immunopathogenesis of multiple sclerosis
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Immunopathogenesis
of
Multiple Sclerosis
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Amr Hasan, MD,FEBN Associate Professor of Neurology - Cairo
University
Famous dictum
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AMR HASAN
2011
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Immunity
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ACQUIRED
INNATE
Immunity
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ACQUIRED
INNATE
Immunity
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First: INNATE IMMUNITY
Cellular Defence Mechanisms:
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1. Phagocytes
• Particles, e.g. bacteria, entering the tissue fluids or blood are rapidly
engulfed by phagocytic cells.
• This process of engulfment (internalization) of particulate matter is
termed phagocytosis.
• There are 2 main types of phagocytic cells: Polymorphonuclear
leucocytes (especially neutrophils)
• Mononuclear phagocytes (monocytes in the blood and
macrophages in the tissues).
Phagocytosis
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First: INNATE IMMUNITY
Cellular Defence Mechanisms:
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2. Natural Killer cells (NK cells)
• Large granular lymphocytes which can be distinguished from B and
T lymphocytes.
• They constitute 10-15% of peripheral blood lymphocytes.
• They are capable of non-specific killing of tumour cells and virus-
infected cells a manner similar to cytotoxic T cells, but differ from
them in the way they recognize their target
3.Eosinophils
Immunity
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ACQUIRED
INNATE
Immunity
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ACQUIRED
INNATE
Second: Acquired Immunity (Adaptive immunity)
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I.CELL MEDIATED IMMUNITY
( T CELL)
II.HUMORAL IMMUNITY
( B CELLS)
Second: Acquired Immunity (Adaptive immunity)
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I. T lymphocytes
A. Produced in the bone marrow, but complete their maturation in the
Thymus.
B. They comprise around 75% of peripheral blood lymphocytes.
Second: Acquired Immunity (Adaptive immunity)
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I. T lymphocytes
There are two main kinds of T cells:
A. Cytotoxic T (Tc) cells
B. Helper T (Th) cells
Second: Acquired Immunity (Adaptive immunity)
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There are two main kinds of T cells:
A. Cytotoxic T (Tc) cells
• These recognize body cells infected with virus.
• Can kill tumour cells
TV
Second: Acquired Immunity (Adaptive immunity)
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There are two main kinds of T cells:
B. Helper T (Th) cells
a- T helper 1 (Th1) cells
Secrete cytokines which help in activation of Macrophages
making macrophages more capable of killing any bacteria inside
them.
b- T helper 2 (Th2) cells
Secrete certain cytokines which help in activation of B cells
plasma cells produce antibodies to deal with those extracellular
pathogens.
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Second: Acquired Immunity (Adaptive immunity)
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Second: Acquired Immunity (Adaptive immunity)
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II. B lymphocytes
• Produced in the Bone marrow, where they complete their
maturation. They comprise around 10% of peripheral blood
lymphocytes.
• When B cells become active plasma cells antibodies, or
immunoglobulins
• When B cells become active plasma cells antibodies, or
immunoglobulins.
• B cells may act as APC
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B cell Surface Molecules
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Antibody structure
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• There are 5 main
types: gamma (γ),
alpha (α), mu (u),
delta (δ) and epsilon
(ε), corresponding
to the 5 isotypes of
Igs IgG, IgA, IgM,
IgD and IgE
respectively.
Antibody classes and class switching
Activation of T cells
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The Professional Antigen Presenting Cells:
• These are the only cells capable of activating naive T cells.
• They are concentrated in the peripheral lymphoid tissues, such as
lymph nodes, where they trap antigen and present it to the
recirculating T cells:
1. Dendritic cells
• The most important &most efficient APCs.
• Their only known function is antigen presentation.
2. Macrophages
3. B cells
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Naïve T cell
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Second: Acquired Immunity (Adaptive immunity)
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Circulation of Lymphocytes between Blood and Lymph:
• Lymphocytes which recognize a certain antigen undergo a series of changes ready to start working against the antigen .
• The changes which occur are:
.lymphoblaststhey become ctivation:Aa.
rapid multiplication. roliferation:Pb.
Effector cell they change into ifferentiation:Dc.
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Effector T cell
CYTOKINES
CYTOKINES
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Definition:
• Cytokines are peptide or glycoprotein mediators that are produced by cells
of the immune system and have an effect on the behaviour and properties
of many cells.
General Characteristics of Cytokines:
1. Highly potent, often acting at very low concentrations.
2. Not specific to antigens that induce their production.
3. Act through action high-affinity cell surface receptors.
4. Transient action.
5. They act mainly in an autocrine manner (affecting the cell which produced them)
or in a paracrine manner (affecting cells close by).
