Autoimmunity in acute ischemic stroke and the role of blood--brain barrier: the dark side or the light one?

Abstract

This article presents a synopsis of the current data on the mechanisms of blood--brain barrier (BBB) alteration and autoimmune response in acute ischemic stroke. Most researchers confirm the relationship between the severity of immunobiochemical changes and clinical outcome of acute ischemic stroke. Ischemic stroke is accompanied by aseptic inflammation, which alters the brain tissue and exposes the co-stimulatory molecules of the immune system and the neuronal antigens. To date, BBB is not considered the border between the immune system and central nervous system, and the local immune subsystems are found within and behind the BBB. BBB disruption contributes to the leakage of brain autoantigens and induction of secondary autoimmune response to neuronal antigens and long-term inflammation. Glymphatic system function is altered and jeopardized both in hemorrhagic and ischemic stroke types. The receptors of innate immunity (toll-like receptor-2 and toll-like receptor-4) are also involved in acute ischemia--reperfusion injury. Immune response is related to the key processes of blood clotting and fibrinolysis. At the same time, the stroke-induced immune activation may promote reparation phenomena in the brain. Subsequent research on the reduction of the acute ischemic brain injury through the target regulation of the immune response is promising.

Keywords

stroke / blood–brain barrier / autoimmunity / innate immunity / inflammation / cell death

Introduction

Stroke incidence has decreased over time but remains one of the global leading causes of death and disability, and as the population ages, the burden of this disease becomes tremendous [¹–³]. Ischemic stroke is the most common (83%) type of stroke, and up to 67% of cases result from two main causes, namely, thrombosis and embolism [³,⁴]. According to the Helsingborg Declaration on European stroke strategies (2006), the priority area for research and development is, among others, the development of the new methods of ischemic stroke treatment. For these purposes, the mechanisms of formation of infarction core and peri-infarction area, including the immune response, need to be studied, because acute ischemia promotes the local and systemic inflammatory reaction and autoreactive immune response [⁵–⁸].

Research on the contribution of the immune system to pathogenesis of cerebrovascular disease was initiated by I.V. Gannushkina in the middle of the 20th century [⁹]. The consequent research on the reduction of the ischemic brain injury through the target regulation of the immune response is also promising [⁷,¹⁰,¹¹].

Blood—brain barrier and immunological privilege of the central nervous system

The immunological privilege of the central nervous system (CNS) implies the isolation of the CNS from the immune system by the blood–brain barrier (BBB) [¹²]. The brain antigens are usually isolated from the immune system. Thus, the autoimmune response to these antigens promotes extensive damage of the brain cells. Patients with stroke have increased levels of circulating antibodies to neurofilaments and components of N-methyl-d-aspartate (NMDA) [¹³].

The BBB provides structural and immune isolation of the CNS. BBB also consists of three main components, namely, endothelium of microvessels of the brain, pericytes, and processes of astrocytes. The endothelial cells in the brain microcirculatory vessels have specific morphological and functional characteristics (deep interendothelial connections, the absence of pores and fenestrae between endotheliocytes, and solid basal membrane), thereby providing the barrier function and the function of transporting substances through the BBB. The strong interendothelial contacts of intact BBB limit the diffusion of the substances to more than 10–15 nm in diameter into the brain. The BBB structure is preserved in most parts of the brain, except for the hypothalamic-pituitary region, in which the basal membrane has pericapillary spaces; the barrier is abundantly fenestrated [¹⁴,¹⁵]. Although self-tolerance is facilitated by relative isolation and sequestration of brain antigens, the whole concept of immunologically privileged antigens “behind barriers” should not be overvalued because “no hiding place exists” completely excluding immune influences in the body. All locations are principally accessible for local and/or systemic immune effectors. Studies in the last decades showed that the real amount of cloistered autoantigens is substantially limited, and their isolation is not absolute. Thus, the contribution of the BBB alteration into the pathogenesis of autoimmune disorders has been overestimated. The alteration of blood–tissue barriers and the expression of cell adhesion molecules on the endothelium promote the migration of immune effectors into altered areas and enhance the alteration of the tissues (Fig. 1). According to Dembič [¹⁶], the increase of autoreactivity depends not only on barrier violation but also on the presence of tissue disintegration signal (or lack of integrity signals), thereby altering the behavior of antigen-presenting cells. Probably, all autoantigens are prone to immunological surveillance. Thus, the disclosure contribution in autoimmunity response may be not so prominent. The following facts prove this statement (and not recently!).

