Hello.
My name is Avery August,
I'm at Cornell University,
and today I'm going to tell you a little bit about allergies
and the immune system.
So, this is an image of some peanuts,
and this simple nut
can have devastating consequences
in some individuals.
And the reason for this
is because they're allergic to proteins
that are found in peanuts.
So what I will be telling you about
is why they're allergic to proteins
found in peanuts.
So, the allergic response
is actually the combination
of the response of a number of different cells,
and these cells are shown over here
-- the innate lymphoid cell,
T helper 2 cell,
B cell,
and a mast cell or basophil --
and these cells interact
to drive the allergic response.
The other thing that's important for allergies
is the antibody IgE.
In the early to late 1960s,
Ishizaka and Lichtenstein discovered
that IgE was actually responsible for allergies.
Now, IgE is an isotype
of an antibody
and it looks just like an antibody.
It has two binding sites,
it has an Fc portion,
and it can interact with a receptor,
and so we'll come back to this structure later
when we look at the actual response to IgE.
Allergies are actually the result
of an immune response
and the immune response is divided
into two main types of responses.
An innate immune response,
on the right,
and an adaptive immune response,
on the left.
Now, the innate immune response
can respond to an allergen very quickly,
within minutes to hours,
but it does so in a non-specific way
because it only recognizes patterns
that are found on allergens.
But this response
can dictate the type of adaptive immune response
that we have.
By contrast, the adaptive immune response
is actually what is responsible for the allergy.
That adaptive immune response
takes some time to respond
-- it takes up to days to respond --
but its exquisitely specific,
and it results in the generation of antibodies,
and those antibodies can then determine
the clearance of pathogens
or, in the case of allergies,
whether the person is allergic or not.
So, what makes something allergenic?
Allergens have to be able to generate a B cell response
because B cells are what make antibodies.
Those allergens are generally proteins,
such as peanut allergens or egg white proteins.
They can be carbohydrates,
such as those found in meat.
Quite a few allergens are actually proteases
or are able to bind lipids.
Most of them are water soluble,
they're stable,
and they're small.
In some cases, they're resistant to heat.
And generally they can bind to pattern recognition receptors
on innate cells,
or protease activated receptors on epithelial cells,
then initiate the immune response to them.
So, how does an allergic response develop?
Well, first, you're exposed to an allergen
and generally that allergen will interact
with an epithelial cell.
That epithelial cell will produce cytokines,
such as IL-33 and interleukin-25 (IL-25),
and those two cytokines can drive the activation
of the innate lymphoid type 2.
That ILC2 cell
will produce a cytokine called interleukin-4,
and what interleukin-4 does...
it can condition dendritic cells
and T cells
to change the nature of that immune response.
Dendritic cells will pick up those allergens,
will process them into small pieces,
and present that allergen to T cells,
and when that T cell is interacting
with the dendritic cell,
under the influence of interleukin-4,
that T cell becomes a T helper 2 cell (Th2),
and that T helper 2 cell
is critical for the development of an allergy
because that T helper 2 cell
is what's responsible for
making interleukin-4 and interleukin-4
is really important for the production of IgE.
IgE is made by B cells.
And so, here,
during the development of that initial immune response
to the allergen,
there's no symptom,
the immune symptom is responding,
and it's responding
by picking up the allergen,
taking it to the lymph nodes,
and when that allergen reaches the lymph node,
it interacts with a B cell, and that B cell,
a very small number of B cells, one or two,
can interact with that allergen
and get activated.
And under the right conditions,
with the right help from T cells,
that B cell divides and multiplies
to become a larger number of B cells,
and so now we have a large number of B cells
that recognize that antigen.
Under the right conditions,
in the presence of help from T helper 2 cells,
particularly interleukin-4,
that B cell undergoes what's called class switch.
It changes the type of [antibody] that it makes
from IgM to IgE.
Once that B cell undergoes class switch,
now it can start to make IgE
by becoming a plasma cell
and secreting IgE.
