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.

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a severe adverse effect of ChAdOx1 nCoV-19 COVID-19 vaccine (Vaxzevria) and Janssen Ad26.COV2.S COVID-19 vaccine, and it is associated with unusual thrombosis. VITT is caused by anti-platelet factor 4 (PF4) antibodies activating platelets through their FcγRIIa receptors. Antibodies that activate platelets through FcγRIIa receptors have also been identified in patients with COVID-19. These findings raise concern that vaccination-induced antibodies against anti-SARS-CoV-2 spike protein cause thrombosis by cross-reacting with PF4. Immunogenic epitopes of PF4 and SARS-CoV-2 spike protein were compared using in silico prediction tools and 3D modeling. The SARS-CoV-2 spike protein and PF4 share at least 1 similar epitope. Reactivity of purified anti-PF4 antibodies from patients with VITT was tested against recombinant SARS-CoV-2 spike protein. However, none of the affinity-purified anti-PF4 antibodies from 14 patients with VITT cross-reacted with SARS-CoV-2 spike protein. Sera from 222 polymerase chain reaction–confirmed patients with COVID-19 from 5 European centers were tested by PF4-heparin enzyme-linked immunosorbent assays and PF4-dependent platelet activation assays. We found anti-PF4 antibodies in sera from 19 (8.6%) of 222 patients with COVID-19. However, only 4 showed weak to moderate platelet activation in the presence of PF4, and none of those patients developed thrombotic complications. Among 10 (4.5%) of 222 patients who had COVID-19 with thrombosis, none showed PF4-dependent platelet-activating antibodies. In conclusion, antibodies against PF4 induced by vaccination do not cross-react with the SARS-CoV-2 spike protein, indicating that the intended vaccine-induced immune response against SARS-CoV-2 spike protein is not the trigger of VITT. PF4-reactive antibodies found in patients with COVID-19 in this study were not associated with thrombotic complications.

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.

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.

The treatment of ischemic stroke is one of the great challenges in modern neurology. The localization and the size of the infarct determine the long-term disability of stroke survivors. Recent observations have revealed that stroke also alters the function of the immune system and vice versa: At the site of the infarct, a local inflammatory response develops that enhances brain lesion development. In experimental stroke, proof-of-concept studies confirm that inhibition of this immune response reduces lesion volume and improves outcome. In the peripheral blood of stroke patients, though, lymphocytopenia and monocyte dysfunction develop. These changes reflect a clinically relevant impairment of bacterial defense mechanisms because they are associated with an enhanced risk to acquire post-stroke infections. Stress hormones have been identified as important mediators of stroke-induced immune suppression. The pharmacological inhibition of beta adrenergic receptors, but not the inhibition of steroids, is effective in reducing infection and improving clinical outcome in experimental stroke; catecholamine release therefore appears causally related to stroke-induced immune suppression. Strong evidence supports the hypothesis that these immune alterations impact the clinical course of stroke patients. Thus, the development of new therapeutic strategies targeted to alter the immunological consequences of stroke appears promising. However, to date, the beneficial effects seen in experimental stroke have not been successfully translated into a clinical trial. This brief review summarizes the current understanding of the immunological consequences of ischemic stroke. Finally, we propose a concept that links the peripheral immune suppression with the development of local inflammation.