Blood—brain barrier alteration and immune response

In the absence of the immune response, sensitive immunodiagnostic procedures (such as ELISA and RIA) revealed impactful amounts of autoantigens, which were formerly regarded as covered, for example, myelin basic protein. This finding does not necessarily provoke encephalomyelitis [¹⁷]. Notably, BBB permeability for macromolecules is restricted predominantly for the blood to CNS direction, and to a lesser extent, for the CNS to blood [¹⁸]. To date, BBB is not considered the border between the immune system and CNS. The local immune subsystems are found within and behind the BBB and consist of local antigen-presenting cells (astrocytes) and effectors (intrathecal lymphocytes) [¹⁹]. In the previous century, Pio del Rio-Hortega insisted on the macrophageal origin of microglial cells [²⁰], which is proven today. Microglial cells express the main histocompatibility complex (MHC) I and also MHC II antigens in cytokine or viral stimulation. Microglial cells produce cytokines and can present CNS autoantigens to local effectors (intrathecal lymphocytes). Remarkably, the activation of BBB endotheliocytes by microglial cells promotes the expression of cell adhesion molecules and increases the BBB permeability for lymphocytes [²¹]. The described local immune mechanisms in the BBB area usually have low activity, but its enhancement can lead to the autoimmune alteration of the CNS. This condition can be clinically relevant, for example, in multiple sclerosis. Immune and phagocytic behavior of microglial cells is sensitive to many factors, such as thyroid hormones, which are essential for the development and function of the brain [²²].

In recent years, these classical data on routine brain–immune interaction have been supported by newly discovered brain lymphatic vessels [²³] and description of so-called glymphatic system of the brain and communication between the cerebrospinal and intracerebral interstitial fluids and the key role of astrocyte aquaporins in brain glymphodynamics [²⁴]. Lymph drainage from the brain to cervical lymph nodes has been recently proven [²⁵]. Glymphatic system function is altered and jeopardized both in hemorrhagic and ischemic cerebral circulatory disorders. Remarkably, all these data considerably modified the BBB concept compared with its classical version.

BBB dysfunction is specific for severe neurological diseases, such as multiple sclerosis, brain tumors, and hemorrhagic and ischemic stroke. To date, most researchers focus on the study of the neurons during acute damage to the CNS, whereas relatively less attention is provided to the BBB changes. The brain areas, which were subjected to ischemia and subsequent reperfusion, usually have massive microcirculatory disorders with relevant clinical implications [²⁶]. In acute cerebral ischemia, capillarostasis, diapedesis, and BBB disruption are found both in the affected basin and at a considerable distance from the zone of vascular catastrophe due to hypoxic alteration of cerebral structures [¹⁴]. The early damage of the BBB may also be the cause but not the result of brain parenchyma cell alteration [²⁷]. O’Connell et al. [²⁸] studied 16 candidate genes that may be predictive for the BBB disruption. ITGA3 gene encodes the adhesion molecule integrin α-3. The overexpression of AKAP7 gene, which is co-expressed with ITGA3, showed the highest prognostic value as a biomarker for BBB alteration after the stroke.

Blood—brain barrier alteration in stroke

Within hours after a stroke, the microvacuoles, eosinophilic cytoplasm, pyknotic nuclei in the neurons, and the first signs of the BBB alteration can be found. These conditions can be divided into three stages. In stage I, the leukocytes begin to penetrate into the damaged area. In stage II, macrophages come through the BBB, and the astrocyte activity remains, and in stage III, a pseudocyst is formed [⁷]. The damage to the BBB after the stroke onset also has two phases. The first starts within a few hours, and the second begins in 24–48 h after the stroke onset. Matrix metalloproteinases (MMPs), especially MMP-2 and MMP-9, are involved in both early and late phases of the BBB damage, but early damage is largely due to MMP-2 activity. Accordingly, an MMP-9 increase, which is considered one of the main factors of BBB disintegration in ischemic stroke, begins in 4 h after the stroke onset and lasts up to 4 days. At this time, the degradation of the dense connective proteins (occludin, claudine-5, and adhesion molecules) starts, naturally constituting the actin–myosin skeleton and are distributed in the form of short filaments and diffuse monomers between the endothelial cells. However, in ischemia, the actin filaments polarize into linear stress fibers, leading to complete BBB destruction and subsequent brain swelling [³⁶].