Once that IgE is in circulation,
now the individual
can now respond to whatever that allergen is
the second time they get exposed.
So, the first time you're exposed to allergen,
you don't really notice it,
but your immune system is responding
and it's generating this whole process
that leads to the production of IgE.
So the second time you get exposed
to the allergen,
now you're more susceptible
to developing a allergic response,
and that occurs
because there are these other cell types in the body,
called mast cells or basophils,
that have receptors for IgE.
And those mast cells are found
in the mucosal areas of the tissues,
the respiratory, GI tract,
and the skin,
and there are basophils that are found in the blood,
and both cell types
have these receptors for IgE.
So here's what a basophil looks like in a blood smear.
You can see the staining
and you can see the granules
that these basophils have,
and red cells around them.
And here is a section of the skin
from a mouse
that we've stained with Toluidine blue
and you can see that the mast cells
are situated in the skin,
and you can see the granules, again,
in these mast cells.
Here is an electron micrograph
of a skin mast cell
and you can see, at very high resolution,
the structures of the granules,
including the one circled here in white,
that are filled with pharmacological agents
that these cells will release
when they get activated.
So, the contents of these granules
include histamine,
heparin,
proteases,
and cytokines,
and these pharmacological agents
have different physiological effects.
For example, histamine increases vascular permeability
and smooth muscle contraction,
whereas heparin induces swelling,
anaphylactic and inflammatory symptoms,
and proteases can remodel the extracellular matrix
and cause changes in the migration of cells.
And the mast cells can also produce cytokines
that can further promote inflammation
and other types of responses.
Mast cells also make other products:
other cytokines that are made later after activation,
chemokines that can attract other immune cells
to the site of activation,
and lipid mediators
that can also have effects on smooth muscle cells
and induce mucous secretion.
So what happens, then,
when this circulating IgE is made
the first time you got exposed to this allergen?
Well, that circulating IgE
can now interact with the receptors
on these mast cells and basophils
and we call that "arming"
of these mast cells and basophils with IgE,
because now the receptors are occupied with the IgE
and the mast cell or basophil
is now primed
to be able to respond a second time,
or subsequent times,
that you actually get exposed to that allergen.
So, here's the structure of IgE.
You can see the antigen binding site
bound to its receptor,
and this is the receptor that will be found
on these basophils and mast cells.
You can see, now, that
when this IgE binds to its receptor
it's now ready and it looks like a receptor
that can respond to antigen.
So, now, the second time
you get exposed to that peanut allergen,
the allergen interacts with the IgE
that's found on the mast cell and basophil
and it triggers the degranulation
of this mast cell or basophil,
where they release all their contents,
and those contents start to have physiological effects.
So, the first thing that happens
when that allergen binds to the IgE
found in the receptor
is the activation of calcium,
and so in this image
you will see that in the upper right-hand corner
antigen is added,
and then the cells start to respond
by increasing intracellular calcium,
shown in bright green,
as the cells get activated,
and you can see that, eventually,
the cells start getting activated in this field.
The next thing that happens after activation
is degranulation,
and in this particular video
what you'll see is that the mast cell is activated,
and as the granules are released
they pick up a dye
that allows you to visualize
the degranulated granules,
and that dye is shown in red.
Now you can start to see
the mast cell degranulate,
you can see the granules reach the cell surface,
they pick up the dye,
and now we can now see that the granules
have been released.
Once those granules have been released,
they now look empty.
So, here's an EM, an electron micrograph,
of a non-degranulated mast cell
on the [left]
and a degranulated mast cell on the [right],
and you can see that the granules are less dark,
indicating that they've released their contents.
So, what happens after these mast cells degranulate?
Well, blood vessels
start to increase in their size
because of the contents of the mast cells.
You get increased blood flow to the area
and this can cause reduced blood pressure,
irregular heart beat,
and, in some cases,
can result in systemic anaphylactic shock.
