Date Published: January 14, 2010
Publisher: Public Library of Science
Author(s): Antje Vogelgesang, Verena E. L. May, Uwe Grunwald, Maren Bakkeboe, Soenke Langner, Henry Wallaschofski, Christof Kessler, Barbara M. Bröker, Alexander Dressel, Derya Unutmaz. http://doi.org/10.1371/journal.pone.0008718
Abstract: Stroke is a major cause of disability and leading cause of death in the northern hemisphere. Only recently it became evident that cerebral ischemia not only leads to brain tissue damage and subsequent local inflammation but also to a dramatic loss of peripheral blood T-cells with subsequent infections. However, only scarce information is available on the activation status of surviving T cells. This study therefore addressed the functional consequences of immunological changes induced by stroke in humans. For this purpose peripheral blood T-cells were isolated from 93 stroke patients and the expression of activation makers was determined. In addition ex vivo stimulation assays were applied to asses the functionality of T cells derived from blood of stroke patients. Compared to healthy controls, stroke patients demonstrated an enhanced surface expression of HLA-DR (p<0.0001) and CD25 (p = 0.02) on T cells, revealing that stroke leads to T cell activation, while CTLA-4 remained undetectable. In vitro studies revealed that catecholamines inhibit CTLA-4 upregulation in activated T cells. Ex vivo, T cells of stroke patients proliferated unimpaired and released increased amounts of the proinflammatory cytokine TNF-α (p<0.01) and IL-6 (p<0.05). Also, in sera of stroke patients HMGB1 concentrations were increased (p = 0.0002). The data demonstrate that surviving T cells in stroke patients remain fully functional and are primed towards a TH1 response, in addition we provide evidence that catecholamine mediated inhibition of CTLA-4 expression and serum HMGB1 release are possible mediators in stroke induced activation of T cells.
Partial Text: Stroke is a major cause of disability and leading cause of death in the northern hemisphere, second only to cardiac disease, and is accompanied by a grave economic impact . The clinical course of stroke patients is not solely determined by the extent of brain damage and the resulting neurological deficit, but often complicated by post stroke infections. These affect between 10% and 35% of patients in the week following stroke , . Only recently it became evident that cerebral ischemia not only leads to brain tissue damage and subsequent local inflammation but also to dramatic alterations of the peripheral immune system. First reported in a mouse model of stroke , we and others have demonstrated that also in humans stroke induces an immediate loss of lymphocytes. The rapid lymphocytopenia, predominantly seen among CD4+ T-cells, is attributed to apoptosis due to increased cortisol and catecholamine release. A delayed recovery of the CD4+ T-cell counts indicates an increased risk for subsequent infection. In addition to cellular parameters, serum cytokine concentrations have also been shown to differ between patients with and without subsequent infections. Of interest, IL-10 a cytokine with strong anti-inflammatory properties and IL-6 known for its proinflammatory capacities are both elevated in stroke patients with subsequent infection , , .
Patients with onset of stroke symptoms less than 12 hours before admission to the stroke unit and without clinical signs of infection on admission were eligible for recruitment into the study. Ischemic stroke was diagnosed clinically and by cerebral CT. Routine cerebral CT images were acquired on a 16-row multislice CT scanner (Somatom 16; SIEMENS Medical Systems). To calculate lesion size, images were analyzed using OSIRIX 2.5.1.
Previous studies have addressed the changes in serum cytokines and cellularity following ischemic stroke in humans , , , , , . This study expands the recent findings and addresses the activation status and the ex vivo functionality of surviving T-lymphocytes from peripheral blood from post- stroke patients, for only little information has been available on this aspect.