00:01
What does this look like
and where does it go?
So, think about this,
and again it's predictable,
I have antibody with antigen
in a complex in a vessel wall.
00:14
That Fc, the constant
region of the antibody
has undergone its
conformational change.
00:19
So we'll recruit Fc
receptor varying cells
and complement it
will be activated,
which will be
causing local damage.
00:26
Between the inflammatory cells that
are recruited and the local damage,
we are going to get
endothelial cell damage,
vessel wall damage,
so we're going to get thrombosis.
00:36
And if there's thrombosis in a
vessel, all the tissue downstream,
not going to have
a blood supply.
00:41
So you will see infarction.
00:44
With time as we organize the
damage that's happened with these,
you will get vascular fibrosis,
the vessels will become scarred
and we're just seeing kind of a
low power of a cutaneous vasculitis
in the middle panel,
and what that looks like up close
and personal in the middle panel.
01:04
The characteristic sites for
immune complexes will typically go
are the kidney so you
get glomerulonephritis.
01:11
You can get arthritis because of
sluggish flow through the synovial tissue
and you can get a pneumonitis
again, the capillary beds
and the lungs are a good place
to get immune complex deposition.
01:23
So those are kind of the characteristic
places in addition to the skin
for immune complex
vasculitis to occur.
01:32
There are two kind of buzz
words or buzz word phrases
that we use to describe the characteristic
changes in immune complex vasculitis.
01:41
On the left hand side,
it's fibrinoid necrosis,
and it's pointing to kind of a
glassy pink hylan-looking thing
in the middle of the media
of that small bore vessel.
01:53
That is because we've
damaged endothelium
and we've got leakiness of proteins
including fibrinogen and other proteins
into the vessel wall which will give
it that kind of hyalinized pink look.
02:05
On the right hand side is the other
buzzword necrotizing vasculitis.
02:09
So we have inflammatory cells
that are marching right through
neutrophils and macrophages,
marching right through
the vessel wall
and destroying
everything in their path,
the smooth muscle cells.
02:19
So fibrinoid necrosis,
necrotizing vasculitis
are the typical things
that pathologists use
to describe immune complex
mediated damage in the vessel wall.
02:32
So, let's look at
a specific example.
02:35
This is post-streptococcal
glomerulonephritis.
02:40
Post-streptococcal.
02:41
So, you remember that antibodies generated
against the strep pharyngitis microorganism
can form cross reactive
antibodies that recognize heart.
02:53
Well, if you also
have immune complexes
that formed because of a
poorly treated strep throat,
then those immune complexes
can be deposited
in vascular beds.
03:06
And this particular vascular bed
is one of the more common ones,
it's the kidney glomerulus, again,
because of a fenestrated endothelium
and access to the underlying
charged basement membrane.
03:18
And what we see is that the
glomerulus is jam packed with cells,
there are many, many more nuclei than
should normally be in that glomerulus.
03:27
That's because we've got immune
complexes that have deposited
and that are expressing
Fc that's rearrange,
that can bind Fc receptors on
neutrophils and monocyte macrophages
that are being recruited
into this glomerulus.
03:44
So the hypercellular glomerulus
is not because we have more
mesangial cells or anything else,
it's because we've recruited
inflammatory cells.
03:52
And as we damage them,
then we're gonna get fibrin thrombi,
we're going to clog off
the entire glomerulus.
03:59
As a result,
these poor patients are going to lose
filtration capacity will
have acute renal failure.
04:07
On immunohistochemistry,
there's a characteristic look and again,
this is for those of you who
will be doing board exams
to distinguish between
Goodpasture's disease,
which is a good example
of Type 2 hypersensitivity
and Post-streptococcal
glomerulonephritis, which is Type 3.
04:23
Remember, in Goodpasture's,
we have antibodies,
acquired antibodies that
recognize a component
of the basement membrane
in the glomerulus.
04:32
And so we're getting a diffuse linear
staining of all of the capillaries.
04:38
That's Goodpasture disease
on the left hand side.
04:40
On the right hand side,
we're getting immune complex deposition.
04:43
So little balls of immune
complex antigen antibody complex
are binding in the basement membrane,
so it's a granular deposition.
04:52
And if you see these
two on your board exam,
you'll be able to recognize one is type 2,
Goodpasture's is type 3 Post-streptococcal.
05:00
A classic immune complex mediated
disease is systemic lupus erythematosus.
05:05
So what is SLE? What is lupus?
And basically it is a
polyclonal B cell stimulation.
05:12
Somehow we've had lost
peripheral tolerance,
and we're turning on a
whole variety of B cells
that are making a whole
variety of antibodies.
05:21
But there are some characteristic
antibodies that drive that disease.
