Multiple Sclerosis Overview

Multiple sclerosis (MS) is the most common inflammatory demyelinating disease of the central nervous
system.[1][2] The disease typically presents between the ages of 20 and 40 and impacts approximately
35,000 individuals in the United States alone. [1][2] MS can lead to substantial disability with deficits
seen in sensory, motor, autonomic, and neurocognitive function.[1] The greatest incidence of the disease
tends to be at the extreme latitudes of the northern and southern hemispheres and has been more
commonly seen in Western European ancestry.[2] In the general population, MS impacts approximately
60-200 per 100,000 people in North America and Northern Europe (high risk areas) and 6-20 per
100,000 people in low risk areas.[1]

Figure 1. Prevalence of Multiple Sclerosis Around the World.

http://www.disease-picture.com/incidence-of-multiple-sclerosis/

Fold
Table of Contents
Multiple Sclerosis Overview
Trifecta Cause of Multiple Sclerosis
Genetic Factors
Environmental Factors
Viral and Bacterial Factors
Pathophysiology
Overview
Mitochondria
Multiple Sclerosis Cellular Component Chart
Clinical Manifestations
Classifications of MS
Disease Course
Disease Modifiers
Cortical lesions
Symptoms
Animal Model of Experimental Autoimmune Encephalomyelitis (EAE)
Overview
Uses
Pharmacologic Interventions
Disease Modifying Agents
Interferon beta (IFN beta)
Glatiramer acetate (GA)
Mitotoxantrone
Natalizumab
Symptomatic Therapies
Conclusion
References
Comments

Trifecta Cause of Multiple Sclerosis

Genetic Factors
Genetic factors play an important role in susceptibility to MS. First-degree relatives of affected individuals
have an approximately 2%–5% higher risk to develop MS, and rates in monozygotic twins vary between
20% and 35% in different studies, with the most recent studies placing it at 25%.[1] The prevalence of
MS is seen 1.6-2 times more in females than in males therefore indicating possible hormonal variables
as risk factors. [1] This hypothesis is supported by (a) lower relapse rates during, and disease rebound
after, pregnancy (b) the worsening of MS during menstruation; (c) the correlation of high estradiol and
low progesterone with increased MRI disease activity; (d) gender differences in EAE susceptibility related
to the protective effect of testosterone; and (e) the therapeutic effects of estriol in Relapsing Remitting-
MS. [1]

The data for the strongest susceptibility is the genes on the 6p21 chromosome in the major
histocompatibility complex (human leukocyte antigen-HLA) which is thought to account for 10%-60% of
the genetic risk.[1][3] The specific genes that provide the risk for MS are the HLA-DR and-DQ genes; the
HLA-DR15 haplotype in caucasians (DRB1*1501, DRB5*0101, DQA1*0102, DQB1*0602).[1][3] The
exact mechanism(s) by which the DRB1 gene influences susceptibility to MS remains undefined, but are
likely related to the physiological function of HLA molecules in immune responses, including antigen
binding and presentation, and T cell repertoire determination by negative selection of high-avidity
autoreactive T cells within the embryonic microenvironment.[3]

Environmental Factors
There is a north to south gradient in MS disease prevalence on the Northern hemisphere and the
opposite for the southern hemisphere. [1] Migration studies have suggested that exposure to the
presumed environment occurs during early adolescence.[4] People who migrate from one area of the
globe to another before adolescence are exposed to the environmental factors of the location to which
they migrate.[1][4] In contrast, those who migrate sometime after adolescence carry with them the MS
incidence of the location they migrated from.[1][4]

High levels of vitamin D decrease the risk for MS.[4] Vitamin D and sunlight exposure has been
recognized as the possible geographical/latitude link for the incidence of MS.[2][4] Sunlight exposure has
direct effects on serum levels of Vitamin D and the immunomodulatory effects of vitamin D on T-cell
homeostasis.[2] Vitamin D status may play a role in a prenatal period and therefore may depend on the
vitamin D status of the mother.[2][4]

Smoking has been identified as a significant risk factor for the development of MS.[4] There is also
evidence to suggest that smoking can negatively impact disease progression in MS.[5]
Viral and Bacterial Factors
Evidence suggests exposure to an infectious agent may contribute to the development of MS. Human
herpesvirus 6 (HHV-6) and Epstein-Barr virus (EBV) have been most strongly implicated as both have
been shown to be present at a high rate in people with MS, at 80% and 90% respectively.[1] HHV-6
demonstrates features similar to MS as it tends to induce repeated infections. HHV-6 has also been
found in oligodendrocytes in plaques associated with MS. EBV has been shown to strongly predict MS
and 100% of patients with MS are reportedly seropositive for the virus. Furthermore, those who were
infected with mononucleosis at a young age have a higher chance of developing MS. Chlamydia
pneumoniae (Cpn) has also been studied in triggering MS, but evidence for this is unclear.[1]

Molecular mimicry is one mechanism proposed to explain how this occurs. During thymic selection, the T
cells recognize the self-antigens, are positively selected, and are moved to the periphery. If these
potentially self-reactive T cells come into contact with an antigen they may activate, cross the blood-brain
barrier, and if antigens are then recognized, an autoimmune disease like MS may be triggered.[1]

Bystander activation is a second mechanism that may explain the infectious agent’s role in MS. During
infection, proinflammatory cytokines and chemokines are produced and may activate CD8+ T cells.
Activated CD8+ T cells have been shown to specifically recognize viral antigens.[1] However, without the
cooperation of several mechanisms autoimmunity is not induced, indicating the role of multiple factors to
produce an autoimmune response as in MS. It is unclear exactly how this process is involved in MS.
Another mechanism of bystander activation is the reaction of T cells to viral tissue damage, where the
viral cells are recognized and killed. This results in destruction of self-tissue and autoantigen release.
When autoantigens and the infectious agent are present together, it may cause activation of the
autoreactive T cells and thus initiate the autoimmune response.[1]

Pathophysiology
Overview
The cascade of cellular events involved with MS differs between individuals. However, the initial
important event in MS occurs when autoreactive CD4+ T helper cells are activated in the
periphery. CD4+ T cells are activated in genetically inclined individuals due to a variety of causes
detailed in the Viral and Bacterial Triggers and Environmental Factors section. While in the periphery
activated CD4+ T cells increase the immune response by recruiting additional immune cells
including: CD8+ cells, B cells, granulocytes, monocytes, and mast cells. Activated CD4+ T and
proinflammatory cells adhere to and then cross the blood brain barrier endothelium. In order to do so,
activated cells produce proinflammatory cytokines (tumor necrosis factor-alpha (TNF-
alpha) and interferon-gamma (IFN-gamma)), which activate adhesion molecules (LFA-1 and VLA-4) on
the blood-brain endothelium.[6]

