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MS Abstracts 02a-2g1


  1. Viral induced DeMyelination
    Brain Pathol 2001 Jan;11(1):92-106

  2. Decreases in InterLeukin-4 secretion by Invariant CD4-CD8-Valpha24JalphaQ T-Cells in Relapsing/Remitting Multiple Sclerosis peripheral blood
    Clin Immunol 2001 Jan;98(1):11-17

  3. Acute posterior Cord lesions in Multiple Sclerosis: an MRI study of clinical course in 20 cases
    Rev Neurol (Paris) 2000 Dec;156(12):1126-1135

  4. Chemokines and chemokine receptors in inflammation of the Nervous System: manifold roles and exquisite regulation
    Immunol Rev 2000 Oct;177:52-67

  5. InterLeukin-1 in the Brain: biology, pathology and therapeutic target
    Trends NeuroSci 2000 Dec;23(12):618-25

  6. Involvement of the Choroid Plexus in Central Nervous System inflammation
    Microsc Res Tech 2001 Jan 1;52(1):112-129

  7. Post-mortem high-resolution MRI of the Spinal Cord in Multiple Sclerosis: A correlative study with conventional MRI, HistoPathology and clinical phenotype
    Brain 2001 Jan;124(Pt 1):154-166

  8. Multiple Sclerosis with very late onset: a report of a case with onset at age 82 years and review of the literature
    J Spinal Disord 2000 Dec;13(6):545-9





#1

Viral Induced DeMyelination

Stohlman SA, Hinton DR
Brain Pathol 2001 Jan;11(1):92-106
Univ of Southern California, Keck School of Medicine, Dept of Neurology, Los Angeles 90033, USA
PMID# 11145206; UI# 21018210
Abstract

Viral induced DeMyelination, in both humans and rodent models, has provided unique insights into the cell biology of Oligodendroglia, their complex cell-cell interactions and mechanisms of Myelin destruction.

They illustrate mechanisms of Viral persistence, including latent infections in which no infectious Virus is readily evident, Virus reactivation and Viral-induced tissue damage.

These studies have also provided excellent paradigms to study the interactions between the Immune System and the Central Nervous System (CNS).

Although of interest in their own right, an understanding of the diverse mechanisms used by Viruses to induce DeMyelination, may shed light into the etiology and PathoGenesis of the common DeMyelinating disorder Multiple Sclerosis (MS).

This notion is supported by the persistent view that a Viral infection acquired during adolescence might initiate MS after a long period of quiescence.

DeMyelination in both humans and rodents can be initiated by infection with a diverse group of enveloped and non-enveloped RNA and DNA Viruses.

The mechanisms that ultimately result in the loss of CNS Myelin appear to be equally diverse as the etiological agents capable of causing diseases which result in DeMyelination.

Although DeMyelination can be a secondary result of Axonal loss, in many examples of Viral induced DeMyelination, Myelin loss is primary and associated with Axonal sparing. This suggests that DeMyelination induced by Viral infections can result from:

  1. A direct Viral infection of Oligodendroglia resulting in cell death with degeneration of Myelin and its subsequent removal

  2. A persistent Viral infection, in the presence or absence of infectious Virus, resulting in the loss of normal cellular homeostasis and subsequent Oligodendroglial death

  3. A vigorous Virus-specific inflammatory response wherein the Virus replicates in a cell type other than Oligodendroglia, but Cytokines and other Immune mediators directly damage the Oligodendroglia or the Myelin sheath

  4. Infection initiates activation of an Immune response specific for either Oligodendroglia or Myelin components.

Virus-induced inflammation may be associated with the processing of Myelin or Oligodendroglial components and their presentation to the host's own T-Cell compartment.

Alternatively, antigenic Epitopes derived from the Viral proteins may exhibit sufficient homology to host components that the Immune Response to the Virus activates autoreactive T-Cells, i.e. Molecular Mimicry.

Although it is not clear that each of these potential mechanisms participates in the PathoGenesis of human DeMyelinating Disease, analysis of the diverse DeMyelinating Viral infections of both humans and rodents provides examples of many of these potential mechanisms.



#2

Decreases In InterLeukin-4 Secretion By Invariant CD4-CD8-Valpha24JalphaQ T-Cells In Relapsing/Remitting Multiple Sclerosis Peripheral Blood

Gausling R, Trollmo C, Hafler DA
Clin Immunol 2001 Jan;98(1):11-17
Brigham and Women's Hospital, Laboratory of Molecular Immunology, Boston, Massachusetts, 02115
PMID# 11141321
Abstract

The Cytokine profile of invariant CD4-CD8-Valpha24JalphaQ T-Cells from patients with Multiple Sclerosis (MS) was compared with that of healthy controls.

