Pathophysiology of multiple sclerosis
Multiple sclerosis is an inflammatory demyelinating disease of the CNS in which activated immune cells invade the central nervous system and cause inflammation, neurodegeneration, and tissue damage.
Current research in neuropathology, neuroimmunology, neurobiology, and neuroimaging, together with clinical neurology, provide support for the notion that MS is not a single disease but rather a spectrum.
[4] There are three phases for how an unknown underlying condition may cause damage in MS: Multiple sclerosis differs from other idiopathic inflammatory demyelinating diseases in its confluent subpial cortical lesions.
[12] Most MS findings take place inside the white matter, and lesions appear mainly in a periventricular distribution (clustered around the ventricles of the brain).
[17] Follicle-like aggregates in the meninges are formed only in secondary progressive MS.[18] and correlate with the degree of subpial cortical demyelination and brain atrophy, suggesting that they might contribute to cortical pathology in SPMS[18] These ectopic lymphoid follicles are composed mainly of EBV infected B-cells.
In any case, understanding lesion patterns can provide information about differences in disease between individuals and enable doctors to make more effective treatment decisions.
The other patterns (III and IV) were highly suggestive of a primary oligodendrocyte dystrophy, reminiscent of virus- or toxin-induced demyelination rather than autoimmunity."
[39] Nevertheless, after some debate among research groups, the four patterns model is accepted and the exceptional case found by Prineas has been classified as NMO[40][41] For some investigation teams this means that MS is an immunopathogenetically heterogeneous disease.
This was already indicated by previous studies that found a relatively high rate of false diagnoses of MS among patients with AQP4-IgG-positive neuromyelitis optica spectrum disorders or MOG encephalomyelitis.
Currently antibodies to lipids and peptides in sera, detected by microarrays, can be used as markers of the pathological subtype given by brain biopsy.
In the former, it is hypothesized that a problem in CNS cells produces an immune response that destroys myelin and subsequently breaks the BBB.
In latter, an external factor produces BBB leaks, enters the CNS, and destroys myelin and axons.
Increased expression of pro-inflammatory cell surface markers have been observed in NAWM and "initial" lesions, corresponding to a so-called loss of homeostatic microglial equilibrium.
BBB disruption is the moment in which penetration of the barrier by lymphocytes occur and has been considered one of the early problems in MS lesions.
[56] The BBB is composed of endothelial cells which line the blood vessel walls of the central nervous system.
Some hypotheses about how the BBB is compromised revolve around the presence of compounds in the blood that could interact with vessels only in the NAWM areas.
These increase BBB T-cell permeability, specially in the case of MMP-9[60] and are supposedly related to the mechanism of action of interferons.
[74] Another protein involved is CXCL12,[75] which is found also in brain biopsies of inflammatory elements,[76] and which could be related to the behavior of CXCL13 under methylprednisolone therapy.
Recent research as of 2019 point to one of the HERV-W viruses (pHEV-W), and specifically one of the proteins of the viral capsid that has been found to activate microglia in vitro.
[90] Supporting this study, a monoclonal antibody against the viral capside (Temelimab) has shown good results in trials in phase IIb.
[91] Whatever the underlying primary condition is, it is expected to be a soluble factor in the CSF,[12] maybe an unknown cytokine or ceramide, or a combination of them.
[131] Others propose an oligodendrocyte stress as primary dysfunction, which activates microglia creating the NAWM areas[132] and others propose a yet-unknown intrinsic CNS trigger induces the microglial activation and clustering, which they point out could be again axonal injury or oligodendrocyte stress.
In particular, some PPMS patients have been found to have a special genetic variant named rapidly progressive multiple sclerosis[47] which would behave differently from what here is explained.
Several biomarkers for diagnosis, disease evolution and response to medication (current or expected) are under research.
