{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,27]],"date-time":"2026-09-27T09:29:39Z","timestamp":1790501379080,"version":"4.1.0"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2017,8,23]],"date-time":"2017-08-23T00:00:00Z","timestamp":1503446400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"funder":[{"name":"Ministero della Universit\u00e0 e della Ricerca Scientifica"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2017,10,6]]},"abstract":"<jats:title>Summary<\/jats:title>\n               <jats:p>T helper 9 (Th9) cells and interleukin (IL)-9 are involved in the pathogenesis of several autoimmune diseases. The exact role of IL-9 and Th9 cells in patients with systemic sclerosis (SSc) have not yet been studied adequately. IL-9, IL-9R, transcription factor PU.1 (PU.1), IL-4, thymic stromal lymphopoietin (TSLP) and transforming growth factor (TGF)-\u03b2 expression were assessed in skin and kidney biopsies of SSc patients and healthy controls (HC) by immunohistochemistry (IHC). The cellular source of IL-9 was also analysed by confocal microscopy analysis. Peripheral IL-9-producing cells were also studied by flow cytometry. The functional relevance of IL-9 increased expression in SSc was also investigated. Our results demonstrated a strong expression of IL-9, IL-9R, IL-4, TSLP and TGF-\u03b2 in skin tissues of patients with both limited and diffuse SSc. IL-9 expression was observed mainly in the context of skin infiltrating mononuclear cells and keratinizing squamous epithelium. IL-9 over-expression was also observed in renal biopsies of patients with SSc. IL-9 producing cells in the skin were identified as Th9 cells. Similarly, Th9 cells were expanded and were the major source of IL-9 among SSc peripheral blood mononuclear cells (PBMC), their percentage being correlated directly with the modified Rodnan skin score. Infiltrating mononuclear cells, mast cells and neutrophils expressed IL-9R. In in-vitro studies stimulation with rIL-9 significantly induced NET (neutrophil extracellular traps) release by dying cells (NETosis) in neutrophils, expansion of mast cells and increase of anti-systemic scleroderma 70 (Scl70) production by B cells. Our findings suggest that Th9 cells and IL-9 could be implicated in the pathogenesis of SSc.<\/jats:p>","DOI":"10.1111\/cei.13009","type":"journal-article","created":{"date-parts":[[2017,7,6]],"date-time":"2017-07-06T10:03:08Z","timestamp":1499335388000},"page":"208-216","source":"Crossref","is-referenced-by-count":42,"title":["Interleukin-9 over-expression and T helper 9 polarization in systemic sclerosis patients"],"prefix":"10.1093","volume":"190","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2479-6958","authenticated-orcid":false,"given":"G","family":"Guggino","sequence":"first","affiliation":[{"name":"Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M","family":"Lo Pizzo","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"D","family":"Di Liberto","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"A","family":"Rizzo","sequence":"additional","affiliation":[{"name":"Azienda Ospedaliera Ospedali riuniti Villa Sofia-Cervello, Anatomia Patologica, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Cipriani","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"P","family":"Ruscitti","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Candore","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"C M","family":"Gambino","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Sireci","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Dieli","sequence":"additional","affiliation":[{"name":"Dipartimento di Biopatologia e Biotecnologie Mediche, Universit\u00e0 di Palermo, Palermo, Italy"},{"name":"Central Laboratory of Advanced Diagnosis and Biomedical Research (CLADIBIOR), Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"R","family":"Giacomelli","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Department of Biotechnological and Applied Clinical Science, School of Medicine, University of L'Aquila, L'Aquila, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"G","family":"Triolo","sequence":"additional","affiliation":[{"name":"Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"F","family":"Ciccia","sequence":"additional","affiliation":[{"name":"Dipartimento Biomedico di Medicina Interna e Specialistica, Sezione di Reumatologia, Universit\u00e0 di Palermo, Palermo, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2017,8,23]]},"reference":[{"key":"2021120808114565700_cei13009-bib-0001","doi-asserted-by":"crossref","first-page":"21","DOI":"10.2147\/ITT.S82037","article-title":"Current perspectives on the immunopathogenesis of systemic sclerosis","volume":"5","author":"Fuschiotti","year":"2016","journal-title":"Immunotargets Ther"},{"key":"2021120808114565700_cei13009-bib-0002","doi-asserted-by":"crossref","first-page":"128","DOI":"10.1684\/ecn.2013.0325","article-title":"T