Type IV Hypersensitivity: Role of CD4+ T Cells in Delayed Hypersensitivity

00:00 Another flavour of type four hypersensitivity is that associated with helper T cells.

00:07 Remember, these are marked by the CD4 protein on their cell surface.

00:12 CD4 helper T cells are recognizing antigen that's being provided by antigen presenting cells, that's with APCs.

00:20 And they will respond appropriately by cranking out cytokines.

00:25 Now those cytokines will do a variety of things, they can drive B cells to make antibodies.

00:31 That can bind potentially to surface antigens, they will make cytokines that will stimulate and activate neutrophils and macrophages and cytokines that will also stimulate natural killer cells and cytotoxic T lymphocytes.

00:43 So the helper T cell is the orchestra conductor, in this form of hypersensitivity response.

00:52 There will be tissue injury, but as opposed to what went on previously, with the cytotoxic T cell, which is relatively specific, there can be a lot of nonspecific innocent bystander damage, because of the recruitment of neutrophils and macrophages who are just being turned on and they don't necessarily know exactly what the target is.

01:13 So examples of this so called delayed-type hypersensitivity.

01:18 It's called delay-type, because it takes 12 to 72 hours, so of half a day to maybe three days to get up and running before we can recognise it.

01:29 That is to be related to immediate type hypersensitivity, which is due to IGE so don't that's why they're given those different names.

01:38 Delayed-type hypersensitivity takes 12 to 72 hours, because we have to recruit the T cells, they have to proliferate and then they have to recruit additional cells, so it takes that much time.

01:50 Interestingly, because the T cells are making all these cytokines, they're recruiting a variety of other T cells that are not necessarily antigen specific.

02:00 So it's a little bit like, frat row where you put up a sign on a Friday night and says toga party tonight.

02:07 Well, 10% of the partiers in that frat are going to be people who actually belong to the frat, and 90% have just been called in by the advertisement, that there's a party going on.

02:20 Same thing here with lay type hypersensitivity, most of the cells are not antigen specific.

02:26 They've called in however a variety of other antigen nonspecific T cells.

02:34 There is a variable macrophage and eosinophil, neutrophil, other cellular inflammatory cell infiltrates based on the cytokines that are being elaborated.

02:45 It's important to understand that it's not just helper T cells, but cytotoxic T cells are called in by the same cytokines, the same chemo kinds that are bringing in the rest of those antigen nonspecific T cells are also calling in those other cell types.

02:59 CD4 activation, the helper T cell activation can also promote B cell proliferation and antibody production so they can have a component of antibody mediated damage as well.

03:10 And the cytokines can also drive natural killer cells to become very, very lint lymphokine activated killers that will kill just very indiscriminately.

03:20 So delayed-type hypersensitivity, pretty potent, but because of all these other kind of mediator driven recruitment of other cell types can have a lot of non specificity.

03:32 What's being shown here is an example of a delayed type hypersensitivity response.

03:36 This is to poison ivy, there is a compound in poison ivy called urushiol or pentadecacatechol is responsible for which will bind to a variety of proteins and elicit a helper T cell response.

03:51 Your first exposure to poison ivy, that's for free.

03:54 But now you will elaborate and generate a memory population of T cells that will recognise that oil, urushiol in the leaves of the poison ivy and the second time you're exposed, then you get that very profound, delayed-type hypersensitivity that occurs over half a day to three days.

04:16 This same response is what we use routinely for the PPD, the purified protein derivative response or the tuberculin response.

04:25 And what happens what's being shown there is the arm actually it's my arm back in the day.

04:30 We did this as an exercise in a lab in my pathology course, where we injected purified protein derivative, that's the P with a circle around it.

04:42 We also then wanted to administer a couple control proteins, such as C, Candida or M mumps antigen, and then we came back 72 hours later and saw which one of these has an area of induration that is this they a little bit of edema.

05:01 And whether there's erythema or not.

05:04 Now I'm PPD negative.

05:05 So I haven't ever been in previously exposed to tuberculosis, so I don't have a response.

05:10 But making sure that my immune system works, we can see that I have a pretty robust response to the mumps antigen that is there.

05:18 And that's that big red, I'll tell you is itchy and painful, lesion region that is marked with the M.

05:25 And very minimal Candida, the Candida is a common agent in diaper rash.

05:30 And I guess my mom was really good about not letting me get diaper rash.

05:35 In any event, that's my arm.

05:37 Back to be the tuberculin PPD response.

05:40 So we take a purified protein mesh from tuberculosis, and we inject it into the subcutaneous skin of a someone we want to test them, we also should always put in a control to make sure their immune system works.

05:57 If you've had prior exposure to tuberculosis, you have circulating CD4 positive T cells that can recognise that and they will localize to the tissue.

06:06 They will then recruit and activate additional cells that will give rise to the cytokine environment that will cause that edema and that vascular congestion that makes for the redness and the swelling.

06:19 Because it's a delayed-type hypersensitivity response, it takes two to three days to get it and that's why you don't go back to the nurse to have your PPD read until that time.

06:29 The vasodilation the increased vascular permeability, with that kind of integration is secondary cytokine mediators.

06:36 Being elaborated by the cells that have been recruited.

06:38 And again, keep in mind that relatively minor populations of those are antigen specific.

06:45 It's exactly the same thing that goes on when you are exposed to poison ivy, same pathway.

06:51 The interestingly enough, the pruritis.

06:53 The itchiness of that is due to the elaboration of kinins in that environment.

06:58 So what does this look like histologically? Well, so it's the kind of a mononuclear inflammatory response around vessels in the dermis.

07:06 That's it.

07:07 In fact, that was taken from a punch biopsy of my skin with that mumps reaction, but it's the same reaction that you would see if you had a positive PPD.

07:17 And what we're looking at is actually just the recruitment of the inflammatory cells, they're activated, they're making cytokines, they're causing vasodilation and increased vascular permeability.

07:25 The vasodilation is seen as a flare around the periphery of a particular lesion.

07:31 And that's the redness and then there will be a central area of integration to increase vascular permeability.

07:36 That's the wheel.

07:38 Finally by way of a summary, talking about mechanisms of delayed-type hypersensitivity mediated pathology.

07:45 You have an antigen specific, helper T cell marked by that CD4 molecule it produces cytokines, and that cytokines will then drive the activation of additional inflammatory cells will get recruitment will get the local DTH type response.

08:03 Unfortunately, all the other guys that are coming in, all the other cells, the NK cells and the macrophages and neutrophils, etc, can be somewhat antigen nonspecific, and can release mediators that can cause local tissue injury.

08:19 And so examples, overall of delayed-type hypersensitivity include the tuberculin response that PPD, great example.

08:27 Type One diabetes that we will cover in a subsequent talk when we talk about autoimmune diseases.

08:33 Hashimotos thyroiditis, another autoimmune disease, with helper T cells directed against the epithelium of a thyroid, scleroderma, rheumatoid arthritis, contact hypersensitivity, that's the poison ivy stuff.

08:47 Those are all great examples of DTH-mediated disease.

08:51 So with that, we've completed type four hypersensitivity, and we'll move on to the next topics, which will be auto immunity and the response to foreign objects.

09:05 And with that, you're there.