Abstract
Infection is highly prevalent and contribute significantly to mortality of stroke patients. In addition to the well described robust systemic lymphocytopenia and skewed T helper 2 (TH2)-immunity after stroke, emerging experimental evidence demonstrate that the development of infection poststroke is attributed by the activation of invariant natural killer T (iNKT) cells. In this prospective study, we examined the levels of a broad spectrum of inflammatory mediators, the activation status of iNKT cell in the blood of patients with various degree of stroke severity, and investigate whether these parameters differ in patients who later develop poststroke infections. We obtained blood from stroke patients and matching controls to perform flow cytometry and multiplex measurement of inflammatory mediators. Our data suggest a pronounced activation of iNKT cells in stroke patients as compared with matched Healthy and Hospital control patients. The magnitude of iNKT activation is positively correlated with the severity of stroke, supporting the hypothesis that iNKT cells may contribute in the modulation of the host immune response after stroke-associated brain injury. In addition, stroke severity is closely correlated with decreased TH1/TH2 ratio, increased production of interleukin (IL)-10, with infected stroke patients showing exacerbated production of IL-10. Stroke triggers a robust and sustained shift in systemic immunity in patients, including specific lymphopenia, robust activation of iNKT cells, systemic production of IL-10, and a prolonged TH2-skewed immunity, all are potential contributors to severe immune suppression seen in patients after stroke. Future studies with large sample size will provide potential causality relationship insights.
Highlights
Ischemic stroke is a common and debilitating cerebrovascular event that is caused by the sudden impairment of blood flow to regions of the brain
In our previous work with an experimental model of ischemic stroke, we demonstrated that invariant natural killer T cells play an important role in regulating poststroke immunosuppression and infections [10]. iNKT cells are a distinct lymphocyte lineage that can rapidly produce large quantities of both TH1 [interferon gamma (IFNγ), TNFα] and T helper 2 (TH2) (IL-4, IL-10) cytokines, giving these cells a unique ability to have wideranging roles in the regulation of immunity [11]
Despite their location in a site remote from the brain, we showed that circulating iNKT cells and iNKT cells resident in the liver were able to rapidly respond to ischemic stroke, and release predominantly a TH2-type cytokine IL-10, rendering the host more susceptible to bacterial infections [10]
Summary
Ischemic stroke is a common and debilitating cerebrovascular event that is caused by the sudden impairment of blood flow to regions of the brain. Stroke patients were found to present with a rapid increase in plasma cytokines resulting in a low ratio of pro-inflammatory tumor necrosis factor alpha (TNFα) to anti-inflammatory interleukin (IL)-10, preceding the appearance of infection [7] This observation supports the hypothesis of stroke-induced immunosuppression via a decrease in systemic TH1/TH2 ratio. In addition to the well described robust systemic lymphocytopenia and skewed T helper 2 (TH2)-immunity after stroke, emerging experimental evidence demonstrate that the development of infection poststroke is attributed by the activation of invariant natural killer T (iNKT) cells In this prospective study, we examined the levels of a broad spectrum of inflammatory mediators, the activation status of iNKT cell in the blood of patients with various degree of stroke severity, and investigate whether these parameters differ in patients who later develop poststroke infections
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