Avery August (Cornell U.) 1: Allergies and the Immune System
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August

By Adem Lewis / in , , , , , , , , , , , , , /


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.


3 thoughts on “Avery August (Cornell U.) 1: Allergies and the Immune System

  1. Thank you for a very helpful video. I just wonder why Dr. August did not mention the vaccine strategy: immunizing people with allergens (antigens) and Th1 promoting adjuvants will induce a class switch from IgE to IgG, from humoral to cellular response. Compared to treatments mentioned above which are short-term, allergy vaccine has significant advantage thanks to its long-lasting effect.

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