BBB disruption in ischemic stroke contributes to the tissue disintegration and leakage of brain autoantigens, including the myelin basic protein, proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG). The leakage of brain autoantigens is followed by the activation of the immune system and migration of immunocytes to the CNS, promoting the local inflammation. MOG-reactive splenocytes secrete neurotoxic Th1-cytokines, tumor necrosis factor-a (TNF-a), and interferon-g and exacerbate brain damage in ischemic stroke. The MOG-reactive splenocytes can promote neuronal death or injury directly or indirectly through the augmentation of the BBB permeability and enhancing of transendothelial transport and infiltration of immune cells into the brain [¹²].

Many authors believe that immune cell activation promotes the production of antibodies to the myelin basic protein. The growth of the serum levels of antibodies to myelin basic protein at the end of acute period of ischemic stroke correlates with the severity of the post-stroke period. By contrast, the patients with good clinical outcome have the decreased level of the organ-specific antibodies at the end of the acute period of stroke [²⁹]. However, whether several active autoimmune cells responding to myelin basic protein contributing to worse recovery of neurological functions or an inability to recover the lost function provokes an autoimmune response to increase neuroplasticity during continuous recovery remains to be elucidated [³⁰]. Recently, Jin et al. [³¹] have demonstrated that brain ischemia induces T cell responses, which are specific to the neuroantigens and enhance brain injury. Using a mouse strain that harbors a transgenic T cell receptor to MOG, the anatomic location and involvement of antigen-presenting cells in the development of T cell reactivity after brain ischemia were determined [³¹].

Aseptic inflammation that occurs in the CNS in ischemic stroke alters the brain tissue and exposes CNS antigens. The experimental study showed the upregulation of autoreactive CD4⁺ T cells, CD8⁺ T cells, and CD19⁺ B cells at 4 days after the stroke onset. The mice with large infarct volume showed early lymph nodes (but not the spleen) and T- and B-cell autoreactivity for the subunit of the NMDA receptor NR2A. If the volume of the brain infarct was low, consequently, MAP-2 and myelin-derived peptide autoreactivity was elevated. Moreover, these autoimmune reactions were present during 10 days after the stroke onset. Thus, ischemic stroke induces secondary autoimmune response to neuronal antigens and long-term inflammation [³⁰]. Wang et al. [³²] also showed the important role of invariant natural killer T cells in brain alteration and brain edema in the model of focal permanent cerebral ischemia. Propagation of CD8⁺ T cell-mediated and natural killer-cell-mediated immunity in acute brain ischemia can be promoted by astrocytic interleukin (IL)-15 [³³]. Future research on T cell activity in acute stroke may be the key for the new strategies for the treatment of the long-term degenerative consequences of stroke [³⁴].

Other evidence proved the expression of the MHC antigens and cell adhesion molecules by the BBB endothelial cells. The loss of the BBB integrity leads to the endothelial and glial cell activation, followed by inflammatory process. During inflammation, the complex interaction of the cytokines and adhesion molecules provokes attraction and invasion of leukocytes, increasing the damage to the brain tissue [¹²,¹⁴,³⁵].

Notably, the immune response is related to blood clotting and fibrinolysis. This dependence is largely due to the presence of active compounds possessing the properties of procoagulants, anticoagulants, and activators of fibrinolysis in T- and B-cells. Proinflammatory cytokines affecting the endothelial cells and macrophages increase the production and secretion of procoagulants but decrease the formation of anticoagulants. The acute focal ischemia of the brain turns the monocytes (macrophages) into a hyperactive state, thereby increasing the IL-1a synthesis. The degree and duration of the increase of IL-1a level are of prognostic importance for the course and outcome of stroke [²⁹].

