minimizing the risk of off-target Tcon stimulation.</p><p>In two randomized, double-blind, placebo-controlled Phase 1b trials in patients with AD or PsO, REZPEG was safe and well-tolerated, demonstrating consistent pharmacokinetics (PK) and clinical efficacy, meeting the primary, secondary, and exploratory objectives in both trials (NCT04081350 and NCT04119557). Notably, AD patients receiving 24 μg/kg REZPEG every 2 weeks (q2w) demonstrated an 83% improvement in Eczema Area and Severity Index (EASI) score after 12 weeks of treatment. EASI improvement of ≥75% (EASI-75) and validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD) responses were maintained for 36 weeks after the end of the treatment period in 71% and 80% of patients responding to treatment at week 12, respectively. These clinical improvements were accompanied by sustained increases in CD25<sup>bright</sup> Tregs over the 12-week treatment period.</p><p>We set about designing an IL-2-based biologic that could be used as a potential therapeutic to drive the proliferation and activation of Tregs over Tcons. We rejected a traditional drug discovery screening approach focused on in vitro ligand binding on our belief that it w","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/all.16271","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994810","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
O Pfaar, M Bastl, M Berger, U E Berger, K Karatzas, T Tasioulis, B Werchan, M Werchan, K C Bergmann
{"title":"Comparison of two different pollen season definitions based on 10 years of birch and grass pollen data from two distant central European cities: An EAACI Task Force report.","authors":"O Pfaar, M Bastl, M Berger, U E Berger, K Karatzas, T Tasioulis, B Werchan, M Werchan, K C Bergmann","doi":"10.1111/all.16252","DOIUrl":"https://doi.org/10.1111/all.16252","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141994808","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":"Proposed amendment to the nomenclature of allergic diseases and hypersensitivity reactions: Looking beyond the classic paradigms.","authors":"Lucyna Mastalerz","doi":"10.1111/all.16277","DOIUrl":"https://doi.org/10.1111/all.16277","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141986952","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}
Maisha F Jabeen, Nicholas D Sanderson, Mariaenrica Tinè, Gillian Donachie, Clair Barber, Adnan Azim, Laurie C K Lau, Thomas Brown, Ian D Pavord, Anoop Chauhan, Paul Klenerman, Teresa L Street, Emanuele Marchi, Peter H Howarth, Timothy S C Hinks
Background: The airway microbiome in severe asthma has not been characterised at species-level by metagenomic sequencing, nor have the relationships between specific species and mucosal immune responses in 'type-2 low', neutrophilic asthma been defined. We performed an integrated species-level metagenomic data with inflammatory mediators to characterise prevalence of dominant potentially pathogenic organisms and host immune responses.
Methods: Sputum and nasal lavage samples were analysed using long-read metagenomic sequencing with Nanopore and qPCR in two cross-sectional adult severe asthma cohorts, Wessex (n = 66) and Oxford (n = 30). We integrated species-level data with clinical parameters and 39 selected airway proteins measured by immunoassay and O-link.
Results: The sputum microbiome in health and mild asthma displayed comparable microbial diversity. By contrast, 23% (19/81) of severe asthma microbiomes were dominated by a single respiratory pathogen, namely H. influenzae (n = 10), M. catarrhalis (n = 4), S. pneumoniae (n = 4) and P. aeruginosa (n = 1). Neutrophilic asthma was associated with H. influenzae, M. catarrhalis, S. pneumoniae and T. whipplei with elevated type-1 cytokines and proteases; eosinophilic asthma with higher M. catarrhalis, but lower H. influenzae, and S. pneumoniae abundance. H. influenzae load correlated with Eosinophil Cationic Protein, elastase and IL-10. R. mucilaginosa associated positively with IL-6 and negatively with FGF. Bayesian network analysis also revealed close and distinct relationships of H. influenzae and M. catarrhalis with type-1 airway inflammation. The microbiomes and cytokine milieu were distinct between upper and lower airways.
Conclusions: This species-level integrated analysis reveals central, but distinct associations between potentially pathogenic bacteria and airways inflammation in severe asthma.
