Functional Status of Peripheral Blood T-Cells in Ischemic Stroke Patients

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.

Stroke Alters Respiratory Burst in Neutrophils and Monocytes

“…In good agreement with previous observations by us and by others, 7,11,25 granulocytes were increased in patients with SAIs (median, SAI+ d0,1,3,5,7 =53.3%, 84.3%, 76.0%, 79.0%, 82.2%; median, SAI− d0,1,3,5,7 =56.8%, 70.3%, 67.5%, 55.7%, 64.1%; P=0.0004); whereas monocytes remained unaltered. Metanephrine serum concentrations did not differ significantly between patients with and without SAI ( Table I in the online-only Data Supplement).…”

“…7 Here we investigated, whether the alterations observed in patients with stroke derived phagocytes could be induced in samples from healthy individuals by in vitro exposure to the catecholamines epinephrine and norepinephrine, the glucocorticoid dexamethasone or acetylcholine. Phagocytosis remained unaltered in monocytes and granulocytes in all conditions investigated (data not shown).…”

Leukocyte response is regulated by microRNA let7i in patients with acute ischemic stroke

“…Previous studies show that HMGB1 increases in patients with ischemic stroke and correlates with the number of circulating leukocytes, 27 stroke severity (NIHSS score, infarct size), and inflammatory markers (TNF-a, IL-1, IL-6, MMP9). [28][29][30][31] These findings are consistent with our study whereby a decrease in let7i was associated with a rise in HMGB1 as well as an increase in inflammatory response, MMP9, and infarct size.…”

Reduced Efficacy of Circulating Costimulatory Cells After Focal Cerebral Ischemia

“…11 This observation, however, is challenged by human data, in which ex vivo proliferation of whole blood lymphocytes was unimpaired and phenotypes of circulating lymphocytes were skewed to a proinflammatory state. 12 Even more complex, the immunologic interaction of antigen-presenting cells and T cells (T cell receptor stimulation, costimulation) as well as between distinct lymphocyte subsets (eg, detrimental CD4ϩ T cells 13 and cerebroprotective CD4ϩCD25ϩ Treg 14 ), which are differentially affected after brain ischemia, 15,16 is unresolved.…”