Do viral infections trigger severe demyelinating
disorders of the Central Nervous System?

An assessment with a special focus on Multiple Sclerosis and
Acute Disseminated encephalomyelitis

By 

Jihane Minh-Chau Belkoura

2004

Abstract

Multiple Sclerosis (MS) is a progressive, disabling, neurological illness that affects the brain and spinal cord. Nerve cells, which are usually surrounded by oligodendrocyte myelin, are damaged, die and won(?)ft be replaced when the Central Nervous System (CNS) is inflamed. As a consequence, progressive loss of the lipid rich myelin sheath surrounding axons result in disrupted, lower fidelity action potentials and slow signal conduction.

MS is thought to have a number of causes, however, none has been identified as the true causative agent.

MS is the most common neurological disease in people below 30 and it affects more than 1 million young adults worldwide. It is five times more common in temperate climates than in tropical areas and women are affected twice as often as men are. Scientists suspect that MS develops because of the influence of genes acting together. However, a common belief held by many scientists is that not only the genetic influences, but also environmental influences, especially those of viral infections, which trigger the disease.

This review considers the evidence in existence implicating viral responsibility in the onset of myelination disorders.

Abriviations used
1,25(OH)2D 1,25 dihydroxyvitaimin D
ADEM Acute Disseminated Encephalomyelitis
ALS Amyotrophic Lateral Sclerosis
APC Antigen presenting cell
BBB Blood bran barrier
CNS Central Nervous System
CSF Cerebrospinal Fluid
DRG Dorsal Root Ganglia
Ds Double stranded
EAE Experimental Autoimmune Encephalomyelitis
EBV Epstein-Barr Virus
GDNF Glial-Derived Neurotrophic Factors
HERV-W Human Endogenous Retrovirus-W
HHV6 Human Herpes Virus 6
HSV1 Herpes Simplex Virus 1
IFN-(?);Á Interferon-(?);Á
IGF2 Insulin-like Growth Factor 2
IL Interleukin
MAG Myelin-Associated Glycoprotein
MBP Myelin Basic Protein
MHV Mouse Herpes Virus
MOG Myelin-oligodendrocyte glycoprotein
MS Multiple Sclerosis
MSRV Multiple Sclerosis associated retrovirus
MVV Maedi Visna Virus
NCAM Neural Cell-Adhesion molecule
NT3 Neurotrophin 3
OSP Oligodendrocyte Specific Protein
P0 Myelin Protein zero
PDGF-BB Platelet-derived Growth Factor BB
PLP Proteolipid Protein
PML Progressive Multifocal Leukoencephalopathy
PMP-22 Peripheral Myelin Protein 22
PNS Peripheral Nervous System
SHH Sonic Hedgehog
TGF-(?);À Transforming growth factor-(?);À
Th T helper cells
Thp Precursor T cell
TMEV Theiler(?)fs Murine Encephalomyelitis Virus
TNF-(?);¿ Tumour necrosis factor (?);¿
Treg Regulatory T cells
TuJ1 Neuron-Specific (?);À-tubulin
Vitamin D VD

ABSTRACT ... I

ABRIVIATIONS USED ... II

1. INTRODUCTION ... 6
1.1 MYELIN  ... 7
1.2 CLINICAL ASPECTS ... 8
1.2.1 Multiple Sclerosis ... 8
1.2.2. Acute Disseminated Encephalomyelitis  ... 8

2. THE PROCESS OF MYELINATION IN THE NERVOUS SYSTEM ... 9
2.1. THE FOUR STAGES OF SCHWANN CELL DEVELOPMENT  ... 9
2.1.2. The mature myelinating Schwann cell  ... 11
2.2. MYELINATION BY SCHWANN CELLS  ... 11
2.3. FROM PRECURSOR CELL TO OLIGODENDROCYTE ... 12
2.4. MYELINATION BY OLIGODENDROCYTES  ... 13
2.4.1. Definition  ... 13
2.4.2. The process of myelination  ... 13

3. THE ACTION POTENTIAL ... 14
3.1. THE AXON ... 14
3.2. GENERATION OF AN ACTION POTENTIAL IN HEALTH  ... 14
3.3. THE ROLE OF MYELIN IN THE CONDUCTION OF THE ACTION POTENTIAL  ... 15
3.4. UNMYELINATED AXONS ... 16
3.5. THE GENERATION OF ACTION POTENTIAL IN DISEASE ... 16

4. MULTIPLE SCLEROSIS: WHAT WE KNOW ... 18
4.1. A POSSIBLE MECHANISM OF THE AUTOIMMUNE REACTION  ... 20
4.2. FACTORS INVOLVED IN THE DEVELOPMENT OF MS ... 21
4.2.1. Genetic factors  ... 21
4.2.3. Environment ... 22

