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
How are EAE models induced?
By immunization with myelin proteins in adjuvant
What is the problem with EAE as a model for MS?
EAE models can be used to study the MS entry to CNS and the disease initiation, but MS is not found before this in humans, so it doesn’t say alot about MS therapy
How can you seperate NMOSD from MOGAD patients, as the diseases are very alike?
NMOSD: serum anti-AQP4 IgG
MOGAD: serum anti MOG IgG
How can MS be diagnosed?
By cerebrospinal fluid oligoclonal bands
How does MS, NMOSD and MOGAD differ?
MS: lesions are tissue resident CD8+ T-cells and B-cells, oligoclonal bands from CSF
NMOSD: serum AQP4 antibodies, symptoms: hiccuping + vomiting
MOGAD: serum anti-MOG auto-antibodies, + mainly CD4+ T-cells
What are the targets for MS therapies?
- immunosuppression
- block cell migration/entry to CNS
- promote repair
- Th1/17-Th2/Treg cytokine switch
