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Antiendothelial Cell Antibodies and Circulating Immune Complexes – Vasculitis

by Richard Mitchell, MD

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    00:01 We'll talk about inflammation involving the vessel wall and there are a whole variety of vasculitides.

    00:06 Vasculitis is in fact a fascinating topic and is frequently a source of questions on the board exams.

    00:15 You will be very lucky in your lifetime as a practicing clinician to see one case of vasculitis.

    00:23 Maybe if you work with geriatric population, you'll see two cases, but in general, these are relatively rare entities except when you're taking the boards.

    00:32 Having said that, let's start looking, again, just as a refresher, at a vessel.

    00:37 So, we have a typical - stereotypical vessel here shown an artery, and most of the vasculitides, I'll say right off the bat, involve arteries more than capillaries or veins.

    00:49 They can be involved, but more likely than not, it's going to be an artery.

    00:53 So, we have an endothelium lining the vessel lumen.

    00:56 Sitting beneath that is a basal membrane or basal lamina or basement membrane.

    01:00 And then, deep to that is an internal elastic membrane.

    01:04 And then, surrounding that are circumferential rings of smooth muscle media with an external elastic membrane that may be somewhat variable, and then we have the adventitia.

    01:13 In vasculitis, all layers of the vessel wall will eventually be involved.

    01:19 And as we get more or less destruction of the different layers, we may have different manifestations. We'll talk about that.

    01:26 But if we enter endothelium just as a broad stroke, we're going to have thrombosis.

    01:30 If we injure the media and cause necrosis, we're going to get aneurysmal dilation.

    01:36 So, just keep those in mind as we go forward.

    01:38 All right. We're going to revisit this particular image over and over and over again.

    01:43 You'll get tired of seeing it, but it's a good way to think about vasculitis.

    01:47 It's going to be organized, as we'll talk about, into going from left to right, large vessel vasculitis that mainly affects the aorta and arteries.

    01:55 There are a set of different entities that are medium vessel vasculitis, and then there are small vessel vasculitides.

    02:03 Usually immune complex mediated, but there are some variations that affect the small arterioles, and then can - not normally, but can affect capillaries and veins and venules.

    02:14 So, mainly, we're going to be looking at things on the left-hand side here.

    02:17 Large vessel, medium vessel, small vessel involving the arteries.

    02:23 Okay. So, let's look at some general mechanisms.

    02:26 Once you understand the mechanisms, the rest of it is just details.

    02:29 Of course, it's just details. But the mechanisms are conceptual, and this will give you kind of a ground framework to think about these.

    02:37 So, you can have, in some forms of vasculitis, antibodies that are directed against endothelial cells.

    02:45 So, here, we have a vessel, and we're going to have things come from left to right through our vessel, but it's lined by an endothelium highlighted there, and underneath it is the basal membrane, and then the internal elastic membrane, and then the smooth muscle cells in the media.

    03:00 When we have antiendothelial cell antibodies, they come along, and will bind to antigens that are expressed on the surface of the endothelial cells.

    03:12 We'll talk about some of those.

    03:14 Once the antibodies have bound, then they can do a variety of things, as we'll talk about.

    03:19 You see the other inflammatory cells that are in the circulation that are also going to be players once the antibodies bind.

    03:26 So, the monocytes and the neutrophils.

    03:28 Okay. So, we have antibody that has bound to some endothelial antigen, not otherwise specified at this point.

    03:36 That antibody bombed will activate complement, so complement will cause local killing.

    03:42 And a combination of the antibodies bound as well as complement fragments will bind to receptors on monocytes and on neutrophils, allowing them to adhere to the endothelium.

    03:54 They will think that they are attacking something that is an organism.

    03:59 They think that they are attacking infection.

    04:01 And so, they will do damage to the endothelium as if it was a big microbe.

    04:06 Endothelial cells will undergo necrosis.

    04:09 And as a result of the activation of the monocytes and neutrophils, we're also going to get various components, cytokines, that are going to also be effective in recruiting additional inflammatory cells.

