Type IV Hypersensitivity Reaction: CD8+ Cytotoxic T Cells

by Richard Mitchell, MD

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    00:00 Hi and welcome back.

    00:03 Thus far we've worked our way through type one hypersensitivity responses, that's due to immunoglobulin E, and mast cells.

    00:10 We've talked about type two, which is antibody against fixed tissue antigen, and type three, which is immune complex mediated disease.

    00:18 So those are all antibody mediated disorders.

    00:21 Now we're going to get into cell type cell mediated disorders, which is type four hypersensitivity.

    00:28 So they're going to be basically two flavours, we're going to talk about the effects related to cytotoxic T cells and effects secondary to helper T cells driving a delayed type hypersensitivity.

    00:40 So this first one is easy to wrap our minds around.

    00:43 If we have cytotoxic T lymphocytes.

    00:46 Again, these are CDA positive they have that marker on their surface.

    00:50 Are they are able to mind to newly synthesized intracellular proteins being expressed by MHC class one, and when they recognise that, they will kill the cell that's expressing that.

    01:03 You get cellulitis and you get injury.

    01:05 Pretty straightforward.

    01:06 So what's an example of this in real life? Well, hepatitis B is a really good example.

    01:12 Here's our normal liver.

    01:14 And you can see the hepatocytes you can see the portal triad central veins, but there's nothing going on here.

    01:22 However, if we now have hepatitis B infection, the hepatitis B has been able to the virus has been able to get into the hepatocytes.

    01:33 New and is proliferating in that environment.

    01:35 It's making new Hepatitis B antigens.

    01:39 The infected cell is sampling all the intracellular proteins, including some of that virus, expresses that on its cell surface in association with MHC class one.

    01:49 And low and behold, cytotoxic T cells specific to that viral peptide and class one are able to recognise it, and we get and chronic T cell, cytotoxic T cell mediated injury that's the hepatitis.

    02:06 Actually, hepatitis is not directly a lytic infection for the most part, the damage that occurs, the disease that occurs is because of the immune host, recognizing the infected hepatocytes and clearing it, that's what it's supposed to do.

    02:22 So for looking at this histologically, that's the top panel.

    02:25 If we're looking at by immunohistochemistry, you can see that on the lower left hand panel, we are, we have cells, hepatocytes not yet killed, that are expressing the hepatitis B surface antigen.

    02:39 That molecule be processed and presented on the surface of this the hepathosite, and then send toxic T lymphocytes, CDA positive T cells will come along on the lower right hand panel and kill them.

    02:51 And that whole process will stop once we've killed off every infected cell.

    02:56 Okay, this all makes sense.

    02:58 It's a type four hypersensitivity response cell-mediated.

    03:02 So the circulating CTLs will kill the virally infected parasites.

    03:06 The amount of infiltrate will correlate with the amount of liver injuries.

    03:10 So if you're measuring the normal liver enzymes that are present, if you have a big inflammatory response, we'll have a big leak of those proteins.

    03:20 And that we can measure in the peripheral blood.

    03:22 And conversely, if it's a little tiny air of inflammation, we may not get much of a leak of those proteins.

    03:30 And once the T cells have done their job, then there's no more cells to kill because all the infected ones have been killed.

    03:39 And we're done.

    03:40 After the viruses cleared, the infiltrate goes away, and the liver that has been irreversibly killed by apoptosis regenerates.

    03:48 That's one of the nice things about liver.

    03:51 Most people who will get Hepatitis B infection will have a self limited infection that runs its course over a couple three weeks, and then we've killed off all the infected cells and the liver comes back. Hooray.

    04:03 That's what's supposed to happen.

    04:05 But if you are one of the 20% or so of people who will get a Hepatitis B infection and not develop a sufficiently robust T cell response to clear the infection, you will have chronic hepatitis.

    04:20 So those T cells for whatever reason, probably because of receptor recognition, etc.

    04:26 Are less effective at killing.

    04:29 And so the virus continues to infect adjacent hepatocytes, we continue to have kind of half hearted attempt by the -- T lymphocytes to get rid of them and you have an ongoing hepatitis.

    04:39 So that's chronic active hepatitis.

    04:44 Carrier states can also occur so about 10% of the population, roughly speaking, doesn't have the T cell repertoire necessary to recognise infected hepatocytes.

    04:56 So that carrier state happens when there's no immune response in you and the virus more or less, live happily ever after together.

    05:03 In that case, now you can transmit virus, you are communicable, but you don't have the disease because you don't have the T cells that can kill off the infected cells.

    05:12 And what's being shown in the lower right panel is just that Hepatitis B carrier, they get so called ground glass cytoplasm and sanded nuclei.