Following entry into the CNS, CD4+ T cells are reactivated by antigen-presenting cells. Following
reactivation, CD4+ T cells release proinflammatory cytokines (IFN-gamma, TNF-alpha) and a variety
of chemokines. These cytokines can amplify local inflammation by activating microglia and astrocytes,
which can induce myelinphagocytosis and cause increased reactivation of CD4+ cells. Damage to CNS
(myelin, oligodendrocytes, axons) occurs as a result of the following additional processes:
-B cells, auto-antibodies, and complement factors enter the CNS once the inflammation process has
started. Upon entering the CNS, B cells and auto-antibodies produce a variety of responses to cause
additional CNS damage. B cells provide co-stimulation to autoreactive T cells and can act as antigen
presenting cells that present antigen to autoreactive T cells. B cells and auto-antibodies also bind to CNS
tissues, which leads to increased autoreactive T cells recruitment, and thus increased T cells,
monocytes, and eosinophils at the site of inflammation. B cells also produce myelin-specific antibodies
that cause myelin destruction.[6]
  Activated complement products also induce antibody opsonization of myelin
and Macrophage uptake.
 Activated CD8+ T cells lead to oligodendrocyte apoptosis and neural cell death by destroying
specific receptors on oligodendrocytes.
 Activated complement products also result in oligodendrocyte lysis and additional attraction of
macrophages
 The activity of phagocytes produces large amounts of toxic reactive oxygen and nitrogen
intermediates, including the free radical nitric oxide. Dyemyelinated axons are susceptible to
further degradation via nitric oxide activity.
 γδ T cells have been shown to lyse oligodendrocytes, via the perforin pathway.
 Glutamate production is increased while destruction and re-uptake is decreased leading to
oligodendrocyte excitotoxicity.

Figure 2. Inflammatory Phase of Multiple Sclerosis

http://www.nature.com/nri/journal/v3/n6/fig_tab/nri1108_F1.html

This inflammation process can last from a few days to two weeks. Following the response, stretches of
axons are left demyelinated, oligodendrocytes are left damaged, and in some areas axon transsection is
present. Oligodendrocytes surviving the procress begin to re-myelinate damaged areas, however the
original myelin thickness is not achieved again. The combination of these events results in decreased
axonal conduction.[6]

Mitochondria
Normal mitochondrial function is described in detail on the mitochondria page. Disease can alter the
function of the mitochondria and therefore alter the energy production of the tissue involved. Specifically,
oxidative phosphorylation is affected, which can impair tissues that are dependent on high ATP supply
such as the brain and nervous system.[7] The trademark of MS is damage to myelin sheaths and
oligodentrocytes, which slows saltatory nerve conduction by increasing the size of the area where the
axon continuously depolarizes. This process increases mitochondrial energy (ATP) production,
decreases impulse velocity, and increases cellular demand for energy. The reduced supply of energy at
damaged tissue has been shown to be associated with further tissue degeneration. This is due to the fact
that in de-energized axonal areas sodium channels produce ectopic electrical potentials across the
neuron, resulting in altered nerve communication. Limited ATP supply also alters ATP-dependent
membrane channels and enzymes leading to increased intra-axonal Na+ and Ca2+. The accumulation of
these processes further increases the cellular demand of mitochondrial energy production.[8]

Increased mitochondrial activity also correlates with increased reactive oxygen species
(ROS) production. ROS has shown to have a significant role in the degenerative alterations seen in MS.
ROS-induced lipid peroxidation can affect membrane utility and structure. Oligodendrocytes and myelin
contain higher lipid content than most cells in the CNS, making them susceptible to ROS-induced
damage and death. Additional, antioxidants that delay or suppress adverse effects of ROS have been
found to be deficient in MS, as a result of chronic inflammation and oxidative stress.[8]

Increased oxidative and nitrative stress in MS also results in production of reactive nitrogen species
(RNS). Stressed mitochondria increase production of nitric oxide (NO), which reacts with superoxide to
form RNS peroxynitrite. This structure causes extensive damage to myelin sheaths, oxidative damage to
mitochondria, and mtDNA damage.[8]

Another trademark of MS is impaired apoptosis of auto-reactive T cells, B cells, and marcophages in the
periphery, which eventually cross the blood brain barrier into the CNS. While the exact cellular
mechanisms are not fully understood, it is believed that damaged and stressed mitochondria
demonstrate a poor ability to regulate this process in MS.[8]

Multiple Sclerosis Cellular Component Chart

The following chart explains in detail the cellular components involved in the Multiple Sclerosis cascade,
as briefly described above. The components are in order according to the cascade.

Cellular Component Normal Response Changes in MS

Cell markers are present on the
surface of all cells known as
Major histocompatibility complex
(MHC) proteins. There are 6
Genes (hereditary specific markers commonly
component) known as human leukocytic
antigens (HLA’s); HLA-A, HLA-B,
HLA-C, referred to as class I
antigens, and HLA-DP, HLA-DQ,
and HLA-DR, referred to as class
The data for the strongest
susceptibility is the genes on the 6p21
chromosome in the major
histocompatibility complex (human
leukocyte antigen-HLA) which is
thought to account for 10%-60% of
the genetic risk.[1][3] The specific
genes that provide the risk for MS are
the HLA-DR and-DQ genes; the HLA-
DR15 haplotype in caucasians
 II antigens. These allow immune (DRB1*1501, DRB5*0101,
cells to recognize and DQA1*0102, DQB1*0602)[1][3]
communicate with each other
and determine which antigen and
how strong an individual will
respond to.[9]

A region of chromosome
6p21.31 that encodes
histocompatability genes. This
region is noted to contain the
most genes in the human
Classes I and II contain alleles that
Major Histocompatibility genome and encodes the most
have been highly linked to
Complex (MHC) proteins known currently. This
autoimmune diseases.[10]
region is divided into subregions
referred to as classes I, II, and
III. Classes I and II contain
genes that are implicated in
immune function.[10]

Hypothalamo-pituitary-adrenal
(HPA) axis: this neuroendocrine
Studies using the EAE model of MS
axis is controlled by the
have shown that the HPA
hypothalamus, which receives
hyporesponsiveness to inflammatory
input from higher cortical areas
stimuli predicts a more severe
and other brain regions,
disease course. However, most
including the limbic system.
clinical studies indicate a hyperactive
Activation of the axis leads to a
HPA axis in MS, particularly in the
HPA axis cascade of hormone releases.
progressive stages of the disease. A
The hormones secreted by the
hyperactive axis can be associated
HPA axis have potent effects on
with neurological disability, cognitive
immune function and other target
impairment and brain atrophy. There
tissues. Among the main
is also some evidence that HPA
activators for the HPA axis are
hyperactivity might predict future
psychological or physiological
development of disability.[12]
stressors, including inflammatory
cytokines.[11]

