Brain-Immune Interactions and Ischemic Stroke Clinical Implications

NEUROLOGICAL REVIEW Brain-Immune Interactions and Ischemic Stroke Clinical Implications

Hooman Kamel, MD; Costantino Iadecola, MD

ncreasing evidence shows that the central nervous system and the immune system interact in complex ways, and better insight into these interactions may be relevant to the treatment of patients with stroke and other forms of central nervous system injury. Atheroscle- rosis, autoimmune disease, and physiological stressors, such as infection or surgery, cause Iinflammation that contributes to vascular injury and increases the risk of stroke. In addition, the immune system actively participates in the acute pathogenesis of stroke. Thrombosis and hypoxia trigger an intravascular inflammatory cascade, which is further augmented by the innate immune response to cellular damage occurring in the parenchyma. This immune activation may cause secondary tissue injury, but it is unclear whether modulating the acute immune response to stroke can produce clinical benefits. Attempts to dampen immune activation after stroke may have ad- verse effects because central nervous system injury causes significant immunodepression that places patients at higher risk of infections, such as pneumonia. The activation of innate immunity after stroke sets the stage for an adaptive immune response directed against brain antigens. The patho- genic significance of adaptive immunity and its long-term effects on the postischemic brain remains unclear, but it cannot be ruled out that a persistent autoimmune response to brain antigens has deleterious and long-lasting consequences. Further research will be required to determine what role, if any, immunity has in long-term outcomes after stroke, but elucidation of potential mechanisms may open promising avenues for the development of new therapeutics to improve neurological recovery after brain injury. Arch Neurol. 2012;69(5):576-581

Mounting evidence indicates that the im- risk of stroke and the potential for novel mune system has a key role in brain in- therapeutic agents to modify the immune jury. A better understanding of the inter- response to stroke. In addition, we high- actions between the immune system and the light the many gaps in our understanding brain can aid physicians who care for pa- of the role of the immune system in CNS tients with stroke and other forms of cen- injury and examine promising avenues of tral nervous system (CNS) injury. In addi- future investigation. Although relevant to tion, advancing our understanding of the the concept of immunity and stroke, pri- immunology of stroke promises to gener- mary and secondary CNS vasculitides fall ate novel clinical strategies, as well as di- outside the scope of this brief overview and agnostic and therapeutic approaches. In this will not be discussed. brief review, we discuss selected aspects of the interactions between CNS injury and IMMUNE ACTIVATION immunity, focusing on its implications for AND THE RISK OF STROKE new diagnostic tools to identify patients at

Author Affiliations: Department of Neurology and Neuroscience (Drs Kamel and Several lines of evidence suggest that acti- Iadecola) and Division of Neurobiology (Dr Iadecola), Weill Cornell Medical vation of the immune system may increase College, New York, New York. the risk of stroke (Table). Numerous pro-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 Table. Examples of Brain-Immune Interactions and Their Clinical Implications in the Care of Patients With Stroke

Examples Potential Clinical Implications Interaction of Inflammation and Stroke Risk Biomarkers of stroke risk include white blood cell count, fibrinogen, D-dimer, Clinical implications include the following capabilities: predict favorable and C-reactive protein. Duration of systemic lupus erythematosus and response to lipid-modifying agents, identify patients at high risk of stroke rheumatoid arthritis correlates with risk of stroke. A transient increased risk after cessation of antithrombotic drugs, stratify risk of stroke and determine of stroke occurs after infection or surgery. A link exists between appropriate antithrombotic strategy in patients with atrial fibrillation, use inflammation and atrial fibrillation. proven measures for stroke prevention in patients with underlying inflammatory disease and after infection or surgery, and control inflammation as a pathway to reducing vascular injury or occurrence of atrial fibrillation. Interaction of Acute Infarction and Immune Activation Intravascular hypoxia from thrombosis activates complement and endothelial Inhibition of the complement cascade reduces ischemic brain damage. cells. Oxidative stress reduces nitric oxide, promoting platelet and leukocyte Lymphocyte depletion protects against penumbral ischemia in experimental aggregation. Platelet activation generates proinflammatory signals. Spread animal models of stroke. Timely use of statin therapy during acute stroke of inflammation into perivascular space activates resident macrophages. seems to improve outcomes, potentially in part from anti-inflammatory Dying cells release signals that promote inflammation. Loss of neurons properties. removes the anti-inflammatory check on adjacent microglia. Interaction of Central Nervous System Injury and Immunosuppression Stroke results in lymphopenia, upregulation of anti-inflammatory cytokines, Vigilance should be exercised for early signs of infection after stroke. and splenic atrophy. Pneumonia and urinary tract infections occur Prophylactic antibiotic use after stroke may reduce infectious complications frequently after stroke. Cortisol and catecholamine levels correlate with and improve outcomes. Modulation of sympathetic activation may reduce susceptibility to infection after stroke. poststroke immunodepression. Interaction of Adaptive Immunity and Outcomes After Stroke Inflammatory brain infiltrates persist for years after stroke. Abnormal Immunomodulation may reduce the burden of long-term sequelae of ischemic blood-brain barrier permeability may be associated with radiographic white stroke. matter disease.

