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.
This work was supported by grants from the Italian Ministry of University and Research and the Italian Ministry of Health (to M.M.D.) and by Istituto di Ricovero e Cura a Carattere Scientifico Istituto Auxologico Italiano, Ricerca Corrente (to P.L.M.).
The online version of this article contains supplemental material.
Abbreviations used in this article:
- autoantibody against phospholipid-binding protein
- antiphospholipid syndrome
- β2 glycoprotein I
- Fas ligand
- low-density lipoprotein
- matrix metalloproteinase
- oxidized low-density lipoprotein
- spot-forming cell
- tissue factor
- tetanus toxoid.
- Received February 23, 2016.
- Accepted January 24, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.