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Agostinis C.,Institute for Maternal and Child Health | Durigutto P.,University of Trieste | Sblattero D.,University Institute of Health Sciences | Borghi M.O.,Laboratory of Immuno rheumatology | And 9 more authors.
Blood | Year: 2014

Asingle-chain fragment variable(scFv) recognizing β2-glycoprotein1 (β2GPI) from humans and other species was isolated from a human phage display library and engineered to contain an IgG1 hinge-CH2-CH3 domain. The scFv-Fc directed against β2GPI domain I-induced thrombosis and fetal loss, thus mimicking the effect of antibodies from patients with antiphospholipid syndrome (APS). Complement is involved in the biological effect of anti-β2GPI scFv-Fc, as demonstrated by its ability to promote in vitro and in vivo complement deposition and the failure to induce vascular thrombosis in C6-deficient rats and fetal loss in C5-depletedmice. A critical role for complement was also supported by the inability of the CH2-deleted scFv-Fc to cause vessel occlusion and pregnancy failure. This antibody prevented the pathological effects of anti-β2GPI antibodies from APS patients and displaced β2GPI-bound patient antibodies. The CH2-deleted antibody represents an innovative approach potentially useful to treat APS patients refractory to standard therapy. © 2014 by The American Society of Hematology.

Pericleous C.,University College London | Ferreira I.,University College London | Borghi O.,Laboratory of Immuno rheumatology | Pregnolato F.,Laboratory of Immuno rheumatology | And 9 more authors.
PLoS ONE | Year: 2016

Introduction Currently available clinical assays to detect antiphospholipid antibodies (aPL) test for IgG and IgM antibodies to cardiolipin (aCL) and β2 -glycoprotein I (aβ2 GPI). It has been suggested that testing for IgA aPL and for antibodies to Domain I (DI), which carries the key antigenic epitopes of β2 GPI, could add value to these current tests. We performed an observational, multicenter cohort study to evaluate the utility of IgG, IgM and IgA assays to each of CL, β2 GPI and DI in APS. Methods Serum from 230 patients with APS (n = 111), SLE but not APS (n = 119), and 200 healthy controls were tested for IgG, IgM and IgA aCL, aβ2 GPI and aDI activity. Patients with APS were further classified into thrombotic or obstetric APS. Logistic regression and receiver operator characteristic analyses were employed to compare results from the nine different assays. Results All assays displayed good specificity for APS; IgG aCL and IgG aβ2 GPI assays however, had the highest sensitivity. Testing positive for IgA aβ2 GPI resulted in a higher hazard ratio for APS compared to IgM aβ2 GPI. Positive IgG, IgM or IgA aDI were all associated with APS, and in subjects positive for aCL and/or aβ2 GPI, the presence of aDI raised the hazard ratio for APS by 3-5 fold. IgG aCL, aβ2 GPI, aDI and IgA aDI were associated with thrombotic but not obstetric complications in patients with APS. Conclusion Measuring IgG aDI and IgA aβ2 GPI and aDI may be useful in the management of patients with APS, particularly thrombotic APS. © 2016 Pericleous et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Gerosa M.,University of Milan | Meroni P.L.,University of Milan | Meroni P.L.,Laboratory of Immuno rheumatology | Erkan D.,New York Medical College
Current Opinion in Rheumatology | Year: 2016

Purpose of review This article summarizes the recent developments in the recognition and management of antiphospholipid syndrome (APS). Recent findings Five Task Forces, created as part of the 14th International Congress on antiphospholipid antibodies (aPL), published their systematic reviews. 'For the recognition of APS': the assessment of aPL profile is crucial for risk stratification; lupus anticoagulant positivity, especially in the context of 'triple aPL positivity' displays the highest risk; a panel of criteria and noncriteria aPL tests may help better risk-stratify the aPL-positive in the future. 'For the management of APS': direct oral anticoagulants are not currently recommended; statins ameliorate the proinflammator/thrombotic markers, whereas hydroxychloroquine reduces the risk of thrombosis in experimental models and lupus patients, which justify their use as an adjunctive treatment in refractory cases; B-cell inhibition may have a role in difficult-to-treat patients with hematologic and microthrombotic/angiopathic manifestations; and complement and mammalian targets of rapamycin complex pathway inhibition are promising targets in APS. Summary Warfarin, heparin, and/or antiplatelet drugs are the standard of care for aPL-positive patients. Recent studies suggest novel approaches that target new coagulation and immunomodulatory pathways; mechanistic and/or controlled clinical studies are needed to determine the effectiveness of these novel approaches. © Copyright 2015 Wolters Kluwer Health, Inc. All rights reserved.

Agostinis C.,Institute for Maternal and Child Health | Biffi S.,Optical Imaging Laboratory | Garrovo C.,Optical Imaging Laboratory | Durigutto P.,University of Trieste | And 9 more authors.
Blood | Year: 2011

In vitro studies have documented β2 glycoprotein I (β2GPI) binding to endothelial cells (ECs) and trophoblast using antiphospholipid antibodies. The in vivo binding of β2GPI to these cells and the conditions that favor their interaction have not been investigated.We analyzed the in vivo distribution of cyanine 5.5-labeled β2GPI in mice and evaluated the effect of pregnancy and circulating antibodies on its tissue localization. The signal was detected in the liver by whole body scan and ex vivo analysis. The β2GPI failed to bind to the vascular endothelium and reacted only with the ECs of uterine vessels. In pregnant mice the protein was localized on ECs and trophoblast at the embryo implantation sites. Immunized mice showed a similar β2GPI biodistribution to naive mice but the immunized pregnant animals exhibited a significant increase in fetal loss associated with C3 and C9 deposition at the implantation sites. Treatment of mice with LPS after β2GPI-Cy5.5 injection promoted protein localization on gut and brain ECs associated with IgG, C1q, and C9 deposition in immunized mice. These findings indicate that β2GPI binding to EC requires priming with pro-inflammatory factors which is not needed for uterine and placental localization probably dependent on hormonal changes. © 2011 by The American Society of Hematology.

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