For
immune cells like T and B cells that means having the right ligand or surface
molecule to get through the blood-brain barrier, this is kind of like having
the VIP pass to get into an exclusive club. Once a T cell makes its way in it
can get activated by something it encounters – in the case of multiple
sclerosis, it’s activated by myelin. Once the T-cell gets activated, it changes
the blood-brain barrier cells to express more receptors, and this allows immune
cells to more easily bind and get in, it’s kind of like bribing the bouncer to
let in a lot of people. Now, multiple sclerosis is a type IV hypersensitivity
reaction or cell-mediated hypersensitivity. And this means that those myelin-specific T-cells release cytokines like IL-1, IL-6, TNF-alpha, and
interferon-gamma, and together dilate the blood vessels which allow more immune
cells to get in, as well as directly cause damage to the oligodendrocytes.
The cytokines also attract B-cells
and macrophages as part of the inflammatory reaction. Those B-cells begin to
make antibodies that mark the myelin sheath proteins, and then the macrophages
use those antibody markers to engulf and destroy the oligodendrocytes. Without
oligodendrocytes, there’s no myelin to cover the neurons, and this leaves
behind areas of scar tissue, also called plaques or sclera. In multiple
sclerosis, these immune attacks typically happen in bouts. In other words, an
autoimmune attack on the oligodendrocytes might happen, and then regulatory T
cells will come in to inhibit or calm down the other immune cells, leading to a
reduction in inflammation.
Early on in multiple sclerosis, the
oligodendrocytes will heal and extend out new myelin to cover the neurons,
which is a process called remyelination. Unfortunately, though, over time as
the oligodendrocytes die off the remyelination stops and the damage becomes
irreversible with the loss of axons. Just like other autoimmune diseases, the
exact cause of multiple sclerosis is unknown but is linked to both genetic and
environmental factors. Genetic risk factors include being a woman and having genes
that encode a specific type of immune molecule called HLA-DR2 which is used to
identify and bind to foreign molecules. Environmental risk factors might
include infections as well as vitamin D deficiency, which is an interesting one
because it might help explain why the rates of multiple sclerosis are higher at
the northern and southern poles compared to the equator where there’s a lot
more sunlight.
.png)
Unfortunately, though, more often
than not, the remyelination process is not complete so there is often some
residual disability that remains, and that means that with each attack, more
and more of the central nervous system gets irreversibly damaged. In the
relapsing-remitting multiple sclerosis type, there’s typically no increase in
disability between bouts, so the line stays flat during that time. Now, the
second type is called secondary progressive multiple sclerosis or SPMS which
initially is pretty similar to the relapse-remitting type, but over time the
immune attack becomes constant which causes a steady progression of disability.
The third type is primary-progressive multiple sclerosis or PPMS, which is
basically one constant attack on myelin that causes a steady progression of
disability over a person’s lifetime.
The final type is progressive relapsing multiple sclerosis or PRMS, which is also one constant attack but this time there are bouts superimposed during which the disability increases even faster. Specific symptoms vary a lot from person to person and largely depend on the location of the plaques. And multiple sclerosis typically affects individuals between the ages of 20 and 40. Symptoms related to bouts can typically worsen over weeks and can linger for months without treatment. One common trio of multiple sclerosis symptoms is called Charcot’s neurologic triad and it includes dysarthria, which is difficulty or unclear speech, nystagmus, which is involuntary rapid eye movements, and intention tremor. Dysarthria is due to plaques in the brainstem that affect nerve fibers that control muscles of the mouth and throat, and this can interfere with conscious movements, like eating and talking, and can lead to things like a new stutter, as well as unconscious movements, like swallowing.
Nystagmus is due to plaques around
the nerves controlling eye movements. Plaques around the optic nerve cause loss
of vision in one or both of the eyes because of damage to the optic nerve,
which is called optic neuritis. Sometimes there’s blurring or graying of the
vision, or alternatively, there might be a dark point in the center of vision. Additionally,
if there’s damage to the nerves controlling eye movement, then eye movements can
be painful and there can even be double vision if the eyes can no longer move
in a coordinated way. Finally, intention tremors can be caused by plaques along
the motor pathways in the spinal cord which can affect outbound signals like skeletal
muscle control. Motor symptoms can include muscle weakness, muscle spasms,
tremors, and ataxia, which is a loss of balance and coordination. In serious
cases, this can lead to paralysis.
In addition, plaques in the sensory
pathways can affect inbound signals like sensations from the skin which causes
symptoms like numbness, pins-and-needles, and paresthesias which are often a
tingling feeling but may also be a painful itching or burning sensation. Occasionally
there can be very specific sensory symptoms like Lhermitte’s sign, which is when
an electric shock runs down the back and radiates to the limbs when a person
bends their neck forward. Plaques can also involve the autonomic nervous system
which can lead to bowel and bladder symptoms like constipation and urinary
incontinence, as well as sexual symptoms like sexual dysfunction.
Finally, multiple sclerosis can also
affect higher-order activities of the brain, causing poor concentration and
critical thinking, as well as depression and anxiety. Multiple sclerosis is
typically suspected when there are multiple neurologic symptoms separated in
space, which is attributable to damage in different locations in the nervous system,
as well as time, meaning separate bouts or flare-ups as well as remission. The
diagnosis of multiple sclerosis is supported by an MRI which shows multiple
central nervous system lesions, called white matter plaques since these
regions tend to have lots of myelin. Also, in the cerebrospinal fluid, there
might be high levels of antibodies, which indicate an autoimmune process. Finally, a visual evoked potential can be helpful as well, which measures the nervous
system’s response to visual stimuli.
For treatment, there is no cure for multiple sclerosis, but there are medications that are particularly effective for the relapsing-remitting type because they lessen the severity of relapses and make them happen less frequently. Medications like corticosteroids, cyclophosphamide which is a cell cycle inhibitor, and intravenous immunoglobulin can all be used to help blunt the autoimmune process. In addition, plasmapheresis can be effective as well, which is when the plasma is filtered to remove disease-causing auto-antibodies. Chronic treatment for multiple sclerosis includes immunosuppressants like recombinant beta-IFN which decreases the level of inflammatory cytokines in the brain and increases the function of T regulatory cells. Other immunosuppressants actually block T cells from getting into the brain by interfering with the cell surface molecules they use to gain passage through the blood-brain barrier.
Unfortunately, though, there are
fewer treatment options available for the progressive MS. Instead, treatments
are often targeted at managing specific symptoms—everything ranging from
depression to bladder dysfunction. Physical therapy and cognitive
rehabilitation therapy can be particularly helpful with sensory, motor, and
cognitive symptoms. Finally, there’s also an increasing interest in the role of
vitamin D as an effective treatment.
All right, as a quick recap,
multiple sclerosis is a chronic and progressive autoimmune disorder, and the
most common pattern is the relapsing-remitting type, where individuals have
flares that come and go, with each one slightly worsening their overall
condition. During a flare, T-cells cause inflammation and damage to oligodendrocytes
in the central nervous system, which leaves behind scarred areas of demyelinated neurons called plaques, which
causes a variety of symptoms depending on the location.
Thank You