00:00
So now they've rolled,
they've slowed down,
they've bumped along,
and now they're getting to a point
where they can have
firm interaction.
00:09
And that's that stable adhesion.
00:11
Following stable adhesion,
we're going to migrate across
the endothelium.
00:15
Let's look at those
next stages in detail.
00:18
So, firm adhesion is mediated
by a different family
of adherent molecules.
00:24
So you have
integrins and their ligands.
00:28
On the endothelial cell,
we have the ligands for integrins.
00:33
Those ligands are an
immunoglobulin superfamily.
00:36
They're on the endothelium,
they stick out,
they have particular domains, as
shown there with disulfide linkages.
00:42
They have names
that are kind of boring,
but you will hear them.
00:46
So, intercellular adhesion molecule
1 and 2,
So, that's not a bad name.
It's just kind of boring.
00:53
And then platelet endothelial cell
adhesion molecule or CD31.
00:58
They have this general structure,
and they sit on the endothelium.
01:01
What are they binding to?
Well, on the other half
of the equation,
we have the leukocyte.
01:06
And the leukocyte has on its surface
integrins.
01:10
Integrins are
alpha and beta heterodimers.
01:13
There's lots of different proteins
in this family,
but they come out as pairs,
and they have different affinities
for different molecules.
01:23
They mediate not only
cell-cell interactions,
such as the inflammatory response,
but we've seen
integrins previously
because they are the molecules
that adhere epithelium
to the basement membrane
underneath it in hemidesmosomes.
01:39
What the integrins recognize
as their receptor
on the other cells,
so this would be the
immunoglobulin superfamilies.
01:47
They see specifically
three amino acids:
arginine-glycine-aspartic acid.
It's a RGD motif.
01:54
And that motif
of three amino acids occurs
in the middle of
a much larger protein
as you see there,
but that's what gets bound.
02:03
But we get specific interactions,
because of the adjacent
portions of the protein.
02:10
The alpha and beta chains
can be many from the family
and so you can get different
alpha and beta heterodimers
on any given cell.
02:18
And as we'll see
on the next slide,
that allows us to have
some specificity
of who gets recruited when?
The specific ones involved
in recruiting inflammatory cells
are called Beta2-integrins.
You may hear that.
02:31
They're also called leukocyte
function-associated integrins.
02:36
And they are not active
at baseline.
02:38
An important point,
we have to activate them
to get them to be maximally adherent
and bind to that RGD motif.
02:48
So, as promised,
neutrophils have a certain subset
of alpha and beta heterodimers
on their surface,
which are different than the ones
expressed on monocytes,
which are different than the
ones expressed on lymphocytes.
03:01
So you can see that depending on
that integrin expression,
and depending on the
immunoglobulin superfamily,
that they will be binding to,
you can at different times
recruit an endothelium neutrophils,
or monocytes, or lymphocytes,
and that gives you
some specificity.
03:22
Do not memorize the names
and the numbers and all of that.
03:25
The concept here is what's important
that there is a unique expression,
a particular integrins
on different cell types.
03:33
And so initially,
we will recruit neutrophils.
03:36
And then the endothelial cells
will change what they express
and then will recruit monocytes,
and maybe even later
will recruit lymphocytes.
03:44
So, these differences
allow specificity in the recruitment
by changing the cognate ligands.
03:50
Okay, the point about
these integrins
are not active at baseline.
03:55
So on the leukocyte,
we have the integrins
alpha and beta heterodimers.
04:00
And they're sitting there and
kind of that closed configuration
not very active.
04:05
We need to activate them.
So this is an extra regulatory step.
04:10
And we activated by having chemokine
specific molecules that
bind to unique receptors
that turn on the lymphocyte or the
leukocyte in this particular case,
and cause the integrins
to change their conformation.
04:23
Now, they're in a form
that will allow them
to get very firm adhesion.
04:31
So we get increased avidity
of the intergrins
because of the stimulation
activation through the chemokine
and chemokine
receptor interaction.