00:01
So let's look a little bit more
at the serologic testing
for myasthenia gravis.
00:05
We said that approximately
85 to 90% of myasthenics
will be seropositive.
00:09
They will have the presence of
circulating antibodies.
00:13
The most common antibody is the
acetylcholine receptor antibody.
00:17
And we can divide that antibody
into three different types.
00:20
There is a binding, blocking,
and modulating
acetylcholine receptor antibody.
00:25
Let's look at what each of those
antibodies does
at the neuromuscular junction.
00:30
The binding antibody
activates complement.
00:33
An activation of complement
leads to loss
of postsynaptic
acetylcholine receptors.
00:37
You don't have as many
acetylcholine receptors,
and so you can't drive as much
end-plate potential.
00:44
The blocking antibodies
impair binding of acetylcholine.
00:48
They get in the way.
00:49
They obstruct the binding
of acetylcholine
to its postsynaptic receptor
leading to poor muscle contraction.
00:56
And the modulating antibodies
result in
what's called
antigenic modulation.
01:02
There's receptor endocytosis
less receptors are available
on the postsynaptic membrane.
01:07
and this results
in clinical symptoms.
01:10
And the degree of antibody
modulation
correlates with the
clinical severity of disease.
01:16
So let's look at each of these
specifically.
01:19
What happens in the case of those
binding antibodies?
Acetylcholine receptor binding
antibodies
bind to the acetylcholine receptor.
01:27
It sits on the postsynaptic terminus
on the muscle
and drives muscles to contract.
01:34
When that binding antibody
binds to acetylcholine
or multiple acetylcholine receptors
together,
we see that complement
is activated.
01:43
As a result of complement
activation,
the postsynaptic acetylcholine
receptors
are moved into the cell
and degraded.
01:50
And so the end result is there are
less acetylcholine receptors
on the postsynaptic terminus
on the muscle.
01:56
And there is less potential to
drive an end-plate potential.
01:59
Less ability
to activate that muscle.
02:03
What about the blocking antibodies?
How do those work?
Well, blocking antibodies are
competitive antagonist
of the postsynaptic acetylcholine
receptor.
02:12
They find their way into the
synaptic cleft,
they bind to the
acetylcholine receptor
and prevent acetylcholine
from binding
to the acetylcholine receptor.
02:21
And therefore, they prevent
end-plate potential activation
and prevent muscle contraction.
02:27
And we can see that here
auto antibodies
to the acetylcholine receptor
are binding
and preventing muscle activation
and contraction.
02:36
What about the
modulating antibodies?
How did they work?
What is antigenic modulation?
Well, here we see that
signal-induced down regulation
of protein expression occurs.
02:47
These antibodies bind
to the acetylcholine receptor.
02:50
As a result of that binding,
we see cross-linking
of the acetylcholine receptors
on the muscle membrane.
02:56
Those cross linked
acetylcholine receptors
are internalized by the cell
they're recognized as abnormal
and they're internalized
and thus degraded.
03:05
And so again, you see a
downregulation of the number
of acetylcholine receptors
that are on the muscle membrane.
03:12
And it takes much, much more
activation of the nerve
and the neuromuscular junction
to drive muscle contraction.