RT Journal Article
SR Electronic
T1 Toll-like receptor and antiphospholipid mediated thrombosis: in vivo studies
JF Annals of the Rheumatic Diseases
JO Ann Rheum Dis
FD BMJ Publishing Group Ltd and European League Against Rheumatism
SP 1327
OP 1333
DO 10.1136/ard.2006.065037
VO 66
IS 10
A1 Mariano E Vega-Ostertag
A1 Elena Raschi
A1 Xiaowei Liu
A1 Zurina Romay-Penabad
A1 Valeria De Micheli
A1 Monica Galli
A1 Marco Moia
A1 Angela Tincani
A1 Maria Orietta Borghi
A1 Tracy Nguyen-Oghalai
A1 Pier Luigi Meroni
YR 2007
UL http://ard.bmj.com/content/66/10/1327.abstract
AB Objective: A study was undertaken to investigate the in vivo pathogenic role of Toll-like receptor 4 (TLR-4) in the antiphospholipid syndrome (APS) by studying the thrombogenic antiphospholipid (aPL) activity in lipopolysaccharide (LPS) non-responsive (LPS–/–) mice and the association between tlr4 gene polymorphisms and APS in patients.Methods: IgGs from two patients with APS, one with aPL negative systemic lupus erythematosus (SLE) and one with normal human serum (NHS), were evaluated for thrombosis, tissue factor (TF) activity and endothelial cell activation in LPS–/– mice displaying a tlr4 spontaneous mutation vs LPS responsive (LPS+/+) mice. Human tlr4 Asp299Gly and Thr399Ile polymorphisms were evaluated by allele-specific PCR in 110 patients with APS with arterial/venous thrombosis and in 220 controls of the same ethnic origin.Results: IgG-APS produced significantly larger thrombi and more leucocytes (WBC) adhering to endothelial cells in the cremaster muscle microcirculation of LPS+/+ mice than IgG-NHS or aPL negative SLE-IgG. These effects were abrogated after absorption of the anti-β2glycoprotein I activity by an affinity column. The two IgG-APS induced significantly smaller thrombi and fewer WBC adhering to endothelial cells in LPS−/− mice than in LPS+/+ mice. IgG-APS induced higher TF activity in carotid artery homogenates of LPS+/+ mice than in LPS−/− mice. The prevalence of Asp299Gly and Thr399Ile tlr4 polymorphisms was significantly lower than in controls.Conclusions: These findings in LPS−/− mice and the reduction in the “protective” polymorphism in patients with APS with thrombosis suggest that TLR-4 is involved in the interaction of aPL with endothelial cells in vivo.