Session 7: Autoimmunity and Allergy
Transcript of Part 1: Allergies and the Immune System
00:00:08.03 Hello. 00:00:09.17 My name is Avery August, 00:00:10.27 I'm at Cornell University, 00:00:12.02 and today I'm going to tell you a little bit about allergies 00:00:15.02 and the immune system. 00:00:16.20 So, this is an image of some peanuts, 00:00:19.12 and this simple nut 00:00:21.28 can have devastating consequences 00:00:23.21 in some individuals. 00:00:24.29 And the reason for this 00:00:26.20 is because they're allergic to proteins 00:00:28.09 that are found in peanuts. 00:00:30.11 So what I will be telling you about 00:00:32.29 is why they're allergic to proteins 00:00:34.23 found in peanuts. 00:00:37.05 So, the allergic response 00:00:39.19 is actually the combination 00:00:41.11 of the response of a number of different cells, 00:00:43.24 and these cells are shown over here 00:00:45.17 -- the innate lymphoid cell, 00:00:47.10 T helper 2 cell, 00:00:48.19 B cell, 00:00:50.07 and a mast cell or basophil -- 00:00:51.28 and these cells interact 00:00:53.22 to drive the allergic response. 00:00:57.17 The other thing that's important for allergies 00:01:01.16 is the antibody IgE. 00:01:03.23 In the early to late 1960s, 00:01:06.07 Ishizaka and Lichtenstein discovered 00:01:09.23 that IgE was actually responsible for allergies. 00:01:13.15 Now, IgE is an isotype 00:01:15.26 of an antibody 00:01:17.23 and it looks just like an antibody. 00:01:19.08 It has two binding sites, 00:01:20.27 it has an Fc portion, 00:01:23.01 and it can interact with a receptor, 00:01:24.08 and so we'll come back to this structure later 00:01:26.25 when we look at the actual response to IgE. 00:01:30.17 Allergies are actually the result 00:01:32.18 of an immune response 00:01:34.00 and the immune response is divided 00:01:35.19 into two main types of responses. 00:01:37.15 An innate immune response, 00:01:38.29 on the right, 00:01:40.13 and an adaptive immune response, 00:01:41.26 on the left. 00:01:43.02 Now, the innate immune response 00:01:44.22 can respond to an allergen very quickly, 00:01:46.12 within minutes to hours, 00:01:47.28 but it does so in a non-specific way 00:01:50.18 because it only recognizes patterns 00:01:52.06 that are found on allergens. 00:01:54.15 But this response 00:01:56.17 can dictate the type of adaptive immune response 00:01:58.23 that we have. 00:02:01.00 By contrast, the adaptive immune response 00:02:03.21 is actually what is responsible for the allergy. 00:02:07.19 That adaptive immune response 00:02:09.15 takes some time to respond 00:02:11.01 -- it takes up to days to respond -- 00:02:12.23 but its exquisitely specific, 00:02:15.17 and it results in the generation of antibodies, 00:02:18.07 and those antibodies can then determine 00:02:20.01 the clearance of pathogens 00:02:21.24 or, in the case of allergies, 00:02:23.06 whether the person is allergic or not. 00:02:26.25 So, what makes something allergenic? 00:02:29.09 Allergens have to be able to generate a B cell response 00:02:32.29 because B cells are what make antibodies. 00:02:35.21 Those allergens are generally proteins, 00:02:37.26 such as peanut allergens or egg white proteins. 00:02:40.23 They can be carbohydrates, 00:02:42.13 such as those found in meat. 00:02:44.03 Quite a few allergens are actually proteases 00:02:46.27 or are able to bind lipids. 00:02:48.29 Most of them are water soluble, 00:02:51.00 they're stable, 00:02:52.17 and they're small. 00:02:53.19 In some cases, they're resistant to heat. 00:02:55.15 And generally they can bind to pattern recognition receptors 00:02:58.02 on innate cells, 00:02:59.20 or protease activated receptors on epithelial cells, 00:03:02.16 then initiate the immune response to them. 00:03:07.12 So, how does an allergic response develop? 