{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,10]],"date-time":"2026-10-10T11:37:41Z","timestamp":1791632261686,"version":"4.3.4"},"reference-count":45,"publisher":"MDPI AG","issue":"14","license":[{"start":{"date-parts":[[2020,7,19]],"date-time":"2020-07-19T00:00:00Z","timestamp":1595116800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100007673","name":"Fondation Centre de Recherches M\u00e9dicales Carlos et Elsie de Reuter","doi-asserted-by":"publisher","award":["2015"],"award-info":[{"award-number":["2015"]}],"id":[{"id":"10.13039\/501100007673","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007636","name":"Fondation Ernst et Lucie Schmidheiny","doi-asserted-by":"publisher","award":["2014-2015"],"award-info":[{"award-number":["2014-2015"]}],"id":[{"id":"10.13039\/501100007636","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100003185","name":"National Psoriasis Foundation","doi-asserted-by":"publisher","award":["2019-21"],"award-info":[{"award-number":["2019-21"]}],"id":[{"id":"10.13039\/100003185","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001711","name":"Schweizerischer Nationalfonds zur F\u00f6rderung der Wissenschaftlichen Forschung","doi-asserted-by":"publisher","award":["grant 310030\u2013159999"],"award-info":[{"award-number":["grant 310030\u2013159999"]}],"id":[{"id":"10.13039\/501100001711","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Ricerca Finalizzata Italy","award":["grant 310030\u2013159999"],"award-info":[{"award-number":["grant 310030\u2013159999"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Systemic sclerosis (SSc) is characterized by skin\/internal organ fibrosis, vasculopathy and autoimmunity. Chemokine (C-X-C motif) ligand 4 (CXCL4) is an SSc biomarker, predicting unfavorable prognosis and lung fibrosis. CXCL4 binds DNA\/RNA and favors interferon (IFN)-\u03b1 production by plasmacytoid dendritic cells (pDCs), contributing to the type I IFN (IFN-I) signature in SSc patients. However, whether CXCL4 is an autoantigen in SSc is unknown. Here, we show that at least half of SSc patients show consistent antibody reactivity to CXCL4. T-cell proliferation to CXCL4, tested in a limited number of patients, correlates with anti-CXCL4 antibody reactivity. Antibodies to CXCL4 mostly correlate with circulating IFN-\u03b1 levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4\u2013DNA complex\u2019s effect on IFN-\u03b1 production by pDCs; CXCL4\u2013DNA\/RNA complexes stimulate purified human B-cells to become antibody-secreting plasma cells in vitro. These data indicate that CXCL4 is indeed an autoantigen in SSc and suggest that CXCL4, and CXCL4-specific autoantibodies, can fuel a harmful loop: CXCL4\u2013DNA\/RNA complexes induce IFN-\u03b1 in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-\u03b1 release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.<\/jats:p>","DOI":"10.3390\/ijms21145102","type":"journal-article","created":{"date-parts":[[2020,7,20]],"date-time":"2020-07-20T06:08:17Z","timestamp":1595225297000},"page":"5102","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":53,"title":["Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature"],"prefix":"10.3390","volume":"21","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8398-4567","authenticated-orcid":false,"given":"Roberto","family":"Lande","sequence":"first","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3870-5332","authenticated-orcid":false,"given":"Anna","family":"Mennella","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"},{"name":"Department of Dermatology, University Hospital CHUV, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raffaella","family":"Palazzo","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6443-9969","authenticated-orcid":false,"given":"Immacolata","family":"Pietraforte","sequence":"additional","affiliation":[{"name":"Department of Oncology and Molecular Medicine, Istituto Superiore di Sanit\u00e0, 00161 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katia","family":"Stefanantoni","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nicoletta","family":"Iannace","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alessia","family":"Butera","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica","family":"Boirivant","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberta","family":"Pica","sequence":"additional","affiliation":[{"name":"Sandro Pertini Hospital, IBD, GE Unit, 00157 