Multiple Sclerosis is an
autoimmune disease, currently estimated to effect nearly one million people in
the United States.1 All
autoimmune diseases are characterized by a malfunctioning immune system that
attacks healthy host cells, instead of the normal function of attacking infection to
prevent illness. Multiple Sclerosis is an autoimmune disease in which the immune
system attacks the myelin sheath that covers and protects nerve fibers. The
myelin sheath protection enables the nerves to successfully carry signals
between the brain and the rest of the body. Through continued damage to the
myelin sheath, the nerves themselves can become and damaged and exposed, affecting
communication between the brain and the body which leads to a multitude of
different problems. When the myelin sheath becomes very damaged, the nerve is
said to be demyelinated. This can cause problems with vision, pain and numbness
in various parts of the body. More about multiple sclerosis can be found here.
2
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| Figure 1: dymelination illustration |
Treating
Multiple Sclerosis has largely been focused on the preventing the attacks from
the immune system that causes the demyelination and its affects, however a new
type of treatment has been recently proposed, focusing on increasing the
patients ability to restore their myelin sheath, in a process called
remyelination.3 One of the research groups currently interested in
restoring and protecting the myelin sheath is Mohammad Javan's lab
in the department of physiology of Tarbiat Modares University. His group
recently published a paper
suggesting a specific way to increase the body’s ability to repair the myelin
sheath.
Mohammad
Javan’s group hypothesized that inactivating the receptor called
Sphingosine-1-phospate receptor 2 (S1PR2) would contribute to more efficient
repair of the myelin sheath. S1PR2 is one of a few receptors for the protein
S1P. This protein and its receptors have various functions, one of which is
playing a part in the differentiation and trafficking of immune cells.4 You
can learn much more about the functions of S1P and its receptors with this article.5
The researchers arrived at their hypothesis because previous research has shown
that when a protein called Nogo-A binds to the S1PR2 receptor, it inhibits the
growth of neurons.6 Normally this is be important to regulate
neuronal growth and control neuron pathways, but when the neurons become
damaged and demyelinated, then S1PR2 is inhibiting repairs to the neuron. In
this paper they investigated how inhibiting the function of S1PR2 in mice would
affect the mice’s ability to repair damaged nerves, and alleviate some of the
symptoms of multiple sclerosis. Since the demyelination is due to immune cell’s
attacks and S1PR2 is involved in trafficking of immune cells, the investigators
also examined how the inactivation of S1PR2 would affect inflammation (inflammation
is caused by immune cells gathering in a localized area).
To
test their hypothesis, they injected a chemical called lysolecithin near the
brain of different groups of mice. Lysolecithin is used to induce demyelination
in mice, because it breaks down membranes that usually keep immune cells away
from the mice’s nerves. The injection of lysolecithin increases the number of
immune cells that come into to contact with the nerves leading to the damage of
the myelin sheath.7 The different groups of mice included one group
that had normal S1PR2, one that was genetically engineered to lack the S1PR2
totally, and one group that was treated with JTE-013, which is a chemical that
has been established to inactivate S1PR2.8 To examine the mice’s ability to repair the
demyelination caused by the lysolecithin injection, they used an procedure called
Sudan Black
staining.9 Essentially this type of staining allows the
researchers to examine the thickness of the myelin sheath. The researchers
concluded that the thin myelin sheaths detected were myelin sheaths in the
process of remyelination. Both groups of mice with inactivated S1PR2 had
significantly more remyelinated nerve cells then the group of mice with
functional S1PR2. The researchers also used a technique called immunofluorescence10 that allowed them to count the
number of macrophage cells,11
which is a specific immune cell that contributes greatly to inflammation and damage to the nerve.
Immunofluorescence allows the researcher to visualize specific proteins, so
they looked for a protein that is expressed on macrophages called Iba1. They
found that the groups of mice with inactivated S1PR2 had significantly less
macrophages in the area of the demyelination, suggesting less inflammation.
