Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature.

Details

Serval ID
serval:BIB_565271192042
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Anti-CXCL4 Antibody Reactivity Is Present in Systemic Sclerosis (SSc) and Correlates with the SSc Type I Interferon Signature.
Journal
International journal of molecular sciences
Author(s)
Lande R., Mennella A., Palazzo R., Pietraforte I., Stefanantoni K., Iannace N., Butera A., Boirivant M., Pica R., Conrad C., Chizzolini C., Riccieri V., Frasca L.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Publication state
Published
Issued date
19/07/2020
Peer-reviewed
Oui
Volume
21
Number
14
Pages
5102
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
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.
Keywords
Adaptive Immunity, Adult, Aged, Antibody Specificity, Autoantibodies/blood, Autoantigens/immunology, B-Lymphocytes/immunology, Biomarkers/blood, Case-Control Studies, Cell Proliferation, Colitis, Ulcerative/immunology, DNA/immunology, Dendritic Cells/immunology, Female, Healthy Volunteers, Humans, Immunity, Innate, Immunologic Memory, In Vitro Techniques, Interferon Type I/blood, Interferon-alpha/blood, Male, Middle Aged, Platelet Factor 4/immunology, Scleroderma, Systemic/immunology, T-Lymphocytes/immunology, CXCL4, adaptive immunity, autoantibodies, innate immunity, lung fibrosis, type I interferon
Pubmed
Web of science
Open Access
Yes
Create date
11/08/2020 11:41
Last modification date
24/02/2022 7:33
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