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2547-3440","authenticated-orcid":false,"given":"Curdin","family":"Conrad","sequence":"additional","affiliation":[{"name":"Department of Dermatology, University Hospital CHUV, 1011 Lausanne, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4849-6335","authenticated-orcid":false,"given":"Carlo","family":"Chizzolini","sequence":"additional","affiliation":[{"name":"Immunology &amp; Allergy and Immunology &amp; Pathology Dept., University Hospital and School of Medicine, CH-1211 Geneva, Switzerland"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valeria","family":"Riccieri","sequence":"additional","affiliation":[{"name":"Division of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6924-3826","authenticated-orcid":false,"given":"Loredana","family":"Frasca","sequence":"additional","affiliation":[{"name":"Istituto Superiore di Sanita\u2019, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, Italy"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,7,19]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1989","DOI":"10.1056\/NEJMra0806188","article-title":"Scleroderma","volume":"360","author":"Gabrielli","year":"2009","journal-title":"N. Engl. J. Med."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"390","DOI":"10.1038\/nrrheum.2014.53","article-title":"Fibrosis\u2014A lethal component of systemic sclerosis","volume":"10","author":"Ho","year":"2014","journal-title":"Nat. Rev. Rheumatol."},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"Frasca, L., and Lande, R. (2020). Toll-like receptors in mediating pathogenesis in systemic sclerosis review. Clin. Exp. Immunol.","DOI":"10.1111\/cei.13426"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2451","DOI":"10.1172\/JCI131700","article-title":"Cytotoxic CD4+ T lymphocytes may induce endothelial cell apoptosis in systemic sclerosis","volume":"130","author":"Maehara","year":"2020","journal-title":"J. Clin. Investig."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"753","DOI":"10.1080\/1744666X.2019.1614915","article-title":"Pathophysiology of systemic sclerosis: Current understanding and new insights","volume":"15","author":"Cutolo","year":"2019","journal-title":"Expert Rev. Clin. Immunol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/j.imlet.2017.09.001","article-title":"Toll-like receptors in systemic sclerosis: An emerging target","volume":"195","year":"2018","journal-title":"Immunol. Lett."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"433","DOI":"10.1056\/NEJMoa1114576","article-title":"Proteome-wide analysis and CXCL4 as a biomarker in systemic sclerosis","volume":"370","author":"Affandi","year":"2014","journal-title":"N. Engl. J. Med."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Ah Kioon, M.D., Tripodo, C., Fernandez, D., Kirou, K.A., Spiera, R.F., Crow, M.K., Gordon, J.K., and Barrat, F.J. (2018). Plasmacytoid dendritic cells promote systemic sclerosis with a key role for TLR8. Sci. Transl. Med., 10.","DOI":"10.1126\/scitranslmed.aam8458"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"2163","DOI":"10.1002\/art.23486","article-title":"Induction of interferon-alpha by scleroderma sera containing autoantibodies to topoisomerase I: Association of higher interferon-alpha activity with lung fibrosis","volume":"58","author":"Kim","year":"2008","journal-title":"Arthritis Rheum."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1396","DOI":"10.1136\/ard.2009.121400","article-title":"Type I interferon system activation and association with disease manifestations in systemic sclerosis","volume":"69","author":"Eloranta","year":"2010","journal-title":"Ann. Rheum Dis."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1567","DOI":"10.1136\/annrheumdis-2015-207392","article-title":"The interferon type I signature is present in systemic sclerosis before overt fibrosis and might contribute to its pathogenesis through high BAFF gene expression and high collagen synthesis","volume":"75","author":"Brkic","year":"2016","journal-title":"Ann. Rheum. Dis."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1731","DOI":"10.1038\/s41467-019-09683-z","article-title":"CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-alpha production in systemic sclerosis","volume":"10","author":"Lande","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Persson, E.K., Verstraete, K., Heyndrickx, I., Gevaert, E., Aegerter, H., Percier, J.