Proteome-Wide Analysis and CXCL4 As a Pathogenic Biomarker in Systemic Sclerosis

Timothy Radstake¹, Lenny van Bon², Alsya Affandi¹, Jasper Broen³, Romy Christmann⁴, Lukasz Stawski⁵, Giuseppina Farina⁶, Allison Mathes⁷, Marta Cossu⁸, MArk Wenink⁹, Roger Hesselstrand¹⁰, Tore Saxne¹¹, Dirk Wuttge¹⁰, John D. Reveille¹², Shervin Assassi¹², Maureen D. Mayes¹³, Wim B van den Berg¹⁴, Vanessa Smith¹⁵, Filip De Keyser¹⁵, Claudio Lunardi¹⁶, Piet L.C. Van Riel¹⁷, Madelon C. Vonk¹⁸, Lorenzo Beretta¹⁹, Maria Trojanowska²⁰ and Robert Lafyatis⁴, ¹Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ²Rheumatology and Clinical Immunology, University Medical Center Utrecht/Radboud University Nijmegen Medical Center, Utrecht/Nijmegen, Netherlands, ³Department of Rheumatology and Clinical Immunology, University Medical Center Utrecht, Utrecht, Netherlands, ⁴Rheumatology, Boston University School of Medicine, Boston, MA, ⁵Rheumatology, Boston Medical Center, Boston, MA, ⁶Arthritis center, Boston University, Boston, MA, ⁷rheumatology, Boston Medical Center, boston, MA, ⁸Rheumatology and Clinical Immunology, University Medical Center Utrecht, utrecht, Netherlands, ⁹rheumatology and Clinical Immunology, university Medical Center Utrecht, utrecht, Netherlands, ¹⁰Rheumatology, Lund University, Lund, Sweden, ¹¹Section of Rheumatology, Deparment of Clinical Sciences, Lund, Lund University, Lund, Sweden, ¹²Rheumatology, University of Texas Health Science Center at Houston, Houston, TX, ¹³University of Texas Health Science Center at Houston, Houston, TX, ¹⁴Experimental Rheumatology, Radboud university medical center, Nijmegen, Netherlands, ¹⁵Department of Rheumatology, Ghent University Hospital, Ghent, Belgium, ¹⁶Department of Medicine, Università degli Studi di Verona, Verona, Italy, ¹⁷Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ¹⁸Department of Rheumatology, Radboud University Nijmegen Medical Centre, Nijmegen, Netherlands, ¹⁹Referral Center for Systemic Autoimmune Diseases, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico di Milano, Milan, Italy, ²⁰Arthritis Center, Boston University, Boston, MA

Meeting: ACR/ARHP Annual Meeting 2013

Keywords: chemokines, Dendritic cells, pathogenesis and systemic sclerosis

Session Information

Title: ACR Late-Breaking Abstract Oral Session

Session Type: Late-Breaking Abstracts

Background/Purpose:

We hypothesized that plasmacytoid dendritic cells are implicated in the pathogenesis of systemic sclerosis via mechanisms beyond previously suggested type I interferon production.

Methods:

We isolated plasmacytoid dendritic cells from healthy persons and from systemic sclerosis patients with distinct clinical phenotypes, exploited proteome-wide analysis and validated these observations in five large systemic sclerosis cohorts and compared results to those in patients with systemic lupus erythematosus (SLE), ankylosing spondylitis and hepatic fibrosis. We correlated plasma CXCL4 levels with systemic sclerosis features. We also studied the direct effects of CXCL4 in vitro and in vivo.

Results:

Proteome-wide analysis and validation demonstrated that CXCL4 is the predominant protein secreted by plasmacytoid dendritic cells in systemic sclerosis, both in the circulation and the skin. CXCL4 was significantly higher in systemic sclerosis patients (25624 ± 2652 pg/ml) compared to controls (92.5 ± 77.9 pg/ml) and to patients with systemic lupus erythematosus (1346 ± 1011 pg/ml), ankylosing spondylitis (1368 ± 1162 pg/ml) and liver fibrosis (1668 ± 1263 pg/ml). CXCL4 levels correlated with skin and lung fibrosis, and with pulmonary arterial hypertension. Among chemokines, only CXCL4 predicted systemic sclerosis disease progression and the risk for systemic sclerosis development. In vitro, CXCL4 downregulated Fli-1 expression, induced markers of endothelial cell activation and potentiated TLR responses. In vivo, CXCL4 induced influx of inflammatory cells and skin transcriptome changes, as in systemic sclerosis.

Conclusion:

CXCL4 is elevated in systemic sclerosis patients, correlates with the presence and progression of complications such as lung fibrosis and pulmonary arterial hypertension and recapitulates pathogenic halmarks seen in SSc. As such, CXCL4 is a novel marker for prognosis and a candidate for therapeutic targetting.

Of Note; This paper is conditionally accepted for publication in the New England Journal of Medicine

Disclosure:

T. Radstake,
None;

L. van Bon,
None;

A. Affandi,
None;

J. Broen,
None;

R. Christmann,
None;

L. Stawski,
None;

G. Farina,
None;

A. Mathes,
None;

M. Cossu,
None;

M. Wenink,
None;

R. Hesselstrand,
None;

T. Saxne,
None;

D. Wuttge,
None;

J. D. Reveille,
None;

S. Assassi,
None;

M. D. Mayes,
None;

W. B. van den Berg,
None;

V. Smith,
None;

F. De Keyser,
None;

C. Lunardi,
None;

P. L. C. Van Riel,
None;

M. C. Vonk,

Actelion Pharmaceuticals US,

L. Beretta,
None;

M. Trojanowska,
None;

R. Lafyatis,
None.

ACR Meeting Abstracts - https://acrabstracts.org/abstract/proteome-wide-analysis-and-cxcl4-as-a-pathogenic-biomarker-in-systemic-sclerosis/