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Laplante P.,McGill University | Laplante P.,Center Hospitalier Of Luniversite Of Montreal Chum Research Center | Fuentes R.,University of North Carolina at Chapel Hill | Fuentes R.,Cato Research Ltd. | And 14 more authors.
Lupus | Year: 2016

Patients with antiphospholipid syndrome (APS) produce antiphospholipid antibodies (aPL) and develop vascular thrombosis that may occur in large or small vessels in the arterial or venous beds. On the other hand, many individuals produce aPL and yet never develop thrombotic events. Toll-like receptor 4 (TLR4) appears to be necessary for aPL-mediated prothrombotic effects in venous and microvascular models of thrombosis, but its role in arterial thrombosis has not been studied. Here, we propose that aPL alone are insufficient to cause thrombotic events in an arterial model of APS, and that a concomitant trigger of innate immunity (e.g. TLR4 activation) is required. We show specifically that anti-β2-glycoprotein I (anti-β2GPI) antibodies, a subset of aPL, accelerated thrombus formation in C57BL/6 wild-type, but not TLR4-deficient, mice in a ferric chloride-induced carotid artery injury model. These aPL bound to arterial and venous endothelial cells, particularly in the presence of β2GPI, and to human TLR4 by enzyme-linked immunoassay. Arterial endothelium from aPL-treated mice had enhanced leukocyte adhesion, compared to control IgG-treated mice. In addition, aPL treatment of mice enhanced expression of tissue factor (TF) in leukocytes induced by the TLR4 ligand lipopolysaccharide (LPS). aPL also enhanced LPS-induced TF expression in human leukocytes in vitro. Our findings support a mechanism in which aPL enhance TF expression by leukocytes, as well as augment adhesion of leukocytes to the arterial endothelium. The activation of TLR4 in aPL-positive individuals may be required to trigger thrombotic events. © The Author(s) 2015.

Wacleche V.S.,University of Montreal | Wacleche V.S.,Center Hospitalier Of Luniversite Of Montreal Chum Research Center | Chomont N.,VGTI Florida | Gosselin A.,Center Hospitalier Of Luniversite Of Montreal Chum Research Center | And 15 more authors.
PLoS ONE | Year: 2012

CD4 + T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8 + T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8 + and CD4 + T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a "signature" for HIV-specific but not CMV-specific CD4 + T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8 + T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4 + versus CD8 + T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8 + T-cells may colocalize in excess with CD4 + T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6 +CD4 + T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8 + T-cells to migrate in the vicinity of CCR6 +CD4 + T-cells may facilitate HIV replication and dissemination at mucosal sites. © 2012 Wacleche et al.

Marquis-Gravel G.,University of Montreal | Marquis-Gravel G.,Center Hospitalier Of Luniversite Of Montreal Chum Research Center | Stevens L.-M.,University of Montreal | Stevens L.-M.,Center Hospitalier Of Luniversite Of Montreal Chum | And 7 more authors.
Canadian Journal of Cardiology | Year: 2014

Background: Stem cell (SC) therapy improves left ventricular function and dimensions in ischemic heart disease. Few small-scale trials have studied the effects of SC therapy on nonischemic cardiomyopathy (CMP), the leading cause of heart transplantation in the adults. The objectives were to gain a better insight into the effects of SC therapy for nonischemic CMP by conducting a systematic review of the literature and meta-analysis of randomized controlled trials. Methods: Medline, EBM Reviews-Cochrane Central Register of Controlled Trials, Embase, and the ClinicalTrials.gov databases were screened for randomized controlled trials involving SC for treatment of nonischemic CMP. Weighted mean differences of improvement of left ventricular ejection fraction (LVEF) and left ventricular end-diastolic diameter (LVEDD) were calculated using a random effect analysis model. Results: Four trials were included in this meta-analysis (244 patients). The weighted mean LVEF improvement was 4.87% (95% confidence interval, 1.32-8.43%) in the treatment group compared with the control group (P= 0.01). The weighted mean decrease of LVEDD in the treatment group was of-2.19 mm (95% confidence interval,-5.69 to 1.30) compared with the control group (P= 0.22). On subgroup analysis, results were similar in studies involving peripheral CD34-positive or bone marrow-derived mononuclear cells (P= 0.33 for subgroup differences). Conclusions: This is the first meta-analysis to show that for the treatment of nonischemic CMP, SC therapy might improve LVEF, but not LVEDD. Further trials should aim to circumscribe the optimal SC regimen in this setting, and to assess long-term clinical outcomes as primary end points. © 2014 Canadian Cardiovascular Society.

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