Pub Date : 2024-11-01DOI: 10.1016/j.jaci.2024.07.021
Joseph Daccache BA , Eunsuh Park , Muhammad Junejo MD , Mariam Abdelghaffar BS , Erica Hwang BS , Chitrasen Mohanty MS , Chandra K. Singh PhD , Guilin Wang PhD , John O. Wheeler MS , Bridget E. Shields MD , Caroline A. Nelson MD , Yiwei Wang PhD , William Damsky MD, PhD
Background
Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear.
Objective
We sought to understand spatial gene expression characteristics in these disorders.
Methods
We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion.
Results
CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation.
Conclusions
Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.
{"title":"Spatial transcriptomics reveals organized and distinct immune activation in cutaneous granulomatous disorders","authors":"Joseph Daccache BA , Eunsuh Park , Muhammad Junejo MD , Mariam Abdelghaffar BS , Erica Hwang BS , Chitrasen Mohanty MS , Chandra K. Singh PhD , Guilin Wang PhD , John O. Wheeler MS , Bridget E. Shields MD , Caroline A. Nelson MD , Yiwei Wang PhD , William Damsky MD, PhD","doi":"10.1016/j.jaci.2024.07.021","DOIUrl":"10.1016/j.jaci.2024.07.021","url":null,"abstract":"<div><h3>Background</h3><div>Noninfectious (inflammatory) cutaneous granulomatous disorders include cutaneous sarcoidosis (CS), granuloma annulare (GA), necrobiosis lipoidica (NL), and necrobiotic xanthogranuloma (NXG). These disorders share macrophage-predominant inflammation histologically, but the inflammatory architecture and the pattern of extracellular matrix alteration varies. The underlying molecular explanations for these differences remain unclear.</div></div><div><h3>Objective</h3><div>We sought to understand spatial gene expression characteristics in these disorders.</div></div><div><h3>Methods</h3><div>We performed spatial transcriptomics in cases of CS, GA, NL, and NXG to compare patterns of immune activation and other molecular features in a spatially resolved fashion.</div></div><div><h3>Results</h3><div>CS is characterized by a polarized, spatially organized type 1-predominant response with classical macrophage activation. GA is characterized by a mixed but spatially organized pattern of type 1 and type 2 polarization with both classical and alternative macrophage activation. NL showed concomitant activation of type 1, type 2, and type 3 immunity with a mixed pattern of macrophage activation. Activation of type 1 immunity was shared among, CS, GA, and NL and included upregulation of IL-32. NXG showed upregulation of CXCR4-CXCL12/14 chemokine signaling and exaggerated alternative macrophage polarization. Histologic alteration of extracellular matrix correlated with hypoxia and glycolysis programs and type 2 immune activation.</div></div><div><h3>Conclusions</h3><div>Inflammatory cutaneous granulomatous disorders show distinct and spatially organized immune activation that correlate with hallmark histologic changes.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1216-1231"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889334","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.08.003
Witchaya Srisuwatchari MD , Mayte Suárez-Fariñas PhD , Andrew D. Delgado PhD , Galina Grishina MS , Maria Suprun PhD , Ashley Sang Eun Lee MD , Pakit Vichyanond MD , Punchama Pacharn MD , Hugh A. Sampson MD
Background
The bead-based epitope assay has been used to identify epitope-specific (es) antibodies and successfully used to diagnose clinical allergy to milk, egg, and peanut.
Objective
We sought to identify es-IgE, es-IgG4, and es-IgG1 of wheat proteins and determine the optimal peptides to differentiate wheat-allergic from wheat-tolerant using the bead-based epitope assay.
Methods
Children and adolescents who underwent an oral food challenge to confirm their wheat allergy status were enrolled. Seventy-nine peptides from α-/β-gliadin, γ-gliadin, ω-5-gliadin, and high- and low-molecular-weight glutenin were commercially synthesized and coupled to LumAvidin beads (Luminex Corporation, Austin, Tex). Machine learning methods were used to identify diagnostic epitopes, and performance was evaluated using the DeLong test.
