L4 - The immunology of multiple sclerosis

Question 1

What is progression of the average person with MS?

Answer 1

severe fatigue and lethargy

numbness in left foot

3 years later pain behind left eye

inflamed optic nerve

Commences on B-interferon therapy

Left leg starts to drag at 40 - slowly starts to weaken

GRADUAL progession of paraplegia or hemiplegia

Question 2

The pain in MS runs through…

Answer 2

unmyelinated neurons

peripheral nerve myelin is produced by different cells to the CNS

optic nerve is part of the CNS

Question 3

the periventricular, subcortical U-fibre and posterior fossa lesions are all…

Answer 3

high intensity areas of inflammation

Question 4

true or false

There is lots of variability in MS genetic patients in terms of severity, relapses and progression

Answer 4

true

Question 5

What are the risk factors for MS?

Answer 5

20-30 fold increase if caucasian or have an effected sibbling

2-3 fold incraese if female or carrier of HLA-DR15 allele of the MCH class 2 molecule presenting antigens

2 fold increase if low Vit D levels

7 fold increase if high latitude of residence

1.3 increase if smoker or obese female

Question 6

What are the lesions in MS?

Answer 6

Occur only in the CNS

Transverse Myelitis/optic Neuritis are examples

Question 7

True or false

lesions for MS are in the perihperal nervous system

Answer 7

False

Question 8

How can we study MS lesion evolution?

Answer 8

Gadolinium enhancing lesion - inject contrast, show the breakdown of BBB

Look for CD68+ve macrophages (could be disguised as a brain tumour)

Look for perivascular T and B cells

Question 9

Myelin is made by oligodendrocytes - how is it damaged? T cells or B cells

Answer 9

T cells or potentially B cells

If B cells are killed MS imrpoves

If T cells are made to not leave the lymph nodes also good

But if we kill both = very toxic

Question 10

Is the inflammation cause or consequence of MS?

Answer 10

If lymphocytes are maintained in lympoid organs (like with Fingolimod drug), MS is improved even though it isnt immunosuppressive

So traffic of T cells into the brain is important - if stoppedMS will improve

Alemtuzumab in hu CD52mice resultsed in depletion of lymphocytes in peripheral blood and lymphoid organs - has a MASSIVE effect on MS relapse rates

Question 11

What are the identified risks from clinical trials with MS?

Answer 11

infusion associated reactions

serious infections

Autoimmune conditions

Nephropathies

Question 12

true or false

When you put the inflammation cause to the test and specifically kill t cells, MS is improved

Answer 12

false

so could be B cells…

Question 13

Could the inflammation just be a response to the oligodendrocyte/myelin death?

Answer 13

This is the ‘inside-out’ hypothesis

the immune response just being a response to the primary pathology in the oligendendrocyte

Could be something here - killing a field of oligodendrocytes to start with

Question 14

Are lesional axons lost?

Answer 14

Yes

when you kill axon - protein blows up initp end bulb

Question 15

The immunology of MS and its drugs treatments show us that….

Answer 15

we really don’t know whats going on

Question 16

The Big Question: What is the most likely reason for disability progression?

Answer 16

Cumulative axon injury by acute and chronic inflammation in and around lesions involving macrophages, T cells and B cells

This is bad because no regeneration in the CNS

Question 17

true or false

MS is an autoimmune disease

Answer 17

False

It MAY be but we don’t know

origin of the acute MS lesion is uncertain

Question 18

true or false

Drugs that reduce MS lesions and relapses work on lymphocytes and macrophages

Answer 18

true

Question 19

What is the strongest genetic risk factor for MS?

Answer 19

HLADR15 carriage

also caucasians, women, low vit D