Lecture 11: Multiple Sclerosis Flashcards
Multiple Sclerosis Lecture
amy lovett-racke
Multiple Sclerosis facts
Chronic inflammatory demyelinating disease of the CNS
Autoimmune disease?
Cause unknown
No cure
Epidemiology of Multiple Sclerosis:
Location Factor
Risk appears to decrease as one gets closer to the equator.
Risk associated with location appears to be determined in childhood.
Epidemiology of Multiple Sclerosis:
MS is the most common neurodegenerative disease of young adults.
Typical age of onset 20-40 years.
The incidence is 1:1000 in the USA.
Women are 3 times more likely to develop MS than men.
Axonal Conduction in MS
Saltatory Conduction
Transmission of action potentials along myelinated axons.
An action potential jumps from node to node.
Voltage-gated Na+ channels are only present at nodes of Ranvier.
Saltatory Conduction
Saltatory conduction (from the Latin saltare, to hop or leap) is the propagation of action potentials along myelinated axons from one node of Ranvier to the next node, increasing the conduction velocity of action potentials.
Demyelination in MS
In MS, myelin is damaged by inflammation in the CNS.
Axonal conduction is slowed, resulting in neurological impairment.
Redistribution and increase in sodium channels
Partially restores axonal conduction in demyelinated axons.
Occurs within a few days of symptom onset.
Partial remyelination occurs over weeks and months.
Typically restores normal function during the early phase of disease.
Relapsing-remitting MS is the most common type.
The 3 Major Components of MS
Inflammation
Demyelination
Axon Damage
Inflammation
A localized physical condition in which part of the body becomes reddened, swollen, hot, and often painful, esp. as a reaction to injury or infection.
The local accumulation of fluid, plasma proteins, and white blood cells that is initiated by physical injury, infection, or a local immune response.
Is MS an Autoimmune Disease??
Autoimmune diseases are caused by T cells or
antibodies that recognize a self protein and damage the tissue expressing that protein.
MS is postulated to be an autoimmune disease in which myelin proteins are the target of CD4 T cells.
Immunology 101
Immune system has 2 basic components: Innate & Adaptive
Innate immune cells respond to danger signals, response is rapid and non-specific
Adaptive immune cells respond to specific proteins, slow to develop, but are very precise and effective.
T-cells and antibodies are components of the Adaptive immune response.
Immunology of MS
Receptors on T-cells (TCR)
recognize fragments of proteins that are very specific.
In the case of MS, the receptors are postulated to recognize peptides derived from myelin proteins.
Cell surface molecules on the surface of activated T-cells are necessary for T-cells to cross the blood brain barrier.
Therapies have been developed to prevent trafficking of T-cells to the CNS.
T-cells must be reactivated in the CNS to mediate pathology.
Antigen presenting cells (APCs) are dendritic cells, macrophages/microglia and B-cells which can process proteins into peptide fragments and present them to T-cells.
Activated T-cells will produce cytokines, such as IFNγ, which can activate microglia & macrophages.
The microglia then produce other inflammatory mediators, such as nitric oxide.
Cytokines and inflammatory
mediators can damage myelin.
Multiple Sclerosis Leaves Plaque in the Brain
….
Remyelination in MS
Oligodendrocytes also can be damaged in MS.
Oligodendrocyte precursor cells (OPCs) can migrate to the site of demyelination, differentiate into oligodendrocytes and partially remyelinated axons.
Axon Damage in MS
Demyelinated axons are susceptible to damage by inflammatory mediators.
Repeated inflammatory demyelination at specific sites results in axonal severing and permanent function deficits in MS patients.
Inhibitors of Axonal Growth
Ligands for the Nogo Receptor (NgR) are not present during development, allowing for axonal growth and normal CNS development.
When oligodendrocytes begin to make myelin, axonal growth ceases. This is to deter growth of excessive numbers of inappropriate connections, which is what occurs with diseases of seizures, excess pain, etc.
Nogo and other myelin proteins are the ligands for the NgR.
NgR signaling inhibits axonal growth.
In MS, oligodendrocytes are making myelin proteins to restore myelin.
However, the myelin proteins also prevent axonal growth which is necessary to repair damaged axons.
Experimental Autoimmune Encephalomyelitis
EAE originated from complications from Rabies vaccination
Pasteur’s rabies vaccine consisted of dessicated spinal cords from rabbits infected with rabies.
Post-rabies vaccination
encephalomyelitis was a rare, but serious complication.
In the 1930s, it was discovered that the post-rabies vaccination
encephalomyelitis could be induced by repeated injections of neural tissue into rabbits or monkeys.
EAE can be induced in 2 ways
Immunization with myelin proteins or peptides.
MBP=myelin basic protein, PLP=proteolipid protein, MOG=myelin oligodendrocyte
glycoprotein.
Transfer of activated myelin-specific T-cells into naïve recipient animals.
Molecular Mimicry?
The T-cells attack myelin because certain myelin proteins look like proteins from pathogens that the T-cell has previously attacked?
The t-cell is confused
T-cells don’t mediate the damage, they just initiate the damage by sending signals to draw inflammatory agents
…
Antigen Presenting Cells
APCs
dendritic cells, macrophages/
microglia and B-cells process proteins into peptide fragments
and present them to T-cells.
The most common site of lesions is around ventricles!!
Myelination is a negative signal for axonal growth.
