BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).
BACKGROUND: Plasmacytoid dendritic cells have been implicated in the pathogenesis of systemic sclerosis through mechanisms beyond the previously suggested production of type I interferon. METHODS: We isolated plasmacytoid dendritic cells from healthy persons and from patients with systemic sclerosis who had distinct clinical phenotypes. We then performed proteome-wide analysis and validated these observations in five large cohorts of patients with systemic sclerosis. Next, we compared the results with those in patients with systemic lupus erythematosus, ankylosing spondylitis, and hepatic fibrosis. We correlated plasma levels of CXCL4 protein with features of systemic sclerosis and studied the direct effects of CXCL4 in vitro and in vivo. RESULTS: Proteome-wide analysis and validation showed that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in circulation and in skin. The mean (±SD) level of CXCL4 in patients with systemic sclerosis was 25,624±2652 pg per milliliter, which was significantly higher than the level in controls (92.5±77.9 pg per milliliter) and than the level in patients with systemic lupus erythematosus (1346±1011 pg per milliliter), ankylosing spondylitis (1368±1162 pg per milliliter), or liver fibrosis (1668±1263 pg per milliliter). CXCL4 levels correlated with skin and lung fibrosis and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted the risk and progression of systemic sclerosis. In vitro, CXCL4 down-regulated expression of transcription factor FLI1, induced markers of endothelial-cell activation, and potentiated responses of toll-like receptors. In vivo, CXCL4 induced the influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis. CONCLUSIONS: Levels of CXCL4 were elevated in patients with systemic sclerosis and correlated with the presence and progression of complications, such as lung fibrosis and pulmonary arterial hypertension. (Funded by the Dutch Arthritis Association and others.).
Authors: O Distler; B Rinkes; U Hohenleutner; J Schölmerich; M Landthaler; B Lang; S Gay; U Müller-Ladner Journal: Rheumatol Int Date: 1999 Impact factor: 2.631
Authors: A Antonelli; C Ferri; P Fallahi; S M Ferrari; D Giuggioli; M Colaci; A Manfredi; S Frascerra; F Franzoni; F Galetta; E Ferrannini Journal: Rheumatology (Oxford) Date: 2008-01 Impact factor: 7.580
Authors: Maija-Leena Eloranta; Karin Franck-Larsson; Tanja Lövgren; Sebastian Kalamajski; Anders Rönnblom; Kristofer Rubin; Gunnar V Alm; Lars Rönnblom Journal: Ann Rheum Dis Date: 2010-05-14 Impact factor: 19.103
Authors: Timothy R D J Radstake; Olga Gorlova; Blanca Rueda; Jose-Ezequiel Martin; Behrooz Z Alizadeh; Rogelio Palomino-Morales; Marieke J Coenen; Madelon C Vonk; Alexandre E Voskuyl; Annemie J Schuerwegh; Jasper C Broen; Piet L C M van Riel; Ruben van 't Slot; Annet Italiaander; Roel A Ophoff; Gabriela Riemekasten; Nico Hunzelmann; Carmen P Simeon; Norberto Ortego-Centeno; Miguel A González-Gay; María F González-Escribano; Paolo Airo; Jaap van Laar; Ariane Herrick; Jane Worthington; Roger Hesselstrand; Vanessa Smith; Filip de Keyser; Fredric Houssiau; Meng May Chee; Rajan Madhok; Paul Shiels; Rene Westhovens; Alexander Kreuter; Hans Kiener; Elfride de Baere; Torsten Witte; Leonid Padykov; Lars Klareskog; Lorenzo Beretta; Rafaella Scorza; Benedicte A Lie; Anna-Maria Hoffmann-Vold; Patricia Carreira; John Varga; Monique Hinchcliff; Peter K Gregersen; Annette T Lee; Jun Ying; Younghun Han; Shih-Feng Weng; Christopher I Amos; Fredrick M Wigley; Laura Hummers; J Lee Nelson; Sandeep K Agarwal; Shervin Assassi; Pravitt Gourh; Filemon K Tan; Bobby P C Koeleman; Frank C Arnett; Javier Martin; Maureen D Mayes Journal: Nat Genet Date: 2010-04-11 Impact factor: 38.330
Authors: Daniel Kim; Anders Peck; Deanna Santer; Prashant Patole; Stephen M Schwartz; Jerry A Molitor; Frank C Arnett; Keith B Elkon Journal: Arthritis Rheum Date: 2008-07
Authors: Elizabeth R Volkmann; Donald P Tashkin; Masataka Kuwana; Ning Li; Michael D Roth; Julio Charles; Faye N Hant; Galina S Bogatkevich; Tanjina Akter; Grace Kim; Jonathan Goldin; Dinesh Khanna; Philip J Clements; Daniel E Furst; Robert M Elashoff; Richard M Silver; Shervin Assassi Journal: Arthritis Rheumatol Date: 2019-11-01 Impact factor: 10.995