spective population-based investigations demonstrated a often do not apply well to humans. Clearly, a more de- correlation between levels of inflammatory biomarkers tailed understanding of the complex relationship be- (such as white blood cell count, fibrinogen, D-dimer, and tween inflammation and stroke is required to better as- C-reactive protein) and the risk of incident and recurrent sess the feasibility of immunomodulation as a potential stroke.1 Biomarkers may allow identification of patient tool for stroke prevention. subgroups who derive greater or lesser degrees of ben- Inflammation is increasingly recognized as a possible efit from standard medications, such as antiplatelet or lipid- pathway in the pathogenesis of atrial fibrillation, which modifying agents. In addition, improved knowledge about is a leading cause of stroke.3 Levels of C-reactive protein the link between inflammation and stroke may lead to are elevated in patients with atrial fibrillation and are as- better and more timely recognition of specially vulner- sociated with incident atrial fibrillation and with its re- able populations, such as patients with recent infection currence after ablation or cardioversion. Inflammatory or surgery who face a transiently heightened risk of stroke. pathways may promote atrial fibrillation by interacting These patients may be at increased risk from inappro- with cell signaling cascades, causing ion channel dys- priate cessation of antithrombotic medications,2 and rec- function, impairing myocyte gap junctions, promoting ognition of their vulnerability to stroke will help to en- atrial fibrosis, and recruiting leukocytes to cardiac tis- sure that antithrombotic drugs are stopped only if sue. The relationship between inflammation and atrial absolutely necessary and as briefly as possible. fibrillation is most likely bidirectional, with atrial fibril- The association between stroke and antecedent in- lation causing some degree of immune activation and flammatory states, such as infection or surgery, comple- inflammation. The prothrombotic state seen in atrial fi- ments recent findings of a correlation between stroke and brillation may reflect this inflammation, and anticoagu- the duration of chronic inflammatory diseases, such as lation with heparinoids seems to reduce biomarkers of systemic lupus erythematosus and rheumatoid arthri- inflammation in patients with atrial fibrillation. On the tis. The increased risk of stroke and coronary artery dis- other hand, perioperative treatment with glucocorti- ease seen in patients with lupus seems to be out of pro- coids reduces the incidence of atrial fibrillation after car- portion to traditional vascular risk factors, implying an diac surgery, which suggests that inflammation may also additive effect of underlying inflammation. Further- have a causal role in the pathogenesis of atrial fibrilla- more, animal models demonstrate that atherosclerosis has tion. Once patients develop atrial fibrillation, their risk an inflammatory component, and inhibition of the im- of stroke varies in proportion to known clinical risk fac- mune response to lipoproteins seems to reduce the pro- tors, such as congestive heart failure, hypertension, age, gression of atherosclerosis. These observations suggest diabetes mellitus, prior stroke, and peripheral vascular that inflammation may have a causal role in vascular in- disease. However, levels of the proinflammatory cyto- jury and subsequent stroke, which would open the door kine interleukin 6 are also associated with stroke risk, for immunomodulatory agents as new tools to prevent suggesting that inflammation is an additional biomarker stroke in these patients. However, observational data are of stroke risk within this population. Given these data, notoriously prone to confounding, and animal models physicians should be mindful that periods of heightened

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Thrombus formation Complement activation Vessel LDL lumen Lipid Leukocytes respond to hypoxia Persistent autoimmune accumulation and tissue damage response to brain antigens?

Hypoxia activates inflammation LDL Cellular damage oxidation and triggers innate aggregation immunity Chronic Adaptive inflammatory immunity Resolution of inflammation, disease Recent engaged clearing of dead cells, and infection Tissue promotion of cellular regrowth or surgery damage Chronic CNS inflammation Immunodepression and immune activation?