T-cells are the main component

of the cell-mediated immune
Macrophages take up an unknown
response. Their role is to help B
foreign substance and present the
cells augment the production of
antigen to T-cells in the blood or
antibodies; activate
lymph nodes, and activation and
macrophages and help to
expansion of the T-cells occur. The
destroy bacteria; help other T-
activated T-cells display adhesion
T- cells cells recognize and destroy
molecules that allow attachment to
virally infected cells; help Natural
and entry through the endothelial
Killer cells kill infected cells. T-
lining of the blood-brain barrier. The
cells also are capable of turning
activated T-cells appear to be reactive
the entire immune system off
against myelin and other antigens
through the actions of the helper
within the CNS.[9]
T4 cells and the cytotoxic T8
cells.[9]

An antigen is any foreign
substance in the body that is
Antigens
capable of triggering an immune
response[9]
CD4+ cells are helper T cells and
are the main cell involved in the
immune response. Normal
mature T cells carry a surface
protein called CD4+ and act to
CD4+ cells defend against pathogenic
infections. There are multiple
subsets based on specific
cytokine production (T1, T2,
T17). These cells recognize
class II MHC molecules.[13]
Cellular Component Normal Response
TH1 cells are a type of CD4+ T
cell that produce interferon
gamma (IF-γ) and IL-2 to
maintain an effective immune
Th1
response. They are associated
with protection against
intracellular bacterial and viral
infections.[13]
TH2 cells are a subset of T-
helper cells that produce
cytokines IL-4, IL-10, and TGF-β.
Th2
These cells produce an anti-
inflammatory response to tissue
damage.[1]
TH17 cells are CD4+ T-cells that
aid in defense against
Th17 pathogens. They are mostly
associated with protection
against extracellular bacterial
The recognition of self-antigens at
intermediate levels of affinity by T
cells leads to positive selection and
export of these T cells to the
periphery. Crossreactivity of these
potentially self-reactive T cells with
foreign antigens can lead to activation
during infection, migration across the
blood-brain barrier, CNS infiltration,
and, if they recognize antigens
expressed in the brain, tissue damage
and potentially an autoimmune
disease such as MS. [1]
Activated CD4+ cells can transfer
EAE in vitro and arguments have
been made for its occurrence in vivo.
MS is considered a CD4+ T cell
mediated disease; however the exact
role of CD4+ cells is much more
complex and not fully understood. In
MS, CD4+ cells contribute to CNS-
and CSF-infiltrating inflammatory cells
and are present at higher frequencies
than normal. Autoreactive CD4+ cells
have been shown to target various
proteins, including MBP, PLP, MOBP,
and MOG,[1] which are explained
below.
Changes in MS
Dysregulation of TH1 levels has been
associated with autoimmune
inflammation,[14] such as with MS.
Studies have shown that TH1 cells
can induce EAE, however its specific
role in MS is not clear.[14]
TH2 cells and its cytokines increase B
cell proliferation, differentiation, and
antibody production. TH2 cells and its
cytokines have also been shown to
proliferate following disease
exacerbations and are important for
disease resolution/prevention. [1]
Dysregulation of T17 levels has been
associated with autoimmune
inflammation,[14] such as in MS. As
with TH1 cells, TH17 cells have also
been shown to be involved in inducing
 and fungal infections.[13]
Group of signaling molecules
that mediate the inflammatory
process in humans. Eicosanoids
are composed from 20-carbon
Eicosanoids polyunsaturated fatty acids.
Examples include:
prostaglandins, thromboxanes,
leukotrienes and
epoxyeicosatrienoic acids.[15]
Cytokines are cell-signaling
polypeptides that are responsible
for inter and intra-cellular
communication. The term
cytokine encompasses a broad
Cytokines family of immunomodulating
agents including interferons and
interleukins.[17] These cell
modulators are major
components of the inflammatory
response.[18]
Cellular Component Normal Response
A type of cytokine that
Chemokines chemically attracts inflammatory
cells to the site of lesion[2]
A cytotoxic T cell that displays
glycoprotein CD8. CD8 cells are
part of the immune response,
CD8+ cells responding to specific antigens.
They express T cell receptors
(TCR) that associate with Class I
MHC cells.[19]
B cells are the main component
in the humoral immune
response. They are able to
produce immunoglobulins (Ig),
also known as antibodies.
B cells
Recent studies show
the cytokines produced by B
cells are important in determining
the nature of the immune
response.[20]
EAE but their exact role in MS is not
clear.[14]
During the inflammation process,
macrophages enable myelin damage
through a variety of cellular
processes, including increasing
eicosanioid production and release in
order to proliferate inflammation.[16]
In general, cytokines have been found
to have a role
in oligodendrocyte apoptosis and
degeneration of axons in patients with
MS.[18]
Changes in MS
Increased activation in MS,
chemokines have been considered a
main activator of virus-specific CD8+
T cells and activator of the
autoimmune response[1]
CD8+ cells have been seen in EAE
with increased presence in plaques,
CSF, and blood of mice with EAE.[19]
CD8+ cells are more prevalent than
CD4+ cells in brain tissue of patients
with MS, however their role in the
disease is less understood.[1][19]
Increased levels of B cells have been
identified in the CSF and CNS lesions
in patients with MS. Clonal expansion
has also been observed in the CSF of
MS patients, along with the presence
of oligoclonal Ig.[20] This data
suggests there is an antigen-driven
response in the CNS that leads to B
cells producing a specific set of
antibodies that produce oligoclonal
banding. The presence of unique Ig
banding in individuals with MS has

