{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,5]],"date-time":"2026-10-05T20:14:32Z","timestamp":1791231272422,"version":"4.1.0"},"reference-count":48,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2023,6,24]],"date-time":"2023-06-24T00:00:00Z","timestamp":1687564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>This study investigated the role of IL-35 in systemic sclerosis (SSc) patients, focusing on CD4+ T cell response and immunomodulatory cytokine production. By comparing the cytokine levels in healthy donors (HD) and SSc patients using ELISAs, we found a significantly lower plasma IL-35 concentration in the SSc patients (52.1 \u00b1 5.6 vs. 143 \u00b1 11.1, p &lt; 0.001). Notably, the IL-35 levels showed a negative correlation with TGF-\u03b2 (p &lt; 0.001) and IL-17 (p = 0.04). Assessing the IL-35R expression across cell types in the SSc patients and HDs via flow cytometry, we found higher levels on monocytes (40.7 + 5.7 vs. 20.3 \u00b1 1.9, p &lt; 0.001) and lower levels on CD8+ T cells (61.8 \u00b1 9.2 vs. 83.4 \u00b1 0.8, p &lt; 0.05) in the SSc patients. The addition of recombinant IL-35 to stimulated peripheral blood mononuclear cells reduced the IL-17+CD4+ T cell percentage (9.0 \u00b1 1.5 vs. 4.8 \u00b1 0.7, p &lt; 0.05) and increased the IL-35+CD4+ T percentage (4.1 \u00b1 2.3 vs. 10.2 \u00b1 0.8, p &lt; 0.001). In a Treg:Tresponder cell Sco-culture assay with HD and SSc samples, rIL35 decreased the cell proliferation and levels of IL-17A (178.2 \u00b1 30.5 pg\/mL vs. 37.4 \u00b1 6.4 pg\/mL, p &lt; 0.001) and TGF-\u03b2 (4194 \u00b1 777 pg\/mL vs. 2413 \u00b1 608 pg\/mL, p &lt; 0.01). Furthermore, we observed a positive correlation between the modified Rodnan skin score (mRSS) and TGF-\u03b2 (p &lt; 0.001), while there was a negative correlation between mRSS and IL-35 (p = 0.004). Interestingly, higher levels of plasmatic IL-35 were detected in individuals with limited disease compared to those with diffuse disease (60.1 \u00b1 8.0 vs. 832.3 \u00b1 4.1, p &lt; 0.05). These findings suggest that IL-35 exhibits anti-inflammatory properties in SSc and it may serve as a marker for disease severity and a therapeutic target.<\/jats:p>","DOI":"10.3390\/ijms241310567","type":"journal-article","created":{"date-parts":[[2023,6,26]],"date-time":"2023-06-26T01:42:32Z","timestamp":1687743752000},"page":"10567","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":10,"title":["Impaired Regulation by IL-35 in Systemic Sclerosis"],"prefix":"10.3390","volume":"24","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2875-4405","authenticated-orcid":false,"given":"Rub\u00e9n","family":"Osuna-G\u00f3mez","sequence":"first","affiliation":[{"name":"Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5410-5807","authenticated-orcid":false,"given":"Ivan","family":"Castellv\u00ed","sequence":"additional","affiliation":[{"name":"Department of Rheumatology and Systemic Autoimmune Diseases, Hospital de la Santa Creu i Sant Pau, 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3639-3291","authenticated-orcid":false,"given":"Maria","family":"Mulet","sequence":"additional","affiliation":[{"name":"Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1574-9861","authenticated-orcid":false,"given":"M\u00aa \u00c0ngels","family":"Ortiz","sequence":"additional","affiliation":[{"name":"Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Douglas E.","family":"Brough","sequence":"additional","affiliation":[{"name":"Precigen, Inc., Germantown, MD 20876, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Helen","family":"Sabzevari","sequence":"additional","affiliation":[{"name":"Precigen, Inc., Germantown, MD 20876, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roshanak T.","family":"Semnani","sequence":"additional","affiliation":[{"name":"Precigen, Inc., Germantown, MD 20876, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3909-6682","authenticated-orcid":false,"given":"Silvia","family":"Vidal","sequence":"additional","affiliation":[{"name":"Inflammatory Diseases, Biomedical Research Institute Sant Pau (IIB Sant Pau), 08041 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,24]]},"reference":[{"key":"ref_1","first-page":"272","article-title":"Pathogenesis of Systemic Sclerosis","volume":"6","author":"Epattanaik","year":"2015","journal-title":"Front. 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