00:01
So let’s look at what actually happens when
you have an area of tissue that’s infected.
00:11
So, overlying that tissue will be a blood
vessel, as we can see at the top on this slide.
00:16
And you’ll see a neutrophil, multilobed
nucleus very typical of a neutrophil.
00:24
And normally this neutrophil along with
all the other white blood cells
and red blood cells will be racing through
the blood vessel, doesn’t need to stop.
00:32
It just needs to carry on its journey.
00:34
But if there’s an infection in the
tissues, those neutrophils and other
immune system cells need to be alerted to
the fact that there’s an infection.
00:43
So how does that happen?
It happens by adhesion molecules becoming
expressed on the blood vessel endothelium.
00:53
It’s a bit like putting your
hand out to stop the bus.
00:55
Okay?
You need to stop that neutrophil.
00:59
You need to tell it, “Stop!
Leave the blood vessel, get out into the tissue because
there’s an infection that you need to deal with."
So a variety of adhesion molecules become
expressed on the blood vessel endothelium.
01:12
For example: E-selectin.
01:16
E-selectin gets expressed on the surface of the blood
vessel endothelium in response to activating molecules that
are released both by the infectious agents themselves, for
example bacteria, but also by any damaged host tissues.
01:33
In other words, our own cells that become
damaged as a result of that infection.
01:38
And the neutrophil begins to slow down in its journey,
and it begins to roll along the blood vessel wall.
01:47
A consequence of that is that other molecules begin
to get expressed on the surface of the neutrophil.
01:55
For example: a receptor for
the cytokine interleukin-8.
02:00
In other words, the
interleukin-8 receptor.
02:03
And the interleukin-8 receptor on
the surface of the neutrophil can
then be recognized by interleukin-8
on the blood vessel endothelium.
02:15
Other molecules begin to be expressed.
02:18
So for example, integrin molecules begin to
be expressed on the surface of the neutrophil.
02:23
And these bind to the cell adhesion
molecule ICAM-1 that now additionally
becomes expressed on the endothelium
in response to substances like
lipopolysaccharide from Gram-negative
bacteria, and cytokines that the response
is producing, like interleukin-1β,
interleukin-6 and tumor necrosis factor α.
02:44
So you see, from an initial start with just recognition of one
adhesion molecule, CD15 by E-selectin
on the blood vessel endothelium.
02:53
This response really gets going.
02:55
Lots of additional adhesion molecules get expressed, both
on the blood vessel endothelium and on the neutrophil.
03:01
And this leads to activation of the
neutrophil and very, very firm adhesion.
03:07
So initially the neutrophil is just rolling along the
blood vessel wall, but it comes to a complete stop.
03:13
And then it squeezes through the gaps between the blood
vessel endothelial cells attracted to the site of the
infection by complement components such as C3a and particularly
C5a by chemotactic cytokines, in other words the chemokines.
03:30
And also, mast cell mediators are involved in
this process of permitting the neutrophil to leave
the blood circulation and enter the tissues to
get to the area where there’s an infection.
03:45
And this process of squeezing through
the blood vessel endothelium, between
the junctions between the blood vessel
endothelium, is called diapodesis.
03:56
And ultimately, the neutrophil will reach its
destination where the infectious material is.
04:03
So just a couple of other things to
round off now, whilst we’re looking
at innate inflammatory responses in the innate immune response.
04:15
There are a variety of different cytokines
that are referred to as interferons.
04:19
And there are two particular interferons
that are referred to as Type I interferons.
04:24
They’re called interferon
α and interferon β.
04:28
And following an infection with a virus, and replication
of viruses within the infected cell, one of the results
is that cells-- and virtually all cells in the body can
do this, they produce interferon α and interferon β.
04:46
The consequence of that production of interferon α and
interferon β is that there is the production in response to
those cytokines, there is a production of proteins inside
cells, surrounding the area where there’s an infection.
05:01
And these proteins prevent
viral replication.
05:04
So the cells surrounding the area of the infection are
no longer able to permit replication of the virus.
05:12
So there may be transmission of the virus
from one cell to another, but that’s it.
05:17
Virus can’t then replicate
in the surrounding cells.
05:20
And this prevents the
spread of the virus.
05:23
A very important type of response,
the Type I interferon response.
05:27
Another important aspect of innate immunity
is the so called natural killer cell, NK cell.
05:35
These are cells that patrol around
the body looking for abnormal cells.
05:42
Normally, all of our nucleated cells
have on their cell surface a variety
of different molecules, including a
group of molecules called MHC Class I.
05:53
What the natural killer cell does is
it goes round looking at every single
cell in the body, looking to see if
a cell does not have MHC Class I.
06:03
And I’ve just told you, all nucleated
cells have MHC Class I, so if there’s no
MHC Class I there, there’s something
really strange or odd about that cell.
06:11
And one of the things that can happen when a cell becomes
infected with a virus, is it can lose expression of MHC Class I.
06:19
So there needs to be some
way of picking up on that.
06:22
That’s what natural killer cells do.
06:24
Essentially they have two groups of receptors on their cell
surface - activating receptors and inhibitory receptors.
06:31
And the activating receptors will look for a variety
of different molecules on the surface of the cells,
apart from MHC Class I, a variety of other molecules
that are normally expressed on all nucleated cells.
06:44
And they’ll send an activation signal into the
natural killer cell, telling it to kill that cell.
06:49
And these activating signals come
through protein tyrosine kinases
that add phosphates to a signaling
pathway to initiate that pathway.
07:01
But you don’t want to
kill a normal cell.
07:04
So to prevent that killing occurring
all the time, as well as having
activating receptors, the natural
killer cells have inhibitory receptors.
07:15
And those inhibitory receptors are
linked to protein tyrosine phosphatases.
07:21
And they remove the phosphate groups and
prevent activation of the natural killer cells.
07:26
So normally, the natural killer cell is not
activated and there is no cell killing.
07:33
However, if a cell has become infected with a virus
and has lost MHC Class I, then there is signaling
through the activating receptors, but there is
no signaling through the inhibitory receptors.
07:44
Because if there’s no MHC Class I, you can’t
signal through the inhibitory receptor.
07:49
That activating signal isn’t overwritten and the
infected cell becomes killed by the natural killer cell.
07:57
So hopefully you now understand the
role of inflammation in innate immunity
and the way that the innate immune response
deals with infection and tissue damage.