{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,11,8]],"date-time":"2025-11-08T18:01:45Z","timestamp":1762624905042,"version":"3.41.2"},"reference-count":39,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T00:00:00Z","timestamp":1667520000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82170037","U1904142"],"award-info":[{"award-number":["82170037","U1904142"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Med."],"abstract":"<jats:sec><jats:title>Background<\/jats:title><jats:p>The unknown etiology of sarcoidosis with variable clinical features leads to delayed diagnosis and limited therapeutic strategies. Hence, exploring the latent mechanisms and constructing an accessible and reliable diagnostic model of sarcoidosis is vital for innovative therapeutic approaches to improve prognosis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>This retrospective study analyzed transcriptomes from 11 independent sarcoidosis cohorts, comprising 313 patients and 400 healthy controls. The weighted gene co-expression network analysis (WGCNA) and differentially expressed gene (DEG) analysis were performed to identify molecular biomarkers. Machine learning was employed to fit a diagnostic model. The potential pathogenesis and immune landscape were detected by bioinformatics tools.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>A 10-gene signature SARDS consisting of <jats:italic>GBP1, LEF1, IFIT3, LRRN3, IFI44, LHFPL2, RTP4, CD27, EPHX2<\/jats:italic>, and <jats:italic>CXCL10<\/jats:italic> was further constructed in the training cohorts by the LASSO algorithm, which performed well in the four independent cohorts with the splendid AUCs ranging from 0.938 to 1.000. The findings were validated in seven independent publicly available gene expression datasets retrieved from whole blood, PBMC, alveolar lavage fluid cells, and lung tissue samples from patients with outstanding AUCs ranging from 0.728 to 0.972. Transcriptional signatures associated with sarcoidosis revealed a potential role of immune response in the development of the disease through bioinformatics analysis.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Our study identified and validated molecular biomarkers for the diagnosis of sarcoidosis and constructed the diagnostic model SARDS to improve the accuracy of early diagnosis of the disease.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fmed.2022.942177","type":"journal-article","created":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T05:40:47Z","timestamp":1667540447000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":7,"title":["Integrative bioinformatics analysis to explore a robust diagnostic signature and landscape of immune cell infiltration in sarcoidosis"],"prefix":"10.3389","volume":"9","author":[{"given":"Mengjie","family":"Duo","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zaoqu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Pengfei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yu","family":"Wang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyuan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Siyuan","family":"Weng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Youyang","family":"Zheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mingwei","family":"Fan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ruhao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hui","family":"Xu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuqing","family":"Ren","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhe","family":"Cheng","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2022,11,4]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"457","DOI":"10.1038\/nrrheum.2011.93","article-title":"Sarcoidosis\u2013scientific progress and clinical challenges","volume":"7","author":"Chen","year":"2011","journal-title":"Nat Rev Rheumatol."},{"key":"B2","doi-asserted-by":"publisher","first-page":"1","DOI":"10.3390\/cells11010059","article-title":"Clinical features, histopathology and differential diagnosis of sarcoidosis","volume":"11","author":"Tana","year":"2021","journal-title":"Cells"},{"key":"B3","doi-asserted-by":"publisher","first-page":"389","DOI":"10.1016\/s2213-2600(18)30064-x","article-title":"Pulmonary sarcoidosis","volume":"6","author":"Spagnolo","year":"2018","journal-title":"Lancet Resp Med."},{"key":"B4","doi-asserted-by":"publisher","first-page":"1432","DOI":"10.1016\/j.chest.2017.11.030","article-title":"The pathogenesis of pulmonary sarcoidosis and implications for treatment","volume":"153","author":"Patterson","year":"2018","journal-title":"Chest."},{"key":"B5","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1001\/jama.2022.1570","article-title":"Diagnosis and treatment of pulmonary sarcoidosis: a review","volume":"327","author":"Belperio","year":"2022","journal-title":"Jama."},{"key":"B6","doi-asserted-by":"publisher","first-page":"S613","DOI":"10.1067\/mai.2003.124","article-title":"16. Immunologic lung disease","volume":"111","author":"Prince","year":"2003","journal-title":"J Allergy Clin Immunol."