Lecture 20 - Multiple Sclerosis Flashcards
What is multiple sclerosis?
The most common disease caused by an inflammatory demyelinating process in the CNS.
When axons become demyelinated the neurons begin to fallout and die leading to MS.
1:1000 sufferers worldwide.
What cells provide the myelin sheaths around axons?
Oligodendrocytes
What is myelin?
A fatty sheath consisting of 70% fat and 30% protein that wraps around axons and solicits fast conduction.
What subgroup of T cells mediate MS?
Th2 and Th17
What is believed to start MS?
Infiltration of auto reactive T cells that can easily cross the BBB.
When in the brain they release pro-inflammatory cytokines to attract macrophages and microglia.
They then kill oligodendrocytes via membrane-bound tumour necrosis factor (TNFa).
Inflammatory cytokines also induce a reactive transformation of the surrounding astrocytes to cause astrogliosis.
Excess inflammation causes the reals of oxygen and nitrogen radicals damaging the mitochondria in oligodendrocytes and the axons.
As oligodendrocytes die, myelin debris is removed leaving the axon denuded and unable to propagate APs.
Why is there periods of remission in MS?
The brain contains large numbers of oligodendrocyte precursor cells (OPCs) that are highly mobile and proliferative.
When oligodendrocytes become damaged they can move into the wound, differentiate into oligodendrocytes and lay down myelin sheath.
The myelin that is formed during this process is usually a lot thinner than the original myelin, consisting of less layers.
OPCs activity eventually diminishes, leading to progressive forms of the disease.
Describe symptoms and different types of MS.
1st symptoms = weakness, disturbance in micturition (passing of urine), optic neuritis, diplopia, paraesthesia, vertigo.
Secondary progressive (SP) forms = rare to recover from.
Relapsing remitting forms (RR) = problems occur but they go back to normal over time.
What investigations can be done to diagnose MS?
Inflammation of the optic disc is common in MS and can be seen in photos.
MRI, EP, CSF. Abnormalities found in 90% of clinically defined MS on MRI.
Serial MRIs can illustrate that the lesions in the brain can be repaired and then new lesions can form. CSF analysis shows protein migrating quickly.
Describe treatment for MS.
IF beta 1B increases the periods of remissions, not a cure and is expensive but does downplay the inflammatory signals produced.
ALpha B crystalline is a negative regulator of the inflammatory signalling cascade, helping glial cells but when there is too much it can become a target for the immune system, tipping the patient into relapse.
Statins that inhibit CIITA and MHC II.
What is the most widely used model for MS?
Experimental autoimmune encephalomyelitis (EAE) mouse.
How are EAE mice models generated?
Induced in susceptible animals by immunisation with CNS-specific antigens, peptides derived from these antigens or CNS tissue homogenates.
Disease can also be provoked by transfer of encephalitogenic CD4+ T cells obtained from draining lymph nodes of animals immunised for active EAE induction.
Describe T cell involvement in MS.
Upon activation T cells differentiate into various subsets, Th1 and Th17 cells that produce IFN gamma and IL-17 are most involved in MS.
The activated T cells express adhesion molecules and chemokine receptors to cross the BBB.
T cells in the brain release cytokine and inflammatory mediators that recruit macrophages and microglia that produce TNFa to damage oligodendrocytes.
Describe the relevance of Tregs in MS.
A subset of T cells that normally help maintain immune tolerance and prevent autoimmunity.
In MS the function of Tregs is often impaired, reducing their ability to suppress the autoimmune response and contributes to the disease process.
