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.