MS Flashcards
What is the average onset of MS and who does it affect more?
around 30yo and affects females more.
What kind of disease is MS?
Chronic inflammatory disease of the CNS- was thought to be a response to microbes, but now more recognised as an autoimmune response against e.g. myelin sheath.
What are 4 common symptoms of MS?
tingling and numbness.
vision issues (fading colours)
fatigue
walking difficulty
2 diferent disease courses for MS?
1) clinically isolated syndrome, can go into remission permanently, or then follow a relapse and remission phase.
remission my never fully improve (due to accumulated damage)
Then go through a secondary progressive phase.
2) progressive worsening of the disease from clinical onset (age of onset around 40).
When is inflammation thought to begin?
Inflammatory episodes thought to occur before clinically isolated syndrome (subclinical).
relapsing and remitting inflammatory episodes in progressive disease may also occur but be subclinical.
What effects on brain volume and axonal loss are there in MS?
decreased brain volume and increased axonal loss with progression.
What features in MRI correlate with inflammatory relapses of MS?
Sclerotic plaques in the brain.
Why are sclerotic plaques formed in the brain?
Immune cell infiltration into the CNS, causing demyelination (schwann cells and oligodendrocytes) and eventually axonal and neuronal damage and death.
Geographic prevalence of MS and reasons?
In developed countries away from the equator:
Sunlight and vitamin D?
Infections or onset of infections?
genetic background reflected by geography?
What percentage of MS thought to be down to genetics? Other factors?
around 30%, other factors could be environmental and chance (e.g. of generating autoreactive repertoire).
Out of the HLA II alleles predisposing risk to MS, what is most important?
HLA-DRB1*1501.
HLA I alleles are associated with protection in MS, what is an example>
HLA-A0201
Why might HLA 1 alleles be protective?
Effects on central and peripheral tolerance and resistance to infections?
What has HLA-DRB1*1501 been shown to bind that could be pathogenic in MS?
CD4+ T cells for Myelin basic protein (MBP) found in MS brain overlapping with MS legions.
However, not all patients have this and the other antigens haven’t been identified and
What is interesting about the TNF risk variant encoding a natural TNF antagonist?
INcreases risk for MS, and is reflective of how anti TNF treatments make the disease worse.
Link between EBV and MS?
All MS patients are seropositive, increased risk with IM. However individual efefcs is like any single non-MHC genetic variant.
Is there evidence for citrunillaitno contributing to MS?
no
What two general models of MS are there?
inside-out
outside-in
Whether triggering of immune response in MS occurs inside or outside of the CNS?
Are there immune surveillance cells in brain? Activation in MS?
there is immune surveillance in the brain that patrol the CSF, lymphocytes could be activated in CSF in this way.
Inside out model?
cytodegeneration or resident innate cell activation in brain could trigger T cell infiltration and activation in the CNS?
Outside in model?
Cytodegeneration could lead to CNS-derived soluble Ag in the cervical lymph nodes, or mimicry etc., which activates T cells in LN which infiltrate CNS.
5 different ways of tolerance broken in general?
Tolerance breakdown against self antigen molecular mimicry neoepitope similar enough to protein bystander activation bispecific TCR T cells.
Where is infiltration seen in CNS in early MS?
perivascular infiltrates, soluble mediators will infiltrate deep into the parenchyma.
Immune cells make way into parenchyma and lesions.
Are CD4 or CD8 T cells seen in CNS lesions? Which is more abundant in demyelinating lesions?
Both are seen in CNS lesions in MS.
CD8+ T cells are more abundant in lesions
What are the characteristics of Th and CD8 T cells infiltrating in MS? What targeted therapy is ineffective?
They are Th1/Th17 and CD8+ MAIT cells secreting IL-17.
However IL-12/23 and IL17 targeted therapies have been ineffective.
HSCT has been effective though.
Are B cells found in CSF, meninges and parenchyma in MS?
Yes, they also increase with age in primary or secondary progressive MS.
What were some potential autoantigen targets in MS?
MOG, neurofascin, contactin and potassium channel (KIR4.1).
Evidence for and against Treg involvement in MS?
Tregs are decreased in number and function.
Natalizumab can also increase regulatory CD103+ CD8+ T cells.
However, IPEX patients do not show autoimmunity against CNS.
What is immune infiltrate like in CNS in late stage?
reduced immune cell infiltrate, but you do have tertiary -like lymphoid structures form (autoantibody production?)
What changes in blood-brain barrier are seen in early and late MS?
leaky blood-brain barrier in early MS, becomes less leaky with age.
If immune infiltration and response isn’t so important for progressive MS, what could be driving it?
neurodegenerative processes, Ca2+ tirggered axonal degradation and oxdiation and autophagy.
Death of one neurone can drive death of others.
What are the first line of drugs in MS and second-line too?
First line: IFN-B (and glatiramer acetate)
second line: natalizumab or mitoxantrone.
How might IFNB in MS work?
inhibits APC activation and perhaps entry across blood-brain barrier.
Other drugs can target immune cell proliferation and depletion
how does Natalizumab and anti S1PR drugs work?
Natalizumab blocks a4B1/7 binding to VCAM1 in endothelial brian cells.
Anti S1PR blocks lymphocyte recirculaiton (stay in LN).
Where might DMF work?
On APCs in the periphery and also inside of the brain- neuroprotective>
Opportunistic fatal disease that lyses oligodendrocytes associate with natalizumab use?
PML, caused by JC virus.
b cell depleting antibody used in MS other than rituximab?
ocrelizumab.