MMP-9 is mainly secreted by neutrophils, which infiltrate BBB, and endothelium of microvessels [²⁷]. Polymorphonuclear granulocytes are the first subset of leukocytes that appear in ischemic brain tissue. Thus, they were previously suspected to alter neurons. However, recently, during the acute phase of ischemic damage, this type of cells is not found in the brain parenchyma. At this time, they remain trapped within the neurovascular units and leptomeningeal spaces. Therefore, the neutrophil-mediated neuronal death may not require the presence of neutrophils near the target brain cells. The observation of the absence of active migration of polymorphonuclear neutrophils through the BBB during the early stage of reperfusion is not only limited to the experimental studies but also is confirmed by postmortem studies in patients with stroke [⁷]. Chronic cerebral ischemia is accompanied by the increase of granular leukocytes with azurophilic granules, containing elastase, myeloperoxidase, cathepsin G, and acid hydrolases. The movement of inflammatory cells into the perivascular space is promoted by the disruption of the connective proteins in the BBB. Involvement of perivascular areas activates resident macrophages and mast cells, thereby promoting the release of proinflammatory cytokines, vasoactive mediators, and the infiltration of leukocytes [³⁷]. The experimental stroke models show that circulating leukocytes penetrate the brain by diapedesis and accumulate in the injury area within a few hours after stroke. CD4⁺ T cells are activated when the peptide antigens are present on the surface of MHC II cells, including dendritic cells, macrophages, and B cells. CD8⁺ T cells react to antigenic peptides of the MHC I, which are present on most types of cells [³⁰].

The cytokines promote the leukocyte infiltration of the ischemic core, activation of microglial cells, inducible form of cyclooxygenase-2, and nitric oxide synthase in ischemic stroke [³⁸]. Brain alteration elevates the serum levels of heat shock proteins-70, i.e., endogenous ligands for the toll-like receptor-4 (TLR4), which is the key receptor of innate immunity. Toll-like receptors (TLRs) initiate the synthesis of pro-inflammatory cytokines by activating the nuclear factor and are capable of triggering the immune response in both infectious and non-infectious diseases [³⁹]. By the structure, TLRs belong to the IL-1 receptor family. IL-1 is a mediator of microglial neuroimmune functions and is secreted locally in response to cerebral ischemia.

All TLRs are integral transmembrane proteins with the same structure. At rest, unactivated TLRs are present on the cell membrane in the monomeric state. Most receptors form homodimers, whereas TLR2 forms heterodimers with TLR1 or TLR6 depending on the ligand. When activated by exogenous or endogenous ligands, the receptors dimerize and lead to subsequent signal transmission inside the cell and activation of cytokine synthesis. TLR2 and TLR4 are involved in ischemia–reperfusion injury. TLR4 mediates immune response to systemic bacterial infection and brain alteration. TLR2 expression rapidly increases after the stroke onset long before the microglial activation. TLR4 activation is accompanied by the expression of cytokines and other signal peptides, including MMP-9 and TNF-a. In ischemic stroke, the effector receptors of TNF-a (type 1 TNF-receptor and Fas-receptor) regulate apoptosis in neurons and non-neural cells involving caspase-dependent and caspase-independent pathways [⁴⁰–⁴²]. Thus, inflammation is regarded as the key mechanism of ischemia–reperfusion injury, and the anti-inflammatory treatment is promising in acute stroke [⁴³–⁴⁶]. In particular, lymphocytes are regarded as the target for the neuroprotection in acute ischemia [⁴⁷]. Li et al. [⁴⁸] showed that C-C chemokine receptor type 5 is a critical molecule for T cell-mediated BBB protection and is a potential target to optimize acute ischemic stroke therapy. Nalamolu et al. [⁴⁹] showed that attenuation of TLR2- and TLR4-mediated inflammation after the stroke prevents ischemic brain damage. At the same time, some TLRs exert a neuroprotective effect after ischemic stroke [⁵⁰].