Results
The analysis included 122 children (83 wheat-allergic and 39 wheat-tolerant; 57.4% male). Machine learning coupled with simulations identified wheat es-IgE, but not es-IgG4 or es-IgG1, to be the most informative for diagnosing wheat allergy. Higher es-IgE binding intensity correlated with the severity of allergy phenotypes, with wheat anaphylaxis exhibiting the highest es-IgE binding intensity. In contrast, wheat-dependent exercise-induced anaphylaxis showed lower es-IgG1 binding intensity than did all the other groups. A set of 4 informative epitopes from ω-5-gliadin and γ-gliadin were the best predictors of wheat allergy, with an area under the curve of 0.908 (sensitivity, 83.4%; specificity, 88.4%), higher than the performance exhibited by wheat-specific IgE (area under the curve = 0.646; P < .001). The predictive ability of our model was confirmed in an external cohort of 71 patients (29 allergic, 42 nonallergic), with an area under the curve of 0.908 (sensitivity, 75.9%; specificity, 90.5%).
Conclusions
The wheat bead-based epitope assay demonstrated greater diagnostic accuracy compared with existing specific IgE tests for wheat allergy.
{"title":"Utility of epitope-specific IgE, IgG4, and IgG1 antibodies for the diagnosis of wheat allergy","authors":"Witchaya Srisuwatchari MD , Mayte Suárez-Fariñas PhD , Andrew D. Delgado PhD , Galina Grishina MS , Maria Suprun PhD , Ashley Sang Eun Lee MD , Pakit Vichyanond MD , Punchama Pacharn MD , Hugh A. Sampson MD","doi":"10.1016/j.jaci.2024.08.003","DOIUrl":"10.1016/j.jaci.2024.08.003","url":null,"abstract":"<div><h3>Background</h3><div>The bead-based epitope assay has been used to identify epitope-specific (es) antibodies and successfully used to diagnose clinical allergy to milk, egg, and peanut.</div></div><div><h3>Objective</h3><div>We sought to identify es-IgE, es-IgG4, and es-IgG1 of wheat proteins and determine the optimal peptides to differentiate wheat-allergic from wheat-tolerant using the bead-based epitope assay.</div></div><div><h3>Methods</h3><div>Children and adolescents who underwent an oral food challenge to confirm their wheat allergy status were enrolled. Seventy-nine peptides from α-/β-gliadin, γ-gliadin, ω-5-gliadin, and high- and low-molecular-weight glutenin were commercially synthesized and coupled to LumAvidin beads (Luminex Corporation, Austin, Tex). Machine learning methods were used to identify diagnostic epitopes, and performance was evaluated using the DeLong test.</div></div><div><h3>Results</h3><div>The analysis included 122 children (83 wheat-allergic and 39 wheat-tolerant; 57.4% male). Machine learning coupled with simulations identified wheat es-IgE, but not es-IgG4 or es-IgG1, to be the most informative for diagnosing wheat allergy. Higher es-IgE binding intensity correlated with the severity of allergy phenotypes, with wheat anaphylaxis exhibiting the highest es-IgE binding intensity. In contrast, wheat-dependent exercise-induced anaphylaxis showed lower es-IgG1 binding intensity than did all the other groups. A set of 4 informative epitopes from ω-5-gliadin and γ-gliadin were the best predictors of wheat allergy, with an area under the curve of 0.908 (sensitivity, 83.4%; specificity, 88.4%), higher than the performance exhibited by wheat-specific IgE (area under the curve = 0.646; <em>P</em> < .001). The predictive ability of our model was confirmed in an external cohort of 71 patients (29 allergic, 42 nonallergic), with an area under the curve of 0.908 (sensitivity, 75.9%; specificity, 90.5%).</div></div><div><h3>Conclusions</h3><div>The wheat bead-based epitope assay demonstrated greater diagnostic accuracy compared with existing specific IgE tests for wheat allergy.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1249-1259"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141999994","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.08.015
James R. Baker Jr. MD , Roopesh Singh Gangwar PhD , Thomas A. Platts-Mills MD, PhD
