The immunology of acute stroke

Comprehensive Stroke Center, Department of Neuroscience, Hospital Clinic, University of Barcelona, 170 Villarroel, 08036 Barcelona, Spain.
Nature Reviews Neurology (Impact Factor: 15.36). 06/2012; 8(7):401-10. DOI: 10.1038/nrneurol.2012.98
Source: PubMed


Recent clinical and experimental studies have highlighted a complex role for the immune system in the pathophysiological changes that occur after acute stroke. Sensors of the innate immune system such as Toll-like receptors, or effectors such as the lectin pathway of complement activation and innate immune cells, are activated by brain ischaemia and tissue damage, leading to amplification of the inflammatory cascade. Activation of the adaptive arm of the immune system, mediated by lymphocyte populations including T and B cells, regulatory T cells, and γδT cells, in response to stroke can lead to deleterious antigen-specific autoreactive responses but can also have cytoprotective effects. Increased incidence of infections is observed after acute stroke, and might result from activation of long-distance feedback loops between the CNS and peripheral immune organs, which are thought to play a part in stroke-induced immunodepression. Ongoing clinical trials are investigating whether the preventive use of antibiotics improves functional outcome after stroke. This Review discusses the multifaceted role of the immune system in the pathophysiology of acute stroke.

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Available from: Diederik van de Beek
    • "Inflammatory mechanisms may have also beneficial effects by contributing to regeneration and tissue repair. The failure of many therapies for ischemic stroke has emphasized the importance of clarifying novel mechanisms that may contribute to its onset as well as the roles of innate and adaptive immune responses (Chamorro et al., 2012; Kamel and Iadecola, 2012). "
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    ABSTRACT: Inflammation and immune response play a pivotal role in the pathophysiology of ischemic stroke giving their contribution to tissue damage and repair. Emerging evidence supports the involvement of epigenetic mechanisms such as methylation, histone modification and miRNAs in the pathogenesis of stroke.Interestingly, epigenetics can influence the molecular events involved in ischemic injury by controlling the switch from pro- to anti-inflammatory response, however, this is still a field to be fully explored. The knowledge of epigenetic processes could to allow for the discovery of more sensitive and specific biomarkers for risk, onset, and progression of disease as well as further novel tools to be used in both primary prevention and therapy of stroke. Indeed, studies performed in vitro and in small animal models seem to suggest a neuroprotective role of HDAC inhibitors (e.g. valproic acid) and antagomir (e.g. anti-miR-181a) in ischemic condition by modulation of both immune and inflammatory pathways. Thus, the clinical implications of altered epigenetic mechanisms for the prevention of stroke are very promising but clinical prospective studies and translational approaches are still warranted.
    No preview · Article · Oct 2015
    • "Membrane-bound immunoglobulin allows B cells to bind antigens with great specificity and, if activated by cytokines from CD4 T cells, to secrete antibodies specific to a particular antigen. It is a common view that unlike T cells, B cells do not contribute to stroke pathology (Chamorro et al., 2012; Kleinschnitz et al., 2010; Yilmaz et al., 2006), though they do have the potential to contribute to neuroprotection and post-stroke repair (Bodhankar et al., 2013; Monson et al., 2014b). "
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    ABSTRACT: IN PRESS Stroke affects millions of people worldwide every year. Despite this prevalence, mechanisms of long-term injury and repair within the ischemic brain are still understudied. Sterile inflammation occurs in the injured brain after stroke, with damaged tissue exposing central nervous system (CNS)-derived antigen that could initiate potential autoimmune responses. We used a standard immunology-based recall response assay for murine immune cells, isolated from the cervical lymph nodes and spleen after transient stroke, to determine if stroke induces autoreactivity to CNS target antigens. Our assays included novel neuronal peptides, in addition to myelin-, nuclear-, glial-, and endothelial-derived peptides. Autoimmune responses to antigen were considered positive based on proliferation and activation over non-stimulated conditions. Stroke induced a significant increase in autoreactive CD4+ and CD8+ T cells, as well as autoreactive CD19+ B cells, as early as 4 days after stroke onset. Mice with large infarct volumes exhibited early T and B cell autoreactivity to NR2A, an NMDA receptor subunit, in cells isolated from lymph nodes but not spleen. Mice with small infarct volumes exhibited high autoreactivity to MAP2, a dendritic cytoskeletal protein, as well as myelin-derived peptides. This autoimmunity was maintained through 10 days post-stroke in both lymph nodes and spleen for all lymphocyte subsets. Sham surgery also induced early autoreactive B cell responses to MAP2 and myelin. Based on these observations, we hypothesize that stroke induces a secondary, complex, and dynamic autoimmune response to neuronal antigens with the potential to potentiate, or perhaps even ameliorate, long-term neuroinflammation.
    No preview · Article · May 2015 · Discovery medicine
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    • "After cerebral ischemia, metabolites of the ischemic molecular cascade and CNS proteins are released to the periphery, putatively enabling the generation of autoimmune responses against brainspecific antigens (Iadecola and Anrather, 2011; Chamorro et al., 2012). Protein markers of cerebral damage, including myelin basic protein (MBP), neuron-specific enolase (NSE), S100β, and glial fibrillary acidic protein (GFAP), are found in CSF and serum after stroke. "
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    ABSTRACT: Brain proteins are detected in the cerebrospinal fluid (CSF) and blood of stroke patients and their concentration is related to the extent of brain damage. Antibodies against brain antigens develop after stroke, suggesting a humoral immune response to the brain injury. Furthermore, induced immune tolerance is beneficial in animal models of cerebral ischemia. The presence of circulating T cells sensitized against brain antigens, and antigen presenting cells (APCs) carrying brain antigens in draining lymphoid tissue of stroke patients support the notion that stroke might induce antigen-specific immune responses. After stroke, brain proteins that are normally hidden from the periphery, inflammatory mediators, and danger signals can exit the brain through several efflux routes. They can reach the blood after leaking out of the damaged blood-brain barrier (BBB) or following the drainage of interstitial fluid to the dural venous sinus, or reach the cervical lymph nodes through the nasal lymphatics following CSF drainage along the arachnoid sheaths of nerves across the nasal submucosa. The route and mode of access of brain antigens to lymphoid tissue could influence the type of response. Central and peripheral tolerance prevents autoimmunity, but the actual mechanisms of tolerance to brain antigens released into the periphery in the presence of inflammation, danger signals, and APCs, are not fully characterized. Stroke does not systematically trigger autoimmunity, but under certain circumstances, such as pronounced systemic inflammation or infection, autoreactive T cells could escape the tolerance controls. Further investigation is needed to elucidate whether antigen-specific immune events could underlie neurological complications impairing recovery from stroke.
    Full-text · Article · Sep 2014 · Frontiers in Cellular Neuroscience
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