Lecture 11: Multiple Sclerosis

Question 1

Multiple Sclerosis Lecture

Answer 1

amy lovett-racke

Question 2

Multiple Sclerosis facts

Answer 2

Chronic inflammatory demyelinating disease of the CNS

Autoimmune disease?

Cause unknown

No cure

Question 3

Epidemiology of Multiple Sclerosis:

Location Factor

Answer 3

Risk appears to decrease as one gets closer to the equator.

Risk associated with location appears to be determined in childhood.

Question 4

Epidemiology of Multiple Sclerosis:

Answer 4

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.

Question 5

Axonal Conduction in MS

Answer 5

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.

Question 6

Saltatory Conduction

Answer 6

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.

Question 7

Demyelination in MS

Answer 7

In MS, myelin is damaged by inflammation in the CNS.

Axonal conduction is slowed, resulting in neurological impairment.

Question 8

Redistribution and increase in sodium channels

Answer 8

Partially restores axonal conduction in demyelinated axons.

Occurs within a few days of symptom onset.

Question 9

Partial remyelination occurs over weeks and months.

Answer 9

Typically restores normal function during the early phase of disease.

Relapsing-remitting MS is the most common type.

Question 10

The 3 Major Components of MS

Answer 10

Inflammation

Demyelination

Axon Damage

Question 11

Inflammation

Answer 11

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.

Question 12

Is MS an Autoimmune Disease??

Answer 12

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.

Question 13

Immunology 101

Answer 13

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.

Question 14

Immunology of MS

Answer 14

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.

Question 15

Multiple Sclerosis Leaves Plaque in the Brain

Answer 15

….

Question 16

Remyelination in MS

Answer 16

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.

Question 17

Axon Damage in MS

Answer 17

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.

Question 18

Inhibitors of Axonal Growth

Answer 18

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.

Question 19

Experimental Autoimmune Encephalomyelitis

Answer 19

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.

Question 20

EAE can be induced in 2 ways

Answer 20

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.

Question 21

Molecular Mimicry?

Answer 21

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

Question 22

T-cells don’t mediate the damage, they just initiate the damage by sending signals to draw inflammatory agents

Answer 22

…

Question 23

Antigen Presenting Cells

APCs

Answer 23

dendritic cells, macrophages/
microglia and B-cells process proteins into peptide fragments
and present them to T-cells.

Question 24

The most common site of lesions is around ventricles!!

Answer 24

Myelination is a negative signal for axonal growth.

Question 25

___ inhibits axonal growth.

Answer 25

NgR signaling inhibits

axonal growth.

Question 26

Targeting NogoA in EAE

Answer 26

Currently there are no treatments for repairing axons in MS.

By reducing NogoA can we prmote axonal growth & repair?

A siRNA (small interfeering RNA) was developed to attack NogoA. The siRNA successfully curbed NogoA expression.

How to get siRNA through blood brain barrier?
It’s not possible in a healthy rat, but it is possible in a rat with EAE

Question 27

Experimental Autoimmune Encephalomyelitis

Useful as a model of MS?

Answer 27

The experimental autoimmune encephalomyelitis (EAE) is an animal model of brain inflammation.

It is an inflammatory demyelinating disease of the (CNS).

It is mostly used with rodents and is widely studied as an animal model of the human CNS demyelinating diseases, including multiple sclerosis.

EAE is also the prototype for T-cell-mediated autoimmune disease in general.