Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature
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)-α production by plasmacytoid den...
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doaj-6477cd402c064c8881e4c46bccbbfb302020-11-25T03:47:58ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672020-07-01215102510210.3390/ijms21145102Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon SignatureRoberto Lande0Anna Mennella1Raffaella Palazzo2Immacolata Pietraforte3Katia Stefanantoni4Nicoletta Iannace5Alessia Butera6Monica Boirivant7Roberta Pica8Curdin Conrad9Carlo Chizzolini10Valeria Riccieri11Loredana Frasca12Istituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalyIstituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalyIstituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalyDepartment of Oncology and Molecular Medicine, Istituto Superiore di Sanità, 00161 Rome, ItalyDivision of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, ItalyDivision of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, ItalyIstituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalyIstituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalySandro Pertini Hospital, IBD, GE Unit, 00157 Rome, ItalyDepartment of Dermatology, University Hospital CHUV, 1011 Lausanne, SwitzerlandImmunology & Allergy and Immunology & Pathology Dept., University Hospital and School of Medicine, CH-1211 Geneva, SwitzerlandDivision of Rheumatology, Internal Medicine and Medical Specialties, University La Sapienza, 00185 Rome, ItalyIstituto Superiore di Sanita’, National Centre for Pre-Clinical and Clinical Drug Research and Evaluation, Pharmacological Research and Experimental Therapy Unit, 00166 Rome, ItalySystemic 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)-α 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-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/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–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.https://www.mdpi.com/1422-0067/21/14/5102autoantibodiesCXCL4type I interferonlung fibrosisinnate immunityadaptive immunity |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Roberto Lande Anna Mennella Raffaella Palazzo Immacolata Pietraforte Katia Stefanantoni Nicoletta Iannace Alessia Butera Monica Boirivant Roberta Pica Curdin Conrad Carlo Chizzolini Valeria Riccieri Loredana Frasca |
spellingShingle |
Roberto Lande Anna Mennella Raffaella Palazzo Immacolata Pietraforte Katia Stefanantoni Nicoletta Iannace Alessia Butera Monica Boirivant Roberta Pica Curdin Conrad Carlo Chizzolini Valeria Riccieri Loredana Frasca Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature International Journal of Molecular Sciences autoantibodies CXCL4 type I interferon lung fibrosis innate immunity adaptive immunity |
author_facet |
Roberto Lande Anna Mennella Raffaella Palazzo Immacolata Pietraforte Katia Stefanantoni Nicoletta Iannace Alessia Butera Monica Boirivant Roberta Pica Curdin Conrad Carlo Chizzolini Valeria Riccieri Loredana Frasca |
author_sort |
Roberto Lande |
title |
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature |
title_short |
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature |
title_full |
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature |
title_fullStr |
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature |
title_full_unstemmed |
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature |
title_sort |
anti-cxcl4 antibody reactivity is present in systemic sclerosis (ssc) and correlates with the ssc type i interferon signature |
publisher |
MDPI AG |
series |
International Journal of Molecular Sciences |
issn |
1661-6596 1422-0067 |
publishDate |
2020-07-01 |
description |
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)-α 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-α levels and are significantly higher in patients with lung fibrosis in two independent SSc cohorts. Antibodies to CXCL4 implement the CXCL4–DNA complex’s effect on IFN-α production by pDCs; CXCL4–DNA/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–DNA/RNA complexes induce IFN-α in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-α release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation. |
topic |
autoantibodies CXCL4 type I interferon lung fibrosis innate immunity adaptive immunity |
url |
https://www.mdpi.com/1422-0067/21/14/5102 |
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