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Basic Immunology
and
Multiple Sclerosis
Ben Thrower M. D.
Shepherd MS Institute
Atlanta, GA
Why Immunology?
disease.
• MS is an autoimmune disease
• Existing and future therapies work by
modulating or suppressing the immune
system.
References
1. AK
1 Abbas AK, Lichtman AH AH.
Basic Immunology: Functions and
System. W.B.
Disorders of the Immune System W B
Saunders Company. 2001.
2. Sospedra M M ti R A
2 S d M, Martin R. Annu. R Rev.
Immunol. 2005; 23: 683-747.
Immunology is like an onion …..
it s
….. not because it’s stinky and makes
you want to cry…..
layers.
….. but because there are lots of layers
Overview of the Immune System
Immune System
Adaptive
Innate
(Specific)
(Nonspecific) o line of defense
2
1o line of defense Protects/re-exposure
Cellular Humoral Cellular Humoral
Components Components Components Components
Function of the Immune System
(Self/Non-self Di
(S lf/N i i ti )
lf Discrimination)
• To protect from pathogens
• ( g
Intracellular (e.g. viruses and some bacteria
and parasites)
• Extracellular (e.g. most bacteria, fungi and
parasites)
• To eliminate modified or altered self
Effects of the Immune System
• Beneficial:
• Protection from invaders
• Elimination of altered self
• Detrimental:
• Discomfort and collateral damage
(inflammation)
(i fl ti )
• Damage to self (hypersensitivity or
autoimmunity)
Innate (Nonspecific) Immunity
Innate Host Defenses Against
Infection
I f ti
• Anatomical barriers
– Mechanical factors
– Chemical factors
– Biological factors
• Humoral components
– Complement
Coagulation system
– C l ti t
– Cytokines
• Cellular components
– Neutrophils
– Monocytes and macrophages
– NK cells
– Eosinophils
The Adaptive Immune System
• Cell-mediated Immunity (Cytotoxicity)
• T cells
• CD4+ (Th1 & Th2)
• CD8+
• Humoral Immunity (Antibody production)
• B Cells
Comparison of Innate and Adaptive
Immunity
I it
Innate Immunity Adaptive Immunity
• No time lag • A lag period
• Not antigen specific • Antigen specific
• No memory • Development
of memory
Cells of the Immune System
Immune System
Myeloid Cells Lymphoid Cells
Granulocytic Monocytic T cells B cells NK cells
Neutrophils Macrophages Helper cells
Basophils
B hil Kupffer ll
K ff cells S
Suppressor cells
ll Pl ll
Plasma cells
Eosinophils Dendritic cells Cytotoxic cells
Immune Interactions
• Cell Receptors
Immune Interactions
• Cell Receptors
Endothelial Lining
Immune Interactions
• Cytokines – Powerful chemical substances
that allow for interactions between cells of
system
the immune system.
Immune Interactions
• Chemokines – Chemicals used by one
immune cell to attract another cell to an
inflammation
area of inflammation.
Cells of the Immune System
• Lymphocytes
1) B cells, T cells,
cells.
Natural killer (NK) cells
2) Have receptors for specific
antigens.
antigens
3) Key mediators of adaptive immunity.
4) Nomenclature based upon surface
proteins called CD (cluster of differentiation).
Cells of the Immune System
• Antigen-presenting cells (APC)
1) Dendritic cells, macrophages,
ll i li (CNS).
B cells, microglia (CNS)
2) Capture of antigen for display to
lymphocytes.
Cytokines
immunity,
• Mediators involved in cellular immunity
including hormone-like glycoproteins
released by activated T cells and
macrophages.
co-stimulators
• Some are co stimulators of T cells and T
cell proliferation.
T cells
T-cells
CD8
T cell
APC Naïve
T cell
CD4
T cell
CD4 T Helper Cells
• Activation of macrophages
• Activation, proliferation and differentiation
of T and B lymphocytes
Major Histocompatibility Complex
(MHC)
• Proteins expressed on the cell surface
which play a role in the immune system
autoimmunity.
and autoimmunity
• Referred to as HLA (human leukocyte
humans.
antigen) in humans
Major Histocompatibility Complex
(MHC)
• MHC class I – present on all nucleated
cells. Present antigen fragments to CD8
cells
cells.
• MHC class II – present on antigen
(APC).
presenting cells (APC) Present antigen to
CD4 cells.
