Loredana Frasca, Italy

Istituto Superiore di Sanità National center for drug research and evaluation
Actual Position: Group Leader for studies in Immunology of autoimmune diseases, (ORCID ID: orcid.org/0000-0001-6924-3826, RESEARCH ID: B-9986-201). Degree in Biological Sciences, 1992, University Sapienza, ROME, IT. PhD in cellular biology and Immunology (1996), Sapienza, ROME. Worked at Imperial College, London, UK (1995-96), MD Anderson Cancer Center, Houston, TX, USA (2007-8); CHUV, Lausanne (dept of Dermatology, 2012-2014) and UNIGE, Dept. Pathology and Immunol, Geneva, Switzerland (2014-15). Field of studies: Basic and translational research on psoriasis, Systemic Lupus Erythematosus, Systemic Sclerosis. Study of pathogenic immunological mechanisms involved in autoimmunity, search for new biomarkers of disease, disease progression, and disease improvement after non-biological and biological therapy. Research on new targets for treatments in autoimmune diseases. Recent selected pubblications: 1. Lande R, Pietraforte I, Mennella A, et al and Frasca L. Complementary Effects of Carbamylated and Citrullinated LL37 in Autoimmunity and Inflammation in Systemic Lupus Erythematosus. Int J Mol Sci. 2021 Feb 6;22(4):1650. doi: 10.3390/ijms22041650.; 2. R. Lande, R. Palazzo, N. Gestermann, et al and L. Frasca. Native/citrullinated LL37-specific T-cells help autoantibody production in Systemic Lupus Erythematosus, Scientific Reports 2020, DOI:10.1038/s41598-020-62480-3; 3. Frasca L and Lande R. Toll-Like receptors in mediating the pathogenesis in systemic sclerosis Clinical and Experimental Immunology, Feb. 2020, DOI: 10.1111/cei.13426 ; 4. Lande R, Lee EY, et al. and Frasca L. CXCL4 assembles DNA into liquid crystalline complexes to amplify TLR9-mediated interferon-α production in systemic sclerosis. Nat Commun. 2019, 1;10(1):1731. doi: 10.1038/s41467-019-09683-z.

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CXCL4-DNA AND CXCL4-RNA IMMUNE COMPLEXES CONTRIBUTE TO TYPE I INTERFERON SIGNATURE AND MEMORY B-CELL ACTIVATION IN SYSTEMIC SCLEROSIS

Session Name
PS26 -NOVELTIES IN SYSTEMIC SCLEROSIS
Session Type
PARALLEL SESSIONS
Date
30.05.2021, Sunday
Session Time
13:30 - 15:30
Room
HALL A
Lecture Time
15:10 - 15:20
Presenter
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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.

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