Prolonged Activation of Invariant Natural Killer T Cells and TH2-Skewed Immunity in Stroke Patients

I got nothing out of this. Our great stroke association should explain each stroke research article and tell us how it improves stroke recovery. But since we have fucking failures of stroke associations YOU will have to do all this work yourself. All 10 million yearly stroke survivors  analyzing research to see how it could help them.What a waste.

Prolonged Activation of Invariant Natural Killer T Cells and TH2-Skewed Immunity in Stroke Patients

Connie H. Y. Wong^1,2*, Craig N. Jenne^2,3, Patrick P. Tam³, Caroline Léger³, Andres Venegas⁴, Karla Ryckborst⁴, Michael D. Hill⁴ and Paul Kubes^2,3*

• ¹Centre for Inflammatory Diseases, Department of Medicine, School of Clinical Science, Monash University, Melbourne, VIC, Australia
• ²Department of Physiology and Pharmacology, Snyder Institute for Chronic Diseases, University of Calgary, Calgary, AB, Canada
• ³Department of Critical Care, Snyder Institute for Critical Care, University of Calgary, Calgary, AB, Canada
• ⁴Stroke Unit, Department of Clinical Neurosciences, Hotchkiss Brain Institute, University of Calgary, Calgary, AB, Canada

Background: 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 (T_H2)-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.

Methods and results: 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 T_H1/T_H2 ratio, increased production of interleukin (IL)-10, with infected stroke patients showing exacerbated production of IL-10.

Conclusion: 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 T_H2-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.

Introduction

Ischemic stroke is a common and debilitating cerebrovascular event that is caused by the sudden impairment of blood flow to regions of the brain. Up to 65% of stroke patients develop infection (1), and more than 30% die as a direct result (2), making infection a highly relevant clinical problem. Increased bacterial infections in stroke patients suggest that the immune response, which normally is responsible for eliminating these infections in healthy individuals, is impaired after ischemic brain injury. Emerging evidence now indicates that stroke induces profound systemic immune effects (3), including severe reductions in the number of circulating lymphocytes and altered lymphocyte and monocyte function (4, 5). Despite accumulating evidence supporting the notion of a stroke-induced peripheral anti-inflammatory state in response to the overwhelming cerebral inflammation following stroke (6), the molecular mechanisms resulting in systemic immune suppression after stroke in humans have, for the most part, remained elusive.

The balance between pro- and anti-inflammatory cytokines determines the proficiency of the immunological response and has the potential to influence both the fate of the injured brain and the threshold to developing complications such as infection. In the clinical setting of stroke, the balance between pro- and anti-inflammatory cytokines is an important prognostic factor (6). 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 T_H1/T_H2 ratio. Surprisingly, poststroke T cell priming to an increased IL-4 expression following mitogenic stimulation was evident in the peripheral blood of patients in the post-acute phase of stroke (8). Despite this, it is important to note of the timing of this apparent immune shift following stroke. Generally, lymphocytes and the adaptive immune response could be expected to control infection 5–7 days after stroke, dysfunction in these cells does not explain the observed increase in infection in the first 3 days (9). In addition, the development of infection in the mouse model of stroke takes only a few hours (10). This difference in the temporal development of a T_H2-skewed immune response following stroke suggests the shift must be orchestrated by mechanisms distinct from the conventional adaptive immune response.

In our previous work with an experimental model of ischemic stroke, we demonstrated that invariant natural killer T (iNKT) 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 T_H1 [interferon gamma (IFNγ), TNFα] and T_H2 (IL-4, IL-10) cytokines, giving these cells a unique ability to have wide-ranging 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 T_H2-type cytokine IL-10, rendering the host more susceptible to bacterial infections (10). This intriguing finding highlighted a connection between brain injury sustained following ischemic stroke and robust functional impairment of peripheral immune cells, in particularly, iNKT cells. In this prospective clinical study, we aimed to delineate the systemic immune profile of stroke patients over time. Specifically, we conducted a matched cohort study to characterize the temporal T_H1/T_H2 cytokine, chemokine, and iNKT cell response in the blood of stroke patients up to 3 months after stroke onset. In addition, we sought to explore whether an association exists between stroke severity with the degree of peripheral iNKT cell activation and T_H2-skewed systemic immunity.