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Understanding the Immunology of
Multiple Sclerosis
Kathleen Costello, MS, ANP-BC, MSCN, and Anne Gocke, PhD
Johns Hopkins Multiple Sclerosis Center and Johns Hopkins University School of
Medicine, Baltimore, Maryland
A REPORT FROM THE 28TH ANNUAL MEETING OF THE CONSORTIUM OF MULTIPLE SCLEROSIS CENTERS AND THE
19TH ANNUAL MEETING OF THE AMERICAS COMMITTEE FOR TREATMENT AND RESEARCH IN MULTIPLE SCLEROSIS
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1
How the Normal
Immune System Works
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2
How the Normal Immune System Works

The normal immune system:
» Protects against infectious threats
» Responds to active infections
» Prevents development of autoimmune conditions

The body’s natural defense barriers (skin, body
fluids, mucus, and cilia in the lungs and gut) work
together to keep infectious threats out of the system.

A breech in this barrier system provokes the cellular
activity of the innate immune system.

Activation of neutrophils, monocytes, macrophages,
and natural killer cells leads to eradication of most
pathogens from the body.
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3
Adaptive Immunity

When an infection requires additional immunologic
intervention, the adaptive immune system is called
to action.

Various messengers signal T and B cells to begin to
defend the body.

Cell-surface molecules are critical to activation of the
adaptive immune system, as are co-stimulatory
molecules that allow for full activation of adaptive
immune cells.

Adhesion molecules on blood vessels and cell walls
are upregulated, allowing cells to move from the
bloodstream to the site of infection in tissues.
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4
Immune-System Cells:
Macrophages

Macrophages under the skin, in the lungs, and in the
tissues surrounding the gut collect waste products
and minimize cellular debris from dead cells.

Receptors on the surface of macrophages recognize
signals from the pathogen that stimulate a “seek 
eat  destroy” mechanism.

Macrophages send out signals called cytokines to
recruit neutrophils and monocytes from the blood to
the site of infection.

Macrophages also can engulf an invader and display
a piece of it on the cell surface so that it can be
recognized by the adaptive immune system.
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5
Immune-System Cells:
Neutrophils and Monocytes

Along with macrophages, the chemokines IL-1 and
TNF-a signal neutrophils circulating in the blood to
slow down, sense the location of the infection, and
migrate from the blood vessel to the infected tissue.

Monocytes mature into activated macrophages,
which stimulate repair mechanisms and produce
IL-1, TNF, and reactive oxygen species.

Monocytes also act as antigen-presenting cells
(APCs) for lymphocyte functioning in adaptive
immunity, and they become further stimulated by
the mechanisms of this protective mechanism.
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6
Immune-System Cells:
Natural Killer (NK) Cells

Circulating NK cells use the same mechanism as
neutrophils to exit the circulation and migrate into
tissues at the infection site.

Upregulation of adhesion molecules allows NK cells
to enter the tissue and become killers.

NK cells deliver powerful enzymes to target cells
infected by viruses, which causes the cells to die,
thereby reducing the number of infected cells.

NK cells also secrete cytokines that help activate
macrophages and prime more macrophages to
participate in the killing.
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7
Complement

Complement is a series of proteins that is activated
very rapidly in a coordinated and orderly way by the
innate and adaptive immune systems.

In innate immunity, proteins in the complement
system can become active when they recognize
common chemical groups on the infected cell
surface.

Complement can ”tag” an invader for destruction or
bore a hole in invading cells to destroy them.
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8
Antigens and Antibodies

Activation of the adaptive immune system induces:
» Cell-mediated activity involving specialized T cells known as
T helper (Th) cells
» Humoral activity, involving B and T cells, antibodies, and
complement

Antigen recognition and binding allows antibodies to
perform four important effector functions that are
important in eliminating invading pathogens:
» Opsonization
» Complement activation
» Toxin neutralization
» Blocking attachment
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9
T-Cell Activation

T cells are activated only if a recognizable antigen is
presented to them by an antigen-presenting cell,
such as a dendritic cell or a macrophage.

