DIP Episode 359 - The Clutch Hypersensitivity Reactions Podcast (for Step 1-3)

Okay, welcome. My name is Divine. This is episode 359 of the Divine Intervention Podcasts. And in today's podcast I'm going to be talking about hypersensitivity reactions. I'm going to be talking about hypersensitivity reactions. As a reminder in the month of January I'll be holding two courses for the USML exams. The first one, I guess maybe three courses. The first one is on the 24th of January. It's going to be an NBME Testicking Strategy course. It's for two and a half hours. I've had tons of people attend these courses and do really well on their exams. We address many different pitfalls that people make on NBME exams and I've had many good testimonials from these courses. So if that's something you're interested in, shoot me an email. And then also if you're taking step to seek your step three, or complex level two or three, I have a 24 hour step to seek your review course. It's taking place from the 25th. That's a Tuesday to the 28th. That's a Friday of January 2022. And then finally, if you're taking the USML step one exam and you're struggling with physiology and pathophysiology or you're taking the step to seek your step three exams and you're struggling and you know you have like a really bad foundation from step one. Let's say that very low step one scores, really low shelf scores across the board. One thing that you may find to be helpful is my foundation scores. That is going to be taking place from the 31st of January 2022 to the 4th of February 2022.

So if you're interested in any of these courses, just shoot me an email through the website. I'll give you some more information. The courses are all held via Zoom. So hypersensitive criteria actions, right? Because the thing is we all know that we have an immune system. Well, the immune system's job is to react in certain situations. It's to notice that we have an invader like a bacteria or a virus or a fungus or TB or whatever and then get rid of it. Take care of it. Fight with it. Now, unfortunately, in some situations, the immune system gets too touchy almost. What do I mean by getting too touchy? It just means that the immune system is just getting too, getting too reactive, right? When you have those kinds of situations many times, that's what gives rise to a hypersensitive reaction. Now, the thing is essentially in a hypersensitive reaction, your immune system is getting too sensitive to things that are ordinarily benign, right? And the thing is it's actually very high yield for purposes of the USMLA exams. This is like literally every USMLA exam to know the major classes of hypersensitive reactions to know like the key examples and to actually understand the mechanisms. This is actually one of those areas where understanding mechanisms absolutely helps, right? And we know that there are four major kinds of hypersensitive reactions, right? There's type one, right? That's like the immediate one. That's the one that's mediated through IGE, right?

You know, many times the cells that are kind of implicated there are things like my cells, basophiles, things like that. You'll see no fields to an extent, right? And then the type two hypersensitive reactions, right? Are the ones that involve antibodies? I'm just giving some broad strokes. I'm going to go into more detail as you go along, right? So type two, those are the ones that are mostly antibodies and really the antibodies that are the big players here, IGG and IGM, right? IGG and IGM. And then type three, those are the ones that involve immune complex deposits, right? immune complexes. Here you're going to be seeing a lot of the vasculities. You're going to be seeing a lot of the nephrodic, nephrodic syndromes. Although one notable example, one notable exception is good posture syndrome, which is a type two hypersensitive reaction, right? And then the type four hypersensitive reactions are more the delayed hypersensitive reactions. Those ones, usually for the most part, involve like macrophages and things like that and lymphoma, and lomas. In fact, let me tell you this. When I see granulomas formed on an NBM exam, you can pretty much almost always take you to the bank. Not in all cases, but most of the time it's going to be a type four hypersensitive reaction. Now, what if they give you a question about a 24-year-old female? You know, she tells you that she has this cough that is worse at night.

And when she runs in cold weather, she has very significant shortness of breath and wheezing and things like that. If you see stuff like this, what should you be thinking about? Well, I really hope you're thinking about this person potentially having asthma, right? Asthma is a classic, is like the classic poster child example of a type one hypersensitive reaction. Right? So when in the world causes a type one hypersensitive reaction, well, the first thing is you're going to be exposed to some kind of allergen, right? It's not like you just have the hypersensitive for no reason. No, you're going to be challenged with an allergen. You know, it could be hey, it could be something just in the atmosphere or whatever, right? And when you're exposed to that thing for the first time, you don't have any problems. But your immune system, your T helper, two cells, somehow get wind of that thing that has come into your body, right? So the thing is many times, you know, your antigen presenting cells, usually your billion foresights, will take up that allergen, right? And then it's going to expose them to T helper two cells. And we know that T helper two cells, they are very important for the process of class switching, right? They make a lot of stuff, but the main stuff that we want to be worried about here is interlooking for and also to an extent interlooking 13.

