Glia Cells In Multiple Sclerosis

  1. Contrasting potential of Nitric Oxide and Peroxynitrite to mediate Oligodendrocyte injury in Multiple Sclerosis
    Glia 2007 Jul;55(9):926-34

  1. NeuroGenesis in the chronic lesions of Multiple Sclerosis
    Brain 2008 Sep;131(Pt 9):2366-75

  2. Microglia instruct SubVentricular Zone NeuroGenesis
    Glia 2006 Dec;54(8):815-25

  3. Multiple Sclerosis and Alzheimer's Disease
    Ann Neurol 2008 Feb;63(2):174-83

  4. Elevated activity and Microglial expression of MyelopPerOxidase in DeMyelinated Cerebral Cortex in Multiple Sclerosis
    Brain Pathol 2008 Jan;18(1):86-95

  5. Elevated MyeloPerOxidase activity in White Matter in Multiple Sclerosis
    Neurosci Lett 2008 Aug 15

  6. Lesion genesis in a subset of patients with Multiple Sclerosis: a role for Innate Immunity?
    Brain 2007 Nov;130(Pt 11):2800-15

  7. Microglia: gatekeepers of Central Nervous System Immunology
    J Leukoc Biol 2009 Mar;85(3):352-70

  8. Microglia and Central Nervous System Immunity
    NeuroSurg Clin N Am 2010 Jan;21(1):43-51


NeuroGenesis In The Chronic Lesions Of Multiple Sclerosis

Chang A, Smith MC, Yin X, Fox RJ, Staugaitis SM, Trapp BD
Brain 2008 Sep;131(Pt 9):2366-75
Lerner Research Institute, Cleveland Clinic, Department of NeuroSciences, Cleveland, OH 44195, USA
PMID# 18669500

SubCortical White Matter in the adult human Brain contains a population of InterNeurons that helps regulate Cerebral blood flow. We investigated the fate of these Neurons following SubCortical White Matter DeMyelination.

ImmunoHistoChemistry was used to examine Neurons in Normal-Appearing SubCortical White Matter and seven acute and 59 chronic DeMyelinated lesions in Brains from nine patients with Multiple Sclerosis and four controls.

Seven acute and 44 of 59 chronic Multiple Sclerosis lesions had marked Neuronal Loss.

Compared to surrounding Normal-Appearing White Matter, the remaining 15 chronic Multiple Sclerosis lesions contained a 72% increase in mature InterNeuron density, increased Synaptic densities and cells with phenotypic characteristics of immature Neurons.

Lesion areas with increased Neuron densities contained a morphologically distinct population of activated Microglia.

SubVentricular Zones contiguous with DeMyelinated lesions also contained an increase in cells with phenotypes of Neuronal Precursors.

These results support NeuroGenesis in a subpopulation of DeMyelinated SubCortical White Matter lesions in Multiple Sclerosis Brains.


Microglia Instruct SubVentricular Zone NeuroGenesis

Walton NM, Sutter BM, Laywell ED, Levkoff LH, Kearns SM, Marshall GP 2nd, Scheffler B, Steindler DA
Glia 2006 Dec;54(8):815-25
University of Florida, Department of NeuroScience, McKnight Brain Institute, Gainesville, FL 32610, USA
PMID# 16977605

Microglia are increasingly implicated as a source of Non-Neural regulation of postnatal NeuroGenesis and Neuronal development.

To evaluate better the contributions of Microglia to Neural Stem Cells (NSCs) of the SubVentricular NeurAxis, we employed an adherent culture system that models the continuing proliferation and differentiation of the dissociated NeuroPoietic SubVentricular tissues.

In this model, NeuroPoietic Cells retain the ability to self-renew and form multipotent Neurospheres, but progressively lose the ability to generate committed Neuroblasts with continued culture.

NeuroGenesis in highly expanded NSCs can be rescued by coculture with Microglial Cells Or Microglia-conditioned medium.

Indicating that Microglia provide secreted factor(s) essential for NeuroGenesis, but not NSC maintenance, self-renewal, or propagation.

Our findings suggest an instructive role for Microglial Cells in contributing to postnatal NeuroGenesis in the largest Neurogenic niche of the mammalian Brain.

(c) 2006 Wiley-Liss, Inc.


