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

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’t 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 dihydroxyvitaimin D 1,25(OH) 2 D

Acute Disseminated Encephalomyelitis ADEM

Amyotrophic Lateral Sclerosis ALS

Antigen presenting cell APC

Blood bran barrier BBB

Central Nervous System CNS

Cerebrospinal Fluid CSF

Dorsal Root Ganglia DRG

Double stranded Ds

Experimental Autoimmune Encephalomyelitis EAE

Epstein-Barr Virus EBV

Glial-Derived Neurotrophic Factors GDNF

Human Endogenous Retrovirus-W HERV-W

Human Herpes Virus 6 HHV6

Herpes Simplex Virus 1 HSV1

Interferon-γ IFN-γ

Insulin-like Growth Factor 2 IGF2

Interleukin IL

Myelin-Associated Glycoprotein MAG

Myelin Basic Protein MBP

Mouse Herpes Virus MHV

Myelin-oligodendrocyte glycoprotein MOG

Multiple Sclerosis MS

Multiple Sclerosis associated retrovirus MSRV

Maedi Visna Virus MVV

Neural Cell-Adhesion molecule NCAM

Neurotrophin 3 NT3

Oligodendrocyte Specific Protein OSP

Myelin Protein zero P 0

Platelet-derived Growth Factor BB PDGF-BB

Proteolipid Protein PLP

Progressive Multifocal Leukoencephalopathy PML

Peripheral Myelin Protein 22 PMP-22

Peripheral Nervous System PNS

Sonic Hedgehog SHH

Transforming growth factor-β TGF-β

T helper cells Th

Precursor T cell Th p

Theiler’s Murine Encephalomyelitis Virus TMEV

Tumour necrosis factor α TNF-α

Regulatory T cells T reg

Neuron-Specific β-tubulin TuJ1

VD Vitamin D

  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’S 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 H 2 O 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.

1.2.1 Multiple Sclerosis

The disease is most common in females, with a ratio 2:1 (female: male). MS will affect individuals between 20-50 years of age. The symptoms include optic neuritis, unsteady gait, weakness or numbness in one or more limbs, tremor and vertigo.

1.2.2. Acute Disseminated Encephalomyelitis

The most common cause of ADEM is non-specific upper respiratory infections and varicella infections. Typical symptoms include fever, headache, vomiting and incontinence. Over 80% of known cases occur in children up to 15 years old, while in adults it is 1-3%,

Unlike MS, which is a relapsing disease, ADEM has a monophasic time course and is caused by infection of vaccination. The onset of ADEM is abrupt and more common in children lacking gender discrimination. ADEM is the more severe syndrome, as the

associated mortality is 10-25%, while MS in its most severe form results in the loss of movement and mobility. Fortunately, the most severe form of MS manifests itself in only 20% of the cases, whereas 60% of individuals suffering from MS will exhibit little deficit and the final 20% moderate deficits.

2. The process of myelination in the Nervous system

As less is known about the myelination process in the CNS performed by the oligodendrocytes, a detailed description of the process performed by the Schwann cells in the PNS will be given.

2.1. The four stages of Schwann cell development

expressed/suppressed

In order to become a mature myelinating Schwann cell, the precursor cell has to undergo four developmental stages (Figure 1). In the first stage, the precursor cell is a neural crest cell, which differentiates into a Schwann cell precursor cell. Following this differentiation, it will migrate out in order to contact the developing axon. Here it has already entered the second developmental stage, where it is a Schwann cell

precursor. The transmission of β-Neuregulin supports the Schwann precursor cell in its development and survival. The latter is able to respond to the β-Neuregulin through erb-B3 receptors, which are crucial for the survival of the Schwann cell precursor. Experiments with erb-B3 Knockout mice have shown the importance of these receptors. Erb-B3 ^-/- mice lack Schwann cell precursors as well as Schwann cells and lose most sensory and motor neurons during the second half of the embryonic development [2].

The timing of maturation of the Schwann cell precursors are regulated by peptides called endothelins. The Schwann cell precursor itself provides a trophic support for other cells and is thought to promote motor neuron and dorsal root ganglia (DRG) cell survival through released glial-derived neurotrophic factors (GDNF) or Neurotrophin 3 (NT3) [2].

The third stage of the development is the immature Schwann cell. Its survival is linked to the autocrine support of Growth Factors, such as Insulin-like growth factor 2 (IGF2) of Platelet-derived growth factor BB (PDGF-BB) [2]. The immature Schwann cells provide trophic support to other cells, such for the connective tissue development (Perineurium, Epineurium, and Endoneurium). Furthermore the task of ensheathing bundles of developing axons also belongs to the immature Schwann cells.

The last and final stage in the development process is the maturation of immature Schwann cell (Figure 1). The mature Schwann cells can be divided into two groups: the myelinating Schwann cell and the non-myelinating Schwann cell. The latter is