When those T helper two cells making to looking for the billion foresights, I'm going to be like, okay, okay, we're not going to make IGM. We're not going to make just IGM anymore. We're going to start making IGE, right? Remember the first antibody you make to any kind of antigen is IGM. But when you're exposed to T helper two cells, they then enable you to class switch by releasing things like interlooking for, interlooking 13. And by doing that, you're able to make auto-antibodies, right? Like for example, if you want a class switch to IGE, right? You need interlooking for, if you want a class switch to IGE, you need interlooking five, right? With these interleukins help you class switch, right? Because again, IGE is the kind of antibody that participates a lot in these type 1-hyper sensitivity reactions. And I'm really hoping that you remember that if they give you a question about a child, it's going to be a boy that has recurring bacterial infections. And you notice that this child has low levels of all the other immunoglobulins with the exception of IGE. I would really hope you're thinking about hyper IGE syndrome, right? That's a class switch in problem. That's a classic immunodeficiency disease that our friends at the NBM is love to test. And it's actually very high yield to remember that it's not going to show up in girls on exams. It's just going to show up in boys. Why? Because it has excellent recessive inheritance, right? So continue on joining, right?

So you're exposed to that allergy and antigen presenting cell like a B lymphocyte takes it up. You pair up with a T-helper 2 cell, right? That T-helper 2 cell produces interlooking, pointer looking 13. So that makes you make IGE, right? And again, those B lymphocyte, so once they want a gone class switching, many times they begin to differentiate towards the plasma cell lineage, right? Those plasma cells, they have like antibody factories. They make a ton of IGE, right? And then that IGE goes and parks on the surfaces of effector cells, right? So effector cells are just cells that do a lot of the damage in a high-percentitivity reaction. So these are going to be things like mass cells, these are going to be things like basophilms. These are going to be things like eoceno-films, right? But the big player, I would say for purposes of the USMLA exams, in a person that has a type 1 high-percentitivity reaction is a mass cell, right? So on the mass cell, right? That IGE that you have made is going to attach to the FC epsilon receptors on those mass cells. Those FC epsilon receptors, basically, the receptors that binds to the constant region of IGE, right? They're receptors that bind to the constant region of IGE. Again, this is one of the ways, Omalizumab, works as an anti-Azmama medication. One very wonderful thing he does is that he disrupts that interaction between the FC epsilon receptor and the constant region of IGE.

So now you have these IGE antibodies parked on the surfaces of mass cells. It's not a big deal. Until you then get exposed to the allergine again, right? When you get exposed to the allergine again, that allergine will bind to the variable region on the IGE antibodies that are already pre-bound on mass cells. And when it binds, it then causes, though, it's almost like, I think of it as like a much making service, the allergine. The allergine, when it shows up, it brings to antibodies together, to IGE antibodies together that are already on mass cells that normally do not interact. And after that, guess what's gonna happen? You're gonna have a lot of problems. Those mass cells will degranulate. And when mass cells degranulate, they do not release anything that is pretty. I'll tell you that right now, right? They release things like histamine, bradycaning, heparine, all those things, right? Things that cause visual dilation. So most times when people are going through a very severe type 1 hypersensitivity, they'll have a decreased systemic vascular resistance, right? Many times they'll have a dima. Why? Because they have increased vascular permeability. Again, some of these very severe type 1 hypersensitivity reactions can lead to ARDS. Remember, the primary mechanism behind ARDS is that your pulmonary capillaries become more leaky, right? So these people are gonna have lots and lots of problems. And that's the immediate reaction.