00:03:11.25 Well, first, you're exposed to an allergen 00:03:15.27 and generally that allergen will interact 00:03:17.24 with an epithelial cell. 00:03:19.06 That epithelial cell will produce cytokines, 00:03:22.00 such as IL-33 and interleukin-25 (IL-25), 00:03:25.13 and those two cytokines can drive the activation 00:03:28.08 of the innate lymphoid type 2. 00:03:31.03 That ILC2 cell 00:03:32.29 will produce a cytokine called interleukin-4, 00:03:36.03 and what interleukin-4 does... 00:03:37.23 it can condition dendritic cells 00:03:40.20 and T cells 00:03:42.27 to change the nature of that immune response. 00:03:45.05 Dendritic cells will pick up those allergens, 00:03:47.20 will process them into small pieces, 00:03:49.28 and present that allergen to T cells, 00:03:52.08 and when that T cell is interacting 00:03:54.07 with the dendritic cell, 00:03:55.19 under the influence of interleukin-4, 00:03:57.25 that T cell becomes a T helper 2 cell (Th2), 00:04:00.11 and that T helper 2 cell 00:04:02.09 is critical for the development of an allergy 00:04:04.07 because that T helper 2 cell 00:04:06.08 is what's responsible for 00:04:08.10 making interleukin-4 and interleukin-4 00:04:10.15 is really important for the production of IgE. 00:04:14.15 IgE is made by B cells. 00:04:17.17 And so, here, 00:04:19.08 during the development of that initial immune response 00:04:21.03 to the allergen, 00:04:22.29 there's no symptom, 00:04:24.07 the immune symptom is responding, 00:04:26.01 and it's responding 00:04:28.09 by picking up the allergen, 00:04:29.16 taking it to the lymph nodes, 00:04:32.11 and when that allergen reaches the lymph node, 00:04:34.07 it interacts with a B cell, and that B cell, 00:04:36.28 a very small number of B cells, one or two, 00:04:38.24 can interact with that allergen 00:04:40.09 and get activated. 00:04:41.13 And under the right conditions, 00:04:42.17 with the right help from T cells, 00:04:44.04 that B cell divides and multiplies 00:04:45.29 to become a larger number of B cells, 00:04:48.18 and so now we have a large number of B cells 00:04:50.27 that recognize that antigen. 00:04:53.05 Under the right conditions, 00:04:54.22 in the presence of help from T helper 2 cells, 00:04:58.23 particularly interleukin-4, 00:05:00.16 that B cell undergoes what's called class switch. 00:05:03.04 It changes the type of [antibody] that it makes 00:05:06.06 from IgM to IgE. 00:05:09.09 Once that B cell undergoes class switch, 00:05:11.20 now it can start to make IgE 00:05:14.02 by becoming a plasma cell 00:05:15.22 and secreting IgE. 00:05:17.22 Once that IgE is in circulation, 00:05:20.02 now the individual 00:05:21.28 can now respond to whatever that allergen is 00:05:24.08 the second time they get exposed. 00:05:27.06 So, the first time you're exposed to allergen, 00:05:29.12 you don't really notice it, 00:05:31.00 but your immune system is responding 00:05:32.22 and it's generating this whole process 00:05:34.27 that leads to the production of IgE. 00:05:37.07 So the second time you get exposed 00:05:39.03 to the allergen, 00:05:40.17 now you're more susceptible 00:05:42.17 to developing a allergic response, 00:05:45.03 and that occurs 00:05:47.01 because there are these other cell types in the body, 00:05:48.23 called mast cells or basophils, 00:05:50.17 that have receptors for IgE. 00:05:53.01 And those mast cells are found 00:05:55.01 in the mucosal areas of the tissues, 00:05:56.22 the respiratory, GI tract, 00:05:58.10 and the skin, 00:05:59.22 and there are basophils that are found in the blood, 00:06:01.18 and both cell types 00:06:02.24 have these receptors for IgE. 00:06:06.01 So here's what a basophil looks like in a blood smear. 00:06:08.26 You can see the staining 00:06:10.19 and you can see the granules 00:06:12.07 that these basophils have, 00:06:14.03 and red cells around them. 00:06:15.25 And here is a section of the skin 00:06:18.04 from a mouse 00:06:20.01 that we've stained with Toluidine blue 00:06:21.14 and you can see that the mast cells 00:06:22.28 are situated in the skin, 00:06:24.15 and you can see the granules, again, 00:06:26.00 in these mast cells. 