Antineutrophil Cytoplasmic Antibodies and Cell-mediated Vasculitis – Vasculitis

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.