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It's recording that. Cool. Hi, everyone. My name is a cash or doctor. A cash for sure. Uh I think I've given you guys a lecture a couple of years ago. Uh If you don't recognize me anymore than, don't worry, I've grown up a lot since then. Uh Today, I'm going to be teaching you about immunology which yeah, I can't like it is really grim and dry, but I do actually think that the questions in the exam are relatively straightforward. So it's one of those things where you just got to go through the pain of learning it for the first time. But then actually in the exam, it's all straightforward. It's all kind of buzzword things. Um There's not a great deal they can really ask about it. Um So obviously path is a memory game and to actually get ready for the exam. I found that brain scape or pain scape was the best way to bash everything out. Um So when the slides released afterwards, I've released, I've included all the links to the DEX that I used um in the notes. Um In general, these lecture slides are gonna be pretty comprehensive in terms of what you need to know. But so that we actually finished before I know half seven or eight. At the latest, I'm mainly gonna highlight the important concepts and show you how they come up in exam questions. So there will be some things that I kind of go through quite quickly. Um So this is what we're going to be covering today. Um So I'll start by explaining how the immune system normally works. And I think if you can get a good understanding of this, then all of the different diseases are quite self explanatory. So I'm gonna be covering all of the uh in logical diseases that you need to know. There'll then be another immune a lecture coming up. I think Becky's doing it, which will cover the different drugs and all the nasty stuff. But um this lecture is going to focus on the normal immune system and what happens when it's not working very well. And what happens when it's working too well before we start the meme here has a double meaning. So Federer. Firstly is the love of my life. But number two, federal is the only one of these two centres players who's vaccinated and as immunology experts who are all going to pass path, you should hopefully no, um the vaccines work. Um So I'm gonna start by explaining the normal immune system and the way I was taught the immune system in school is the idea that there are three lines of defence protecting us from infection. So the first line is made up of our anatomical barriers, like the skin and the mucosal surfaces. And this is completely non specific. It'll stop absolutely anything from getting past it, whether it's pathogens, harmless particles or, you know, insects. And so it's completely non specific. So I kind of think of it like Trump's wall, however, just like there are gaps in Trump's wall, there are gaps in our skin as well. So some organisms can get through and then they need to be stopped by a second line of defense. And this is what's called the innate immune system. I sort of think of this as like a racist immigration system is very quick and simple to set up. So it'll start working early on in our immune response. Um But it's very nonspecific in terms of keeping absolutely anything foreign out of the body. Um And so naturally, this also has a lot of unpleasant self harming effects, like having a fever which can cause damage to our different organs. The same way, having a racist immigration system isn't exactly good for the host country itself. And finally, our third line of defense is a much more sophisticated and specific adaptive immune system which will specifically target the pathogens and nothing else. Um So this takes longer to set up, it'll only really occur later on in our immune response, but it's much more effective. And ultimately, it's, it's going to be our adaptive immunity which fights off the infection and clears up all the remaining debris as well. Um And so this kind of describes the three lines of defence without any controversial analogies. So first line, like I said earlier is the anatomical barriers like the skin. The second line is made up of our innate immune cells which will phagocytose absolutely anything foreign to our body. And then our third line is our adaptive immune cells which will target a specific pathogen using things like antibodies, anti killer cells as well. And then we have this other aspect of the immune system which doesn't really fall under these three lines of defence. Um And this is the complement cascade which I know everyone hates. I'll explain this in more detail later on, but essentially the way I think of it is that it's this extra adjunct which will enhance or complement all of the other aspects of the immune system and make them more effective. So you have your three lines of defence and then when the complement cascade works as this extra adjunct, it will enhance all of our three lines of defence. And I'll explain exactly how this does this a bit later on. So uh starting with the first line, I'm not going to talk too much about the anatomical barriers because it's kind of obvious um the main thing is that the skin will protect most of our body but then there are gaps in the skin, like our nose and the mouth. And then these are going to be protected by mucosal surfaces. Instead, there's a whole list of adaptations that these anatomical barriers have, which have included in the notes. But it's all pretty low yield. They don't usually ask questions on it and really, it just needs rote learning. There's not really much explaining as to how the skin protects um, an infection moving on to the next line of defense. Um The overall principle of this innate immune system is that you have various cells, especially neutrophils and macrophages, which will attack anything foreign. And this is efficient. It will start working straight away as soon as you become infected by something. But it's not specific after phagocytose iss, the neutrophils will just die. But then our macrophages will become activated and start releasing chemicals which trigger other immune processes. So for example, macrophages can produce some cytokines and a specific site. Skin is responsible for generating a fever which is beneficial in that it slows down the growth of pathogens. Um And then you have these other soluble components of the innate immune system as well, which again will have various effects that kind of make you feel a bit rubbish when you're fighting off an infection. So this is a really useful diagram which was provided by a previous lecturer which shows the different steps of the normal innate immune response. And I think it's important to get a good understanding of this because all of the innate immune system, immuno deficiencies can be explained as a failure of one of these steps. So I'll just go through this briefly. But firstly, we will produce and develop faga sites in our bone marrow and then release them into the blood. Next, the endothelial cells within our blood vessel balls will express these molecules called adhesion molecules, which kind of makes the blood vessel walls stickier. This will allow faga sites to stick to the blood vessel wall and then migrate into the tissues where the infection is present. So it can fight off the infection. Once our finger sites have moved into the tissues and are actually able to access these microorganisms, they will then phagocyte toes or engulf them and then kill them using either oxidative or non oxidative methods. The idea is that it's kind of like Pacman, the neutrophil, oh, macrophage will eat up the pathogen, but then once it's eaten it, it needs to digest it and um and kill