Lecture 5Multiple Sclerosis

1. Symptoms2. Epidemiology3. What causes MS ?4. The major histocompatibility complex (MHC)5. Possible etiology of MS: Molecular mimicry

(1mm) (1-2 μm)

Transmission of action potentials along myelinated axons.An action potential “jumps” from node to node.Voltage-gated Na+ channels are present only at the nodes of Ranvier

Saltatory Conduction

Action potentials(Active current)

No Action potentials(Passive current)

Inward Na currents through the voltage-gated Na+ channels cause an action potential It regenerates the passive current to flow through the next segment of myelinated axon.

Results of Demyelination

slower conduction time along the affected nerve

Normal Axon

Demyelinated Axon

Degenerated Axon

Multiple Sclerosis

Multiple sclerosisCharacterized by patches of demelination in the brain and spinal cord, resulting in multiple neurological symptomsAutoimmune disorder of the CNS

SymptomsWeakness and clumsiness Stiffness and gait disturbancesVisual defects Mental defects, including lack of judgment, emotional liability, sudden weeping or laughter

MS: epidemiology

Affects mainly Caucasians (N. Europe)Most common neurodegenerative disease of young adults (1 per 400)Average age at onset 28(f)/30(m) years.Female : male ratio = 2:1Etiology – UnknownAutoimmune attack (of T cells and B cells) against oligodendrocytes

What causes multiple sclerosis?

Genes - many (polygenic)

Example: the MHC genes (on chromosome 6) have been consistently linked with MS

Sospedra 2005

What causes multiple sclerosis?

Environmental agents – ‘molecular mimicry’Viruses (measles, rubella, mumps, and the herpes viruses)

Bacterial infections, dietary factors, exposure to animals, minerals, chemical agents, metals, organic solvents, and various occupational hazards.

Sospedra 2005

What causes multiple sclerosis?

Combination of Genes and Environmental agents

Sospedra 2005

The majorhistocompatibilitycomplex (MHC)

Class I, II, & III

A cluster of genes encoding cell-surface antigen-presenting proteins

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The major histocompatibility complex (MHC)

Plays pivotal role in the immune systemContains 140 genes coding for class I, II, and III proteins Found on antigen-presenting cells (APCs)They display an epitope of a foreign antigen to T cells, via the T cell receptors (TCRs)

T cells should ignore self peptides while reacting appropriately to the foreign peptides

A subset of genes in MHC region implicated in MS

Found on specialized antigen-presenting cells (APCs) - macrophagesInteract with CD4+ ("helper") T cells (Th).Antigen is digested in lysosomesAn epitope is displayed by MHC-IITh cells divide rapidly and secrete small proteins called cytokines that "help" the immune response

MHC Class II

Th2

Th1

B cells

Macrophagescytokines

cytokines

The inflammation seen in MS appears to be largely due to an overactive Th1 response.

CD4+ ("helper") T cell (TH) Secrete cytotoxins

Secrete antibodies

Possible etiology of MS: ‘Molecular mimicry’

A ‘foreign’ antigen initiates an immune response

How is the CNS destroyed ?

A self antigen (auto-antigen) “mimics” the foreign antigen

The self protein is destroyed.

Autoreactive Th1 cells activated outside the CNS by microbial antigens (cross-reactive with the self antigen –myelin proteins).

Stages of MS

1. Inflammation 2. Partial recovery3. Demyelination

4. Axonal degeneration 5. Permanent clinical disability

Blood Brain Barrier

Endothelium

Astrocyte end feet

Basement membrane

It is a physical barrierbetween the blood vesselsand the central nervous systemControls the passage of substances from the bloodinto the CNSIn MS the white blood cells can cross BBB

Demyelination results from a defect of immune function

1. Initial infection (i.e. virus, bacteria, foreign antigen)

2. The antigen gets into the blood stream and is ‘processed’ by macrophages (APCs)

3. Macrophages display the antigen with MHC molecules

4. The MHC displayed antigen can be recognized by special receptors on the surface of T cells (TCR)

Inflammatory Phase

5. Th1 cells are activated in the blood– Bind to adhesion molecules on the

surface of the BBB endothelium– Secrete chemicals called proteases that

facilitate migration through the endothelial cells

– Proteases breakdown the BBB – Th1 cells cross the BBB and enter the CNS– Proteolysis (degradation) of myelin

components.