Now, the thing is, remember, we also have IG Es parked on the surfaces of your synophiles, right? So the thing is, many times you have an immediate reaction, but down the line of a few hours later, you have a late phase reaction. The reason that that reaction is late phase is that IG Es synophiles, they're kind of gearing up to produce all the other things that can cause some serious havoc, right? So, you know, the Eucino feels they release their nasty nasty stuff and those things can cause lots of problems. So, we're honest with you, this is one of the reasons why when people come in for like an asthma exacerbation, you're gonna treat them immediately with like a beta-toygonist like a beta-roll, you're gonna give them IV-corectosteroids. But many times, you know, those IV-corectosteroids are actively helping you to prevent the late phase reaction from happening in the first place. Again, so that's the mechanism behind the type 1 hypersensitivity reaction. And again, what are the classic types of type 1 hypersensitivity reactions? Again, asthma is like the poster child. If you see a person like a food allergy of some sort, that is almost always a type 1 hypersensitivity reaction, right? Of a person has like hay fever, right?

When there's a lot of pulling outside, a lot of dust mites outside and you, or you know, they're exposed to animal dander, I see them having respiratory symptoms like they're, you know, the anosis are very irritated, they have a dim of the nostrils and all those things. A allergic ryanitis hay fever, think about a type 1 hypersensitivity reaction. Whenever you see a person, have an aphylactic transfusion reaction. That's also a kind of type 1 hypersensitivity. Basically, remember, this is classically found in people that have IGA deficiency, right? IGA deficiency. If a person has IGA deficiency, then those people, IGA is not a native protein to their buddies. So since IGA is not a native protein to their buddies, if you give them a first blood transfusion and you don't take, you don't like really clean up that blood and there's some IGA in it. The thing that will happen is those people will form IGA antibodies against that IGA. So the first blood transfusion they get not a big deal, but when you get a second blood transfusion, that if that second blood transfusion contains IGA, those IGA antibodies that have made against you, that's already prebound to muscles, will link up with that IGA. You're gonna get cross-linking, you're gonna get an aphylaxis, right? An aphylactic transfusion reactions, an example of a type 1 hypersensitivity reaction. I remember the drug of choice one aphylaxis is epinephrine, right?

Because in an aphylaxis, the thing that is gonna kill you is bronchoconstriction, your early feeling. So the thing that happens is you give a very powerful bit of to agonist, like your epinephrine that will open up your earways and relieve your symptoms. So again, these are all the classic types of type 1 hypersensitivity reactions, right? So what if they give you a question about a 24-year-old female? They tell you that she has a history of lupus, right? And for the last two weeks, she has been having shortness of breath, she's been having like jaundice, and then they give you some labs. You notice that a total bilirubin is three, and her indri bilirubin is two point. Okay, let's say a total bilirubin is like six, right? And her indri bilirubin is like 3.9, her indri bilirubin is like 2.1, right? And then the tell you that a cumstest is positive, right? If you see that, that's obviously an autoimmune hypolytic anemia, right? Remember, an autoimmune hypolytic anemia is you're making antibodies against your red blood cells, right? Remember, it's pretty classic if people that have lupus. And you may be like, divine, why does this person have jaundice? Well, think about it. Those antibodies are going to be causing a lot of himoluses, right? And all that himoluses that is happening is going to lead to the formation of a lot of indirect bilirubin, right? It's going to lead to the formation of a lot of indirect bilirubin, right?

And some of you may also be wondering, okay, divine, why is the direct bilirubin also elevated? It's like 2.1. Well, let me explain. The thing is whenever you have, this is like a concept that's probably addressed in a different podcast. But let me tell you this, there are two kinds of indirect type of bilirubinemia you can get. You can get an indirect type of bilirubinemia because there is something wrong with the enzyme that conjugates bilirubin. That's UDP, glucoronousel transfer is UDPGT, right? So things like krydlanahar syndrome or geobers syndrome, right? Whenever you have indirect type of bilirubinemia, it's from that particular cause where like UDPGT does not work. You have an indirect type of bilirubinemia, but you will not have any kind of direct hyperbibiliorubinemia. Why? Because the bottleneck causing the indirect hyperbiliorubinemia is at the level of the enzyme that conjugates bilirubin. Now, the second kind of indirect type of bilirubinemia you can have is one that is secondary to a non-UDPGT problem. Whenever you have an indirect type of bilirubinemia from a non-UDPGT problem, so say for example, like he molasses, as you are making more indirect bilirubin, UDPGT will be working over time and it will make more direct bilirubin, right? So whenever UDPGT is working just fine, if you have an indirect type of bilirubinemia, you will almost certainly also have some kind of direct hyperbiliorubinemia.