CD4+ T Helper Cells
MHC II – Major Histocompatibility Complex*
CD4
APC TCR
CD8
Immature CD4+/CD8+ T Cell
* MHC = HLA (Human Lymphocyte Antigen)
CD4+ T Helper Cells
CD4
TCR
CD8
Mature CD4+ Cell
CD4 / APC Receptors
CD4
TCR Class II MHC
CD3
CD28 B7-1/B7-2 (CD80/CD86)
LFA-1 ICAM -1
VLA-4
CD4 T Helper Cell APC
Immunological Synapse”
The “Immunological Synapse
• The interaction
between the TCR and
MHC molecules is not
strong
• Accessory molecules
stabilize the interaction
– CD4/Class II MHC or
CD8/Class I MHC
– CD2/LFA-3
LFA 1/ICAM 1
– LFA-1/ICAM-1
Immunological Synapse”
The “Immunological Synapse
• Specificity for antigen
resides solely in the
TCR
• The accessory
molecules are
invariant
• Expression is
increased i response
i d in
to cytokines
Immunological Synapse”
The “Immunological Synapse
g g
• Engagement of TCR and
Ag/MHC is one signal
needed for activation of T
cells
• Second signal comes from
costimulatory molecules
– CD28 on T cells interacting
with B7-1 (CD80) or B7-2
(CD86)
– Others
• Costimulatory molecules
are invariant
CD4 / APC Receptors
CD4
Costimulatory TCR Class II MHC
p
Receptor
CD3
CD28 B7-1/ B7-2
LFA-1 ICAM -1
VLA-4
CD4 T Helper Cell APC
CD4 / APC Receptors
CD4
Adhesion TCR Class II MHC
Receptors
R t
CD3
CD28 B7-1/ B7-2
LFA-1 ICAM -1
VLA-4
CD4 T Helper Cell APC
CD4 / APC Receptors
CD4
TCR Class II MHC
g
Integrins
CD3
CD28 B7-1/ B7-2
LFA-1 ICAM -1
VLA-4
CD4 T Helper Cell APC
Costimulation is Necessary for T Cell
Activation
• Engagement of TCR and
Ag/MHC in h b f
A /MHC i the absence of co-
stimulation can lead to anergy
• Engagement of co-stimulatory
E t f ti l t
molecules in the absence of
TCR engagement results in no
p
response
• Activation only occurs when
both TCR and co-stimulatory
molecules are engaged with
their ti li d
th i respective ligands
• Downregulation occurs if CTLA-
4 interacts with B7
– CTLA 4 sends an inhibitory
CTLA-4 inhibitor
signal
Key Steps in T cell Activation
p
• APC must process and p peptides to T cells
present p p
• T cells must receive a costimulatory signal
– Usually from CD28/B7
• Accessory adhesion molecules help to stabilize binding
of T cell and APC
– CD4/MHC-class II or CD8/MHC class I
LFA-1/ICAM-1
– LFA 1/ICAM 1
– CD2/LFA-3
• Signal from cell surface is transmitted to nucleus
– Second messengers
• Cytokines produced to help drive cell division
– IL-2 and others
Naïve CD4 T cells differentiate into TH1 and TH2
cells
Naïve
CD4
T cell
Th1 Th2
Anti-
Pro-inflammatory
inflammatory
Cytokines
• IL-2
Cytokines
• Il-12
Reciprocal Inhibition • IL-4
• IL-5
• IFN-γ
• Il-10
• TNF
• IL-13
• TGF-β (TH3)
B cell
Macrophage
Yong, W
CD4 Subsets
CD4
T cell
IL-12
IL 12
IL-6/IL-23
IL-4
CD4 CD4
Th1 cell CD4 Th17 cell
Th2 cell
Cells
CD4 Th17 C ll
• Recently described subset of CD4 cells.
IL-17 TNF
• Cytokines produced = IL 17 and TNF-
alpha.
Stimulated by IL-6 d IL-23 t ki
• Sti l t d b IL 6 and IL 23 cytokine.
Bettelli E, Carrier Y, Gao W, et al. Nature 2006; 441(7090):235-238.
T cells
T-cells
CD8
T cell
APC Naïve
T cell
CD4
T cell
CD8 T Cells
• Cytotoxic CD8 cells are the only T cells
capable of killing other cells by direct
contact.
contact
• CD8 cells may also serve a regulatory or
role.