{"title":"Species-level, metagenomic and proteomic analysis of microbe-immune interactions in severe asthma.","authors":"Maisha F Jabeen, Nicholas D Sanderson, Mariaenrica Tinè, Gillian Donachie, Clair Barber, Adnan Azim, Laurie C K Lau, Thomas Brown, Ian D Pavord, Anoop Chauhan, Paul Klenerman, Teresa L Street, Emanuele Marchi, Peter H Howarth, Timothy S C Hinks","doi":"10.1111/all.16269","DOIUrl":"https://doi.org/10.1111/all.16269","url":null,"abstract":"<p><strong>Background: </strong>The airway microbiome in severe asthma has not been characterised at species-level by metagenomic sequencing, nor have the relationships between specific species and mucosal immune responses in 'type-2 low', neutrophilic asthma been defined. We performed an integrated species-level metagenomic data with inflammatory mediators to characterise prevalence of dominant potentially pathogenic organisms and host immune responses.</p><p><strong>Methods: </strong>Sputum and nasal lavage samples were analysed using long-read metagenomic sequencing with Nanopore and qPCR in two cross-sectional adult severe asthma cohorts, Wessex (n = 66) and Oxford (n = 30). We integrated species-level data with clinical parameters and 39 selected airway proteins measured by immunoassay and O-link.</p><p><strong>Results: </strong>The sputum microbiome in health and mild asthma displayed comparable microbial diversity. By contrast, 23% (19/81) of severe asthma microbiomes were dominated by a single respiratory pathogen, namely H. influenzae (n = 10), M. catarrhalis (n = 4), S. pneumoniae (n = 4) and P. aeruginosa (n = 1). Neutrophilic asthma was associated with H. influenzae, M. catarrhalis, S. pneumoniae and T. whipplei with elevated type-1 cytokines and proteases; eosinophilic asthma with higher M. catarrhalis, but lower H. influenzae, and S. pneumoniae abundance. H. influenzae load correlated with Eosinophil Cationic Protein, elastase and IL-10. R. mucilaginosa associated positively with IL-6 and negatively with FGF. Bayesian network analysis also revealed close and distinct relationships of H. influenzae and M. catarrhalis with type-1 airway inflammation. The microbiomes and cytokine milieu were distinct between upper and lower airways.</p><p><strong>Conclusions: </strong>This species-level integrated analysis reveals central, but distinct associations between potentially pathogenic bacteria and airways inflammation in severe asthma.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910898","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}
Cristina Martin-Garcia, Andrea Dionelly Murillo-Casas, Milagros Lázaro-Sastre, Miguel Estravís, Francisco Javier Muñoz-Bellido, Elena Mazoteras-Martinez, Ignacio Dávila
{"title":"Assessment of sIgE to rLep d 2 for detecting Lepidoglyphus destructor sensitization.","authors":"Cristina Martin-Garcia, Andrea Dionelly Murillo-Casas, Milagros Lázaro-Sastre, Miguel Estravís, Francisco Javier Muñoz-Bellido, Elena Mazoteras-Martinez, Ignacio Dávila","doi":"10.1111/all.16272","DOIUrl":"https://doi.org/10.1111/all.16272","url":null,"abstract":"","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141910897","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}
Madeline Kim, Ester Del Duca, Dante Dahabreh, Daniel Lozano-Ojalvo, Britta Carroll, Meredith Manson, Swaroop Bose, Digpal Gour, Monali NandyMazumdar, Ying Liu, Mitchelle Yu Ekey, Amira Chowdhury, Michael Angelov, Benjamin Ungar, Yeriel Estrada, Emma Guttman-Yassky
Background: Alopecia areata (AA) is a chronic, nonscarring hair-loss disorder associated with significant quality-of-life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1- and Th2-driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking.
Methods: Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA-seq, RT-PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold-change| > 1.5 and false-discovery rate <0.05.
Results: AA scalp exhibited robust upregulation of Th1- (IFNG, CXCL9, CXCL10, CXCL11) and Th2-related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2-skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40+ and OX40L+ leukocytes, regardless of atopic background.