them. And then finally, we said that we said earlier that once the neutrophils have done phagocytosis, they're just going to die straight away and they'll end up forming puss. Whereas the macrophages will become activated and start releasing cytokines to communicate with other cells. Um And specifically, they're going to communicate with the T cells. So, neutrophils just die macrophages will survive and have other effects on the immune system as well. So, yeah, this is quite a lot and it's something that you might need to go over a few times. But essentially we have this journey of the innate immune cells being produced then moving into the tissue where the infection is killing the organism. And then with macrophages, they're gonna released cytokines to activate other immune components as well. Okay. So I'll just move the men to you on. Um, So our first question I'm gonna in court to use like a mixture of SBA nvs A is like the path exam. Uh The first one is which immune cell is post mainly composed of. Um See if you can just submit what answers you think they are. I'll give you like 30 seconds for this because it's quite a straightforward one. Okay. All right. Um So, as I said earlier, I can't be asked to switch between the mentee slide. I'm just gonna tell you what I'm seeing come up. But yeah, you're correct so far. Um The answer is neutrophils. Um So yeah, just explain why. So already said earlier that when neutrophils um do phagocytosis, they will die straight away. The reason is that to go citosis is quite an energy consuming process, they deplete the glycogen stores of the neutrophil and then that results in neutrophil death. And then when you get this accumulation of dying neutrophils, that's what forms puss. So it's pretty straightforward. Macrophage is on the other hand, as I said, we'll survive and they'll do other things as well. It's kind of like bees and wasps. You know how, when bee sting someone they die straight away, wasps can sting you and then carry on and do other stuff. Okay. So, um, so far we've talked about two types of fungus sites. They're involved in the innate immune system which are the neutrophils and the macrophages. We then have this special type of phagocyte called dendritic cells. And these are really important because they mediate the transition from our innate immunity. Our second line of defense towards our third line of defense with adaptive immunity and the way they do this is that once they do fade oxytosis, they become activated and they migrate to our lymph nodes present antigens and they'll present antigens to the T cells that are in the lymph nodes in order to prime them in order to get them ready for what they're going to do as part of the adaptive immune response. Um So I've kind of listed here a couple of other things that happen to dendritic cells once they become activated, which will help with this, which will help with this transition. So for example, um we, you might remember from 1st and 2nd year that antigens are presented on HLA molecules. So obviously, this idea of up regulating HLA expression is going to help with presenting these antigens, presenting these antigens to the T cells, also expressing costa military molecules also helps um when the dendritic cells are trying to activate T cells in the lymph flows. So yeah, these things you kind of just need to write, learn. But the main principle is the idea that dendritic cells take us from innate immunity towards adaptive immunity by getting our T cells ready. So now we've reached the third line of defense with our specific immune cells. So we've got B cells which produce antibodies and then T cells which do a whole variety of things. All of these cells are going to be produced and matured in the primary lymphoid organs, which is the bone marrow and the thymus. Before they go, they go on to attack the pathogens in our secondary lymphoid organs. So just like we have that diagram for innate immunity, this is another useful diagram showing the journey of adaptive immune cells. And again, this is going to be useful when we look at the diseases later on. Um But to take you through this, both are B and T cells are going to be produced in the bone marrow. But then T cells undergo further maturation in the thymus where they get selected and then they differentiate into either CD four or CD eight T cells. We'll have more on what those different T cells do later on B cells. On the other hand, they will be completely formed and matured within our bone marrow. But those initially formed B cells will only produce I G M antibodies. So to begin with the basic B cell is only gonna produce I G M later on, they might develop further and become capable of producing other types of antibodies like I G G. Um I'll explain how this happens later on, but this is a really important principle that will come up quite a lot during this lecture, which is that B cells by default, only produce I G M. But then with some help, they can go on to produce other kind of better types of antibodies like I G. So again, quite a lot, but it's gonna this diagram will come up a few times during this lecture. So don't worry about it if you have got it so far. So a bit more detail on T cell development. Um So we said that initially R T cells are produced in the bone marrow. And what comes out of the bone marrow is called pre T cells. Once they arrive in the thymus, they're going to be selected. So they're going to survive or not based on how strongly they bind to our self HLA. So basically, we're testing how strongly will these T cells bind to our own cells because we want to ensure that they do work. But the same time they aren't going to be self destructive. So the idea is that if the affinity is two week, so if the affinity for self HLA is too weak then these T cells are useless, we go say goodbye to them. On the other hand, if the affinity is too strong, then that means they're dangerous. So also we say goodbye to them. And then we have about 10% which is just right. And those are the T cells that are actually going to be selected from the thymus. So only 10% of the T cells that arrive in the thymus will actually survive and be used. And then those T cells will differentiate further into either CD four or C D A T cells depending on whether they're affinity is for HLA class one or for HLA class too. So kind of two step process. First step is selecting them based on how strongly they bind to H L A. And then the second step is differentiating them based on which type of HLA they bind to. Um So that's how we develop T cells in terms of what these T cells actually do. Uh We've already discussed how CD four cells have an affinity for HLA class too. So, naturally, they're going to recognize peptides that are presented on those molecules on those HLA class two molecules. Whereas CD eight cells will recognize peptides that are presented on HLA class one instead. Um So that's the general principle and then they have specific roles. So our CD eight cells are also known as T killer cells and that's exactly what they do. They kill pathogens either by punching holes in the membranes and releasing an enzyme called grams, I'm or they can induce program cell death by binding to the target cell. Uh using something called fast Ligon. You don't really need to know much detail about this. Really, the idea that T killer cells can kill um can kill infected cells. And so the CD eight cells are particularly important for killing virus infected cells and tumor's as well. The C D, the idea of CD four cells that actually encompasses quite a range of cells, which includes your regulator T cells. But the majority of them and the ones that I'm gonna refer to during this