CD4-CD8-Valpha24+ T-Cells from the peripheral blood of 12 patients with Relapsing/Remitting MS (RR-MS), 5 patients with Progressive MS (CP-MS), and 9 control individuals were directly sorted into single wells and expanded in vitro for analysis of IL-4 and IFN-gamma (IFN-gamma) secretion.

315 Valpha24JalphaQ T-Cell clones were generated and their T-Cell Receptor (TCR) sequenced. T-Cell functionality was determined by examining Cytokine secretion upon TCR cross-linking.

RR-MS patients exhibited lower frequencies of IL-4 secreting CD4-CD8-Valpha24JalphaQ T-Cell clones than patients with CP-MS and controls.

No differences in IFN-gamma secretion were observed between the groups. An IL-4 positive Cytokine profile could be correlated to the cloning efficiency of the Valpha24JalphaQ T-Cells.

We conclude that alterations in Cytokine secretion patterns of CD4-CD8-Valpha24JalphaQ T-Cells may influence the Immune System and thus contribute to Relapsing/Remitting MS.

Copyright 2001 Academic Press.



#3

Acute Posterior Cord Lesions In MS: MRI Study Of Clinical Course In 20 Cases

Pou Serradell A, Roquer Gonzalez J, Perich Alsina X
Rev Neurol (Paris) 2000 Dec;156(12):1126-1135
Universitat Autonoma de Barcelona, Service de Neurologie, Hospital Universitari del Mar, Barcelona, Spain
PMID# 11139729
Abstract

Twenty patients with Multiple Sclerosis (MS) were selected among 138 new patients with MS assisted in our Neurological unit over the past five years.

19 women and 1 man, with acute Propioceptive Sensory disturbances related to the presence of plaques on the Posterior Columns (Posterior Column Syndrome) at the Cervical or Thoracic levels of the Spinal Cord.

In 17 of these patients, the acute Posterior Cordonal Syndrome was responsible for the first clinical manifestations of the disease. The other 3 patients had a history suggestive of MS.

These 20 patients were followed with a minute analysis of Neurological function with repeated clinical evaluation combined with repeated MRI study of the Spinal Cord.

Brain MRI (strongly suggestive of MS in 15 patients), Evoked Potentials (EP) and CerebroSpinal Fluid electrophoresis analysis (with OligoClonal Bands present in all patients were it was performed) were also obtained at least once in each paient.

Spinal Cord MRI demonstratd more lesions in the Cervical region (90 p.100) than in the Thoracic regions (10 p.100). Eighty percent of the Cervical lesions were located high, between C1 and C4. The most characteristic clinical expression was the deafferentation of one upper limb.

Preferentially, the "useless hand" (Oppenheim) or even a PseudoAthetosic or Dystonic limb. Propioceptive Ataxia or spontaneous Cervical or Brachial pain were other forms of clinical expression.

No major motor deficit or Sphincter Disorders were noted at any time in the clinical course in any of the patients. There was a good correlation between localization and morphology of the plaques detected by Spinal Cord MRI and clinical signs.

Intrinsic Medullary lesions were seen as high intensity signals on T2-weighted images, which were enlarged more than the same lesion visualized on T1-weighted images, after injection of paramagnetic contrast agents.

This reflected the presence of Edema extending beyond the main inflammatory lesion.

There was also a good correlation between improvement of clinical symptoms and total or, more frequently, partial reduction of the Plaques, analyzed morphologically by successive Spinal Cord MRI series.

The diagnosis of MS was Clinically Definitive in 60 p.100 of cases and Laboratory-Supported Definitive in 40 p.100.

During the follow-up period (average 36 months), 15 patients (75 p.100) presented one or more exacerbations, all of them presenting a favorable course: at last follow-up, 9 patients were asymptomatic, EDSS was 1 in 6 patients, 1.5 in 4 patients and 2 in 1 patient.

This study confirms the contribution of serial Spinal Cord MR studies to understanding the natural history and PathoPhysiology of Medullary forms of MS presenting as a Cordonal Posterior Syndrome.

It also shows a good relationship between the clinical manifestations and course of this form of MS and the localization and variable morphology of plaques.

Finally, our results suggest the predictive Benign course for this Medullary form of MS that seems to be almost exclusively restricted to the female gender.



#4

Chemokines And Receptors In Inflammation Of The Nervous System: Manifold Roles And Exquisite Regulation

Huang D, Han Y, Rani MR, Glabinski A, Trebst C, Sorensen T, Tani M, Wang J, Chien P, O'Bryan S, Bielecki B, Zhou ZL, Majumder S, Ransohoff RM
Immunol Rev 2000 Oct;177:52-67
The Cleveland Clinic Foundation, Dept of Neurology, and The Lerner Research Institute, Cleveland, Ohio 44195, USA
PMID# 11138785; UI# 21019720
Abstract

This article focuses on the production of Chemokines by resident Glial Cells of the Nervous System. We describe studies in two distinct categories of inflammation within the Nervous System.

