00:00
Another flavour of type
four hypersensitivity
is that associated
with helper T cells.
00:07
Remember, these are marked by the
CD4 protein on their cell surface.
00:12
CD4 helper T cells
are recognizing antigen
that's being provided
by antigen presenting
cells, that's with APCs.
00:20
And they will respond appropriately
by cranking out cytokines.
00:25
Now those cytokines will
do a variety of things,
they can drive B cells
to make antibodies.
00:31
That can bind potentially
to surface antigens,
they will make cytokines that
will stimulate and activate
neutrophils and macrophages
and cytokines that
will also stimulate
natural killer cells and
cytotoxic T lymphocytes.
00:43
So the helper T cell is
the orchestra conductor,
in this form of
hypersensitivity response.
00:52
There will be tissue injury,
but as opposed to what went on
previously, with the cytotoxic T cell,
which is relatively specific,
there can be a
lot of nonspecific
innocent bystander damage,
because of the recruitment
of neutrophils and macrophages
who are just being turned on
and they don't necessarily know
exactly what the target is.
01:13
So examples of this so called
delayed-type hypersensitivity.
01:18
It's called delay-type,
because it takes 12 to 72 hours,
so of half a day to maybe three days
to get up and running
before we can recognise it.
01:29
That is to be related to
immediate type hypersensitivity,
which is due to IGE so don't that's why
they're given those different names.
01:38
Delayed-type hypersensitivity takes 12
to 72 hours, because we have to recruit
the T cells,
they have to proliferate
and then they have to recruit additional
cells, so it takes that much time.
01:50
Interestingly, because the T cells
are making all these cytokines,
they're recruiting a
variety of other T cells
that are not necessarily
antigen specific.
02:00
So it's a little bit
like, frat row
where you put up a
sign on a Friday night
and says toga party tonight.
02:07
Well, 10% of the
partiers in that frat
are going to be people who
actually belong to the frat,
and 90% have just been called
in by the advertisement,
that there's a party going on.
02:20
Same thing here with lay
type hypersensitivity,
most of the cells are
not antigen specific.
02:26
They've called in however a variety
of other antigen nonspecific T cells.
02:34
There is a variable macrophage
and eosinophil, neutrophil,
other cellular inflammatory
cell infiltrates
based on the cytokines
that are being elaborated.
02:45
It's important to understand that
it's not just helper T cells,
but cytotoxic T cells are
called in by the same cytokines,
the same chemo kinds that are bringing in the
rest of those antigen nonspecific T cells
are also calling in
those other cell types.
02:59
CD4 activation,
the helper T cell activation
can also promote B cell
proliferation and antibody production
so they can have a component of
antibody mediated damage as well.
03:10
And the cytokines can also drive
natural killer cells to become
very, very lint lymphokine
activated killers
that will kill just
very indiscriminately.
03:20
So delayed-type
hypersensitivity,
pretty potent,
but because of all these other
kind of mediator driven
recruitment of other cell types
can have a lot of
non specificity.
03:32
What's being shown here
is an example of a delayed
type hypersensitivity response.
03:36
This is to poison ivy,
there is a compound in poison ivy
called urushiol or pentadecacatechol
is responsible for which will
bind to a variety of proteins
and elicit a helper
T cell response.
03:51
Your first exposure to poison
ivy, that's for free.
03:54
But now you will
elaborate and generate
a memory population of T cells
that will recognise that oil,
urushiol in the leaves of the poison
ivy and the second time you're exposed,
then you get that very profound,
delayed-type hypersensitivity
that occurs over half
a day to three days.
04:16
This same response is what
we use routinely for the PPD,
the purified protein derivative
response or the tuberculin response.
04:25
And what happens what's
being shown there is the arm
actually it's my
arm back in the day.
04:30
We did this as an exercise in
a lab in my pathology course,
where we injected
purified protein derivative,
that's the P with a circle around it.
