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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    • "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.
    Frontiers in Cellular Neuroscience 09/2014; 8. DOI:10.3389/fncel.2014.00278 · 4.29 Impact Factor
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    • "In contrast to the disease-promoting role of cdT cells, CD4 + /CD25 + /Foxp3 + regulatory T cells (so-called Treg cells) were found to play a crucial role as counterregulators of cerebral inflammation after experimental stroke in mice (Chamorro et al., 2012; Magnus et al., 2012). Analyses of underlying mechanisms revealed anti-inflammatory properties of IL-10, down-regulating TNF-a and IFN-c as the probably most potent inflammatory cytokines (Liesz et al., 2009; Chamorro et al., 2012). Although the present work did not focus on Treg cells, their course and functional impact needs to be verified in the thromboembolic model of stroke in order to gain translationally relevant details. "
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    ABSTRACT: Inflammatory mechanisms were recently identified as contributors to delayed neuronal damage after ischemic stroke. However, therapeutic strategies are still lacking, probably related to the outstanding standardization on inflammatory cell recruitment emerging from predominantly artificial stroke models, and the uncertainty on functional properties of distinct subpopulations. Using a rodent model of stroke that closely reflects human embolic ischemia, this study was focused on the local recruitment of immunoreactive cells as well as their functional and regional characterization. Wistar rats underwent thromboembolic middle cerebral artery occlusion, followed by intravenous injection of the blood-brain barrier permeability marker FITC-albumin at 24 hours. One hour later, brain tissue was subjected to multi-parameter flow cytometry and Pappenheim staining to characterize cells invaded into the ischemia-affected hemisphere, compared to the contralateral side. Immunofluorescence labeling was applied to explore the distribution patterns of recruited cells and their spatial relationships with the vasculature. One day after ischemia onset, a 6.12-fold increase of neutrophils and a 5.43-fold increase of monocytes/macrophages was found in affected hemispheres, while these cells exhibited enhanced MHC class II expression and allocation with vessels exhibiting impaired blood-brain barrier integrity. Microglia remained numerically unaltered in ischemic hemispheres, but shifted to an activated phenotype indicated by CD45/CD86 expression and morphological changes towards an ameboid appearance in the bordering zone. Ischemia caused an increase of lymphoid cells in close vicinity to the affected vasculature, while further analyses allowed separation into NK cells, NKT cells, T cells (added by an unconventional CD11b(+)/CD3(+) population) and 2 subpopulations of B cells. Taken together, our study provides novel data on the local inflammatory response to experimental thromboembolic stroke. As concomitantly present neutrophils, monocytes/macrophages and lymphoid cells in the early stage after ischemia induction correspond to changes seen in human stroke, future stroke research should preferably use animal models with relevance for clinical translation.
    Neuroscience 08/2014; 279. DOI:10.1016/j.neuroscience.2014.08.023 · 3.36 Impact Factor
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    • "Dead cells can behave like damage-associated molecular patterns (DAMPs) and activate the innate and adaptive arms of the immune system (Kono and Rock, 2008). Moreover, DAMPs are produced after brain ischemia and may affect the clinical course and outcome of patients with acute stroke (Iadecola and Anrather, 2011; Chamorro et al., 2012). Brain-derived antigens may leave the central nervous system (CNS) via the blood stream (Hochmeister et al., 2010) or via the bulk flow of intracranial fluids along cranial nerves and perivascular spaces of brain cortical arteries and arterioles (Bradbury et al., 1981; Weller et al., 2008). "
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    ABSTRACT: Heat shock protein 70 (Hsp-70) can act as a danger signal and activate immune responses. We studied the presence of Hsp-70 in lymphoid tissue and plasma of acute stroke patients and asymptomatic controls free of neurological disease. Immunofluorescence, Western blotting, qRT-PCR and flow cytometry studies were performed. Plasma Hsp-70 concentration at day 7 was similar in patients and controls, whereas patients disclosed stronger immunoreactivity to Hsp-70 in lymphoid tissue than controls. Most Hsp-70 + cells were antigen presenting cells located in T cell zones. Stronger immunoreactivity to Hsp-70 was associated with smaller infarctions and better functional outcome.
    Journal of neuroimmunology 05/2014; 270(1-2). DOI:10.1016/j.jneuroim.2014.03.004 · 2.47 Impact Factor
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