Inflammatory Phase

adhesion molecules

BBB CNS

Inflammatory Phase6. Th1 cells arrive in the CNS;

may encounter local APCs(i.e. microglia)

7. The APCs display an ‘epitope’ of a self-antigen (i.e. breakdown product of myelin) on MHC proteins -"mistaken identity”

8. The Th1 cells are re-activated in the CNS

APC

BBB

Inflammatory Phase9. In the CNS: the activated Th1 cells secrete

cytokines that stimulate microglial cells and astrocytesrecruit additional inflammatory cells from peripheral blood (microphages, B cells)Production of more cytokines and antibodies Complement system production

DemyelinationOligodendrocyte apoptosis

Primary oligodendrocyte degeneration

Homology between Foreign proteins (i.e. viral or bacterial epitope) andSelf protein (myelin epitope)

myelin basic protein - MBP, myelin oligodendrocyte glycoprotein - MOG, or myelin associated glycoprotein (MAG).

Sospedra 2005

Inflammatory Phase

Molecular mimicry

Certain amino acid positions in a peptide are more critical than others for the interactions (complete sequence matching is a rare event)

Sospedra 2005

Partial recovery

Voltage-gated Na+ channels

a high densityclustered at the nodes of Ranvier

Partial recoverydue to an increase in the number of Na channels along the demyelinated parts of the axon, partially restoring axon conduction

At least 9 genes : NaV1.1 - NaV1.9

NaV1.2 channels distributed diffusely along non-myelinated axonssupport AP conduction that is known to occur in pre-myelinated axonsafter myelination, there is a loss of NaV1.2 channels

NaV1.6 channels distributed along myelinated axonscluster at the Nodes of Ranviernot detectable under myelinpreferentially associated with axonal injuryLarger current that NaV1.2 channels

Voltage-gated Na+ channels

Waxman et al. 2004

Multiple Sclerosis

Waxman et al. 2004

NaV1.6

↓ NaV1.6

NaV1.6 & NaV1.2

Very low Na+ channels density cannot support secure AP conduction

Some demyelinated axons acquire higher than normal densities of Na+ channels in demyelinated regions (restoration of conduction)

Degeneration of axons also occurs in MS permanent loss of function

Multiple SclerosisNaV1.2 channels in demyelinated axons

Increased NaV1.2 channel expression

Multiple SclerosisNaV1.6 channels in demyelinated axons

Both NaV1.2 and NaV1.6 channels produce rapidly activating and inactivating currents that can support action potential but

NaV1.6 channels produce larger Na+ current than NaV1.2 channels

Multiple SclerosisNaV1.6 channels in demyelinated axons

Na+ channels and Na+/Ca2+ exchangerco-localize in demyelinating axons (usually with NaV1.6)The activity of Na+ channels can trigger Ca2+ - mediated injury of axons,

Na+ influx through Na+ channels andreverse activity Na+ efflux and Ca2+ influx through Na+/Ca2+ exchanger

Multiple SclerosisNaV1.6 channels in demyelinated axons

Nature Reviews Immunology 3, 483-492 (June 2003)

Cytotoxins

B cells

Degenerative Phase Axonal Damage

Myelin/oligodendrocyte and axonal damage due to:inflammatory cytokines - microphagesantibody-dependent cellular cytotoxicity – B cellsdirect complement activationglutamate released by activated glial cellsincreased Ca2+ levels (i.e. via Na+/Ca2+ exchanger)increase of free radicals (ROS) - mitochondrianitric oxide (NO) formation - causes structural changes to axons and apoptosis of oligodendrocytes and neurons

‘Plaques’ formation in the CNS white matter

RemyelinationRemyelination

limited myelin is usually thinnerwith shorter internodes

The regenerative potential of the CNS: oligodendrocyte precursor cells (OPCs),neural precursor cells (NPCs) or stem cells (SCs) to differentiate into myelinating oligodendrocytes or functional axons – limited

Disease progression-Demyelination.

Inhibition of remyelination in MS: 1. the loss of oligodendrocytes and

oligodendrocyte precursors (OPC)2. inhibitory signals produced by inflammation3. the obstruction of oligodendrocytes by

astrocytic scars4. inhibitory signals between axonal proteins

(i.e. Nogo) and myelin proteins (i.e. MOG, MAG)

The loss of myelin causes neurons to bemuch more susceptible

Fox 2004

Lecture 6 Multiple sclerosis

1. Types of MS2. Diagnosis3. Pathology4. Symptoms

Supplementary readings –pdf articles posted on the website