lecture are known as T helper cells. And again, they do what the name suggests, they can help the CD eight cell response, but most importantly, they help B cells carry out a full response as well. And again, they'll be more on this later. But this principle that CD four cells are required to help B cells perform to their full ability is something that's going to come up quite a lot during this lecture. Um So that's T cells. So moving on to B cell development, again, the selection of these cells is going to be based on the affinity for self. But unlike T cells, this is just gonna be completely binary. So either the cells don't recognize the self at all, in which case they will survive or if there's any recognition of the self, then they're not going to survive, they're going to be deleted to avoid any autoimmune disease. So, unlike the T cells are like low affinity in media affinity, high affinity with B cells, it's just yes or no, either it recognizes itself in which case we get rid of them or they don't recognize itself in which case they can survive and do their job. So the you have all this B cell development and selection and these selected B cells will initially only be capable of producing I GM antibodies like I said earlier and fine, this is okay, but it's not the most effective type of antibody. So in order to not be immunodeficient, it's important that these B cells can undergo a process called a germinal center reaction, which is, you know, you don't need to know a great deal of detail about exactly what happens in this. But this process will turn these kind of baseline B cells into fully fledged B cells that are capable of producing other antibodies as well. However, this germinal center reaction requires help from the CD four T helper cells. So as I said earlier, the CD four helper cells, they help uh the B cells mounted for response. And this is why this germinal center reaction requires help. Um And what happens that the CD four T helper cells will bind to the B cells via the CD 40 ligand, which triggers this further development allows the B cells to start producing other types of antibodies as well. And so again, I'm going to keep doing this in. But this idea of B cells needing help from the T cells in order to produce the full range of antibodies other than I GM, it's really important and it's going to come up quite a few times during the, actually, I think it's different diseases. Um And yeah, I'm sure if you know the role of B cells to produce antibodies. So I'm not going to dwell on this. Um The one thing to remember is that antibodies are particularly useful for fighting bacteria. So kind of two ways the adaptive immune system is killing organisms. You've got your t killer cells which are good for virus infected cells and tumor's and then your antibodies are good for fighting things that are like outside of the cells. So, in this case for fighting off bacteria. Okay. Um All right, I'll move onto the next test. So we had VSA earlier. Now we're moving on to an S B A. I'll give you again 30 seconds for this because it's quite straightforward question. Uh But let's see where you guys come up with. Yeah. Yeah. All right. Um Cool. So most of you gone for the correct answer. Um The other answer that was selected I was kind of expecting. So that's fine. So um the correct answer is the dendritic cells, I guess the first thing just going back to the question that we need to think that presents antigens. So the only two options that present antigens are the macrophages and dendritic cells. I guess the main difference is that macrophages main role is to remove, move to remove cell debris. So they're supposed to remove a pop ptotic cells um as well as microbes using phagocytosis. Whereas as we talked about earlier, dendritic cells have this key role of mediating the innate to adaptive transition. And the way they do that is by presenting antigens to the T cells after they've migrated to the lymph nodes. So I know that I also mentioned the macrophage T cell communication earlier on with the hole in your innate immunity flow chart slide. But that was more to do with cytokine signaling, not actually presenting antigens to the T cells. So a bit of a tricky question, but yeah, dendritic cells are what mediate this innate to adaptive transition, which is what I was showing with the question. Okay. Um So the last bit of normal immunity um is the complement cascade. So out, we've done our three lines of defence and now we have this adjunct which enhances our immune response. Um So, as I said earlier, the complement cascade is this pageant which will complement our three lines of defense. Our starting point is a bunch of inactive proteins that are produced by the liver and they exist within our circulation. If there's any sort of trigger which is generated by the infection. Then a series of enzymes will cleave the proteins and trigger this domino like cascade of reactions which eventually generates this endpoint called the membrane attack complex. This memory attack complex on mac is pretty self explanatory. It punches holes in the pathogen some membrane which obviously is pretty helpful when you're trying to fight off a pathogen. But on top of this, on top of this kind of domino chain of reactions, the process of cleaving all these proteins to get our membrane attack complex is also going to generate a load of fragments like a load of byproducts, which have their own beneficial effect on the immune response as well. So I've listed them here, but for example, increasing vascular permeability is going to help our immune cells reach the tissues more easily and obviously activating phagocyte is going to help phagocyte host all those um all those microbes as well. So along with our memory, an attack complex, we've got all these additional benefits of the complement cascade. And you can see how these effects are enhancing the innate immunity and the adaptive immunity that we've already talked about so far. Um So again, compliment, it's something that requires a bit of time to get your head around. Um But it's gonna come up more times during this lecture. So hopefully we'll get it by the end. Uh This diagram is pretty good for understanding this principle. So you've got this formation of the membrane attack complex. But on the side, you've got these fragments that are having other beneficial effects on the immune response. Uh You don't need to worry about what all these specific components are and exactly what they do. It's just more for understanding the principle of how this complement cascade is hopeful for us. This is the diagram that's important to learn and honestly, you just need to wrote, learn it. Um And this shows the three different ways of activating our complement cascade. The main take home for now is that the classical pathway is the one that's actually activated by an antigen antibody complex. So this is going to require a functioning active immune system, whereas all of the other pathways can trigger the competent cascade earlier on in the immune response. So the other pathways, they don't require that antibody antigen complex. So they can be started off pretty much as soon as you get infected. Um I've got a bit more detail in the notes about exactly how these pathways work. But it's the main principle. It's, it's what I've said so far. All right. So we can read that is our normal immune system. And really just getting a good grasp of that will mean that when we now start talking about these other diseases, you'll see how they all fit in and you can see which part of a normal immune system has gone wrong. So now we're gonna talk about immuno deficiencies, which is where immune system