If this happens in the airways,
you get airway smooth muscle contraction,
you get an increase in mucus production,
and this can cause difficulty breathing,
swallowing, or wheezing
in those people who have allergic responses
in the airways.
If it happens in the GI tract,
if you get exposed to peanut allergen in the GI tract,
here the GI smooth muscle cells contract,
and that then leads to peristalsis
and fluid secretion,
it can cause stomach cramps,
vomiting, diarrhea...
classic symptoms of food allergy.
So, in the airways,
one can actually see mast cells
lining the trachea
in between the epithelial cells,
and those mast cells actually
reach in between the epithelial cells
and sample antigens and allergens
that are coming into the airways,
and you can see that here.
You can see that these are sections of trachea
that are stained with a mast cell protein,
mMCP6,
and you can see it's stained in red,
and you can see an airway, here,
that is lined with mast cells.
And those mast cells actually
are continually sampling, in the video on the left,
continually sampling contents
that are passing through the airways
to determine whether there's anything
that they recognize and,
if there's something that they recognize,
then they will respond and degranulate,
and you can have some of these symptoms.
And so, in the end,
if this happens in the airway,
there's a cartoon, here,
of an open airway on the [left]
-- this is a normal airway
, the individual can breathe very clearly --
when the individual is exposed to allergens,
the airway smooth muscle cells expand,
the epithelial cells expand,
and you have mucus
that partially blocks the airway,
making it more difficult to breathe.
So, how do we actually block this response?
Well, you can prevent
the release of these granules
by blocking either the activation of the mast cell
or you can block the release of the contents,
and if you do that then
you can potentially reduce symptoms of allergies.
And so there are a number of agents that have been discovered
over the years
that can actually block
the release of mast cell contents,
including drugs that are based on Chromolyn,
such as Nasacrom,
and what that does,
in a way that we don't quite understand,
is it prevents the mast cell from releasing its granules
when it gets activated,
so by preventing the release of the granules,
you prevent the release of
histamine, heparin, TNF,
and all the other cytokines
that are responsible for the allergic response.
In other cases,
we don't actually block the release of the granules,
but we in some cases can block
the effects of the granule contents,
such as antihistamines,
which can reduce increased vascular permeability
and smooth muscle contraction
due to the histamine release.
So, when you get an allergic response,
you take an anti-histamine.
What you're actually doing
is preventing histamine
from having an effect on these smooth muscle cells.
If the histamine release has already occurred,
in the case of systemic anaphylactic shock,
we can actually counter the effects of histamine
by taking epinephrine,
which counteracts the effects of histamine,
and here's a picture of an EpiPen
that individuals who have severe allergies
will carry around with them
to use in case of an emergency,
so that they can counteract the effects of histamine.
In addition, there are other types of drugs,
such as the drugs that are based on the Singulair series,
and these drugs actually do
similar things to the anti-histamines.
They actually block the effects
of the leukotrienes that are produced by mast cells,
which have the same effects
-- smooth muscle contraction and edema.
And the way they do this is by competing
with the leukotrienes for the receptors
on these smooth muscle cells,
therefore preventing their action on these cells.
Another drug that was recently discovered
by a company called Genentech
is a drug that actually targets the IgE
and blocks it from interacting with its receptor,
and in that particular drug
-- it's a drug called Xolair --
what it actually does is...
actually it's an antibody
that binds to the Fc portion of IgE
and prevents it from interacting with its receptor.
And when it does so,
now the mast cell or basophil
can no longer respond,
because they don't have the IgE on their surface,
they cannot recognize the allergen,
and so you reduce the symptoms
of all allergic responses.
And so Xolair has actually worked very well
in reducing the symptoms of allergies
because it reduces the ability
of mast cells and basophils to respond.
So, in summary, then,
what we see is that
the first time you get exposed to an allergen,
you generate an immune response
that leads to the generation of IgE.
That IgE then coats
the mast cells and basophils,
and when those mast cells and basophils
actually come in contact with the allergen,
they respond to the allergen
and release their contents,
leading to the symptoms of allergies.