Years Minutes Hours Days WeeksWeeks Months Years

Figure. Progression of inflammation and immune activation in the development of stroke. Chronic inflammation from atherosclerosis, autoimmune disease, and physiological stress results in progressive vascular injury that increases the risk of stroke. Acute occlusion of the cerebral vasculature produces intravascular hypoxia that triggers a rapid inflammatory response. As tissue damage proceeds, cellular components activate the innate immune response and set the stage for the engagement of adaptive immunity. Questions remain about whether this immune activation after stroke causes autoimmunity that affects neurological recovery. CNS indicates central nervous system; LDL, low-density lipoprotein.

inflammation (such as acute medical illness or recent sur- pression on the surface of platelets and endothelial cells gery) place patients at higher risk of atrial fibrillation and rapidly leads to cell adhesion. Trafficking of inflamma- stroke. With further development, biomarkers of inflam- tory cells into the perivascular space is facilitated by down- mation may help to stratify patients’ risk of developing regulation of junctional proteins that maintain the in- atrial fibrillation and stroke, allowing targeted screen- tegrity of the endothelial lining and the blood-brain ing, risk factor modification, and timely treatment. A bet- barrier. Involvement of the perivascular space then ac- ter understanding of the interactions among atrial fibril- tivates resident macrophages and mast cells, leading to lation, inflammation, and thromboembolism may lead to the release of vasoactive mediators and proinflamma- the development of therapeutic agents that modulate in- tory cytokines, which in turn recruit and promote the flammatory pathways to reduce the risk of atrial fibril- infiltration of more leukocytes. lation and stroke. As cells die of ischemia, they release signals that further activate the immune system. Extracellular accumu- IMMUNE SIGNALING lation of adenosine triphosphate released from dying cells DURING ACUTE INFARCTION activates microglia, which develop characteristics of macrophages and release proinflammatory mediators. Nu- Besides its background role in stroke risk, the immune merous normally intracellular components serve as system actively participates in the acute pathogenesis of danger-associated molecular pattern molecules on their stroke4 (Figure). Independent of any immune re- release from dying cells, and these molecules activate toll- sponse, brain ischemia quickly causes failure of ion like receptors and scavenger receptors on microglia, peri- pumps, overaccumulation of intracellular sodium and cal- vascular macrophages, dendritic and endothelial cells, and cium, loss of membrane integrity, and necrotic cell death. infiltrating leukocytes. This activation induces the ex- In addition, arterial occlusion immediately leads to in- pression of proinflammatory molecules and primes den- travascular hypoxia, changes in shear stress, and the pro- dritic cells for antigen presentation. Such proinflamma- duction of reactive oxygen species, all of which in turn tory changes are initially counterbalanced by the release activate the coagulation cascade, complement, plate- of neurotransmitters, which activate anti-inflammatory lets, and endothelial cells. This results in a vicious cycle, receptors on microglia, and by the presence of cell-cell with fibrin formation entrapping platelets and leuko- interactions between microglia and adjacent neurons, cytes and causing further vascular occlusion. In addi- which usually keep microglia quiescent. However, as is- tion, oxidative stress reduces the bioavailability of nitric chemic cell death progresses, neurons die and neurotrans- oxide, undermining its protective role in promoting va- mitters are depleted, releasing this brake on proinflam- sodilation and inhibiting platelet aggregation and leu- matory signaling. kocyte adhesion, causing further vascular occlusion and The clinical implications of the immediate immune ischemia. Central in this cascade of events is the trans- involvement in the ischemic cascade are unclear. On the location of P-selectin, an adhesion molecule whose ex- face of it, proinflammatory signals seem to promote mi-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 crovascular occlusion and should tend to increase the size After stroke, the number of antigen-presenting cells of the resulting infarct. In fact, in experimental models in the brain increases, along with costimulatory mol- of stroke, mice deficient in adhesion receptors or comple- ecules required for