isn't working properly and we can become more susceptible to infection. And I mean, I've had so many colds this year, I was starting to wonder if I have an immunodeficiency, but there are actually some proper Hallmark features that define an immunodeficiency, like having multiple major infections in one year or taking ages to fight an infection off. So they're actually properly severe. Um, and sometimes having a weak immune system like this is just a normal part of being old, newborn or pregnant or it can happen secondary to infections like HIV or immunosuppressive drugs, which, you know, I'm sure you can imagine. Unfortunately, the purpose of path, you need to focus on a bunch of these rare primary immuno deficiencies which, you know, you're never going to see in real life. Um And all of these tend to present young in life, they're associated with a family history and these patient's, you know, we'll probably have a failure to thrive as well. So, um that's really how you can distinguish the fact that it's probably a primary immunodeficiency rather than something a bit more straightforward. Like, you know, someone being on steroids, the primary immune efficiencies can then be further categorized based on which part of the immune system is faulty. So whether it's the innate adaptive or the compliment, um that is, that is deficient. Um So we'll start with the innate immuno deficiencies and as I said, earlier, this diagram is really key for understanding them because all of these immuno deficiencies can be explained as a failure of one of these steps. So we'll go through it step by step. And this will literally cover all of the disease is you need to know. Um So firstly, the disorder could be at the level of the bone marrow where you're unable to produce neutrophils, you know, which is clearly a problem. And there are three conditions in which this happens. The most severe of these is reticular dis genesis. Um And this is where you're unable to produce any immune cells whatsoever. So, I've put this under innate immuno deficiencies, but it's also going to come up later as an adaptive immunodeficiency as well. Then you have two conditions which are specific to not being able to produce neutrophils only. Um So you've got Cosmin Syndrome. Um and then you've got cyclical neutropenia which is similar, but this is going to happen in episodes or cycles. Like the name suggests another way of distinguishing the two in exams. So, Cosmin and cyclical neutropenia is that Cosmin syndrome is a recessive condition. So, you know, Children may have this even if their parents don't have the condition where cyclical neutropenia is dominant. So you'd expect one of the parents to have it as well. Um Any particular just genesis will be so severe, it would be like obvious, you know, you're gonna have an absence of lymphocytes as well. So that's how you can tell that apart with all of these conditions, a potential treatment option is to just stimulate the production of neutrophils. Um And you can do this by giving something called G CSF, which I think is granulocyte colony stimulating factor. Obviously, this isn't gonna resolve all of the issues created by ridiculous genesis and it's not an absolute cure, but it's something that can just treat the immunodeficiency um in patients who are lacking neutrophils. Um So you can have even, even if people are producing the fungus sites, the next potential issue is with the migration of the phagocyte into the tissues where are infection is present because just having all these new fills in the blood isn't actually gonna help fight off the infection. And so the condition in which this happens is called leukocyte adhesion deficiency. And after the lecture, you can wrote, learn the lecture, the receptors involved. But the kind of stereotypical district description in exams is this immunodeficiency where for some reason you still have a high blood neutrophil count because in an infection anyway, the bone marrow is still producing these neutrophils, but they're going to be immunodeficient because none of those neutrophils are actually helping to fight off an infection. And importantly, there's there's going to be no pus as well because those neutrophils are staying in the blood, they're not moving into the tissues. Um So in terms of treatment, in this case, these neutrophils which have deficient adhesion receptors are inherently useless. So you actually need a stem cell transplant to create normal neutrophils. Instead giving the G CSF that we used earlier. It's not gonna have an effect. It's just gonna keep producing these neutrophils that are unable to migrate. So, we've got say you've produced neutrophils, they're able to a deer and migrating our tissues. They still need to be able to kill the pathogens. And so you can have conditions where there's a failure of killing and specifically a failure of oxidative killing mechanisms. Um, and this condition is called chronic granulomatous disease, which is where the phagocyte are deficient in an enzyme called NADPH oxidase. And if you're deficient in that, that's going to prevent you from killing the pathogens using that oxidative killing mechanism. So, even though they're unable to kill these organisms, the problem, another kind of additional problem you're going to get is that you'll end up with this low level excessive inflammation because you're going to end up accumulating neutrophils and macrophages that are all struggling to degrade the antigens. It's like you've got neutrophils and macrophages which are trying to kill the androgen, they're not working. So the body kind of recruits more and more neutrophils and macrophages and that triggers the successive inflammatory response. And so that's why some of the hallmark features of this condition will be granuloma formation, lymphadenopathy, you know, excessive past because you know, you're, you're, you're releasing more and more new huge pills and mac phases into the infected area. Um So I didn't know this when I was studying for the exam, but apparently these patient's are particularly susceptible to catalyst positive organism infections. And if you want to learn this list of catalyst positive bacteria, then there is uh an acronym. But I mean, I didn't know this or bother learning it from my exam. Uh So I don't think it's particularly important, but just that's another another feature of chronic granulomatous disease. Um So aside from the clinical presentation, um when they mentioned chronic granulomatous disease and exams, they will probably mention these tests as well. I was looking at past papers and you know, this comes up quite a lot in in the context of this convention, both of these tests are looking at the ability of neutrophils to produce hydrogen peroxide and oxidative stress. So basically testing the ability of neutrophils to do oxidated killing. And so that's why the positive tests here where you have a color change are actually normal results. Whereas there would be a lack of color change that would suggest that the patient has chronic granulomatous disease. The treatment for this is giving gamma interfere on the idea is that this stimulates superoxide release, which enables oxidize for killing, to taste, to take place. To be honest, they don't really focus much on the treatment for any of these innate immune deficiencies, but that's kind of an extra thing you can learn if you're, if you're going for distinctions or whatever. Um So finally, we saw earlier how the neutrophils as long as they can do oxidative killing than their jobs done. But macrophages will survive after phagocytose iss and then communicate with T cells via cytokine signaling. So we do have issues where issues