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

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.

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Vascular pathology in multiple sclerosis: reframing pathogenesis around the blood-brain barrier

Journal of Neurology Neurosurgery & Psychiatry ◽

10.1136/jnnp-2017-316011 ◽

2017 ◽

Vol 89 (1) ◽

pp. 42-52 ◽

Cited By ~ 52

Author(s):

Jonathan I Spencer ◽

Jack S Bell ◽

Gabriele C DeLuca

Keyword(s):

Multiple Sclerosis ◽

Immune Response ◽

Blood Brain Barrier ◽

Immune Cell ◽

Neurological Diseases ◽

Specific Immune Response ◽

Brain Barrier ◽

Vascular Pathology ◽

Current Evidence ◽

Blood Brain

Blood-brain barrier (BBB) disruption has long been recognised as an important early feature of multiple sclerosis (MS) pathology. Traditionally, this has been seen as a by-product of the myelin-specific immune response. Here, we consider whether vascular changes instead play a central role in disease pathogenesis, rather than representing a secondary effect of neuroinflammation or neurodegeneration. Importantly, this is not necessarily mutually exclusive from current hypotheses. Vascular pathology in a genetically predisposed individual, influenced by environmental factors such as pathogens, hypovitaminosis D and smoking, may be a critical initiator of a series of events including hypoxia, protein deposition and immune cell egress that allows the development of a CNS-specific immune response and the classical pathological and clinical hallmarks of disease. We review the changes that occur in BBB function and cerebral perfusion in patients with MS and highlight genetic and environmental risk factors that, in addition to modulating immune function, may also converge to act on the vasculature. Further context is provided by contrasting these changes with other neurological diseases in which there is also BBB malfunction, and highlighting current disease-modifying therapies that may also have an effect on the BBB. Indeed, in reframing current evidence in this model, the vasculature could become an important therapeutic target in MS.

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Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing–remitting multiple sclerosis compared to healthy controls

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2006.09.008 ◽

2007 ◽

Vol 183 (1-2) ◽

pp. 168-174 ◽

Cited By ~ 31

Author(s):

K.F. Haegele ◽

C.A. Stueckle ◽

J.-P. Malin ◽

E. Sindern

Keyword(s):

Multiple Sclerosis ◽

Peripheral Blood ◽

Effector Memory ◽

Healthy Controls ◽

Memory Cells ◽

Relapsing Remitting ◽

Effector Memory Cells ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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

Future Virology ◽

10.2217/fvl-2020-0132 ◽

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.

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Neurofilament levels are associated with blood–brain barrier integrity, lymphocyte extravasation, and risk factors following the first demyelinating event in multiple sclerosis

Multiple Sclerosis Journal ◽

10.1177/1352458520912379 ◽

2020 ◽

pp. 135245852091237 ◽

Cited By ~ 4

Author(s):

Tomas Uher ◽

Mason McComb ◽

Shery Galkin ◽

Barbora Srpova ◽

Johanna Oechtering ◽

...

Keyword(s):

Risk Factors ◽

Multiple Sclerosis ◽

Blood Brain Barrier ◽

Immune Cell ◽

Disease Onset ◽

Cell Subset ◽

Immunoglobulin M ◽

Brain Barrier ◽

Cns Inflammation ◽

Blood Brain

Background: Increased blood brain barrier (BBB) permeability, CNS inflammation and neuroaxonal damage are pathological hallmarks in early multiple sclerosis (MS). Objective: To investigate the associations of neurofilament light chain (NfL) levels with measures of BBB integrity and central nervous system (CNS) inflammation in MS during the first demyelinating event. Methods: Blood and cerebrospinal fluid (CSF) were obtained from 142 MS (McDonald 2017) treatment-naive patients from the SET study (63% female; age: 29.7 ± 7.9 years) following the disease onset. NfL, albumin, immunoglobulin G (IgG), and immunoglobulin M (IgM) levels were measured in CSF and blood samples. Albumin quotient was computed as a marker of BBB integrity. Immune cell subset counts in CSF were measured using flow cytometry. MS risk factors, such as Human leukocyte antigen DRB1 locus gene ( HLA DRB1)*1501, anti-Epstein–Barr virus (EBV) antibodies, and 25-hydroxy vitamin D3, were also measured. Results: Higher serum NfL (sNfL) levels were associated with higher albumin quotient ( p < 0.001), CSF CD80+ ( p = 0.012), and CD80+ CD19+ ( p = 0.015) cell frequency. sNfL levels were also associated with contrast-enhancing and T2 lesions on brain magnetic resonance imaging (MRI; all p ⩽ 0.001). Albumin quotient was not associated with any of the MS risk factors assessed. sNfL levels were associated with anti-EBV viral capsid antigen (VCA) IgG levels ( p = 0.0026). Conclusion: sNfL levels during the first demyelinating event of MS are associated with greater impairment of BBB integrity, immune cell extravasation, and brain lesion activity on MRI.

