CXCL4-DNA AND CXCL4-RNA IMMUNE COMPLEXES CONTRIBUTE TO TYPE I INTERFERON SIGNATURE AND MEMORY B-CELL ACTIVATION IN SYSTEMIC SCLEROSIS
- Loredana Frasca, Italy
Abstract
Background and Aims
Systemic sclerosis (SSc) is a chronic autoimmune disease characterized by tissue fibrosis, vasculopathy and autoimmunity. Half of the SSc-patients show a type I interferon signature in blood/tissues, which correlates with poor prognosis. CXCL4 is a chemokine overexpressed in SSc, and by binding to nucleic acids can induce IFN-alpha in plasmacytoid dendritic cells (pDCs). Here we tested the ability of CXCL4-DNA and RNA complexes to drive IFN-alpha production, and activate immune cell other then pDCs.
Methods
We combined X-ray scattering to clarify how CXCL4 binds nuclei acids, and in vitro immune cell experiments, using purified human plasmacytoid dendritic cells (pDCs) and memory B-cells. We analyzed CXCL4-DNA and CXCL4-RNA complexes in circulation and skin of SSc patients by enzyme-immune-sorbent assay (ELISA), and by confocal microscopy of SSc skin biopsies, respectively.
Results
We elucidated an unanticipated mechanism for CXCL4-mediated immune amplification in SSc: CXCL4 organizes not only “self” DNA but also self-RNA into immune complexes that drastically amplify pDC-activation and interferon-alpha production. The same complexes induce the differentiation of antibody secreting plasma cells from human memory B-cells in vitro. Of interest, CXCL4 becomes the target of autoantibodies in SSc, which also correlate with blood IFN-alpha. CXCL4-DNA and -RNAcomplexes were detected in vivo and correlated with IFN-alpha levels in SSc plasma.
Conclusions
Thus, we established a direct link between CXCL4-DNA/CXCL4-RNA complexes and pDCs and memory B-cells activation and differentiation of antibody-secreting plasma cells. These data indicate the potential of strategies that disrupt inflammation in SSc, by inhibiting the self-assembly of CXCL4-DNA and/or CXCL4-RNA complexes.