with cytokine signaling specifically if you have a deficiency of the important cytokines. Um And so I've kind of describe this in more detail in the notes, exactly what's happening with the cytokine interactions. But essentially, when macrophages interact with T cells and vice versa, the important cytokines R I L 12 and gamma interferon. Um and obviously, the receptors for these two sides schemes are also going to be important. So it's a deficiency of I'll 12 gamma interferon and their two receptors which can cause an immuno deficiency. Um For exams, the I'll 12 deficiency will especially increase vulnerability to microbacteria mycoba bacterial infection. So things like TB um and that will kind of be the Hallmark thing, the Hallmark buzzword in an exam question. Otherwise all of the investigation results are gonna be pretty much normal, like there's gonna have normal neutrophil count, they're gonna be producing pass, you know, because they're gonna be killing the organisms is just this lack of cytokines um that will, that will present in these patient's okay. So I'm gonna move on to the next question. Um This is a VSA so just type in what you think the answer is, this is actually more like past paper questions. I'll give you a full minute to answer this. That's about 30 seconds left. All right. Um So we'll move on to the answer. Um Yeah, I got the number results. So, um yeah, the correct answer is chronic grand lotus cities which pretty much all of you have put. Um So like I said, in exam questions, they're usually going to refer to this nitro blue tetrazolium test or the Dihydrocodein test as well when they're talking about the possibility of this condition and remember that the presence of the color change is indicating that neutrophils are capable of producing oxidative stress and doing this oxidative killing if there is no color change and you actually have a negative result that is abnormal. That's what suggests that the patient has chronic granulomatous disease. So I think some people put um leukocyte adhesion deficiency with that. They're probably gonna mention the absence of pus or having a high blood neutrophil count in the middle of an infection. Um They wouldn't, if they mentioned this test, they would mention that the color changes actually present. Um And I think someone to put reticularis genesis um with that, they'll probably refer to both lymphocytes and neutrophils and stuff being low as well. Um So this isn't really consistent with that. Uh But well done to pretty much all of you put chronic problems is um so this is a summary slide that you can look at later on. I'd say once you've done the lecture, see if these summary, I've included quite a few of these to see if these summary slides make sense. Once you've listened to the lecture, see if you can kind of work out why all of these results are the way they are. Um So now we'll move on to adaptive immunodeficiency just like we had the other diagram. This is the important diagram for understanding all of these adaptive immunity deficiencies. So, the first potential issue is with the production of lymphoid cells in the bone marrow because it's these that are going to give rise to your lymphocytes. Um And again, we have three of these, I've already mentioned reticular dis genesis because you've got this complete absence of progenitor cells, including the ones that are required for the innate immune system as well. We then have excellent skid. Um So skid stands for severe combined immunodeficiency. Um And this is um basically you have a mutation in an important cytokine receptor which then leads this inability to respond to cytokines. And the effect of this is going to be arrested T and NK cell development, you're gonna have low T and NK cells and then B cells you'll still produce them. They're just gonna be immature. Um So that's excellent skid. And then the other one uh adenosine deaminase deficiency. This is where you get a failure of maturation along any lineage. So here you're gonna have low B T and NK cells as well. So to kind of distinguish all of these three excellence gives the easiest one to distinguish because firstly, it's excellent. So it's mainly gonna affect males. And you're also gonna have B cells present when you're looking at the cell counts, they're just gonna be immature B cells, two separate reticular dis genesis and added efficiency. The main thing is that with, with, with reticular just genesis, you always have a lack of neutrophils and innate immune cells as well with added efficiency. It's just all of the adaptive immune cells that gonna be low. You can have low B T and NK cells, but neutrophils and stuff should be normal. You also have the relevant mutations. If you want to write loan, there's, they might help. But I don't think I've seen a past paper question and I certainly wouldn't have any last year where they referred to these uh mutations. So it'll be pretty low yield. Um The other thing which is going to be another theme throughout this lecture is that um with these patient's that have an adaptive immunodeficiency, especially where they aren't producing antibodies. Patient's will initially be protected for the first three months of their life because as you probably know from pedes and no energy as well, um you get maternal I G G that gets transferred through breast milk and stuff which protects the baby for the first three months, but then after that, that wears off. And so then that's when these patient's will tend to present. So presenting after the first three months of life, the treatments. So again, you know, giving a stem cell transplant is the ideal for added efficiency. You can specifically give this kind of artificial adder which which helps treat these patient's. Um So we started with the lymphoid development. Now we'll follow the T cell developmental pathway first. And so with this, the next step is going to be t cells maturing in the thymus. So we said other pre T cells arrive in the thymus and get selected. But in a condition called Die George syndrome, which you have learned about impedes, you haven't, you have either a small or absent thymus which is going to affect this maturation. So, Di George syndrome has a bunch of other issues and there's a good acronym for learning all of this. But in path, what they're typically gonna focus on is the immune issue as well as hypercalcemia because they're gonna lack parathyroid glands as well. And they may mention the heart problems too. Um So in terms of how this presents, remember this running theme that we've talked about where T cells are needed to have full B cell function. So these patient's will have a reduced I G. But at the same time with the presentation of Die George, it's probably one of the milder immuno deficiencies because patient's tend to improve with age. There's something called homeostatic proliferation where as these patient's get older, they just start producing more T cells. So this small famous becomes less of an issue. So yeah, that, that those have cried me, the main things um for, for identifying die George syndrome. So once the T cells are selected in the thymus, we said they then differentiate into CD four or CD eight cells based on which MHC slash HLA class they have affinity for. Um but in their lymphocyte syndrome, you're going to have a a defect of MHC. So if it's bare lymphocytes syndrome type one, here, you have a defect of MHC class one. And so there's going to be a lack of C D A T cell selection with type two, which is the one that usually comes up in exams. This is going to affect MHC class too. And so here you're going to have a lack of CD four T cells. And okay. I said with Dye George, you need T cells