β₂-Glycoprotein-1 autoantibodies from patients with antiphospholipid syndrome are sufficient to potentiate arterial thrombus formation in a mouse model.
Antiphospholipid syndrome is characterized by thrombosis, recurrent fetal loss, and the presence of the lupus anticoagulant, anticardiolipin antibodies, or anti-β(2)-glycoprotein-1 (anti-β(2)-GP1) antibodies. Although anti-β(2)-GP1 antibodies have been documented as a biomarker for diagnosis of antiphospholipid syndrome, their direct role in the pathogenesis of thrombosis is unknown. We have demonstrated using intravital microscopy that anti-β(2)-GP1 autoantibodies purified from the sera of patients with antiphospholipid syndrome complicated by thrombosis greatly amplify thrombus size after laser-induced vessel wall injury in live mice. Anti-β(2)-GP1 autoantibodies from 3 patients with antiphospholipid syndrome were affinity-purified using human β(2)-GP1 bound to agarose. The effects of purified anti-β(2)-GP1 IgG autoantibodies, of anti-β(2)-GP1-depleted IgG, and of IgG from normal human sera on thrombus formation were measured in mice after arterial injury in the cremaster muscle. Before injury, purified anti-β(2)-GP1 IgG autoantibodies, anti-β(2)-GP1 antibody-depleted IgG, or IgG from normal human sera were infused. Increasing amounts of purified anti-β(2)-GP1 autoantibodies increased thrombus size in a dose-dependent manner, whereas neither anti-β(2)-GP1 antibody-depleted IgG nor IgG from normal serum affected thrombus size. These results indicate that anti-β(2)-GP1 IgG autoantibodies in antiphospholipid syndrome patient sera are not only a marker of antiphospholipid syndrome but are directly involved in the pathogenesis of thrombosis.
Division of Hemostasis and Thrombosis, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02115, USA.
Ariela
A
Arad
Valerie
V
Proulle
Richard A
RA
Furie
Barbara C
BC
Furie
Bruce
B
Furie
D000328:Adult; D000818:Animals; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology*; D001158:Arteries / Q000473:pathology; D001323:Autoantibodies / Q000009:adverse effects* / Q000302:isolation & purification; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D013927:Thrombosis / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D053482:beta 2-Glycoprotein I / Q000276:immunology* / Q000378:metabolism
D001323:Autoantibodies; D053482:beta 2-Glycoprotein I
Blood. 2000 Aug 15;96(4):1594-5
10942413
J Thromb Haemost. 2006 Feb;4(2):295-306
16420554
Circulation. 1996 Oct 1;94(7):1746-51
8840870
Lupus. 1994 Aug;3(4):247-51
7804310
J Biol Chem. 2001 Apr 27;276(17):13817-21
11145969
Blood. 2005 Oct 1;106(7):2340-6
15956288
Blood. 2010 Jan 21;115(3):713-23
19805618
Genomics. 1992 Aug;13(4):1082-7
1339387
Br J Haematol. 2006 May;133(3):323-30
16643435
Blood. 2005 Mar 1;105(5):1964-9
15471954
J Immunol. 1996 Dec 15;157(12):5732-8
8955227
Blood. 2003 Oct 15;102(8):2717-23
12816875
Proc Natl Acad Sci U S A. 1996 Aug 6;93(16):8606-11
8710918
J Thromb Haemost. 2007 Jul;5(7):1538-44
17470198
J Biol Chem. 2003 Sep 5;278(36):33831-8
12807892
J Autoimmun. 1994 Aug;7(4):441-55
7980847
Biochem J. 1991 Jul 15;277 ( Pt 2):387-91
1650181
Proc Natl Acad Sci U S A. 1990 Jun;87(11):4120-4
2349221
Proc Natl Acad Sci U S A. 1991 Apr 15;88(8):3069-73
2014226
Blood. 2003 Jan 1;101(1):157-62
12393462
J Clin Invest. 2008 Mar;118(3):1123-31
18292814
Lupus. 1996 Oct;5(5):451-5
8902780
J Mol Recognit. 2003 May-Jun;16(3):125-30
12833567
Blood. 2005 Sep 1;106(5):1629-35
15890686
J Thromb Haemost. 2009 May;7(5):833-42
19220729
Nat Med. 2002 Oct;8(10):1175-81
12244306
FEBS Lett. 1991 Sep 9;289(2):183-6
1655523
Blood. 2010 Aug 26;116(8):1336-43
20462962
Arthritis Rheum. 2002 May;46(5):1399-404
12115248
Blood. 1983 Apr;61(4):684-92
6403077
Blood. 2004 Nov 1;104(9):2783-90
15242878
Lupus. 2006;15(6):358-65
16830882
Atherosclerosis. 2000 Oct;152(2):337-46
10998461
Thromb Haemost. 2000 Sep;84(3):388-95
11019960