DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients
Article first published online: 28 FEB 2006
Copyright © 2006 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 54, Issue 3, pages 963–973, March 2006
How to Cite
Hénault, J., Robitaille, G., Senécal, J.-L. and Raymond, Y. (2006), DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients. Arthritis & Rheumatism, 54: 963–973. doi: 10.1002/art.21646
- Issue published online: 28 FEB 2006
- Article first published online: 28 FEB 2006
- Manuscript Accepted: 21 NOV 2005
- Manuscript Received: 17 JUN 2005
- Fonds de la Recherche en Santé du Québec
- Canadian Institutes of Health Research. Grant Number: MOP-68966
- Comité Fonds Sainte-Jeanne-d'Arc of the Dollard-Cormier Foundation
Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis due to excessive and dysregulated collagen production by fibroblasts. Previously, we reported that anti–DNA topoisomerase I (anti–topo I) antibodies bound specifically to fibroblast surfaces; however, we had not identified their antigenic target. We undertook this study to characterize the target of anti–topo I antibodies on fibroblasts and the effects of their binding.
Purified topo I or topo I released from apoptotic cells was tested for surface binding to a number of human cell types by cell-based enzyme-linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. Antibodies purified from SSc patient and normal control sera were used to detect topo I binding. The consequences of topo I and anti–topo I binding to fibroblasts were assessed by coculture with THP-1 monocytes.
The autoantigen topo I itself was found to bind specifically to fibroblasts in a dose-dependent and saturable manner, where it was recognized by anti–topo I from SSc patients. The binding of anti–topo I subsequently stimulated adhesion and activation of cocultured monocytes. Topo I released from apoptotic endothelial cells was also found to bind specifically to fibroblasts.
The findings of this study thus confirm and extend the findings of our previous study by showing that topo I binding to fibroblast surfaces is both necessary and sufficient for anti–topo I binding. Second, topo I–anti–topo I complex binding can then trigger the adhesion and activation of monocytes, thus providing a plausible model for the amplification of the fibrogenic cascade in anti–topo I–positive SSc patients.