Drs. Arcand and Robitaille contributed equally to this work.
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Systemic Sclerosis
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Heparin inhibits the interaction of DNA topoisomerase I/anti–topoisomerase I immune complexes with heparan sulfate on dermal fibroblasts
Article first published online: 26 APR 2012
DOI: 10.1002/art.33484
Copyright © 2012 by the American College of Rheumatology
Additional Information
How to Cite
Arcand, J., Robitaille, G., Koenig, M., Senécal, J.-L. and Raymond, Y. (2012), Heparin inhibits the interaction of DNA topoisomerase I/anti–topoisomerase I immune complexes with heparan sulfate on dermal fibroblasts. Arthritis & Rheumatism, 64: 1632–1641. doi: 10.1002/art.33484
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Drs. Arcand and Robitaille contributed equally to this work.
- ‡
Dr. Senécal holds the University of Montréal Scleroderma Research Chair.
- §
Drs. Senécal and Raymond contributed equally to this work.
Publication History
- Issue published online: 26 APR 2012
- Article first published online: 26 APR 2012
- Accepted manuscript online: 17 NOV 2011 09:26AM EST
- Manuscript Accepted: 9 NOV 2011
- Manuscript Received: 9 JUN 2011
Funded by
- Canadian Institutes of Health Research. Grant Numbers: MOP-68966, MOP-81252
- Sclérodermie Québec
- Donations from Mrs. Gisèle Sarrazin-Locas and the Scleroderma Society of Ontario
- Studentships from Sclérodermie Québec and the Université de Montréal
- Abstract
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- Cited By
Abstract
Objective
Previous studies have demonstrated that the systemic sclerosis (SSc)–associated autoantigen DNA topoisomerase I (topo I) binds specifically to the surface of fibroblasts when released in the extracellular environment and recruits anti–topo I autoantibodies, which subsequently leads to the adhesion and activation of monocytes. This study aimed to characterize the molecular interactions of topo I with fibroblast surfaces in order to elucidate the pathogenic role of topo I/anti–topo I immune complexes (ICs) in SSc.
Methods
Topo I directly coupled to fluorochromes was used to follow its binding to fibroblast surfaces by flow cytometry and fluorescence microscopy. Purified IgG from normal subjects or SSc patients was added with topo I to the cells; unfractionated heparin (UFH) and low molecular weight heparin (LMWH) were used to determine their effects on the binding of topo I and topo I/anti–topo I IC to fibroblast surfaces.
Results
Heparan sulfate (HS) proteoglycans on fibroblast surfaces were found to act as coreceptors for topo I binding. The addition of anti–topo I autoantibodies from SSc sera led to the amplification of topo I binding to HS chains. UFH and LMWH were shown to inhibit topo I and topo I/anti–topo I IC binding to HS chains.
Conclusion
This study is the first to show that topo I binds specifically to HS proteoglycans on fibroblast surfaces and that anti–topo I autoantibodies from SSc patients amplify topo I binding to HS chains. The accumulation of topo I on cell surfaces by anti–topo I autoantibodies could contribute to the initiation of an inflammatory cascade stimulating the fibrosis. UFH and LMWH inhibited the binding of topo I/anti–topo I IC to fibroblasts, suggesting a potential therapeutic role in SSc-associated fibrosis.