to help with the full B cell response. Remember that specifically the CD four cells that are needed to help B cells produce these different antibodies. And so the low I G G and low antibody levels is only going to be the case with bare lymphocytes syndrome type two, with their lymphocyte syndrome type one, you're just going to have this lack of tea killer cells, but your t helper cells will still be normal. So I'll still be able to help our B cells produce more and more antibodies. So, again, quite a lot. But um we have a summary slide of all the different T cells deficiencies. And again, if you look at it afterwards, hopefully we'll make some sense. Hopefully you can kind of work out why these investigation results will be like this. Okay. So we've done the T cell pathway now going to the B cell pathway instead. Um So the first issue is going to be with development and selection of B cells in the bone marrow. Um And this condition is a bit of a mouthful and it's called Bruton's excellent A gamma globally agammaglobulinemia. Um And the main features, the main hallmarks for exams is that it's excellent. So usually affect boys and they'll present again because of that maternal I G protection, they're going to present once they lose this protection after about three months. Um Again, you can really learn the relevant mutations and stuff. Um The general principle of treating any of these B cell deficiencies is using intravenous immunoglobulin to replace um the relevant antibodies. Um So yeah, it's kind of it's relatively straightforward this condition, you're just not producing mature Beatles. Um But even if we have B cells, they might be faulty and unable to produce immunoglobulin. So you can end up with a deficiency of immunoglobulins. Um and there are two conditions like this. So as the name suggests selective iga deficiency is only going to reduce your iga levels. And I think it's the most common immunodeficiency. Whereas combined variable immunodeficiency is going to affect a variety of antibodies. Um and this one is kind of a diagnosis of exclusion. Like you need to make sure that the B cells and the T cells are normal and a normal level before you actually diagnose combined variable uh immunodeficiency because obviously remember that, say if you have low T cells, that might be the explanation for having low I G, low IGA levels and stuff. Um So with this specifically, you'll have normal cell count. But then for some reason, you have this deficiency of these various antibodies. And the final issue is with class switching. So again, this running theme of T cells helping the B cells produce things other than I GM. Um So in this case, it's not really a B cell issue is going to be a defect of the T cell. Um So if you remember, we have that CD 40 ligand, which allows the T cell to fully activate the B cell to produce all these different antibodies. If you have a defect of this ligand, that's what causes hyper I G M syndrome. And so again, it's another excellent condition that will probably affect a boy. Um when you have the exam question on it. And the other key feature is that you have this elevation of my GM as the name suggests. Um, but with an absence of other antibodies that is that you've got all these B cells, normal amount of B cells producing um, antibodies, but none of them able to produce anything other than I GM. So the total amount of my GM is going to be high because um, it's not able to produce anything else. Um And funny, here's the summary slide of all of our B cell immune efficiencies. Again, look at it later on to see if it makes sense to you in terms of investigations. It's quite self explanatory. The main part of investigating and adaptive immune deficiency is going to be looking at the lymphocytes present and then the antibodies present as well is pretty straightforward. Okay. So now we'll move on to the next um the next question. So here's a VSA just type of what you think the answer is again, this is um, I think taken from a past paper or like very similar to a past paper question. So I'll give you a full minute to answer this. Uh huh. Alright. About 20 more seconds. All right. I think we've got enough responses. So yeah, this is like a classic path question, you know, imagine diagnosing someone's condition based on this amount of information, but this is how it tends to come up. But the answer which most of you put is die George syndrome and that is correct. So what we're seeing here is an immuno deficiency. Um but also the convulsions is a feature of hypocalcemia because as we said, with Dye George syndrome, the pathology is that you have an absence or a defect of the found your pouch and everything that's contained within the, found your pouch. So, yeah, you've got the thymus and that's why you got this immunodeficiency, but you also can have hyperplasia or aplasia of the parathyroids which then leads to hypocalcaemia. Um So that's like I said, that's typically how they're gonna present this an exam questions having immune deficiency and then either the hypercalcemia or maybe a cardiac issue as well. Obviously, in really, in reality, it's a bit strange for them to have not been diagnosed with Dye George when the hypercalcemia was detected in the first place. Um But yeah, this is this is path. Uh but yeah, well, the most of you put Dye George um a couple of other ones, I'm not in time. Obviously, if you have questions about the lecture, I can answer them at the end. Okay. So moving on the last type of immunodeficiency involves issues with the complement cascade. And so even though I've generally described compliment as something that enhances the rest of the immune system, it's still important in its own, right. And so having deficiencies with this can have pretty severe effects, like, you know, you can die of having a compliment immunodeficiency. But the main hallmark feature is an increased susceptibility to encapsulated organisms. So things like streptococcus, uh so pneumococcus, meningococcus, uh and haemophilus as well. And these, you might have kind of come across these organisms as well in the past when looking at patient's who have had a splenectomy or hypersplenism. So people without a spleen are kind of susceptible to the same encapsulated organisms as well. This is what affects complement deficient patient's too. Um So, going through the different causes of this. So firstly, we can have deficiencies affecting the classical pathway. And of these see to deficiencies, the most common. Um so all of these classical pathway deficiencies can result in lupus. And it's quite a complicated explanation. But in simple terms, the classical pathway is really important for clearing out your self antigens. So if you're unable to clear off these self antigens, that's naturally going to promote the production of self antibodies or auto antibodies, which we know are a feature of Lupus, the cause of Lupus, the classical pathways also needed for clearing immune complexes. So, if you have a deficiency, these immune complexes will end up accumulating and stimulating inflammation in tissues, which again is what happens in in sle. So two reasons why classical pathway deficiencies can lead to lupus, one inability to clear yourself antigens to an inability to clear immune complexes, some other features of classical pathway deficiencies you can look at later on. Um Next, we have a deficiency of the manners binding lectin pathway. Um And this is actually relatively common but on its own, this is not associated with an immuno deficiency. It's only going to be an issue if you have something else compromising the immune system as well. So for example, if patient has manners, binding lectin