Multiple Sclerosis And Alzheimer's Disease

Dal Bianco A, Bradl M, Frischer J, Kutzelnigg A, Jellinger K, Lassmann H
Ann Neurol 2008 Feb;63(2):174-83
Medical University of Vienna, Center for Brain Research, Austria
PMID# 17924575

Chronic inflammation with Microglia activation is thought to play a major role in the formation or clearance of Alzheimer's Disease (AD) lesions, as well as in the induction of DeMyelination in Multiple Sclerosis (MS).

In MS, the cortex is severely affected by chronic, long-lasting inflammation, Microglia activation, and DeMyelination. To what extent chronic inflammation in the Cortex of MS patients influences the development of AD lesions is so far unresolved.

The study was performed on autopsy tissue of 45 MS cases, 9 AD cases, and 15 control subjects. We analyzed Lymphocyte and Plasma Cell infiltration in relation to Microglia activation, to the presence of beta-Amyloid plaques and (AT8+) NeuroFibrillary tangles, and to Myelin pathology.

Profound Microglia activation, determined by a broad spectrum of markers, was found in both MS and AD Cortices, and the patterns of Microglia activation were closely similar.

Microglia activation in MS Cortex, in contrast with that in AD and control cortex, correlated with Lymphocyte and Plasma-Cell infiltrates in the Meninges.

MS cases older than 64 years experienced development of AD pathology in comparable incidence as seen in the course of normal aging.

The density of beta-Amyloid plaques and NeuroFibrillary tangles did not differ between DMyelinated and NonDeMyelinated Cortical areas.

Our data suggest that Microglia activation in the MS Cortex alone has little or no influence on the development of Cortical AD pathology.


Elevated Activity And Microglial Expression Of MyelopPerOxidase In DeMyelinated Cerebral Cortex In Multiple Sclerosis

Gray E, Thomas TL, Betmouni S, Scolding N, Love S
Brain Pathol 2008 Jan;18(1):86-95
University of Bristol Institute of Clinical NeuroScience, Glial Cell Biology Laboratories, Frenchay Hospital, Bristol, UK
PMID# 18042261

Recent studies have revealed extensive Cortical DeMyelination in patients with Progressive Multiple Sclerosis (MS).

DeMyelination in Gray Matter lesions is associated with activation of Microglia. Macrophages and Microglia are known to express MyeloPerOxidase (MPO) and generate Reactive Oxygen Species during Myelin Phagocytosis in the White Matter.

In the present study we examined the extent of Microglial activation in the Cerebral Cortex and the relationship of Microglial activation and MPO activity to Cortical DeMyelination.

Twenty-one cases of NeuropPathologically confirmed Multiple Sclerosis, with 34 Cortical lesions, were used to assess Microglial activation.

HLA-DR immunolabeling of activated Microglia was significantly higher in DeMyelinated MS Cortex than control Cortex and, within the MS cohort, was significantly greater within Cortical Lesions than in matched Non-DeMyelinated areas of Cortex.

In homogenates of MS Cortex, Cortical DeMyelination was associated with significantly elevated MPO activity.

ImmunoHistoChemistry revealed MPO in CD68+ Microglia within Cortical plaques, particularly toward the edge of the plaques, but not in Microglia in adjacent Non-DeMyelinated Cortex.

Cortical DeMyelination in MS is associated with increased activity of MPO, which is expressed by a CD68+ subset of activated Microglia, suggesting that Microglial production of Reactive Oxygen Species is likely to be involved in Cortical DeMyelination.


Elevated MyeloPerOxidase Activity In White Matter In Multiple Sclerosis

Gray E, Thomas TL, Betmouni S, Scolding N, Love S
Neurosci Lett 2008 Aug 15
University of Bristol Institute of Clinical NeuroSciences, MS Laboratories, Burden Centre, Frenchay Hospital, Bristol BS16 1JB, United Kingdom
PMID# 18723077

Recent studies have revealed extensive Axonal Damage in patients with Progressive Multiple Sclerosis (MS).

Axonal Damage can be caused by a plethora of factors including the release of ProteoLytic Enzymes and CytoToxic Oxidants by activated Immune Cells and Glia within the lesion.

Macrophages and Microglia are known to express MyeloPerOxidase (MPO) and generate Reactive Oxygen Species during Myelin Phagocytosis in the White Matter.

In the present study we have measured MPO levels in post-mortem homogenates of DeMyelinated and Non-DeMyelinated regions of White Matter from nine patients with MS and seven controls, and assessed MPO ImmunoReactivity within MS Brain.

In homogenates of MS White Matter, DeMyelination was associated with significantly elevated MPO activity when compared to controls.