Naïve T cells are stimulated by antigen presentation
and differentiate into various T-cell subsets:
» Th1 differentiation results from stimulation by IL-23 and
interferon γ.
» Th2 differentiation results from stimulation by IL-4.
» Th17 differentiation results from stimulation by IL-6, IL-1,
and IL-23.

T cells become activated and multiply based upon
the antigen presented and the cellular environment.
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10
T-Cell Activation continued
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11
B-Cell Activation

B cells recognize antigen in the circulation and bind
to the antigen and internalize it.

After internal processing, a small piece or peptide of
the antigen is presented on the cell surface in a
groove of the major histocompatibility complex
(MHC) molecule, where an activated or memory T
cell can recognize and interact with it.

This contact sends signals to the B and T cells to
allow the T cells to stimulate production of receptors
and cytokines and provide a second co-stimulatory
signal for B cells.
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12
B-Cell Activation continued
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13
Summary

A highly complex immune system protects the body
from pathogens and purges invasive proteins from
the circulation.

The normal immune system is characterized by
specificity, diversity, and memory, and it can
differentiate the body’s own cells from foreign cells.

If the immune system malfunctions, however,
autoimmunity and disease may develop.
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14
What Causes Inflammation of the
Central Nervous System in MS?
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15
Pathogenesis of MS

Multiple sclerosis (MS) is an immune-mediated
inflammatory disease characterized by myelin
destruction, damage to CNS-resident cells, and loss
of mobility and cognition.

In acute and chronic active lesions, axons commonly
are preserved; macrophages that have taken up
myelin debris are evident.

In contrast, inactive lesions feature a loss of axons
and oligodendrocytes and few macrophages.

Cortical plaques, which involve the gray matter, also
may be found.
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16
Risk Factors for Development of MS

The antigens that are targeted in MS may include
neuronal proteins and astrocytic proteins.

Genetic predisposition has been linked with
mutations in cytokine receptor genes (IL2RA, IL7R)
as well as HLA-DR2B.

Environmental factors, including vitamin D, EpsteinBarr virus, and gut and lung immunity, also play an
important role in MS susceptibility.

Gender is another risk factor for development of the
disease; approximately two thirds of MS patients are
female.
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17
Actions of T and B Cells in MS

CD4+ T cells and cytotoxic CD8+ T cells play a
pathogenic role in MS, likely due to their ability to:
» Secrete pro-inflammatory cytokines
» Recruit peripheral monocytes and B cells to MS lesions

B cells may secrete antibodies that can mediate direct
damage to axons.

The presence of lymphoid follicles in the meninges of
some patients points toward a pathogenic role for B
cells in MS.

B cells also help in neuronal repair and remyelination
by promoting clearance of myelin debris via
opsonization.
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18
Other Pathologic Changes

Microglia sense changes in the CNS and release
cytokines and chemokines that pave the way for
entry of other immune cells into the lesion site.

Peripheral monocytes infiltrate the CNS and secrete
proinflammatory cytokines and toxic molecules,
such as nitric oxide, IL-1, IL-6, and matrix
metalloproteinases, that can directly damage
oligodendrocytes and neurons.

The most important determinants of permanent
neurologic disability in MS patients are axonal
damage and loss; axonal damage may occur even
early in the course of the disease.
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19
Hypothetical Pathologic Mechanisms

Activation of CD8+ T cells to target neurons directly

Vigorous CD4+ T-cell responses that recruit
macrophages, resulting in the release of
inflammatory mediators and toxic molecules

Binding of antibodies to neuronal surface antigens,
followed by complement fixation or antibodymediated phagocytosis of axons

Invasion by immune cells resulting in secondary,
inflammation-independent neurodegeneration

Chronic inflammation leading to mitochondrial
dysfunction, dysregulation of ion channels, and
release of glutamate or nitric oxide
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20
Summary

The etiology of MS is unknown; however, the
immune system is important to the development of
the disease, and lesions affect both the gray and
white matter.

