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.
Highlights
Systemic sclerosis (SSc) is an autoimmune disease whose hallmarks are autoimmunity, fibrosis and vasculopathy [1]
Anti-CXCL4 antibodies appear to correlate with blood IFN-α and are higher in pulmonary fibrosis in both SSc cohorts examined. This is of interest, as here we show that anti-CXCL4–huDNA–IgG immune complexes can induce plasmacytoid dendritic cells (pDCs)-mediated immune amplification via implementation of the IFN-α secretion already mediated by CXCL4–huDNAcomplexes [12]
This paper found that: (1) CXCL4 is a new autoantigen for both B-cells and T-cells in SSc; (2) antibodies to CXCL4 correlate with the IFN-I signature; and (3) anti-CXCL4 antibodies implement IFN-α induced by CXCL4–DNA complexes in pDCs via TLR9
Summary
Systemic sclerosis (SSc) is an autoimmune disease whose hallmarks are autoimmunity, fibrosis and vasculopathy [1]. Anti-CXCL4 Antibody Reactivity in SSc Patients Correlates with Serum/Plasma IFN-α and Is Higher in SSc Patients with Lung Fibrosis 2.3. Anti-CXCL4 antibodies appear to correlate with blood IFN-α and are higher in pulmonary fibrosis in both SSc cohorts examined. This is of interest, as here we show that anti-CXCL4–huDNA–IgG immune complexes can induce pDC-mediated immune amplification via implementation of the IFN-α secretion already mediated by CXCL4–huDNAcomplexes [12]. It is interesting that in our discovery cohort, patients with pulmonary fibrosis are the ones with higher anti-CXCL4 antibody reactivity, and those with a higher IFN-I signature in the blood.
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