Immunopathogenesis of inflammatory demyelinating disease Flashcards
What are some inflammatory demyelinating diseases of the CNS?
Multiple sclerosis, neuromyelitis optica spectrum disorder (NMOSD), and myelin oligodendrocyte glycoprotein-associated disease (MOGAD)
Describe multiple sclerosis.
Inflammatory, white matter disease:
- demyelination –> early axonal loss
- axonal and neuronal loss
What type of T-cells are believed to be affected in multiple sclerosis?
Both CD4+ and CD8+ T-cells, but the dominant tissue resident T-cell are CD8+ effector memory T-cells
Are multiple sclerosis a genetic disease?
It’s believed to be an autoimmune disease, triggered by environment in a genetically susceptible host (so yes, but not entierly)
- also a link to virus infection suspected
Describe NMOSD.
MS subtype:
- AQP4 (auqaporin on astrocytes) seropositiv
- depletion of antibodies and activated complement
- astrocytopathy: 2ndary demyelination
- brainstem involvement
- spinal cord and optic nerve inflammation
Describe MOGAD.
- MOG seropositive
- depletion of antibodies and complement
- demyelination (partial preserved axons and neurons)
What are the symptoms of MS?
Optic neuritis, limb tingling, weakness and paralysis
Describe MS as a genetic disease.
Risk increases with genetic identity: susceptibility is multi-genic
- strongest association is to MHC II, but also associations with MHC I
Describe how MS are believed to be associated with viral infections.
CD4+ T-cells derived from a MS patient recognizes a protein from Epstein-Barr virus (kyssesyge). The MHC molecule involved in this recognition are part of the MS-suceptible gene profile.
–> EPV believed to be a trigger for MS
Describe hos TNF-alfa might be involved in MS.
TNF-alfa blockage –> MS like symptoms
GWAS studies identified a soluble TNFRI that blocks TNF –> a susceptibility gene for MS
What are the main two hypotheses for MS?
Outside-in: autoimmunity –> cytodegeneration
Inside-out: cytodegeneration –> autoimmunity (primarily genetic)
What are the criterias for neuroinflammation to occur?
- effector cells and molecules must access the CNS
- effector T cells must be reactivated
- local milieu should suppor the inflammatory process
- inflammation should be regulated
What do all of these pathologies derive from?
Leukocyte infiltration and converge to microglial activation and neurodegeneration
How can CD20-targeting therapies be used to treat MS?
CD20 is a protein expressed on B-cells:
- B-cells expressing GM-CSF is increased in patients with RRMS
- these B-cells activate myeloid cells
–> B-cell depletion therapy reduced the pro-inflammatory responses of myeloid cells
What are some animal models for MS?
- Autoimmune inflammatory - experimental autoimmune encephalomyelitis (EAE)
- Viral inflammatory
- Inflammatory demyelinating
- Non-inflammatory demyelinating