Conclusion: Our results suggest some atopy-associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.
{"title":"Alopecia areata exhibits cutaneous and systemic OX40 activation across atopic backgrounds.","authors":"Madeline Kim, Ester Del Duca, Dante Dahabreh, Daniel Lozano-Ojalvo, Britta Carroll, Meredith Manson, Swaroop Bose, Digpal Gour, Monali NandyMazumdar, Ying Liu, Mitchelle Yu Ekey, Amira Chowdhury, Michael Angelov, Benjamin Ungar, Yeriel Estrada, Emma Guttman-Yassky","doi":"10.1111/all.16268","DOIUrl":"https://doi.org/10.1111/all.16268","url":null,"abstract":"<p><strong>Background: </strong>Alopecia areata (AA) is a chronic, nonscarring hair-loss disorder associated with significant quality-of-life impairment and limited treatment options. AA has been recently linked to atopy and shown to exhibit both Th1- and Th2-driven inflammation. However, a comprehensive molecular and cellular characterization across blood and scalp compartments in both atopic and nonatopic patients is lacking.</p><p><strong>Methods: </strong>Lesional and nonlesional scalp biopsies obtained from AA patients with (n = 16) or without (n = 20) atopic history, and 17 demographically matched healthy controls were analyzed with RNA-seq, RT-PCR, and immunohistochemistry. Flow cytometry was also performed on peripheral blood mononuclear cells (PBMCs) from a subset of patients. Differential expression was defined using |fold-change| > 1.5 and false-discovery rate <0.05.</p><p><strong>Results: </strong>AA scalp exhibited robust upregulation of Th1- (IFNG, CXCL9, CXCL10, CXCL11) and Th2-related products (CCL26, CCR4, IL10, IL13, TSLP, TNFRSF4/OX40) and shared downregulation of hair keratins, regardless of atopic background, with variable Th17/Th22 modulation. AA patients with atopy exhibited greater inflammatory tone and Th2-skewing (IL10, IL13, IL33, CCR4, CCL26). Disease severity correlated significantly with immune and hair keratin biomarkers and with perifollicular cellular infiltrates. Cutaneous OX40/OX40L upregulation was paralleled by increases in circulating OX40<sup>+</sup> and OX40L<sup>+</sup> leukocytes, regardless of atopic background.</p><p><strong>Conclusion: </strong>Our results suggest some atopy-associated immune differences in AA and highlight the OX40 axis as a potential novel therapeutic target that may broadly benefit AA patients.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900175","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}
Michael Fricker, John Harrington, Sarah A Hiles, Peter G Gibson
Background: Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.
Methods: We performed a cross-sectional observational study of severe asthma (eosinophilic n = 32, non-eosinophilic n = 23, mepolizumab-treated n = 25), with longitudinal follow-up of 30 eosinophilic participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.
Results: iEO proportion was significantly lower in mepolizumab-treated participants in both the cross-sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow-up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non-eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab-treated participants, which was associated with significantly better asthma control and spirometry.
Conclusions: Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab-treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.
