Myelination/Demyelination

- Auto reactive T cells (CD4+ and CD8+) can result in inflammatory

demyelination of the CNS.
- Healthy patients and MS patients have the same number of T cells in
peripheral blood that react to myelin, however in the MS patient they are
activated, are relatively more inflammatory and are thought to be
mediated by Th1 cells that produce interferon-y
- In addition, the anti inflammatory cytokines released by Th2 cells are less
likely to be produced in MS patients.
- Histological features of acute MS lesions include:
o Indistinct margins
o Hypercellularity
o Intense perivascular infiltration by small lymphocytes.
o Parenchymal oedema
o Loss of myelin and oligodendrocytes
o Widespread axonal damage
o Plasma calls
o Myelin-laden macrophages
o Hypertrophic astrocytes
o Occasional remyelination
- Histological features of chronic active MS include:
o A sharp edge
o Along the edge are perivascular cuffs of infiltrating cells
o Lipid laden and myelin laden macrophages
o Hypertrophic astrocytes
o Some degerating axons and demyelination
- The primary differences between chronic and acute lesions is that in
chronic, the demyelination is associated with the deposition of
immunoglobulin and the dissolution of myelin into droplets, which
undergo phagocytosis once that are attached to macrophages.
- The demyelination only partly explains the axonal injury in MS- there is
also the proliferation of abnormal expression of sodium channels within
the membrane. It is an attempt to normalise conduction, but with the
increased entry of sodium slows the nerve conduction, and possibly even
blocks it totally. This is followed by reversal of the sodium calcium
exchanger (ie: calcium influx and sodium efflux) which can trigger
intracellular calcium cascade mediated injury, leading to neuronal
degeneration.
- A factor which is overlooked is the cumulative effects of axonal loss,
which correlates with irreversible disability. The factors that have been
associated with axonal damage include:
o Cytokines
o Nitric acid
o Proteases
o Superoxides
o CD8+ T cells
o Glutamate excitotoxicity
- The is often a degree of remyelination seen in lesions that appear early on
in the disease process. The remyelination comes about from the transport
of oligodendrocyte precusors cells that are attracted to the lesion site by
chemokines.
- Within a lesion of an MS patient there are a number of growth inhibiting
substances which perpetuate developmental arrest, stopping axonal
outgrowth and myelin repair.
- Another pathway which may be implicated into the remyelination (does
anyone actually read these? Email me if you do…) is the Jagged-Notch
signaling pathway. Jagged is expressed on axons and astrocytes, while
Notch is the opposite, and expressed principally on oligodendrocyte cells
around active lesions. The interaction between these two pathways
signals a block in oligodendrocyte differentiation.
- Oligodendrocyte apoptosis has been suggested as a mechanism, but hasn’t
been proved, however most of the opposition to the effect can be
explained by the fixing method of cells used for study.
- One funky finding that is curious is the sharply defined zones of
myelination vs demyelination found in chronic MS- the mechanism for
why the lesion stopped (or why the repair mechanisms didn’t advance
into the lesion) is unknown.

For more info check out the recommended reading under

myelination/demyelination, for the NEJM article.