00:01
Welcome. With this talk we're going to
discuss the major blistering lesions
pemphigoid and pemphigus.
00:09
Now they seem like it's the same thing.
00:11
Well it is the same root word but they have
very different outcomes as we'll talk about.
00:17
So pemphigoid and pemphigus are blistering
autoimmune diseases.
00:21
Pemphigus is going to be the worst one.
00:23
And I'll emphasize that with some comments
later on.
00:26
Pemphigoid is kind of like pemphigus hence
the name,
oid. So pemphigoid and pemphigus but they're
both autoimmune.
00:34
They just attack different parts of the
epidermis.
00:38
So first off the not so bad one bullous
pemphigoid.
00:42
It is a nonlife-threatening .
00:44
Okay. That's important but it is chronic
autoimmune disease.
00:48
What you get are subepithelial bullae.
00:51
Okay. Those words probably don't mean a lot
right now.
00:54
In a moment when you see the images,
they'll make all the sense in the world.
00:59
The location of where the blister is is
important,
because that also indicates which component
of the epidermis has been affected,
and in this case it's loss of adhesion
molecules or breakdown.
01:14
Proteolytic catabolism of the adhesion
molecules between the epidermis and the
dermis. So the whole epidermis is coming up
as part of the blister.
01:25
In comparison, pemphigus vulgaris,
it is life-threatening .
01:29
This can be a lethal disease.
01:31
It is also chronic. It's also autoimmune and
it's characterized by intraepithelial bullae.
01:37
So it's not a separation between the dermis
and epidermis.
01:41
It's a separation within the epidermis.
01:44
And again the words don't mean so much.
01:46
But when you see the image it will make all
the sense in the world.
01:49
In this case the antibodies that are
responsible are causing loss of adhesion
between keratinocytes.
01:57
So not between the keratinocytes and the
basement membrane at the dermoepidermal
junction, but rather between keratinocytes
within the epidermis proper.
02:08
So let's discuss the epidemiology of both as
you see in this chart.
02:13
Bullous pemphigoid and pemphigus vulgaris
have very comparable incidences per year.
02:18
So this is not a major health crisis.
02:21
But nevertheless they do occur.
02:24
The age is slightly older for the bullous
pemphigoid.
02:28
Women and men are equally affected in both
cases.
02:32
There's no real ethnic or racial predilection
for bullous pemphigoid.
02:37
We do see pemphigus vulgaris more commonly in
certain populations as you see there.
02:43
The etiology in both are not well
established.
02:48
And as in most diseases of the skin where we
don't have a good cause,
we invoke things like drugs and and
particularly certain types of drugs that may
drive an immune response.
03:03
Genetics certainly play a role,
and particularly in pemphigus vulgaris,
where certain HLA haplotypes are more
prevalent in pemphigus.
03:12
That may also explain why we see pemphigus
more commonly in the Southeastern Europe,
Middle Eastern and Indian populations.
03:21
Radiation therapy and and other kind of
causes can be invoked,
but we don't know in most cases.
03:31
So the pathophysiology this we do understand.
03:35
But in order to understand this you also have
to go back to basic cell biology.
03:39
So my apologies if this is giving you like
tremors.
03:43
Um we have to understand where the
autoantibodies are acting.
03:47
The epithelium is held together and is held
to the basement membrane by a variety of
adhesion molecules between individual
epithelial cells are desmosomes.
03:59
These are junctional complexes.
04:01
They can they connect via transmembrane
proteins between the cells.
04:06
It's a homotypic interaction.
04:08
Desmogleins. Desmocollin.
04:10
They have a variety of names.
04:12
These transmembrane proteins link one to
another across the gap between epithelial
cells. They also then connect with
intermediate filaments keratin that sits
within the cytoplasm. And they may link from
side to side from desmosomes across the cell
to the next desmosome to allow some
structural integrity.
04:35
So that's one junctional complex we have to
pay attention to.
04:39
The other one is the hemidesmosome,
appropriately named because half of the
structure is the same as the desmosomes.
