{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T03:27:23Z","timestamp":1790393243904,"version":"4.1.0"},"reference-count":68,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T00:00:00Z","timestamp":1611705600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100006492","name":"Division of Intramural Research, National Institute of Allergy and Infectious Diseases","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100006492","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:p>Autoimmune-polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED), a monogenic disorder caused by biallelic mutations in the <jats:italic>AIRE<\/jats:italic> gene, has historically been defined by the development of chronic mucocutaneous candidiasis together with autoimmune endocrinopathies, primarily hypoparathyroidism and adrenal insufficiency. Recent work has drawn attention to the development of life-threatening non-endocrine manifestations such as autoimmune pneumonitis, which has previously been poorly recognized and under-reported. In this review, we present the clinical, radiographic, autoantibody, and pulmonary function abnormalities associated with APECED pneumonitis, we highlight the cellular and molecular basis of the autoimmune attack in the AIRE-deficient lung, and we provide a diagnostic and a therapeutic roadmap for patients with APECED pneumonitis. Beyond APECED, we discuss the relevance and potential broader applicability of these findings to other interstitial lung diseases seen in secondary AIRE deficiency states such as thymoma and RAG deficiency or in common polygenic autoimmune disorders such as idiopathic Sj\u00f6gren\u2019s syndrome.<\/jats:p>","DOI":"10.3389\/fimmu.2020.609253","type":"journal-article","created":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T07:10:31Z","timestamp":1611731431000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":19,"title":["An AIREless Breath: Pneumonitis Caused by Impaired Central Immune Tolerance"],"prefix":"10.3389","volume":"11","author":[{"given":"Elise M. N.","family":"Ferr\u00e9","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michail S.","family":"Lionakis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2021,1,27]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"e289","DOI":"10.1371\/journal.pmed.0030289","article-title":"Anti-interferon autoantibodies in autoimmune polyendocrinopathy syndrome type 1","volume":"3","author":"Meager","year":"2006","journal-title":"PLoS Med"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.1111\/imr.12714","article-title":"Lessons from primary immunodeficiencies: Autoimmune regulator and autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"287","author":"Constantine","year":"2019","journal-title":"Immunol Rev"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1172\/jci.insight.88782","article-title":"Redefined clinical features and diagnostic criteria in autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"1","author":"Ferre","year":"2016","journal-title":"JCI Insight"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1002\/hep.31421","article-title":"APECED-Associated Hepatitis: Clinical, Biochemical, Histological and Treatment Data from a Large Predominantly American Cohort","author":"Chascsa","year":"2020","journal-title":"Hepatology"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav5597","article-title":"Lymphocyte-driven regional immunopathology in pneumonitis caused by impaired central immune tolerance","volume":"11","author":"Ferre","year":"2019","journal-title":"Sci Transl Med"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.86.10.7884","article-title":"A novel mutation of the autoimmune regulator gene in an Italian kindred with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy, acting in a dominant fashion and strongly cosegregating with hypothyroid autoimmune thyroiditis","volume":"86","author":"Cetani","year":"2001","journal-title":"J Clin Endocrinol Metab"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199006283222601","article-title":"Clinical variation of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in a series of 68 patients","volume":"322","author":"Ahonen","year":"1990","journal-title":"N Engl J Med"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-2611","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy","volume":"91","author":"Perheentupa","year":"2006","journal-title":"J Clin Endocrinol Metab"},{"key":"B9","doi-asserted-by":"publisher","first-page":"595","DOI":"10.1210\/jc.2006-1873","article-title":"Autoimmune polyendocrine syndrome type 1 in Norway: phenotypic variation, autoantibodies, and novel mutations in the autoimmune regulator gene","volume":"92","author":"Wolff","year":"2007","journal-title":"J Clin Endocrinol Metab"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.1515\/JPEM.2006.19.11.1343","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) in the Irish population","volume":"19","author":"Dominguez","year":"2006","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2011-2461","article-title":"Autoimmune polyendocrine syndrome type 1: an extensive longitudinal study in Sardinian patients","volume":"97","author":"Meloni","year":"2012","journal-title":"J Clin Endocrinol Metab"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-07-0843","article-title":"Autoimmune