-M., Deswarte, K., Verschueren, K.H.G., Dansercoer, A., and Gras, D. (2019). Protein crystallization promotes type 2 immunity and is reversible by antibody treatment. Science, 364.","DOI":"10.1126\/science.aaw4295"},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Arepally, G.M., and Cines, D.B. (2020). Pathogenesis of heparin-induced thrombocytopenia. Transl. Res.","DOI":"10.1016\/j.trsl.2020.04.014"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Ye, L., Zhang, Y.-P., Yu, N., Jia, Y.-X., Wan, S.-J., and Wang, F.-Y. (2017). Serum platelet factor 4 is a reliable activity parameter in adult patients with inflammatory bowel disease: A pilot study. Medicine, 96.","DOI":"10.1097\/MD.0000000000006323"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1721","DOI":"10.1093\/rheumatology\/kes145","article-title":"Heparin-dependent and -independent anti-platelet factor 4 autoantibodies in patients with systemic lupus erythematosus","volume":"51","author":"Satoh","year":"2012","journal-title":"Rheumatology"},{"key":"ref_17","unstructured":"Melsens, K.F., De Keyser, S., Decuman, Y., Piette, E., Vandecasteele, E., and Smith, V. (2016). Disease activity indices in systemic sclerosis: A systematic. Clin. Exp. Rheumatol., 34."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"498","DOI":"10.1038\/icb.2012.10","article-title":"Role of type I interferons in the activation of autoreactive B cells","volume":"90","author":"Kiefer","year":"2012","journal-title":"Immunol. Cell Biol."},{"key":"ref_19","first-page":"30","article-title":"The programming of an antibody-secreting machine","volume":"49","author":"Tellier","year":"2019","journal-title":"J. Immunol."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"3364","DOI":"10.4049\/jimmunol.1700778","article-title":"Netting neutrophils activate autoreactive B cells in Lupus","volume":"200","author":"Gestermann","year":"2018","journal-title":"J. Immunol."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2281","DOI":"10.1093\/rheumatology\/keq226","article-title":"Pharmacological inhibition of TLR9 activation blocks autoantibody production in human B cells from SLE patients","volume":"49","author":"Capolunghi","year":"2010","journal-title":"Rheumatology"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"5786","DOI":"10.4049\/jimmunol.1202195","article-title":"B cell TLR7 expression drives anti-RNA autoantibody production and exacerbates disease in systemic lupus erythematosus-prone mice","volume":"189","author":"Hwang","year":"2012","journal-title":"J. Immunol."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"1884","DOI":"10.3389\/fimmu.2018.01884","article-title":"Insights Into the Molecular Mechanisms of T Follicular Helper-Mediated Immunity and Pathology","volume":"9","author":"Qin","year":"2018","journal-title":"Front. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"5621","DOI":"10.1038\/ncomms6621","article-title":"The antimicrobial peptide LL37 is a T-cell autoantigen in psoriasis","volume":"5","author":"Lande","year":"2014","journal-title":"Nat. Commun."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"5851","DOI":"10.1038\/s41598-020-62480-3","article-title":"Native\/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus","volume":"10","author":"Lande","year":"2020","journal-title":"Sci. Rep."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"66","DOI":"10.1016\/j.humimm.2003.10.004","article-title":"High Resolution HLA-DRB1 Identification of a Caucasian Population","volume":"65","author":"Williams","year":"2004","journal-title":"Hum. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1111\/1756-185X.12528","article-title":"Value of HLA-DR genotype in systemic lupus erythematosus and lupus nephritis: A meta-analysis","volume":"18","author":"Niu","year":"2015","journal-title":"Int. J. Rheum. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"207","DOI":"10.1002\/cyto.b.21092","article-title":"CD38 and CD157: A Long Journey From Activation Markers to Multifunctional Molecules","volume":"84","author":"Quarona","year":"2013","journal-title":"Clin. Cytom."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1059","DOI":"10.1089\/107999099313299","article-title":"Upregulation of CD38 Gene Expression in Leukemic B Cells by Interferon Types I and II","volume":"19","author":"Bauvois","year":"1999","journal-title":"J. Interferon Cytokine Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/j.cytogfr.2010.10.011","article-title":"The role of the CXC chemokines platelet factor-4 (CXCL4\/PF-4) and its variant (CXCL4L1\/PF-4var) in inflammation, angiogenesis and cancer","volume":"22","author":"Vandercappellen","year":"2011","journal-title":"Cytokine Growth Factor Rev."