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Coagulation & its Disorders
Interleukin-17/Interleukin-21 and Interferon-g producing T cells specific for β2 Glycoprotein I in atherosclerosis inflammation of systemic lupus erythematosus patients with antiphospholipid syndrome
Ferrata Storti Foundation
Haematologica 2019 Volume 104(12):2519-2527
Marisa Benagiano,1 Maria Orietta Borghi,2,3 Jacopo Romagnoli,4 Michael Mahler,5 Chiara Della Bella,1 Alessia Grassi,1 Nagaja Capitani,1 Giacomo Emmi,1,6 Arianna Troilo,1 Elena Silvestri,1 Lorenzo Emmi,6 Heba Alnwaisri,1 Jacopo Bitetti,1 Simona Tapinassi,1 Domenico Prisco,1,6 Cosima Tatiana Baldari,7 Pier Luigi Meroni2* and Mario Milco D'Elios1,6*
1Department of Experimental and Clinical Medicine, University of Florence, Florence, Italy; 2IRCCS, Istituto Auxologico Italiano, Laboratory of Immunorheumatology, Cusano Milanino, Italy; 3Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy; 4Department of Surgery, Rome Catholic University, Rome, Italy; 5Inova Diagnostics La Jolla, La Jolla, CA, USA.; 6Internal Interdisciplinary Medicine, Lupus Clinic, AOU Careggi, Florence, Italy and 7Department of Life Sciences, University of Siena, Siena, Italy
ABSTRACT
Systemic lupus erythematosus is frequently associated with antiphos- pholipid syndrome. Patients with lupus-antiphospholipid syndrome are characterized by recurrent arterial/venous thrombosis, miscar- riages, and persistent presence of autoantibodies against phospholipid- binding proteins, such as β2-Glycoprotein I. We investigated the cytokine production induced by β2-Glycoprotein I in activated T cells that infiltrate in vivo atherosclerotic lesions of lupus-antiphospholipid syndrome patients. We examined the helper function of β2-Glycoprotein I-specific T cells for tissue factor production, as well as their cytolytic potential and their helper function for antibody production. Lupus-antiphospholipid syndrome patients harbor in vivo activated CD4+ T cells that recognize β2- Glycoprotein I in atherosclerotic lesions. β2-Glycoprotein I induces T-cell proliferation and expression of both Interleukin-17/Interleukin-21 and Interferon-g in plaque-derived T-cell clones. β2-Glycoprotein I-specific T cells display strong help for monocyte tissue factor production, and pro- mote antibody production in autologous B cells. Moreover, plaque-derived β2-Glycoprotein I-specific CD4+ T lymphocytes express both perforin- mediated and Fas/FasLigand-mediated-cytotoxicity. Altogether, our results indicate that β2-Glycoprotein I is able to elicit a local Interleukin- 17/Interleukin-21 and Interferon-g inflammation in lupus-antiphospholipid syndrome patients that might lead, if unabated, to plaque instability and subsequent arterial thrombosis, suggesting that the T helper 17/T helper 1 pathway may represent a novel target for the prevention and treatment of the disease.
Introduction
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is fre- quently associated with antiphospholipid syndrome (APS) characterized by recur- rent vascular thrombosis and pregnancy morbidities associated with the persistent presence of autoantibodies against phospholipid-binding proteins, namely antiphospholipid antibodies (aPL), such as β2-glycoprotein I (β2GPI).1 Besides its role in the acquired pro-coagulant diathesis, aPL have been also associated with accelerated atherosclerosis to explain cardiovascular manifestations of the syn- drome.2-4 An accelerated atherosclerosis in SLE was first demonstrated in 1975 by
Correspondence:
MARIO MILCO D’ELIOS
mariomilco.delios@unifi.it/delios@unifi.it
PIERLUIGI MERONI
pierluigi.meroni@unimi.it
Received: October 18, 2018. Accepted: March 6, 2019. Pre-published: March 14, 2019.
doi:10.3324/haematol.2018.209536
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