polyendocrine syndrome type I in Slovakia: relevance of screening patients with autoimmune Addison\u2019s disease","volume":"158","author":"N","year":"2008","journal-title":"Eur J Endocrinol"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.29.11.824","article-title":"Polyglandular autoimmune syndrome type I among Iranian Jews","volume":"29","author":"Zlotogora","year":"1992","journal-title":"J Med Genet"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1159\/000313585","article-title":"Autoimmune polyglandular syndrome type 1 in Russian patients: clinical variants and autoimmune regulator mutations","volume":"73","author":"Orlova","year":"2010","journal-title":"Horm Res Paediatr"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1086\/302145","article-title":"A common and recurrent 13-bp deletion in the autoimmune regulator gene in British kindreds with autoimmune polyendocrinopathy type 1","volume":"63","author":"Pearce","year":"1998","journal-title":"Am J Hum Genet"},{"key":"B16","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2265.2001.01201.x","article-title":"Autoimmune polyendocrine syndrome type 1 (APS I) in Norway","volume":"54","author":"Myhre","year":"2001","journal-title":"Clin Endocrinol (Oxf)"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2005-0418","article-title":"Autoimmune regulator-1 messenger ribonucleic acid analysis in a novel intronic mutation and two additional novel AIRE gene mutations in a cohort of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy patients","volume":"90","author":"Podkrajsek","year":"2005","journal-title":"J Clin Endocrinol Metab"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1111\/j.1399-0004.2006.00690.x","article-title":"Molecular background of polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome in a Polish population: novel AIRE mutations and an estimate of disease prevalence","volume":"70","author":"Stolarski","year":"2006","journal-title":"Clin Genet"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1159\/000363537","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy: report of seven additional sicilian patients and overview of the overall series from sicily","volume":"82","author":"Valenzise","year":"2014","journal-title":"Horm Res Paediatr"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2016-1821","article-title":"A Longitudinal Follow-up of Autoimmune Polyendocrine Syndrome Type 1","volume":"101","author":"Bruserud","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1002\/ppul.21520","article-title":"Autoimmune polyendocrine syndrome type 1: Utility of KCNRG autoantibodies as a marker of active pulmonary disease and successful treatment with rituximab","volume":"47","author":"Popler","year":"2012","journal-title":"Pediatr Pulmonol"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(91)90215-J","article-title":"Frequent occurrence of asplenism and cholelithiasis in patients with autoimmune polyglandular disease type I","volume":"91","author":"Friedman","year":"1991","journal-title":"Am J Med"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2013-0328","article-title":"Polyglandular autoimmune syndrome type I - a novel AIRE mutation in a North American patient","volume":"27","author":"Huibregtse","year":"2014","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-198109000-00003","article-title":"Two types of autoimmune Addison\u2019s disease associated with different polyglandular autoimmune (PGA) syndromes","volume":"60","author":"Neufeld","year":"1981","journal-title":"Medicine (Baltimore)"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2017-00139","article-title":"Expanding the Phenotypic and Genotypic Landscape of Autoimmune Polyendocrine Syndrome Type 1","volume":"102","author":"Orlova","year":"2017","journal-title":"J Clin Endocrinol Metab"},{"key":"B26","doi-asserted-by":"publisher","DOI":"10.1007\/s00431-008-0668-3","article-title":"Sicilian family with autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED) and lethal lung disease in one of the affected brothers","volume":"167","author":"De Luca","year":"2008","journal-title":"Eur J Pediatr"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0809986106","article-title":"Pulmonary autoimmunity as a feature of autoimmune polyendocrine syndrome type 1 and identification of KCNRG as a bronchial autoantigen","volume":"106","author":"Alimohammadi","year":"2009","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1101\/gr.7.8.820","article-title":"High-resolution physical and transcriptional mapping of the autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy locus on chromosome 21q22.3 by FISH","volume":"7","author":"Aaltonen","year":"1997","journal-title":"Genome Res"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/7.10.1547","article-title":"Gene defect behind APECED: a new clue to autoimmunity","volume":"7","author":"Bjorses","year":"1998","journal-title":"Hum Mol Genet"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2015.04.021","article-title":"Dominant Mutations in the Autoimmune Regulator AIRE Are Associated with Common Organ-Specific Autoimmune Diseases","volume":"42","author":"Oftedal","year":"2015","journal-title":"Immunity"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1016\/j.jaut.2017.10.010","article-title":"Dominant-negative