杜匹单抗治疗特应性皮炎患者的纵向综合蛋白质组学和代谢组学皮肤变化。

IF 11.2 1区医学 Q1 ALLERGY

Journal of Allergy and Clinical Immunology Pub Date : 2025-05-01 Epub Date: 2025-01-23 DOI:10.1016/j.jaci.2025.01.020

Elena Goleva PhD , Evgeny Berdyshev PhD , Simion Kreimer PhD , Julie A. Reisz PhD , Angelo D’Alessandro PhD , Irina Bronova PhD , Taras Lyubchenko PhD , Brittany N. Richers BS , Clifton F. Hall MS , Olivia Xiao BS , Anna-Sofia Bronoff BS , Shantanu Bafna MS , Inoncent Agueusop PhD , Emilie Gloaguen PhD , Joseph Zahn MD , Robert Bissonnette MD , Annie Zhang MD , Donald Y.M. Leung MD, PhD

{"title":"杜匹单抗治疗特应性皮炎患者的纵向综合蛋白质组学和代谢组学皮肤变化。","authors":"Elena Goleva PhD , Evgeny Berdyshev PhD , Simion Kreimer PhD , Julie A. Reisz PhD , Angelo D’Alessandro PhD , Irina Bronova PhD , Taras Lyubchenko PhD , Brittany N. Richers BS , Clifton F. Hall MS , Olivia Xiao BS , Anna-Sofia Bronoff BS , Shantanu Bafna MS , Inoncent Agueusop PhD , Emilie Gloaguen PhD , Joseph Zahn MD , Robert Bissonnette MD , Annie Zhang MD , Donald Y.M. Leung MD, PhD","doi":"10.1016/j.jaci.2025.01.020","DOIUrl":null,"url":null,"abstract":"<div><h3>Background</h3><div>Inhibition of IL-4/IL-13–driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).</div></div><div><h3>Objective</h3><div>Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.</div></div><div><h3>Methods</h3><div>Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography–mass spectrometry proteomic analysis and targeted metabolomics.</div></div><div><h3>Results</h3><div>Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both <em>P</em> < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (<em>P</em> < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants.</div></div><div><h3>Conclusion</h3><div>Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity.</div></div>","PeriodicalId":14936,"journal":{"name":"Journal of Allergy and Clinical Immunology","volume":"155 5","pages":"Pages 1536-1546"},"PeriodicalIF":11.2000,"publicationDate":"2025-05-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Longitudinal integrated proteomic and metabolomic skin changes in patients with atopic dermatitis treated with dupilumab\",\"authors\":\"Elena Goleva PhD , Evgeny Berdyshev PhD , Simion Kreimer PhD , Julie A. Reisz PhD , Angelo D’Alessandro PhD , Irina Bronova PhD , Taras Lyubchenko PhD , Brittany N. Richers BS , Clifton F. Hall MS , Olivia Xiao BS , Anna-Sofia Bronoff BS , Shantanu Bafna MS , Inoncent Agueusop PhD , Emilie Gloaguen PhD , Joseph Zahn MD , Robert Bissonnette MD , Annie Zhang MD , Donald Y.M. Leung MD, PhD\",\"doi\":\"10.1016/j.jaci.2025.01.020\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><h3>Background</h3><div>Inhibition of IL-4/IL-13–driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).</div></div><div><h3>Objective</h3><div>Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.</div></div><div><h3>Methods</h3><div>Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography–mass spectrometry proteomic analysis and targeted metabolomics.</div></div><div><h3>Results</h3><div>Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both <em>P</em> < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (<em>P</em> < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants.</div></div><div><h3>Conclusion</h3><div>Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity.</div></div>\",\"PeriodicalId\":14936,\"journal\":{\"name\":\"Journal of Allergy and Clinical Immunology\",\"volume\":\"155 5\",\"pages\":\"Pages 1536-1546\"},\"PeriodicalIF\":11.2000,\"publicationDate\":\"2025-05-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Journal of Allergy and Clinical Immunology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0091674925000715\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"2025/1/23 0:00:00\",\"PubModel\":\"Epub\",\"JCR\":\"Q1\",\"JCRName\":\"ALLERGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Journal of Allergy and Clinical Immunology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0091674925000715","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"2025/1/23 0:00:00","PubModel":"Epub","JCR":"Q1","JCRName":"ALLERGY","Score":null,"Total":0}