Immune cell that migrate to
inflamed tissue and differentiate
into macrophage cells. These
Monocytes/Macrophages cells can produce cytokines,
including TNF-alpha.
Macrophages also induce
phagocytosis.[6]
Mast cells are effector cells of
the immune system. They
express cytokines including:
TNF-alpha, IL-3, IL-4, IL-5, IL-6,
IL-8, IL-10, IL-12, IL-13, and IL-
Mast Cells
16. Mast cells and its mediators
are crucial components of the
inflammatory response in
humans. Normally found in low
quantity within the CNS.[21]
Cellular Component Normal Response
An anti-inflammatory cytokine
that is produced by CD4+ cells
and Th2 cells. It induces
differentiation of CD4 helper T-
cells and stimulates growth and
IL-4 differentiation of B cells. It’s role
is to inhibit the activation
of Th1 pro-inflammatory cells IL-
1 and TNF-alpha and amplify the
Th2 anti-inflammatory
response.[18][22]
An anti-inflammatory cytokine
that is produced
IL-10 by Macrophages, Monocytes, B
cells and Th2 cells. Its’ role is to
inhibit the
shown antibody specificities against
components of myelin.[20]This
includes MOG, MBP, and
oligodendrocyte proteins. While this
data does suggest B cell involvement
in MS, not all studies are in
agreement in Ig’s specific role in the
pathogenesis of MS.[20]
Monocytes enter the CNS through the
blood brain barrier and differentiate to
macrophages, which produce TNF-a
at the inflamed site. Macrophages
also induce phagocytosis of myelin
and oligodendrocytes within the CNS.
Monocytes and macrophages are
found in abundance in active MS
lesions.[6]
Mast cells contain TNF-α, which can
increase adhesion molecule
production. This process increases
the blood brain barrier infiltration
process. Within the CNS mast cells
and its mediators cause direct
damage to CNS by causing damage
to oligodendrocytes and neurons.[1]
Changes in MS
In one study, patients with multiple
sclerosis, the level of IL-4 producing
T-cells is significantly lower than in
controls.[22] Some studies have
found that IL-4 deficient mice develop
more severe form of EAE than
controls.[18][22]. However, a review
by Imitola et al.[18] concluded that a
deficiency of IL-4 does not necessarily
alter the disease course of EAE, but
its’ upregulation may help reduce EAE
severity. This may mean that other
Th2 cytokines can substitute for the
lack of IL-4. The review by Imitola et
al. states that studies of IL-4 and MS
are limited and its’ role in unclear.
In EAE models, mice with IL-10
deficiency developed more severe
EAE compared to controls and even
to IL-4 deficient mice, suggesting IL-
10 has a unique role that can't be
 proinflammatory Cytokines (IL-
1and TNF-alpha) produced by
macrophages.[18]
Activated by Cytokines which
then produce pro-inflammatory
Endothelial cells
cytokines, such as IL-1 and TNF-
alpha.[2]
Cellular Component Normal Response
Adhesion molecules are up-
regulated by pro-
inflammatory cytokines, such
Adhesion molecules as IL-1 and TNF-alpha, and
aid chemokines in attracting
inflammatory cells to the site of
lesion.[2]
A cytokine that provides
immunity against intracellular
pathogens and controls tumor
formation. IFN-gamma either
upregulates or
downregulates Major
Histocompatibility Complex
(MHC) classes I and II. It also
Interferon-gamma (IFN- initiates the production of pro-
gamma) inflammatory cytokines to
increase macrophage activity.
IFN-gamma controls
differentiation of the CD4+
cells into Th1 effectors which are
vital in adjusting immunity
against viral and bacterial
infections, essentially acting to
clear infectious antigens.[13]
Tumor necrosis factor-alpha
(TNF-A) is an
TNF-alpha inflammatory cytokine with
similar functions as IL-1. It is
produced by several types of
cells, but especially
substituted by other Th2
cytokines.[18] Treatment with IL-10
has also been shown to prevent EAE
in mice.[23] In general there is
decreased expression of IL-10 in
patients with MS. Also, treatment with
interferon beta induces an increased
production of IL-10 and has lead to
decreases in Th1 responses and
clinical benefits.[23]
In MS, T cells present adhesion
molecules and are able to attach to
endothelial cells and enter blood brain
barrier.[9]
Changes in MS
In MS, activated T cells display
adhesion molecules in order to cross
the blood brain barrier.[9]
Natalizumab, a monoclonal antibody
approved for treatment in the U.S.
and Europe, is an antagonist of VLA4,
thus blocking it from binding to
adhesion molecues and preventing
inflammatory cells from migrating to
the area.[2]
Found to be increased in the CSF and
CNS of patients with MS.
Administration of IFN-gamma also
was seen to exacerbate MS.
However, recent evidence has
contradicted these findings and leads
to questioning of IFN-gamma’s role in
MS. Most notable are studies showing
exacerbation of EAE in mice deficient
in IL-2, TNF, and IFN-gamma.[24]
The expression of TNF-alpha is
elevated in active demyelinating
lesions compared with
inactive/remyelinating lesions.[1]
There are different theories of
mechanisms for this demyelination:
 by macrophages. It affects most
organs in the body and serves a
variety of functions based on its
locations. The primary role of
TNF is in the regulation of
immune cells. TNF-alpha is a
key intermediary during local
inflammation processes. TNF is
able to induce apoptotic cell
death and inflammation, and it
possesses both growth
stimulating and growth inhibitory
abilities. TNF-alpha causes
necrosis of some tumors while
promoting the growth of other
types of tumor cells.[25]
Cellular Component Normal Response
A cytokine with similar functions
as tumor necrosis factor (TNF).
IL1 has a number of local actions
that promote the inflammatory
reaction. It also has some
systemic actions that induce
metabolic, hemodynamic, and
hematologic alterations. IL1
IL-1 causes a fever by raising the
production of prostaglandins in
the hypothalamus; it causes
characteristic changes in blood
chemistry; and it increases the
number of neutrophils and
decreases the number
of lymphocytes in the
circulation.[9]
Auto-antibodies are antibodies
produced by the body after the
immune systems fails to
recognize the body’s cells and
Auto-antibodies tissues. Through a cascade of
events the auto-antibodies are
synthesized to attack “self”
proteins, leading to increased
inflammation and cell death. [26]
Part of small immune cell
Microglia presence normally in CNS, along
with astrocytesand other immune
cells that get through the tight
TNF-alpha and IFN-gamma may be
toxic for oligodendrocytes; or
cytokines may activate macrophages
and microglia, which then
phagocytosize myelin; or
proinflammatory cytokines may be
involved in apoptosis
induction/execution and subsequent
demyelination.[1] Elevated numbers
of blood cells expressing TNF-alpha
mRNA, serum TNF-alpha
concentrations, and peripheral blood
mononuclear cells secreting TNF-
alpha have been reported in MS
patients.[1]
Changes in MS
Proinflammatory cytokines can
participate in the pathogenesis of MS
at different points. They are thought to
play a role in the pathogenesis of MS
via immune system activation in the
periphery and perhaps also by directly
damaging the oligodendrocyte and
myelin unit within the CSF and
brain.[1] Proinflammatory cytokines
have also been found in active MS
lesions.[1]
Auto-antibodies can contribute to the
disease process through a variety of
ways. Research has shown that auto-
antibodies attached to neural tissues
can elicit additional cell damage by
increasing T-cells, monocytes, and
eosinophils activity at the
inflammation site.[27] Antibodies can
also induce demyelination by
increasing macrophage phagocytosis.
Research has shown increased
serum antimyelin antibodies is
present in MS.[28]
Post-mortem studies have proposed
widespread microglial activation with
associated axonal injury is
characteristic of the global
 blood brain barrier.[9] Activated
by cytokines which then produce
pro-inflammatory cytokines, such
as IL-1 and TNF-alpha.[2]
inflammatory response affecting the
CNS in the MS disease
process.[2][29] One study went further
to say microglia activation was more
profound in new symptomatic lesions
in myelinated tissue that contains few
or no lymphocytes or myelin
phagocytes when compared to older
lesions, thus raising speculation about
the presumed pathogenesis and
aetiology of MS.[2][30]

Cellular Component Normal Response Changes in MS

These are the main source of

CNS complement, an auxiliary
line of defense.[1] Normally, a
minimal presence of astrocytes
along with microglia and other
Plaques, common in MS, are
immune cells get through the
Astrocytes characterized by increased numbers
tight blood brain barrier.[9]
of astrocytes and scar deposition.[1]
Proliferate in damaged parts of
the CNS, activated
by cytokines which then produce
pro-inflammatory cytokines, such
as IL-1 and TNF-alpha.[2]

