scholarly journals Brain tissue-resident immune memory cells are required for long-term protection against CNS infection with rabies virus

2020 ◽  
Vol 15 (11) ◽  
pp. 755-761
Author(s):  
Aurore Lebrun ◽  
Rhonda B Kean ◽  
D. Craig Hooper
Keyword(s):  
Blood Brain Barrier ◽  
Secondary Infection ◽  
Immune Surveillance ◽  
Recurrent Infection ◽  
Brain Barrier ◽  
Immune Memory ◽  
Cns Infection ◽  
Memory Cells ◽  
Wild Type ◽  
Blood Brain

Immune memory cells residing in previously infected, nonlymphoid tissues play a role in immune surveillance. In the event that circulating antibodies fail to prevent virus spread to the tissues in a secondary infection, these memory cells provide an essential defense against tissue reinfection. CNS tissues are isolated from circulating immune cells and antibodies by the blood–brain barrier, making the presence of tissue-resident immune memory cells particularly needed to combat recurrent infection by neurotropic viruses. Wild-type and laboratory-engineered rabies viruses are neurotropic, differ in pathogenicity, and have varying effects on BBB functions. These viruses have proven invaluable tools in demonstrating the importance of tissue-resident immune memory cells in the reinfection of CNS tissues. Only Type 1 immune memory is effective at therapeutically clearing a secondary infection with wild-type rabies viruses from the CNS and does so despite the maintenance of blood–brain barrier integrity.

scholarly journals Novel Role of MCP-Induced Protein 1 in Ischemic Brain Damage in Animals of Transient Focal Ischemia

2018 ◽  
Author(s):  
Zhuqing Jin ◽  
Jian Liang ◽  
Jiaqi Li ◽  
Pappachan E. Kolattukudy
Keyword(s):  
Cerebral Ischemia ◽  
Matrix Metalloproteinases ◽  
Tight Junction ◽  
Western Blot ◽  
Blood Brain Barrier ◽  
Wild Type Mouse ◽  
Brain Barrier ◽  
Wild Type ◽  
Blood Brain

Focal cerebral ischemia can lead to blood-brain barrier (BBB) breakdown, which is implicated in neuroinflammation and elevation of matrix metalloproteinases (MMPs). The role of the anti-inflammatory protein, monocyte chemotactic protein–induced protein 1 (MCPIP1) plays in the injury of BBB in stroke has not yet been reported. This study was conducted to identify and characterize the role MCPIP1 plays in BBB breakdown. Transient middle cerebral artery occlusion (MCAO) is induced in both wild-type and Mcpip1-/- mice for 2 hours of occlusion periods followed by reperfusion for 24 or 48 hours. BBB permeability was measured by FITC-dextran extravasation, MMP-9/3 expression was analyzed by western blot, and claudin-5 and zonula occludens-1 (ZO-1) were analyzed by immunohistochemistry and western blot. After MCAO in wild type mouse is induced, there is significantly increase in MCPIP1 mRNA and protein levels. Absence of MCPIP1 leaded to significant increase in FITC-dextran leakage in peri-infarct brain, significant upregulation of MMP-9, MMP-3 and reduced levels of tight junction components, claudin-5 and ZO-1 in the brain after MCAO. Our data demonstrate that absence of MCPIP1 exacerbates ischemia-induced blood-brain barrier disruption by enhancing the expression of matrix metalloproteinases and degradation of tight junction proteins. Overall data indicate that MCPIP1 is important protective role against BBB disruption in cerebral ischemia.

scholarly journals Human CCR5high effector memory cells perform CNS parenchymal immune surveillance via GZMK-mediated transendothelial diapedesis

Brain ◽  
2019 ◽  
Vol 142 (11) ◽  
pp. 3411-3427 ◽  
Author(s):  
Sebastian Herich ◽  
Tilman Schneider-Hohendorf ◽  
Astrid Rohlmann ◽  
Maryam Khaleghi Ghadiri ◽  
Andreas Schulte-Mecklenbeck ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Blood Brain Barrier ◽  
Immune Cell ◽  
Immune Surveillance ◽  
Brain Barrier ◽  
Effector Memory ◽  
Cell Populations ◽  
Memory Cells ◽  
Hiv Patients ◽  
Effector Memory Cells

Specific immune-cell populations patrol the CNS in search of pathogens and tumours. Herich et al. identify CD4+ CCR5high GzmK+ effector-memory cells as a brain-surveilling subpopulation capable of crossing the uninflamed blood-brain barrier, and reveal alterations in this population in HIV+ patients with neurological symptoms and in patients with multiple sclerosis.