The infarct core becomes a source of MMPs, various proteins, and molecules that initiate an autoimmune response accompanied by the production of immunoglobulins with abnormal temperature solubility and immune complexes with cryoproperties. The cerebrospinal fluid level of nerve growth factor autoantibodies in patients with ischemic stroke is 180%–190% as compared with the reference values. The decrease of the nerve growth factor level diminishes neurotrophic support. As for the S100-b protein, on the 1st day after the stroke onset, the concentration of S100-b protein antibodies is also increased by 25%–50% [²⁹]. Notably, all these processes are not a sequence of events but a complex network of intertwining cascades [⁶].

Altered brain cells can promote the activation of immune system. Numerous intracellular components, which vacate destroyed cells, can activate TLRs on various cells, followed by upregulation of proinflammatory molecules and presentation of antigens by dendritic cells. Escalation of cell death reduces the anti-inflammatory effect of neurons and neurotransmitters on the microglia [³⁷]. Some researchers suggest that autoimmune reactions promote chronic inflammation and can be a risk factor of dementia. They are also associated with the phenomenon of “anamnestic recall,” which results from autoreactive T cell activation and comprises the temporary reoccurrence of stroke symptoms that have been regressed in this patient usually in systemic infection [¹³].

Blood—brain barrier alteration: the light side

The protective role of autoimmunity was previously shown in experimental CNS trauma in rats [⁵¹] and can be boosted by immunizing with neural constituents or neural-derived peptides, promoting motor recovery in experimental moderate spinal cord contusion or incomplete spinal cord transection [⁵²]. Copolymer-1, also known as glatiramer acetate, stimulates protective autoimmunity and has been approved in the treatment of multiple sclerosis. Cruz et al. demonstrated enhancing of neuroprotection and neurogenesis by copolymer-1 in acute cerebral ischemia models [⁵³,⁵⁴].

Summary and perspectives

Most researchers confirm the relationship between the severity of immunobiochemical changes and clinical outcome of ischemic stroke. Ischemic stroke is accompanied by aseptic inflammation that exposes co-stimulatory molecules of the immune system and neuronal antigens. The increase of autoreactivity in ischemic stroke depends predominantly not on BBB violation but on the presence of tissue disintegration signal, activation of innate immunity, and probably alteration of glymphodynamics.

Despite the large number of studies on immune-inflammatory status in patients with ischemic stroke, many questions remain. First is the role of stroke-induced immune activation in neuroreparation. A study on immune response and inflammatory reaction in pathogenesis of ischemic stroke and its influence on the clinical outcome is also important for the new approaches to diagnostics and searching for the new molecular therapeutic targets.

References

[1] Kim AS, Cahill E, Cheng NT. Global stroke belt: geographic variation in stroke burden worldwide. Stroke 2015; 46(12): 3564–3570

[2] Madsen TE, Khoury J, Alwell K, Moomaw CJ, Rademacher E, Flaherty ML, Woo D, De Los Rios La Rosa F, Martini S, Ferioli S, Adeoye O, Khatri P, Broderick JP, Kissela BM, Kleindorfer D. Sex-specific stroke incidence over time in the Greater Cincinnati/Northern Kentucky Stroke Study. Neurology 2017; 89(10): 990–996

[3] Benjamin EJ, Virani SS, Callaway CW, Chamberlain AM, Chang AR, Cheng S, Chiuve SE, Cushman M, Delling FN, Deo R, de Ferranti SD, Ferguson JF, Fornage M, Gillespie C, Isasi CR, Jiménez MC, Jordan LC, Judd SE, Lackland D, Lichtman JH, Lisabeth L, Liu S, Longenecker CT, Lutsey PL, Mackey JS, Matchar DB, Matsushita K, Mussolino ME, Nasir K, O’Flaherty M, Palaniappan LP, Pandey A, Pandey DK, Reeves MJ, Ritchey MD, Rodriguez CJ, Roth GA, Rosamond WD, Sampson UKA, Satou GM, Shah SH, Spartano NL, Tirschwell DL, Tsao CW, Voeks JH, Willey JZ, Wilkins JT, Wu JH, Alger HM, Wong SS, Muntner P; American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics-2018 update: a report from the american heart association. Circulation 2018; 137(12): e67–e492

