Potential causes of MS are:
- Inside-out or outside-in model
- Genetic risk factors
- Infectious factors
- Environment
- Life style
The ‘inside-out’ model entails:
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
The ‘outside-in’ model entails:
CNS demyelination, induced by anti-myelin autoimmune cells
Why could Infectious factors be related to MS?
- Similarities with viral-induced demyelination (PML, Theiler’s)
- Association with viral infections (Epstein Barr, HHV6, measles)
What role do viruses most likely play in the development of MS?
Virus infections precede MS exacerbations: they likely have an indirect role as activator of disease.
Through what mechanisms can viral infections be associated to MS?
- Molecular mimicry
2. Bystander activation
Molecular mimicry
Activation of autoreactive cells by cross-reactivity between self-antigens and foreign agents
Bystander activation
Autoreactive cells are activated because of nonspecific inflammatory events
What are potential non-infectious factors of MS?
- Sunlight: interplay melatonin (high at night) and vitamine D (induced by sunlight)
- Geographical distribution (MS Asia low; high Northern America and Europe)
- Diet (fish?)
- Delayed/reduction infections: hygiene hypothesis
- Microbiome
Where is MS prevalence highest (globally)?
Western countries
What immune response is predominantly present in the relapsing-remitting phase?
Adaptive immunity (antigen-specific T and B cells)
What immune response is predominantly present in the secondary progressive phase?
Innate immunity (miroglia, monocytes, DCs)
What is EAE?
EAE: experimental autoimmune encephalomyelitis (model for MS)
- Mice are immunization with myelin (components in CFA)
Passive transfer EAE
transfer of T-cells of active EAE animals into naïve animal causes same EAE symptoms
Spontaneous EAE
mice expressing the receptor of autoreactive T-cells as a trangene
Myelin function
- Produced by oligodendrocytes
- Essential for rapid conduction of nerve impulses
- Supports axonal survival and growth
Myelin components
- Proteolipid protein (50% of myelin proteins) PLP
- Myelin basic protein (30%) MBP
- Myelin oligodendrocyte glycoprotein (2.5%) MOG
- Myelin associated glycoprotein (1%) MAG
CD4+ cells in MS:
- Th1 mediated diseases
- Tregs are reduced
- Th17 mediated tissue damage
- autoreactive T-cells recognize myelin
- CD4 cells from EAE transfer disease
What is PLP and what does it have to do with MS?
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
CD8+ T cells in MS:
- 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
B cells in MS:
- 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)