antigen presentation to lympho- ment subunits seem to be protected from acute ische- cytes. This antigen presentation results in the produc- mia, and healthy mice treated with inhibitors of adhe- tion of antibodies against brain antigens and T cells sion molecules or the complement cascade also develop sensitized to brain antigens. Furthermore, successive mu- less ischemic brain injury. In addition, mice engineered cosal administration of myelin antigens in experimental to lack selected T-cell subgroups are protected from is- models results in the development of immune tolerance chemic damage to the penumbral zone around areas of and protection from subsequent ischemic injury, sug- infarction.5 Available data indicate that the protective ef- gesting that this immune response involves adaptive im- fect of lymphocyte suppression does not stem from an munity and that modulating it may be protective. On the inability to propagate thrombus and that no significant other hand, although lymphocyte-deficient mice are pro- differences in cerebral blood flow exist between healthy tected from ischemic brain damage, reconstituting them and lymphocyte-deficient mice.6 It is possible that lym- with T cells directed against non-CNS antigens worsens phocytes instead produce cell damage directly or through ischemic damage. In addition, mice lacking the neces- proinflammatory signaling and activation of down- sary costimulatory molecules for antigen-specific T-cell stream microglia and macrophages. Or, the early dam- responses are nevertheless vulnerable to ischemic damage associated with lymphocyte infiltration of the ische- age. Therefore, it is unclear whether the release and pre- mic brain may be due to the natural killer T-cell subtype sentation of CNS antigens during and after stroke result that harbors a simplified T-cell receptor and may not re- in an adaptive immune response directed against the CNS. quire antigen processing. The available data do not pro- If such an autoimmune response was directed against vide a clear picture of how lymphocytes participate in the brain after stroke, its long-term implications would acute infarction. potentially be significant (Table). Such immune activity Clinical attempts to explicitly modify the immune re- would be expected to impair neuronal plasticity and func- sponse after stroke (such as trials of recombinant neu- tional recovery and contribute to the frequent incidence trophil inhibitory factor or antibodies against adhesion of poststroke dementia. Such concerns are supported by molecules) have been ineffective to date, and these fail- the presence of inflammatory infiltrates in damaged areas ures highlight the complexity and redundancy of the path- of the brain years after stroke, as well as by persistently ways involved in the immune response to stroke. On the elevated titers of antibodies to brain antigens. Abnor- other hand, observational data and a randomized clini- mal permeability of the blood-brain barrier has been linked cal trial indicate that acute use of statin medications at to the radiographic white matter changes frequently as- the time of stroke improves long-term outcomes and re- sociated with vascular disease and cognitive decline, and duces mortality. Because this time window is not con- levels of inflammatory biomarkers such as C-reactive pro- sistent with the lipid-lowering effects of statin medica- tein are associated with white matter changes, lacunar tions, the benefit of their use during the acute stage of strokes, and loss of microstructural integrity as mea- stroke has been attributed to their anti-inflammatory prop- sured by diffusion-tensor imaging.7 Therefore, it cannot erties. This suggests that, despite the absence of specific be discounted that immune activation contributes to the clinical strategies or drugs proven to beneficially modu- alterations in this endothelial permeability and vascular late immune functioning during acute brain infarction, dysfunction. On the other hand, immune cells such as further elucidation of this complex interplay may yield microglia may be important for clearing deleterious cel- more sophisticated and pleiotropic therapeutics to aug- lular debris that can cause neurodegeneration. Further ment the limited repertoire of antithrombotic agents avail- research will be required to determine what role, if any, able to physicians today. immunity has in long-term outcomes after stroke, but elucidation of any potential mechanisms may open prom- THE ROLE OF ADAPTIVE IMMUNITY ising avenues for the development of new therapeutics AFTER STROKE to improve neurological recovery after brain injury.

