00:01
So, immune complex mediated arteritis include things like
polyarteritis nodosa.
00:08
That's in the medium to large size vessels all the way over
on the left-hand side.
00:13
Small vessel vasculitis that has a similar pathogenesis,
etiology,
include things like a lupus vasculitis, systemic lupus
erythematous,
SLE vasculitis, or IGA associated vasculitis that is
Henoch-Schonlein purpura,
or other sorts of vasculitides due to antibodies binding.
00:35
In that case, Goodpasture's disease where the antibodies
are actually directed against a component of the basement
membrane.
00:43
Okay, so those are examples.
00:44
We'll spend more time talking about the specifics at the
back end of this talk.
00:49
All right, a third kind of pathogenic mechanism to think
about.
00:54
So, we've had antiendothelial cell antibody, we had immune
complex deposition.
00:58
There's an entity called antineutrophil cytoplasmic
antibodies,
so called ANCA, antineutrophil cytoplasmic antibodies.
01:08
These ANCA antibodies can be elaborated after a variety of
infections or other triggers.
01:14
And what they do is bind to cytoplasmic components of
neutrophils.
01:20
In particular, proteinase 3, PR3, and myeloperoxidase.
01:25
And you're thinking, okay, now, these are normally
cytoplasmic antigens.
01:29
How are they getting on the surface? Well, when a neutrophil
gets activated,
it can actually have translocation of a number of proteins
to the cell surface.
01:38
Now, we have an antibody against PR3 or antibody against
myeloperoxidase
that's on the surface of a neutrophil, and it come along
with an antibody and bind to it, wow.
01:48
Now, I'm going to really turn on that neutrophil.
01:52
We're going to activate complement,
but we're also going to have Fc receptor interactions even
on the same cell.
01:59
And so, that's going to drive a pretty profound inflammatory
response.
02:04
So, again, we have some sort of trigger.
02:07
We develop antibodies against PR3 or myeloperoxidase.
02:10
Those bind to neutrophils. The neutrophils also - as they
translocate these contents to the surface,
can also deposit them on various other surfaces such as the
endothelium.
02:23
So, we can have now antibodies bound to the endothelium as
well,
because of the PR3 or myeloperoxidase that have glommed onto
the endothelium.
02:32
In any event, we're going to get activation of the
neutrophils.
02:34
We're going to get activation and injury of the endothelial
cells as a result of the antibody binding.
02:40
And then, we're off and running. Same process.
02:43
Complement fragments, Fc receptor bearing cells, et cetera,
giving rise to a vasculitis.
02:49
So, examples of the ANCA associated vasculitides
include now vasculitis without asthma or granulomas.
02:59
That's microscopic polyangiitis, kind of in the middle top
of your screen.
03:03
There are granulomas without asthma or Wegener's
granulomatosis.
03:08
And then, there's vasculitis associated with eosinophils,
asthma, and granulomas,
otherwise known as Chrug-Strauss syndrome.
03:16
So, that's an example of ANCA associated vasculitides.
03:21
Okay, we built up our repertoire. There's one more.
03:24
So, we've had antiendothelial cell antibodies, immune
complex antibodies, ANCA antibodies.
03:31
What about just a typical cell mediated vasculitis?
Well, indeed, there are cell mediated injury of vessel walls
just like everything else.
03:40
So, lymphocytes can be targeted to antigens
that are expressed in various parts of the vessel wall
from endothelium to smooth muscle cells and even adventitial
cells.
03:50
When those lymphocytes identify their particular antigen, so
they get activated, will recruit
and activate additional mononuclear cells, monocytes, and
macrophages.
04:01
And then, we're off and running.
04:03
They will elaborate mediators that will cause the formation
of granulomas.
04:08
Activated nodules epithelioid macrophages,
but also profoundly activate the lymphocytes and macrophages
that are there.
04:16
Elaborating cytokines, reactive oxygen species, proteases,
et cetera,
that cause damage to the vessel wall. Boom.
04:23
Vessel wall is damaged, and now we have the same process. We
have a vasculitis.
04:28
Now, due to T cells, T lymphocytes that are directed against
antigens of the vessel wall,
an example of this, over on the left-hand side at the
bottom,
are granulomatous diseases such as Takayasu's arteritis and
giant cell arteritis,
and we'll talk a little bit more in specifics later.