{"title":"The processed milk hypothesis: A major factor in the development of eosinophilic esophagitis (EoE)?","authors":"James R. Baker Jr. MD , Roopesh Singh Gangwar PhD , Thomas A. Platts-Mills MD, PhD","doi":"10.1016/j.jaci.2024.08.015","DOIUrl":"10.1016/j.jaci.2024.08.015","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1123-1126"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142093181","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.07.028
Matthew A. Rank MD
{"title":"Mepolizumab for episodic angioedema with eosinophilia","authors":"Matthew A. Rank MD","doi":"10.1016/j.jaci.2024.07.028","DOIUrl":"10.1016/j.jaci.2024.07.028","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1340-1341"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142276875","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.06.023
Margot E. Starrenburg MD, MSc , Manal Bel Imam MSc , Juan F. Lopez MD, MSc , Laura Buergi BSc , N. Tan Nguyen MD , Anouk E.M. Nouwen MD , Nicolette J.T. Arends MD, PhD , Peter J. Caspers PhD , Mübeccel Akdis MD, PhD , Suzanne G.M.A. Pasmans MD, PhD , Willem van de Veen PhD
Background
A preference for type 2 immunity plays a central role in the pathogenesis of atopic dermatitis (AD). Dupilumab, an mAb targeting the IL-4 receptor α (IL-4Rα) subunit, inhibits IL-4 and IL-13 signaling. These cytokines contribute significantly to IgE class switch recombination in B cells, critical in atopic diseases. Recent studies indicate IgG+CD23hiIL-4Rα+ type 2 memory B cells (MBC2s) as IgE-producing B-cell precursors, linked to total IgE serum levels in atopic patients. Total IgE serum levels decreased during dupilumab treatment in previous studies.
Objective
We sought to assess the effects of dupilumab treatment in comparison with alternative therapies on the frequency of MBC2s and the correlation to total IgE levels in pediatric patients with AD.
Methods
Pediatric patients with AD, participating in an ongoing trial, underwent randomization into 3 treatment groups: dupilumab (n = 12), cyclosporine (n = 12), and topical treatment (n = 12). Plasma samples and PBMCs were collected at baseline (T0) and at 6 months after starting therapy (T6). Flow cytometry was used for PBMC phenotyping, and ELISA was used to assess total IgE levels in plasma.
Results
Our findings revealed a significant reduction in MBC2 frequency and total IgE levels among patients treated with dupilumab. In addition, a significant correlation was observed between MBC2s and total IgE levels.
Conclusions
Systemic blocking of the IL-4Rα subunit leads to a decrease in circulating MBC2 cells and total IgE levels in pediatric patients with AD. Our findings unveiled a novel mechanism through which dupilumab exerts its influence on the atopic signature.
背景：2型免疫偏好在特应性皮炎（AD）的发病机制中起着核心作用。Dupilumab是一种靶向IL-4α受体亚基的单克隆抗体，可抑制IL-4和IL-13信号传导。这些细胞因子对 B 细胞中的 IgE 类开关重组有重要作用，对特应性疾病至关重要。最近的研究表明，IgG+CD23hiIL-4RA+ 记忆 B 细胞（MBC2）是产生 IgE 的 B 细胞前体，与特应性患者的总 IgE 血清水平有关。在之前的研究中，总IgE血清水平在dupilumab治疗期间有所下降：目的：评估杜比单抗治疗与其他疗法相比对MBC2频率的影响，以及与AD儿科患者总IgE水平的相关性：参加一项正在进行的试验的儿科AD患者被随机分为三个治疗组：杜匹单抗组（12人）、环孢素组（12人）或局部治疗组（12人）。在基线（T0）和 6 个月后（T6）收集血浆和外周血单核细胞（PBMC）。流式细胞术用于 PBMC 表型分析，ELISA 用于评估血浆中的总 IgE 水平。详细方法请参阅本文在线资料库中的方法部分，网址：www.jacionline.org 结果：我们的研究结果显示，接受杜比单抗治疗的患者的MBC2频率和总IgE水平显著降低。此外，还观察到 MBC2 与总 IgE 水平之间存在明显的相关性 结论：全身阻断 IL-4RA 亚基可导致循环中的 MBC2 细胞减少，并降低儿科 AD 患者的总 IgE。我们的研究结果揭示了一种新的机制，即杜匹单抗通过这种机制对特应性特征产生影响。