loss of function arises from a second, more frequent variant within the SAND domain of autoimmune regulator (AIRE)","volume":"88","author":"Abbott","year":"2018","journal-title":"J Autoimmun"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.1038\/ni.2820","article-title":"The transcriptional regulator Aire coopts the repressive ATF7ip-MBD1 complex for the induction of immunotolerance","volume":"15","author":"Waterfield","year":"2014","journal-title":"Nat Immunol"},{"key":"B33","doi-asserted-by":"publisher","DOI":"10.1172\/JCI84440","article-title":"LYN- and AIRE-mediated tolerance checkpoint defects synergize to trigger organ-specific autoimmunity","volume":"126","author":"Proekt","year":"2016","journal-title":"J Clin Invest"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1126\/science.1075958","article-title":"Projection of an immunological self shadow within the thymus by the aire protein","volume":"298","author":"Anderson","year":"2002","journal-title":"Science"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1016\/j.immuni.2005.07.005","article-title":"The cellular mechanism of Aire control of T cell tolerance","volume":"23","author":"Anderson","year":"2005","journal-title":"Immunity"},{"key":"B36","doi-asserted-by":"publisher","first-page":"287","DOI":"10.1146\/annurev.immunol.25.022106.141532","article-title":"Aire","volume":"27","author":"Mathis","year":"2009","journal-title":"Annu Rev Immunol"},{"key":"B37","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.181.6.4072","article-title":"Effector mechanisms of the autoimmune syndrome in the murine model of autoimmune polyglandular syndrome type 1","volume":"181","author":"Devoss","year":"2008","journal-title":"J Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.7554\/eLife.55053","article-title":"Identification of novel, clinically correlated autoantigens in the monogenic autoimmune syndrome APS1 by proteome-wide PhIP-Seq","volume":"9","author":"Vazquez","year":"2020","journal-title":"Elife"},{"key":"B39","doi-asserted-by":"publisher","DOI":"10.1126\/sciimmunol.aav6778","article-title":"AIRE expression controls the peripheral selection of autoreactive B cells","volume":"4","author":"Sng","year":"2019","journal-title":"Sci Immunol"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0806874105","article-title":"B cells are required for Aire-deficient mice to develop multi-organ autoinflammation: A therapeutic approach for APECED patients","volume":"105","author":"Gavanescu","year":"2008","journal-title":"Proc Natl Acad Sci U S A"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1016\/j.cell.2016.06.024","article-title":"AIRE-Deficient Patients Harbor Unique High-Affinity Disease-Ameliorating Autoantibodies","volume":"166","author":"Meyer","year":"2016","journal-title":"Cell"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2008-03-144634","article-title":"Interferon autoantibodies associated with AIRE deficiency decrease the expression of IFN-stimulated genes","volume":"112","author":"Kisand","year":"2008","journal-title":"Blood"},{"key":"B43","doi-asserted-by":"publisher","first-page":"20104","DOI":"10.1038\/srep20104","article-title":"Proteome-wide survey of the autoimmune target repertoire in autoimmune polyendocrine syndrome type 1","volume":"6","author":"Landegren","year":"2016","journal-title":"Sci Rep"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20091983","article-title":"Autoantibodies against IL-17A, IL-17F, and IL-22 in patients with chronic mucocutaneous candidiasis and autoimmune polyendocrine syndrome type I","volume":"207","author":"Puel","year":"2010","journal-title":"J Exp Med"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1210\/edrv.23.3.0466","article-title":"Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction","volume":"23","author":"Betterle","year":"2002","journal-title":"Endocr Rev"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1210\/jcem.84.1.5414","article-title":"DRB1*04 and DQ alleles: expression of 21-hydroxylase autoantibodies and risk of progression to Addison\u2019s disease","volume":"84","author":"Yu","year":"1999","journal-title":"J Clin Endocrinol Metab"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1016\/0140-6736(92)91829-W","article-title":"21-Hydroxylase, a major autoantigen in idiopathic Addison\u2019s disease","volume":"339","author":"Winqvist","year":"1992","journal-title":"Lancet"},{"key":"B48","doi-asserted-by":"publisher","first-page":"206ra139","DOI":"10.1126\/scitranslmed.3006998","article-title":"BPIFB1 is a lung-specific autoantigen associated with interstitial lung disease","volume":"5","author":"Shum","year":"2013","journal-title":"Sci Transl Med"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1111\/resp.12582","article-title":"Sputum matrix metalloproteinase-8 and -9 and tissue inhibitor of metalloproteinase-1 in bronchiectasis: clinical correlates and prognostic implications","volume":"20","author":"Guan","year":"2015","journal-title":"Respirology"},{"key":"B50","doi-asserted-by":"publisher","first-page":"1","DOI":"10.2147\/JIR.S40081","article-title":"Airway inflammatory markers in individuals with cystic fibrosis and non-cystic fibrosis bronchiectasis","volume":"6","author":"Bergin","year":"2013","journal-title":"J Inflammation