MS may begin with an invasion of the CNS by T and
B cells; these events may be secondary to activation
of microglia and macrophages and the local release
of self or foreign antigens.

A small number of antigens present in the CNS may
drive the highly focused, persistent acquired immune
response in MS.
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21
How Current Disease-Modifying
Therapies Affect the Altered
Immune Response in MS
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22
Disease-Modifying Therapies (DMTs)
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23
Interferon b-1a and b-1b

Reduce T-cell activation and proliferation

Reduce secretion of matrix metalloproteinases that
disrupt the blood-brain barrier (and thus allow fewer
immune cells entry into the CNS)

Inhibit interferon g release (reduces antigen
presentation to T cells)

Limit T-cell migration across the blood-brain barrier

Reduce antigen processing and antigen presentation
to T cells
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24
Interferon b-1a and b-1b continued

At low doses, minor side effects include flu-like
symptoms, headache, transaminitis, and depression;
major side effects include suicidal ideation,
anaphylaxis, hepatic injury, blood dyscrasias,
seizures, and autoimmune hepatitis.

At high doses, all of these effects may be seen, in
addition to injection-site reactions and skin necrosis.

Patients should be followed with complete blood
counts with differential, liver and thyroid function
tests, and interferon-neutralizing antibodies, if
clinically warranted.
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25
Glatiramer Acetate

Causes migration of Th2 cells into the CNS,
modification of antibody production by plasma cells,
and regulation of B-cell properties.

Recent evidence suggests that glatiramer acetate
may produce cytokine modulation, inhibition of
antigen presentation to T cells, and effects on
oligodendrocyte precursor cells (myelin repair).

Minor side effects include injection-site reactions
and post-injection vasodilatory reactions.

Major side effects include lipoatrophy, skin necrosis,
and anaphylaxis.
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26
Fingolimod

Antagonizes sphingosine 1-phosphate receptors,
blocking lymphocyte egress from secondary
lymphoid organs to the peripheral blood circulation

Minor side effects include mild lymphopenia and
transaminitis.

Major side effects include bradycardia, heart block,
hypertension, increased risk of herpetic infections,
lymphopenia, macular edema, skin cancer, reactive
airway, and posterior reversible encephalopathy
syndrome.
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27
Teriflunomide

Mimics pyrimidine as a DNA building block,
interfering with DNA synthesis and inhibiting
dihydro-orotate dehydrogenase.

Reduces T-cell proliferation and activation and
production of cytokines, and it interferes with the
interaction between cells and APCs.

Minor side effects include diarrhea, nausea, and
thinning of the hair.

More severe effects include transaminitis,
lymphopenia, teratogenicity, latent tuberculosis,
neuropathy, and hypertension.
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28
Dimethyl Fumarate

Changes the balance of Th1 to Th2 cells

Activates the transcription factor Nrf2
transcriptional pathway, reducing oxidative stress.

Minor side effects include flushing and GI distress

More severe effects include transaminitis and
leukopenia.
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29
Mitoxantrone

Inhibits DNA topoisomerase II, suppressing the
proliferation of T and B cells and macrophages.

Side effects range from nausea, vomiting, hair
thinning, infections, liver dysfunction, and menstrual
irregularities to cardiotoxicity, acute myelogenous
leukemia, serious infections, and infertility.

Owing to its high-risk profile and the availability of
other effective DMTs with fewer and less severe side
effects, mitoxantrone currently is used infrequently
for the treatment of MS.
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30
Natalizumab

Block the expression of a4-integrin on the surface of
lymphocytes, limiting the number of lymphocytes
that enter the CNS.

Side effects include headaches, joint pain, fatigue,
and a wearing-off phenomenon, wherein patients
feel a temporary recrudescence of their MS
symptoms just prior to each infusion.