cell abnormalities in systemic sclerosis with a focus on Th17 cells","volume":"23","author":"Brembilla","year":"2012","journal-title":"Eur Cytokine Netw"},{"key":"2021120808114565700_cei13009-bib-0003","doi-asserted-by":"crossref","first-page":"101","DOI":"10.5114\/aoms.2015.47877","article-title":"Aberrant expression of cytokine interleukin 9 along with interleukin 4 and interferon gamma in connective tissue disease-associated interstitial lung disease: association with severity of pulmonary fibrosis","volume":"12","author":"Jiang","year":"2016","journal-title":"Arch Med Sci"},{"key":"2021120808114565700_cei13009-bib-0004","doi-asserted-by":"crossref","first-page":"18694","DOI":"10.1038\/srep18694","article-title":"A deleterious role for Th9\/IL-9 in hepatic fibrogenesis","volume":"6","author":"Qin","year":"2016","journal-title":"Sci Rep"},{"key":"2021120808114565700_cei13009-bib-0005","doi-asserted-by":"crossref","first-page":"295","DOI":"10.1038\/nri3824","article-title":"The development and in vivo function of T helper 9 cells","volume":"15","author":"Kaplan","year":"2015","journal-title":"Nat Rev Immunol"},{"key":"2021120808114565700_cei13009-bib-0006","doi-asserted-by":"crossref","first-page":"360","DOI":"10.1016\/j.immuni.2013.01.007","article-title":"Interleukin-9 is required for allergic airway inflammation mediated by the cytokine TSLP","volume":"38","author":"Yao","year":"2013","journal-title":"Immunity"},{"key":"2021120808114565700_cei13009-bib-0007","doi-asserted-by":"crossref","first-page":"4665","DOI":"10.1182\/blood-2011-11-392589","article-title":"Maturation-related histone modifications in the PU.1 promoter regulate Th9-cell development","volume":"119","author":"Ramming","year":"2012","journal-title":"Blood"},{"key":"2021120808114565700_cei13009-bib-0008","doi-asserted-by":"crossref","first-page":"3731","DOI":"10.1128\/IAI.00646-13","article-title":"Interleukin-25 (IL-25) promotes efficient protective immunity against Trichinella spiralis infection by enhancing the antigen-specific IL-9 response","volume":"81","author":"Angkasekwinai","year":"2013","journal-title":"Infect Immun"},{"key":"2021120808114565700_cei13009-bib-0009","doi-asserted-by":"crossref","first-page":"250","DOI":"10.1038\/ni.1846","article-title":"Regulation of IL-9 expression by IL-25 signaling","volume":"11","author":"Angkasekwinai","year":"2010","journal-title":"Nat Immunol"},{"key":"2021120808114565700_cei13009-bib-0010","doi-asserted-by":"crossref","first-page":"2193","DOI":"10.3899\/jrheum.110268","article-title":"Serum interleukin 9 levels are increased in patients with systemic sclerosis: association with lower frequency and severity of pulmonary fibrosis","volume":"38","author":"Yanaba","year":"2011","journal-title":"J Rheumatol"},{"key":"2021120808114565700_cei13009-bib-0011","doi-asserted-by":"crossref","first-page":"e105008","DOI":"10.1371\/journal.pone.0105008","article-title":"High IL-17E and low IL-17C dermal expression identifies a fibrosis-specific motif common to morphea and systemic sclerosis","volume":"9","author":"Lonati","year":"2014","journal-title":"PLOS ONE"},{"key":"2021120808114565700_cei13009-bib-0012","doi-asserted-by":"crossref","first-page":"1335","DOI":"10.1002\/art.37859","article-title":"Thymic stromal lymphopoietin is up-regulated in the skin of patients with systemic sclerosis and induces profibrotic genes and intracellular signaling that overlap with those induced by interleukin-13 and transforming growth factor beta","volume":"65","author":"Christmann","year":"2013","journal-title":"Arthritis Rheum"},{"key":"2021120808114565700_cei13009-bib-0013","doi-asserted-by":"crossref","first-page":"1747","DOI":"10.1136\/annrheumdis-2013-204424","article-title":"2013 classification criteria for systemic sclerosis: an American college of rheumatology\/European league against rheumatism collaborative initiative","volume":"72","author":"van den Hoogen","year":"2013","journal-title":"Ann Rheum Dis"},{"key":"2021120808114565700_cei13009-bib-0014","first-page":"84","article-title":"The modified Rodnan skin score is an accurate reflection of skin biopsy thickness in systemic sclerosis","volume":"25","author":"Furst","year":"1998","journal-title":"J Rheumatol"},{"key":"2021120808114565700_cei13009-bib-0015","doi-asserted-by":"crossref","first-page":"239","DOI":"10.1093\/rheumatology\/36.2.239","article-title":"Comparison of Doppler echocardiography and right heart catheterization to assess pulmonary hypertension in systemic sclerosis","volume":"36","author":"Denton","year":"1997","journal-title":"Br J Rheumatol"},{"key":"2021120808114565700_cei13009-bib-0016","doi-asserted-by":"crossref","first-page":"2951","DOI":"10.1084\/jem.20130071","article-title":"IL-9-mediated survival of type 2 innate lymphoid cells promotes damage control in helminth-induced lung inflammation","volume":"210","author":"Turner","year":"2013","journal-title":"J Exp