04:45
So it's hemidesmosome.
04:47
This one anchors through a transmembrane
protein to the extracellular matrix of the
basement membrane. Now,
instead of linking intracellularly to
intermediate filaments,
it links through integrins and then to
intermediate filaments.
05:04
And those proteins are again provide
structural integrity and allow the epithelium
to be adherent to the basement membrane.
05:12
So recall desmosomes and hemidesmosomes.
05:15
And in the two diseases pemphigus and bullous
pemphigoid we are going to see different
antibodies attacking different structures.
05:24
Okay. Here's our normal skin.
05:26
Again kind of a refresher.
05:28
We have the dermis on top of which is a
basement membrane on top of which is the
basal layer of the epidermis.
05:35
And then we have all the keratinocytes in the
stratum spinosum going all the way up to the
granular layer. And the stratum corneum.
05:44
That's our normal structure.
05:47
So that was the normal skin.
05:48
Let's talk about our blistering lesions.
05:51
So the first one up is bullous pemphigoid.
05:53
In bullous pemphigoid we have an IgG
autoantibody that attacks the hemidesmosome
proteins. Those are the proteins that connect
the basal layer to the underlying basement
membrane. We know what the proteins are.
06:07
They have various names. You don't need to
remember those. But we should know that when
you have IgG binding there we're going to
activate complement.
06:14
And we're going to also recruit other
inflammatory cells which will release in turn
proteases and other inflammatory mediators.
06:22
But it's the proteases in particular that
break those connections between the
hemidesmosome integrins and the underlying
basement membrane.
06:31
And when that happens,
the whole epidermis lifts off and then we
have a blister underneath.
06:36
Importantly, the desmosomes that connect the
keratinocytes one to another,
they're fine okay. So there's no problem
there.
06:44
And that gives us a fairly good hunk of
epidermis that has normal integrity.
06:50
And that's why bullous pemphigoid is not as
bad as pemphigus vulgaris that we'll talk
about next. Here's where the blister is.
06:59
That basement membrane.
07:00
That's fine. But the blister is above that.
07:04
And then we have the whole layer of the
epidermis the all of the stratum spinosum
corneum granulosa all that stuff.
07:13
So it is a subepidermal blister okay.
07:18
All right. In comparison pemphigus vulgaris
in this case the autoantibodies are against
desmosomal proteins. So the ones that connect
keratinocyte to keratinocyte.
07:28
And when they bind they don't activate
complement so much.
07:32
But what they do do is that they turn on the
epithelial cells to make a urokinase like
plasminogen activator,
a protease that will break those connections.
07:44
Oh, that's a problem,
because now I have disruption of the
connections between individual keratinocytes.
07:50
That whole layer of epidermis begins to fall
apart.
07:54
And when that happens,
I lose barrier function.
07:58
We get fragile flaccid bullae blisters that
very easily rupture.
08:04
And this gives no barrier function.
08:07
You're very prone to loss of fluid.
08:10
So you need a hypervolemia.
08:12
But more importantly you're very susceptible
to secondary bacterial infections.
08:16
And so this is just a schematic demonstrating
what's going on there.
08:19
The basal layer is connected to the
underlying basement membrane.
08:24
That's fine. But that's just one layer of
cells.
08:27
Now all the other cells are dissociating.
08:30
They're dis cohesive one to another as they
as they dissociate,
they also die. But we end up with a blister
that is intraepithelial,
not subepithelial, but intraepithelial.
08:42
Okay, Hopefully now you have very clearly in
your mind what's different between bullous
pemphigoid and pemphigus vulgaris.
The lecture Pemphigus and Bullous Pemphigoid: Pathophysiology by Richard Mitchell, MD, PhD is from the course Blistering Skin Disorders.
Which characteristic correctly distinguishes pemphigus vulgaris from bullous pemphigoid?
In bullous pemphigoid, where do blisters form in relation to the epidermis?
Which structural component is targeted by autoantibodies in pemphigus vulgaris?
What mechanism leads to blister formation in pemphigus vulgaris?
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