YOUR BRAIN ON PATHOGENS
The reading in class and the discussion in the last class
has made me interested in what actually happens with the blood brain barrier
(BBB) and antibodies when something foreign enters the brain. There are many
diseases that I can think of that cause neurological problems which lead me to believe
that some bacteria or viruses actually do, or can, cross the blood brain
barrier.
The examples that I could think of were West Nile Virus
(WNV) and Meningitis. Meningitis is inflammation of the meninges; in this case
the inflammation is being caused by some foreign marker such as bacteria. The
brain needs some kind of defense to be able to protect itself or our species
would likely no longer exist. Although the BBB needs to be extremely specific
to make sure we don’t have an immune response to our own brain. I believe that
we do have immune responses that are brain specific.
The following is the
information that I discovered while researching this topic.
The brain does not have a lymphatic system that can initiate
an immune response from the body to the brain. Antibodies are not able to enter
the brain through the BBB, which for our brains, creates a major problem in
order to control infection via bacteria, viruses, or even some parasites that
are able to cross the BBB. Seeing white
blood cells in the brain is something that is possible but it seems to be very
rare in cases of severe disease. Since we know that phagocytes are not specific
in what they target they can actually cause more harm to the body’s normal cells
while they are engulphing and killing the infected cells. In turn this could
destroy neurons and other essential elements of the brain; not good.
In the recent research articles that I was reading through
it seems that the brain does have some sort of its own immune system. These immune cells that are in the brain are
called microglia and they form an extensive defense network in the brain
without the need of the Lymph System to help fight disease and foreign
pathogens. Microglial cells are essentially the innate immune system of the
brain. Like the immune system of the body they respond not only to injury of the
brain but also to foreign pathogens that get past the BBB. Microglial cells
cause inflammation when activated, similar to the peripheral innate immune
system, so it’s worth asking if these cells do more harm than good when there
is a pathogen in the brain. It does not seem that swelling in the brain would
be anything to look lightly at as there is very little room for expansion in
the skull. The microglial cells that are in the brain work without harming the
neuronal tissue.
Astrocytes are another
cell in the brain that helps with the brains immunity. These cells respond more
vigorously in the brain than do the microglial cells. It seems that neurons will also express a type
of protein that is a paired- immunoglobin-like receptor which can inhibit the brain’s plasticity, this protein is
expressed in the neurons and aids in brain trauma. In the case of parasites
entering the brain, such as toxoplasmosis (think kitty litter), the brain will
actually respond with T cells that can cross the BBB and enter the brain. It
seems that little is known about this process but I find it very interesting
that these cells are allowed to cross the BBB at a time of parasite toxicity. Perhaps
the T-cells are already in the brain; I’m not sure on this one, anyone have
some insight?
Ultimately what I found out about the immune system of
the brain seems like I’m barely scratching the surface. There is so much more
to the brain’s immune system than I ever would have thought to begin with. I’m looking forward to learning more about it
in class and in my own time. There are tons of research articles on this topic
and it seems as if scientist though researchers have only just begun to
understand the brain’s immune system.
http://www.nature.com/nri/journal/v9/n6/fig_tab/nri2565_F5.html
Molecular
Medicine Reports, May 8, 2012, http://www.spandidos-publications.com/mmr/6/2/339
Stimulating
the brain’s immune response may provide treatment for Alzheimer’s disease,
Jan 26, 2011, http://phys.org/news/2011-01-brain-immune-response-treatment-alzheimer.html
Science Daily,
Brain Structure Assists in Immune Response. Jan 30,2009. http://www.sciencedaily.com/releases/2009/01/090128132652.htm
While my research is primarily in Neuro-Oncology (brain cancer), I do believe in times of disease the blood brain barrier (BBB) breaks down. Although, the level of dysregulation (breakdown) of the BBB does vary between neurological diseases. During times of acute and chronic cerebral ischemia(1), excitotoxic injury(2), japanese encephalitis virus infection (3), brain tumors(4), etc. the blood brain barrier will break down as a result of the disease, commonly associated with encephalitis (swelling of the brain). I say "associated with" because I am not sure if the breakdown occurs due to swelling of if the breakdown induces swelling.
ReplyDeleteParticularly there are a few researchers on campus that work predominantly with the immune response in brain cancers. One shows an increase in macrophage and microglial response, but also shows increased expression of immune cytokines. Though I am not positive they have proved systemic traveling to brain, but it has been sited before in ependymomas. Another lab has data that suggests glioblastoma induce granulocytes to release a molecule that suppresses the immune response, and that molecule is found in both the brain tissue and blood of mice, suggesting breakdown of the BBB.
And lastly to address your point about the potential of antibodies to cross the BBB. Again I believe that they may be able to in times of disease. I only say this because Cetuximab, an antibody used to treat gliomas, is currently in use IV.
Sorry, this is so cancer heavy.
References
(1)Yang Y, et al. Blood-brain barrier breakdown in acute and chronic cerebrovascular disease. Stroke. 2011 Nov;42(11):3323-8.
(2)Chen ZL, et al. Neuronal Death and Blood–Brain Barrier Breakdown after Excitotoxic Injury Are Independent Processes. The J of NeuroSci. 1999 Nov;19(22):9813-20.
(3)Mathur A, et al. Breakdown of blood-brain barrier by virus-induced cytokine during Japanese encephalitis virus infection. Int J Exp Pathol. 1992 Oct;73(5):603-11.
(4)Davies DC. J Anat. Blood-brain barrier breakdown in septic encephalopathy and brain tumour. 2002 Jun;200(6):639-46.
I recently posted about an article that used two-photon imaging to see how T cells crossed into the CNS (in this case, the spinal cord). The model was EAE, in which CNS extracts are injected into mice so that they create an immune response to CNS materials (like myelin basic protein, MBP). The mice were then injected with T cells that were specific for MBP and also labeled with GFP. It is amazing to watch how the T cells stick to the epithelial walls of the blood vessels (of the BBB) and pass through, then link up with APCs! There is also a link to the article, which has more information.
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