Med"},{"key":"2021120808114565700_cei13009-bib-0017","doi-asserted-by":"crossref","first-page":"623","DOI":"10.1136\/annrheumdis-2015-207388","article-title":"Type 2 innate lymphoid cell counts are increased in patients with systemic sclerosis and correlate with the extent of fibrosis","volume":"75","author":"Wohlfahrt","year":"2016","journal-title":"Ann Rheum Dis"},{"key":"2021120808114565700_cei13009-bib-0018","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1136\/ard.46.4.302","article-title":"Polymorphonuclear neutrophil function in systemic sclerosis","volume":"46","author":"Czirjak","year":"1987","journal-title":"Ann Rheum Dis"},{"key":"2021120808114565700_cei13009-bib-0019","doi-asserted-by":"crossref","first-page":"81","DOI":"10.2177\/jsci.33.81","article-title":"Involvement of mast cells in systemic sclerosis","volume":"33","author":"Yukawa","year":"2010","journal-title":"Nihon Rinsho Meneki Gakkai Kaishi"},{"key":"2021120808114565700_cei13009-bib-0020","doi-asserted-by":"crossref","first-page":"1367","DOI":"10.3109\/10428194.2012.745072","article-title":"The role of interleukin-9 in lymphoma","volume":"54","author":"Lv","year":"2013","journal-title":"Leuk Lymphoma"},{"key":"2021120808114565700_cei13009-bib-0021","doi-asserted-by":"crossref","first-page":"93","DOI":"10.1016\/j.cytogfr.2016.02.002","article-title":"IL-9 signaling as key driver of chronic inflammation in mucosal immunity","volume":"29","author":"Neurath","year":"2016","journal-title":"Cytokine Growth Factor Rev"},{"key":"2021120808114565700_cei13009-bib-0022","doi-asserted-by":"crossref","first-page":"125","DOI":"10.1111\/cei.12807","article-title":"Interleukin-9 and T helper type 9 cells in rheumatic diseases","volume":"185","author":"Ciccia","year":"2016","journal-title":"Clin Exp Immunol"},{"key":"2021120808114565700_cei13009-bib-0023","doi-asserted-by":"crossref","first-page":"e51752","DOI":"10.1371\/journal.pone.0051752","article-title":"Involvement of IL-9 in Th17-associated inflammation and angiogenesis of psoriasis","volume":"8","author":"Singh","year":"2013","journal-title":"PLOS ONE"},{"key":"2021120808114565700_cei13009-bib-0024","doi-asserted-by":"crossref","first-page":"83","DOI":"10.4049\/jimmunol.1001183","article-title":"IL-9 production by regulatory T cells recruits mast cells that are essential for regulatory T cell-induced immune suppression","volume":"186","author":"Eller","year":"2011","journal-title":"J Immunol"},{"key":"2021120808114565700_cei13009-bib-0025","doi-asserted-by":"crossref","first-page":"3283","DOI":"10.4049\/jimmunol.1003049","article-title":"A brief history of IL-9","volume":"186","author":"Goswami","year":"2011","journal-title":"J Immunol"},{"key":"2021120808114565700_cei13009-bib-0026","doi-asserted-by":"crossref","first-page":"9255","DOI":"10.1074\/jbc.273.15.9255","article-title":"Heteromerization of the gammac chain with the interleukin-9 receptor alpha subunit leads to STAT activation and prevention of apoptosis","volume":"273","author":"Bauer","year":"1998","journal-title":"J Biol Chem"},{"key":"2021120808114565700_cei13009-bib-0027","doi-asserted-by":"crossref","first-page":"547","DOI":"10.1093\/intimm\/dxt039","article-title":"IL-9 and Th9 cells: progress and challenges","volume":"25","author":"Zhao","year":"2013","journal-title":"Int Immunol"},{"key":"2021120808114565700_cei13009-bib-0028","doi-asserted-by":"crossref","first-page":"14017","DOI":"10.1038\/ncomms14017","article-title":"A mast cell-ILC2-Th9 pathway promotes lung inflammation in cystic fibrosis","volume":"8","author":"Moretti","year":"2017","journal-title":"Nat Commun"},{"key":"2021120808114565700_cei13009-bib-0029","doi-asserted-by":"crossref","first-page":"1208","DOI":"10.1016\/j.jaci.2007.08.022","article-title":"Expression of IL-9 receptor alpha chain on human germinal center B cells modulates IgE secretion","volume":"120","author":"Fawaz","year":"2007","journal-title":"J Allergy Clin Immunol"}],"container-title":["Clinical and Experimental Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1111%2Fcei.13009","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/190\/2\/208\/41644063\/cei13009.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/cei\/article-pdf\/190\/2\/208\/41644063\/cei13009.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,1,1]],"date-time":"2022-01-01T16:28:02Z","timestamp":1641054482000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/cei\/article\/190\/2\/208\/6412360"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,8,23]]},"references-count":29,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2017,8,23]]},"published-print":{"date-parts":[[2017,10,6]]}},"URL":"https:\/\/doi.org\/10.1111\/cei.13009","relation":{},"ISSN":["0009-9104","1365-2249"],"issn-type":[{"value":"0009-9104","type":"print"},{"value":"1365-2249","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2017,11]]},"published":{"date-parts":[[2017,8,23]]}}}