The major risk of taking natalizumab is a severe,
potentially fatal infection known as progressive
multifocal leukoencephalopathy (PML)

Infusion reactions, hypersensitivity reactions, and
other serious infections also may occur.
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31
Peginterferon b-1a

Peginterferon b-1a is a chemically modified version
of interferon b-1a where polyethylene glycol has been
attached to the interferon molecule, thus allowing it
to remain active in the circulation for 2–4 weeks
after a single subcutaneous injection.

Adverse effects include injection-site reactions and
flu-like symptoms.

Laboratory monitoring of MS patients receiving this
peginterferon b-1a should be similar to that of other
beta interferons.
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32
How Does Progressive MS
Differ from Relapsing MS?
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33
Disease Progression

Most patients with MS will experience progression at
some stage of their disease.

A definitive disease mechanism for progressive and
relapsing MS has not been identified, although the
role of environmental triggers, genetics, and other
factors has been scrutinized.

A number of interlinked pathways may contribute to
pathogenesis of the disease.
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34
Primary-Progressive MS (PPMS)

Patients with PPMS exhibit a steady increase in
disability without attacks.

Men are more likely to be affected by PPMS than by
any other form of the disease.

This form of disease progression typically beings
about 10 years after the onset of relapsing-remitting
MS (RRMS).

Genetic susceptibility and the pathology of this
disorder are similar to those of other forms of MS,
and an underlying neurodegenerative problem could
be involved.
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35
Primary-Progressive MS (PPMS) continued

Meningeal infiltrates of B and T cells are particularly
prominent in patients with PPMS.

In addition, lymphoid follicles associated with
underlying microglia activation and cortical plaques
may be evident.

White-matter plaques often are neuroinflammatory
at their center, but microglia, macrophages, and
ongoing simmering and possibly concentrically
expanding axonopathy may be found.

Diffuse, low-grade parenchymal inflammation also
has been reported.
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Primary-Progressive MS (PPMS) continued

In PPMS, brain damage is driven by inflammation
similar to that of RRMS but with an intact bloodbrain barrier.

This condition starts as an inflammatory disease;
however, chronic inflammation then leads to
neurodegeneration or disease progression
independent of inflammation.

This neurodegeneration might cause intact neurons
to lose control over microglial activation.

In early stages of the disease, inflammation amplifies
progression of primarily neurodegenerative disease.
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37
Primary-Progressive MS (PPMS) continued

Therapeutic failures could be explained by
perivascular inflammation, which often occurs
without associated disruption of the blood-brain
barrier.

Axonal and neuronal death may result from
glutamate-mediated excitotoxicity, oxidative injury,
iron accumulation, and/or mitochondrial failure.

Currently, a lack of full understanding about the
biology of MS impedes development of effective
treatments for PPMS.
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38
Differences Between RRMS and PPMS

RRMS is characterized by acute focal inflammatory
lesions in the white matter and is associated with
inflammatory demyelinating lesions in the brain and
spinal cord, which herald axonal damage and loss
related to the foci of inflammation.

The gray matter is involved less prominently than it
is in progressive MS.

In contrast, PPMS is characterized by diffuse (rather
than focal) inflammation and involves more
prominent cortical demyelination, diffuse axonal
injury, and, frequently, the presence of microglial
nodules in the brain.
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39
Pathogenesis:
Inflammation

Inflammation occurs in all stages of MS and is
characterized by perivascular and parenchymal
infiltrates of lymphocytes and macrophages.

The initial inflammatory response in patients with
RRMS mainly involves the proliferation of CD8+
T cells in active lesions, as abundant macrophages
are recruited and activated.

In the secondary response, T and B cells and
macrophages are recruited as a result of myelin
destruction.
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40
Pathogenesis:
Inflammation continued

Profound damage to the blood-brain barrier, as
evidenced by the presence of gadolinium-enhancing
lesions on MRI, results from infiltration of
inflammatory cells into the CNS.

The relationship between inflammation and damage
to the blood-brain barrier is less obvious in patients
with progressive MS, because impairment can occur
with or without inflammatory infiltrates.