{"title":"Dupilumab treatment decreases MBC2s, correlating with reduced IgE levels in pediatric atopic dermatitis","authors":"Margot E. Starrenburg MD, MSc , Manal Bel Imam MSc , Juan F. Lopez MD, MSc , Laura Buergi BSc , N. Tan Nguyen MD , Anouk E.M. Nouwen MD , Nicolette J.T. Arends MD, PhD , Peter J. Caspers PhD , Mübeccel Akdis MD, PhD , Suzanne G.M.A. Pasmans MD, PhD , Willem van de Veen PhD","doi":"10.1016/j.jaci.2024.06.023","DOIUrl":"10.1016/j.jaci.2024.06.023","url":null,"abstract":"<div><h3>Background</h3><div>A preference for type 2 immunity plays a central role in the pathogenesis of atopic dermatitis (AD). Dupilumab, an mAb targeting the IL-4 receptor α (IL-4Rα) subunit, inhibits IL-4 and IL-13 signaling. These cytokines contribute significantly to IgE class switch recombination in B cells, critical in atopic diseases. Recent studies indicate IgG<sup>+</sup>CD23<sup>hi</sup>IL-4Rα<sup>+</sup> type 2 memory B cells (MBC2s) as IgE-producing B-cell precursors, linked to total IgE serum levels in atopic patients. Total IgE serum levels decreased during dupilumab treatment in previous studies.</div></div><div><h3>Objective</h3><div>We sought to assess the effects of dupilumab treatment in comparison with alternative therapies on the frequency of MBC2s and the correlation to total IgE levels in pediatric patients with AD.</div></div><div><h3>Methods</h3><div>Pediatric patients with AD, participating in an ongoing trial, underwent randomization into 3 treatment groups: dupilumab (n = 12), cyclosporine (n = 12), and topical treatment (n = 12). Plasma samples and PBMCs were collected at baseline (T0) and at 6 months after starting therapy (T6). Flow cytometry was used for PBMC phenotyping, and ELISA was used to assess total IgE levels in plasma.</div></div><div><h3>Results</h3><div>Our findings revealed a significant reduction in MBC2 frequency and total IgE levels among patients treated with dupilumab. In addition, a significant correlation was observed between MBC2s and total IgE levels.</div></div><div><h3>Conclusions</h3><div>Systemic blocking of the IL-4Rα subunit leads to a decrease in circulating MBC2 cells and total IgE levels in pediatric patients with AD. Our findings unveiled a novel mechanism through which dupilumab exerts its influence on the atopic signature.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1333-1338.e4"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141748260","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}
Pub Date : 2024-11-01DOI: 10.1016/j.jaci.2024.07.014
Derek Croote PhD , Joyce J.W. Wong PhD , Paige Creeks BS , Venu Aruva MS , Jeffrey J. Landers BS , Matthew Kwok MSc , Zainab Jama BSc , Robert G. Hamilton PhD , Alexandra F. Santos MD, PhD , Jessica J. O’Konek PhD , Roger Ferrini PhD , G. Roger Thomas PhD , Henry B. Lowman PhD
Background
Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions.
Objective
Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies.
Methods
We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. In vitro mast cell activation tests, basophil activation tests, ELISAs, and an in vivo peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs.
Results
We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation in vitro as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model.
Conclusions
We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.
{"title":"Preclinical efficacy of peanut-specific IgG4 antibody therapeutic IGNX001","authors":"Derek Croote PhD , Joyce J.W. Wong PhD , Paige Creeks BS , Venu Aruva MS , Jeffrey J. Landers BS , Matthew Kwok MSc , Zainab Jama BSc , Robert G. Hamilton PhD , Alexandra F. Santos MD, PhD , Jessica J. O’Konek PhD , Roger Ferrini PhD , G. Roger Thomas PhD , Henry B. Lowman PhD","doi":"10.1016/j.jaci.2024.07.014","DOIUrl":"10.1016/j.jaci.2024.07.014","url":null,"abstract":"<div><h3>Background</h3><div>Existing therapeutic strategies are challenged by long times to achieve effect and often require frequent administration. Peanut-allergic individuals would benefit from a therapeutic that provides rapid protection against accidental exposure within days of administration while carrying little risk of adverse reactions.</div></div><div><h3>Objective</h3><div>Guided by the repertoire of human IgE mAbs from allergic individuals, we sought to develop a treatment approach leveraging the known protective effects of allergen-specific IgG4 antibodies.