suppressive role
CD8+ T Cells
MHC I – Major Histocompatibility Complex*
CD4
APC TCR
CD8
Immature CD4+/CD8+ T Cell
* MHC = HLA (Human Lymphocyte Antigen)
CD8+ T Cells
TC
Cytotoxic
CD4
TCR
CD8
TS
Suppressor
Mature CD8+ Cell
CD8 / APC Receptors
CD8
TCR Class I MHC
CD3
CD28 B7-1/ B7-2
LFA-1 ICAM -1
VLA-4
CD8 T Cell APC
Cytotoxic T Cell (Tc)
, , y
• TC cells, or killer T cells, are the only T cells that
can directly attack and kill other cells
• They circulate throughout the body in search of
body ll h display h i hi h h
b d cells that di l the antigen to which they
have been sensitized
• Their targets include:
– Virus-infected cells
– p
Cells with intracellular bacteria or parasites
– Cancer cells
– Foreign cells from blood transfusions or transplants
Mechanisms of Tc A ti
M h i f Action
• In some cases, TC cells:
– Bind to the target cell and release perforin into
its membrane
• In the presence of Ca2+ perforin causes cell lysis
by creating transmembrane pores
• Other TC cells induce cell death by:
– Secreting lymphotoxin, which fragments the
target cell’s DNA
– Secreting gamma interferon, which stimulates
phagocytosis by macrophages
B Cells
• B cells may mature into antibody
producing plasma cells.
APC s.
• B cells may function as APC’s
B Cell – CD4 Th Interactions
CD40 CD 40 Ligand
CD4 Th
B Cell TCR C ll
Cell
MHCII
CD28
B7
Cytokine Receptor
B Cell Proliferation CD4 Activation
and Differentiation
CD40 CD 40 Ligand
CD4 Th
B Cell TCR Cell
C ll
MHCII
CD28
B7
Antibodies
• Also called immunoglobulins
– Constitute the gamma globulin portion of
blood proteins
– Are soluble proteins secreted by activated B
cells and plasma cells in response to an
antigen
p g p y
– Are capable of binding specifically with that
antigen
• There are five classes of antibodies:
IgD, IgM, IgG, IgA, and IgE
Natural Killer (NK) Cells
antibody coated cells.
• Bind to and kill antibody-coated cells
• Called “natural killers” because they do not
first.
have to recognize antigen first
g
Immunological tolerance
• Definition:
– Specific immune unresponsiveness to an antigen that
is induced by exposure of lymphocytes to that antigen
(tolerogen vs immunogen)
• Significance:
– All individuals should be tolerant of their own
antigens (self-tolerance); breakdown -->autoimmunity
p
– The induction of tolerance could be exploited to treat
autoimmune diseases
– Mechanisms of tolerance must first be understood
Mechanisms of unresponsiveness
to lf ti
t self antigens
• Central tolerance
– Immature self-reactive T lymphocytes that recognize self
g y g g
antigens in the thymus undergo negative selection
(deletion).
• Peripheral tolerance
Mature self-reactive T lymphocytes th t escape central
–M t lf ti l h t that t l
tolerance and recognize self antigens in peripheral tissues
(anergy), ( ) g
can be inactivated (anergy killed (deletion) or regulated
gy),
gy
(suppressed).
• “Clonal ignorance”
– Mature self-reactive lymphocytes do not respond to self
antigens in non-inflamed settings.
Multiple Sclerosis
What went wrong?
Key Steps in the MS Process
1.
1 A breakdown in the ability to distinguish
self from non-self.
2.
2 Upregulation of myelin reactive CD4 Th1
cells.
3. Increased permeability of the BBB.
3 I d bilit f th BBB
4. The role of B cells and CD8 cells.
Requirements for the development
of an autoimmune disease
Nature Immunology (9): 759-761 (2001)
HLA Type and MS Risk
• Many autoimmune diseases in humans
are linked to particular HLA alleles.
• HLA DR2 and DR4 haplotypes are
associated with an increased risk for MS.
Environmental Factors
• Many pathogens have been proposed to
have a role in the pathogenesis of MS.
HHV-6, EBV,
• HHV 6 EBV Chlamydia pneumonia
Molecular Mimicry
• The pathogen contains similar peptide
sequences to peptides found in myelin
(MBP, MAG others).
(MBP MAG, MOG others)
• The pathogen may have similar three-
di i l t t th t t
dimensional structures that promote cross-
reactive immunity.
Immune Dysfunction in MS
• Myelin autoreactive CD4 cells may have
less of a need for co-stimulation to
become activated in a person with MS MS.
• Downregulation of CD4 cells via CTLA-4
MS.
may be impaired in MS
Innate and Adaptive Immune
Responses
TLR (Toll Like Autoreactive
Cytokines
Receptor)
CD4/CD8
Pathogen
Innate Immune Cell
I t I C ll
Naïve CD4 T cells differentiate into TH1 and TH2
cells
Naïve
T cell
Th1 Th2
Anti-
Pro-inflammatory
inflammatory
Cytokines
• IL-2
Cytokines
• Il-12
Reciprocal Inhibition • IL-4
• IL-5
• IFN-γ
• Il-10
• TNF
• IL-13
• TGF-β (TH3)
B cell
Macrophage
Yong, W
Th1 / Th2 Imbalance
Th1 Th2
Normal
Th1 / Th2 Imbalance
MS
Increased BBB Permeability
increased,
• Some chemokine levels are increased
leading to increased adhesion and
attraction of autoreactive T cells into the
CNS.