Additionally,
the researchers showed that the inactivation of S1PR2 resulted in decreased
loss of vision for the mice. For this experiment, they injected the different
groups of mice with lysolecithin to demyelinate their optic nerves. The vision
of individual mice was measured by placing the mouse in front of a virtual
rotating system shown below. It is striped black and white so the mouse will
follow the direction of movement with its head if it perceives the rotation. The
rotation rate was increased until the mouse no longer could follow it with
their eyes.
On the third day after the lysolecithin injection, all the mice
groups tested worse than the baseline test, confirming that the demyelination
affected their vision. On day fourteen, the mice were re-tested, resulting in
the group of mice lacking the S1PR2 gene testing significantly better than both
the control group and the group treated with JTE-013. This suggests that the
mice lacking the S1PR2 gene, had increased remyelination, resulting in the
increased rate of recovery of their vision. In another experiment involving
live mice, the severity of a very similar condition to multiple sclerosis that
can be induced in mice was recorded over time. This condition is called
experimental autoimmune encephalitis. After inducing the experimental autoimmune encephalitis condition in the mice, they found that the mice that had
inactivated S1PR2, either by the JTE-013, or by the lack of the gene, had far less severe symptoms then the mice with a functional S1PR2. They had less demyelination,
less overall inflammation, and a higher number of cells that lead to remyelination.
 |
| Figure 2: Mouse vision test illustration |
These
results show that the inactivation of S1PR2 leads to less demyelination and more
remyelination associated with the relief of the multiple sclerosis symptoms.
The researchers suggest that using JTE-013 to inactivate S1PR2 has the
potential to be an effective treatment for multiple sclerosis because in most
of their experiments, the JTE-013 mice mirrored the results of the mice lacking
S1PR2 entirely. This is a promising avenue to supplement treatment of multiple
sclerosis as research continues to try and identify the reason that the immune
system malfunctions. This research has the potential to apply to other diseases
as well because multiple sclerosis is one of many different demyelinating
diseases.12 However, not all demyelinating diseases come
from damage done by the immune system. Some are caused by viruses and others
result from genetics, so more research must be done to investigate the effect
of inactivating S1PR2 on remyelination in these other conditions. Also, a
better understanding of the exact functions of the S1PR2 gene is necessary to
investigate possible side effects of inactivating S1PR2 in humans. Further
advances into increasing the efficiency of myelin sheath repair will lead to
more effective treatments for multiple sclerosis and other demyelinating
diseases.
References:
1. “MS Prevalence” 2018. Retrieved from
2. “Multiple Sclerosis”
2017. Retrieved from
3. R.J.M. Franklin, C. French. 2017. Regenerating CNS myelin — from mechanisms to
experimental
medicines.
Nat.
Rev. Neurosci., 18: 753-769
4. Jolly, P. S. et al. 2004. Transactivation of sphingosine-1-phosphate receptors by FcεRI
triggering is
required for
normal mast cell degranulation and chemotaxis. J. Exp. Med. 199: 959–970
5. H.
Rosen, E.J. Goetzl. 2005. Sphingosine
1-phosphate and its receptors: an autocrine and
paracrine network. Nature Reviews Immunology 5: 560–570
6. A.
Kempf, et. al 2014. The sphingolipid
receptor S1PR2 is a receptor for nogo-A Repressing synaptic
plasticity
PLoS
Biol., article published Jan, 14. 2014.
7. F. Huang, et. al 200. A novel lysophospholipid- and
pH-sensitive receptor, GPR4, in brain endothelial
cells regulates monocyte
transmigration. J. Endothel. Cell Res 14:
25-34
8. M. Osada et. al 2002. Enhancement of sphingosine
1-phosphate-induced migration of vascular
endothelial cells and smooth
muscle cells by an EDG-5 antagonist. Biochem. Biophys. Res. Commun., 299: 483-487
9. B. V. Ineichen, et. al 2017. Sudan
black: a fast, easy and non‐toxic
method to assess myelin repair
in
demyelinating diseases. Neuropathology and Applied
Neurobiology 43:
242–251
10. “Principle of Immunofluorescence”
Retrieved from
11. M.A Elheu. 1983. The Role of
Macrophages in Immunology. Journal of the
National Medical Association
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12. S. Love. 2006. Demyelinating
Diseases. J Clin Pathol. 59(11): 1151–1159.
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