Neuroimmunology

Question 1

Describe multistep model on how immune cells get access into the brain

Answer 1

1 = tethering
2 = rolling
3 = attachment
4 = firm adhesion & communication to the endothelial cells (via ICAM1 and LFA1)
5 = transmigration

Endothelial cells have cell adhesion molecules expressed on their surface for example ICAM1
They interact with integrins on the leukocyte for instance LFA1
This communication leads to the migration

Question 2

What molecular interaction in this process does this compound block?

Answer 2

Natalizumab > This compound blocks the integrin on the leukocyte in such way that it cannot longer interact with a cell adhesion molecule on the endothelial cells (VCAM1)

Acts by targeting the a4-integrin-containing adhesion molecules required for migration

Question 3

How do patients benefit from this treatment?

Answer 3

Immune cells can no longer enter the CNS via the BBB > number of new lesions decreases

Question 4

What are reported side effects of the compound and how is this explained?

Answer 4

Human carry a harmless virus in us, animals don’t
John Cunningham-virus
Virus can reside in tonsils or kidney, bone marrow but also in the brain
CD8 cells enter CNS and can contain virus
When you completely block migration of these cells into the CNS > virus can proliferate and infect themselves > leading to severe and acute brain inflammation
Gave a lot of vascular damage and a lot of leakage of cells, compounds etc leading into the CNS

Question 5

2 characteristics of microglia in AD’s

Answer 5

• Impaired clearance of Abeta
• Secretion of neurotoxins and cytokines (IL-1B, TNFa)
• Reactivity to > neurofibrillary tangles
• Reactivation

Question 6

Name 2 characteristics of microglia in a healthy situation

Answer 6

• Clearance of: apoptotic cells
  Abeta
  debris
• secretion:
  neurotrophins and cytokines (IL-6, TGFb)

-migration:
chemotactic response by ATP receptor to damaged tissues

Expression:
IBA1
CD11b
TREM2
P2Y12

Question 7

As a researcher you are developing a new molecule to influence the activation of microglia as treatment for AD’s. describe how you would test such a compound, give the experimental design and name at least 2 different read-out parameters on which you are convinced the compound has beneficial effects.

Answer 7

2 different read-outs:

• Check whether microglia cells get activated by amyloidbeta
• check whether the microglia cells produce chemokines and cytokines contributing to an inflammation

Question 8

If a patients nowadays wants to start using Tysabri / Natalizumab, what should the physician do?

Answer 8

Nowadays if a patient wants to be at this drug > virus titer is measured > antibodies against the virus
New guidelines for patients to be able to start the drug or not

Question 9

Name several ways in which BBB plays an important role in MS

Answer 9

• Impaired barrier function
• Endothelial inflammation
• Immune cell trafficking
• CNS cell damage
• Target for treatment

Question 10

Blood-meningeal barrier can also get infected. Which cells play a role here?

Answer 10

A lot of Bcells accumulate in these vessels
Bcells in meninges activate microglia in MS – neuron phagocytosis
- Close interaction of microglia cells with synapses
- DAPI nucleus (nuclei of the microglia cells)
- IBA1-microglia ( microglia cells)
- HuC/D synaptic marker (neuronal or synaptic marker = red)
- In these microglia cells the proteins of the synapses are present

Question 11

What is the role of meninges in MS development?

Answer 11

Meninges in MS

• Accumulation B-cells
• Microglia activation
• Neurodegeneration?
• Ocrelizumab–targets B-cells: potential MoA?

The meninges play a dominant role in the progression of the disease
May lead to accumulation of Bcells > locally activate microglia cells > which then eat up parts of the neurons

Ocrelizumab is targeting Bcells > potential MoA?