6. They are pleiotropic, i.e. the same cytokine may have multiple effects.
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CYTOKINES
Th1 Th2
Cytokines produced
IL-2 IFN-Ɣ TNF-a and B GM-CSF
IL-3
IL-4 ,IL-5 ,IL-6 ,IL-10, TGF-B GM-CSF IL-3
Development promoted by IL-12 &IFN-Ɣ
Large doses of antigen
IL-4
Small doses of antigen
Development inhibited by IL-4 &IL-10 IFN-Ɣ
Promote Cell-mediated immunity Humoral immunity
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CYTOKINES
Cytosolic "endogenous" Vesicular "exogenous"
Examples • Viruses
• Intracellular bacteria e.g.T.B.
• Extracellular bacteria and their products
when internalized
Degraded in • Cytoplasm • Vesicles
Peptides bind to • MHC I molecules • MHC II molecules
Presented to • CD8 T cells • CD4 T cells
Result • Cytotoxic killing of presenting cell by
CD8 T cell
• Secretion of cytokines by CD4 T cells,
giving help to macrophages, B cells and
others
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Epitopes
Heterophil antigens
HETEROPHIL ANTIBODIES CROSS REACTIVITY
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Super antigen
MHC
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• MHC antigens are a group of molecules expressed on cell surface
membranes.
• They are also called HLA because they were first discovered on the
surface of Human Leucocytes.
• MHC genes are divided into 3 major classes; class I, II and class III
MHC
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• Class I
• There are three class I loci (HLA-A, B and C). Each locus is highly
polymorphic i.e. a single HLA locus contains one of many possible
alleles( Alleles: variants of a single genetic locus)
• The various possible alleles are given consecutive numbers, e.g.
HLA- A1, HLA-A2, etc.
MHC
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• Class II
• Molecules are encoded by three principal loci (HLA-DP, -DQ and -
DR), which also show polymorphism.
• MHC molecules have a much more limited cellular distribution.
• They are mainly found on the surface of (APCs).
• Class III
• The class III genes code for a number of complement components
and are grouped together in a region between HLA-D and HLA-B.
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MHC Restriction
TOLERANCE
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• Tolerance = the absence of specific immune response against some
antigens in an otherwise fully immunocompetent person.
• It includes: autotolerance and aquired (induced) tolerance.
Autotolerance:
• It is a tolerance to self antigens that is acquired early in life,
probably in utero.
• Failure of autotolerance may result in autoimmune disease.
Mechanisms of Autotolerance
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1. Central tolerance
• During development in the primary lymphoid organs, B and T
lymphocytes go through a phase in which contact with antigen leads
to their death or permanent inactivation.
• Such antigens are most likely to be self-antigens. The elimination of
immature self-reactive lymphocytes during their maturation is called
negative selection (clonal deletion).
2. Peripheral tolerance
AUTOIMMUNITY
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• It is an adaptive immune response to self-antigens. Normally, this is
prevented by autotolerance.
• Breakdown in autotolerance leads to production of autoantibodies
and/or self-reactive T cells which may cause autoimmune diseases.
Mechanisms of Autoimmune Diseases
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Cross reactivity
Breakdown in the immune network which may occur as
a result of:
• Interference with the mechanisms which normally suppress
surviving self- reactive T cells.
• Polyclonal activation of lymphocytes: Certain agents (e.g. viruses or
bacteria) are capable of non-specifically stimulating many clones of
lymphocytes, including self-reactive clones.
• Over production of IL-2 by Th1 cells.
Famous dictum
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AMR HASAN
2011
Immunopathogenesis of multiple sclerosis
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Genetics
Environmental Autoimmunity
The Virus Hypothesis
Viruses thought to be associated with MS
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• Measles, rubella, mumps.
• Herpes viruses, including epstein barr virus (EBV), herpes simplex
virus (HSV) 1 and 2.
• Varicella zoster virus.
• HHV6.
How Do Autoreactive T Cells Become Activated
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Molecular mimicry:
• Antigenic epitopes of an infectious agent mimic a self protein
epitope.
Superantigens:
• Bind to Class II MHC and specific TCR V segments and may occur
during the course of a bacterial or viral infection.
Frequency Of Autoreactive T Cells
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• T Cells recognizing MBP and PLP are present in normal individuals.
• No difference in the frequency of these cells between MS patients
and normal individuals.
Clonal expansion and persistence of autoreactive
T cells
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1) Engagement of T cell receptor by
crossreactive microbial antigen
CD28 2) B7
APC
3) IL-12
TH P
auto-reactive
TH 1
auto-reactive
TH 1
auto-reactive
TH 1
auto-reactive
TH 1
auto-reactive
Pathogenesis of MS
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Immunopathogenesis of M.S.
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Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
B.B.B.
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B.B.B.
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Chemokines
Matrix Metallproteinase
Adhesion Molecules
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Matrix metalloproteinases
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• MMPs are endopeptidases that serve as effectors of cell migration, cytotoxicity,
inflammation and tissue remodeling via degradation of ECM components.
• MMPs can be secreted by activated T cells and macrophages.
• In the normal CNS, the expression of MMP-2, -7 and -9 by astrocytes and microglia is
thought to control physiological processes such as cell migration, differentiation and
survival via ECM remodelling.