},{"key":"B7","doi-asserted-by":"publisher","first-page":"822094","DOI":"10.3389\/fmed.2022.822094","article-title":"Transcriptome analysis of peripheral blood mononuclear cells in pulmonary sarcoidosis","volume":"9","author":"Yoshioka","year":"2022","journal-title":"Front Med."},{"key":"B8","doi-asserted-by":"publisher","first-page":"639321","DOI":"10.3389\/fcell.2021.639321","article-title":"Novel long non-coding RNA expression profile of peripheral blood mononuclear cells reveals potential biomarkers and regulatory mechanisms in systemic lupus erythematosus","volume":"9","author":"Cheng","year":"2021","journal-title":"Front Cell Dev Biol."},{"key":"B9","doi-asserted-by":"publisher","first-page":"4214","DOI":"10.1038\/s41598-017-04086-w","article-title":"Upregulation of circulating microRNA-134 in adult-onset Still's disease and its use as potential biomarker","volume":"7","author":"Liao","year":"2017","journal-title":"Sci Rep."},{"key":"B10","doi-asserted-by":"publisher","first-page":"4246965","DOI":"10.1155\/2018\/4246965","article-title":"Gene expression profiling in behcet's disease indicates an autoimmune component in the pathogenesis of the disease and opens new avenues for targeted therapy","volume":"2018","author":"Puccetti","year":"2018","journal-title":"J Immunol Res."},{"key":"B11","doi-asserted-by":"publisher","first-page":"1714","DOI":"10.3390\/ijms21051714","article-title":"Circulating RNAs as potential biomarkers in amyotrophic lateral sclerosis","volume":"21","author":"Ravnik-Glava\u010d","year":"2020","journal-title":"Int J Mol Sci"},{"key":"B12","doi-asserted-by":"publisher","first-page":"12952","DOI":"10.1073\/pnas.1912839117","article-title":"Inflammation-related plasma and CSF biomarkers for multiple sclerosis","volume":"117","author":"Huang","year":"2020","journal-title":"Proc Natl Acad Sci U S A."},{"key":"B13","doi-asserted-by":"publisher","first-page":"973","DOI":"10.1038\/nature09247","article-title":"An interferon-inducible neutrophil-driven blood transcriptional signature in human tuberculosis","volume":"466","author":"Berry","year":"2010","journal-title":"Nature."},{"key":"B14","doi-asserted-by":"publisher","first-page":"559","DOI":"10.1186\/1471-2105-9-559","article-title":"an R package for weighted correlation network analysis","volume":"9","author":"Langfelder","year":"2008","journal-title":"BMC Bioinformatics."},{"key":"B15","doi-asserted-by":"publisher","first-page":"284","DOI":"10.1089\/omi.2011.0118","article-title":"clusterProfiler: an R package for comparing biological themes among gene clusters","volume":"16","author":"Yu","year":"2012","journal-title":"Omics."},{"key":"B16","doi-asserted-by":"publisher","first-page":"103750","DOI":"10.1016\/j.ebiom.2021.103750","article-title":"Integrative analysis from multi-center studies identities a consensus machine learning-derived lncRNA signature for stage II\/III colorectal cancer","volume":"75","author":"Liu","year":"2022","journal-title":"EBioMedicine."},{"key":"B17","doi-asserted-by":"publisher","first-page":"816","DOI":"10.1038\/s41467-022-28421-6","article-title":"Machine learning-based integration develops an immune-derived lncRNA signature for improving outcomes in colorectal cancer","volume":"13","author":"Liu","year":"2022","journal-title":"Nat Commun."},{"key":"B18","doi-asserted-by":"publisher","first-page":"790214","DOI":"10.3389\/fcell.2022.790214","article-title":"Gene Expression profile reveals a prognostic signature of non-MSI-H\/pMMR colorectal cancer","volume":"10","author":"Liu","year":"2022","journal-title":"Front Cell Deve Biol."},{"key":"B19","doi-asserted-by":"publisher","first-page":"108","DOI":"10.1038\/nature08460","article-title":"Systematic RNA interference reveals that oncogenic KRAS-driven cancers require TBK1","volume":"462","author":"Barbie","year":"2009","journal-title":"Nature."},{"key":"B20","doi-asserted-by":"publisher","first-page":"856","DOI":"10.1016\/j.it.2020.08.001","article-title":"Modeling potential autophagy pathways in COVID-19 and sarcoidosis","volume":"41","author":"Calender","year":"2020","journal-title":"Trends Immunol."},{"key":"B21","doi-asserted-by":"publisher","first-page":"421","DOI":"10.1183\/09031936.03.00083002","article-title":"Alveolar macrophages are the main source for tumour necrosis factor-alpha in patients with sarcoidosis","volume":"21","author":"Fehrenbach","year":"2003","journal-title":"Eur Respir J."},{"key":"B22","doi-asserted-by":"publisher","first-page":"78","DOI":"10.1007\/s10875-008-9225-0","article-title":"Higher monocyte expression of TLR2 and TLR4, and enhanced pro-inflammatory synergy of TLR2 with NOD2 stimulation in sarcoidosis","volume":"29","author":"Wik\u00e9n","year":"2009","journal-title":"J Clin Immunol."},{"key":"B23","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1165\/rcmb.2017-0207OC","article-title":"A circulating MicroRNA signature serves as a diagnostic and prognostic indicator in sarcoidosis","volume":"58","author":"Ascoli","year":"2018","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B24","doi-asserted-by":"publisher","first-page":"139","DOI":"10.1007\/s00005-014-0315-9","article-title":"Differential inflammatory microRNA and cytokine expression in pulmonary sarcoidosis","volume":"63","author":"Jazwa","year":"2015","journal-title":"Arch Immunol Ther Exp."