5. IS MULTIPLE SCLEROSIS LINKED TO VIRAL INFECTION?  ... 23
5.1. THE VIRAL PATHWAYS ... 24
5.1.1. Viral entry into the cell  ... 24
5.2.1. Viral entry into the CNS ... 25
5.2. THE MECHANISMS CAUSING DAMAGE  ... 26
5.3. MS AND THE HUMAN HERPES VIRUS 6 ... 27
5.4. MS AND THE EPSTEIN-BARR VIRUS ... 28
5.5. EVIDENCE FOR A VIRAL INDUCTION OF MS ... 30

6. ACUTE DISSEMINATED ENCEPHALOMYELITIS: A DISEASE OF ITS OWN OR A VARIANT OF MS?  ... 33
6.1. OLIGODENDROCYTE PATHOLOGY IN MYELINATION DISORDERS  ... 34
6.2. AXONAL DEATH ... 35

7. ANIMAL MODELS OF DEMYELINATING DISEASES  ... 36
7.1. MOUSE HEPATITIS VIRUS  ... 36
7.2. THEILER(?)fS MURINE ENCEPHALOMYELITIS VIRUS  ... 38
7.2.1. The time course of the TMEV infection ... 38
7.3. EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS  ... 40

8. FUTURE RESEARCH ... 41
8.1. RESEARCH DIRECTED AT ROLE OF IMMUNE SYSTEM IN MS ... 41
8.2. ETIOLOGY OF MS  ... 41
8.2.1. Immunologic  ... 41
8.2.2. Environmental:  ... 42
8.2.3. Infectious agents  ... 42
8.2.4. Genetic ... 42
8.3. THE FUTURE OF MYELIN REPAIR ... 43

9. SUMMARY  ... 43

1. Introduction

In this report the focus will be on the outline the cellular and molecular changes accompanying oligodendrocyte myelination deficit disorders in the central nervous system (CNS), in particular Multiple Sclerosis (MS). More and more people are suffering from disabilities caused by the loss of myelin.

It is important to have a cellular and molecular understanding of the disorder in order to find effective and efficient treatments. This report will review the process of myelination and the molecules involved as well as the principle function of myelin in the propagation of the action potential. Finally, scientific investigation aimed at the distinguishing characteristic features of the disease that have improved our understanding of the possible causes of the three most common demyelination diseases will be reviewed.

Initially, it is important to define the type of myelination disorder that exist. 

DEMYELINATIION:

This describes the loss of existing myelin.

(i) Primary demyelination disorder: (without known or associated etiology) This is characterised by the loss of myelin sheath without any significant reduction in axon numbers. The loss of myelin can be caused by oligodendrocyte or Schwann cell injury as well as direct myelin sheath damage. 

(ii) Secondary demyelination disorder: (with known or associated etiology) Disorders of this type are characterised by the loss of myelin sheath after axonal degeneration.

DYSMYELINATION:

Unlike demyelination, it is not the existing myelin that is degraded, but the individual fails to form normal myelin or maintain the normal myelination.

Myelination disorders occur in the CNS and in the peripheral nervous system (PNS). The causes of the CNS demyelination are the damage to the oligodendrocyte cell body and its associated myelin sheath. The exact causes of primary demyelinating diseases such as MS are unknown, as well as its underlying basis. The etiology of diseases such as Acute Disseminated Encephalomyelitis (ADEM) and Progressive Multifocal Leukoencephalopathy (PML) are known, being post infectious and associated with viral infection respectively [1].

1.1 What is Myelin?

Myelin is a high resistance specialised wrapping that insulates the axons of neurons, enabling the quick conduction and improved fidelity of electrical signals in the nervous system. Its task is the same in the CNS as in the PNS. Myelin consists mostly of lipids, such as cholesterol and phospholipids and proteins, as the Myelin Basic Protein (MBP), the myelin Proteolipid Protein (PLP) and the Peripheral Myelin Protein (PMP22). Myelin possesses its insulating properties through its lipid richness, structure, thickness and its low H2O content, which is about 40% by volume. 

Depending on the type of the nerves, the extent of myelination varies, with motor and sensory nerves in the PNS being the most heavily myelinated and sympathetic nerves are unmyelinated.

As demyelinating diseases are becoming increasingly common, it is important to understand the process of myelination and how it is regulated. This is found to be different in the CNS and in PNS, where oligodendrocytes and Schwann Cells perform the myelination, respectively.

1.2 Clinical aspects

The purpose of this section is to give two examples of each type of the demyelinating diseases, with a brief summary of their clinical features and a short comparison of the latter.

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