Antje Vogelgesang

Analysis of Lymphocyte Subsets in Patients With Stroke and Their Influence on Infection After Stroke

Background and Purpose— Recent studies have attributed the increased infection vulnerability of patients with stroke to stroke-induced immunosuppression. We have therefore explored the immunological changes in patients with ischemic stroke. Methods— Blood from 46 patients with stroke was analyzed by fluorescent-activated cell sorter to determine leukocyte subsets. To identify changes that represent clinically relevant immunosuppression, we compared patients who developed infection within 14 days after stroke with those who did not. Results— Stroke induced a dramatic and immediate loss of T-lymphocytes, most pronounced within 12 hours after stroke onset. Only patients with subsequent infection exhibited a delay in the recovery of CD4+ T-lymphocyte counts. Conclusions— Our data suggest that a loss of CD4+ T cell function contributes to the stroke-induced immunosuppression. The CD4+ T cell count on the day after stroke may emerge as a predictive marker for poststroke infection allowing, early identification of patients at risk.

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

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 (pu200a=u200a0.02) 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 (pu200a=u200a0.0002). 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.

Immunological consequences of ischemic stroke: immunosuppression and autoimmunity.

Stroke may be accompanied by immunological consequences including local autoimmunity and peripheral immune suppression. Since the blood brain barrier is disturbed cells of the immune system gain direct access to the brain parenchyma. Here local autoimmunity contributes to lesion formation and, in experimental stroke, inhibition of this immune response has been shown to be beneficial. More recently, however, stroke has been shown to also induce severe peripheral immune suppression which predisposes for subsequent bacterial infections that impair the clinical outcome. Here we summarize current knowledge on the immunological consequences of ischemic stroke and will discuss implications of these findings for our understanding of the immunopathogenesis of Multiple Sclerosis.

Stroke Alters Respiratory Burst in Neutrophils and Monocytes

Background and Purpose— Stroke-induced immune alterations predispose patients to infections. Although the relationship between stroke and the adaptive immune system has been investigated in detail, to date it is unknown whether the innate immune system, which forms the first line of antibacterial defense, is also impaired in patients with stroke. Therefore, we investigated whether chemotaxis, phagocytosis, oxidative burst, degranulation of defensins, and NETosis in monocytes and in neutrophil granulocytes are altered in patients with stroke compared with controls. Methods— Sixty-three patients having acute ischemic stroke were recruited within 12 hours of symptom onset; blood was sampled on admission and on days 1, 3, 5, and 7. Thirty-seven age-matched controls were also recruited. Cell migration, phagocytosis, and oxidative burst of phagocytes were determined in vitro. Human neutrophil peptides 1 to 3 and serum metanephrine levels were measured by enzyme-linked immunosorbent assay, and NETosis was quantified by immunohistochemistry. Results— The key mechanisms required for bacterial killing, oxidative burst, and NETosis were significantly reduced in samples taken from patients with stroke compared with controls, whereas migration, phagocytic function, and defensin production remained unimpaired in monocytes and granulocytes from patients with stroke. Conclusions— Stroke-induced immune alterations include impairment of the first-line defense performed by specialized phagocytes against bacteria. The hypothesis that these changes enhance susceptibility to acquired infections is supported by our observation that on admission oxidative burst in monocytes was more impaired in patients with stroke with subsequent stroke-associated infections.

Thrombosis, Neuroinflammation, and Poststroke Infection: The Multifaceted Role of Neutrophils in Stroke

Immune cells can significantly predict and affect the clinical outcome of stroke. In particular, the neutrophil-to-lymphocyte ratio was shown to predict hemorrhagic transformation and the clinical outcome of stroke; however, the immunological mechanisms underlying these effects are poorly understood. Neutrophils are the first cells to invade injured tissue following focal brain ischemia. In these conditions, their proinflammatory properties enhance tissue damage and may promote ischemic incidences by inducing thrombus formation. Therefore, they constitute a potential target for therapeutic approaches and prevention of stroke. Indeed, in animal models of focal brain ischemia, neutrophils have been targeted with successful results. However, even in brain lesions, neutrophils also exert beneficial effects, because they are involved in triggering immunological removal of cell debris. Furthermore, intact neutrophil function is essential for maintaining immunological defense against bacterial infections. Several studies have demonstrated that stroke-derived neutrophils displayed impaired bacterial defense capacity. Because infections are known to impair the clinical course of stroke, therapeutic interventions that target neutrophils should preserve or even restore their function outside the central nervous system (CNS). This complex situation requires well-tailored therapeutic approaches that can effectively tackle immune cell invasion in the brain but avoid increasing poststroke infections.