00:06:30.07 Here is an electron micrograph 00:06:31.28 of a skin mast cell 00:06:33.09 and you can see, at very high resolution, 00:06:35.08 the structures of the granules, 00:06:37.23 including the one circled here in white, 00:06:40.11 that are filled with pharmacological agents 00:06:42.21 that these cells will release 00:06:44.15 when they get activated. 00:06:48.23 So, the contents of these granules 00:06:50.09 include histamine, 00:06:52.01 heparin, 00:06:53.17 proteases, 00:06:55.09 and cytokines, 00:06:56.15 and these pharmacological agents 00:06:58.07 have different physiological effects. 00:06:59.11 For example, histamine increases vascular permeability 00:07:01.22 and smooth muscle contraction, 00:07:03.24 whereas heparin induces swelling, 00:07:06.01 anaphylactic and inflammatory symptoms, 00:07:08.10 and proteases can remodel the extracellular matrix 00:07:11.10 and cause changes in the migration of cells. 00:07:15.27 And the mast cells can also produce cytokines 00:07:17.27 that can further promote inflammation 00:07:19.23 and other types of responses. 00:07:23.13 Mast cells also make other products: 00:07:25.12 other cytokines that are made later after activation, 00:07:29.02 chemokines that can attract other immune cells 00:07:30.28 to the site of activation, 00:07:32.13 and lipid mediators 00:07:34.18 that can also have effects on smooth muscle cells 00:07:36.17 and induce mucous secretion. 00:07:39.25 So what happens, then, 00:07:42.01 when this circulating IgE is made 00:07:44.28 the first time you got exposed to this allergen? 00:07:46.17 Well, that circulating IgE 00:07:48.00 can now interact with the receptors 00:07:50.03 on these mast cells and basophils 00:07:52.05 and we call that "arming" 00:07:54.04 of these mast cells and basophils with IgE, 00:07:56.14 because now the receptors are occupied with the IgE 00:08:00.04 and the mast cell or basophil 00:08:01.24 is now primed 00:08:03.19 to be able to respond a second time, 00:08:04.25 or subsequent times, 00:08:06.07 that you actually get exposed to that allergen. 00:08:09.23 So, here's the structure of IgE. 00:08:12.07 You can see the antigen binding site 00:08:14.07 bound to its receptor, 00:08:15.27 and this is the receptor that will be found 00:08:17.25 on these basophils and mast cells. 00:08:19.21 You can see, now, that 00:08:21.28 when this IgE binds to its receptor 00:08:23.07 it's now ready and it looks like a receptor 00:08:25.13 that can respond to antigen. 00:08:29.12 So, now, the second time 00:08:31.09 you get exposed to that peanut allergen, 00:08:33.16 the allergen interacts with the IgE 00:08:35.19 that's found on the mast cell and basophil 00:08:39.02 and it triggers the degranulation 00:08:41.19 of this mast cell or basophil, 00:08:43.00 where they release all their contents, 00:08:44.29 and those contents start to have physiological effects. 00:08:48.12 So, the first thing that happens 00:08:49.29 when that allergen binds to the IgE 00:08:52.28 found in the receptor 00:08:54.17 is the activation of calcium, 00:08:56.01 and so in this image 00:08:57.21 you will see that in the upper right-hand corner 00:08:58.24 antigen is added, 00:09:00.07 and then the cells start to respond 00:09:01.20 by increasing intracellular calcium, 00:09:03.14 shown in bright green, 00:09:05.05 as the cells get activated, 00:09:06.20 and you can see that, eventually, 00:09:08.03 the cells start getting activated in this field. 