Res"},{"key":"B51","doi-asserted-by":"publisher","first-page":"9ra20","DOI":"10.1126\/scitranslmed.3000284","article-title":"Identification of an autoantigen demonstrates a link between interstitial lung disease and a defect in central tolerance","volume":"1","author":"Shum","year":"2009","journal-title":"Sci Transl Med"},{"key":"B52","doi-asserted-by":"publisher","first-page":"16","DOI":"10.1086\/504811","article-title":"Infectious complications associated with alemtuzumab use for lymphoproliferative disorders","volume":"43","author":"Martin","year":"2006","journal-title":"Clin Infect Dis"},{"key":"B53","doi-asserted-by":"publisher","DOI":"10.1097\/QCO.0000000000000656","article-title":"Infections associated with the new \u2018nibs and mabs\u2019 and cellular therapies","volume":"33","author":"Maus","year":"2020","journal-title":"Curr Opin Infect Dis"},{"key":"B54","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-012-9755-3","article-title":"Use of combination chemotherapy for treatment of granulomatous and lymphocytic interstitial lung disease (GLILD) in patients with common variable immunodeficiency (CVID)","volume":"33","author":"Chase","year":"2013","journal-title":"J Clin Immunol"},{"key":"B55","doi-asserted-by":"publisher","DOI":"10.4049\/jimmunol.1401068","article-title":"Clinical and serologic parallels to APS-I in patients with thymomas and autoantigen transcripts in their tumors","volume":"193","author":"Wolff","year":"2014","journal-title":"J Immunol"},{"key":"B56","doi-asserted-by":"publisher","DOI":"10.1172\/JCI80477","article-title":"Broad-spectrum antibodies against self-antigens and cytokines in RAG deficiency","volume":"125","author":"Walter","year":"2015","journal-title":"J Clin Invest"},{"key":"B57","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2010-02-267583","article-title":"Hypomorphic Rag mutations can cause destructive midline granulomatous disease","volume":"116","author":"De Ravin","year":"2010","journal-title":"Blood"},{"key":"B58","doi-asserted-by":"publisher","DOI":"10.1007\/s10875-018-0537-4","article-title":"RAG Deficiency: Two Genes, Many Diseases","volume":"38","author":"Delmonte","year":"2018","journal-title":"J Clin Immunol"},{"key":"B59","article-title":"A case of nonspecific interstitial pneumonia associated with thymoma","volume":"20","author":"Maiolo","year":"2003","journal-title":"Sarcoidosis Vasc Diffuse Lung Dis"},{"key":"B60","doi-asserted-by":"publisher","DOI":"10.1556\/AMicr.53.2006.1.8","article-title":"Early autoimmune complications after thymomectomy in a patient with interstitial lung disease. Case report","volume":"53","author":"Gonlugur","year":"2006","journal-title":"Acta Microbiol Immunol Hung"},{"key":"B61","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1007\/s10067-020-05236-8","article-title":"Characteristics of primary Sjogren\u2019s syndrome related lymphocytic interstitial pneumonia","volume":"1","author":"Dong","year":"2020","journal-title":"Clin Rheumatol"},{"key":"B62","doi-asserted-by":"publisher","DOI":"10.1097\/00063198-200009000-00007","article-title":"Interstitial lung disease in systemic lupus erythematosus","volume":"6","author":"Cheema","year":"2000","journal-title":"Curr Opin Pulm Med"},{"key":"B63","doi-asserted-by":"publisher","DOI":"10.1136\/ard.58.1.61","article-title":"Lung involvement in primary Sjogren\u2019s syndrome is mainly related to the small airway disease","volume":"58","author":"Papiris","year":"1999","journal-title":"Ann Rheum Dis"},{"key":"B64","doi-asserted-by":"publisher","DOI":"10.1164\/ajrccm.164.7.2103110","article-title":"Polymyositis-dermatomyositis-associated interstitial lung disease","volume":"164","author":"Douglas","year":"2001","journal-title":"Am J Respir Crit Care Med"},{"key":"B65","doi-asserted-by":"publisher","DOI":"10.1182\/blood-2014-09-602763","article-title":"Early-onset lymphoproliferation and autoimmunity caused by germline STAT3 gain-of-function mutations","volume":"125","author":"Milner","year":"2015","journal-title":"Blood"},{"key":"B66","doi-asserted-by":"publisher","DOI":"10.1126\/science.1255904","article-title":"Immune dysregulation in human subjects with heterozygous germline mutations in CTLA4","volume":"345","author":"Kuehn","year":"2014","journal-title":"Science"},{"key":"B67","doi-asserted-by":"publisher","DOI":"10.1038\/nm.3746","article-title":"Autosomal dominant immune dysregulation syndrome in humans with CTLA4 mutations","volume":"20","author":"Schubert","year":"2014","journal-title":"Nat Med"},{"key":"B68","doi-asserted-by":"publisher","DOI":"10.1126\/science.aaa1663","article-title":"AUTOIMMUNE DISEASE. Patients with LRBA deficiency show CTLA4 loss and immune dysregulation responsive to abatacept therapy","volume":"349","author":"Lo","year":"2015","journal-title":"Science"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.609253\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2021,1,27]],"date-time":"2021-01-27T07:10:33Z","timestamp":1611731433000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2020.609253\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,1,27]]},"references-count":68,"alternative-id":["10.3389\/fimmu.2020.609253"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2020.609253","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,1,27]]},"article-number":"609253"}}