期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 21, 期 14, 页码 -出版社
MDPI
DOI: 10.3390/ijms21145102
关键词
autoantibodies; CXCL4; type I interferon; lung fibrosis; innate immunity; adaptive immunity
资金
- Ernst et Lucie Schmidheiny Foundation, Geneva, Switzerland
- Carlos and Elsie de Reuter Foundation
- Centre Medical Universitaire, Geneva, Switzerland
- Ricerca Finalizzata, Ministry of Health, Italy [CO-2013-02356463]
- Swiss National Found, Switzerland [310030-159999]
- National Psoriasis Fundation, USA
- ISS-Ricerca Corrente
- Bangerter-Rhyner Foundation, Switzerland
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)-alpha 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-alpha 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-alpha 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-alpha in pDCs and direct B-cell stimulation, including the secretion of anti-CXCL4 antibodies. Anti-CXCL4 antibodies may further increase pDC stimulation and IFN-alpha release in vivo, creating a vicious cycle which sustains the SSc IFN-I signature and general inflammation.
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