scholarly journals Imaging the dynamic recruitment of monocytes to the blood–brain barrier and specific brain regions during Toxoplasma gondii infection

2019 ◽  
Vol 116 (49) ◽  
pp. 24796-24807 ◽  
Author(s):  
Christine A. Schneider ◽  
Dario X. Figueroa Velez ◽  
Ricardo Azevedo ◽  
Evelyn M. Hoover ◽  
Cuong J. Tran ◽  
...  
Keyword(s):  
Toxoplasma Gondii ◽  
Blood Brain Barrier ◽  
Light Sheet ◽  
Brain Regions ◽  
Brain Barrier ◽  
Cell Segmentation ◽  
Cns Infection ◽  
Light Sheet Microscopy ◽  
Blood Brain ◽  
The Brain

Brain infection by the parasite Toxoplasma gondii in mice is thought to generate vulnerability to predation by mechanisms that remain elusive. Monocytes play a key role in host defense and inflammation and are critical for controlling T. gondii. However, the dynamic and regional relationship between brain-infiltrating monocytes and parasites is unknown. We report the mobilization of inflammatory (CCR2+Ly6Chi) and patrolling (CX3CR1+Ly6Clo) monocytes into the blood and brain during T. gondii infection of C57BL/6J and CCR2RFP/+CX3CR1GFP/+ mice. Longitudinal analysis of mice using 2-photon intravital imaging of the brain through cranial windows revealed that CCR2-RFP monocytes were recruited to the blood–brain barrier (BBB) within 2 wk of T. gondii infection, exhibited distinct rolling and crawling behavior, and accumulated within the vessel lumen before entering the parenchyma. Optical clearing of intact T. gondii-infected brains using iDISCO+ and light-sheet microscopy enabled global 3D detection of monocytes. Clusters of T. gondii and individual monocytes across the brain were identified using an automated cell segmentation pipeline, and monocytes were found to be significantly correlated with sites of T. gondii clusters. Computational alignment of brains to the Allen annotated reference atlas [E. S. Lein et al., Nature 445:168–176 (2007)] indicated a consistent pattern of monocyte infiltration during T. gondii infection to the olfactory tubercle, in contrast to LPS treatment of mice, which resulted in a diffuse distribution of monocytes across multiple brain regions. These data provide insights into the dynamics of monocyte recruitment to the BBB and the highly regionalized localization of monocytes in the brain during T. gondii CNS infection.

scholarly journals Elevated levels of homocysteine compromise blood-brain barrier integrity in mice

Blood ◽  
2006 ◽  
Vol 107 (2) ◽  
pp. 591-593 ◽  
Author(s):  
Atul F. Kamath ◽  
Anil K. Chauhan ◽  
Janka Kisucka ◽  
Vandana S. Dole ◽  
Joseph Loscalzo ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Brain Barrier ◽  
Blue Dye ◽  
Wild Type ◽  
Rolling Velocity ◽  
Cystathionine Beta Synthase ◽  
Blood Brain ◽  
Increased Risk ◽  
Microscopy Analysis ◽  
Blood Brain Barrier Integrity

Abstract Elevated levels of plasma homocysteine (Hcy) correlate with increased risk of cardiovascular and Alzheimer diseases. We studied the effect of elevated Hcy on the blood-brain barrier (BBB) to explore the possibility of a vascular link between the 2 diseases. On a hyperhomocysteinemic diet, cystathionine beta-synthase (Cbs)–heterozygous mice develop hyperhomocysteinemia. Intravital microscopy analysis of the mesenteric venules showed that leukocyte rolling velocity was markedly decreased and numbers of adherent cells were increased in the mutant mice. This was due at least in part to increased expression of P-selectin. BBB permeability was measured by Evans blue dye permeation and was found to be 25% greater in the Cbs+/– cortex compared with wild-type controls. Our study suggests an important toxic effect of elevated Hcy on brain microvessels and implicates Hcy in the disruption of the BBB.

scholarly journals Systemic Immune Deficiency Necessary for Cytomegalovirus Invasion of the Mature Brain

2004 ◽  
Vol 78 (3) ◽  
pp. 1473-1487 ◽  
Author(s):  
Jon D. Reuter ◽  
Daniel L. Gomez ◽  
Jean H. Wilson ◽  
Anthony N. van den Pol
Keyword(s):  
Blood Brain Barrier ◽  
Mononuclear Cells ◽  
Regional Distribution ◽  
Brain Barrier ◽  
Neurological Deficits ◽  
Ependymal Cells ◽  
Cns Infection ◽  
Immunodeficient Mice ◽  
Blood Brain ◽  
The Brain