00:09:14.03 The next thing that happens after activation 00:09:16.19 is degranulation, 00:09:18.00 and in this particular video 00:09:19.23 what you'll see is that the mast cell is activated, 00:09:21.29 and as the granules are released 00:09:23.25 they pick up a dye 00:09:25.17 that allows you to visualize 00:09:27.09 the degranulated granules, 00:09:29.27 and that dye is shown in red. 00:09:42.02 Now you can start to see 00:09:43.25 the mast cell degranulate, 00:09:45.09 you can see the granules reach the cell surface, 00:09:46.21 they pick up the dye, 00:09:48.06 and now we can now see that the granules 00:09:49.24 have been released. 00:09:57.28 Once those granules have been released, 00:10:00.09 they now look empty. 00:10:01.14 So, here's an EM, an electron micrograph, 00:10:03.16 of a non-degranulated mast cell 00:10:06.22 on the [left] 00:10:08.08 and a degranulated mast cell on the [right], 00:10:09.24 and you can see that the granules are less dark, 00:10:12.14 indicating that they've released their contents. 00:10:18.08 So, what happens after these mast cells degranulate? 00:10:20.25 Well, blood vessels 00:10:23.01 start to increase in their size 00:10:25.19 because of the contents of the mast cells. 00:10:28.08 You get increased blood flow to the area 00:10:30.14 and this can cause reduced blood pressure, 00:10:32.23 irregular heart beat, 00:10:34.28 and, in some cases, 00:10:36.14 can result in systemic anaphylactic shock. 00:10:39.03 If this happens in the airways, 00:10:40.15 you get airway smooth muscle contraction, 00:10:42.20 you get an increase in mucus production, 00:10:44.24 and this can cause difficulty breathing, 00:10:46.21 swallowing, or wheezing 00:10:48.20 in those people who have allergic responses 00:10:50.23 in the airways. 00:10:51.24 If it happens in the GI tract, 00:10:53.13 if you get exposed to peanut allergen in the GI tract, 00:10:55.20 here the GI smooth muscle cells contract, 00:10:58.22 and that then leads to peristalsis 00:11:00.26 and fluid secretion, 00:11:02.13 it can cause stomach cramps, 00:11:03.22 vomiting, diarrhea... 00:11:05.03 classic symptoms of food allergy. 00:11:08.23 So, in the airways, 00:11:10.20 one can actually see mast cells 00:11:12.18 lining the trachea 00:11:14.04 in between the epithelial cells, 00:11:16.08 and those mast cells actually 00:11:18.16 reach in between the epithelial cells 00:11:19.23 and sample antigens and allergens 00:11:21.26 that are coming into the airways, 00:11:23.13 and you can see that here. 00:11:24.19 You can see that these are sections of trachea 00:11:27.12 that are stained with a mast cell protein, 00:11:30.04 mMCP6, 00:11:32.04 and you can see it's stained in red, 00:11:33.16 and you can see an airway, here, 00:11:36.02 that is lined with mast cells. 00:11:39.17 And those mast cells actually 00:11:41.21 are continually sampling, in the video on the left, 00:11:43.22 continually sampling contents 00:11:46.00 that are passing through the airways 00:11:47.15 to determine whether there's anything 00:11:49.04 that they recognize and, 00:11:50.29 if there's something that they recognize, 00:11:52.11 then they will respond and degranulate, 00:11:54.15 and you can have some of these symptoms. 00:12:00.07 And so, in the end, 00:12:01.19 if this happens in the airway, 00:12:03.15 there's a cartoon, here, 00:12:04.25 of an open airway on the [left] 00:12:06.07 -- this is a normal airway 00:12:07.17 , the individual can breathe very clearly -- 00:12:09.29 when the individual is exposed to allergens, 00:12:12.14 the airway smooth muscle cells expand, 00:12:14.20 the epithelial cells expand, 00:12:16.18 and you have mucus 00:12:18.06 that partially blocks the airway, 00:12:19.16 making it more difficult to breathe. 00:12:25.25 So, how do we actually block this response? 00:12:28.22 Well, you can prevent 00:12:31.16 the release of these granules 00:12:32.25 by blocking either the activation of the mast cell 00:12:36.02 or you can block the release of the contents, 00:12:37.19 and if you do that then 00:12:40.04 you can potentially reduce symptoms of allergies. 