Antiphospholipid antibodies: Lessons from the bench

Journal of Autoimmunity 28 (2007) 129e133 www.elsevier.com/locate/jautimm

Review

Antiphospholipid antibodies: Lessons from the bench Takao Koike*, Miyuki Bohgaki, Olga Amengual, Tatsuya Atsumi Department of Medicine II, Hokkaido University Graduate School of Medicine, N15 W7, Kita-ku, Sapporo 060-8638, Japan

Abstract Antiphospholipid antibodies (aPL) are an heterogeneous group of circulating immunoglobulins arising in a wide range of infectious and autoimmune diseases. Since the early 80 s, the interest on anticardiolipin antibodies (aCL) has exponentially increased due to their association with thrombosis. The antiphospholipid syndrome (APS) was defined as a clinical disorder characterized by thrombosis and pregnancy morbidity associated to the persistent presence of aCL and/or lupus anticoagulant (LA). Thrombosis is the major manifestation in patients with aPL, but the spectrum of symptoms and signs associated with aPL has considerably broadened, and other manifestations such as thrombocytopenia, nonthrombotic neurological syndromes, psychiatric manifestations, livedo reticularis, skin ulcers, haemolytic anemia, pulmonary hypertension, cardiac valve abnormality and atherosclerosis have also been related to the presence of those antibodies. Numerous mechanisms have been proposed to explain the thrombotic tendency of patients with aPL, but the pathogenesis seems to be multifactorial. Ó 2007 Elsevier Ltd. All rights reserved. Keywords: Thrombosis; Antiphospholipid antibodies; Inflammation; Autoantibodies; Phospholipid antibody syndrome

1. Anticardiolipin and anti-b2-Glycoprotein I antibodies

2. Anti-b2-Glycoprotein I antibodies

The mechanisms involved in defining the thrombosis of patients with antiphospholipid antibody have been extensively studied by numerous investigators [1e9] (Table 1). Anticardiolipin antibodies (aCL) were detected using immunoassays with solid phase cardiolipin as a putative antigen [10,11]. However, antibodies directed to phospholipid-binding plasma or serum proteins, in particular b2-Glycoprotein I (b2GPI), are present in serum samples and can be components of the sample diluent and blocking buffer in various types of immunoassay systems. b2GPI-dependent aCL represent a predictor of future stroke and myocardial infarction in men, and are predictors of arterial thrombosis in patients with APS [12e14]. And also, antib2GPI antibodies have been often associated with venous thrombosis [15]. In contrast, aPL associated with infectious diseases bind directly to these negatively charged phospholipids, showing little association with thrombosis [16e19].

The mechanisms by which anti-b2GPI antibodies bind to b2GPI is unclear. It has been proposed that one antibody must bind two b2GPI molecules to obtain considerable avidity, the ‘‘dimerization theory’’ [20,21]. Another theory is based on the recognition of a cryptic epitope on b2GPI by aPL antib2GPI antibodies. This cryptic epitope is only exposed when b2GPI interacts with a lipid membrane composed of negatively charged phospholipids or when adsorbed on a polyoxygenated polystyrene plate treated with g-irradiation or electrons [22]. Consistent with this story, some reports showed the binding of aPL to b2GPI adsorbed on various commercially available oxidatively modified polystyrene plates, on a nitrocellulose membrane or on an experimentally g-ray/ UV-irradiated polystyrene plates [23,24]. Moreover, an epitope for aPL is exposed on the b2GPI molecule modified with glutaryldialdehyde [25]. The location of the epitope(s) on b2GPI for anti-b2GPI antibodies from APS patients has been largely discussed. Anti-b2GPI antibodies recognize different epitopes located in all five domains. In 1996, Igarashi et al. [26] firstly reported that domain IV or I are candidates for epitopic location on the

* Corresponding author. Tel.: þ81 11 706 5913; fax: þ81 11 706 7710. E-mail address: [email protected] (T. Koike). 0896-8411/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.jaut.2007.02.009

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Table 1 Proposed mechanism of antiphospholipid antibody-mediated thrombosis 1 2 3 4 5