Although most times the indirect bilirubin will be numerically higher than the direct bilirubin, just because of enzyme kinetics, but again I'm not going to go into that deep biochemistry discussion right now. If you understand what I've just said, you're pretty much set, right? So what causes a type 2 hypersensitivity reaction? Basically, a type 2 hypersensitivity reaction is mediated by antibodies, right? The big players here are IGM and IGG, right? The way easy way to remember that is just remember like Game Stop. You know Game Stop is like a big name stop, it was a big name stop, earlier this year, it's probably still a mean stop now, but that's a different conversation. But remember the game, the G and the M in game, right? It's mediated by IGG and IGM, right? And basically, when IGG and IGG, because if you're like, oh, do I hope you, what do these antibodies actually do that causes the destruction? Well, let me explain. When IGG and IGM binds to yourselves, the thing that's going to happen is IGG and IGM, they are capable of activating the classic complement cascade. When you activate the classic complement cascade, complement combs, forms the membrane attack complex and explodes yourself, right? So that's really what happens. So if you're exploding your head blood cells, you're literally having him all theses of those red blood cells, right? So again, what are the classic types of hyperseptive, type two hypersensitivity reactions? You may see on your example.

Well, if you see a person that has again, like an autoimmune hemolytic anemia, as I describe you remember, those people will have a hemolytic anemia and the comstase will be positive, right? That's an example of a type two hypersensitivity reaction. Again, the comstase being positive tells you that, oh, the hemolysis is being mediated by antibodies, right? As an aside, if you're thinking about something like g6pd deficiency or people that have hereditary cytoces, g6pd deficiency, hereditary cytoces, those are also examples of hemolytic anemias. But those things are for the most part not antibody mediated, right? So those will be examples of combs negative, right? More specifically direct comstase, right? Direct coms negative hemolytic anemias, right? If you see a child, right? That has like a lot of joint problems, has mitro stenosis, so any of those issues, right? Romantic fever, right? That's also an example of a type two hypersensitivity reaction, right? Basically, there's some molecular mimicry at play there where the antibodies that your body makes against strep pyogenes, that's group A strep, also happen to cross-reacts with antigens that we see like in the myocardium antigens that we see in joints, antigens that we see in the bizoganglia. In fact, those antigens that you see in the bizoganglia, those antibodies are attacking them, it's part of what causes a synenhamser Korea, right? Or this condition called pandas. But again, that's a different conversation.

But again, Romantic fever is a type two hypersensitivity reaction, right? Or if they give you a question about a young male, he's a smoker, right? And he has hematuria. And then they tell you that, oh, you know, they get a kidney biopsy and they see a linear pattern on the middle floor, right? Good posture syndrome. That's an example of a type two hypersensitivity reaction. You basically have made antibodies against type four collagen, right? Antibodies against type four collagen, right? In your, you know, in your, you know, in the basement membrane of your kidneys, and he also attacks the lungs as well, right? And again, if you have an acute hemolytic transition reaction, right? So be a person, they get a blood transfusion, a few minutes in, they start complying no flung pain and hematuria. That's like the classic thing. Friends that the MBM is love to throw in flung pain and hematuria. When they see stuff like that, right? That's an acute hemolytic transition reaction. Even a delayed hemolytic transition reaction. Those are all examples of type two hypersensitivity reactions, right? Again, those preformed IgG, IgM antibodies, and the things that are throwing you into big, into big problems. Remember, those people, they need fluids, right? And then you need to do a direct comb test to figure out what in the world happened, right? What in the world happened? And also, if they give you a question about like a child, right? Or a patient with a history of lupus, right?