Eosinophils are granulocytes

cells produced in bone marrow
Eosinophil activity and attraction is
that circulate to damaged tissue
increased in MS. Following lesion
in response to inflammation.
Eosinophils creation eosinophils pass into the
These cells have the ability to
CNS and increase the inflammatory
create specific cytokines, such
response.[6]
as IL-1, IL-3, IL-4, IL-5, IL-8, and
TNF-α.[31]

There are several types of

excitotoxic factors but glutamate
is one of the most important in
cellular function. Glutamate is an
excitatory neurotransmitter found Glutamate-mediated excitotoxicity
throughout the central nervous of oligodendrocytesoccurs due to an
system. Most commonly, increased production and decreased
glutmate is packaged in vesicles breakdown/re-uptake of glutamate
Excitotoxic factors in pre-synaptic axons and by astrocytes. This process leads to
released into the synaptic cleft additional calcium influx through
following input from a nerve NMDA receptors and eventual
impulse. Once released into the oligodendrocyte and axonal
cleft, glutamate binds to post- damage.[33]
synaptic receptors, including
NMDA receptors. In a normal
functioning cell, glutamate is
rapidly removed by glutamate
transporters following action
 potential signaling.[32]
The outgrowth of a neuroglial cell
(i.e. oligodendrocytes). It forms a
protien-like, fatty, insulating
Myelin sheath around the axon of a
neuron that helps increase the
speed at which nerve impulses
propagate.[9]
Cellular Component Normal Response
Glial cells are non neural cells
found in the CNS that provide
support, structure, and maintain
homeostasis. Glial cells are
Glial cells
important in the formation and
maintenance
of myelin. Astrocytes are one
type of glial cell.[9]
Type of glial cell. Role is to
Oligodendrocytes myelinate axons of the central
nervous system.[9]
NK cells are a main component
of innate immunity through both
effector and regulatory functions
by means of their cytotoxic
Natural killer cells (NK
activity against tumor cells and
cells)
virally infected cells. NK cells are
able to initiate their cytotoxic
activity with their ability to
secrete different cytokines.[35]
The most abundant protein in
Proteolipid protein
CNS myelin.[1]
MS is considered to be an
autoimmune disorder with an end
result of the immune attack causing
toxicity and destruction of the myelin
sheath.[9]
Changes in MS
Glial cells, particularly astrocytes
become activated during the acute
inflammatory process.[1]
Oligodendrocytes (OLG) are the
targets of the inflammatory and
immune attacks in MS and become
deficient.[9] Oligodendrocyte death by
apoptosis or necrosis causes the cell
loss seen in MS plaques.[34]
Following an acute inflammatory
response, surviving olidogendrocytes
remyelinate the damaged axons.
They are not able to myelinate the
axons to their original thickness,
resulting in a slower signal
transduction.[1]
Through EAE models it has been
showed that NK cells can have both
pathologic and protective effects in
MS.[35][36] In vitro NK cells have
demonstrated cytotoxic activity
toward oligodendrocytes, astrocytes,
and microglial cells during
inflammation.[35] NK cells can also
play a protective role in the CNS as
they have the ability to produce
neurotrophic factors such as brain-
derived neurotrophic factor (BDNF)
and neurotrophin-3 (NT-3).[35]
PLP has been shown to have more
significant encephalogenic properties
than MBP in some EAE models and is
considered to be the main target of

MBP is the second most
abundant protein in myelin,
found on the intracellular surface
Myelin basic protein of the membrane. Its role is to
(MBP) maintain adhesion of the
cytoplasmic surfaces to and
allow efficient signal
transfer.[1][37]
The third most abundant protein
found in myelin in the CNS,
possibly involved in its
maintenance. Regulates the
Myelin oligodendrocyte
radical component of myelin and
basic protein (MOBP)
may also regulate axon
diameter. MOBP is also
important in stabilizing the multi-
layer structure of myelin.[38]
Cellular Component Normal Response
A large glycoprotein found on the
Myelin oligodendrocyte outer surface of the
glycoprotein (MOG) oligodendrocyte membrane in
the CNS. [1]
Reactive oxygen species (ROS)
Reactive oxygen species is a collective term that includes
(ROS) chemically-reactive molecules
containing oxygen such as
oxygen radicals, such as
activated T cells. PLP has also been
shown to be immunodominant in
humans and is elevated in people with
MS. Its specific role in the
pathophysiology of MS is not yet
clear.[1]
MBP has been extensively studied in
EAE models, showing ability to induce
EAE in mouse, rat, and nonhuman
primates. A significant overlap of
encephalogenic epitopes of MBP
have been identified between rodent
and human models, supporting the
suggestion that MBP is highly
involved in the human version of EAE:
MS. However, further research is
necessary to confirm its role in MS.[1]
MOBP is encephalitogenic and can
induce EAE in rodent models. Recent
studies using EAE have shown MOBP
may be a primary target of
autoimmune T cells in MS. Attack on
this important protein may result in
destabilization of the multi-layer
myelin and lead to its breakdown.
This has not been confirmed with
evidence, but is proposed to be highly
likely based on animal study results
and cellular properties of the
protein.[38]
Changes in MS
Due to its location, MOG is highly
accessible to antibodies and has been
thought to be a target of immune
responses in MS. In certain EAE
models, MOG has induced a chronic,
nonrelapsing form of EAE. This
protein’s role in MS has not been
studied as extensively as PLP or
MBP; however it has been seen in
activated T cells in patients with the
disease. More research is necessary
to identify MOG’s specific role in
MS.[1]
Oxygen and nitrogen free radicals
may be important in the pathogenesis
of EAE and MS. Numerous studies of
patients with MS have shown
increased free radical activity. They
 superoxide (O2), hydroxyl (OH ),
peroxyl (RO2 ), and hydroperoxyl
(HO2) radicals, and certain
nonradical oxidizing agents, such
as hydrogen peroxide (H2O2),
hypochlorous acid (HOCl), and
ozone (O3), that can be
converted easily to
radicals.[39][40] The signature
unpaired electrons make these
species highly reactive. While
they are a natural byproduct of
typical metabolism, they do have
the potential to cause cellular
damage to DNA, RNA, and
proteins.[39] ROS can have
negative effects on cell
metabolism such as apoptosis,
though it is also able to function
to signal mobilization of ion
transport and oxidative signaling.
They are released by platelets
during wound healing to recruit
additional platelets to the site of
the injury. They are involved in
enzymatic reactions,
mitochondrial electron transport,
signal transduction, activation of
nuclear transcription factors,
gene expression, and the
antimicrobial action
of neutrophils and
macrophages.[39]
Reactive nitrogen species (RNS)
are a family of molecules derived
from nitric oxide and superoxide.
They are produced
by neutrophils.[43] They work
with reactive oxygen species and
are harmful to cells particularly in
the nervous system. RNS
molecules participate as
Reactive nitrogen signaling molecules that regulate
species (RNS) signaling pathways; they also
modulate protein and lipid
kinases and phosphatases,
membrane receptors, ion
channels, and transcription
factors, including NF-κB. During
the inflammatory response, it
modulates phagocytosis,
secretion, gene expression, and
apoptosis.[43]
Cellular Component Normal Response
have been implicated as mediators of
demyelination and axonal injury in
both EAE and MS. Free radicals can
activate certain transcription factors,
such as nuclear transcription factor-
kappa B (NF-κB), which upregulate
the expression of many genes
involved in EAE and MS, including
tumor necrosis factor-α (TNF-α).[1]
Studies have demonstrated that
activated mononuclear cells of MS
patients produce high amounts of
ROS and nitric oxide and that
oxidative damage to DNA, including
mitochondrial DNA develops in
association with inflammation in
chronic active plaques.[41][42]
NOS has been found in MS lesions,
suggesting a role in MS pathology. [1]
The actual role of NOS in CNS injury
in MS is not clear. Results from
blocking NOS in EAE are not
conclusive, and additional data
suggest that it may even have an
antiapoptotic effect or modulate
immune responses and be
beneficial.[1] Indirect evidence that
reactive nitrogen species play a role
in MS lesions includes the findings
that proinflammatory cytokines
including TNF have been identified in
MS lesions. IL-1 and TNF have also
been found within peripheral
mononuclear cells and cells within the
cerebrospinal fluid.[44]
Changes in MS

