Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome

Ortona, Elena; Capozzi, Antonella; Colasanti, Tania; Conti, Fabrizio; Alessandri, Cristiano; Longo, Agostina; Garofalo, Tina; Margutti, Paola; Misasi, Roberta; Khamashta, Munther A.; Hughes, G. R. V.; Valesini, Guido; Sorice, Maurizio

doi:10.1182/blood-2010-04-279208

Cited by 94 publications

(80 citation statements)

References 46 publications

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“…However, routine screening tests (aCL, anti-β 2 -GP1 and LA) might miss some cases of true SP-APS by failing to pick up cases with other antibodies directed against different phospholipids or protein cofactors, such as prothrombin, phosphatidylethanolamine, annexin V and vimentin/cardiolipin complex 9. Nevertheless, their main disadvantage is that there is no standardisation for such assays 10.…”

Section: Discussionmentioning

confidence: 99%

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

et al. 2011

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Section: Discussionmentioning

confidence: 99%

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

et al. 2011

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“…The "research use only" tests included ELISA to detect IgG and IgM antiphosphatidylethanolamine antibodies (aPE) and IgG anti-cardiolipin/vimentin antibodies (aCL/Vim). Testing was done at the Lupus Research Unit, King's College London, for aPE and at the Department of Experimental Medicine at La Sapienza, Rome, for aCL/Vim, as previously described 19,20 .…”

Section: Patientsmentioning

confidence: 99%

Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of “Non-criteria” Antiphospholipid Antibodies

Zohoury

Bertolaccini²,

Rodríguez-García³

et al. 2017

J Rheumatol

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Objective.Most clinicians use the 2006 Sydney classification criteria to evaluate patients suspected of having antiphospholipid syndrome (APS). Although sensitive and specific for APS, many patients fulfilling clinical criteria for the syndrome are persistently negative for the specific serological tests (“laboratory criteria”). These “seronegative APS” (SN-APS) patients can go undiagnosed and untreated until they experience serious clinical events. This study’s objective was to describe antibody profiles of SN-APS patients using non-criteria markers, assess the clinical utility of these markers separately and in combination, and suggest incorporation into guidelines for patients suspected of APS.Methods.We categorized 175 consecutive patients suspected of APS into 2 subgroups: 107 fulfilling Sydney APS classification for seropositive APS (SP-APS) and 68 with clinical manifestations suggestive of APS but having negative serology, on 2 occasions, for criteria markers (SN-APS). On study inclusion, samples were retested for criteria and 11 non-criteria markers, including antiphosphatidylserine/prothrombin antibodies.Results.Using 4 of 11 non-criteria tests, a cumulative 30.9% of SN-APS patients were detected. Combining results of all 11 non-criteria tests, 25 SN-APS (36.8%) and 89 SP-APS (83.2%) were positive for 1 or more non-criteria antibodies.Conclusion.Failure to diagnose APS can result in severe clinical consequences. Patients displaying clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria biomarkers. In our cohort, around one-third of SN-APS patients showed reactivity to 1 or more non-criteria markers. An update to the current classification criteria incorporating new serological markers should be considered to identify and stratify patients with APS for more effective treatment and management.

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“…For example, we also detected vimentin in our mass spectrometric analysis, and vimentin-cardiolipin complexes have been implicated in EC activation by anti-␤ 2 GPI Abs. 50 Additional studies focused on defining the interactions between the component proteins of this complex and the mechanisms by which they assemble may provide further insight into anti-␤ 2 GPI Ab-induced thrombosis and opportunities for therapeutic intervention in APS. …”

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A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

Allen

Fonseca

Betapudi

et al. 2012

Blood

127

114

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Antiphospholipid Abs (APLAs) are associated with thrombosis and recurrent fetal loss. These Abs are primarily directed against phospholipid-binding proteins, particularly ␤ 2 GPI, and activate endothelial cells (ECs) in a ␤ 2 GPI-dependent manner after binding of ␤ 2 GPI to EC annexin A2. Because annexin A2 is not a transmembrane protein, the mechanisms of APLA/anti-␤ 2 GPI Ab-mediated EC activation are uncertain, although a role for a TLR4/myeloid differentiation factor 88-dependent pathway leading to activation of NF-B has been proposed. In the present study, we confirm a critical role for TLR4 in anti-␤ 2 GPI Ab-mediated EC activation and demonstrate that signaling through TLR4 is mediated through the assembly of a multiprotein signaling complex on the EC surface that includes annexin A2, TLR4, calreticulin, and nucleolin. An essential role for each of these proteins in cell activation is suggested by the fact that inhibiting the expression of each using specific siRNAs blocked EC activation mediated by APLAs/anti-␤ 2 GPI Abs. These results provide new evidence for novel proteinprotein interactions on ECs that may contribute to EC activation and the pathogenesis of APLA/anti-␤ 2 GPI-associated thrombosis and suggest potential new targets for therapeutic intervention in antiphospholipid syndrome. (Blood. 2012; 119(3):884-893) IntroductionAntiphospholipid syndrome (APS) is characterized by thrombosis and recurrent fetal loss in patients with circulating antiphospholipid Abs (APLAs) and is the most important cause of acquired thrombophilia. [1][2][3] Prospective studies have demonstrated that patients with APS experience significant morbidity and mortality despite recommendations for indefinite anticoagulation. 4 The term "antiphospholipid" is actually a misnomer, because the majority of APLAs are directed against phospholipid-binding proteins, of which ␤ 2 -glycoprotein I (␤ 2 GPI) is the most common. 5,6 The clinical importance of anti-␤ 2 GPI Abs has been demonstrated in several previous reports, 7 and recent studies have shown that affinity-purified human anti-␤ 2 GPI Abs induce thrombosis in mice. 8 Despite the clinical importance of APS, however, its pathogenesis has not been well defined. 1,3,9 One mechanism by which APLAs/anti-␤ 2 GPI Abs may promote thrombosis is through ␤ 2 GPI-dependent activation of endothelial cells (ECs). [10][11][12] ECs play a critical role in the maintenance of blood fluidity through expression of anticoagulant proteins on their luminal surface and the elaboration of antithrombotic substances. 13 However, EC activation leads to loss of these anticoagulant properties and transformation to a pro-adhesive, procoagulant phenotype. 13 APLAs/anti-␤ 2 GPI Abs induce EC activation in vitro and in vivo, as determined by their ability to increase the expression of adhesion molecules (E-selectin, ICAM-1, VCAM-1), and tissue factor (TF) and to enhance the expression, synthesis, and/or secretion of pro-inflammatory cytokines and chemokines. 3,[10][11][12] These effects may account for the ab...

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Vimentin/cardiolipin complex as a new antigenic target of the antiphospholipid syndrome

Cited by 94 publications

References 46 publications

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called ‘seronegative APS’)

Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of “Non-criteria” Antiphospholipid Antibodies

A novel pathway for human endothelial cell activation by antiphospholipid/anti-β2 glycoprotein I antibodies

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