</div></div><div><h3>Methods</h3><div>We applied our single-cell RNA-sequencing SEQ SIFTER platform (IgGenix, Inc, South San Francisco, Calif) to whole blood samples from peanut-allergic individuals to discover IgE mAbs. These were then class-switched by replacing the IgE constant region with IgG4 while retaining the allergen-specific variable regions. <em>In vitro</em> mast cell activation tests, basophil activation tests, ELISAs, and an <em>in vivo</em> peanut allergy mouse model were used to evaluate the specificity, affinity, and activity of these recombinant IgG4 mAbs.</div></div><div><h3>Results</h3><div>We determined that human peanut-specific IgE mAbs predominantly target immunodominant epitopes on Ara h 2 and Ara h 6 and that recombinant IgG4 mAbs effectively block these epitopes. IGNX001, a mixture of 2 such high-affinity IgG4 mAbs, provided robust protection against peanut-mediated mast cell activation <em>in vitro</em> as well as against anaphylaxis upon intragastric peanut challenge in a peanut allergy mouse model.</div></div><div><h3>Conclusions</h3><div>We developed a peanut-specific IgG4 antibody therapeutic with convincing preclinical efficacy starting from a large repertoire of human IgE mAbs from demographically and geographically diverse individuals. These results warrant further clinical investigation of IGNX001 and underscore the opportunity for the application of this therapeutic development strategy in other food and environmental allergies.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1241-1248.e7"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141788085","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}
Pub Date : 2024-11-01DOI: 10.1016/j.jaci.2024.07.017
Kelsey R. van Straalen MD, PhD , Joseph Kirma BS , Christine M. Yee BS , Luke F. Bugada BCE , Syed M. Rizvi PhD , Fei Wen PhD , Rachael Wasikowski MS , Jennifer Fox , Tran H. Do MD, PhD , Charles F. Schuler IV MD , Enze Xing BS , Amanda S. MacLeod MD , Paul W. Harms MD, PhD , Celine C. Berthier PhD , J. Michelle Kahlenberg MD, PhD , Monica W.L. Leung PhD , Lam C. Tsoi PhD , Johann E. Gudjonsson MD, PhD
Background
Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non–pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE).
Objective
We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis.
Methods
We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples.
Results
Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell–associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity.
Conclusion
A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.
{"title":"Disease heterogeneity and molecular classification of inflammatory palmoplantar diseases","authors":"Kelsey R. van Straalen MD, PhD , Joseph Kirma BS , Christine M. Yee BS , Luke F. Bugada BCE , Syed M. Rizvi PhD , Fei Wen PhD , Rachael Wasikowski MS , Jennifer Fox , Tran H. Do MD, PhD , Charles F. Schuler IV MD , Enze Xing BS , Amanda S. MacLeod MD , Paul W. Harms MD, PhD , Celine C. Berthier PhD , J. Michelle Kahlenberg MD, PhD , Monica W.L. Leung PhD , Lam C. Tsoi PhD , Johann E. Gudjonsson MD, PhD","doi":"10.1016/j.jaci.2024.07.017","DOIUrl":"10.1016/j.jaci.2024.07.017","url":null,"abstract":"<div><h3>Background</h3><div>Palmoplantar pustulosis (PPP) is an inflammatory disease characterized by relapsing eruptions of neutrophil-filled, sterile pustules on the palms and soles that can be clinically difficult to differentiate from non–pustular palmoplantar psoriasis (palmPP) and dyshidrotic palmoplantar eczema (DPE).</div></div><div><h3>Objective</h3><div>We sought to identify overlapping and unique PPP, palmPP, and DPE drivers to provide molecular insight into their pathogenesis.</div></div><div><h3>Methods</h3><div>We performed bulk RNA sequencing of lesional PPP (n = 33), palmPP (n = 5), and DPE (n = 28) samples, as well as 5 healthy nonacral and 10 healthy acral skin samples.