PMID- 22095242
OWN - NLM
STAT- MEDLINE
DCOM- 20120713
LR  - 20120427
IS  - 1529-0131 (Electronic)
IS  - 0004-3591 (Linking)
VI  - 64
IP  - 5
DP  - 2012 May
TI  - Heparin inhibits the interaction of DNA topoisomerase I/anti-topoisomerase I 
      immune complexes with heparan sulfate on dermal fibroblasts.
PG  - 1632-41
LID - 10.1002/art.33484 [doi]
AB  - 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.
CI  - Copyright (c) 2012 by the American College of Rheumatology.
FAU - Arcand, Julie
AU  - Arcand J
AD  - Notre-Dame Hospital, Centre Hospitalier de l'Universite de Montreal, and 
      Universite de Montreal, Montreal, Quebec, Canada.
FAU - Robitaille, Genevieve
AU  - Robitaille G
FAU - Koenig, Martial
AU  - Koenig M
FAU - Senecal, Jean-Luc
AU  - Senecal JL
FAU - Raymond, Yves
AU  - Raymond Y
LA  - eng
GR  - MOP-68966/Canadian Institutes of Health Research/Canada
GR  - MOP-81252/Canadian Institutes of Health Research/Canada
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Arthritis Rheum
JT  - Arthritis and rheumatism
JID - 0370605
RN  - 0 (Antigen-Antibody Complex)
RN  - 0 (Antigens, Surface)
RN  - 0 (Autoantibodies)
RN  - 0 (Fibrinolytic Agents)
RN  - 9005-49-6 (Heparin)
RN  - 9050-30-0 (Heparitin Sulfate)
RN  - EC 5.99.1.2 (DNA Topoisomerases, Type I)
SB  - IM
MH  - Antigen-Antibody Complex/*drug effects/immunology
MH  - Antigens, Surface/immunology
MH  - Autoantibodies/immunology/pharmacology
MH  - Cells, Cultured
MH  - DNA Topoisomerases, Type I/*immunology
MH  - Dermis/pathology
MH  - Fibrinolytic Agents/*pharmacology
MH  - Fibroblasts/*drug effects/immunology/pathology
MH  - Heparin/*pharmacology
MH  - Heparitin Sulfate/*immunology
MH  - Humans
MH  - Protein Binding
MH  - Scleroderma, Systemic/immunology
EDAT- 2011/11/19 06:00
MHDA- 2012/07/14 06:00
CRDT- 2011/11/19 06:00
PHST- 2011/11/19 06:00 [entrez]
PHST- 2011/11/19 06:00 [pubmed]
PHST- 2012/07/14 06:00 [medline]
AID - 10.1002/art.33484 [doi]
PST - ppublish
SO  - Arthritis Rheum. 2012 May;64(5):1632-41. doi: 10.1002/art.33484.