引用次数: 0

摘要

背景：dupilumab抑制IL-4/IL-13驱动的炎症在治疗特应性皮炎（AD）中显示出显着的临床益处。目的：评估杜匹单抗治疗期间AD皮肤纵向蛋白和代谢物组成。方法：收集20例AD患者在16周的dupilumab治疗期间的病变/非病变皮肤，以及20例健康志愿者（HV）随访16周的皮肤胶带条（STS）。通过LC-MS蛋白质组学分析和靶向代谢组学检测STS提取物。结果：在STS提取物中鉴定出大约2500个单独的蛋白质。≥80%的AD和HV皮肤样本中存在490种蛋白，并在AD皮肤中存在差异表达。在AD皮肤中，249种蛋白显著减少（第1类），136种蛋白显著增加（第2类）。结论：对dupilumab治疗的AD患者皮肤蛋白质组和代谢组进行纵向综合评估，发现dupilumab可显著抑制表皮增生，改善表皮分化。确定的变化与临床AD皮肤评估的改善有关，包括TEWL和疾病严重程度。临床意义：质谱分析确定了AD患者皮肤蛋白和代谢物组成的分子改善及其与dupilumab治疗和临床反应靶向抑制IL-4/IL-13信号传导的关系。本研究对dupilumab治疗的AD患者皮肤样本进行纵向采样和分析，评估皮肤屏障结构和炎症蛋白组分、皮肤代谢物及其在治疗过程中的变化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

查看原文本刊更多论文

Longitudinal integrated proteomic and metabolomic skin changes in patients with atopic dermatitis treated with dupilumab

Background

Inhibition of IL-4/IL-13–driven inflammation by dupilumab has shown significant clinical benefits in treatment of atopic dermatitis (AD).

Objective

Our aim was to assess longitudinal protein and metabolite composition in AD skin during dupilumab treatment.

Methods

Skin tape strips (STSs) were collected from lesional/nonlesional skin of 20 patients with AD during a 16-week dupilumab treatment course and from 20 healthy volunteers (HVs) followed for 16 weeks. STS extracts were examined by liquid chromatography–mass spectrometry proteomic analysis and targeted metabolomics.

Results

Approximately 2500 individual proteins were identified in the STS extracts. Of those proteins, 490 were present in at least 80% of the AD and HV skin samples and differentially expressed in the AD skin; the levels of 249 proteins were significantly reduced (cluster 1), and the levels of 136 were significantly increased (cluster 2) in the AD skin versus in the HV skin (both P < .0001). Functionally, cluster 1 included proteins involved in epidermal barrier formation, lysosomal enzymes required for lamellae assembly, and oxidative response. Cluster 2 was enriched for markers of epidermal hyperplasia, glycolytic enzymes, and actin filament proteins. A significant increase in cluster 1 and a significant inhibition of cluster 2 proteins expression were achieved in AD skin by 16 weeks of dupilumab treatment (P < .0001 for both vs baseline), approaching the levels in HV skin. These improvements were also revealed in differential metabolite changes in the STS extracts, including amino acids, nucleotide breakdown products, and antioxidants.

Conclusion

Longitudinal integrated assessment of the skin proteome and metabolome in patients with AD who were treated with dupilumab established significant inhibition of epidermal hyperplasia and improvement in epidermal differentiation. The identified changes were linked to improvements in clinical AD skin assessments, including improvements in transepidermal water loss and disease severity.

求助全文

通过发布文献求助，成功后即可免费获取论文全文。去求助

来源期刊

Journal of Allergy and Clinical Immunology 医学-过敏

CiteScore

25.90

自引率

7.70%

发文量

1302

审稿时长

38 days

期刊介绍： The Journal of Allergy and Clinical Immunology is a prestigious publication that features groundbreaking research in the fields of Allergy, Asthma, and Immunology. This influential journal publishes high-impact research papers that explore various topics, including asthma, food allergy, allergic rhinitis, atopic dermatitis, primary immune deficiencies, occupational and environmental allergy, and other allergic and immunologic diseases. The articles not only report on clinical trials and mechanistic studies but also provide insights into novel therapies, underlying mechanisms, and important discoveries that contribute to our understanding of these diseases. By sharing this valuable information, the journal aims to enhance the diagnosis and management of patients in the future.