    05:23 That ground glassy ascena philic cytoplasm is because the cells basically become viral factories, and they're just chock full of all the little viral particles.

    05:33 If you're constantly producing antibody to viral antigens, and the viral antigens continue to be expressed, you form immune complexes and those immune complexes can deposit.

    05:46 So in fact, polyarteritis nodosa, which is what is being shown there with a necrotizing vasculitis, fibrinoid necrosis, a typical type three hypersensitivity response due to immune complex deposition.

    06:00 A significant number of patients with polyarteritis nodosa come from patients who have chronic hepatitis.

    06:12 So, immune complex disease can occur.

    06:15 Hopefully the viruses cleared by the activities of the cytotoxic T lymphocytes.

    06:22 That's how you clear the primary infection.

    06:24 How do you prevent against a secondary infection? Because you have protective now antibodies that neutralize the virus.

    06:32 So the next time you see that Hepatitis B virus, you are immune cells, your antibodies will bind to the virus and clear it before we can ever access the liver.

    06:45 So that you have protection against subsequent infection due to a B cell response.

    06:51 So the virus will be cleared by a cytotoxic T cell response and protection is conferred by antibodies to the virus.

    07:00 Another disease that cytotoxic T lymphocyte mediated is myocarditis.

    07:05 This is an example of a lymphocytic myocarditis, where there are a number of cytotoxic T cells that are directly killing the myocytes.

    07:14 So we will have apoptotic death of many of the myocytes.

    07:19 But it's important point as shown in that first bullet, although there is parenchymal cell killing in the setting, that's not only or even necessarily the major mode of injury.

    07:30 So, there will be similar recognition of MHC molecules on the endothelium.

    07:38 So we will get endothelial cell damage.

    07:40 When that happens, you get thrombosis and with that, you get ischemia or infarction.

    07:46 There will also be cytokines that are elaborated so there are helper T cells in here, there are cytotoxic T cells that are in here, they are making a variety of cytokines including things like interferon gamma, which will cause vascular leakiness, so the heart becomes boggy becomes a edematous, and we separate the individual myocytes so there isn't good connection cell to cell to cell.

    08:10 There's also the production by the cytokines will also affect the ability of the heart to squeeze.

    08:16 So the heart normally has a fairly robust squeezing, relaxation, squeezing, relaxation.

    08:22 If I dump onto them or release from the inflammatory cells that are present things like interferon gamma, we will cause those my sites to contract less forcefully.

    08:34 So in particular, interferon gamma acting in our cardiac myocyte causes the production of nitric oxide through nitric oxide synthase.

    08:44 And that will cause relaxation of those cells.

    08:48 So instead of squeezing vigorously, like a New Yorker walking down the street, they're squeezing kind of like a California on the beach.

    08:56 And that's why you can get significant functional damage even in the setting of not so much individual cell death in myocarditis.

    09:06 So kind of an overview of the mechanisms of CTL mediated pathology.

    09:10 Cytotoxic CDA positive T cells can kill their targets directly.

    09:15 Okay, we've we've covered that.

    09:17 It's important to know that during this process, these killer T cells are also elaborating cytokines that can recruit additional inflammatory cells, or can have secondary effects directly on the tissue.

    09:29 But in general, with this form of hypersensitivity response, type four, due to CTLs, there's usually minimal bystander injury.

    09:40 This is pretty targeted.

    09:42 Yes, there can be a substantial amount of injury, but there's not much by standard, there's not much collateral damage.

    09:50 So Examples of this include hepatitis, which we talked about myocarditis, encephalitis due to certain viruses, and HIV, AIDS is going to be because we have CTLs killing virally infected helper T cells.

    About the Lecture

    The lecture Type IV Hypersensitivity Reaction: CD8+ Cytotoxic T Cells by Richard Mitchell, MD is from the course Immune-mediated Diseases.

    Included Quiz Questions

    1. T cells
    2. B cells
    3. NK cells
    4. Eosinophils
    5. Neutrophils
    1. Myocarditis
    2. Myasthenia gravis
    3. Poststreptococcal glomerulonephritis
    4. Autoimmune hemolytic anemia
    5. Goodpasture disease
    1. Hepatitis B
    2. Asthma
    3. Systemic lupus erythematosus
    4. Anaphylactic shock
    5. Acute rheumatic fever
    1. HIV/AIDS
    2. Graves disease
    3. ANCA-associated vasculitis
    4. Pemphigus vulgaris
    5. Hay fever
    1. Encephalitis due to certain viruses
    2. Serum sickness
    3. Rheumatoid arthritis
    4. Polyarteritis nodosa
    5. Food allergy

    Author of lecture Type IV Hypersensitivity Reaction: CD8+ Cytotoxic T Cells

     Richard Mitchell, MD

    Richard Mitchell, MD

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