},{"key":"B25","doi-asserted-by":"publisher","first-page":"147","DOI":"10.1165\/rcmb.2017-0196TR","article-title":"Non-coding RNAs: new players in pulmonary medicine and sarcoidosis","volume":"58","author":"Salamo","year":"2018","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B26","doi-asserted-by":"publisher","first-page":"514","DOI":"10.1016\/j.coph.2009.05.003","article-title":"microRNAs and the immune response","volume":"9","author":"Tsitsiou","year":"2009","journal-title":"Curr Opin Pharmacol."},{"key":"B27","doi-asserted-by":"publisher","first-page":"2","DOI":"10.1186\/s12881-016-0266-6","article-title":"Altered miRNA expression in pulmonary sarcoidosis","volume":"17","author":"Kisza\u0142kiewicz","year":"2016","journal-title":"BMC Med Genet."},{"key":"B28","doi-asserted-by":"publisher","first-page":"56","DOI":"10.1016\/j.jaut.2018.07.012","article-title":"Molecular profiling of regulatory T cells in pulmonary sarcoidosis","volume":"94","author":"Kachamakova-Trojanowska","year":"2018","journal-title":"J Autoimmun."},{"key":"B29","doi-asserted-by":"publisher","first-page":"1129","DOI":"10.3389\/fimmu.2020.01129","article-title":"T-bet expression in peripheral Th170 cells is associated with pulmonary function changes in sarcoidosis","volume":"11","author":"Arger","year":"2020","journal-title":"Front Immunol."},{"key":"B30","doi-asserted-by":"publisher","first-page":"484","DOI":"10.1183\/13993003.00092-2016","article-title":"Expanded lung T-bet+ROR\u03b3T+ CD4+ T-cells in sarcoidosis patients with a favourable disease phenotype","volume":"48","author":"Kaiser","year":"2016","journal-title":"Eur Respir J."},{"key":"B31","doi-asserted-by":"publisher","first-page":"1281","DOI":"10.1164\/rccm.201507-1499OC","article-title":"IFN-\u03b3-producing T-helper 171 cells are increased in sarcoidosis and are more prevalent than T-Helper type 1 cells","volume":"193","author":"Ramstein","year":"2016","journal-title":"Am J Resp Crit Care Medi."},{"key":"B32","doi-asserted-by":"publisher","first-page":"423","DOI":"10.2147\/jir.S346505","article-title":"Transcriptomic analysis reveals a link between hippo signaling pathway and macrophages in lungs of mice with OVA-induced allergic asthma","volume":"15","author":"Xiao","year":"2022","journal-title":"J Inflamm Res."},{"key":"B33","doi-asserted-by":"publisher","first-page":"1403","DOI":"10.1164\/rccm.202012-4423OC","article-title":"Follicular helper-like T cells in the lung highlight a novel role of B cells in sarcoidosis","volume":"204","author":"Bauer","year":"2021","journal-title":"Am J Respir Crit Care Med."},{"key":"B34","doi-asserted-by":"publisher","first-page":"1291","DOI":"10.1002\/jcsm.12584","article-title":"Age-related decline of interferon-gamma responses in macrophage impairs satellite cell proliferation and regeneration","volume":"11","author":"Zhang","year":"2020","journal-title":"J Cachexia Sarcopenia Muscle."},{"key":"B35","doi-asserted-by":"publisher","first-page":"106","DOI":"10.21037\/atm-22-180","article-title":"BATF2 and PDK4 as diagnostic molecular markers of sarcoidosis and their relationship with immune infiltration","volume":"10","author":"He","year":"2022","journal-title":"Annals Translat Med."},{"key":"B36","doi-asserted-by":"publisher","first-page":"788502","DOI":"10.3389\/fimmu.2021.788502","article-title":"The role of diverse immune cells in sarcoidosis","volume":"12","author":"Zhang","year":"2021","journal-title":"Front Immunol."},{"key":"B37","doi-asserted-by":"publisher","first-page":"32","DOI":"10.1165\/rcmb.2009-0033TR","article-title":"Dendritic cells in the pathogenesis of sarcoidosis","volume":"42","author":"Zaba","year":"2010","journal-title":"Am J Respir Cell Mol Biol."},{"key":"B38","doi-asserted-by":"publisher","first-page":"594133","DOI":"10.3389\/fmed.2020.594133","article-title":"Emerging molecular targets for the treatment of refractory sarcoidosis","volume":"7","author":"Boleto","year":"2020","journal-title":"Front Med."},{"key":"B39","doi-asserted-by":"publisher","first-page":"20","DOI":"10.1183\/13993003.03794-2020","article-title":"Single-cell RNA sequencing identifies macrophage transcriptional heterogeneities in granulomatous diseases","volume":"57","author":"Liao","year":"2021","journal-title":"Eu Resp J"}],"container-title":["Frontiers in Medicine"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.942177\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,4]],"date-time":"2022-11-04T05:41:02Z","timestamp":1667540462000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fmed.2022.942177\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,11,4]]},"references-count":39,"alternative-id":["10.3389\/fmed.2022.942177"],"URL":"https:\/\/doi.org\/10.3389\/fmed.2022.942177","relation":{},"ISSN":["2296-858X"],"issn-type":[{"type":"electronic","value":"2296-858X"}],"subject":[],"published":{"date-parts":[[2022,11,4]]},"article-number":"942177"}}