Lecture 5 Multiple Sclerosis
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Transcript of Lecture 5 Multiple Sclerosis
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
6
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