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"266","DOI":"10.3389\/fimmu.2013.00266","article-title":"The role of type 1 interferon in systemic sclerosis","volume":"4","author":"Wu","year":"2013","journal-title":"Front. Immunol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1126\/scitranslmed.3001180","article-title":"Neutrophils activate plasmacytoid dendritic cells by releasing self-DNA-peptide complexes in systemic lupus erythematosus","volume":"3","author":"Lande","year":"2011","journal-title":"Sci. Transl. Med."},{"key":"ref_33","first-page":"245","article-title":"From Raynaud\u2019s Phenomenon to Very Early Diagnosis of Systemic Sclerosis\u2014The VEDOSS approach","volume":"9","year":"2013","journal-title":"Curr. Rheumatol. Rev."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"157","DOI":"10.1038\/nm0202-157","article-title":"CCL27-CCR10 interactions regulate T cell-mediated skin inflammation","volume":"8","author":"Homey","year":"2002","journal-title":"Nat. Med."},{"key":"ref_35","unstructured":"Frasca, L. (2015). Personal Observations."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"625","DOI":"10.1016\/j.autrev.2018.01.012","article-title":"Systemic lupus erythematosus and systemic sclerosis: All roads lead to platelets","volume":"17","author":"Scherlinger","year":"2018","journal-title":"Autoimmun. Rev."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1189","DOI":"10.1160\/TH15-01-0062","article-title":"Polyphosphates form antigenic complexes with platelet factor 4 (PF4) and enhance PF4- binding to bacteria","volume":"114","author":"Brandt","year":"2015","journal-title":"Thromb. Haemost."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"62","DOI":"10.1182\/bloodadvances.2016000877","article-title":"Polyphosphate\/platelet factor 4 complexes can mediate heparin-independent platelet activation in heparin-induced thrombocytopenia","volume":"1","author":"Cines","year":"2016","journal-title":"Blood Adv."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1322","DOI":"10.1038\/s41467-019-09160-7","article-title":"Neutrophil activation and NETosis are the major drivers of thrombosis in heparin-induced thrombocytopenia","volume":"10","author":"Perdomo","year":"2019","journal-title":"Nat. Commun."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"42","DOI":"10.1172\/jci.insight.99445","article-title":"Neutrophil accumulation and NET release contribute to thrombosis in HIT","volume":"3","author":"Gollomp","year":"2018","journal-title":"JCI Insight."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"3651","DOI":"10.1182\/blood-2014-01-549741","article-title":"Spontaneous heparin-induced thrombocytopenia syndrome: 2 new cases and a proposal for defining this disorder","volume":"123","author":"Warkentin","year":"2014","journal-title":"Blood"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"208","DOI":"10.1182\/blood.V94.1.208.413a06_208_215","article-title":"Complexes of heparin and platelet factor 4 specifically stimulate T cells from patients with heparin-induced thrombocytopenia\/thrombosis","volume":"94","author":"Bacsi","year":"1999","journal-title":"Blood"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1182\/blood-2004-12-4955","article-title":"PF4\/heparin complexes are T cell-dependent antigens","volume":"106","author":"Suvarna","year":"2005","journal-title":"Blood"},{"key":"ref_44","first-page":"288","article-title":"Systemic lupus erythematosus disease activity index 2000","volume":"29","author":"Gladman","year":"2002","journal-title":"J. Rheumatol."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"2462","DOI":"10.1056\/NEJMoa050516","article-title":"Infliximab for induction and maintenance therapy for ulcerative colitis","volume":"353","author":"Rutgeerts","year":"2005","journal-title":"N. Engl. J. Med."}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5102\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T09:49:50Z","timestamp":1760176190000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/21\/14\/5102"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,7,19]]},"references-count":45,"journal-issue":{"issue":"14","published-online":{"date-parts":[[2020,7]]}},"alternative-id":["ijms21145102"],"URL":"https:\/\/doi.org\/10.3390\/ijms21145102","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,7,19]]}}}