背景:嗜酸性粒细胞是严重哮喘的关键治疗靶点,IL5(mepolizumab)和IL5受体(benralizumab)阻断剂可抑制嗜酸性粒细胞。IL5通路生物制剂对最近描述的静态(hEOs)和炎症(iEOs)嗜酸性粒细胞亚群的影响尚不清楚。我们旨在确定mepolizumab和benralizumab治疗对嗜酸性粒细胞亚群和表型的相对影响,并探讨嗜酸性粒细胞亚群与严重哮喘特征和治疗反应的临床关联:我们进行了一项重症哮喘横断面观察研究(嗜酸性粒细胞患者 n = 32,非嗜酸性粒细胞患者 n = 23,甲泼尼单抗治疗患者 n = 25),并在甲泼尼单抗(n = 20)或苯拉利珠单抗(n = 10)开始治疗后的两个时间点(4-24 周,>24 周)对 30 名嗜酸性粒细胞患者进行了纵向随访。通过流式细胞术评估表面CD62L蛋白,测量血液中的hEO和iEO。美泊利珠单抗和苯拉利珠单抗对iEO的消耗程度相似,但在随访中,美泊利珠单抗参与者中仍有更多的hEO。在嗜酸性粒细胞性哮喘中,较高的iEO比例与较差的哮喘控制率相关,但与非嗜酸性粒细胞性哮喘无关。残留的iEO比例越高,mepolizumab治疗者的哮喘控制效果越差。约半数接受过美泊珠单抗治疗的患者血液中的嗜酸性粒细胞存活率降低,这与哮喘控制率和肺活量显著改善有关:结论:在严重哮喘患者中,美泊利珠单抗会消耗iEOs并降低循环中嗜酸性粒细胞的活力,但会保留循环中残余的hEOs。相比之下,苯拉利珠单抗会同时消耗iEO和hEO。较高的iEO丰度和嗜酸性粒细胞活力与mepolizumab治疗后较差的临床结果有关。监测循环中嗜酸性粒细胞的表型和活力可能有助于预测重症哮喘的生物治疗反应。
{"title":"Mepolizumab depletes inflammatory but preserves homeostatic eosinophils in severe asthma.","authors":"Michael Fricker, John Harrington, Sarah A Hiles, Peter G Gibson","doi":"10.1111/all.16267","DOIUrl":"https://doi.org/10.1111/all.16267","url":null,"abstract":"<p><strong>Background: </strong>Eosinophils are key therapeutic targets in severe asthma that are suppressed by IL5 (mepolizumab) and IL5 receptor (benralizumab) blockade. The effect of IL5 pathway biologics on recently described homeostatic (hEOs) and inflammatory (iEOs) eosinophil subsets is unknown. We aimed to determine the relative impact of mepolizumab and benralizumab treatment on eosinophil subset and phenotype, and explore clinical associations of eosinophil subsets with severe asthma characteristics and treatment response.</p><p><strong>Methods: </strong>We performed a cross-sectional observational study of severe asthma (eosinophilic n = 32, non-eosinophilic n = 23, mepolizumab-treated n = 25), with longitudinal follow-up of 30 eosinophilic participants at two timepoints (4-24 weeks, >24 weeks) post-commencement of mepolizumab (n = 20) or benralizumab (n = 10). Blood hEOs and iEOs were measured by flow cytometry assessment of surface CD62L protein.</p><p><strong>Results: </strong>iEO proportion was significantly lower in mepolizumab-treated participants in both the cross-sectional and longitudinal study. Mepolizumab and benralizumab depleted iEOs to a similar extent, however a significantly greater number of hEOs remained in mepolizumab participants at follow-up. Greater iEO proportion correlated with poorer asthma control in eosinophilic but not non-eosinophilic asthma. Higher residual iEO proportion correlated with poorer asthma control in mepolizumab-treated individuals. Reduced blood eosinophil viability was observed in around half of mepolizumab-treated participants, which was associated with significantly better asthma control and spirometry.</p><p><strong>Conclusions: </strong>Mepolizumab depletes iEOs and reduces circulating eosinophil viability in severe asthma but preserves a residual population of circulatory hEOs. In contrast benralizumab depleted both iEOs and hEOs. Higher iEO abundance and eosinophil viability are associated with poorer clinical outcomes following mepolizumab-treatment. Monitoring circulating eosinophil phenotype and viability may be useful to predict biologic treatment response in severe asthma.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141900176","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}
Patrick Huber, Ulrike Förster-Ruhrmann, Heidi Olze, Sven Becker, Friederike Bärhold, Mandy Cuevas, Nadine Gunder, Jan Hagemann, Christoph Matthias, Ludger Klimek, Moritz Gröger
Background: Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent chronic inflammatory condition affecting the nose and paranasal sinuses, posing a significant socio-economic impact with substantial challenges in management. Biologics targeting type 2 inflammation such as dupilumab, have emerged as promising options. This study addresses a critical knowledge gap by comprehensively evaluating the 3-year impact of sustained dupilumab therapy in CRSwNP.
