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":19,"journal":{"name":"ACS Materials Letters","volume":null,"pages":null},"PeriodicalIF":9.6000,"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\":19,\"journal\":{\"name\":\"ACS Materials Letters\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":9.6000,\"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\":\"ACS Materials Letters\",\"FirstCategoryId\":\"92\",\"ListUrlMain\":\"https://doi.org/10.1164/rccm.202401-0078OC\",\"RegionNum\":1,\"RegionCategory\":\"化学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MATERIALS SCIENCE, MULTIDISCIPLINARY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"ACS Materials Letters","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1164/rccm.202401-0078OC","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MATERIALS SCIENCE, MULTIDISCIPLINARY","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：
ACS Materials Letters is a journal that publishes high-quality and urgent papers at the forefront of fundamental and applied research in the field of materials science. It aims to bridge the gap between materials and other disciplines such as chemistry, engineering, and biology. The journal encourages multidisciplinary and innovative research that addresses global challenges. Papers submitted to ACS Materials Letters should clearly demonstrate the need for rapid disclosure of key results. The journal is interested in various areas including the design, synthesis, characterization, and evaluation of emerging materials, understanding the relationships between structure, property, and performance, as well as developing materials for applications in energy, environment, biomedical, electronics, and catalysis. The journal has a 2-year impact factor of 11.4 and is dedicated to publishing transformative materials research with fast processing times. The editors and staff of ACS Materials Letters actively participate in major scientific conferences and engage closely with readers and authors. The journal also maintains an active presence on social media to provide authors with greater visibility.
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