[4] Ornello R, Degan D, Tiseo C, Di Carmine C, Perciballi L, Pistoia F, Carolei A, Sacco S. Distribution and temporal trends from 1993 to 2015 of ischemic stroke subtypes: a systematic review and meta-analysis. Stroke 2018; 49(4): 814–819

[5] Poletaev AB, Stepanyuk VL, Gershwin ME. Integrating immunity: the immunculus and self-reactivity. J Autoimmun 2008; 30(1-2): 68–73

[6] Konstantinova EV, Kochetov AG, Shostak NA, Shurdumova MK, Eremin II, Lyang OV, Skvortsova VI. Characteristics of immune response and inflammatory reaction in atherothrombotic stroke and myocardial infarction. Zh Nevrol Psikhiatr Im S S Korsakova 2015; 115(12 Pt 2): 48–53 (in Russian)

[7] Lopes Pinheiro MA, Kooij G, Mizee MR, Kamermans A, Enzmann G, Lyck R, Schwaninger M, Engelhardt B, de Vries HE. Immune cell trafficking across the barriers of the central nervous system in multiple sclerosis and stroke. Biochim Biophys Acta 2016; 1862(3): 461–471

[8] Janyou A, Wicha P, Jittiwat J, Suksamrarn A, Tocharus C, Tocharus J. Dihydrocapsaicin attenuates blood brain barrier and cerebral damage in focal cerebral ischemia/reperfusion via oxidative stress and inflammatory. Sci Rep 2017; 7(1): 10556

[9] Zhirnova IG, Maximova MYu, Komelkova LV, Varakin YuA, Bolotova TA. Immunological changes in acute ischemic stroke. Ann Clin Exp Neurology 2012; 6: 25–30 (in Russian)

[10] Zhao X, Wang H, Sun G, Zhang J, Edwards NJ, Aronowski J. Neuronal interleukin-4 as a modulator of microglial pathways and ischemic brain damage. J Neurosci 2015; 35(32): 11281–11291

[11] Zhou K, Shi L, Wang Y, Chen S, Zhang J. Recent advances of the NLRP3 inflammasome in central nervous system disorders. J Immunol Res 2016; 2016: 9238290

[12] Ren X, Akiyoshi K, Grafe MR, Vandenbark AA, Hurn PD, Herson PS, Offner H. Myelin specific cells infiltrate MCAO lesions and exacerbate stroke severity. Metab Brain Dis 2012; 27(1): 7–15

[13] Becker K. Autoimmune responses to brain following stroke. Transl Stroke Res 2012; 3(3): 310–317

[14] Odinak MM, Voznyuk IA. Damage and protection of the blood brain barrier in ischemia. In: Petrischev NN. Endothelial Dysfunction. Causes, Mechanisms, Pharmacological Correction. St. Petersburg: Publishing House of Saint-Petersburg State Medical University, 2003: 146–171 (in Russian)

[15] Berezhanskaya SB, Lukyanova EA, Zhavoronkova TE, Kaushanskaya EY, Sozaeva DI. The modern concept of blood-brain barrier structural-functional organization and basic mechanisms of its resistance disorder. Pediatria Zh im GN Speransky 2017; 96(1): 135–141 (in Russian)

[16] Dembič Z. Immune system protects integrity of tissues. Mol Immunol 2000; 37(10): 563–569

[17] Roitt IM. Prevailing theories in autoimmune disorders. Triangle 1984; 23: 67–76

[18] Aarli JA. The immune system and the nervous system. J Neurol 1983; 229(3): 137–154

[19] Shevelyov AS. Territorial problems of the immune system. Immunologiya 1991; 4: 68–72 (in Russian)

[20] del Río-Hortega P. Microglia. In: Penfield W. Cytology and Cellular Pathology of the Nervous System. vol. 2. New York: Hoeber, 1932: 483–534

[21] Zweiman B, Levinson AI. Immunologic aspects of neurological and neuromuscular diseases. JAMA 1992; 268(20): 2918–2922

[22] Mori Y, Tomonaga D, Kalashnikova A, Furuya F, Akimoto N, Ifuku M, Okuno Y, Beppu K, Fujita K, Katafuchi T, Shimura H, Churilov LP, Noda M. Effects of 3,3′5-triiodothyronine on microglial functions. Glia 2015; 63(5): 906–920

