00:01
Hi, welcome back.
00:03
We've talked about type
one hypersensitivity,
that's due to
immunoglobulin isotype II,
binding to mast cells,
and being crosslinked.
00:11
We talked about type two,
that's antibody against
fixed tissue antigen.
00:17
At the end of the
previous talk on type two,
we also talked a little bit
about the how immune complexes
can occur and how
they drive disease.
00:26
And that's we're going to
talk about in this session,
it's type three hypersensitivity
due to IG,
antibody antigen antibody
immune complex formation.
00:36
So let's think about this
in a little bit of detail.
00:38
Again, once we've deposited
antibodies that have
been bound to an antigen,
we can predict what are
going to be the mediators,
we've already
developed the toolbox.
00:50
So a lot of this is going to
be hopefully straightforward.
00:53
So we are always generating
circulating immune complexes,
that is antibody that
binds to an antigen,
we get multiple kinds
of proteins interacting,
and most of us,
we clear those
quite effectively,
mainly in the spleen
and in the liver
through the activity
of phagocytic cells.
01:12
But every now and then,
you can get circulating
immune complexes
that can deposit
in the vessel wall.
01:17
Again, they're circulating,
so where immune complex
deposition is going occurs
is going to be in vascular beds.
01:23
So once we have that,
predictably, we're going to
get some consequences of that.
01:30
So we're going to
activate complement,
and we're going to recruit
FC receptor bearing cells
to the site where the antigen antibody
immune complexes have deposited.
01:40
Those neutrophils
are going to come in,
they're not going
to be able to eat
all of the immune complex
and they're going to end up
dumping their contents
there proteases
and their arachidonic
acid metabolites,
all the things that
neutrophils will do
on to that tissue,
which will cause vascular damage.
01:59
And when vascular damage occurs,
we're going to get thrombosis,
we'll have a schemia
in that vascular bed.
02:06
And eventually we'll
develop scarring.
02:07
These are all predictable consequences
once the immune complexes deposit.
02:14
This is just showing you how the
neutrophil granules are being released.
02:17
And there are reactive
oxygen species,
the Ross remember of
superoxide and all that stuff,
that's going to
cause tissue damage.
02:25
We recognise this as vasculitis,
an inflammation and
itis of the vessels.
02:32
So, I already told you,
most of the time the immune
complexes don't deposit,
they circulate,
we pull them out
very effectively
by macrophages in the liver and
the spleen,
and we're good to go.
02:44
But sometimes they do deposit
and we'll talk about that.
02:47
So why might they deposit?
Well, sometimes it's the size.
02:51
And remember in the
previous session,
we are talking about giving someone
a whole bunch of horse serum albumin
and watching them
form immune complexes.
03:00
Smaller immune complexes are
going to be harder to clear
because they have less FC,
and they're going to be
much more likely to deposit.
03:07
So bigger complexes
tend to get cleared
more effectively,
smaller complexes not so much.
03:14
It's also going to be the
physical chemical characteristics.
03:17
So charge,
how effectively the
antibody is bound.
03:22
The kind of three
dimensional conformation
of the antigen antibody
complex will deposit,
will determine whether
it deposits or not.
03:32
If the macrophages in the
spleen, in
in the liver or
otherwise compromised,
they are sopping up
lipid or something else,
you may not have adequate
phagocyte clearance capacity.
03:45
And then those circulating
immune complexes
will be able to go
around much more
within the circulation and
eventually will deposit.
03:53
Hemodynamics plays
a big role in this.
03:56
So, smaller vascular beds where there's
more sluggish flow such as joints
and the kidney nephron
are going to be favoured targets for
the deposition of immune complexes.
04:08
The endothelial characteristics are
also going to be very important.
04:11
Remember that the endothelium
in the renal glomerulus
is a fenestrated endothelium,
it's got holes in it.
04:18
So it's possible are much easier
in that environment for immune
complexes to get deposited
in the basement membrane.
04:26
It will also depend to some
extent on vascular permeability.
04:29
So if we make the vessels
leaky because of injury,
or because cytokines or
because of an allergy
or mast cell degranulation,
all those things will
potentially open up gaps
in the microvasculature where
the immune complexes can deposit
and also, if we are activating
neutrophils for any variety of reasons,
and they are causing local
damage that will also create
an opportunity and environment
by which the immune
complexes can be deposited.
05:00
So all these things
will potentially impact
whether or not you get
immune complex deposition.