Protease refers to a group of
enzymes that hydrolyze the
peptide bonds that link amino
acids together in proteins. They
can break a specific peptide
bond depending on the
sequence of the amino acids, or
break down a complete peptide
chain. Involved in a multitude of
physiological reactions including
Proteases
highly-regulated cascades such
as apoptosis pathways.[45]
There are six general
classifications of proteases
based on composition of active
site: 1) Serine proteases 2)
Threonine proteases 3)Cysteine
proteases 4) Aspartate
proteases 5) Matalloprotease 6)
Glutamic acid proteases.[45]
A series of
serine proteases released
Granzyme from natural killer cells and
cytotoxic T cells that induce
apoptosis within a target cell.[47]
Perforin is a pore forming protein
found in most natural killer cells
and cytotoxic T-cells. This
protein binds to a target cell
Perforin
membrane in order to form a
pore in the cell membrane in
order to allow entry
for granzyme.[47]
Transforming Growth Factor-
beta (TGF-beta) is a growth
factor that is part of the tissue
repair response and is
responsible for regulating the
TGF-beta number of cellular reactions
involved in the inflammatory
response. TGF-beta specifically
inhibits growth of cells and
causes macrophages to become
inactive.[9]
May be responsible for axonal
degeneration as a result of axons
undergoing changes to restore
impulse conduction after
demyelination via redistribution of
sodium channels along the axons.
Due to the redistribution, ATP
consumption is greatly increased and
axonal ion concentrations may result
in axon degeneration. The energy
imbalance impairs the function of
ATP-dependent ion chanels which
leads to an increase in intracellular
sodium concentrations. This ultimately
increases intracellular calcium and
calcium dependent enzymes and
damages the axon. This activates
proteases as a mechanism of axon
degeneration[46] Electron
microscopic imaging has found that
individuals with MS have significant
pathological changes suggesting
increased calcium activated proteases
activity.[46]
Due to the breakdown of the blood
brain barrier, granzyme cells are more
likely to circulate into the CNS, where
they cause oligodendrocyte and
axonal damage.[48]
Perfornin activity increases in the
inflamed state, allowing for additional
perforin to be released and cause
eventual cell damage due to the
perforin⁄ granzyme pathway.[48]
In EAE, when TGF-beta is
administered peripherally, it has been
shown to play a role in the down-
regulation of the immune response.
However, increases in TGF-beta in
the central nervous system have been
found to do the opposite, and is
associated with enhanced EAE with
earlier onset.[18] In humans, TGF-
beta is typically under-expressed and
patients undergoing therapies that
increase TGF-beta levels have shown
the potential for decreased
inflammation.[18]
Clinical Manifestations

Figure 3. Classifications of Multiple Sclerosis

http://askdrrobert.dr-robert.com/MS.html

Classifications of MS
There are two main forms of MS; relapsing-remitting (RR)-MS and secondary-progressive (SP)-MS. RR-
MS is the most common form, with 85-90% of cases presenting as this type.[1] Most of these people will
go on to develop SP-MS, which is associated with gradual loss of neurological function and eventual
paralysis.[2] A third form is present in 10-15% of patients and is characterized by a steady disease
progression with no relapses. This type is called primary-progressive (PP)-MS.[1]

Disease Course
It is important to first understand that the disease course for an individual with MS is diverse and
variable. Initially, patients typically experience the clinical onset of an acute or subacute episode of
neurological disturbance of the CNS.[49] Clinically, this is known as clinically isolated syndrome and may
present with optic neuritis, isolated brain stem, partial spinal cord syndrome, or hemispheric
syndromes.[49] As the disease progresses into MS, diagnoses can be made in a variety of ways using
the McDonald Criteria for MS.

As the disease progresses, no patterns are visible in the timing or location of the lesions.[49] Most
patients with MS (up to 85%) experience a relapsing-remitting course of MS (RRMS) that is
characterized by episodes of symptoms over several weeks followed by full recovery or lasting residual
symptoms.[1] Relapse is defined by the presence of new signs or symptoms for at least 24 hours that are
unrelated to fever or elevated body temperature.[1]
Approximately 20% of patients will display benign MS, which is categorized as clinically stable
presentation with full functionality of all neurological systems for 20 years.[1] The other 80% of
individuals with MS will develop secondary progressive phase (SP) of MS.[1][49] There are two subtypes
of this classification relapsing-SP disease in which progression results from a failure to recover from
relapses and non-relapsing-SP disedase in which disability is acquired in the absence of superimposed
relapses.[1][49]

Another disease course, though highly uncommon, is progressing relapsing MS which is progressive in
nature from onset with clear acute relapses that occur with or without recovery while the periods between
relapses continue progression in severity.[1]

Once again, MS is an unpredictable disease. Good prognostic signs include, female sex, a younger age
of onset, an initial presentation of either optic neuritis or sensory symptoms, full recovery from the first
attack, a long period between the first and second attacks and a low baseline lesion load on MRI but
these prognostic factors cannot predict the course of the disase.[2] At 15 years after the onset of MS
approximately 30% of patients have benign MS; this figure drops to 15% at 25 years and 5% after 30
years disease duration.[2]

MS is typically not a fatal disease; survival in MS is only marginally shortened by 5–7 years compared
with general population in Western countries. Malignant MS occurs very rarely which typically refers to
subjects who have frequent and disabling attacks with poor recovery. As a result of this rapidly
progressive course, severe disability or death can occur within two years.[2][49]