deficiency and then they start chemo that might then trigger an immunodeficiency. But man is binding lectin deficiency on its own is not, is not actually going to make a patient immunodeficient because you know, otherwise 6 to 10% the population would have an immuno deficiency. And that's obviously not, not really true. I don't think um there's not anything specific to know about alternative pathway deficiencies. It's the same idea. They're just gonna be susceptible to encapsulated bacteria and same with these deficiencies of the final common pathway as well. Um But alongside having all of these primary deficiencies of complement components. So just being born with deficiencies of a casco pathway or or the alternative pathway, we can also have low complement levels which are secondary to other diseases. So having another disease which then causes excessive consumption of complement, therefore causing a compliment deficiency. So for example, although I've already said how a compliment deficiency can cause Lupus lupus itself can cause a secondary complement deficiency as well. And the reason is that when you have active Lupus, you're getting this persistent production of immune complexes. Remember the antibody antigen binding that immune complex formation is what triggers the classical pathway of the complement cascade. And so if you keep producing all these immune complexes, you're gonna keep activating the classical pathway and that's going to cause over consumption of the different uh of the different complement components causing a compliment deficiency. So, on one hand, you've got competent efficiency causing lupus. On the other hand, you've got lupus, which can end up causing a compliment deficiency as well. And so that's why as an important investigation in patient's with active lupus, they can have low levels of C three and C four. Um So something which I've seen come up in an exam before is that it's just important. Remember that loop if the lupus is due to a compliment deficiency. So a problem with the classical pathway, then the C three and C four levels won't be reduced because you're not getting this kind of, you know, activation of the classical path way. You're not getting this cascade to consume all this C three and C four. But if you have lupus on its own, and then that triggers complement deficiency that causes over consumption of competent components, that's when you have um C three and C four deficiency. So it's a bit confusing and you can ask questions later on if that, that didn't make sense because I don't think explain that very well. Another cause of complement deficiency, another secondary cause um is a group of auto antibodies called nephritic factors. And what nephritic factors do is stabilize an enzyme called C three convert is, which usually breaks down. See three. So if you're stabilizing it, you're going to get over activity of the C three converts, which is gonna excessively breakdown. See three, you get excessive, see three activation and consumption. The hallmark of this um in exams anyway, is that these patient's will present with glomerulonephritis. Um And they also get something called partial lipodystrophy, which is where you get fat, build up or fat distribution in like an abnormal way. Um So this condition's very buzz worthy in exams. But the principle is you've got an enzyme um which is uh you got these auto antibodies which are stabilizing the enzyme that will uh that will break down. See three to investigate complement deficiency. Obviously, the main thing is to measure the different complement levels. So I've already said how C three and C for a low in active lupus. Um And then there's another component called the C one esterase inhibitor and a deficiency in this is associated with hereditary angioedema sounds a bit niche, but it has come up in exams before. Uh the more special tests are called the CH 50 and the A P 50 tests, which are these functional tests that can help you identify which pathway in particular is affected. So obviously, if you measure all the different complement levels that in itself will give you an indicator of which pathway might be affected. But also CH 50 and A P 50 will specifically tell you either this is a classical pathway deficiency or an alternative pathway issue. Remember which one refers to which it's literally the first letter of the test. So ch 50 for classical pathway A P 50 for alternative pathway and management all about proactively preventing and treating all of these encapsulated bacterial infections. So, pretty straightforward. Okay. Um Move on to the next question. Uh Here we've got an S B A. Uh This was literally passed paper question. Um So I'll give you a minute to answer this. Um All right. So let's see what you guys have put. Um So yeah, most of you have put low C one esterase inhibitor, which is the correct answer. Really. The reason I wanted to put this question is that it seems like quite a niche thing, but it's actually come up in the past. So if you are gunning for high marks and stuff and sometimes you do need to know these, these weird niche things, but it's not really the most important part of the complement pathway. Uh But yeah, just to go through these answers. C one esterase inhibitor is supposed to be preventing inappropriate, see one activation. So if you have a deficiency of it, you're going to get excessive activation of the complement cascade, which can then cause vasodilation in and that results in angioedema. That's why it's a feature of hereditary angioedema because if you remember with the complement cascade some of the fragments can, can cause increase vascular permeability. So having excessive complement activity can cause things like an gee edema. Um Obviously, it would be quite natural to mistake this for an allergy. So I think one person has put high mast cells, reasonable idea. But um actually the patient's had these episodes unprovoked in the past. So it's kind of less likely to be an allergy. Um A P 50. So ch 50 would be a useful test. Um A P 50 is irrelevant because it's a classical pathway that's being affected instead. Um And with see for a couple of people put high, see for reasonable suggestion. But actually, the C four is likely to be low because when you get excessive activation of the complement cascade, the components that are downstream and the pathway are going to end up being over consumed and they end up being, they end up being low as a result. Um So yeah, the answer here is low C one esterase inhibitor, but yeah, don't lose too much sleep. Oh This, it's quite a, it's quite an each question, for example. Um So here's a useful summary of how the different complement deficiencies tend to be described in our exam questions. Again. Hopefully, this will make sense when you look back at it later on. Okay. Um So that is our immune deficiencies done and that's kind of the main chunk of the lecture. Uh The last two parts will be relatively quick because a lot of this is is kind of 30 year stuff, you know, the conditions that will come across in 30 years. So it's a lot easier to understand, generally requires road, uh just a load of rote learning. Um So in the last section, we talked about having an underperforming immune system which will then struggle to fight off infection. In this section, we're talking about an immune system that will continue to fight even when there's no infection. So basically, it's gonna end up fighting with our own body. Instead, these diseases can be categorized as either autoinflammatory, which is where the issue is with the innate immune system. Obviously, the innate immune system doesn't produce any antibodies. So naturally, auto antibodies are