</div></div><div><h3>Results</h3><div>Acral skin showed a unique immune environment, likely contributing to a unique niche for palmoplantar inflammatory diseases. Compared to healthy acral skin, PPP, palmPP, and DPE displayed a broad overlapping transcriptomic signature characterized by shared upregulation of proinflammatory cytokines (TNF, IL-36), chemokines, and T-cell–associated genes, along with unique disease features of each disease state, including enriched neutrophil processes in PPP and to a lesser extent in palmPP, and lipid antigen processing in DPE. Strikingly, unsupervised clustering and trajectory analyses demonstrated divergent inflammatory profiles within the 3 disease states. These identified putative key upstream immunologic switches, including eicosanoids, interferon responses, and neutrophil degranulation, contributing to disease heterogeneity.</div></div><div><h3>Conclusion</h3><div>A molecular overlap exists between different inflammatory palmoplantar diseases that supersedes clinical and histologic assessment. This highlights the heterogeneity within each condition, suggesting limitations of current disease classification and the need to move toward a molecular classification of inflammatory acral diseases.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1204-1215.e9"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141874875","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.06.005
{"title":"Central trained immunity and its impact on chronic inflammatory and autoimmune diseases","authors":"","doi":"10.1016/j.jaci.2024.06.005","DOIUrl":"10.1016/j.jaci.2024.06.005","url":null,"abstract":"","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1113-1116"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141310784","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.07.019
Serena Yun-Chen Tsai MD, MMSc , Wanda Phipatanakul MD, MS , Elena B. Hawryluk MD, PhD , Michiko K. Oyoshi PhD , Lynda C. Schneider MD , Kevin Sheng-Kai Ma DDS, FRSPH, FRSM
Background
Systemic Janus kinase inhibitors (JAKi) and dupilumab both have emerged as promising therapeutics for atopic dermatitis (AD). Dupilumab has a favorable safety profile, but oral JAKi therapy has been established in other diseases that carry potential comorbid susceptibilities that influence safety.
Objective
We sought to provide real-world evidence of the comparative safety of oral JAKi versus dupilumab in patients with AD.
Methods
The study used observational data from multiple healthcare organizations in the US. Patients with AD treated with either oral JAKi (upadacitinib, abrocitinib, and baricitinib) or dupilumab were enrolled. The 2 treatment groups were propensity score matched 1:1 on the basis of demographics, comorbidities, and prior medications. Safety outcomes within 2 years after the initiation of medications were measured by hazard ratios (HRs) with 95% confidence intervals (CIs).
Results
A total of 14,716 patients were included, with 942 patients treated with oral JAKi and 13,774 with dupilumab. The 2 treatment groups respectively included 938 patients after matching. Treatment with oral JAKi was not associated with increased risks of mortality, malignancies, major adverse cardiovascular events, venous thromboembolism, renal events, or serious gastrointestinal events. However, patients receiving oral JAKi showed significantly higher risks of skin and subcutaneous tissue infection (HR = 1.35, 95% CI = 1.07-1.69), herpes infection (herpes simplex, HR = 1.64, 95% CI = 1.03-2.61; herpes zoster, HR = 2.51, 95% CI = 1.14-5.52), acne (HR = 2.09, 95% CI = 1.54-2.84), cytopenia (anemia, HR = 1.83, 95% CI = 1.39-2.41; neutropenia, HR = 4.02, 95% CI = 1.91-8.47; thrombocytopenia, HR = 1.76, 95% CI = 1.08-2.89), and hyperlipidemia (HR = 1.45, 95% CI = 1.09-1.92); the risk of ophthalmic complications was higher in those receiving dupilumab (HR = 1.49, 95% CI = 1.03-2.17).
Conclusion
Oral JAKi did not exhibit concerning safety issues in treating patients with AD but increased the risk of infections and abnormalities in laboratory findings. Long-term follow-up data are required to validate these results.