• Higher levels of TIMP-1(a negative regulator of MMPs) are found in astrocytes surrounding
perivascular infiltrated areas and microglial nodules.
• In acute and chronic MS lesions, astrocytes express moderate levels of MMP-2-, -3 and -9.
• Unlike astrocytes, microglia seem to be contributing to the inflammatory process by
upregulating the expression of pro-inflammatory MMPs that in conjunction with those
produced by infiltrating leukocytes further destabilize the BBB.
Activated Autoreactive T cells expressing VLA-4 adhere to
endothelium via interactions with VCAM and enter into the tissue
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Peripheral Immune System
1) Engagement of T cell receptor by
crossreactive microbial antigen
CD28 2) B7
3) IL-12
TH P
auto-reactive
TH 1
auto-reactive
VLA-4
VCAM
TH 1
auto-reactive
TH 1
auto-reactive
Inflammed
Tissue
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Structure of chemokine classes
Chemokines and Chemokine Receptor
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• the CC chemokine ligands CCL3, CCL4 and CCL5, and the receptors
CCR2, CCR3 and CCR5 were found to be elevated in CNS tissue
recovered from MS patients.
• Levels of the CC chemokine CCL2 and the CXC chemokine CXCL10
were found to vary inversely in the cerebrospinal fluid of patients
with acute MS: CCL2 levels were much lower than controls, whereas
CXCL10 chemokines were markedly increased.
• CCR5 — one of the receptors for CCL3, CCL4 and CCL5 — is a key
receptor in T-cell trafficking into the CNS.
Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
Activated autoråeactive T cells enter into tissue, recognize self
antigen presented by local APC with costimulation and induce
inflammation
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Tissue Damage
IL-2
IFN-
TNF-
CD154 CD40
IL-12
tissue
APC
autoantigens
CD28 B7
TH 1
auto-reactive
Peripheral Immune System
1) Engagement of T cell receptor by
crossreactive microbial antigen
CD28 2) B7
3) IL-12
TH P
auto-reactive
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Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
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More Than a Demyelinating Disease
Immunopathogenesis of M.S.
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Peripheral activation
Migration of autoreactive T cells
Central reactivation
Myeline damage
Remyelination Axonal loss
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Myelin
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Myelin
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Inflammation and Neurodegeneration in MS
Disease
Stage
Dominant
Component
Main Clinical
Outcome MRI
Early
INFLAMMATION
Edema
Demyelination (axonal loss,
brain atrophy)
Relapses Gd enhancement
Late NEURODEGENERATION
Severe axonal injury
Permanent tissue loss
Disability Black Holes
Gd enhancement
Brain Atrophy
Filippi et al., EJN 2001, 8:291-297
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More Than a Demyelinating Disease
Time (Years)
Dis
ease P
ara
mete
rINFLAMMATORY ACTIVITYINFLAMMATORY ACTIVITY
NEURODEGENERATIONNEURODEGENERATION
PROGRESSIONPROGRESSION
RelapsesRelapses
cMRIcMRI WMLsWMLsFLAIRFLAIR T1 Gd+T1 Gd+
FLAIRFLAIR
Rx effectRx effect
Poor Rx effectPoor Rx effect
No New No New WMLsWMLs
B Cells in MS
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• Function as antigen presenting cells (APC) and contribute to T cell
activation.
• Produce effector cytokines that may modulate the local immune
environment.
• Function at the innate-adaptive interface.
• Play a role in formation and maintenance of new lymphoid foci,
including at ectopic sites such as the inflamed CNS.
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B cell directed therapies
DMT
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Existing & Emerging MS therapies
Modified from P. Vermersch
Phase I
Phase II
Phase III
Marketed
Interferons
Antiproliferative agents
Cytolytic mAbs
Symptomatic Tx Vaccine, tolerization
Lymphocyte trafficking
Immune regulation
Other
Idebenone
BIIB033
Fingolimod
Firategrast
Siponimod
ONO-4641
CS-0777
ELND-002
Tysabri
Daclizumab
Laquinimod BG12
NI-0801
AZD5904
GRC4039
CCX-140
AIN457
Cladribine
Nerispirdine Ofatumumab
Belimumab
Ampyra
Ocrelizumab
Sativex
Alemtuzumab
Copaxone
IPX-056
RPI-78M
LY-2127399
Novantrone
Rebif Betaferon
Pixantrone
Peg IFN
(BIIB017)
ATX-MS-1467
PI2301
RTL1000
Copaxone generics x2
Azathioprine
Teriflunomide
LV Copaxone
Avonex
= Oral administration
= Injectable
Extavia
Ponesimod
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Mechanism of action of DMD (IFN)
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Mechanism of action of DMD (GA)
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Mechanism of action of DMD (Natalizumab)
90
Mechanism of action of DMD (Natalizumab)
91
Mechanism of action of DMD (Fingolimod)
92
Mechanism of action of DMD (Fingolimod)
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