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

Int J Mol Sci. 2020 Jul 19;21(14):5102. doi: 10.3390/ijms21145102.


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: CXCL4; adaptive immunity; autoantibodies; innate immunity; lung fibrosis; type I interferon.

MeSH terms

  • 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


  • Autoantibodies
  • Autoantigens
  • Biomarkers
  • Interferon Type I
  • Interferon-alpha
  • PF4 protein, human
  • Platelet Factor 4
  • DNA