Catecholamines, Steroids and Immune Alterations in Ischemic Stroke and Other Acute Diseases

The outcome of stroke patients is not only determined by the extent and localization of the ischemic lesion, but also by stroke-associated infections. Stroke-induced immune alterations, which are related to stroke-associated infections, have been described over the last decade. Here we review the evidence that catecholamines and steroids induced by stroke result in stroke-induced immune alterations. In addition, we compare the immune alterations observed in other acute diseases such as myocardial infarction, brain trauma, and surgical trauma with the changes seen in stroke-induced immune alterations.

Mitoxantrone treatment in multiple sclerosis induces TH2-type cytokines

Vogelgesang A, Rosenberg S, Skrzipek S, Bröker BM, Dressel A. Mitoxantrone treatment in multiple sclerosis induces TH2‐type cytokines.u2028Acta Neurol Scand: 2010: 122: 237–243.u2028© 2009 The Authors Journal compilation

Glatiramer acetate-specific human CD8+ T cells: Increased IL-4 production in multiple sclerosis is reduced by glatiramer acetate treatment

Glatiramer acetate (GA) is an approved drug for therapy of relapsing remitting MS that acts as a T cell antigen. Here, we report the cloning of HLA restricted, GA-specific human CD8(+) T cells. In addition, we analyzed the cytokine profile of GA-reactive CD8(+) T cell lines. Unexpectedly, IL-4 was increased in untreated MS patients as compared to healthy individuals (p<0.001). In GA-treated patients, however, IL-4 (p<0.001), IL-10 (p<0.001) and TNF-alpha (p<0.001) were decreased. Thus, while GA is known to induce a TH2 bias in CD4(+) T cells, we detected a distinct pattern in GA-reactive CD8(+) T cells.

Reduced Numbers and Impaired Function of Regulatory T Cells in Peripheral Blood of Ischemic Stroke Patients.

Background and Purpose. Regulatory T cells (Tregs) have been suggested to modulate stroke-induced immune responses. However, analyses of Tregs in patients and in experimental stroke have yielded contradictory findings. We performed the current study to assess the regulation and function of Tregs in peripheral blood of stroke patients. Age dependent expression of CD39 on Tregs was quantified in mice and men. Methods. Total FoxP3+ Tregs and CD39+FoxP3+ Tregs were quantified by flow cytometry in controls and stroke patients on admission and on days 1, 3, 5, and 7 thereafter. Treg function was assessed by quantifying the inhibition of activation-induced expression of CD69 and CD154 on T effector cells (Teffs). Results. Total Tregs accounted for 5.0% of CD4+ T cells in controls and <2.8% in stroke patients on admission. They remained below control values until day 7. CD39+ Tregs were most strongly reduced in stroke patients. On day 3 the Treg-mediated inhibition of CD154 upregulation on CD4+ Teff was impaired in stroke patients. CD39 expression on Treg increased with age in peripheral blood of mice and men. Conclusion. We demonstrate a loss of active FoxP3+CD39+ Tregs from stroke patients peripheral blood. The suppressive Treg function of remaining Tregs is impaired after stroke.

Differential effects of interferon-ß1b on cytokine patterns of CD4+ and CD8+ T cells derived from RRMS and PPMS patients

The influence of interferon (IFN)-β on cytokine release by immune cells remains controversial. This study compared IFN-β1b effects on mononuclear cells, CD4+ and CD8+ T cells derived from healthy controls and relapsing–remitting multiple sclerosis (RRMS) and primary progressive multiple sclerosis (PPMS) patients. Effects of IFN-β1b (0-10,000 U/ml) on cytokine release were determined in cell culture. IFN-β1b inhibited IFN-γ and induced interleukin (IL)-4 selectively in RRMS-derived CD4+ T cells. IL-10 was significantly induced in all cell populations from RRMS but only marginally in PPMS. IL-5 was always inhibited; IL-17A remained unaltered. These in vitro data parallel clinical observations that IFN-β is most effective in RRMS.