Disease Modifiers
Pregnancy is a disease modifying factor of MS but it does not have a negative effect on the course of
MS. In fact, women with MS who have no children have a poorer long-term outcome than those with
children.[2] Recent findings also confirm that the relapse rate decreases significantly during the second
and third trimester of pregnancy and increases after birth.[1][2] Hormone levels during menstruation and
gender differences in EAE susceptibility related to the effects of testosterone also impact the disease
course.[1] Finally, increasing MS disease activity as demonstrated on an MRI correlates to high estradiol
and low progesterone levels.[1]

Viral or bacterial infections can also trigger an MS attack. Inactive influenza and hepatitis B component
vaccines have found to be safe.[1] No other data exists for other vaccines but researchers have
assumed that other inactive or hepatitis B component vaccines would be equally safe.[1] Live attenuated
viral vaccines have not yet been found to be safe. Administering a live vaccine to an individual with an
MS diagnosis has the potential risk for triggering an MS attack so the risk must be weighed between an
MS attack or the infection as a result of not receiving the vaccine.[1]

Cortical lesions
Post-mortem research has shown that increased cortical demyelination is most commonly associated
with progressive MS. Cortical lesions and damage to adjacent white matter is evident by diffuse axonal
injury relating to the whole brain and meninges. Currently, there are three types of cortical lesions:
cortico-subcortical (affecting cortical and related white matter), intracortical, and subpial (affecting areas
adjoined to the subarachnoid space). Grey matter lesions occur with less inflammation compared to
white matter lesions, as evident by decreased macrophage and lymphocyte activity at the lesion sites.
Despite this finding, critical axonal transection and neuronal damage is present within lesions. Subpial
cortical lesions are associated with follicle-like structures within the meninges containing B-cells and
dendrite cells. These structures have been found in a subgroup of secondary progressive MS. Within this
subgroup patients experienced more severe symptoms, increased disability, and earlier death.[2]
Figure 4. Clinical Manifestations of Multiple Sclerosis
http://www.msconnections.org/

Symptoms
Most common symptoms: [50]
• Fatigue - one of the most common symptoms of MS, occurring in about 80% of people.
• Numbness
• Walking (gait), balance, and coordination problems
• Bladder dysfunction - occurs in at least 80% of people with MS
• Bowel dysfunction
• Vision problems
• Dizziness and vertigo
• Sexual dysfunction
• Pain - up to 55% of people with MS have “clinically significant pain” at some time; almost 50% have
chronic pain
• Cognitive function - approximately 50% of people with MS will develop problems with cognition.
• Emotional changes
• Depression
• Spasticity

Less common symptoms:

• Speech disorders - Speech and voice problems occur in approximately 25-40% of people with MS,
particularly during relapses or periods of extreme fatigue.
• Swallowing problems
• Headache
• Hearing loss - approximately 6% of people who have MS report impaired hearing
• Seizures - fairly uncommon in people with MS, approximately 2% to 5% incidence rate compared to 3%
incidence rate in the general population
• Tremors
• Respiration/breathing problems
• Itching

Animal Model of Experimental Autoimmune

Encephalomyelitis (EAE)

Figure 5. Animal Models of Multiple Sclerosis.

http://www.nature.com/nri/journal/v7/n9/fig_tab/nri2153_F3.html

Overview
EAE is an animal model of brain inflammation used to study central nervous system (CNS) demyelinating
disorders such as MS as well as general T cell-mediated autoimmune diseases. The disease is
introduced to animals by injection of a myelin antigen, which is activated in the periphery by myelin-
specific T cells. The components of the injection include proteins found in myelin (primarily MBP) along
with Freund’s adjuvant.[19] The inflammatory process is triggered by the body identifying its own myelin
as a pathogen and mounting an attack, acting to "activate" the myelin antigen. The blood-brain barrier is
permeated by these activated myelin antigens and they are then reactivated once in the CNS by
activated antigen-presenting cells. These cells display MHC class II-associated peptides, which initiate
the inflammatory process. This inflammatory process within the CNS leads to demyelination and axonal
damage, similar to MS. EAE can present in animals as acute, chronic, or relapsing-remitting, depending
on the protocol used and the background of the animals used.[19] EAE is induced in animals to
investigate the viral and bacterial infection model for triggers of MS and is the most widely used model
for the study of this disease. However, there is conflicting evidence for EAE as the primary trigger of MS
in humans and thus its ability to predict disease course and treatment responses in humans has been
questioned. Researchers are now reaching a stage where the immunology of EAE and animals models
is understood very well while the mechanisms in human MS are still poorly understood. Some
researchers are now turning their attention towards the further characterization of cytokines, growth
factors, and developmental pathways and their effects upon cells of the nervous system.[6] Despite this,
it remains the primary model to study CNS inflammatory diseases.[1]

Uses
EAE has helped provide a better understanding of the inflammatory processes involved in the course of
a disease similar to MS, also helping in the development of treatments for MS such as glatiramer acetate
and natalizumab.[13] Utilizing EAE has helped identify which factors are present at certain stages of the
disease, which factors are initiating the process, and is helping to clarify specific cells’ roles in the
pathogenesis of MS. Specifically, the role of T cells in MS has been studied and their specific function in
MS remains controversial.[13]

Pharmacologic Interventions
Disease Modifying Agents
Interferon beta (IFN beta)

Overview:
Interferon beta is a drug that is approved for the treatment of MS.[18] Brand names of this drug include
Betaferon®, Extavia®, Avonex® and Rebif®.[2] It is theorized to have a modifying effect on several
aspects of the disease course of MS. It has the ability to alter the inflammatory response, improve self-
regulation of the immune system, restore the balance of the blood brain barrier and help repair cell
damage.[51]

 Mechanisms of action:
o Effects on Cytokines and T-cells
 Increases Th2 anti-inflammatory cytokines (IL-4 and IL-10) while
decreasing Th1 pro-inflammatory cytokines (IFN-gamma, IL-12, IL-23)[18][51]
 Reduces the percentage of T cells that produce IL-17, an inflammatory
cytokine[51]
 Increases presence of IL-1R alpha and TNF-RII which are able to block cell
responses to IL-1 and TNF (inflammatory cytokines) [51]
 Causes apoptosis of activated T cells due to an increase in survivn levels, a
modulator of apoptosis [18][51]
  Restores function and causes expansion of regulatory T cells[51]
o Effects on Chemokines and Adhesion molecules
 VLA-4 and LFA-1 adhesion molecules on T cells are decreased. This may
contribute to apoptosis of the activated T cells mentioned above[51]
 Surpresses expression of CNS neutrophil chemokines and T cell
chemokines[51]
 Causes beneficial changes in Matrix metallo-proteases (MMPs) by increasing
the levels of TIMP-1 which is an MMP inhibitor. MMP’s are important for the
passage of immune cells through the blood brain barrier[51]
 Increases adenosine levels which helps to prevent lymphocytes from crossing
the blood brain barrier[51]
o Other Effects
 Decreases B-cell stimulatroy effects[51]
 ReducesMHC II expression on a variety of cells[51]
 Increases B7-H1 expression, which is found on dendritic cells and monocytes
and supresses T-cell inflammatory responses[51]
 Increases number of CD56(bright) natural killer cells[51]
 Acts to turn cells towards a Th2 phenotype as opposed to Th1 phenotype [51]
 Side Effects:
o Hepatotoxicity, which is life-threatening, is very rare [51]
o Hypothyroidism, fatigue, depression and myalgias common but managable [51]
o Flu-like symptoms that usually reside after 2-3 months on the drug [2]
o Possible liver abnormalities and mild lymphopaenia require regular blood testing [2]

