Elsevier

Autoimmunity Reviews

Volume 10, Issue 10, August 2011, Pages 609-616
Autoimmunity Reviews

Review
New autoantigens in the antiphospholipid syndrome

https://doi.org/10.1016/j.autrev.2011.04.011Get rights and content

Abstract

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis, recurrent miscarriages or fetal loss, and circulating antiphospholipid antibodies (aPL). Enzyme-linked immunosorbent assays for anticardiolipin and anti-β2-glycoprotein I antibodies and clotting assays for the lupus anticoagulant are the tests recommended for detecting aPL. However, the aPL are a heterogeneous group of antibodies directed against anionic phospholipids but also toward phospholipid-binding plasma proteins or phospholipid–protein complexes. β2-glycoprotein I (β2GPI) is the playmaker antigen of APS, however during apoptosis, lysophospholipids can become exposed on the cell surface, and mainly through their interaction with β2GPI, they can become targets of aPL. Some CL metabolites are likely to escape from the remodeling cycle. This would account for the progressive loss of mitochondrial CL during apoptosis, as well as for the presence of CL and lyso-CL at the cell surface, where they can interact with β2GPI and become targets of aPL. Other recognized targets of aPL are represented by phosphatidylserine, lyso(bis)phosphatidic acid, Phosphatidylethanolamine, vimentin, and annexin A5. These molecules may allow improving the knowledge on the pathogenesis, and the early identification of APS. Although several studies have shown the presence of antibodies directed against other antigens in APS, their clinical relevance is still a matter of debate, and it needs to be confirmed with experimental data and longitudinal studies.

Introduction

The antiphospholipid syndrome (APS) is an autoimmune disease characterized by arterial and venous thrombosis, recurrent miscarriages or fetal loss, and circulating antiphospholipid antibodies (aPL) [1]. It is an important cause of acquired hypercoagulability in the general population and a major source of morbidity in pregnancy [2], [3], [4]. Diagnosis of APS requires that at least one clinical and one laboratory criterion are met [1]. The tests recommended for detecting aPL are standardized ELISA of anticardiolipin (aCL) and anti-β2-glycoprotein I (aβ2GPI) antibodies and clotting assays for the lupus anticoagulant (LA) performed according to the guidelines of the International Society of Thrombosis and Haemostasis [1], [2]. Since persistent positivity is required for the diagnosis, these tests should be repeated on two or more occasions at least 12 weeks apart. In clinical practice, one may also encounter patients with clinical signs suggestive of APS who are persistently negative in all of the above assays. The term seronegative APS (SN-APS) has been proposed for these cases [5].

Antiphospholipid antibodies are a heterogeneous group of antibodies directed against anionic phospholipids, phospholipid-binding plasma proteins, and phospholipid–protein complexes [1], [6]. This article reviews current knowledge of the major target antigens involved in APS. Space constraints preclude the inclusion of all the cutting-edge issues that are emerging in this field of research. For more information on these topics, the reader is referred to other recent publications [2], [5], [6].

Section snippets

History

In 1906 Wasserman discovered reagin, an antibody that targeted liver extracts from a fetus with syphilis. Some 40 years later, Pangborn identified cardiolipin (CL), a phospholipid extracted from beef heart, as the antigen targeted by reagin [7]. Over the years, it became clear that not all patients who were reagin-positive had syphilis, but they occasionally experienced thrombotic events [8], [9] and recurrent pregnancy losses [10]. In 1952 Conley and Hartman described two patients with systemic

The antigen targets of antiphospholipid antibodies

Several of the antigens targeted by aPL have already been identified. The best known and most widely studied is the plasma glycoprotein β2GPI; other aPL targets are still being investigated (Table 1). Our team, for example, recently identified vimentin as a new protein cofactor for aPL, and this discovery may prove useful, particularly in the setting of the so-called SN-APS [17]. As Shoenfeld et al. have pointed out, more complete knowledge of the multiple autoantibodies in APS might improve

Conclusions

Large bodies of evidence point to aPL as a heterogeneous group of autoantibodies with partially overlapping specificities and characteristics. The best characterized target antigen of aPL is the plasma protein β2GPI. Combined positivity for LA and aCL/aβ2GPI displays good correlation with the diagnosis of APS, and routine testing of other antigens is expensive and does not significantly improve the diagnosis. Although most studies have shown a higher prevalence of antibodies to several other

Take-home messages

  • Combined testing for LA and aCL/aβ2GPI is routinely used to diagnose APS because it is strongly correlated with clinical manifestations of the syndrome.

  • The best characterized antigenic target in APS is the β2GPI, but several other antigens have already been identified and others are being explored.

  • During apoptosis, lysophospholipids can become exposed on the cell surface, and mainly through their interaction with β2GPI, they can become targets of aPL.

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