00:12:42.28 And so there are a number of agents that have been discovered 00:12:45.06 over the years 00:12:46.14 that can actually block 00:12:48.23 the release of mast cell contents, 00:12:51.07 including drugs that are based on Chromolyn, 00:12:53.12 such as Nasacrom, 00:12:55.07 and what that does, 00:12:56.18 in a way that we don't quite understand, 00:12:57.28 is it prevents the mast cell from releasing its granules 00:13:00.16 when it gets activated, 00:13:01.21 so by preventing the release of the granules, 00:13:04.02 you prevent the release of 00:13:06.02 histamine, heparin, TNF, 00:13:07.28 and all the other cytokines 00:13:10.06 that are responsible for the allergic response. 00:13:12.18 In other cases, 00:13:14.18 we don't actually block the release of the granules, 00:13:16.26 but we in some cases can block 00:13:18.28 the effects of the granule contents, 00:13:20.14 such as antihistamines, 00:13:22.21 which can reduce increased vascular permeability 00:13:25.11 and smooth muscle contraction 00:13:27.05 due to the histamine release. 00:13:28.15 So, when you get an allergic response, 00:13:30.03 you take an anti-histamine. 00:13:31.17 What you're actually doing 00:13:32.28 is preventing histamine 00:13:34.18 from having an effect on these smooth muscle cells. 00:13:38.26 If the histamine release has already occurred, 00:13:42.18 in the case of systemic anaphylactic shock, 00:13:44.24 we can actually counter the effects of histamine 00:13:47.14 by taking epinephrine, 00:13:48.23 which counteracts the effects of histamine, 00:13:51.23 and here's a picture of an EpiPen 00:13:54.02 that individuals who have severe allergies 00:13:56.27 will carry around with them 00:13:59.00 to use in case of an emergency, 00:14:00.18 so that they can counteract the effects of histamine. 00:14:04.24 In addition, there are other types of drugs, 00:14:07.10 such as the drugs that are based on the Singulair series, 00:14:10.12 and these drugs actually do 00:14:13.00 similar things to the anti-histamines. 00:14:14.12 They actually block the effects 00:14:16.12 of the leukotrienes that are produced by mast cells, 00:14:18.28 which have the same effects 00:14:20.14 -- smooth muscle contraction and edema. 00:14:22.13 And the way they do this is by competing 00:14:25.07 with the leukotrienes for the receptors 00:14:26.24 on these smooth muscle cells, 00:14:28.09 therefore preventing their action on these cells. 00:14:31.19 Another drug that was recently discovered 00:14:34.15 by a company called Genentech 00:14:36.14 is a drug that actually targets the IgE 00:14:40.24 and blocks it from interacting with its receptor, 00:14:43.19 and in that particular drug 00:14:45.00 -- it's a drug called Xolair -- 00:14:46.08 what it actually does is... 00:14:48.01 actually it's an antibody 00:14:49.25 that binds to the Fc portion of IgE 00:14:51.25 and prevents it from interacting with its receptor. 00:14:54.16 And when it does so, 00:14:55.22 now the mast cell or basophil 00:14:57.07 can no longer respond, 00:14:58.13 because they don't have the IgE on their surface, 00:15:00.11 they cannot recognize the allergen, 00:15:01.27 and so you reduce the symptoms 00:15:03.17 of all allergic responses. 00:15:06.05 And so Xolair has actually worked very well 00:15:08.09 in reducing the symptoms of allergies 00:15:10.20 because it reduces the ability 00:15:12.21 of mast cells and basophils to respond. 00:15:14.28 So, in summary, then, 00:15:16.17 what we see is that 00:15:18.02 the first time you get exposed to an allergen, 00:15:19.27 you generate an immune response 00:15:21.26 that leads to the generation of IgE. 00:15:24.18 That IgE then coats 00:15:27.23 the mast cells and basophils, 00:15:29.06 and when those mast cells and basophils 00:15:30.22 actually come in contact with the allergen, 00:15:32.14 they respond to the allergen 00:15:34.08 and release their contents, 00:15:35.20 leading to the symptoms of allergies.