Glatiramer acetate (GA)

Overview:
Glatiramer acetate (GA), also known as Copaxone®, is an approved treatment for MS.[18] It is
composed of amino acids that are similar to the peptide fragments found in myelin basic protein.[2][51] It
is theorized to work by modifying the inflammatory response, improving self-regulation of the immune
system and helping to augment damage.[51] Compared to Interferon beta, GA is more specific to myelin
antigen targeting cells.[51] In general, GA causes a long-term shift from the pro-inflammatory Th1
response, to an anti-inflammatory Th2 response in the central nervous system.[18][51]

 Mecahnisms of Action:
o Effects on Cytokines and T-cell populations
 T-cells that respond specifically to GA have increased expression of brain-
derived neurotrophic factor (BDNF) and the anti-inflammatory cytokines IL-
10 and TGF-beta .[18][51]
 Increased production of BDNF may be what helps repair myelin damage.
 Causes decrease in Th1 cell expression of cytokines and chemokines,
surpressing IL-12, IL-17, and INF-gamma.[18][51]
 Surpresses lymphocyte proliferation.[51]
 Causes apoptosis of CD4+ cells.[51]
o Effects on Chemokines and Adhesion Molecules
 Decreases expression of certian chemokines which results in a decrease in the
ability of T-cells to cross the blood brain barrier.[51]
 Reduces expression of RANTES, a cytokine that attracts T lymphocytes, in
astroglial cells.[51]
o Other Effects
 Causes production of IgG4 which affects the humoral immune response so that
patients with stronger antibody responses had fewer relapses. [51]
 Competes with MBP epitpoes and can prevent responses of antigen presenting
cells and T-cell receptors to myelin antigens.[51]
 Can cause antigen presenting cells to secrete Th2 cytokines.[51]
 Enhances dendritic cell migration from the periphery into the CNS and
enhances survival of neural cells under oxidaitve stress.[51]
  Side Effects:
o Possible skin reactions at injection site [2][51]
o No reported significant toxicities or systemic effects [2][51]

Mitotoxantrone

Overview:
Mitotoxantrone works as a broad spectrum immunosuppresive cytotoxic drug.[2][51]
It is theorized to work mainly by modulating the inflammatory response of the immune system.[51] It
induces apoptosis of active immune cells and inhibits activation of several pro-inflammatory cells and
macrophages.[2][51]

 Mechanisms of Action:
o Effects on Cytokines and T-cell populations
 Reduces active, circulating CD4+ and CD8+ T cell numbers[51]
 Possibly decreases the level of IL-10 [51]
o Effects on Chemokines and Adhesion Molecules
 May reduce migration of CD4+, CD8+ and CD14+ monocytes across the
endothelium
 Inhibits CNS MMP -9 activity in EAE models.
o Other Effects
 In mice models, dendritic cells exposed to Mitoxantrone are less able to break
down myelin .[51]

 Side Effects:
o Rare but significant is the possibility of treatment related leukemia. [2][51]
 Dose-dependent cardiotoxicity is possible and therefore use of the drug must be limited.[51]

Natalizumab

Overview:
Natalizumab is theorized to work by modulating inflammation and restoring the integrity of the blood brain
barrier.[51] It is a monoclonal antibody specific to VLA-4 that blocks VLA-4 from binding to VCAM, an
immune cell ligand that is upregulated on the endothelium during inflammation [2][51] Overall, this leads
to apoptosis of activated T-cells and decreased migration across the blood brain barrier.[51]

 Mechanisms of Action:
o Effects on Cytokines and T-cell populations
 Decreases numbers of CD4+ and CD8+ lymphocytes in the cerebrospinal fluid
 However, CD4+ and CD8+ cells producing IFN-gamma, TNF-
alpha and IL-17 increase in peripheral circulation, possibly due to a
decrease in migration across the blood brain barrier to the CNS[51]
 This raises concern of a rebound effect of the disease once
treatment with Natalizumab is stoppped.[51] The significance
and consequences of this effect are currently unclear[51]
 Decreases production of IFN-ϒ
 Increases production of IL-10
o Effects on Chemokines and Adhesion Molecules
 Directly affects the α4 integrin adhesion molecule which is expressed on
lymphocytes, monocytes, basophils and eosinophils and is part of the VLA-4
antigen that pairs with vascular cell adhesion molecule- 1, or VCAM-1. VLA-4
and VCAM interactions allow lymphocytes to cross the blood brain barrier and
proliferate. This is thought to play an important role in contributing to lesions in
MS.[51]
 The rational then for treatment with Natalizumab is that it inhibits the
relationship between VLA-4 and VCAM-1 and therefore decreases
 transmission across the blood brain barrier and decreases proliferation of
lymphocytes.[51]
o Other Effects:
 Decreases number of B cells in the cerebrospinal fluid (also via inhibition of
VLA-4 signaling).[51]
 Reduces number of dendritic cells in perivascular spaces of the brain.[51]

 Side Effects:
o Rare but devastating possibility of progressive multifocal leukoencephalopathy, a viral
disease that also causes white matter degeneration.[2][51]

* Also rare, but a few patients reported CNS lymphoma [51]

 The effects on fertility and pregnancy for all of the above mentioned therapies is unknown.[51]

Symptomatic Therapies
Many patients use pharmacological therapies to treat the disease process, however, often, these
medications do not resolve the associated symptoms of multiple sclerosis. In fact, some patients may
forego disease-modifying therapies in exchange for symptom-based therapies if thought to be more
beneficial. The most commonly reported MS-related symptoms include fatigue, spasticity, weakness,
bladder/ bowel/ and sexual dysfunction, depression, cognitive problems, tremor, vertigo, nystagmus, and
pain.[52]

The following chart was composed from information taken from a literature review, by Schwendimann
2006 [52], of current treatments of MS symptoms:

Symptomatic Therapies Chart

Conclusion
Clearly, many cellular factors are involved in the pathogenesis and perpetuation of Multiple Sclerosis.
The multi-factorial cause of MS makes it challenging to isolate a definitive pathway for the development
of the disease. Despite advanced understanding of the pathogenesis and perpetuation of CNS auto-
immune inflammatory diseases through EAE models, a cure has not yet been developed. Further
research in this area is necessary to fully understand this disease and develop a cure.

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References
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