[23] Louveau A, Smirnov I, Keyes TJ, Eccles JD, Rouhani SJ, Peske JD, Derecki NC, Castle D, Mandell JW, Lee KS, Harris TH, Kipnis J. Structural and functional features of central nervous system lymphatic vessels. Nature 2015; 523(7560): 337–341

[24] Bacyinski A, Xu M, Wang W, Hu J. The paravascular pathway for brain waste clearance: current understanding, significance and controversy. Front Neuroanat 2017; 11: 101

[25] Eide PK, Vatnehol SAS, Emblem KE, Ringstad G. Magnetic resonance imaging provides evidence of glymphatic drainage from human brain to cervical lymph nodes. Sci Rep 2018; 8(1): 7194

[26] Tsygan NV, Odinak MM, Khubulava GG, Tsygan VN, Peleshok AS, Andreev RV, Kurasov ES, Litvinenko IV. Postoperative cerebral dysfunction. Zh Nevrol Psikhiatr Im S SKorsakova 2017; 117(4): 34–39 (in Russian)

[27] Zhang QY, Wang ZJ, Sun DM, Wang Y, Xu P, Wu WJ, Liu XH, Zhu YZ. Novel therapeutic effects of leonurine on ischemic stroke: new mechanisms of BBB integrity. Oxid Med Cell Longev 2017; 2017: 7150376

[28] O’Connell GC, Treadway MB, Petrone AB, Tennant CS, Lucke-Wold N, Chantler PD, Barr TL. Peripheral blood AKAP7 expression as an early marker for lymphocyte-mediated post-stroke blood brain barrier disruption. Sci Rep 2017; 7(1): 1172

[29] Gubarev YD, Sheremet AO. The role of the immune system in the pathogenesis of acute and chronic ischemic damages of the brain. Sci Bull Belgorod State University 2009; 4: 47–52 (in Russian)

[30] Ortega SB, Noorbhai I, Poinsatte K, Kong X, Anderson A, Monson NL, Stowe AM. Stroke induces a rapid adaptive autoimmune response to novel neuronal antigens. Discov Med 2015; 19(106): 381–392

[31] Jin WN, Gonzales R, Feng Y, Wood K, Chai Z, Dong JF, La Cava A, Shi FD, Liu Q. Brain ischemia induces diversified neuroantigen-specific T-cell responses that exacerbate brain injury. Stroke 2018; 49(6): 1471–1478

[32] Wang ZK, Xue L, Wang T, Wang XJ, Su ZQ. Infiltration of invariant natural killer T cells occur and accelerate brain infarction in permanent ischemic stroke in mice. Neurosci Lett 2016; 633: 62–68

[33] Li M, Li Z, Yao Y, Jin WN, Wood K, Liu Q, Shi FD, Hao J. Astrocyte-derived interleukin-15 exacerbates ischemic brain injury via propagation of cellular immunity. Proc Natl Acad Sci USA 2017; 114(3): E396–E405

[34] Gill D, Veltkamp R. Dynamics of T cell responses after stroke. Curr Opin Pharmacol 2016; 26: 26–32

[35] Zhang H, Park JH, Maharjan S, Park JA, Choi KS, Park H, Jeong Y, Ahn JH, Kim IH, Lee JC, Cho JH, Lee IK, Lee CH, Hwang IK, Kim YM, Suh YG, Won MH, Kwon YG. Sac-1004, a vascular leakage blocker, reduces cerebral ischemia–reperfusion injury by suppressing blood-brain barrier disruption and inflammation. J Neuroinflammation 2017; 14(1): 122

[36] Venkat P, Chopp M, Chen J. Blood–brain barrier disruption, vascular impairment, and ischemia/reperfusion damage in diabetic stroke. J Am Heart Assoc 2017; 6(6): e005819

[37] Kamel H, Iadecola C. Brain-immune interactions and ischemic stroke: clinical implications. Arch Neurol 2012; 69(5): 576–581

