Pathophysiological Mechanisms in Antiphospholipid Syndrome

Review Pathophysiological mechanisms in antiphospholipid syndrome 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 identified as b2-glycoprotein I (b2GPI), which mediates binding of aPL antibodies to target cells including endothelial cells, monocytes, platelets and trophoblasts, leading to prothrombotic and proinflammatory changes that ultimately result in thrombosis and fetal loss. This article summarizes recent insights into the role of b2GPI in normal hemostasis, interactions between aPL antibodies, b2GPI and cell- surface molecules, molecular prothrombotic and proinflammatory changes induced by aPL antibodies and pathogenic changes leading to fetal loss in antiphospholipid syndrome. New directions in therapy using these insights are examined. 1 n n Brock E Harper , KEYWORDS: annexin anti-b2-glycoprotein I antibody antiphospholipid antibodies n antiphospholipid syndrome n endothelial cell activation n pathogenesis n platelet Rohan Willis1 activation n pregnancy loss n thrombosis n treatment & Silvia S Pierangeli†1 1Department of Internal Medicine, Division of Rheumatology, University Antiphospholipid syndrome (APS) is a systemic and use of hormone-replacement therapy or oral of Texas Medical Branch, Galveston, autoimmune disease characterized by recurrent contraceptives [9]. By contrast, venous thrombo- TX, USA †Author for correspondence: thrombosis and fetal loss in the presence of per- sis was associated with presence of hypertriglyc- [email protected] sistently positive antiphospholipid (aPL) antibod- eridemia, presence of a hereditary thrombophilia ies (Abs) including lupus anticoagulant (LAC), or aCL IgG more than 40 IU [9]. IgG/IgM anticardiolipin (aCL) Abs and anti-b2- Antiphospholipid syndrome causes significant glycoprotein I (b2GPI) Abs [1–3]. aPL Abs are a morbidity with positive LAC and/or aPL Abs heterogenous group of autoantibodies that react conferring an increased risk of thrombosis with to phospholipids (PLs), PL-binding proteins and an odds ratio ranging from 3.1 to 9.4 [10,11]. The PL–protein complexes. aPL Abs mainly target the risk of recurrent thrombosis in APS over 5 years antigen b2GPI and along with Abs acting against is 16.6% despite the use of anticoagulants and/or prothrombin (PT) account for more than 90% aspirin. APS is also associated with a 5-year mor- of the Ab-binding activity in APS patients [4–6]. tality of 5.3% with most deaths occurring within While many aPL Abs exhibit specificity for a sin- the first year of diagnosis, with the leading causes gle antigen, purified aPL Abs from some patients of death being bacterial infections, myocardial bind multiple proteins involved in coagulation, infarction, stroke and cerebral hemorrhage [12]. suggesting a single aPL Ab clone can induce Catastrophic APS – multiple simultaneous arte- multiple changes in coagulation and cell activity rial or venous thromboses in the presence of aPL resulting in thrombosis or fetal loss [7]. Abs – is a much-feared, albeit rare complication Presence of aPL Abs per se does not guaran- occurring in 0.9% of patients with APS. Despite tee a patient will develop APS as only 8.1% of aggressive treatment, mortality rates still range patients with aPL Abs without a history of clini- between 44 and 55.6% [12,13]. These data under- cal thrombosis developed thrombosis during a score the need for development of more effec- 5-year follow-up period, suggesting that a patient tive therapies that target the pathologic processes needs an additional insult to develop the clinical involved in APS without the toxicities associated disease [8]. Supporting this ‘two-hit’ hypothesis, with chronic anticoagulation. comorbidities that have been identified as significant risk factors for thrombosis in APS include Structure & binding of b2GPI hypertension, presence of an autoimmune dis- Studies into the structure of b2GPI have revealed ease, hypercholesterolemia, presence of anti- that the individual domains are important for dsDNA Abs or medium-to-high titer aCL Abs interaction with aPL Abs as well as cell-sur- [8]. Risk factors particularly for arterial thrombo- face molecules leading to the pathologic fea- sis include hypertension, hyperhomocysteinemia tures of APS. Anti-b2GPI Abs associated with 10.2217/IJR.11.9 © 2011 Future Medicine Ltd Int. J. Clin. Rheumatol. (2011) 6(2), 157–171 ISSN 1758-4272 157 Review Harper, Willis & Pierangeli Pathophysiological mechanisms in antiphospholipid syndrome Review thrombosis have been shown to bind readily to aPL-mediated pathogenic effects in vivo, in domain I of recombinant b2GPI but interact experiments that utilized ApoER2´-deficient only with plasma b2GPI attached to an anionic mice and specific