Immune-mediated inflammation as seen in Experimental AutoImmune EncephaloMyelitis (EAE) or Multiple Sclerosis (MS) and post-traumatic inflammation.

We provide evidence that Chemokines play a role in amplifying the inflammatory reaction in EAE (and, probably, MS). In the context of Neural trauma, Chemokines appear to be primary stimuli for Leukocyte recruitment.

Strikingly, expression of Monocyte ChemoAttractant Protein-1 (MCP-1) and Interferon-gamma-Inducible Protein-10 (IP-10) are largely restricted to Astrocytes or other Glial Cells in these diverse pathological states.

The remainder of the review focuses on studies that address the molecular mechanisms which underlie transcriptional regulation of three Astrocyte-derived Chemokines: MCP-1, IP-10 and beta-R1/Interferon-gamma-Inducible T-Cell ChemoAttractant (I-TAC).

Based on these studies, we propose that the complex promoters of these Genes are marvelously organized for flexible and efficient response to challenge.

In the case of MCP-1, several different stimuli can elicit Gene transcription, acting through a conserved mechanism that includes binding of inducible transcription factors and recruitment of the constitutive factor Sp1.

For IP-10 and beta-R1/I-TAC, it appears that efficient Gene transcription occurs only in highly inflammatory circumstances that produce aggregates of simultaneous stimuli.

These characteristics, in turn, mirror the expression patterns of the endogenous Genes: MCP-1 is expressed under a variety of circumstances.

While, IP-10 appears primarily during Immune-mediated processes that feature exposure of resident Neuroglia to high levels of inflammatory Cytokines.



#5

InterLeukin-1 in the Brain: Biology, Pathology And Therapeutic Target

Rothwell NJ, Luheshi GN
Trends NeuroSci 2000 Dec;23(12):618-25
Univ of Manchester, School of Biological Sciences, 1.124 Stopford Building, M13 9PT, Manchester, UK
PMID# 11137152; UI# 20580007
Abstract

The Cytokine InterLeukin-1 (IL-1) has diverse actions in the Brain. In normal Brain the IL-1 system is expressed at low levels and is upregulated rapidly in response to local or peripheral insults.

IL-1 mediates host defence responses to local and Systemic Disease and injury: e.g. fever, slow-wave sleep, appetite suppression and NeuroEndocrine responses.

And, to NeuroInflammation and cell death in NeuroDegenerative conditions, such as Stroke and Head Injury.

It has also been implicated in Chronic Degenerative Diseases, in particular, Multiple Sclerosis, Parkinson's and Alzheimer's Diseases.

The mechanisms regulating the expression and action of IL-1 are poorly understood, but involve multiple effects on Neuronal, Glial and Endothelial Cell function.

Thus, the IL-1 system provides an attractive and intensely competitive target for therapeutic intervention.



#6

Choroid Plexus Involvement In Central Nervous System Inflammation

Engelhardt B, Wolburg-Buchholz K, Wolburg H
Microsc Res Tech 2001 Jan 1;52(1):112-129
Max-Planck Institut fur physiologische und klinische Forschung, W. G. Kerckhoff-Institut, Bad Nauheim, Germany
PMID# 11135454
Abstract

During inflammatory conditions in the Central Nervous System (CNS), Immune Cells immigrate into the CNS and can be detected in the CNS Parenchyma and in the CerebroSpinal Fluid (CSF).

The most comprehensively investigated model for CNS inflammation is Experimental AutoImmune EncephaloMyelitis (EAE), which is considered the prototype model for the human disease Multiple Sclerosis (MS).

In EAE autoagressive CD4+, T-Cells gain access to the CNS and initiate the molecular and cellular events leading to Edema, Inflammation, and DeMyelination in the CNS.

The Endothelial Blood-Brain Barrier (BBB) has been considered the obvious place of entry for the circulating Immune Cells into the CNS.

A role of the Choroid Plexus in the PathoGenesis of EAE or MS, i.e., as an alternative entry site for circulating Lymphocytes directly into the CSF, has not been seriously considered before.

However, during EAE, we observed massive ultrastructural changes within the Choroid Plexus, which are different from changes observed during Hypoxia.

Using ImmunoHistoChemistry and in situ hybridization, we observed expression of VCAM-1 and ICAM-1 in the Choroid Plexus and demonstrated their upregulation and also de novo expression of MAdCAM-1 during EAE.

Ultrastructural studies revealed polar localization of ICAM-1, VCAM-1, and MAdCAM-1 on the apical surface of Choroid Plexus Epithelial Cells and their complete absence on the fenestrated Endothelial Cells within the Choroid Plexus Parenchyme.