ABSTRACT Cytomegalovirus (CMV) is a significant opportunistic pathogen associated with AIDS and immunosuppressive therapy. Infection of the mature central nervous system (CNS) can cause significant pathology with associated neurological deficits, mental disorders, and cognitive impairment and may have potentially fatal consequences. Using genetically immunocompromised mice, we studied mechanisms of CMV invasion into, and behavior within, the CNS. Adult immunodeficient (nude and SCID) and control mice were peripherally infected with recombinant mouse CMV expressing a green fluorescent protein reporter gene. Control mice actively eliminated acute peripheral infection and were resistant to invasion of CMV into the brain. In contrast, virus infected brains of immunodeficient mice but only after a minimum of 21 days postinoculation. After inoculation, CMV was found in circulating leukocytes (MAC-3/CD45+) and in leukocytes within the brain, suggesting these cells as a possible source of CMV entry into the CNS. CNS infection was observed in many different cell types, including neurons, glial cells, meninges, ependymal cells, and cells of cerebral vessels. Infection foci progressively expanded locally to adjacent cells, resulting in meningitis, choroiditis, encephalitis, vasculitis, and necrosis; clear indication of axonal transport of CMV was not found. Regional distribution of CMV was unique in each brain, consisting of randomly distributed, unilateral foci. Testing whether CMV gained access to brain through nonspecific vascular disruption, vascular injections of a tracer molecule revealed no obvious disruption of the blood brain barrier in mice with CMV in the brain. Results indicate the importance of host adaptive immunity (particularly T cells) in controlling entry and dissemination of CMV into the brain and are consistent with the view that virus may be carried into the brain by circulating mononuclear cells that traffic through the blood brain barrier.

scholarly journals Brain endothelial tricellular junctions as novel sites for T cell diapedesis across the blood–brain barrier

2021 ◽  
Vol 134 (8) ◽  
Author(s):  
Mariana Castro Dias ◽  
Adolfo Odriozola Quesada ◽  
Sasha Soldati ◽  
Fabio Bösch ◽  
Isabelle Gruber ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Blood Brain Barrier ◽  
Immune Surveillance ◽  
Brain Barrier ◽  
Activated T Cells ◽  
Blood Brain ◽  
Primary Mouse ◽  
Underlying Mechanisms

ABSTRACT The migration of activated T cells across the blood–brain barrier (BBB) is a critical step in central nervous system (CNS) immune surveillance and inflammation. Whereas T cell diapedesis across the intact BBB seems to occur preferentially through the BBB cellular junctions, impaired BBB integrity during neuroinflammation is accompanied by increased transcellular T cell diapedesis. The underlying mechanisms directing T cells to paracellular versus transcellular sites of diapedesis across the BBB remain to be explored. By combining in vitro live-cell imaging of T cell migration across primary mouse brain microvascular endothelial cells (pMBMECs) under physiological flow with serial block-face scanning electron microscopy (SBF-SEM), we have identified BBB tricellular junctions as novel sites for T cell diapedesis across the BBB. Downregulated expression of tricellular junctional proteins or protein-based targeting of their interactions in pMBMEC monolayers correlated with enhanced transcellular T cell diapedesis, and abluminal presence of chemokines increased T cell diapedesis through tricellular junctions. Our observations assign an entirely novel role to BBB tricellular junctions in regulating T cell entry into the CNS. This article has an associated First Person interview with the first author of the paper.

Immune surveillance of the normal human CNS takes place in dependence of the locoregional blood-brain barrier configuration and is mainly performed by CD3+/CD8+ lymphocytes

2010 ◽  
Vol 31 (3) ◽  
pp. 230-238 ◽  
Author(s):  
Christian Loeffler ◽  
Klaus Dietz ◽  
Ariane Schleich ◽  
Holger Schlaszus ◽  
Manuel Stoll ◽  
...  
Keyword(s):  
Blood Brain Barrier ◽  
Immune Surveillance ◽  
Brain Barrier ◽  
Blood Brain ◽  
Normal Human

scholarly journals Efficacy of prophylactic flavan-3-ol in permanent focal ischemia in 12-mo-old mice

2015 ◽  
Vol 308 (6) ◽  
pp. H583-H591 ◽  
Author(s):  
Christopher C. Leonardo ◽  
Monique Mendes ◽  
Abdullah S. Ahmad ◽  
Sylvain Doré
Keyword(s):  
Blood Brain Barrier ◽  
Calcium Binding ◽  
Brain Barrier ◽  
Protective Mechanism ◽  
Adhesive Tape ◽  
Related Factor ◽  
Wild Type ◽  
Blood Brain ◽  
Old Mice ◽  
Young Mice

