00:01
In this talk, we're going to review
neuroinflammatory disorders.
00:05
And we'll begin with an introduction
to neuroinflammatory disorders.
00:10
To begin, let's talk about
the pathophysiology.
00:13
What's going on
when there's an immune attack
in the brain or
central nervous system?
Well, we start with the brain.
00:20
And in the brain lives,
the neurons.
00:22
The neurons are protected
from the immune system
by the blood–brain barrier.
00:26
What we see here is a schematic
showing the neurons in the brain,
a blood vessel
and the blood-brain barrier.
00:33
The immune system is composed
as we know
of T cells, B cells,
and natural killer cells
and those are maintained
within the blood vessels
and separated from the
central nervous system
by the blood-brain barrier.
00:45
The blood-brain barrier
is made up of astrocytes.
00:48
Astrocytes form a
thick and protective wall
between the blood vessels
in the brain
and prevent immune cells
from infiltrating into
the central nervous system.
00:59
In the central nervous system,
the primary immune cell
in the immune compartment
are the microglia.
01:05
And they're the resident
immune mediators
that function
as immune regulators.
01:11
And also pericytes.
01:13
Pericytes are immune cells
located around the periphery
of the blood vessels,
primarily around
meningeal blood vessels
and serve an immune function.
01:22
In autoimmune conditions,
what we see is that
there's infiltration
of that systemic immune response,
the T cells, the B cells,
the natural killer cells,
or some combination of the three
into the brain
through the blood-brain barrier,
resulting in damage to the nerve,
to the myelin, to the axon,
or some aspect of the
central nervous system.
01:44
When I think about
autoimmune conditions
in the central nervous system,
there's five key mechanisms.
01:49
And I want you to understand
and at least appreciate
some of the things that happen
that cause CNS autoimmunity.
01:56
The first thing we'll talk about
is molecular mimicry.
01:59
Where an antigen on a virus mimics
an antigen in the brain.
02:03
And as a result of the
immune response to the virus,
we see an attack in the brain.
02:08
The second cause or underlying
pathophysiology of CNS autoimmunity
are sequestered proteins.
02:15
And we'll talk about how proteins
are normally sequestered
from the immune system
as a result of an infection,
they can be released.
02:21
and this results in an immune attack
in the central nervous system.
02:26
I want you to know about
the bystander activation
or altered regulation,
where as a result of
some infectious process.
02:32
There's activation of cytokines
which revs up the immune system
and can result in a CNS attack.
02:39
We'll also talk about an
abnormal host development
and normally,
the thymus is involved
in creating B cells and T cells
that attack foreign antigens
and are not auto reactive.
02:51
And in some circumstances,
the body can generate
autoreactive immunity
that can result in
CNS immune attacks.
02:59
And then the last thing is we'll
talk about paraneoplastic causes
of CNS autoimmunity.
03:03
And I want you to understand
each of these five,
underlying
pathophysiologic processes
that contribute to
neuroinflammatory disorders.
03:13
First, let's talk about
molecular mimicry.
03:15
So here we're looking at
a schematic of a neuron,
the blood-brain barrier,
and the blood vessel
as well as a new virus that
is expressing an antigen.
03:25
In the setting of
molecular mimicry,
the immune system responds
to the virus, which is normal.
03:29
That's what you want the body to do
to attack the virus and clear it.
03:33
But in this case,
the virus is expressing an antigen
that's also expressed in the brain.
03:39
And so in some circumstances,
there is a hyperactive
immune response
to that antigen to kill the virus,
but this also results in attacking
of that same antigen in the brain
and that contributes
to the development
of a neuroinflammatory disorder
or CNS autoimmunity.
03:57
This is the first type
of CNS autoimmunity.
04:01
The first cause, underlying cause,
of a neuroinflammatory disorder.
04:06
What about sequestered proteins?
How does this work?
Well, again,
we have our same neurons
which are expressing an antigen
protected from the
systemic circulation
by the blood-brain barrier.
04:16
Here some infectious process
results in release
of an intracellular antigen
that was previously not seen
by the immune system.
04:25
So here you can see in this
schematic infection with a virus
can result in release of
those intracellular proteins.
04:32
Normally, the body's
immune system should attack
that antigen recognizing
it as unfamiliar.
04:38
But in this case, the antigen is
also contained within the neurons.
04:42
As a result of a
hyperactive immune response,
we see infiltration of that systemic
inflammatory response into the brain
and this can contribute to the
development of CNS autoimmunity
or a neuroinflammatory disorder.
04:57
What about bystander activation?
How does that work?
Well, again, we have
the neurons in the brain
separated from
the systemic circulation
by the blood-brain barrier.
05:05
Here as a result of some process
that irritates activates cells,
we have release of cytokines
due to an infectious process.
05:13
Those cytokines rev up
the immune system,
the immune system is able
to infiltrate into the brain
and that sets off
this CNS autoimmune attack.
05:22
So this is another underlying cause
for the development
of a neuroinflammatory disorder.
05:28
What about
abnormal host development?
How does that work?
Normally, the thymus
is the organ in the body
that results in development
of B and T cells,
normal immune cells
that respond to foreign antigens
and destroy potentially autoreactive
antibodies, and immune cells.
05:49
In some circumstances
of abnormal development,
the body fails to
degenerate, discard, and destroy
those autoreactive
immune effector cells.
06:00
And as a result,
they're able to identify antigens
such as those on neurons
infiltrate into the brain
and result in the development
of CNS autoimmune conditions.
06:11
And then the last
underlying process
that can contribute
to CNS autoimmunity
is a paraneoplastic process.
06:18
Here, patients may develop a tumor.
06:19
In fact, we're all really
developing tumors at all times
throughout our lifetime.
06:24
And the normal process for is
for the body's immune system
to recognize that tumor,
to see it as abnormal
and to kill and destroy it.
06:32
In some circumstances, that antigen
that is contained on the tumor
is also present on the surface
or inside of nerves.
06:40
The body's immune system
is revved up
as a result of that cancer.
06:43
And when the immune system
can infiltrate into the brain,
we have the development of a
paraneoplastic neurologic disorder.
06:51
In many cases,
the neurologic disorder
can precede the development
or recognition of the cancer.
06:56
The body's immune system
is doing a good job
at keeping the cancer at bay,
but we see this neurologic syndrome
that develops
and really should herald
additional workup
for an underlying cancer.
07:08
And so these five causes
or underlying
pathophysiologic mechanisms
are the mechanisms
by which CNS autoimmunity
can develop.