The inflammatory processes detailed thus far occur in a RESOLUTION OF INFLAMMATION short time window after infarction and rely on the in- AND THE ROLE OF THE IMMUNE SYSTEM nate immune system, which involves the rapid activa- IN TISSUE REPAIR tion of low-affinity receptors that recognize a wide range of targets. The immediate onset of this inflammatory cas- The inflammation unleashed by cerebral infarction is fol- cade and the available experimental data on patterns of lowed by a carefully orchestrated process to clear ne- signaling during early immune activation do not sup- crotic debris and foster tissue repair. This reparative port a substantial role in this process for the adaptive im- process releases mediators that actively bring the inflam- mune system, which relies on the clonal expansion of spe- matory process to a close. Phagocytosis of dead cells by cific lymphocytes with high-affinity receptors to specific microglia and macrophages promotes the production of antigens. However, the general immune activation caused immunomodulatory cytokines, such as transforming by cerebral ischemia raises the questions of whether the growth factor ␤ and interleukin 10. Although transform- adaptive immune system is eventually activated and how ing growth factor ␤ has numerous proinflammatory efit may contribute to the propagation and repair of brain fects, in this context it helps to suppress inflammation injury after stroke. by inhibiting helper T-cell responses and promoting regu-

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 latory T-cell development. Interleukin 10 has neuropro- otic use reduced the rate of infections but not mortality. tective and anti-inflammatory properties, and its release However, these studies were underpowered to detect a helps to facilitate the resolution of inflammation and pro- meaningful difference in mortality rates, and further large motes the survival of remaining viable neurons. trials will be required to answer this question. If antibi- In this evolving process, the same cells that were ini- otic use is eventually shown to improve outcomes after tially recruited in the inflammatory phase serve as im- stroke, questions will remain about the effects of such a portant sources of growth factors required for neuronal strategy on microbial resistance patterns. Nevertheless, sprouting, neurogenesis, angiogenesis, gliogenesis, and it is possible that a strategy of prudent poststroke anti- matrix reorganization. For example, microglia are re- biotic use may emerge as a cost-effective and safe strat- quired for the full expression of insulinlike growth fac- egy for improving outcomes in these vulnerable pa- tor 1, which promotes neuronal sprouting after injury. tients. In the meantime, physicians should be cognizant Reactive astrocytes produce vascular endothelial growth of the immunosuppressed state of their patients with factor, which is required for angiogenesis. Circulating stroke and should remain vigilant to expeditiously iden- CD34ϩ immune progenitor cells promote revasculariza- tify and appropriately treat infections in these patients. tion in infarcted brain tissue. This reparative aspect of immune cells raises expectations that they can be har- RELATIONSHIP BETWEEN POSTSTROKE nessed to augment neuronal repair and recovery after CNS IMMUNODEPRESSION AND ADAPTIVE IMMUNITY injury. However, experimental efforts so far provide cau- tionary tales; for example, increasing vascular endothe- In speculating about why poststroke immunodepres- lial growth factor levels early after ischemia or in exces- sion occurs, on the surface it would seem to harm pa- sive amounts actually worsens injury. Such findings tients by increasing their risk of infectious complica- highlight the complexity of the immune response to CNS tions. Although it may simply be a maladaptive response injury and indicate that attempts to modify these inter- that stems from inherent aspects of the design of the CNS actions must be undertaken with care. and immune system, immunodepression may serve to protect the CNS from the development of adaptive immune BRAIN INJURY AND IMMUNOSUPPRESSION responses directed against self. Recent data indicate that the CNS undergoes regular immune surveillance by cir- Thus far, we have focused on the effects exerted by the culating lymphocytes. Central nervous system compo- immune system on the CNS after stroke. However, this nents are not routinely presented to these lymphocytes interaction is bidirectional, and CNS injury has pro- in such a way as to sensitize them and launch an im- found effects on immune function (Table). Within days mune response against the CNS. However, in the ab- of stroke, patients develop significant immunodepres- sence of countervailing factors, such antigen presenta- sion, marked by lymphopenia, upregulation of anti- tion would be expected to occur after CNS injury and inflammatory cytokines, and splenic atrophy.8 This im- compromise of the blood-brain barrier. Therefore, the immunodepression clinically manifests in the high rate of munodepression seen after stroke may serve a benefi- systemic infections seen in the immediate poststroke pe- cial purpose in limiting the development of such auto- riod. Patients with stroke are especially at risk of pneu- immunity. Such considerations suggest that a detailed monia and urinary tract infections, and such infections understanding of the many facets of the interactions be- may independently worsen neurological outcomes and tween the CNS and the immune system is needed to guide increase mortality. Immunodepression may account for any interventions to modify these interactions and im- the inability of other factors (such as dysphagia) to fully prove outcomes. account for the high rates of pneumonia seen in survi- vors of stroke. CONCLUSIONS Poststroke immunodepression seems to be mediated by catecholamines and steroids released by sympathetic The relationship between the CNS and the immune sys- activation after stroke. Cortisol and serum catechol- tem is complex and remains incompletely understood. amine levels correlate with susceptibility to infection af- It has particular salience after stroke and other forms of ter stroke, and experimental models have shown that ste- CNS injury, which trigger immune processes that seem roid and adrenergic antagonists counteract lymphocyte to be both beneficial and harmful. A major frontier in apoptosis and reduce rates of infection after brain in- stroke research involves efforts to better understand these jury. Intriguing clinical observations associate ␤-blocker interactions to develop new strategies and drugs that will use with lower rates of pneumonia and mortality after prevent and reduce the burden of stroke. Based on cur- stroke,9 but given the sparse nature of these data and the rent knowledge, physicians should be mindful that un- pleiotropic effects of ␤-blockers, further research will be derlying inflammation is a biomarker of stroke risk and required to determine the usefulness of such widely avail- should carefully consider antithrombotic, statin, and an- able drugs to modulate the immune response after stroke. tihypertensive therapy in vulnerable populations. Fur- Other efforts to counteract poststroke immunode- ther work will be needed to delineate precise clinical strat- pression have involved the prophylactic administration egies for risk factor modification based on specific of antibiotics after stroke to protect patients from com- biomarkers. In addition, it would be reasonable to ad- mon infections. Several randomized trials investigated minister statin drugs to patients with acute stroke given whether this strategy improves outcomes after stroke, and data suggesting that this improves outcomes, possibly as a meta-analysis10 of their results indicates that antibi- a result of anti-inflammatory properties. Furthermore,

