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Welcome back.
00:02
We've laid the groundwork for talking
about immune mediated diseases
by talking about innate and
adaptive immune components.
00:10
We've talked about
macrophages and neutrophils
and complement
and natural killer cells
as part of the innate response.
00:18
We've talked about helper
T cells and killer T cells.
00:22
And B cells produce the antibodies as
part of the adaptive immune response.
00:27
And now we're going
to put them together
and start talking about
immune mediated diseases.
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There are kind of four general
categories as we'll see on the next slide.
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This one is just type 1.
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We're gonna emphasize
just type one on this slide,
which is IgE allergen mediated.
00:47
So, there are various mechanisms
of immune mediated diseases,
and these are generically
called hypersensitivity reactions.
00:54
And for purposes of board
examinations and other things,
they're classically broken
down into four basic types.
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Type One is hypersensitivity response
driven by Immunoglobulin E by IgE.
01:09
This is so called immediate
type hypersensitivity,
because the initial effects
happen almost instantaneously
once we've had a
particular stimulus.
01:19
And these are going to be
the hypersensitivity reactions
that underlie allergy
and anaphylaxis.
01:25
Type 2 that will come
up in a subsequent talk
that you're also going to
enjoy famously, is type 2.
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And this is antibody that is
generated against a fixed antigen.
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So an antibody that somehow
recognizes the surface of a red cell
because it binds to one
of the surface molecules.
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That will be type 2.
01:47
Type 3 is due to antigen
antibody complexes.
01:51
Immune complexes that form with
circulating proteins and antibodies.
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And type 4 is cell-mediated.
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And that could be
cytotoxic T cells or it can be
things related, diseases related to
hypersensitivity from helper T cells.
02:10
A so called delayed
type hypersensitivity,
since it takes a while
to get an accumulation
of the the necessary
effector cells
and for them to
elaborate their cytokines.
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Once we have understood,
which you now have understood,
the fundamental kind of toolkit of the
way that the immune system can respond
with innate and
adaptive immunity,
the consequences of each of
these types of hypersensitivity
become completely predictable.
02:41
Okay, and so hopefully by is
having said the predicate before,
the details we're going to go into now
we'll be just like, "Yeah, I got that."
"Okay, I completely understand."
As I said, we're going to emphasize type
1 hypersensitivity reactions in this talk.
02:57
So type one is mediated by IgE.
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It's immediate type
hypersensitivity.
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We're looking at in the middle
of the screen there a mast cell,
a stylized version
of a mast cell.
03:08
And on its surface, as you can
see, on the upper right hand side,
there are a number of IgE Fc
receptors, so called Fc epsilon receptors.
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Those are pre-loaded
with immunoglobulin E.
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So it's circulating antibody
of a particular isotype
that has bound
to those receptors.
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And basically, now
it's it's a little landmine.
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If allergens come along, and
bind to the surface of the IgE
that's already on its
receptors will crosslink
those IgE molecules
and their receptors,
and we'll get activation
of the mast cell.
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So that's exactly what
happens with allergens.
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And whether that's cockroach
droppings, or cat dander, or pollens,
they all have a polyvalent.
03:57
So multiple antigens
lined up on a backbone
that can crosslink
the bound IgE.
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Once that happens, that's a
signal immediately for degranulation.
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And release a various mediators.
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So the granule contents
include histamine and proteases,
and various chemotactic factors.
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That happens immediately.
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That's why it's called
immediate type hypersensitivity.
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And histamine, for example, would
cause increased vascular permeability,
and vasodilation.
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That's why if you have an
allergy, you take an antihistamine.
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That's to block the
effects of the histamine
causing the vasodilation
increased vascular permeability.
04:39
It turns out that in the vessel
bed, you get vasodilation,
but in the airway beds
and along the bronchioles,
you'll get bronchoconstriction.
04:50
So you can begin to understand
how asthma is going to happen,
due to the effects of
mast cell degranulation.
04:57
But that's not all
the mast cells do
once they've been activated
through their Fc receptors.
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They will also make a variety
of arachidonic acid metabolites.
05:09
So once we've activated the mast
cell, we activate phospholipids A2,
which will break down various lipids
present in the nuclear membrane,
and will release
arachidonic acid.
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That's a 20 carbon with
four unsaturation molecule
that can then be converted into
a variety of additional molecules,
including leukotrienes
and prostaglandins.
05:34
And we've talked about these
previously when we talked about
acute inflammatory responses.
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Those membrane phospholipids breaking down
will also make platelet activating factor,
which is a very potent bronco
constrictor and also vasodilator.
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So we get PAF on
the right hand side,
we get arachidonic acid
metabolites on the left hand side.
05:55
The effects of these
take a little while.
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It's not just I'm
releasing granules.
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Here, I actually have
to activate an enzyme,
it has to cleave, I have
to get new synthesis.
06:05
So over the course
of a couple hours,
we're going to see the
effects related to now,
this membrane
phospholipid metabolism.
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Those effects that take minutes to hours
are going to include bronchoconstriction.
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And there will be
inflammatory cell recruitment
as a result of the effects of
say, for example, leukotriene B4.
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So we have an immediate effect,
we have an intermediate effect.
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And now we also have
a longer term effect.
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So at the same time, we're
activating these other pathways,
we're also activating the cell
to make additional cytokines.
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Those cytokines are
going to have late effects.
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To hours to even a couple days.
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And they're going to be important
for recruiting inflammatory cells
and for secondary effects on the
epithelial cells that are in the vicinity.
06:58
So the late effects include inflammatory
cell recruitment, just as I said.
07:02
They're going to be
chemokines and cytokines
that will drive and
recruit neutrophils,
macrophages,
eosinophils, for example.
07:11
There will also be a more prolonged
effect on vasodilation and edema.
07:16
So the longer term effects
of the mast cell degranulation,
or the mast cell activation, are going
to be prolonged visit dilation and edema.
07:25
As I said, cytokines will increase mucus
production in areas such as the airways.
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And there's potential
for epithelial injury.
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So some of the inflammatory
cells that are coming in
are going to themselves
release their proteases
or release mediators that are going
to cause potential epithelial injury.
07:47
So you're thinking to yourself, "Why would
I have an immune response like this,"
"that could potentially
be so damaging?"
Well, in fact, probably,
IgE mediated responses,
including the recruitment of
eosinophils and cells of that nature,
were probably evolutionarily
developed, to deal with worms,
to ailments and
things like that.
08:11
So this is not just to keep
the allergist in business.
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There's probably a real reason
that this occurred over time.