Amy Y Zhao, Avraham Unterman, Nebal S Abu Hussein, Prapti Sharma, Fadi Nikola, Jasper Flint, Xiting Yan, Taylor S Adams, Aurelien Justet, Tomokazu S Sumida, Jiayi Zhao, Jonas C Schupp, Micha Sam B Raredon, Farida Ahangari, Giuseppe Deluliis, Yingze Zhang, Ivette Buendia-Roldan, Ayodeji Adegunsoye, Anne I Sperling, Antje Prasse, Changwan Ryu, Erica Herzog, Moises Selman, Annie Pardo, Naftali Kaminski
{"title":"单细胞揭示纤维化超敏性肺炎的新型免疫紊乱","authors":"Amy Y Zhao, Avraham Unterman, Nebal S Abu Hussein, Prapti Sharma, Fadi Nikola, Jasper Flint, Xiting Yan, Taylor S Adams, Aurelien Justet, Tomokazu S Sumida, Jiayi Zhao, Jonas C Schupp, Micha Sam B Raredon, Farida Ahangari, Giuseppe Deluliis, Yingze Zhang, Ivette Buendia-Roldan, Ayodeji Adegunsoye, Anne I Sperling, Antje Prasse, Changwan Ryu, Erica Herzog, Moises Selman, Annie Pardo, Naftali Kaminski","doi":"10.1164/rccm.202401-0078OC","DOIUrl":null,"url":null,"abstract":"<p><p><b>Rationale:</b> Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. <b>Objectives:</b> To elucidate immune aberrations in FHP in single-cell resolution. <b>Methods:</b> Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). <b>Measurements and Main Results:</b> Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted-<i>P</i> = 2.5 × 10<sup>-3</sup>) and is enriched in CCL3<sup>hi</sup>/CCL4<sup>hi</sup> and S100A<sup>hi</sup> classical monocytes (adjusted-<i>P</i> < 2.2 × 10<sup>-16</sup>). Trajectory analyses demonstrate that S100A<sup>hi</sup> classical monocytes differentiate into SPP1<sup>hi</sup> lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZM<sup>hi</sup> cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. <b>Conclusions:</b> Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZM<sup>hi</sup> cytotoxic CD4<sup>+</sup> and CD8<sup>+</sup> T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100A<sup>hi</sup> and CCL3<sup>hi</sup>/CCL4<sup>hi</sup> classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.</p>","PeriodicalId":7664,"journal":{"name":"American journal of respiratory and critical care medicine","volume":" ","pages":"1252-1266"},"PeriodicalIF":19.3000,"publicationDate":"2024-11-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568434/pdf/","citationCount":"0","resultStr":"{\"title\":\"Single-Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.\",\"authors\":\"Amy Y Zhao, Avraham Unterman, Nebal S Abu Hussein, Prapti Sharma, Fadi Nikola, Jasper Flint, Xiting Yan, Taylor S Adams, Aurelien Justet, Tomokazu S Sumida, Jiayi Zhao, Jonas C Schupp, Micha Sam B Raredon, Farida Ahangari, Giuseppe Deluliis, Yingze Zhang, Ivette Buendia-Roldan, Ayodeji Adegunsoye, Anne I Sperling, Antje Prasse, Changwan Ryu, Erica Herzog, Moises Selman, Annie Pardo, Naftali Kaminski\",\"doi\":\"10.1164/rccm.202401-0078OC\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p><b>Rationale:</b> Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. <b>Objectives:</b> To elucidate immune aberrations in FHP in single-cell resolution. <b>Methods:</b> Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). <b>Measurements and Main Results:</b> Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted-<i>P</i> = 2.5 × 10<sup>-3</sup>) and is enriched in CCL3<sup>hi</sup>/CCL4<sup>hi</sup> and S100A<sup>hi</sup> classical monocytes (adjusted-<i>P</i> < 2.2 × 10<sup>-16</sup>). Trajectory analyses demonstrate that S100A<sup>hi</sup> classical monocytes differentiate into SPP1<sup>hi</sup> lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZM<sup>hi</sup> cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. <b>Conclusions:</b> Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZM<sup>hi</sup> cytotoxic CD4<sup>+</sup> and CD8<sup>+</sup> T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100A<sup>hi</sup> and CCL3<sup>hi</sup>/CCL4<sup>hi</sup> classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.</p>\",\"PeriodicalId\":7664,\"journal\":{\"name\":\"American journal of respiratory and critical care medicine\",\"volume\":\" \",\"pages\":\"1252-1266\"},\"PeriodicalIF\":19.3000,\"publicationDate\":\"2024-11-15\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11568434/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"American journal of respiratory and critical care medicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.1164/rccm.202401-0078OC\",\"RegionNum\":1,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"CRITICAL CARE MEDICINE\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"American journal of respiratory and critical care medicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1164/rccm.202401-0078OC","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CRITICAL CARE MEDICINE","Score":null,"Total":0}
Single-Cell Analysis Reveals Novel Immune Perturbations in Fibrotic Hypersensitivity Pneumonitis.
