GFAP Is Necessary For The Integrity Of CNS White Matter Architecture & Long-Term Maintenance Of Myelination
Liedtke W, Edelmann W, Bieri PL, Chiu FC, Cowan NJ, Kucherlapati R, Raine CS
Neuron 1996 Oct;17(4):607-15
Albert Einstein College of Medicine, Division of NeuroPathology, Dept of Pathology, Bronx, New York 10016, USA
To investigate the structural role of Glial Fibrillary Acidic Protein (GFAP) in vivo, mice carrying a null mutation in GFAP were generated.
In 7/14 mutant animals older than 18 months of age, Hydrocephalus associated with White Matter loss was detected.
Mutant mice displayed abnormal Myelination including the presence of actively Myelinating Oligodendrocytes in adults, NonMyelinated Axons in Optic Nerve, and reduced Myelin thickness in Spinal Cord.
White Matter was poorly vascularized and the Blood-Brain Barrier was structurally and functionally impaired.
Astrocytic structure and function were abnormal, consisting of shortened Astrocytic Cell processes, decreased septation of White Matter, and increased CNS ExtraCellular Space.
Thus, GFAP expression is essential for normal White Matter architecture and Blood-Brain Barrier integrity, and its absence leads to late-onset CNS DysMyelination.
Mechanisms Of Immune Injury In
Brosnan CF, Raine CS
Brain Pathol 1996 Jul;6(3):243-57
Albert Einstein College of Medicine, Dept of Pathology, Bronx, NY 10461, USA
In this review, we address current concepts regarding the mechanisms of tissue damage that lead to DeMyelination and Oligodendrocyte loss in Multiple Sclerosis.
Particular emphasis has been placed on examining the MS lesion for evidence for PathoGenetic processes that have been implicated from various in vivo and in vitro model systems.
Central in this analysis has been the evaluation of the various Effector Cell types and their products (Cytokines).
The results strongly support the conclusion that ProInflammatory Cytokines are major mediators of tissue damage, through the activation of inflammatory cells and resident Glial Cells (Microglia).
A role for AntiBody is also discussed, particularly as part of an AntiBody-dependent cell mediated DeMyelinating process.
Minor populations of Lymphocytes may also participate by defining the nature of the Immunological MicroEnvironment.
Multiple Sclerosis: A Protective Or A Pathogenic Role For Heat Shock Protein 60 In
The Central Nervous System?
Raine CS, Wu E, Ivanyi J, Katz D, Brosnan CF
Lab Invest 1996 Jul;75(1):109-23
Albert Einstein College of Medicine, Dept of Pathology, Bronx, New York, USA
The stress proteins belonging to the Heat Shock Protein 60 (hsp6O) family of molecular chaperones with known ImmunoGenic properties are expressed at increased levels in a number of AutoImmune conditions.
Because previous studies from this laboratory suggested that hsp6O may be involved in the PathoGenesis of the chronic Multiple Sclerosis (MS) plaque, we have examined autopsied Central Nervous System tissue from 10 cases of MS, ranging in clinical history from acute to chronic inactive.
MS Lesions ranged from acute, actively DeMyelinating and edematous, to fibrous Astrogliotic and chronically DeMyelinated. As controls, Central Nervous System tissue from other Neurologic Diseases and NonNeurologic conditions was used.
Frozen, paraffin, and epoxy-embedded sections were studied ImmunoCytoChemically with the ML30 mAb to hsp6O.
Acute MS lesions displayed the greatest reactivity, with particularly prominent staining of hypertrophic Astrocytes, reactive Macrophages, and hyperplastic Oligodendrocytes.
In all these cells, elevated expression occurred in the constitutive site for hsp6O (Mitochondria) and within the Cytosol, which is suggestive of a shift in expression.
The hsp6O-reactive Oligodendrocytes were structurally intact. Chronic active MS lesions also revealed the highest levels of hsp6O in HyperTrophic Astrocytes and Oligodendrocytes.
Chronic silent MS lesions displayed elevated hsp6O in HyperTrophic Astrocytes only while constitutive expression occurred elsewhere in the Central Nervous System at levels slightly higher than normal.
Other Neurologic Disease tissue displayed expression elevated above that found in NonNeurologic cases, but this was considerably less than that seen in acute MS.
Of the other Neurologic Diseases, AIDS Encephalitis revealed the greatest activity
for hsp6O, with both Mitochondrial and cytosolic staining of Astrocytes.
It is proposed that the high levels of hsp6O in hyperplastic, structurally intact Oligodendrocytes in acute MS Lesions may bespeak a protective mechanism, whereas hsp6O in chronic active lesions may serve a Pathogenic role in the later depletion of these cells.
Multiple Sclerosis: Immune System Molecule Expression in the Central Nervous System
J Neuropathol Exp Neurol 1994 Jul;53(4):328-37
Albert Einstein College of Medicine, Dept of NeuroPathology, Bronx, NY 10461
The fundamental message emerging from Immunologic and ImmunoPathologic analyzes of the Brain and Spinal Cord in Multiple Sclerosis (MS) is that during inflammation, the Central Nervous System (CNS) is capable of interactions with the Lymphoid System.
Mainly through induced (as opposed to constitutive) expression of Immune System-specific molecules on CNS elements.
CNS Endothelium, Astrocytes and Microglia Cells are the main participants, with Oligodendrocytes and Neurons remaining essentially inert.
There appears to be nothing unique about the manner in which the CNS responds to inflammation or in the molecules expressed.
The ensuing Adhesion Molecules, pro-inflammatory and regulatory Cytokines, HistoCompatibility Molecules, and T and B-Cell markers, are difficult to distinguish from those occurring in Peripheral Lymphoid tissue.
However, differences certainly exist in the outcome of an inflammatory insult in the CNS versus other, peripheral tissues, whereby there is generally a poor reparatory response.
Reasons for the latter appear to lie in the anatomical complexity of the CNS, its vulnerability to damage by soluble mediators, and in the White Matter (the battlefield for the inflammatory attack in MS), the exquisite sensitivity of the Oligodendrocyte and its Myelin to exogenous factors.
With the aid of examples drawn from Experimental Allergic EncephaloMyelitis, the prime animal model for MS, a number of approaches to prevent or downregulate CNS Inflammation during Immune-mediated DeMyelination are presented as possible therapeutic avenues for MS, some of which are already under investigation.