ImmunoHistoChemistry showed MPO to be expressed mainly by Macrophages within and adjacent to plaques.

DeMyelination in MS is associated with increased activity of MPO, suggesting that this production of Reactive Oxygen Species may contribute to Axonal injury within plaques.


Lesion Genesis In A Subset Of Patients With Multiple Sclerosis: A Role For Innate Immunity?

Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ
Brain 2007 Nov;130(Pt 11):2800-15
Medical University of Vienna, Centre for Brain Research, Austria
PMID# 17956913

Lesions obtained early in the course of Multiple Sclerosis (MS) have been studied ImmunoCytoChemically, and compared with the early stages of the experimental lesion induced in rats by the IntraSpinal injection of Lipopolysaccharide.

Large Hemispheric or double Hemispheric sections were examined from patients who had died in the course of acute or early Relapsing Multiple Sclerosis.

In MS patients exhibiting Hypoxia-like lesions [Pattern III; Lucchinetti et al. Ann Neurol (2000) 47: 707-17], focal areas in the White Matter showed mild Edema, Microglial activation and mild Axonal injury in the absence of overt DeMyelination.

In such lesions T-Cell infiltration was mild and restricted to the PeriVascular Space.

Myeloperoxidase and the inducible form of Nitric Oxide Synthase were expressed primarily by Microglia, and the activated form of these cells was associated with ExtraCellular deposition of precipitated Fibrin.

In addition, these lesions showed up-regulation of proteins involved in tissue preconditioning. When active DeMyelination started, lesions were associated with massive T-Cell infiltration and Microglia and Macrophages expressed all activation markers studied.

Similar tissue alterations were found in rats in the Pre-DeMyelinating stage of lesions induced by the focal injection of bacterial Lipopolysaccharide into the Spinal White Matter.

We suggest that the areas of Microglial activation represent an early stage of tissue injury, which precedes the formation of Hypoxia-like DeMyelinated Plaques.

The findings indicate that mechanisms associated with Innate Immunity may play a role in the formation of Hypoxia-like DeMyelinating lesions in MS.


Microglia: Gatekeepers Of Central Nervous System Immunology

Tambuyzer BR, Ponsaerts P, Nouwen EJ
J Leukoc Biol 2009 Mar;85(3):352-70
University of Antwerp, Laboratory of NeuroBiology and NeuroPharmacology, Department of BioMedical Sciences, and Vaccine and Infectious Disease Institute, Universiteitsplein 1, Wilrijk, Belgium
PMID# 19028958

Microglia are perhaps the most underestimated cell type of our Immune System. Not only were Immunologists unaware of their capabilities until recently, but also, some NeuroScientists denied their actual existence until the late 20th century.

Nowadays, their presence is confirmed extensively, as demonstrated by numerous reports describing their involvement in virtually all NeuroPathologies.

However, despite distinct approaches, their origin remains a point of controversy.

Although many agree about their Myeloid-Monocytic ancestry, the precise Progenitor Cells and the differentiation mechanisms, which give rise to Microglia in the different developmental stages of the CNS, are not unraveled yet.

Mostly, this can be attributed to their versatile phenotype. Indeed, Microglia show a high Morphological Plasticity, which is related to their functional state.

This review about Microglia aims to introduce the reader extensively into their Ontogeny, Cell Biology, and involvement in different MeuroPathologies.


Microglia And Central Nervous System Immunity

Kaur G, Han SJ, Yang I, Crane C
NeuroSurg Clin N Am 2010 Jan;21(1):43-51
University of California at San Francisco, Department of Neurological Surgery, 505 Parnassus Avenue, One Shrader Street, Suite 650, San Francisco, CA 94117, USA
PMID# 19944965

The Central Nervous System (CNS) has evolved as an Immune-privileged site to protect its vital functions from damaging Immune-mediated inflammation.

There must be a CNS-adapted system of surveillance that continuously evaluates local changes in the Nervous System and communicates to the Peripheral Immune System during an injury or a disease.

Recent advances leading to a better understanding of the CNS disease processes has placed Microglia, the CNS-based resident Macrophages, at center stage in this system of active surveillance.

Evidence points to Microglia Cells contributing to the ImmunoSuppressive environment of Gliomas and actually promoting Tumor growth.

Microglia accumulation exists in almost every CNS disease process, including CNS Tumors. This article discusses the role of Microglia in CNS Immunity and highlights key advances made in Glioma Immunology.

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