C5a receptor-deficient mice are protected from thrombophilia and endothelial cell activation induced by some antiphospholipid antibodies.
Recent findings indicate that complement activation--involving specifically C3 and C5--contributes to antiphospholipid (aPL)-mediated thrombosis. Two complement effector pathways are initiated by the cleavage of C5, C5a and C5b, which leads to the formation of the C5b-9 membrane attack complex. To delineate and distinguish the role of C5a from the C5b-9 membrane attack complex seeded by C5b, we examined the in vivo effects (thrombosis) of aPL on C5a receptor-deficient (C5aR-/-) mice. C5aR-/- and C5aR+/+ mice were injected with IgM or with IgG from two different patients with APS (IgM-APS or IgG-APS) or with control IgM or IgG (IgM-NHS or IgG-NHS) twice. Complement fixing activity of the Ig fractions and anticardiolipin activity in the sera of the mice were determined by enzyme-linked immunosorbent assay. Surgical procedures to study thrombus dynamics were performed. IgM-APS but not IgG-APS fixed C1q to cardiolipin-coated plates. IgM-APS significantly enhanced thrombus size in C5aR+/+ mice compared to C5aR+/+ mice treated with IgM-NHS (3198 +/- 2361 microm2 versus 585 +/- 460 microm2). C5aR-/- mice treated with IgM-APS showed a significant reduction in thrombi size as compared with C5aR+/+ mice (676 +/- 690 microm2 versus 3198 +/- 2361 microm2; P = 0.001). IgG-APS enhanced thrombus formation significantly in C5aR+/+ when compared to IgG-NHS-treated mice (3507 +/- 965 microm2 versus 1321 +/- 798 microm2), and these effects were not altered in C5aR-/- mice (3400 +/- 1681 microm2). The data indicate that C5aR-/- mice are protected from the thrombogenic effects of some aPL antibodies.
Romay-Penabad
Zurina
Z
Division of Rheumatology, Department of Internal Medicine, University of Texas Medical Branch, Galveston, Texas 77555-1165, USA.
Liu
Xiaowei X
XX
Montiel-Manzano
Guadalupe
G
Papalardo De Martínez
Elizabeth
E
Pierangeli
Silvia S
SS
D000328:Adult; D000818:Animals; D017152:Antibodies, Antiphospholipid / Q000378:metabolism*; D016736:Antiphospholipid Syndrome / Q000097:blood / Q000276:immunology; D042783:Endothelial Cells / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007075:Immunoglobulin M / Q000276:immunology; D051379:Mice; D008817:Mice, Mutant Strains; D044087:Receptor, Anaphylatoxin C5a / Q000172:deficiency*; D019851:Thrombophilia / Q000378:metabolism*
D017152:Antibodies, Antiphospholipid; D007074:Immunoglobulin G; D007075:Immunoglobulin M; D044087:Receptor, Anaphylatoxin C5a