Inhibition of endothelial cell prostacyclin production Procoagulant effects on platelets Impairment of fibrinolysis Interference with the thrombomodulin-protein S-protein C pathway Induction of procoagulant activity on cells (endothelial cells or monocytes)

b2GPI molecule by using a series of deletion mutant proteins of b2GPI. Wang et al. [27] showed the presence of antib2GPI antibodies directed to domain V. George et al. [28] demonstrated that domain IV of b2GPI is one of the major epitopic location for aCL raised in APS patients. In contrast, Iverson et al. [29] reported that anti-b2GPI antibodies, in the major population of APS patients, recognized a particular structure in domain I of b2GPI, and antibody binding was diminished by replacement of a related amino acid locates in the domain. However, it was also shown that some particular mutations made in domain IV also affected to antibody binding to b2GPI in anti-b2GPI antibody ELISA [30]. Recently, it has been showed that pathogenic aPL bind a cryptic epitope on domain I of b2GPI (G40eR43). This epitope is accessible for aPL only after conformational change which is induced by the binding of b2GPI to a negatively charged surface via a positive-charge patch in domain V of b2GPI [31,32]. Our group revealed that epitopic structures recognized by anti b2GPI antibodies are cryptic and that electrostatic interaction between domain IV and V are involved in their exposure [33]. 3. Cellular interaction and anti-b2GPI antibodies Intensive research works, performed in the last decade, have greatly advanced our knowledge of the mechanisms that explain why these antibodies may play a direct role in clot formation. Procoagulant cell activation, accompanied with TF expression, and TF pathway up-regulation is one of the key events considered to explain the pathophysiology of thrombosis in patients with APS. TF is the major initiator of the extrinsic coagulation system, functioning in coagulation by serving as the protein cofactor for the activated factor VII (FVIIa) [34]. Induced TF forms a complex with FVIIa that triggers blood clotting cascade by activating factors IX and X, leading to thrombin generation. In normal conditions, TF is not expressed on intravascular cells but it can be induced under some stimuli such as lipopolysaccharide, tumor necrosis factor a (TNFa), interleukin-1 (IL-1) and shear stress [35]. We showed elevated plasma levels of soluble TF in APS patients [36,37], and Cuadrado et al. [38] reported that monocytes prepared from APS patients had high TF expression. Tissue factor pathway inhibitor (TFPI), a physiological inhibitor of the extrinsic coagulation system, was also increased in plasma from patients with APS [36], suggesting up-regulation of TF and TFPI in affected patients. In in vitro experiments, there are numerous reports shown that IgG fraction from

patients with aPL induced procoagulant activity on cells [39e43]. Our previous observation that human monoclonal aCL/b2GPI induced TF mRNA and TF activity on PBMC or endothelium, was confirmed by Reverter et al. [44] using the same monoclonal antibodies. Apart from the TF molecule, other procoagulant substances induced by aPL were extensively investigated. Del Papa, Meroni et al. [45e48] have reported a series of molecules associated with endothelium activation by aPL in vitro, and other groups [49,50] have shown adhesion molecules expression induced by IgG with aPL activity in vitro and in vivo models. Thus, it is widely accepted that aPL can induce the expression of TF or other procoagulant substances on cells in some conditions. Vega-Ostertag et al. [51] reported that phosphorylation of p38 MAPK is involved in aPL-mediated production of thromboxane by platelets. Pretreatment of platelets with SB203580, a p38 MAPK specific inhibitor, completely abrogated aPLmediated platelet aggregation. We demonstrated that the p38 MAPK-dependent signaling pathway participates in aPLmediated TF expression. The multi-screening by cDNA array system combined with real time PCR analysis indicated that the MAPK pathway was related to TF expression when cells were treated with monoclonal aCL/b2GPI. We performed western blotting studies to confirm the result of cDNA array in protein level that p38 MAPK protein was phosphorylated. The specific p38 MAPK inhibitor decreased TF mRNA expression by aCL/b2GPI stimulation, suggesting a crucial role of the p38 MAPK pathway in this system [52]. The involvement of p38MAPK activation on endothelial cells has been preliminarily reported to be required in aPL-mediated prothrombotic status [53]. The association between aPL and the occurrence of thrombosis is widely recognized. The effect of aCL in the inhibition of natural anticoagulant systems, the impairment of fibrinolytic activity and the direct effect of these antibodies on cell functions or injury are some of the proposed mechanisms to explain the thrombotic tendency of patients with APS. Endothelial cells, monocytes and activated platelets may be a predominant target of aCL/b2GPI associated with the procoagulant state in characteristic of APS. Recently, the signal transduction mechanism has been explored and associated with the increased expression of procoagulant substances in response to aPL. Dunoyer-Geindre et al. [54] presented an indirect but essential role of NF-kB in endothelial cell activation by aPL. IgG purified from APS patients induced the nuclear translocation of NF-kB leading to the transcription of a large numbers of genes that have a NF-kB responsive element in their promoter. This nuclear translocation of NF-kB mediates, at least in part, can explain the increased expression of TF by endothelial cell. Activation of p38 MAPK increases activities of proinflammatory cytokines, such as TNF-a and IL-1b. Up-regulation of TNF-a, IL-1b and MIP3b was also found in our previous study [52]. Downstream of activated p38 MAPK, MAPK-activated protein kinase 2/3 (MAPKAPK-2/3) is a substrate for p38 that undergoes post-transcriptional regulation of TNF-a. P38 also activates transcriptional factors such as activating