Methods: A multicentric, retrospective collection of real-world data from five tertiary referral centers in Germany was conducted, enrolling 150 adult patients. The study investigated patient-reported outcomes, disease-specific indices and clinical measures, focusing on therapeutic response persistence, adverse events, and factors influencing treatment continuity.
Results: Results indicate significant improvements in clinical parameters from baseline (n = 150) with sustained effectiveness after 36 months (n = 138) as indicated in mean score ± standard deviation. Dupilumab treatment significantly improved overall disease-related impairment (VAS score: 7.5 ± 2.5 to 1.6 ± 1.3) and rhinosinusitis symptoms (SNOT-22: 59.4 ± 19.4 to 18.0 ± 15.0). Nasal Polyp Scores (NPS) decreased (5.3 ± 1.8 to 0.7 ± 1.1), and olfactory function improved (3.2 ± 2.5 to 8.4 ± 2.8), with three out of four patients achieving normosmia or hyposmia after 36 months. An "Excellent" treatment response according to EUFOREA23 criteria was observed in 76.5% of patients after 36 months. Sixteen patients discontinued Dupilumab, 12 permanently. Adverse events totaled 69 in 48 patients, commonly self-limiting.
Conclusion: The study highlights the enduring effectiveness and lack of habituation to dupilumab after a sustained therapy of 3 years, providing valuable insights into its long-term therapeutic implications for CRSwNP patients.
{"title":"Real-world data show sustained therapeutic effects of dupilumab in chronic rhinosinusitis with nasal polyps (CRSwNP) over 3 years.","authors":"Patrick Huber, Ulrike Förster-Ruhrmann, Heidi Olze, Sven Becker, Friederike Bärhold, Mandy Cuevas, Nadine Gunder, Jan Hagemann, Christoph Matthias, Ludger Klimek, Moritz Gröger","doi":"10.1111/all.16263","DOIUrl":"https://doi.org/10.1111/all.16263","url":null,"abstract":"<p><strong>Background: </strong>Chronic rhinosinusitis with nasal polyps (CRSwNP) is a prevalent chronic inflammatory condition affecting the nose and paranasal sinuses, posing a significant socio-economic impact with substantial challenges in management. Biologics targeting type 2 inflammation such as dupilumab, have emerged as promising options. This study addresses a critical knowledge gap by comprehensively evaluating the 3-year impact of sustained dupilumab therapy in CRSwNP.</p><p><strong>Methods: </strong>A multicentric, retrospective collection of real-world data from five tertiary referral centers in Germany was conducted, enrolling 150 adult patients. The study investigated patient-reported outcomes, disease-specific indices and clinical measures, focusing on therapeutic response persistence, adverse events, and factors influencing treatment continuity.</p><p><strong>Results: </strong>Results indicate significant improvements in clinical parameters from baseline (n = 150) with sustained effectiveness after 36 months (n = 138) as indicated in mean score ± standard deviation. Dupilumab treatment significantly improved overall disease-related impairment (VAS score: 7.5 ± 2.5 to 1.6 ± 1.3) and rhinosinusitis symptoms (SNOT-22: 59.4 ± 19.4 to 18.0 ± 15.0). Nasal Polyp Scores (NPS) decreased (5.3 ± 1.8 to 0.7 ± 1.1), and olfactory function improved (3.2 ± 2.5 to 8.4 ± 2.8), with three out of four patients achieving normosmia or hyposmia after 36 months. An \"Excellent\" treatment response according to EUFOREA23 criteria was observed in 76.5% of patients after 36 months. Sixteen patients discontinued Dupilumab, 12 permanently. Adverse events totaled 69 in 48 patients, commonly self-limiting.</p><p><strong>Conclusion: </strong>The study highlights the enduring effectiveness and lack of habituation to dupilumab after a sustained therapy of 3 years, providing valuable insights into its long-term therapeutic implications for CRSwNP patients.</p>","PeriodicalId":122,"journal":{"name":"Allergy","volume":null,"pages":null},"PeriodicalIF":12.6,"publicationDate":"2024-08-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141896195","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}