Furthermore, ICAM-1, VCAM-1, and MAdCAM-1 expressed in Choroid Plexus Epithelium mediated binding of Lymphocytes via their known Ligands.

In vitro, Choroid Plexus Epithelial Cells can be induced to express ICAM-1, VCAM-1, MAdCAM-1, and, additionally, MHC Class I and II molecules on their surface.

Taken together, our observations imply a previously unappreciated function of the Choroid Plexus in the ImmunoSurveillance of the CNS.

Copyright 2001 Wiley-Liss, Inc.



#7

Post-Mortem High-Resolution MRI Of The Spinal Cord In Multiple Sclerosis

A Correlative Study With Conventional MRI, HistoPathology And Clinical Phenotype
Nijeholt GJ, Bergers E, Kamphorst W, Bot J, Nicolay K, Castelijns JA, van Waesberghe JH, Ravid R, Polman CH, Barkhof F
Brain 2001 Jan;124(Pt 1):154-166
Dutch MR Center for MS Research, Vrije Universiteit Hospital, Depts of Radiology, Pathology and Neurology, and Image Sciences Institute, Univ, Medical Centre, Utrecht and Dutch Brain Bank, Amsterdam, The Netherlands
PMID# 11133795
Abstract

We used high-resolution MRI to study the post-mortem appearance of Spinal Cord Multiple Sclerosis in relation to HistoPathology and low-resolution images.

Fifty-nine 3 cm long formalin-fixed Spinal Cord specimens from 19 Multiple Sclerosis patients and three controls were studied. Clinical characteristics of each patient were reviewed.

High-field MRI consisted of Proton-Density weighted Spin-Echo imaging with an in-plane resolution of 80 mum. Specimens were also imaged at 1.0 T, with 1 mm pixel resolution.

After MRI, the specimens were cut at 5 mm intervals and stained for Myelin (Luxol fast blue/cresyl violet) and Axons (Bodian method).

Two observers scored the MRIs for abnormalities and divided them into:

  1. Cell-delineated areas of high Signal Intensity (SI)
  2. Poorly defined areas of mildly increased SI

Abnormalities were scored semiquantitatively, White Matter and Gray Matter separately. In 81 sections the total area of abnormalities per section was measured on both HistoPathology sections and on matched high-field MRIs.

Abnormalities ranged from just a few abnormal areas to complete involvement of the Spinal Cord specimen. Patients with an aggressive disease course had more abnormalities than patients with a mild or intermediate disease course.

Areas of mildly increased SI were seen in all specimens, and were often found around Focal high-SI lesions. However, in six patients, areas of mildly increased SI were the predominant finding on the MRIs, correlating with a Primary/Progressive disease course.

HistoPathologically, high-SI areas correlated with complete DeMyelination, while mildly increased SI corresponded with partial DeMyelination.

All areas scored as abnormal by the NeuroPathologist were also found on the MRIs, and sizes measured using both methods correlated well (r = 0.85, P: < 0.01).

On conventional MRIs, abnormalities could be recognized fairly well. However, better differentiation could be made between high-SI and mildly increased SI abnormalities on the 4.7 T images.

In conclusion, high-resolution MRI revealed a great range of abnormalities in Spinal Cord Multiple Sclerosis, which related to disease course during life.

Furthermore, we found very good correlation between the extent of abnormalities shown by HistoPathology and the SI changes on Proton-Density MRIs, mainly relating to DeMyelination revealed HistoPathologically.



#8

Multiple Sclerosis With Very Late Onset

A report of a case with onset at age 82 years and review of the literature
Abe M, Tsuchiya K, Kurosa Y, Nakai O, Shinomiya K
J Spinal Disord 2000 Dec;13(6):545-9
Tokyo Medical and Dental University, Dept of Orthopaedic Surgery, Kudanzaka Hospital, Tokyo, Japan
PMID# 11132990; UI# 21019041
Abstract

This is a report of a patient with late-onset Multiple Sclerosis at age 82 years. The lesion involved was located on the Spinal Cord.

Multiple Sclerosis mainly affects young adults, making late onset of Multiple Sclerosis a rarity, particularly for cases after age 80 years.

Common characteristics of late-onset Multiple Sclerosis reported in other publications are predominant involvement of the Spinal Cord and a progressively worsening course with a serious prognosis.

In this case, Magnetic Resonance Imaging revealed a large area of high signal intensity in the Cervical and upper Thoracic Spinal Cord on T2-weighted images.

An increased ImmunoGlobulin G level in CerebroSpinal Fluid also played a diagnostic role in ruling out Cervical Spondylotic Myelopathy.

Spontaneous improvement occurred 2 months after the onset. Unlike other patient described in the literature, the clinical course of this man was not as bleak.



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