    04:22 So, the damage to the vessel, to the endothelium, and the activation of those inflammatory cells is going to give rise to an inflammatory infiltrate.

    04:31 The damage will cause a thrombus to form a platelet fibrin thrombus in which will be trapped neutrophils and red cells and all the other things.

    04:41 But as part of that thrombus formation, we will also recruit additional inflammatory cells, and we will elaborate mediators that can drive a further inflammatory response.

    04:51 That's part of the normal response to vascular wall injury.

    04:54 Okay. So, that is an example of antibodies directed against a vessel wall antigen, an endothelial cell antigen.

    05:05 An example of this when we'll - and we'll discuss in greater detail further on is Kawasaki's disease.

    05:11 Okay? Antiendothelial cell antibodies occur in Kawasaki's disease.

    05:16 We'll come back to that. Hold that thought. All right. Let's do another one.

    05:19 Circulating immune complexes.

    05:22 Here, we have immune complexes that are formed through a variety of antigens.

    05:27 And this can be infectious antigen, this could be haptens that come from drug administration, whatever, but you have these circulating immune complexes.

    05:36 If those deposit in the vascular bed, they will elicit the same complement activation in the same recruitment of Fc and complement receptor bearing cells, neutrophils and monocytes.

    05:49 So, that's what's happened here.

    05:51 The immune complex has settled down and is sticking somewhat nonspecifically to the underlying basement membrane.

    05:58 And that, by virtue of having those antibodies in that complex present, we will now recruit and activate Fc receptor bearing cells.

    06:09 So, the neutrophils and monocytes. We will also activate compliment.

    06:13 A combination of the inflammatory cells in complement will cause endothelial cell damage and were off and running in exactly now the same downstream mechanisms as we describe for direct antiendothelial cell binding antibodies.

    06:28 So, same granular release, same enzyme, same reactive oxygen species, all of those things, just however driven by the deposition of immune complexes.

    06:38 Now, the immune complexes can be circulating, and that's what the title says, but they can also be antibodies that nonspecifically adhere to a basement membrane.

    06:47 And this actually happens with a fair degree of frequency in the renal capillary bed.

    06:52 The glomerulus has a fenestrated capillary that has big holes in it, and antibodies can nonspecifically stick to things within that basement membrane.

    07:01 The result will be the same as if there had been an immune complex.

    07:05 All right. So, the various lesions that we described that we see with immune complex deposition, one is called fibrinoid necrosis.

    07:16 The vessels become so leaky, a lot of proteins that are normally present within the vessel lumen, albumin, fibrinogen, a whole variety of other things, will insudate into the underlying media, and it looks like a hyaline pink proteinaceous deposition that we recognize and call fibrinoid necrosis. So, that's a buzzword, fibroid necrosis.

    07:35 The other thing that happens is because the inflammatory cells are marching through that media and causing death and destruction of smooth muscle cells in there.

    07:44 We get a necrotizing vasculitis.

    07:47 So, those are the two buzz words that you should think about when we talk about immune complex deposition in particular.


    About the Lecture

    The lecture Antiendothelial Cell Antibodies and Circulating Immune Complexes – Vasculitis by Richard Mitchell, MD is from the course Vasculitis.


    Included Quiz Questions

    1. Media
    2. Basal membrane
    3. Endothelium
    4. Adventitia
    5. Lumen
    1. Complement
    2. Monocytes
    3. Leukocytes
    4. Fibrin
    5. Eosinophils
    1. Circulating immune complexes
    2. Antiendothelial cell antibodies
    3. Basement membrane antibodies
    4. Lipase activation
    5. Granuloma formation
    1. Thrombosis
    2. Aneurysm
    3. Dissection
    4. Liver failure
    5. Heart failure

    Author of lecture Antiendothelial Cell Antibodies and Circulating Immune Complexes – Vasculitis

     Richard Mitchell, MD

    Richard Mitchell, MD


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