背景：全身性 Janus 激酶抑制剂（JAKi）和杜比单抗都已成为治疗特应性皮炎（AD）的有前途的疗法。尽管杜比鲁单抗具有良好的安全性，但口服 JAKi 已被用于其他疾病，而这些疾病具有影响安全性的潜在并发症：为口服 JAKi 在 AD 患者中的安全性提供实际证据：研究使用了 TriNetX（马萨诸塞州剑桥市）的观察数据。接受口服 JAKi（upadacitinib、abrocitinib 和 baricitinib）或 dupilumab 治疗的 AD 患者被纳入研究。两个治疗组根据人口统计学、合并症和既往用药情况进行了倾向得分匹配，比例为1:1。用危险比和95%置信区间来衡量用药后两年内的安全性结果：共纳入14716名患者，其中942名患者接受了口服JAKi治疗，13774名患者接受了dupilumab治疗。两个治疗组在匹配后共纳入938名患者。口服JAKi治疗与死亡率、恶性肿瘤、主要不良心血管事件、静脉血栓栓塞、肾脏事件或严重胃肠道事件的风险增加无关。然而，接受口服JAKi治疗的患者发生皮肤和皮下组织感染、疱疹感染、痤疮、全血细胞减少症和高脂血症的风险明显较高，而接受dupilumab治疗的患者发生眼科并发症的风险较高：这项研究发现，口服JAKi在治疗AD患者时并没有表现出令人担忧的安全性问题，但会增加感染和实验室异常的风险。需要长期随访数据来验证这些发现。
{"title":"Comparative safety of oral Janus kinase inhibitors versus dupilumab in patients with atopic dermatitis: A population-based cohort study","authors":"Serena Yun-Chen Tsai MD, MMSc , Wanda Phipatanakul MD, MS , Elena B. Hawryluk MD, PhD , Michiko K. Oyoshi PhD , Lynda C. Schneider MD , Kevin Sheng-Kai Ma DDS, FRSPH, FRSM","doi":"10.1016/j.jaci.2024.07.019","DOIUrl":"10.1016/j.jaci.2024.07.019","url":null,"abstract":"<div><h3>Background</h3><div>Systemic Janus kinase inhibitors (JAKi) and dupilumab both have emerged as promising therapeutics for atopic dermatitis (AD). Dupilumab has a favorable safety profile, but oral JAKi therapy has been established in other diseases that carry potential comorbid susceptibilities that influence safety.</div></div><div><h3>Objective</h3><div>We sought to provide real-world evidence of the comparative safety of oral JAKi versus dupilumab in patients with AD.</div></div><div><h3>Methods</h3><div>The study used observational data from multiple healthcare organizations in the US. Patients with AD treated with either oral JAKi (upadacitinib, abrocitinib, and baricitinib) or dupilumab were enrolled. The 2 treatment groups were propensity score matched 1:1 on the basis of demographics, comorbidities, and prior medications. Safety outcomes within 2 years after the initiation of medications were measured by hazard ratios (HRs) with 95% confidence intervals (CIs).</div></div><div><h3>Results</h3><div>A total of 14,716 patients were included, with 942 patients treated with oral JAKi and 13,774 with dupilumab. The 2 treatment groups respectively included 938 patients after matching. Treatment with oral JAKi was not associated with increased risks of mortality, malignancies, major adverse cardiovascular events, venous thromboembolism, renal events, or serious gastrointestinal events. However, patients receiving oral JAKi showed significantly higher risks of skin and subcutaneous tissue infection (HR = 1.35, 95% CI = 1.07-1.69), herpes infection (herpes simplex, HR = 1.64, 95% CI = 1.03-2.61; herpes zoster, HR = 2.51, 95% CI = 1.14-5.52), acne (HR = 2.09, 95% CI = 1.54-2.84), cytopenia (anemia, HR = 1.83, 95% CI = 1.39-2.41; neutropenia, HR = 4.02, 95% CI = 1.91-8.47; thrombocytopenia, HR = 1.76, 95% CI = 1.08-2.89), and hyperlipidemia (HR = 1.45, 95% CI = 1.09-1.92); the risk of ophthalmic complications was higher in those receiving dupilumab (HR = 1.49, 95% CI = 1.03-2.17).</div></div><div><h3>Conclusion</h3><div>Oral JAKi did not exhibit concerning safety issues in treating patients with AD but increased the risk of infections and abnormalities in laboratory findings. Long-term follow-up data are required to validate these results.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1195-1203.e3"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141889333","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 : 2024-11-01DOI: 10.1016/j.jaci.2024.07.024
Fabian Bick MSc , Claudia M. Brenis Gómez MD , Inés Lammens MD , Justine Van Moorleghem BSc , Caroline De Wolf BSc , Sam Dupont BSc , Laure Dumoutier PhD , Neal P. Smith MSc , Alexandra-Chloé Villani PhD , Robin Browaeys PhD , Jehan Alladina MD , Alexis M. Haring BSc , Benjamin D. Medoff MD , Josalyn L. Cho MD , René Bigirimana PhD , Joao Vieira MSc , Hamida Hammad PhD , Christophe Blanchetot PhD , Martijn J. Schuijs PhD , Bart N. Lambrecht MD, PhD
Background
Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5, and IL-13 cytokines produced by TH2 lymphocytes or type 2 innate lymphoid cells (ILC2s). IL-2 family cytokines play a key role in the differentiation, homeostasis, and effector function of innate and adaptive lymphocytes.
