MS

Question 1

What is the average onset of MS and who does it affect more?

Answer 1

around 30yo and affects females more.

Question 2

What kind of disease is MS?

Answer 2

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.

Question 3

What are 4 common symptoms of MS?

Answer 3

tingling and numbness.
vision issues (fading colours)
fatigue
walking difficulty

Question 4

2 diferent disease courses for MS?

Answer 4

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).

Question 5

When is inflammation thought to begin?

Answer 5

Inflammatory episodes thought to occur before clinically isolated syndrome (subclinical).

relapsing and remitting inflammatory episodes in progressive disease may also occur but be subclinical.

Question 6

What effects on brain volume and axonal loss are there in MS?

Answer 6

decreased brain volume and increased axonal loss with progression.

Question 7

What features in MRI correlate with inflammatory relapses of MS?

Answer 7

Sclerotic plaques in the brain.

Question 8

Why are sclerotic plaques formed in the brain?

Answer 8

Immune cell infiltration into the CNS, causing demyelination (schwann cells and oligodendrocytes) and eventually axonal and neuronal damage and death.

Question 9

Geographic prevalence of MS and reasons?

Answer 9

In developed countries away from the equator:

Sunlight and vitamin D?
Infections or onset of infections?
genetic background reflected by geography?

Question 10

What percentage of MS thought to be down to genetics? Other factors?

Answer 10

around 30%, other factors could be environmental and chance (e.g. of generating autoreactive repertoire).

Question 11

Out of the HLA II alleles predisposing risk to MS, what is most important?

Answer 11

HLA-DRB1*1501.

Question 12

HLA I alleles are associated with protection in MS, what is an example>

Answer 12

HLA-A0201

Question 13

Why might HLA 1 alleles be protective?

Answer 13

Effects on central and peripheral tolerance and resistance to infections?

Question 14

What has HLA-DRB1*1501 been shown to bind that could be pathogenic in MS?

Answer 14

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

Question 15

What is interesting about the TNF risk variant encoding a natural TNF antagonist?

Answer 15

INcreases risk for MS, and is reflective of how anti TNF treatments make the disease worse.

Question 16

Link between EBV and MS?

Answer 16

All MS patients are seropositive, increased risk with IM. However individual efefcs is like any single non-MHC genetic variant.

Question 17

Is there evidence for citrunillaitno contributing to MS?

Answer 17

no

Question 18

What two general models of MS are there?

Answer 18

inside-out
outside-in

Whether triggering of immune response in MS occurs inside or outside of the CNS?

Question 19

Are there immune surveillance cells in brain? Activation in MS?

Answer 19

there is immune surveillance in the brain that patrol the CSF, lymphocytes could be activated in CSF in this way.

Question 20

Inside out model?

Answer 20

cytodegeneration or resident innate cell activation in brain could trigger T cell infiltration and activation in the CNS?

Question 21

Outside in model?

Answer 21

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.

Question 22

5 different ways of tolerance broken in general?

Answer 22

Tolerance breakdown against self antigen
molecular mimicry
neoepitope similar enough to protein
bystander activation
bispecific TCR T cells.

Question 23

Where is infiltration seen in CNS in early MS?

Answer 23

perivascular infiltrates, soluble mediators will infiltrate deep into the parenchyma.

Immune cells make way into parenchyma and lesions.

Question 24

Are CD4 or CD8 T cells seen in CNS lesions? Which is more abundant in demyelinating lesions?

Answer 24

Both are seen in CNS lesions in MS.

CD8+ T cells are more abundant in lesions

Question 25

What are the characteristics of Th and CD8 T cells infiltrating in MS? What targeted therapy is ineffective?

Answer 25

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.

Question 26

Are B cells found in CSF, meninges and parenchyma in MS?

Answer 26

Yes, they also increase with age in primary or secondary progressive MS.

Question 27

What were some potential autoantigen targets in MS?

Answer 27

MOG, neurofascin, contactin and potassium channel (KIR4.1).

Question 28

Evidence for and against Treg involvement in MS?

Answer 28

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.

Question 29

What is immune infiltrate like in CNS in late stage?

Answer 29

reduced immune cell infiltrate, but you do have tertiary -like lymphoid structures form (autoantibody production?)

Question 30

What changes in blood-brain barrier are seen in early and late MS?

Answer 30

leaky blood-brain barrier in early MS, becomes less leaky with age.

Question 31

If immune infiltration and response isn’t so important for progressive MS, what could be driving it?

Answer 31

neurodegenerative processes, Ca2+ tirggered axonal degradation and oxdiation and autophagy.

Death of one neurone can drive death of others.

Question 32

What are the first line of drugs in MS and second-line too?

Answer 32

First line: IFN-B (and glatiramer acetate)

second line: natalizumab or mitoxantrone.

Question 33

How might IFNB in MS work?

Answer 33

inhibits APC activation and perhaps entry across blood-brain barrier.

Other drugs can target immune cell proliferation and depletion

Question 34

how does Natalizumab and anti S1PR drugs work?

Answer 34

Natalizumab blocks a4B1/7 binding to VCAM1 in endothelial brian cells.
Anti S1PR blocks lymphocyte recirculaiton (stay in LN).

Question 35

Where might DMF work?

Answer 35

On APCs in the periphery and also inside of the brain- neuroprotective>

Question 36

Opportunistic fatal disease that lyses oligodendrocytes associate with natalizumab use?

Answer 36

PML, caused by JC virus.

Question 37

b cell depleting antibody used in MS other than rituximab?

Answer 37

ocrelizumab.