Rationale: Fibrotic hypersensitivity pneumonitis (FHP) is a debilitating interstitial lung disease driven by incompletely understood immune mechanisms. Objectives: To elucidate immune aberrations in FHP in single-cell resolution. Methods: Single-cell 5' RNA sequencing was conducted on peripheral blood mononuclear cells and BAL cells obtained from 45 patients with FHP, 63 patients with idiopathic pulmonary fibrosis (IPF), 4 patients with nonfibrotic hypersensitivity pneumonitis, and 36 healthy control subjects in the United States and Mexico. Analyses included differential gene expression (Seurat), TF (transcription factor) activity imputation (DoRothEA-VIPER), and trajectory analyses (Monocle3 and Velocyto-scVelo-CellRank). Measurements and Main Results: Overall, 501,534 peripheral blood mononuclear cells from 110 patients and control subjects and 88,336 BAL cells from 19 patients were profiled. Compared with control samples, FHP has elevated classical monocytes (adjusted-P = 2.5 × 10-3) and is enriched in CCL3hi/CCL4hi and S100Ahi classical monocytes (adjusted-P < 2.2 × 10-16). Trajectory analyses demonstrate that S100Ahi classical monocytes differentiate into SPP1hi lung macrophages associated with fibrosis. Compared with both control subjects and IPF, cells from patients with FHP are significantly enriched in GZMhi cytotoxic T cells. These cells exhibit TF activities indicative of TGFβ and TNFα and NFκB pathways. These results are publicly available at http://ildimmunecellatlas.com. Conclusions: Single-cell transcriptomics of patients with FHP uncovered novel immune perturbations, including previously undescribed increases in GZMhi cytotoxic CD4+ and CD8+ T cells-reflecting this disease's unique inflammatory T cell-driven nature-as well as increased S100Ahi and CCL3hi/CCL4hi classical monocytes also observed in IPF. Both cell populations may guide the development of new biomarkers and therapeutic interventions.
期刊介绍：
The American Journal of Respiratory and Critical Care Medicine focuses on human biology and disease, as well as animal studies that contribute to the understanding of pathophysiology and treatment of diseases that affect the respiratory system and critically ill patients. Papers that are solely or predominantly based in cell and molecular biology are published in the companion journal, the American Journal of Respiratory Cell and Molecular Biology. The Journal also seeks to publish clinical trials and outstanding review articles on areas of interest in several forms. The State-of-the-Art review is a treatise usually covering a broad field that brings bench research to the bedside. Shorter reviews are published as Critical Care Perspectives or Pulmonary Perspectives. These are generally focused on a more limited area and advance a concerted opinion about care for a specific process. Concise Clinical Reviews provide an evidence-based synthesis of the literature pertaining to topics of fundamental importance to the practice of pulmonary, critical care, and sleep medicine. Images providing advances or unusual contributions to the field are published as Images in Pulmonary, Critical Care, Sleep Medicine and the Sciences.
A recent trend and future direction of the Journal has been to include debates of a topical nature on issues of importance in pulmonary and critical care medicine and to the membership of the American Thoracic Society. Other recent changes have included encompassing works from the field of critical care medicine and the extension of the editorial governing of journal policy to colleagues outside of the United States of America. The focus and direction of the Journal is to establish an international forum for state-of-the-art respiratory and critical care medicine.
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