The consumption of flavan-3-ol-containing foods, including (−)-epicatechin (EC), has been linked to lower incidence of cardiovascular disease and stroke. We previously demonstrated nuclear transcription factor erythroid 2p45-related factor-2 (Nrf2) -dependent EC efficacy in reducing stroke-induced deficits in 2-mo-old mice; yet stroke is primarily a disease of the elderly. Because neuroinflammation, oxidative stress, and vascular dysfunction are hallmarks of aging, we tested whether Nrf2 mediates EC efficacy in aging mice through modulation of glial responses and blood brain barrier permeability. First, we compared anastomosis in naïve wild-type and C57BL/6 Nrf2−/− mice to identify potential differences in cerebrovascular architecture. Data showed no significant differences in the number of anastomoses or mean intersection points, indicating similar gross vascular physiology. To assess efficacy and mechanisms of protection, wild-type or Nrf2−/− mice were administered the minimum effective EC dose established in our previous studies before the permanent distal middle cerebral artery occlusion. Similar to previous results with young mice, 12-mo-old wild types also showed significant reductions in infarct volume (41.01 ± 29.57%) and improved performance in removing adhesive tape relative to vehicle-treated controls, whereas a trend toward protection was observed in Nrf2−/−. However, EC did not reduce immunoreactivity for the microglia/macrophage marker anti-ionized calcium-binding adapter molecule 1, suggesting that dampened activation/recruitment did not account for EC protection. Furthermore, there were no differences in mouse IgG extravasation or spontaneous hemorrhage between EC-treated groups. These data demonstrate that EC protection occurs independent of microglia/macrophage modulation or blood brain barrier preservation, suggesting that the glial cell responses in young mice are compensatory to another, and potentially novel, protective mechanism.

scholarly journals Polymorphisms of the drug transporter gene ABCB1 predict side effects of treatment with cabergoline in patients with PRL adenomas

2012 ◽  
Vol 167 (3) ◽  
pp. 327-335 ◽  
Author(s):  
A P Athanasoulia ◽  
C Sievers ◽  
M Ising ◽  
A C Brockhaus ◽  
A Yassouridis ◽  
...  
Keyword(s):  
Side Effects ◽  
Mouse Model ◽  
Blood Brain Barrier ◽  
Human Study ◽  
Brain Barrier ◽  
Wild Type ◽  
Max Planck ◽  
Blood Brain ◽  
Experimental Mouse Model ◽  
Experimental Mouse

IntroductionTreatment with dopamine agonists in patients with prolactin (PRL) adenomas and Parkinson's disease is associated with central side effects. Central side effects may depend on a substance's ability to pass the blood–brain barrier, which can be actively controlled by transporter molecules such as the P-glycoprotein (P-gp) encoded by theABCB1gene.Materials and methodsWe aimed to determine whether cabergoline is transported by the P-gp and whether polymorphisms of its encodingABCB1gene predict central side effects of cabergoline therapy in patients with PRL adenomas. i) In an experimental mouse model lacking the homologues of the humanABCB1gene (Abcb1abdouble knockout mouse model), we examined whether cabergoline is a substrate of the P-gp using eight mutant and eight wild-type mice. ii) In a human case–control study including 79 patients with PRL adenomas treated with cabergoline at the Max Planck Institute of Psychiatry in Munich, we investigated the association of four selectedABCB1gene single nucleotide polymorphisms (SNPs) (rs1045642, rs2032582, rs2032583 and rs2235015), with the occurrence of central side effects under cabergoline therapy.Resultsi) In the experimental mouse model, we observed that brain concentrations of cabergoline were tenfold higher in the mutant mice compared with their wild-type littermates, implying that cabergoline is indeed a substrate of the transporter P-gp at the blood–brain barrier level. ii) In the human study, we observed significant negative associations under cabergoline for the C-carriers and heterozygous CT individuals of SNP rs1045642 with two central side effects (frequency of fatigue and sleep disorders) and for the G-carriers of SNP rs2032582 with the enhancement of dizziness. For the SNPs rs2235015 and rs2032583, no associations with central side effects under cabergoline were found.DiscussionThis is the first study demonstrating that individualABCB1gene polymorphisms, reflecting a different expression and function of the P-gp, could predict the occurrence of central side effects under cabergoline. Our findings can be viewed as a step into personalised therapy in PRL adenoma patients.

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