title: A Novel Prothrombotic Pathway in Systemic Sclerosis Patients: Possible Role of Bisphosphonate-Activated γδ T Cells.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Laboratory of Immunoregulation, Sheba Medical Center , Ramat Gan , Israel.
authors.forename: Victoria
authors.initials: V
authors.lastname: Marcu-Malina
authors.affiliation: B Shine Rheumatology Unit, Rambam Health Care Campus, Rambam Medical Center , Haifa , Israel.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Balbir-Gurman
authors.affiliation: Institutes of Thrombosis and Hemostasis, Sheba Medical Center , Ramat Gan , Israel.
authors.forename: Rima
authors.initials: R
authors.lastname: Dardik
authors.affiliation: B Shine Rheumatology Unit, Rambam Health Care Campus, Rambam Medical Center , Haifa , Israel.
authors.forename: Yolanda
authors.initials: Y
authors.lastname: Braun-Moscovici
authors.affiliation: Institute of Pulmonary Diseases, Sheba Medical Center , Ramat Gan , Israel.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Segel
authors.affiliation: Laboratory of Immunoregulation, Sheba Medical Center , Ramat Gan , Israel ; Department of Medicine F, Sheba Medical Center , Ramat Gan , Israel ; Department of Medicine, Sackler School of Medicine, Tel Aviv University , Tel Aviv , Israel.
authors.forename: Ilan
authors.initials: I
authors.lastname: Bank
keywords: T cells; Vγ9δ2 T cells; aminobisphosphonate; scleroderma; thrombosis; tissue factor; γδ T cell