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

3

AMR HASAN

2011

Immunity

5

ACQUIRED

INNATE

Immunity

6

ACQUIRED

INNATE

Immunity

7

First: INNATE IMMUNITY

Cellular Defence Mechanisms:

8

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

9

First: INNATE IMMUNITY

Cellular Defence Mechanisms:

10

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

11

ACQUIRED

INNATE

Immunity

12

ACQUIRED

INNATE

Second: Acquired Immunity (Adaptive immunity)

13

I.CELL MEDIATED IMMUNITY

( T CELL)

II.HUMORAL IMMUNITY

( B CELLS)


14

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.


15

I. T lymphocytes

There are two main kinds of T cells:

A. Cytotoxic T (Tc) cells

B. Helper T (Th) cells


16


A. Cytotoxic T (Tc) cells

• These recognize body cells infected with virus.

• Can kill tumour cells

TV


17


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.


20


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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

24

• 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

25

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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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

32

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

39

• 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

40

• 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

43

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

44

• 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

45

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

46

AMR HASAN

2011

Immunopathogenesis of multiple sclerosis

47

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

49

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

50

• 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

52

Immunopathogenesis of M.S.

53


54

Peripheral activation

Migration of autoreactive T cells

Central reactivation

Myeline damage

Remyelination Axonal loss


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Myeline damage



56




Myeline damage


B.B.B.

57

B.B.B.

58

Chemokines

Matrix Metallproteinase

Adhesion Molecules

Matrix metalloproteinases

60

• 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

61

Peripheral Immune System



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

64

Structure of chemokine classes

Chemokines and Chemokine Receptor

65

• 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.


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Myeline damage



67




Myeline damage


Activated autoråeactive T cells enter into tissue, recognize self

antigen presented by local APC with costimulation and induce

inflammation

68

Tissue Damage

IL-2

IFN-

TNF-

CD154 CD40

IL-12

tissue

APC

autoantigens

CD28 B7

TH 1

auto-reactive

Peripheral Immune System



CD28 2) B7

3) IL-12

TH P

auto-reactive


70




Myeline damage


72

More Than a Demyelinating Disease


73




Myeline damage


Myelin

76

Myelin

80

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

81

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

82

• 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

84

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)

88

Mechanism of action of DMD (GA)

89

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)

THANK YOU

immunopathogenesis of multiple sclerosis

Health & Medicine