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©2012 American Medical Association. All rights reserved. Downloaded From: https://jamanetwork.com/ on 09/27/2021 physicians caring for patients with stroke should recog- important intellectual content: Kamel and Iadecola. Ob- nize that poststroke immunodepression increases the risk tained funding: Iadecola. of infection and should adjust their clinical suspicion and Financial Disclosure: None reported. treatment strategies accordingly. Whether a strategy of Funding/Support: This study was supported by grants routine prophylactic antibiotic administration after stroke NS34179 and NS73666 from the National Institute of is beneficial remains unknown, but it holds promise as Neurological Disorders and Stroke, National Institutes a simple method for improving poststroke outcomes. Fi- of Health. nally, the care of patients with stroke may be improved by advances in specific areas, including investigation of REFERENCES whether modulating inflammatory pathways can reduce the risk of stroke and decrease penumbral ische- 1. Kaptoge S, Di Angelantonio E, Lowe G, et al; Emerging Risk Factors Collaboration. mia during acute stroke, whether immunity has a role C-reactive protein concentration and risk of coronary heart disease, stroke, and mor- in poststroke functional recovery and dementia, and tality: an individual participant meta-analysis. Lancet. 2010;375(9709):132-140. whether strategies to prevent poststroke immunodepres- 2. Broderick JP, Bonomo JB, Kissela BM, et al. Withdrawal of antithrombotic agents and its impact on ischemic stroke occurrence. Stroke. 2011;42(9):2509-2514. sion can reduce the incidence of infection after stroke 3. Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrilla- without increasing dangerous autoimmunity against the tion: Virchow’s triad revisited. Lancet. 2009;373(9658):155-166. brain. The immune system has not traditionally been the 4. Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. subject of therapeutic manipulation in patients with Nat Med. 2011;17(7):796-808. 5. Yilmaz G, Arumugam TV, Stokes KY, Granger DN. Role of T lymphocytes and stroke, but given its intertwined relationship with the CNS, interferon-␥ in ischemic stroke. Circulation. 2006;113(17):2105-2112. it promises to be an exciting avenue for future attempts 6. Kleinschnitz C, Schwab N, Kraft P, et al. Early detrimental T-cell effects in ex- to reduce the high burden of disability and death from perimental cerebral ischemia are neither related to adaptive immunity nor throm- stroke. bus formation. Blood. 2010;115(18):3835-3842. 7. Farrall AJ, Wardlaw JM. Blood-brain barrier: ageing and microvascular disease— systematic review and meta-analysis. Neurobiol Aging. 2009;30(3):337-352. Accepted for Publication: December 9, 2011. 8. Offner H, Vandenbark AA, Hurn PD. Effect of experimental stroke on peripheral Correspondence: Costantino Iadecola, MD, Division of immunity: CNS ischemia induces profound immunosuppression. Neuroscience. Neurobiology, Department of Neurology and Neurosci- 2009;158(3):1098-1111. ence, 407 E 61st St, PO Box 64, Room RR303, New York, 9. Dziedzic T, Slowik A, Pera J, Szczudlik A. ␤-Blockers reduce the risk of early death in ischemic stroke. J Neurol Sci. 2007;252(1):53-56. NY 10065 ([email protected]). 10. van de Beek D, Wijdicks EF, Vermeij FH, et al. Preventive antibiotics for infec- Author Contributions: Drafting of the manuscript: Ka- tions in acute stroke: a systematic review and meta-analysis. Arch Neurol. 2009; mel and Iadecola. Critical revision of the manuscript for 66(9):1076-1081.

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