Immunological processes in Multiple Sclerosis

Question 1

Potential causes of MS are:

Answer 1

1. Inside-out or outside-in model
2. Genetic risk factors
3. Infectious factors
4. Environment
5. Life style

Question 2

The ‘inside-out’ model entails:

Answer 2

CNS degeneration and subsequent recruitment of immune cells

Case report: patients who died shortly after the onset of a relapse had only few or no lymphocytes or myelin phagocytes in lesions

Question 3

The ‘outside-in’ model entails:

Answer 3

CNS demyelination, induced by anti-myelin autoimmune cells

Question 4

Why could Infectious factors be related to MS?

Answer 4

1. Similarities with viral-induced demyelination (PML, Theiler’s)
2. Association with viral infections (Epstein Barr, HHV6, measles)

Question 5

What role do viruses most likely play in the development of MS?

Answer 5

Virus infections precede MS exacerbations: they likely have an indirect role as activator of disease.

Question 6

Through what mechanisms can viral infections be associated to MS?

Answer 6

1. Molecular mimicry

2. Bystander activation

Question 7

Molecular mimicry

Answer 7

Activation of autoreactive cells by cross-reactivity between self-antigens and foreign agents

Question 8

Bystander activation

Answer 8

Autoreactive cells are activated because of nonspecific inflammatory events

Question 9

What are potential non-infectious factors of MS?

Answer 9

1. Sunlight: interplay melatonin (high at night) and vitamine D (induced by sunlight)
2. Geographical distribution (MS Asia low; high Northern America and Europe)
3. Diet (fish?)
4. Delayed/reduction infections: hygiene hypothesis
5. Microbiome

Question 10

Where is MS prevalence highest (globally)?

Answer 10

Western countries

Question 11

What immune response is predominantly present in the relapsing-remitting phase?

Answer 11

Adaptive immunity (antigen-specific T and B cells)

Question 12

What immune response is predominantly present in the secondary progressive phase?

Answer 12

Innate immunity (miroglia, monocytes, DCs)

Question 13

What is EAE?

Answer 13

EAE: experimental autoimmune encephalomyelitis (model for MS)
- Mice are immunization with myelin (components in CFA)

Question 14

Passive transfer EAE

Answer 14

transfer of T-cells of active EAE animals into naïve animal causes same EAE symptoms

Question 15

Spontaneous EAE

Answer 15

mice expressing the receptor of autoreactive T-cells as a trangene

Question 16

Myelin function

Answer 16

• Produced by oligodendrocytes
• Essential for rapid conduction of nerve impulses
• Supports axonal survival and growth

Question 17

Myelin components

Answer 17

• Proteolipid protein (50% of myelin proteins) PLP
• Myelin basic protein (30%) MBP
• Myelin oligodendrocyte glycoprotein (2.5%) MOG
• Myelin associated glycoprotein (1%) MAG

Question 18

CD4+ cells in MS:

Answer 18

• Th1 mediated diseases
• Tregs are reduced
• Th17 mediated tissue damage
• autoreactive T-cells recognize myelin
• CD4 cells from EAE transfer disease

Question 19

What is PLP and what does it have to do with MS?

Answer 19

Proteolipid protein (50% of myelin proteins)
PLP 184-209 strong candidate gene for MS:
- PLP 184-209 encephalitogenic in mice
- immuno-dominant
- extracellular surface of myelin sheath
- T-cell reactivity with MS disease activity

Question 20

CD8+ T cells in MS:

Answer 20

• CNS cells (besides microglia) express no MHC class II: role for CD8 cells in immune mediated cell death
• CD8 > CD4 T-cells in MS brains
• CD8 cells in infiltrates: clonal expansion within CNS
• Promote vascular permeability
• Number correlate with axonal damage
• CD8 cells transect axons

Question 21

B cells in MS:

Answer 21

• Clonally expanded B-cells within CSF
• Intrathecal production of oligoclonal Ig bands in CSF (diagnostics)
• Inflamed CNS favors B-cell homing, survival, and maturation by chemokines and cytokines
• Pathogenic antibodies targeting oligodendrocytes
• Follicle like aggregates (germinal center-like structures) in meninges
• Ablation of B-cells beneficial (Ocrelizumab = anti-CD20 therapy)