05:25
So there's multiple
auto antibodies include
antibodies that are
against nuclear material,
anti-double stranded DNA,
all of us have antibodies
against single stranded DNA,
but not against double stranded or
against ribonucleoprotein or RNP
or against other
components of the nucleus.
05:45
Characteristically, that anti-nuclear
anti-double stranded DNA is a major drive.
05:52
And if there's damage anywhere,
so you get sun exposure
and you get UV damage,
we have cells that are dying,
releasing their
double-stranded DNA,
circulating autoantibodies
against a double-stranded DNA bind
to all of that release DNA and now
we have immune complex deposition
in that sun exposed
vascular bed.
06:14
That's how you get type III
hypersensitivity lesions
in a patient who has lupus.
06:21
In addition to the
anti-double stranded DNA,
which is classic
in characteristic.
06:26
Patients with lupus also have
antibodies against their red cells.
06:29
So they can have an
autoimmune hemolytic anaemia.
06:32
They have anti-platelet
antibodies in many, many cases,
so that they can get abnormal
thrombosis and/or thrombocytopenia.
06:41
They also have antibodies that will bind
to a variety of phospholipid surfaces,
which will cause
endothelial cell activation,
which will cause thrombosis.
06:49
So these poor patients because of the
various natures of their antibodies
can have a variety of diseases,
but it's the immune complex deposition
that's going to cause the
most profound pathology.
07:03
What's happening?
So in patients who have lupus, they are
said to have protein manifestations.
07:08
Well, yeah, that's happening because
wherever the immune complexes deposit
is where we're going to
get complement activation,
recruitment of FC
receptor bearing cells.
07:18
And it could be for whatever reason
that they deposit in the brain,
in which case you will have
neuro psychological problems.
07:26
It could be that they
deposit in the kidney,
and you will have the
Maryland nephritis.
07:31
It can be the deposit in
the lungs or the skin.
07:34
It depends on
where they deposit.
07:36
So the manifestations of
lupus can be multiple protein,
because of the vagaries of where
the immune complexes deposit.
07:46
Wherever they do deposit, there's going
to be thrombosis and tissue ischemia.
07:50
And again, this final bullet point
that I've been hammering to death,
wherever the immune complexes deposit,
that will determine the presentation.
07:59
So you can have patients with
lupus who just have joint disease,
or just have cutaneous disease,
or just have renal disease,
or they may have a combination
of all of the above
or something
completely different,
again depending on the
site of deposition.
08:14
One final entity and you may never see
one of these patients in your entire life.
08:19
However, this disease, the antineutrophil
cytoplasmic antibody (ANCA)
associated vasculitis is something
that they like to put on the boards
with some regularity just because
it's a rare disease and they don't,
they don't expect
you to know it.
08:36
I'm going to mention this,
you'll review it when you take your boards.
08:39
And you may never see a patient
who has this, it's relatively rare.
08:44
So we are starting with
inflammatory trigger,
and/or neutrophils that are
expressing a variety of things,
including Fc receptors,
as you see on the right hand side,
but also the neutrophils have
intracytoplasmic granules
that contain myeloperoxidase and
proteinase 3, that's a PR3 is.
09:07
And if they get activated,
they released that material,
the cytoplasmic material
to their cell surface,
they can also dump it
onto associated tissues.
09:17
So the little red balls
or myeloperoxidase,
the little yellow
balls or proteinase 3,
they are derived from
cytoplasmic granules,
and that's why this is called ANCA
(antineutrophil cytoplasmic antibody)
-associated vasculitis.
09:32
Activated neutrophils,
put these various molecules on their
surface or on to adjacent tissues.
09:39
And in a patient,
if they have ANCA antibodies,
antineutrophil
cytoplasmic antibodies,
they can then bind either to
the PR3 or myeloperoxidase
that are present on
the neutrophil surface.
09:52
Or they can bind to
the underlying tissues
that have also deposited these
various granule contents.
10:00
Regardless, having those antibodies that
are directed against PR3 or myeloperoxidase
will then lead to the recruitment and
activation, complement activation, etc.
10:11
But it tends to be
relatively antibody poor.
10:14
It doesn't take very many
antibodies to drive this process
and that's why it's called
pauci-immune vasculitis.
10:23
If we crosslink the molecules on
the surface of the neutrophil,
we can get auto activation,
but we're also going to get neutrophils
that are recruited and damaging
wherever the antibodies have
deposited in the tissues.
10:36
So this is ANCA-associated
vasculitis.
10:38
You've seen it now.
10:40
And hopefully you'll never
have a patient who has it.
10:44
And with that, we've completed type
III hypersensitivity responses.