[38] Boyajyan AS, Arakelov EA, Ayvazyan VA, Manukyan LA. Interleukins and chemokins in acute ischemic stroke, burdened and not burdened by diabetes. Cytokines Inflammation 2008; 1: 40–43 (in Russian)

[39] Tsygan VN, Bubnov VA, Tsygan NV, Zinovev EV, Ivchenko EV, Anichkov NM, Mirolyubov AV,  Dergunov AV,  Kazachenko AI. The innate immunity and activation of the atherogenesis. Voen Med Zh 2016; 337: 47–54 (in Russian)

[40] Caso JR, Pradillo JM, Hurtado O, Lorenzo P, Moro MA, Lizasoain I. Toll-like receptor 4 is involved in brain damage and inflammation after experimental stroke. Circulation 2007; 115(12): 1599–1608

[41] Broughton BRS, Reutens DC, Sobey CG. Apoptotic mechanisms after cerebral ischemia. Stroke 2009; 40(5): e331–e339

[42] Arslan F, Keogh B, McGuirk P, Parker AE. TLR2 and TLR4 in ischemia reperfusion injury. Mediators Inflamm 2010; 2010: 704202

[43] Wang Q, Tang XN, Yenari MA. The inflammatory response in stroke. J Neuroimmunol 2007; 184(1-2): 53–68

[44] Arumugam TV, Woodruff TM, Lathia JD, Selvaraj PK, Mattson MP, Taylor SM. Neuroprotection in stroke by complement inhibition and immunoglobulin therapy. Neuroscience 2009; 158(3): 1074–1089

[45] Cheon SY, Kim EJ, Kim JM, Kam EH, Ko BW, Koo BN. Regulation of microglia and macrophage polarization via apoptosis signal-regulating kinase 1 silencing after ischemic/hypoxic injury. Front Mol Neurosci 2017; 10: 261

[46] Mizuma A, Yenari MA. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front Neurol 2017; 8: 467

[47] Gee JM, Kalil A, Shea C, Becker KJ. Lymphocytes: potential mediators of postischemic injury and neuroprotection. Stroke 2007; 38(2Suppl): 783–788

[48] Li P, Wang L, Zhou Y, Gan Y, Zhu W, Xia Y, Jiang X, Watkins S, Vazquez A, Thomson AW, Chen J, Yu W, Hu X. C-C chemokine receptor type 5 (ccr5)-mediated docking of transferred tregs protects against early blood-brain barrier disruption after stroke. J Am Heart Assoc 2017; 6(8): e006387

[49] Nalamolu KR, Smith NJ, Chelluboina B, Klopfenstein JD, Pinson DM, Wang DZ, Vemuganti R, Veeravalli KK. Prevention of the severity of post-ischemic inflammation and brain damage by simultaneous knockdown of Toll-like receptors 2 and 4. Neuroscience 2018; 373: 82–91

[50] Fadakar K, Dadkhahfar S, Esmaeili A, Rezaei N. The role of Toll-like receptors (TLRs) in stroke. Rev Neurosci 2014; 25(5): 699–712

[51] Yoles E, Hauben E, Palgi O, Agranov E, Gothilf A, Cohen A, Kuchroo V, Cohen IR, Weiner H, Schwartz M. Protective autoimmunity is a physiological response to CNS trauma. J Neurosci 2001; 21(11): 3740–3748

[52] Martiñón S, García E, Gutierrez-Ospina G, Mestre H, Ibarra A. Development of protective autoimmunity by immunization with a neural-derived peptide is ineffective in severe spinal cord injury. PLoS One 2012; 7(2): e32027

[53] Cruz Y, Lorea J, Mestre H, Kim-Lee JH, Herrera J, Mellado R, Gálvez V, Cuellar L, Musri C, Ibarra A. Copolymer-1 promotes neurogenesis and improves functional recovery after acute ischemic stroke in rats. PLoS One 2015; 10(3): e0121854

[54] Cruz Y, García EE, Gálvez JV, Arias-Santiago SV, Carvajal HG, Silva-García R, Bonilla-Jaime H, Rojas-Castañeda J, Ibarra A. Release of interleukin-10 and neurotrophic factors in the choroid plexus: possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia. Neural Regen Res 2018; 13(10): 1743–1752

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