title: β2 Glycoprotein I Recognition Drives Th1 Inflammation in Atherosclerotic Plaques of Patients with Primary Antiphospholipid Syndrome.
abstract: Antiphospholipid syndrome (APS) is characterized by recurrent arterial/venous thrombosis and miscarriages in the persistent presence of autoantibodies against phospholipid-binding proteins (aPLs), such as β2 glycoprotein I (β2GPI). In addition to the aPL thrombophilic effect, arterial thrombosis was related to accelerated atherosclerosis in animal models; however, contrasting findings were reported in primary APS patients with regard to the increased number of plaques or abnormal arterial wall thickness. We investigated the cytokine production induced by β2GPI in activated T cells that infiltrate in vivo atherosclerotic lesions of primary APS patients with atherothrombosis. We also examined the helper function of β2GPI-specific T cells for monocyte matrix metalloproteinase-9 and tissue factor production, as well as their cytolytic potential and their helper function for Ab production. APS patients with atherothrombosis harbor in vivo-activated CD4+T cells that recognize β2GPI in atherothrombotic lesions. β2GPI induces T cell proliferation and IFN-γ expression in plaque-derived T cell clones. β2GPI-specific T cells display helper function for monocyte matrix metalloproteinase-9 and tissue factor production and promote Ig production in autologous B cells. Moreover, plaque-derived β2GPI-specific CD4+T lymphocytes express perforin-mediated and Fas/Fas ligand-mediated cytotoxicity. β2GPI, and especially the DI domain, drive a local Th1 inflammatory response, with subsequent plaque instability that eventually favors atherothrombosis. This finding may explain the association between aPLs and arterial thrombosis, despite the lack of evidence of surrogate markers for atherosclerosis in primary APS.
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Marisa
authors.initials: M
authors.lastname: Benagiano
authors.affiliation: Department of Clinical Sciences and Community Health, Lupus Clinic, Institute Gaetano Pini, University of Milan, 20122 Milan, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Gerosa
authors.affiliation: Department of Surgery, Catholic University of Rome, 00136 Rome, Italy.
authors.forename: Jacopo
authors.initials: J
authors.lastname: Romagnoli
authors.affiliation: Inova Diagnostics, La Jolla, CA 92131.
authors.forename: Michael
authors.initials: M
authors.lastname: Mahler
authors.affiliation: Department of Clinical Sciences and Community Health, Lupus Clinic, Institute Gaetano Pini, University of Milan, 20122 Milan, Italy.|Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, 20095 Cusano Milanino, Italy; and.
authors.forename: Maria O
authors.identifier: 0000-0001-8967-9678
authors.initials: MO
authors.lastname: Borghi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Alessia
authors.identifier: 0000-0002-3916-8631
authors.initials: A
authors.lastname: Grassi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Chiara
authors.identifier: 0000-0002-2565-6220
authors.initials: C
authors.lastname: Della Bella
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Giacomo
authors.initials: G
authors.lastname: Emmi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.|Internal Interdisciplinary Medicine, Lupus Clinic, Florence Careggi Hospital, 50134 Florence, Italy.
authors.forename: Amedeo
authors.initials: A
authors.lastname: Amedei
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Silvestri
authors.affiliation: Internal Interdisciplinary Medicine, Lupus Clinic, Florence Careggi Hospital, 50134 Florence, Italy.
authors.forename: Lorenzo
authors.initials: L
authors.lastname: Emmi
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy.|Internal Interdisciplinary Medicine, Lupus Clinic, Florence Careggi Hospital, 50134 Florence, Italy.
authors.forename: Domenico
authors.identifier: 0000-0002-7787-9610
authors.initials: D
authors.lastname: Prisco
authors.affiliation: Department of Clinical Sciences and Community Health, Lupus Clinic, Institute Gaetano Pini, University of Milan, 20122 Milan, Italy; delios@unifi.it pierluigi.meroni@unimi.it.|Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, 20095 Cusano Milanino, Italy; and.
authors.forename: Pier Luigi
authors.identifier: 0000-0002-3394-1451
authors.initials: PL
authors.lastname: Meroni
authors.affiliation: Department of Experimental and Clinical Medicine, University of Florence, 50134 Florence, Italy; delios@unifi.it pierluigi.meroni@unimi.it.|Internal Interdisciplinary Medicine, Lupus Clinic, Florence Careggi Hospital, 50134 Florence, Italy.
authors.forename: Mario M
authors.initials: MM
authors.lastname: D'Elios
mesh_terms: D000328:Adult; D016736:Antiphospholipid Syndrome / Q000276:immunology* / Q000473:pathology; D050197:Atherosclerosis / Q000276:immunology* / Q000473:pathology; D005260:Female; D006801:Humans; D007249:Inflammation / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D058226:Plaque, Atherosclerotic / Q000276:immunology* / Q000473:pathology; D018417:Th1 Cells / Q000276:immunology*; D053482:beta 2-Glycoprotein I / Q000276:immunology*
chemical_list: D053482:beta 2-Glycoprotein I