That, you know, is having like BTKI, having puprar, having like nose bleeds, gum bleeds, right? And you notice that the red blood cell count is fine. The hemoglobin hematocryl is okay. The white blood cell count is fine. But you notice that, mean, the applicable accounts are really low, like 3000, right? That's ITP, right? Immune thrombocytopenic puprar. Remember, in this case, the antigen that you've made IgG and IgM antibodies against is GP2 B3 A, right? Again, that's an example of a type 2 hypersensitivity reaction. That's an example of a type 2 hypersensitivity reaction. Okay. So again, type 2 hypersensitivity is going to be IgG, IgM, right? And it's antibodies that are causing the problem. Okay. Now, in type 30 hypersensitivity reactions, right? So what if they give you a question about like a patient, they tell you that, oh wow, this person just started like an infusion of retoximab for some malignancy. And then you notice that, you know, over the last three days, they've been having a lot of like joint pain, they've been having like their creatinines been going up and all those things, you know, they just feel unwell, right? That's serum sickness, right? Again, remember, serum sickness is associated with like infusions of stuff like monoclonal antibodies, antitoxins, things like that. That's actually an example of a type 3 hypersensitivity reaction, right? So what exactly is a type 3 hypersensitivity reaction?

Basically, the big thing to remember is that you form antigen antibody complexes, right? But in this case, these antigen antibody complexes are mobile. They are mobile. They move around the body. Basically, it's almost like you form an antigen, you form an antibody again, you have an antigen, a form an antibody against it. And then those things are like, let's go crush the party at many different parts of the body, right? So they go to the kidneys, cause kidney damage, they go to joints, they cause joint damage, right? So the antibody, right, that is bound to that antigen. Again, triggers the complement cascade and causes a lot of problems, right? Like, for example, if you see a child, let's say they had like an upper respiratory infection like three weeks ago, right? Or they had like a skin infection like three weeks ago. And then, so like skin infection, like I don't know, like they're assepolars or, you know, like cellulitis. And they're now they're having hematuria and they have like three plus proteinuria with dysmorphic erythrocytes. In those circumstances, right? You absolutely want to think about post-triptococcal glomerulone arthritis, right? That's an example of a type three hypersensitivity reaction, right? In fact, like many of the vasculidities, right? Many of the nephrodic nephrodic syndromes, again, with the exception of good pastures, which is type two, all examples of type three hypersensitivity reactions, right?

So again, that's something that's kind of high yield to know for, for example, right? Okay, now as we begin to wrap up, let's go to the type four hypersensitivity reactions, right? So the thing is, basically, let me just tell you this. If you see any words like delete type hypersensitivity or TB skin test or coin allergy or metallology, just stop thinking, you know, look for the answer that says type four hypersensitivity reaction, pick up that answer and move on, right? So the thing is type five percentitivity reactions, right? Like how do they arise? I'll give you some examples, but I think this is one of those hypersensitivities that many people don't really understand, right? Many people don't really understand, but let me explain exactly how this works. The thing is, there are two major players in a type four hypersensitivity reaction. Those are your T-helper one cells and those are your macrophages, right? Your T-helper one cells are your macrophages, right? So let me describe in a few steps, let's say, for example, poison ivy, right? Poison ivy is like the classic, classic poster child for type four hypersensitivity reactions, right? So let's describe how this happens. Well, the very first step is that your skin comes in contact with poison ivy. Whoops, that sucks, right? It's going to be a person that was exploring the woods or something, right? And then step two is that that poison ivy will bind to some skin antigens. It's almost like you're priming the pump, right?

With some of these skin antigens. Now, the thing is, in step three, the macrophages in your skin will be like, what is this, right? It's going to bind up that poison ivy, right? The macrophage will gobble up that antigen. And remember, macrophages are antigen presenting cells, right? So since they are antigen presenting cells and they've just gobbled up some antigen, they will literally present that antigen to a particular cell, right? They are going to present that antigen on MHC class two to your CD4 positive T-helper one cells. And when they presented, well, those CD4 positive T-helper one cells, they are very good at releasing something I'll call interferon gamma. So that'll be step four. They're going to release interferon gamma, right? And then in step five, the thing is interferon gamma is like giving like a big Thanksgiving meal to a macrophage. It's going to ginger that macrophage. It's going to supercharge that macrophage, right? So that macrophage will get activated. That is step five. That macrophage will get activated and it will go back to the place where gobbled up that antigen, right? And we know that macrophages, when they show up to a party, they kill everything inside. They just absolutely destroy everything inside, right? So, you know, that'll be step six, right? The macrophage comes and it just damages everything, right? Cause these phagocytosis, releases interlooking one, interlooking 60 NF alpha.

