MS: A primary inflammatory or a neurodegenerative disease? Jack Horssen pov Flashcards
Timetable of lesions. - Stages
Timeline:First a lesion starts in a dot, and that area cleared out, then it becomes hypo-cellular, where the areas that it is slowly expanding (outer edges – rims) are still hyper-cellular, and later they die too.
All stages are morphologically differentiated.
So there’s 4 stages:
Preactive lesion
Active lesion: still macrophages are found, solid lesion.
Due to an unknown reason, immune cells infiltrate the brain. B cells/T cells/monocytes* = macrophages when they enter tissue. Macrophages continuously remove/phagocytose the myelin.
Myelin fragments inside the cytosol are seen in the active lesion. Vessel in the middle is completely damaged and leaky / due to all microbials, proteases etc. produced by immune cells. Radiologists use it, when you normally inject a substance for tracking inside brain, you can’t pass BBB – but these vessels allow the pass.
Massive infiltration of monocytes + accumulation of foamy macrophages + activated microglia observed.
B cells stay in perivascular space generally and don’t infiltrate the CNS tissue itself. Area around vessels!
White matter + gray matter + B/T cells can also be found in meninges.
Axonal injury is also seen. Oligodendrocyte death as well. Macrophages also secrete free radicals/proteolytic enzymes that increase more damage, or cytokines to recruit more immune cells, cause more tissue damage.
2nd stage: Chronic active, center died, outside (rims) still has cells./macrophages = expand the lesion and eat more myelin = then they stop after a while. Why, we don’t know.
If it continued, in couple of months entire brain should have been demyelinated. Does CNS sometime stop it, or immune cells stop themselves, and stop migrating? Not known.
The blood vessel in the middle closes, and the vessels on the rims (sides) of the lesion open. Now in lesion MRI, you see more whiteness on the edges = active parts. In middle, activity dead = ring-like lesion/smoldering/slowly expanding lesion.
Innate immune system is quite involved in this stage.
3rd stage: no cell left - Chronic inactive - scarlike
Astrocytes secrete ECM and fill the gap. Complete demyelination of axons/axonal damage.
In early stage, there’s mainly active lesions. Progressive = more inactive lesions/smoldering chronic active lesions. Atrophy. Shadow plaques = re-myelinating lesions.
Importance of gray matter lesions
MS is not a white matter disease = especially in late stages they show huge gray matter pathology.
There’s huge cortical lesions.
Early stages= more white matter.
These lesions are mainly subpial.
Neuronal loss is observed in cerebral, cerebellar and spinal cord gray matter lesions
Also leads to axonal loss
Gray matter lesions are in close proximity to the immune systems accumulating in meninges. Perhaps meningeal infiltration has something to do with it? Not known.
Demyelination of hippocampus - gray matter
In hippocampus = short term memory is controlled, demyelination is observed.
It’s not surprising that later in their lives MS patients experience memory loss/cognitive impairments that might depend on hippocampus = spectrum is wider than only motor problems.
Axonal degeneration experiment - father of axons
Father of neurohistology = Santiago Cajal, surgeon, but he hated medicine. He was interested in how neurons communicate with each other. Golgi invented silver dyes, Golgi illustrated the entire neuronal network. Cajal optimized the staining technique of golgi, and make these drawings. = no microscopy. They found the synapses = how neurons communicate.
This staining technique invented 100 years ago still used:
Used to stain entire network, not only cell bodies, small dendrites, axons, even synapses can be visualized.
They showed that even in the cortex of MS patients, where there’s no lesions = massive pathology is observed, communication between neurons were effected. Pathology is way more extensive than just lesions.
Incomplete remyelination - reasoning
Incomplete remyelination: So at some point oligodendrocytes must be getting exhausted. At first they are able to remyelinate in early stages, then they can’t do it that fast anymore.
Or oligodendrocytes are just killed too fast.
Inside out/outside in
Inside out: Initial failure in oligodendrocytes/axon/neuron/myelin sheet = 2nd leading to immune cells
Primary effect is in CNS, not immune system
Primary neurodegenerative disorder with 2nd inflammatory demyelination
Outside in: Initial failure is in immune cells, recognizing myelin as foreign
Autoimmune disorder
Inside out - Is oligodendrocyte injury a primary event in MS?
Cuprizone is a toxin that demyelinates the corpus callosum. This myelin goes LN and presented, but doesn’t cause autoimmunity.
You can also kill oligodendrocytes with gene CKO. No T cell responses against myelin is observed in this model too.
Change protocol:
In week 10, demyelination is remyelinated.
In 40 weeks, something happened. Mice lost their running abilities + got T cell infiltrates. Even when you get those T cells and give it to another animal = they got the symptoms too! If you wait long enough = primary neurodegeneration can result in autoimmunity!
What about humans?
Try to find oligodendrocyte injury in very young patients
They found apoptotic oligodendrocytes in brain tissue! Sometimes even in kids. No evidence for Tcells, B cells, only innate immunity found = activated microglia/infiltrated macrophages
Inside out proven. Oligodendrocytes went wrong, then autoimmunity happened.
Problem: Quite unusual group of MS cases, young patients with very aggressive disease course, are they even MS?
Autoimmunity evidence types?
Direct evidence: Inject T cells of someone sick to another healthy individual = unethical.
diseases we call autoimmune are all dependent on indirect evidence.
Indirect evidence: Recreation of human disease in a animal model. We can create EAE model, it might not show all aspects = arguable.
Outside in proofs - arguments against it
Because of EAE, people think that MS is an autoimmune disease, but models cannot reflect it that good.
GWAS almost completely shows problems in immune genes. They all point that there’s something really wrong in autommunity. Th1, Th17, Treg, Tfh, Th2 = all problematic. All SNPs show autoimmunity.
Also other autoimmune diseases show more or less the same genes as well.
Argument: Genetic variants identified here only make small contributions to susceptibility
All MS medicine focuses on dampening immune system, and they work. They are good at blocking relapses /new lesion formation. Depleting lymphocytes, blocking their proliferation, reducing microglia/monocyte activation all works.
Argument: Histopathology doesn’t always show too many lymphocyte
Drugs only can stop inflammation, not progression = underlying neurodegeneration possible