04:42
We also then wanted to administer
a couple control proteins,
such as C,
Candida or M mumps antigen,
and then we came back
72 hours later and saw
which one of these has
an area of induration
that is this they a
little bit of edema.
05:01
And whether there's
erythema or not.
05:04
Now I'm PPD negative.
05:05
So I haven't ever been in
previously exposed to tuberculosis,
so I don't have a response.
05:10
But making sure that
my immune system works,
we can see that I have
a pretty robust response
to the mumps antigen
that is there.
05:18
And that's that big red,
I'll tell you is itchy and painful,
lesion region that
is marked with the M.
05:25
And very minimal Candida,
the Candida is a common
agent in diaper rash.
05:30
And I guess my mom was really good
about not letting me get diaper rash.
05:35
In any event, that's my arm.
05:37
Back to be the
tuberculin PPD response.
05:40
So we take a purified protein
mesh from tuberculosis,
and we inject it into
the subcutaneous skin
of a someone we
want to test them,
we also should always
put in a control
to make sure their
immune system works.
05:57
If you've had prior
exposure to tuberculosis,
you have circulating
CD4 positive T cells
that can recognise that and they
will localize to the tissue.
06:06
They will then recruit and
activate additional cells
that will give rise to
the cytokine environment
that will cause that edema
and that vascular congestion
that makes for the
redness and the swelling.
06:19
Because it's a delayed-type
hypersensitivity response,
it takes two to
three days to get it
and that's why you don't
go back to the nurse
to have your PPD
read until that time.
06:29
The vasodilation the increased
vascular permeability,
with that kind of integration
is secondary cytokine mediators.
06:36
Being elaborated by the cells
that have been recruited.
06:38
And again, keep in mind
that relatively minor populations
of those are antigen specific.
06:45
It's exactly the same thing that goes
on when you are exposed to poison ivy,
same pathway.
06:51
The interestingly
enough, the pruritis.
06:53
The itchiness of that is due to
the elaboration of kinins
in that environment.
06:58
So what does this look
like histologically?
Well, so it's the kind of a
mononuclear inflammatory response
around vessels in the dermis.
07:06
That's it.
07:07
In fact, that was taken from
a punch biopsy of my skin
with that mumps reaction,
but it's the same reaction
that you would see
if you had a positive PPD.
07:17
And what we're looking at is actually just
the recruitment of the inflammatory cells,
they're activated,
they're making cytokines,
they're causing vasodilation and
increased vascular permeability.
07:25
The vasodilation is seen as
a flare around the periphery
of a particular lesion.
07:31
And that's the redness
and then there will be a
central area of integration
to increase vascular
permeability.
07:36
That's the wheel.
07:38
Finally by way of a summary,
talking about mechanisms of delayed-type
hypersensitivity mediated pathology.
07:45
You have an antigen specific,
helper T cell marked by that CD4
molecule it produces cytokines,
and that cytokines will
then drive the activation
of additional inflammatory
cells will get recruitment
will get the local
DTH type response.
08:03
Unfortunately,
all the other guys
that are coming in,
all the other cells,
the NK cells and the macrophages
and neutrophils, etc,
can be somewhat
antigen nonspecific,
and can release mediators that
can cause local tissue injury.
08:19
And so examples,
overall of delayed-type
hypersensitivity
include the tuberculin
response that PPD,
great example.
08:27
Type One diabetes that we will
cover in a subsequent talk
when we talk about
autoimmune diseases.
08:33
Hashimotos thyroiditis,
another autoimmune disease,
with helper T cells directed
against the epithelium of a thyroid,
scleroderma,
rheumatoid arthritis,
contact hypersensitivity,
that's the poison ivy stuff.
08:47
Those are all great examples
of DTH-mediated disease.
08:51
So with that,
we've completed type
four hypersensitivity,
and we'll move on
to the next topics,
which will be auto immunity
and the response
to foreign objects.
09:05
And with that,
you're there.