Features of lymphoid follicle are found in large
aggregates of inflammatory cells in the meninges; as
the disease progresses, inflammation becomes
compartmentalized behind the intact blood-brain
barrier.
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41
Pathogenesis:
Demyelination

The pathology of both acute and relapsing MS is
dominated by focal inflammatory demyelinated
plaques in the white matter.

In progressive MS, slow expansion of preexisting
lesions results in pronounced cortical demyelination
associated with extensive diffuse injury in white and
gray matter that appears to be normal.

Cortical lesions occur most abundantly during
disease progression; these lesions are most prominent
in subpial cortical layers and can be linked to local
meningeal inflammation.

Activated microglia are associated with active lesions.
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42
Pathogenesis:
Tissue Injury

The brains of patients with MS exhibit widespread
inflammation, microglial activation, astrogliosis, and
mild demyelination and axonal loss in normalappearing white matter.

The extent and severity of these changes increase
with disease duration and most closely are asociated
with progressive MS; small-caliber axons are most
affected.

However, the extent of diffuse injury does not
correlate with the number, size, or destructiveness of
focal lesions; instead, it correlates moderately with
the extent of cortical demyelination.
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43
Pathogenesis:
Tissue Injury continued

RRMS is related to distinct patterns of
demyelination and tissue injury, probably because
the inflammatory lesions present in RRMS possess
distinct immune processes.

In contrast, patterns of tissue injury largely are
homogeneous in secondary-progressive MS (SPMS)
and PPMS, probably because of the slow expansion
of existing lesions with sparse remyelination.
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44
Disease Processes:
Microglial Activation

In both RRMS and progressive MS, active tissue
injury is associated with microglial activation.

In addition, microglial nodules are seen in
progressive MS.

Oxidative bursts by activated microglia my help to
induce demyelination and progressive axonal injury.

Microglia may be neuroprotective and could
promote remyelination after debris is removed and
neurotrophic molecules are secreted.
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45
Disease Processes:
Mitochondrial Injury

The pathogenesis of MS may be related to energy
deficiency or “virtual hypoxia.”

Impaired NADH dehydrogenase activity and
increases in complex IV activity have been noted in
the mitochondria of MS lesions.

Mitochondrial injury may reflex oxidative damage in
areas of initial tissue injury.

The increased susceptibility to neurodegeneration
seen in patients with SPMS and PPMS may be
explained partially by an accumulation of
mitochondrial DNA deletions.
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46
Disease Processes:
Mitochondrial Injury continued

Oxidative stress encourages mitochondrial
dysfunction in a number of ways:
» Free radicals disrupt mitochondrial enzyme function.
» Oxidative stress modifies mitochondrial proteins and
accelerates their degeneration.
» Further, oxidative stress interferes with de novo synthesis of
respiratory chain components and induces mitochondrial
DNA damage.

Oxidative injury is pronounced in progressive MS
lesions, even though inflammation is low; therefore,
it may be driven by factors other than inflammatory
processes.
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47
Disease Processes:
Iron Accumulation

In the aging brain, iron accumulates and is stored in
oligodendrocytes; subsequently, it is detoxified when
it binds to ferritin.

Intracytoplasmic iron accumulation may explain why
these cells are so susceptible to degeneration during
oxidative stress.

In MS lesions, activated macrophages and microglia
take up iron, leading to dystrophy, fragmentation,
and cellular degeneration.

The process depends upon patient age and may be
more pronounced among patients with progressive
MS than among those with RRMS.
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48
Summary

A number of interlinked pathways contribute to
development of MS, and inflammation mediated by
T and B cells and macrophages orchestrate the
demyelination and degeneration seen in all patients.

Tissue injury may be affected by microglia activation,
oxidative injury, and damage to mitochondria.

In progressive MS, liberation of iron may enhance
oxidative damage and result in increased
neurodegeneration.

Accumulated tissue damage exhausts functional
reserve brain capacity and may accelerate clinical
deterioration, with slow, progressive tissue injury.
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49