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New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats.

ABSTRACT: Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of β₂glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the in vivo pro-coagulant effect of two groups of 5 sera IgG each reacting selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treated rats. Antibody-induced thrombus formation in mesenteric vessels was followed by intravital microscopy, and vascular deposition of β₂glycoproteinI, human IgG and C3 was analyzed by immunofluorescence. Five serum IgG with undetectable anti-β₂glycoproteinI antibodies served as controls. All the anti-domain 1-positive IgG exhibited potent pro-coagulant activity while the anti-domain 5-positive and the negative control IgG failed to promote blood clot and vessel occlusion. A stronger granular deposit of IgG/C3 was found on the mesenteric endothelium of rats treated with anti-domain 1 antibodies, as opposed to a mild linear IgG staining and absence of C3 observed in rats receiving anti-domain 5 antibodies. Purified anti-domain 5 IgG, unlike anti-domain 1 IgG, did not recognize cardiolipin-bound β₂glycoproteinI while being able to interact with fluid-phase β₂glycoproteinI. These findings may explain the failure of anti-domain 5 antibodies to exhibit a thrombogenic effect in vivo, and the interaction of these antibodies with circulating β₂glycoproteinI suggests their potential competitive role with the pro-coagulant activity of anti-domain 1 antibodies. These data aim at better defining "really at risk" patients for more appropriate treatments to avoid recurrences and disability.

SUBMITTER: Durigutto P

PROVIDER: S-EPMC6442945 | biostudies-literature | 2019 Apr

REPOSITORIES: biostudies-literature

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New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats.

Durigutto Paolo P Grossi Claudia C Borghi Maria Orietta MO Macor Paolo P Pregnolato Francesca F Raschi Elena E Myers Michael P MP de Groot Philip G PG Meroni Pier Luigi PL Tedesco Francesco F

Haematologica 20181115 4

Clinical studies have reported different diagnostic/predictive values of antibodies to domain 1 or 4/5 of β<sub>2</sub>glycoproteinI in terms of risk of thrombosis and pregnancy complications in patients with antiphospholipid syndrome. To obtain direct evidence for the pathogenic role of anti-domain 1 or anti-domain 4/5 antibodies, we analyzed the <i>in vivo</i> pro-coagulant effect of two groups of 5 sera IgG each reacting selectively with domain 1 or domain 5 in lipopolysaccharide (LPS)-treate ...[more]

PMID: 30442725

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Project description:Background The presence of antiphospholipid antibodies (aPLs) plays a pivotal role in the pathogenesis of antiphospholipid antibody syndrome (APS). This study aimed to examine the diagnostic value of a set of non−criteria aPLs and their relevance with APS-related criteria and extra-criteria manifestations. Methods From a prospectively constructed database, consecutive APS patients consisting of 114 primary APS (PAPS group), 54 with APS secondary to SLE (SAPS group), 9 seronegative APS (SNAPS), as well as 209 patients with systemic lupus erythematosus (SLE) and 88 healthy controls were included in this study. Levels of criteria aPLs, baseline information, and APS-related criteria and extra-criteria features were extracted from the database. Serum levels of non-criteria aPLs including aPC IgG/IgM, aPI IgG/IgM, aPE IgG/IgM/IgA, aPG IgG/IgM/IgA, anti-phosphatidic acid (aPA) IgG/IgM, aSM IgG/IgM, and aPS/PT IgG/IgM were analyzed with AESKULISA® ELISA Test Kits. Results The addition of aPC IgG/M, aPI IgG/M, aPE IgG/M/A, aSM IgG/M, and aPA IgG/M to aCL or aβ2GPI IgG/M could significantly increase diagnostic sensitivity and accuracy. A significant difference between PAPS or SAPS and HC was presented in all non-criteria aPLs except for aSM IgM and aPG IgA. Eight out of nine SNAPS patients were positive for at least 1 aPL. Pregnancy morbidity was associated with aSM IgM (r = 0.22) and aSM IgG (r = 0.15). Pre-eclampsia or premature birth was associated with aSM IgG (r = 0.16), aPI IgG (r = 0.22), aPC IgG (r = 0.16), and aPG IgG (r = 0.18). Stroke was associated with aPI IgG (r = 0.2). The clinical association was also observed in DVT with aPS/PT IgG (r = 0.17). Valve lesion was positively associated with aSM IgM (Fisher test p = 0.039), APS nephropathy was associated with aPC IgG (OR 3.797), and livedo reticularis was associated with aPE IgM (OR 15.391). Conclusion Additional detection of non-criteria aPLs including aPC IgG/M, aPE IgG/M/A, aPI IgG/M, aSM IgG/M, and aPA IgG/M could assist in APS diagnosis. The positivity of certain aPLs was statistically associated with both criteria and extra-criteria APS clinical manifestations.

Dataset Information

New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats.

Publications

New insight into antiphospholipid syndrome: antibodies to β2glycoprotein I-domain 5 fail to induce thrombi in rats.

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