Pathophysiological mechanisms in antiphospholipid syndrome

Abstract

Antiphospholipid syndrome is a systemic autoimmune disease associated with thrombosis and recurrent fetal loss in the setting of detectable antiphospholipid (aPL) antibodies. The major antigenic target has been identifed as β2-glycoprotein I (β2GPI), which mediates binding of aPL antibodies to target cells including endothelial cells, monocytes, platelets and trophoblasts, leading to prothrombotic and proinfammatory changes that ultimately result in thrombosis and fetal loss. This article summarizes recent insights into the role of β2GPI in normal hemostasis, interactions between aPL antibodies, β2GPI and cell-surface molecules, molecular prothrombotic and proinfammatory changes induced by aPL antibodies and pathogenic changes leading to fetal loss in antiphospholipid syndrome. New directions in therapy using these insights are examined.

An A1–A1 mutant with improved binding and inhibition of β2GPI/antibody complexes in antiphospholipid syndrome

“…In in vivo studies of mice, significant β2GPI deposition was detected only on the endothelium of the uterus, and the deposition pattern remained the same in mice with circulating anti‐β2GPI antibodies . In the presence of anti‐β2GPI antibodies, β2GPI/antibody complexes enhance thrombus size in rodent models of thrombosis, and activate endothelial cells, monocytes and platelets in vitro and in vivo . Several receptors and cell‐surface molecules, including toll‐like receptor 4 (TLR4), Annexin II, ApoE receptor 2 (ApoER2) and other receptors of the low‐density lipoprotein receptor (LDLR) family, GPIbα and anionic phospholipids have been shown to bind β2GPI and contribute to cellular activation by β2GPI/antibody complexes .…”

Inhibition of thrombotic properties of persistent autoimmune anti-β2GPI antibodies in the mouse model of antiphospholipid syndrome

“…10,12 Treatment with anti-b2GPI antibodies or recombinant dimers of b2GPI mimicking b2GPI/antibody complexes results in increased thrombus size in animal models of thrombosis and cellular activation in vitro. 2,3,[17][18][19][20] It was demonstrated both in vitro and in vivo that exposure of endothelial cells, monocytes, and platelets to b2GPI/anti-b2GPI antibody complexes shifts the cellular phenotype to prothrombotic and proinflammatory (reviewed in Giannakopoulos and Krilis, 2 Tripodi et al, 3 and Harper et al 20 ). Anionic phospholipids, Toll-like receptors 2 and 4 (TLR2 and TLR4), annexin A2, and ApoER2 are cell-surface molecules involved in binding and activation of endothelial cells and monocytes by b2GPI/antibody complexes.…”

Soluble analog of ApoER2 targeting beta2‐glycoprotein I in immune complexes counteracts hypertension in lupus‐prone mice with spontaneous antiphospholipid syndrome

“…Beta2-glycoprotein I (b2GPI), which acquires prothrombotic properties only after association with antibodies, is the major antigen in APS [6][7][8][9][10]. Exposure to anti-b2GPI antibodies results in increased thrombus size in animal models of thrombosis and cellular activation in vitro [11][12][13][14][15][16]. Several cell-surface receptors, including TLR2, TLR4, Annexin A2, GPIba and ApoER2 as well as anionic phospholipids, are involved in the binding and activation of endothelial cells, monocytes and platelets by b2GPI in the presence of anti-b2GPI antibodies, and in increasing thrombus size [17][18][19][20][21][22][23][24].…”