T. Koike et al. / Journal of Autoimmunity 28 (2007) 129e133

transcriptional factor-2 (ATF2), which forms a herterodimer with Jun family transcriptional factors and associates with the activator protein-1 (AP-1) binding site. After LPS stimulation of dendritic cells, NH2-termini of histone H3 undergoes structural alteration in a p38-dependent pathway, which results in enhancement of accessibility of the cryptic NF-kB binding sites [55]. The promoter region of the TF gene contains two AP-1 binding sites and one NF-kB binding site, and these transcription factors are proven required for maximal induction of TF gene transcription. Moreover, p38 MAPK pathway has been implicated in the regulation of TF expression in monocytes, endothelial cells, and smooth muscle cells [56e60]. Very recently, Lopez-Pedrera et al suggested that aPL induced TF in monocytes from APS patients by activating, simultaneously and independently, the phosphorylation of MEK-1/ ERK proteins, and the p38 MAP kinase-dependent nuclear translocation and activation of NF-kappa B/Rel proteins [61]. Antib2GPI antibodies activate endothelial cell in a b2GPIdependent manner, and this cell activation might require an interaction between b2GPI and a specific endothelial cell receptor. It has been shown that annexin II, an endothelial cell receptor for tissue plasminogen activator and plasminogen, behaved as a receptor for b2GPI [62]. However it is still unclear whether such a putative receptor is actually involved in cell activation because annexin II does not span the cell membrane and the presence of an unknown ‘‘adaptor’’ was suggested to be necessary to induce activation. Raschi et al. [63] suggested a possible association between b2GPI and members of the Toll-like receptors (TLRs) family. They speculated that antib2GPI antibodies might cross-link b2GPI molecules likely together with TLRs, eventually favoring the receptor polymerization and the signaling cascade activation. Furthermore, Lutters et al. [64] showed that dimeric b2GPI can interact with apolipoprotein E receptor 2 (apoER2), a member of the low density lipoprotein receptor family present in platelets and that dimeric b2GPI induces increased platelet adhesion and thrombus formation, which depend on the activation of apoER2. 4. Conclusion The recognition of the crucial role of p38 MAPK in the intracellular activation mediated by aPL is a novel finding that represents a great advance in the understanding of the mechanisms involved in the production of the hypercoagulable state in patients with APS [51e53,61]. Those researches may open new insights in the therapeutic approach of patients with APS and give a clue to establish a more specific target therapy by down-regulating the specific pathway of signal transduction. Further studies are needed to clarify how aPL-phospholipid-binding complexes affect to cell surface molecule and how signal transduction events occur upstream of p38 MAPK. References [1] Khamashta MA. Hughes syndrome: history. In: Khamashta MA, editor. Hughes Syndrome: antiphospholipid syndrome. London: Springer-Verlag; 2006. p. 3e8.

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