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Welcome back.
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Previously we talked about
immediate type hypersensitivity
or type 1 hypersensitivity
driven by immunoglobulin E.
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Now we're going to talk about type 2,
which are due to immunoglobulin antibody
bound to fixed
surface molecules.
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So type two hypersensitivity.
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Let's see how this happens.
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If I have a cell that I happen
to have antibody bind to,
that will activate complement and we
will get on the surface of the cell C3b.
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Remember C3b is
one of those fragments
that gets generated during
the activation of complement.
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Antibody binding either to
the C3b or to the initial antigen
is going to cause
opsonization and lisis.
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So, here we have a macrophage,
that's got an Fc receptor,
bound now to the antibody that
is recognised a particular antigen
or via the C3b receptor
and that macrophage
is going to ingest,
degrade and kill that cell.
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So, we can imagine
that if this orange blob
all the way on the
left is a red cell,
then I'm going to have
the loss of those red cells
by having an antibody
that binds to it.
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Which is exactly
what we have here.
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When we talk about
autoimmune hemolytic anaemia.
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We have a red cell, it's got
a variety of surface antigens.
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And if we break tolerance, or if we have
antibodies to those surface molecules,
we will bind the antibody.
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How might that happen?
Well, in fact, if we give
the wrong blood group,
we've give an A type
blood to a B type person,
they will have
circulating A antibodies,
which will bind to the
surface of the red cell.
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That binding of the antibody
will cause complement activation
and deposition with
rupture the cells.
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So that's the autoimmune
hemolytic anaemia,
but we've also made
these cells tasty.
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We've opsonized them by
binding complements C3b
and by having an antibody
present with a rearranged Fc portion,
and it will be pulled out.
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Those cells will be
pulled out by macrophages
as they go through
the liver and the spleen.
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So that's what happens if we
have antibodies against red cells.
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And it can be a
transfusion reaction.
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It can be due to mom having
antibodies against baby's Rh.
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Or it could be a primary autoimmune
disorder, autoimmune hemolytic anaemia.
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What does this look like?
Not only is the patient anaemic,
we're destroying red cells,
were eating up red cells,
were fragmenting red cells.
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So there's lower numbers of red
cells, but we're also getting fragments.
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And the arrow that's pointing to
that funny looking red cell at the top
is actually identifying a cell that
was coated with antibody and C3b.
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And as it went through the gauntlet of
macrophages in the red pulp in the spleen,
bits and pieces of that
red cell got nibbled away at.
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And so we have, in
fact, just the sides.
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We've got fragmented red cells, and that's
just an example on our peripheral smear.
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Okay, that's on
circulating cells.
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That one's pretty easy
to wrap our minds around.
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But what about antigen that's on a
tissue, such as a basement membrane.
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So here we have a basement
membrane that's indicated along the bottom
and we have particular
proteins that are inserted into it.
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And oh my goodness, now we have
antibodies that are bound to those.
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Those antibodies will have
rearrangement of the Fc portion
and now neutrophils
or macrophages,
things that have Fc
receptors will be able to bind.
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We will also by virtue of having that
antibody bound activate complement.
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So we're going to get
complement fragments
that will settle down onto the surface
including C3b and bind to those proteins,
while also make
complement byproduct.
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So C3a and C5a that will activate
mast cells and recruit neutrophils
and activate
inflammatory response.
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So we'll get neutrophils that come
in response to the complement.
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But we will also have
the cells trying to ingest
what is functionally a very large
surface and they won't be able to do so.
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So they'll be dumping their
mediators, their proteases,
their arachidonic acid
metabolites directly onto the tissue,
potentially causing damage.
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Remember, our old
friend the natural killer cell,
has on its surface Fc receptors
that can bind to bound antibody
on the surface of a target.
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So the NK cell,
as you see there,
is interacting with the orange
blob in the upper right hand corner
via antibody
receptor interaction,
so called antibody dependent
cell mediated cytotoxicity.
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So binding antibody to tissues will
cause cell death in that way as well.
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And this notion of frustrated phagocytosis
is pretty important to understand.
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So here, this is a normal
neutrophil with something it can eat.
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It can get its
pseudopods around.
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So it's recognised that
microbe via antibody bound to it,
or via complement
receptor fragments.
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And it now will
ingest phagocytosis
and it will be able to get
it completely enclosed.
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And now, it can fuse lysosomes with that
phagosomes and destroy whatever it ate.
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That's great for smaller things but if
we an antibody binding to big things,
like a basement membrane, neutrophil
comes up, and wants to do same thing.
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It's binding through its Fc receptor
and its complement receptor
and it's ready to rock and roll except
that it can't ever get it all inside.
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So now what it does is it basically
spews its lysosomal content
on to the surface.
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It's frustrated phagocytosis,
it can't get its arms around it.
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And now I will get damaged because
of the release of extracellular enzymes
and other mediators
on to the tissue.
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Oh my god, does this happen?
Oh yes, it does.