inhibitors [29]. surface, implying that a conformational change b2-glycoprotein I interacts with annexins, is necessary for b2GPI binding [14–16]. This was a family of phospholipid-binding proteins of recently confirmed and expanded upon by which annexin (Ann) A2 and Ann A5 have Agar et al. who demonstrated that b2GPI has a been implicated in the pathogenesis of APS. native circular structure in plasma maintained Ann A2 acts as an endothelial cell-surface by interaction of domains V and I. Exposure receptor for plasminogen and tissue plas- to an anionic surface leads to the opening of minogen activator (tPA), and also mediates the structure into a fish-hook shape via interac- the binding of b2GPI/anti-b2GPI complexes tion between the anionic surface and domain V. to endothelial cells and monocytes, leading This conformational change facilitates binding to cell activation and expression of a proco- of anti-b2GPI to b2GPI by exposing an epitope agulant phenotype [30–33]. Furthermore, aPL in domain I that is hidden in the circular con- Ab-induced increases in endothelial cell adhe- formation [17]. The light chain fragments of sion molecules, ICAM and E-selectin have anti-b2GPI Abs carry the antigen specificity, been shown to be abrogated by treatment with establishing that the interaction is with b2GPI anti-Ann A2 Abs [34]. Also, knockout of Ann itself and not immunoglobulin in general [18]. A2 in mice significantly blunted thrombus for- Polymorphisms of b2GPI are also found in APS mation and diminished vascular tissue factor with the replacement of leucine by valine at (TF) and VCAM expression induced by aPL position 247 being found more frequently in Ab exposure [34]. Similarly, Zhou et al. have APS patients in certain populations [19–22]. This found that increased expression of ANX2, the polymorphism, particularly in the homozygous gene coding for Ann A2, leads to increased state, has been shown to be associated with the anti-b2GPI Ab-induced TF expression while production of anti-b2GPI Abs, which may be silencing of ANX2 partially blocks this increase due to the presence of valine at this site, caus- in TF expression in HEK 293 T cells [31]. All ing an increase in the antigenicity of b2GPI [20]. this evidence highlights the essential role that Providing clinical evidence of the importance of Ann A2 plays as a cell-surface receptor for aPL domain I binding in APS, de Laat et al. demon- in the induction of a procoagulant state in APS strated that presence of domain I-specific anti- patients. However, it is important to note that b2GPI Abs was associated with increased risk of although cell-surface Ann A2 lacks an intra- thrombosis, while there was no increased risk cellular tail and is unable to induce intracel- from anti-b2GPI Abs targeting other domains lular signal transduction by itself, it can act of b2GPI [15,23]. as a binding partner for intracellular surface Recent studies have established that domain V molecules in lipid rafts [34,35]. This means that is the primary site of interaction between Ann A2 most likely utilizes a coreceptor for b2GPI and the various cell-surface molecules intracellular signal transduction and subse- with which it interacts. Rahgozar et al. demon- quent cell activation as a result of aPL action. strated that b2GPI binds to thrombin and this The effects of anti-b2GPI Ab binding appear binding prevents the inactivation of thrombin to be dependent upon Ann A2 crosslinking, by heparin/heparin cofactor II [24,25]. Binding suggesting anti-b2GPI Abs may exert their of anti-b2GPI Abs potentiates this interaction, effects on cell signaling by inducing interaction leading to increased thrombin activity [24,25]. between Ann A2-associated intracellular sign- b2GPI also binds to ApoER2´, a splice variant of aling molecules [36]. There is evidence for Toll- ApoE receptor 2 (ApoER2) found on platelets, like receptors (TLRs), particularly TLR4 and and this interaction is dependent upon domain TLR2, functioning as coreceptors for Ann A2 V [26,27]. Binding to ApoER2´ by dimerized in aPL-mediated cell activation, both of these b2GPI induces platelet activation and platelet TLRs being present on endothelial cells and aggregation. This effect was reproduced with monocytes [37,38]. Abs directed against Ann A2 anti-b2GPI Abs but not normal plasma b2GPI, itself have also been detected in 14.8–40.4% indicating that anti-b2GPI Abs exert some of of patients with APS and are associated with their effects by dimerization of b2GPI and in vitro prothrombotic changes including interaction of dimerized b2GPI with cell-sur- increased expression of TF and inhibition of face receptors [28]. In a recent study, Romay- tPA-mediated plasmin

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