• Increased production of matrix
metalloproteinase leads to increased BBB
permeability.
permeability
The Role of B Cells in MS
• Increased immunoglobulin (Ig) production
in the CSF, but not the serum.
• CSF Ig in MS shows an oligoclonal
distribution, i.e. a limited number of B cell
production.
clones contribute to the Ig production
How Do B Cells and Ab Contribute
h Pathogenesis i MS?
to the P h i in
APC’s
• B cells may serve as APC s for
autoreactive T cells.
• B cells provide costimulation for
autoreactive T cells.
ll help it t ti
• B cells may h l recruit autoreactive T
cells into the CNS.
• B cells produce myelin-specific
autoantibodies that destroy myelin.
The Role of CD8 Cells in MS
• Cells in the CNS express MHC I much
more so than MHC II.
Myelin-reactive
• Myelin reactive CD8 cells are more
common than myelin-reactive CD4 cells in
tissue
MS brain tissue.
• Myelin-reactive CD8 cells secrete
h ki for li ti ll
chemokines f myelin-reactive CD4 cells.
Mechanism of Action of
Current Therapies
• Glatiramer acetetate
• Beta interferons
• Natalizumab
MOA: Glatiramer acetate (GA)
• Anti-inflammatory effects
– Th2/ T ll
Treg cells
• GA promotes the development of Th2 and Treg cells
• Release anti-inflammatory cytokines reducing the
activity of Th1 cells in the periphery and CNS
– Innate immune effects
• Direct effect on monocytes/APCs yielding anti-
inflammatory cytokine producing phenotype
• Polarizes CD4+ T cell development down a Th2 and
Treg path
CD8
– Possible role for regulatory CD8+ cells
• Induces a population of GA-reactive CD8+ T cells that
can suppress or even kill CD4+ T cells
Weber MS, et al. Neurotherapeutics. 2007;4:647-53., Arnon R, et al. Mol Neurobiol. 2007;36:245-53.
MOA: Glatiramer acetate (GA)
p
• Enhanced reparative p processes
– Neurotrophic factors
• GA reactive cells and resident CNS cells produce
BDNF, NT-3/4, IGF-1, and GDNF
– Remyelination
• Increases proliferation, differentiation, and survival of
OPCs
– Neurogenesis
• Augments neuronal progenitor cell proliferation,
differentiation, and migration to sites of damage; axonal
sprouting noted
Weber MS, et al. Neurotherapeutics. 2007;4:647-53., Arnon R, et al. Mol Neurobiol. 2007;36:245-53.
MOA: GA
MOA: GA
MOA: GA
IFN β may shift T cells from a pro-inflammatory to
y profile in the p p y
an anti-inflammatory p periphery
IFN β IL-4, IL-10, IL-131,2
Th2
IFN-α/βR
T cells T suppressor Activity3
X
IFNγ4
Th1
1. Mei E, et al. J Neurol Sci 2006; 246(1-2): 71-7
2. Wiesemann E, et al. J Neuroimmunol 2002; 123(1-2): 160-9
3. Noronha A, et al. Ann Neurol 1990; 27(2): 207-10
4. Sega S, et al. Clin Neurol Neurosurg 2004; 106(3): 255-8
IFN β decreases adhesion molecule and MMP
expression, blocking T-cell migration across the BBB
p g g
Periphery BBB CNS
Increase in soluble IFN β
adhesion molecules
sVCAM-11
MMP-9 is required
VLA4/VCAM-1
VLA4/VCAM 1 for migration of T
cells through the
X basement
membrane of the
BBB2-4
IFN β
Activated
VLA4 T cell
Decreased
MMP-9
1. Trojano M, et al. Neurology 1999; 53(7): 1402-08
j , gy ; ( )
Downregulation of 2. Nelissen I, et al. Brain 2003; 126(Pt6): 1371-81
VLA4 in T cells5,6 sVCAM-1 (decoy) 3. Stone LA, et al. Ann Neurol 1995; 37(5): 611-19
4. Stuve O, et al. Ann Neurol 1996; 40(6): 853-63
VCAM-1=vascular cell adhesion molecule ; VLA-4=very 5. Soilu-Hanninen M, et al. J Neuroimmunol 2005; 167(1-2): 175-82
late antigen 4; MMP-9=matrix metalloproteinase 9 6. Murano PA, et al. J Neuroimmunol 2000; 111(1-2): 186-94
Natalizumab MOA
Natalizumab
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