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The objective of this study was to investigate the pathogenicity of SSc-ICs in endothelial cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      ICs were purified from the sera of SSc patients bearing different autoantibody specificities (antibodies against DNA topoisomerase I, centromeric proteins, RNA polymerase, and Th\/To), patients with systemic lupus erythematosus (SLE) and primary anti-phospholipid syndrome (PAPS), or healthy controls (NHS) using polyethylene glycol precipitation. Human umbilical vein endothelial cells (HUVECs) were incubated with ICs, positive and negative controls. mRNA levels of\n                      <jats:italic>endothelin-1 (et-1)<\/jats:italic>\n                      ,\n                      <jats:italic>collagenI\u03b11 (colI\u03b11)<\/jats:italic>\n                      ,\n                      <jats:italic>interferon (IFN)-\u03b1<\/jats:italic>\n                      , and\n                      <jats:italic>IFN-\u03b2<\/jats:italic>\n                      were investigated by real-time PCR;\n                      <jats:italic>et-1<\/jats:italic>\n                      and\n                      <jats:italic>il-6<\/jats:italic>\n                      mRNA levels were assessed after pre-treatment with bafilomycin. ICAM-1 expression was evaluated by cell ELISA; secretion of IL-6, IL-8, and transforming growth factor (TGF)-\u03b21 in culture supernatants was measured by ELISA. The expression of Fc\u03b3 receptors (CD64, CD32, and CD16) was assessed in endothelial cells at FACS analysis. Intracellular signaling pathways culminating with NF\u03baB, p38MAPK, SAPK-JNK, and Akt were assessed by Western blotting. Healthy skin fibroblasts were stimulated with supernatants from HUVECs incubated with ICs, and TGF-\u03b21 secretion and mRNA levels of\n                      <jats:italic>colI\u03b11<\/jats:italic>\n                      and\n                      <jats:italic>matrix metalloproteinase (mmp)-1<\/jats:italic>\n                      , protein expression of \u03b1 smooth muscle actin (\u03b1-SMA), and IL-6 were evaluated by Western blotting;\n                      <jats:italic>et-1<\/jats:italic>\n                      mRNA levels were assessed in fibroblasts pre-treated with IL-6 and TGF-\u03b2 inhibitors and stimulated with ATA-ICs.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      All SSc stimulated IL-6 secretion; ACA-ICs and anti-Th\/To-ICs increased ICAM-1 expression; all SSc-ICs but anti-Th\/To-ICs augmented IL-8 levels; all SSc-ICs but ACA-ICs and ARA-ICs upregulated\n                      <jats:italic>et-1<\/jats:italic>\n                      , and all SSc-ICs but ARA-ICs affected TGF-\u03b21 secretion. c\n                      <jats:italic>olI\u03b11<\/jats:italic>\n                      ,\n                      <jats:italic>IFN-\u03b1<\/jats:italic>\n                      , and\n                      <jats:italic>IFN-\u03b2<\/jats:italic>\n                      mRNA levels were not affected by any SSc-IC. Fc\u03b3RII (CD32) and Fc\u03b3RIII (CD16) were not detectable on HUVECs, while Fc\u03b3RI (CD64) was minimally expressed. A differential modulation of\n                      <jats:italic>tlr<\/jats:italic>\n                      expression was observed:\n                      <jats:italic>tlr2<\/jats:italic>\n                      ,\n                      <jats:italic>tlr3<\/jats:italic>\n                      , and\n                      <jats:italic>tlr4<\/jats:italic>\n                      were upregulated by ATA-ICs and ACA-ICs, while anti-Th\/To-ICs resulted in\n                      <jats:italic>tlr9<\/jats:italic>\n                      upregulation. Pre-treatment with bafilomycin did not affect the upregulation of\n                      <jats:italic>et-1<\/jats:italic>\n                      and\n                      <jats:italic>il-6<\/jats:italic>\n                      induced by ATA-ICs, ACA-ICs, and anti-Th\/To-ICs; a 23% reduction in both genes was reported for ARA-ICs. All SSc-ICs activated p38MAPK and Akt, and all SSc-ICs but ARA-ICs yielded the activation of NF\u03baB; ATA-ICs and ACA-ICs increased the activation rate of both subunits of SAPK-JNK. When healthy skin fibroblasts were stimulated with supernatants from HUVECs incubated with SSc-ICs, TGF-\u03b21 secretion,\n                      <jats:italic>colI\u03b11<\/jats:italic>\n                      , \u03b1-SMA, and IL-6 expression levels were significantly modulated. Pre-treatment with IL-6 and TGF-\u03b2 inhibitors prevented\n                      <jats:italic>et-1<\/jats:italic>\n                      upregulation induced by ATA-ICs by 85% and 77%, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p>These data provide the first demonstration of the pathogenicity of ICs from scleroderma patients with different autoantibodies on the endothelium. Endothelial activation induced by SSc-ICs ultimately led to a pro-fibrotic phenotype in healthy skin fibroblasts.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1186\/s13075-020-02360-3","type":"journal-article","created":{"date-parts":[[2020,11,9]],"date-time":"2020-11-09T19:09:00Z","timestamp":1604948940000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":73,"title":["Scleroderma-specific autoantibodies embedded in immune complexes mediate endothelial damage: an early event in the pathogenesis of systemic sclerosis"],"prefix":"10.1186","volume":"22","author":[{"given":"Elena","family":"Raschi","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniela","family":"Privitera","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Caterina","family":"Bodio","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paola Adele","family":"Lonati","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria Orietta","family":"Borghi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Francesca","family":"Ingegnoli","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pier Luigi","family":"Meroni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3787-9632","authenticated-orcid":false,"given":"Cecilia Beatrice","family":"Chighizola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,11,9]]},"reference":[{"key":"2360_CR1","doi-asserted-by":"publisher","first-page":"1809","DOI":"10.1136\/ard.2009.114264","volume":"69","author":"AJ Tyndall","year":"2010","unstructured":"Tyndall AJ, Bannert B, Vonk M, Air\u00f2 P, Cozzi F, Carreira PE, et al. 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