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The liver and muscle secreted Hfe2-protein maintains blood brain barrier integrity

10.21203/rs.3.rs-1028867/v1 ◽

2021 ◽

Author(s):

Xue Fan Wang ◽

Robin Vigouroux ◽

Yuriy Baglaenko ◽

Angeliki Nikolakopoulou ◽

Dene Ringuette ◽

...

Keyword(s):

Multiple Sclerosis ◽

Blood Brain Barrier ◽

Immune Cell ◽

Three Dimensional ◽

Light Sheet ◽

Brain Barrier ◽

Behavioral Deficits ◽

Central Nervous System Damage ◽

Blood Brain ◽

Blood Brain Barrier Integrity

Abstract Liver failure causes blood-brain-barrier (BBB) breakdown leading to central nervous system damage, however the mechanisms whereby the liver influences BBB-integrity remain elusive. One possibility is that the liver secretes an as-yet to be identified molecule(s) that circulate in the serum to directly promote BBB integrity. We developed light-sheet imaging for three-dimensional study of BBB function. We show that liver- or muscle-specific knockout of Hfe2 induces BBB breakdown, leading to accumulation of toxic-blood-derived fibrinogen in the brain, lower cortical neuron numbers, and behavioral deficits. In healthy animals, soluble Hfe2 competes with its homologue RGMa for binding to Neogenin, thereby blocking RGMa-induced downregulation of PDGF-B and Claudin-5 in endothelial cells and the ensuing BBB disruption. Hfe2 administration in an animal model of multiple sclerosis prevented paralysis and immune cell infiltration by inhibiting RGMa-mediated BBB alteration. This study has implications for the pathogenesis and potential treatment of diseases associated with BBB dysfunction such as multiple sclerosis.

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Contribution of Tissue Inflammation and Blood-Brain Barrier Disruption to Brain Softening in a Mouse Model of Multiple Sclerosis

Frontiers in Neuroscience ◽

10.3389/fnins.2021.701308 ◽

2021 ◽

Vol 15 ◽

Author(s):

Rafaela Vieira Silva ◽

Anna S. Morr ◽

Susanne Mueller ◽

Stefan Paul Koch ◽

Philipp Boehm-Sturm ◽

...

Keyword(s):

Multiple Sclerosis ◽

Blood Brain Barrier ◽

Immune Cell ◽

Brain Barrier ◽

Brain Atlas ◽

Similar Degree ◽

Iron Oxide Particles ◽

Whole Brain ◽

Blood Brain ◽

Inflammatory Processes

Neuroinflammatory processes occurring during multiple sclerosis cause disseminated softening of brain tissue, as quantified by in vivo magnetic resonance elastography (MRE). However, inflammation-mediated tissue alterations underlying the mechanical integrity of the brain remain unclear. We previously showed that blood-brain barrier (BBB) disruption visualized by MRI using gadolinium-based contrast agent (GBCA) does not correlate with tissue softening in active experimental autoimmune encephalomyelitis (EAE). However, it is unknown how confined BBB changes and other inflammatory processes may determine local elasticity changes. Therefore, we aim to elucidate which inflammatory hallmarks are determinant for local viscoelastic changes observed in EAE brains. Hence, novel multifrequency MRE was applied in combination with GBCA-based MRI or very small superparamagnetic iron oxide particles (VSOPs) in female SJL mice with induced adoptive transfer EAE (n = 21). VSOPs were doped with europium (Eu-VSOPs) to facilitate the post-mortem analysis. Accumulation of Eu-VSOPs, which was previously demonstrated to be sensitive to immune cell infiltration and ECM remodeling, was also found to be independent of GBCA enhancement. Following registration to a reference brain atlas, viscoelastic properties of the whole brain and areas visualized by either Gd or VSOP were quantified. MRE revealed marked disseminated softening across the whole brain in mice with established EAE (baseline: 3.1 ± 0.1 m/s vs. EAE: 2.9 ± 0.2 m/s, p < 0.0001). A similar degree of softening was observed in sites of GBCA enhancement i.e., mainly within cerebral cortex and brain stem (baseline: 3.3 ± 0.4 m/s vs. EAE: 3.0 ± 0.5 m/s, p = 0.018). However, locations in which only Eu-VSOP accumulated, mainly in fiber tracts (baseline: 3.0 ± 0.4 m/s vs. EAE: 2.6 ± 0.5 m/s, p = 0.023), softening was more pronounced when compared to non-hypointense areas (percent change of stiffness for Eu-VSOP accumulation: −16.81 ± 16.49% vs. for non-hypointense regions: −5.85 ± 3.81%, p = 0.048). Our findings suggest that multifrequency MRE is sensitive to differentiate between local inflammatory processes with a strong immune cell infiltrate that lead to VSOP accumulation, from disseminated inflammation and BBB leakage visualized by GBCA. These pathological events visualized by Eu-VSOP MRI and MRE may include gliosis, macrophage infiltration, alterations of endothelial matrix components, and/or extracellular matrix remodeling. MRE may therefore represent a promising imaging tool for non-invasive clinical assessment of different pathological aspects of neuroinflammation.

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