Objective
IL-9 and IL-21 boost activation and proliferation of TH2 and ILC2s, but the relative importance and potential synergism between these γ common chain cytokines are currently unknown.
Methods
Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human subjects with allergic asthma compared with nonasthmatic controls. Here, we also measured IL-21 in both groups.
Results
IL-9 played a central role in controlling innate IL-33–induced lung inflammation by promoting proliferation and activation of ILC2s in an IL-21–independent manner. Conversely, chronic house dust mite–induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, which controlled TH2 activation, eosinophilia, total serum IgE, and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, as combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage samples we measured elevated IL-21 protein within the allergic asthmatic group compared with the allergic control group. We also found increased IL21R transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.
Conclusions
IL-9 and IL-21 play important and nonredundant roles in allergic asthma by boosting ILC2s and TH2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.
{"title":"IL-2 family cytokines IL-9 and IL-21 differentially regulate innate and adaptive type 2 immunity in asthma","authors":"Fabian Bick MSc , Claudia M. Brenis Gómez MD , Inés Lammens MD , Justine Van Moorleghem BSc , Caroline De Wolf BSc , Sam Dupont BSc , Laure Dumoutier PhD , Neal P. Smith MSc , Alexandra-Chloé Villani PhD , Robin Browaeys PhD , Jehan Alladina MD , Alexis M. Haring BSc , Benjamin D. Medoff MD , Josalyn L. Cho MD , René Bigirimana PhD , Joao Vieira MSc , Hamida Hammad PhD , Christophe Blanchetot PhD , Martijn J. Schuijs PhD , Bart N. Lambrecht MD, PhD","doi":"10.1016/j.jaci.2024.07.024","DOIUrl":"10.1016/j.jaci.2024.07.024","url":null,"abstract":"<div><h3>Background</h3><div>Asthma is often accompanied by type 2 immunity rich in IL-4, IL-5, and IL-13 cytokines produced by T<sub>H</sub>2 lymphocytes or type 2 innate lymphoid cells (ILC2s). IL-2 family cytokines play a key role in the differentiation, homeostasis, and effector function of innate and adaptive lymphocytes.</div></div><div><h3>Objective</h3><div>IL-9 and IL-21 boost activation and proliferation of T<sub>H</sub>2 and ILC2s, but the relative importance and potential synergism between these γ common chain cytokines are currently unknown.</div></div><div><h3>Methods</h3><div>Using newly generated antibodies, we inhibited IL-9 and IL-21 alone or in combination in various murine models of asthma. In a translational approach using segmental allergen challenge, we recently described elevated IL-9 levels in human subjects with allergic asthma compared with nonasthmatic controls. Here, we also measured IL-21 in both groups.</div></div><div><h3>Results</h3><div>IL-9 played a central role in controlling innate IL-33–induced lung inflammation by promoting proliferation and activation of ILC2s in an IL-21–independent manner. Conversely, chronic house dust mite–induced airway inflammation, mainly driven by adaptive immunity, was solely dependent on IL-21, which controlled T<sub>H</sub>2 activation, eosinophilia, total serum IgE, and formation of tertiary lymphoid structures. In a model of innate on adaptive immunity driven by papain allergen, a clear synergy was found between both pathways, as combined anti-IL-9 or anti-IL-21 blockade was superior in reducing key asthma features. In human bronchoalveolar lavage samples we measured elevated IL-21 protein within the allergic asthmatic group compared with the allergic control group. We also found increased <em>IL21R</em> transcripts and predicted IL-21 ligand activity in various disease-associated cell subsets.</div></div><div><h3>Conclusions</h3><div>IL-9 and IL-21 play important and nonredundant roles in allergic asthma by boosting ILC2s and T<sub>H</sub>2 cells, revealing a dual IL-9 and IL-21 targeting strategy as a new and testable approach.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"154 5","pages":"Pages 1129-1145"},"PeriodicalIF":11.4,"publicationDate":"2024-11-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141987945","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}
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