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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.

This material is based upon work supported by the National Science Foundation and the National Institute of General Medical Sciences under Grant No. 2122350 and 1 R25 GM139147. Any opinion, finding, conclusion, or recommendation expressed in these videos are solely those of the speakers and do not necessarily represent the views of the Science Communication Lab/iBiology, the National Science Foundation, the National Institutes of Health, or other Science Communication Lab funders.

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