Abstract
Objectives: Infusions of aminobisphonates (ABP) activate Vγ9δ2T cells in vivo and induce an acute inflammatory response in 30% of patients treated for osteoporosis. Following the observation of digital thrombosis in a systemic sclerosis (SSc) patient after treatment with an intravenous ABP, zoledronate (Zol), we evaluated whether patient and control peripheral blood (PB) mononuclear cell (MC, PBMC) acquire a prothrombotic phenotype in response to Zol.Results: Vγ9δ2T cells of both patients and healthy donors (HD) upregulated the CD69 activation antigen and secreted tumor necrosis factor (TNF)α in response to Zol in vitro. In addition, exposure to either Zol or lipopolysaccharide (LPS), or to both additively, induced expression of the highly procoagulant, tissue factor (TF)-1 on CD14+ monocytes. Importantly, only Zol-induced TF-1 was blocked by a monoclonal antibody to TNFα. Interestingly, we found that SSc, but not HD, Vδ1+ T cells were concurrently activated by Zol to produce interleukin (IL)-4. Addition of plasma from the blood of the SSc patient who developed critical digital ischemia after infusion of Zol, but neither plasma from a second patient with no adverse clinical response to Zol infusion nor of a HD, strongly enhanced Zol-induced monocyte TF-1, which could still be blocked by anti-TNFα.Conclusion: Aminobisphonates induced secretion of TNFα by Vγ9δ2+ T cells may lead to TNFα-dependent induction of procoagulant TF-1 induction on monocytes. In certain clinical settings, e.g., SSc, TF-1+ monocytes could play a role in triggering clinically relevant thrombosis.
Highlights
INTRODUCTION γδT cells are a subset of T cells combining innate and adaptive functions [1]
We found that systemic sclerosis (SSc), but not healthy donors (HD), Vδ1+ T cells were concurrently activated by Zol to produce interleukin (IL)-4
Addition of plasma from the blood of the SSc patient who developed critical digital ischemia after infusion of Zol, but neither plasma from a second patient with no adverse clinical response to Zol infusion nor of a HD, strongly enhanced Zol-induced monocyte tissue factor (TF)-1, which could still be blocked by anti-TNFα
Summary
T cells are a subset of T cells combining innate and adaptive functions [1]. Vγ9δ2 TCR recognize metabolites produced in the classical (isopentenyl pyrophosphate, IPP) and alternative [(E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP)] mevalonate metabolic pathways. These antigens are presented for TCR-mediated recognition by CD277, a ubiquitously expressed cell surface membrane antigen presenting molecule (APM) [3]. Together with co-stimulatory signals delivered by antigen presenting cells (APC), Vγ9δ2 TCR– CD277/IPP cognitive interactions activate the Vγ9δ2 T cells to secrete cytokines and exert cytotoxic effects. A second major subset of γδ T cells expresses the Vδ1 gene in the TCR structure, among which a major portion recognize phospholipid antigens (e.g., sulfatide) presented by CD1 family molecules [4]
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