So you get like local tissue damage on all these things, right? And then in step seven, you notice, oh gee, what's wrong with my skin, right? Again, that's why it's called a delayed type hypersensitivity reaction, right? There are many, many types of type four hypersensitivity reactions, right? Like the classic one is like a TB skin test, right? TB skin test, right? That's an example of a delayed hypersensitivity. If you see a person would like contact dermatitis of any sort, right? Like nickel, like a nickel problem or poison IV problem or whatever, right? Think about a type four hypersensitivity. Rumatoid arthritis is in fact a type four hypersensitivity reaction, right? Even Hashimoto's thyroiditis, right? Hashimoto's is an example for the most part of a type four hypersensitivity reaction, although because it's merely T cells that do the killing of the of the of the presence of thyroid gland, right? Although to a minor extent, it also involves type two. It is almost like a crossover kind of hypersensitivity reaction, right? Multiple sclerosis, right? That is a type four hypersensitivity reaction, right? If a person has Crohn's disease, Celiac disease, again, many times these things are type four hypersensitivity reactions, right? Although again, they have some crossover, right? So the big ones I'll say to know for you exams, the TB skin test, contact dermatitis, those are kind of like the two big ones you want to know from that perspective for your exams.

So I think I'm going to go ahead and wrap up here, again, as I do at the end of every podcast. Again, I do offer USMLE review courses. Again, if I always encourage you to make decisions for themselves, if you've seen the quality of my teaching that I give over these podcasts, that gives you a pretty clear solid idea of how I teach in a group setting. So I offer you courses that are targeted towards step one, towards step two, see it towards step three. And then I'll also offer one on one tutoring for the USMLE exams. USMLE step one all the way through to three, the preclinical medical exams, the third year clerkship shelf exams, I offer tutoring for all those things. And then again, I have a new website called Divine Intervention Life Lessens.com. Right now, I have almost 50 podcasts. Again, they are lifeless, sends podcasts, they are Bible based, and you know, again, they're short, they're sweet, and they're just targeted at addressing common problems that are faced by people. And then I also have these and actually have those podcasts on Apple podcasts as well. And then I have these podcasts for this, you know, USMLE materials on Apple podcasts, on Google podcasts, and on Spotify. And I also have a You Tube channel, Divine Intervention, USMLE podcast and videos. So thank you for listening to me today, have a wonderful rest of your day. God bless you and happy new year. Thank you.

IgE antibodies, which bind to mast cells and basophils.

Type III hypersensitivity (e.g., serum sickness, post-streptococcal glomerulonephritis).

Contact dermatitis or positive Tuberculin skin test (PPD).

Type II hypersensitivity, due to preformed IgG/IgM antibodies attacking transfused red blood cells.

IgA deficiency (due to the formation of anti-IgA antibodies that cross-link with incoming IgA).

Interferon gamma (IFN-$\gamma$).

IgG and IgM.

It indicates that the hemolysis is mediated by antibodies (Type II), as complement activation requires these preformed antibodies.

Poison ivy/Contact dermatitis, Tuberculin skin test (PPD).

Mast cells, basophils, and IgE.

Type III hypersensitivity.

They develop anti-IgA antibodies that cross-link when exposed to incoming IgA, triggering mast cell degranulation (Type I).

IgG and IgM.

It indicates that the hemolysis is mediated by antibodies (Type II), as complement activation requires these preformed antibodies.

Poison ivy/Contact dermatitis, Tuberculin skin test (PPD).

Mast cells, basophils, and IgE.

Type III hypersensitivity.

They develop anti-IgA antibodies that cross-link when exposed to incoming IgA, triggering mast cell degranulation (Type I).