Welcome to the lecture on hypersensitivity. Hypersensitivity is a functional medical term. Historically, it's been used to describe immune responses that didn't seem to be useful or were excessive or were generally a pain in the butt for treating physicians. So, the term is used to describe any inappropriate or misdirected immune response whatever it's intensity. To my mind, this makes the term somewhat misleading. Hypersensitivity doesn't cover genuinely excessive reactions like toxic or septic shock. The reactions it does include may be quite mild, like a typical mosquito bite or many allergies to pollen. Hypersensitive reactions can also however be lethal. For example, the reaction to a mismatched blood transfusion. Moreover, many of these reactions are normal and useful in one context but dangerous in another. Thus, the term hypersensitivity includes excessive responses to pathogens that result in tissue damage. It includes allergic reactions which respond to non pathogenic stimuli. These are reactions designed to protect you from environmental pollutants. The term anaphylaxis refers to the excessive response to an antigenic stimulus that may result in vomiting, diarrhea, asphyxia, shock, that is a drop in blood pressure, and death. Doctors have traditionally divided hypersensitive reactions into four major categories. These form a very standard way of analyzing these reactions. I'll present this analysis because it provides the framework for inquiry and diagnosis in this area. But, if you stuck with me for enough of these lectures, you know that I don't entirely trust rigid biological categories, especially when it comes to the immune system. To complicate matters further, a single antigenic source may trigger more than one kind of response. Penicillin for example, can induce any of these reactions. However, keeping true tradition, what ties these four types of responses together? They are all triggered by elements of the adaptive immune system and therefore require a period of sensitization to some antigen before they can be induced. They can be triggered by antibodies or they can be triggered by T cells, but they will also recruit and involve myeloid cells, that is the innate immune system will become involved in the response. Finally, the reactions will be inappropriate in all four cases, in that, they may seem to do you more harm than good. At the end of the outline for this lecture, there is a table that summarizes the characteristics of these responses. Keep it handy during the lecture and it will help you organize the characteristics of these reactions as we slog our way through all four kinds and then maybe add a little extra on the end. As we begin our survey of the different kinds of hypersensitivity, I want to direct you to the end of this lecture on your outline where I have a table that summarizes the four kinds and puts a lot of the miscellaneous information in some reasonable order. We're going to go through the column on type one hypersensitivity. Just to remind you, this is what is generally considered classical allergy. So, it's something you may or may not have personal familiarity with because it includes things like hay fever and hives and eczema. It also includes some kinds of serious food allergies, asthma, and we'll see, anaphylactic shock. So, we refer to these things as being annoying to lethal. We get an immediate response here. By immediate response, we mean seconds to minutes. If you have an allergic response that occurs that quickly, it is going to be antibody mediated. So, in this case, the antibodies are IgE. Now, when you have an IgE mediated response, in general, you are not killing individual cells with these antibodies, you're potentiating a TH2 response. But that doesn't mean you can't die from it because as we will see, you can get some kind of shock response that can kill you. But just to set up the distinction, there's a difference between the cells being actively killed by apoptosis and the whole body being killed by an overall excess response. So, you might ask, what is this good for? Why have something that could possibly kill you and kill you because you've been exposed to something relatively harmless? Well, it's like anything else. Anything that can go wrong will and this particular response does have a very useful defense in part of your body, which is to say, this is involved in something that we've referred to as barrier flushing. If you're exposed to parasites, if you're exposed to pollution, you generally want to clear off your barriers and not kill everything inside, and you might say, "Oh my goodness, this is industrial pollution, how could we possibly have evolved something that deals with that?" Well, life really wasn't that easy for our ancestors. They often were enclosed in spaces with wood smoke, they certainly got exposed to other kinds of damaging things in the air. So, we have this particular barrier response and unfortunately like anything else, it can go awry and be excessively directed or directed at something relatively harmless. So, that's what you have with rhinitis. The thing you're most likely to be familiar with is something that's a response to pollen, which is certainly not a pathogen. Mold, well, maybe you want to do flush that out before it takes over but these things are all considered part of the atrophy, which is an atopic response, which means a local response. So, rhinitis is a local response in the nose and upper respiratory tract and nasal mucosa. Generally, nobody has really figured out why some pollen elicits it and why some doesn't. Now, we can also have atopic dermatitis, and that's called eczema. So, here we have a really unfortunate person who's got a red itchy rash with local pustules. Again, this is very unpleasant and it's often not remotely a sign of infection, but rather an excess response in your skin. Recall, your skin is a very important immune organ and has a lot of cells in it that patrol your body. They can get upregulated when they probably should be left alone. Food allergies can be much more serious, peanut allergies in particular. Food allergies are something that breastfeeding is supposed to help you with in order to educate the gut as to what's safe and what's not. Indeed, you don't have peanut allergies in the third world. When we look at tolerance, we look at mechanisms to prevent this thing. Indeed, if the allergen is in the gut, you can get nausea diarrhea, but if it gets into the rest of your body, you can get hives and you can get asthmatic types of attack, and those things can indeed be lethal. In the case of peanuts, of course, sometimes even breathing them or maybe especially breathing peanut allergens is something that can have a very serious and possibly lethal consequence. So, what do we get when we get asthma? This is technically atopic and you might think of something that completely compromises your ability to oxygenate your entire body shouldn't be called a local response, but indeed, the response is a local. It is primarily in the lower respiratory tract and that is a thing that can of course starve you for oxygen and kill you. So, in this case, you can see we get a narrowed airway because the tissue has swelled up. So, here you can see a cross-section of a happy airway, and here you can see a cross-section of an airway wall that has swollen from edema, which has been triggered by the, we'll see the specific compounds that are released in this response, we even get tightened muscles in the airway and you can get loosened muscles in the rest of the body which is how you get shock. So, this is again nothing to take lightly. What will happen to is if you have this over the years, your actual lung tissue can become thickened and scarred from repetitive essentially damage by this response. Sometimes you can get an asthmatic attack from stress, you can get it from cold. So, it doesn't even necessarily take a particular allergen, which means that clearing the offending allergen out of your environment doesn't necessarily help you. It's hard to see how something like this could be part of a process designed to offend you. So, it's clearly something that's gone awry. There's evidence that people who get asthma have an abnormal production of neurotransmitters. Once the process begins, it seems to take on a life of it's own. This kind of swelling here in the tissue and I've put it next to a normal tracheal tissue to show you, the scale is a little bit different, the trachea is more enlarged. But you can see that this doesn't look like a very happy tissue here and you can see that it's thicken and it's going to make it harder for oxygen to pass into the circulation. All right. So, the worst possible symptom would be anaphylaxis, which is a case of shock. Shock comes from a precipitous decline in blood pressure. If it's part of a type one response, that will also include all kinds of swelling of various mucous membranes. So, the bronchioles will constrict, but the epithelial will swell and the GI and skin responses often include also swelling, mucus, rashes, and what have you. What really kills you of course though, is the fact that you can't aerate your tissues anymore. So, the central nervous system response is you'll start to feel lightheaded, you might lose your consciousness or get confusion or a headache. My favorite, I'm amused by this, not that it's really funny, is that they say you get anxious. I mean you can't breathe, what else are you going to get? You're going to get anxious. So, this is the symptoms of anaphylactic. A lot of people carry these epipens around. I think doctors have decided better safe than sorry. So, if you've had any kind of allergic responses, they will prescribe this for you, you can take it around and in case you get a really abnormal strong one, you can hit yourself with the epipen, which will release epinephrine, and the epinephrine will relax those smooth muscles, increase cardiac output and raise cyclic AMP levels, block further degranulation and get you time to get to the emergency room.