not going to be a feature of these conditions. On the other side, they can be autoimmune, which is where the adaptive immune system is defective instead. And these patient's will have autoantibodies because obviously, our adaptive immune system comprises of B cells which produce antibodies. Um So that's kind of the easy way to distinguish between the two and then you have some diseases which are in the middle. So you have issues with both types of immunity. And here you do have HLA associations um like the HLA B 27 1, which will come, which I'll talk about that later on. But for some reason, they don't tend to have autoantibodies. So it's kind of halfway between autoinflammatory autoimmune. Um So on one end of the spectrum, we have these rare monogenic autoinflammatory diseases like familial mediterranean fever, which is where a specific mutation, a single mutation, we'll make our neutrophils go into overdrive and trigger this excessive innate immune response. And I have the notes after. So when you look at the size after one, I've detailed exactly how this happens in the notes. But honestly, for the sake of exams, if you become familiar with the words M E F V pyre in marin Estrin and stuff like that, that would probably be enough to figure out what they're talking about or to figure out that they're talking about this condition in the exam. So if you're really interested in learning exactly how uh FMF happens, then I'll leave the notes later on. But really the way it will present any exam question is that they'll mention kind of pirate marin Estrin or pyre in or an M E F G mutation. And as long as you're familiar with it, you'll go, yeah, it must be, it must be familial mediterranean fever. Then we have. So that was, you know, your rare single mutation, autoinflammatory diseases. Then we have more common autoinflammatory conditions like Crohn's and Ulcerative colitis, which may be associated with some mutations, but they're also influenced by lifestyle factors. So for example, um smoking worsens Crohn's disease. I'm sure that you will know that there's no such thing as a Krones or ulcerative colitis auto antibody. So that's how you can tell that these conditions are autoinflammatory rather than auto mean. And I've put the other examples of these autoinflammatory conditions uh there as well. Then you've got these, these mixed pattern disease and they're quite a few of them and a lot of them are associated with specifically this HLA B 27 mutation. The reason is that this um HLA B 20 mutation will affect both the CD eight cells, um CDA and th 17 cells which are both parts of the adaptive immune system. But they will also affect this mutation also affects our natural killer cells which are part of the innate immune response. So you can see that this mutation, you're getting this mixture of adaptive and innate uh immune cell defects. Um So yeah, the conditions, if you remember from year three, some of those HLA B 27 conditions include enclosing spondylitis, scoriatic arthritis and reactive arthritis. As well as I said earlier. The mixed pattern disease is often have HLA associations like this B 27 1 but no auto antibodies and that you can kind of, you know, you kind of know that because there is no such thing as an an closing spondylitis um auto antibody. So you do have the HLA association but no no auto antibodies in any of these conditions. Okay. Now, moving on to the autoimmune conditions and I'm sure you have heard a lot of, you have heard of all of these common polygenic conditions and hopefully you'll know the antibodies for them. So, I mean, you can put them in the chat if you're feeling keen but don't know if you're not. Um because they're palla genic, there isn't a specific mutation that's causing them, but they are influenced by multiple factors such as HLA associations. Again, if you can think in your head of what the HLA association condition of rheumatoid arthritis, etcetera is, then then feel free. But also you get these mutations with um these T cell regulation as well. Um So yeah, it's Paula genic, you've got this combination of factors which are associated with the development of the diseases. But all of these palla genic autoimmune diseases should be familiar to you and you know that auto antibodies are present in these conditions. Um So here's the, if you were thinking here are the important HLA associations for the autoimmune conditions. Um I mean, I didn't learn good pastures. One, I think generally most people were familiar with graves, Sle Taipan and rheumatoid arthritis. So it's worth learning. It's worth learning those age we associations, okay. And then finally, you've got these three really rare monogenic oughta mean conditions that you need to have learned this slide. I think it explains this app aside condition in as much detail as you need. But the general idea is that you're gonna have some bad T cells that managed to get through the process of thymus selection that we talked about earlier. And as a result, all of these bad T cells can cause a variety of autoimmune diseases. So specifically, I've listed them in the notes. You can get hyperparathyroidism, addison's and vitiligo as well. Those are the really kind of hallmark autoimmune diseases that occur in this condition. But it's a problem with the famous deleting autoreactive t cells, meaning that some of these faulty T cells go into the circulation and start causing autoimmunities. Another one of these monogenic conditions is I pecks. Um And even though this effects are regulated T cells instead of the thymus, the end result is going to be similar in that you're going to have these dodgy T cells that remain in the circulation and cause autoimmune disease. So in this case, it's diabetes, hypothyroidism and entra pathy uh which the autoimmunities, the key ones here. Uh But yeah, just this similar principle of bad T cells uh entering the circulation, causing autoimmune disease. And then finally, we have ALPS, which is kind of similar to apple's said in the, it's the famous failing to remove these dodgy T cells. But this time, it's for a different reasons. So with episode, it was to do with expression of self antigens in the thymus, meaning that the T cells aren't exposed to these different self antigens with alps. It's just that the dodgy T cells aren't able to be killed in the thymus which allows these dodgy ones um to enter our circulation society, different path physiology. But the same principle that it's an issue with famous selection. The main difference between these two conditions though, how they'll present in exams is that the patient's in ALPS can get lymphoma. So, within our acronym, um so the, the acronym for ALPS is um autoimmune lymphoproliferative that makes up the L and the P in the name. Um So that's probably gonna be mentioned if, if this condition comes up, in example, the patient has this um autoimmune condition. Uh But for some reason, they also have lymphoma as well, that should point you towards this, this particular condition. Um Okay. So moving on to the next question, this is a VSA so just type in what you think the answer is again, I'll give you a minute. All right. Keep them coming in. Uh just a few more seconds. All right. Um So good. Most of you put ulcerative colitis, which is the correct answer. Um Really what I want to show you with this question is that because path isn't all immuno, you have histo and all the other, all the other topics as well. Sometimes you get these sort of crossover questions. So it's really important to just be familiar. So I haven't gone into much detail about how these common year three conditions present, but just make sure you're familiar with that from, you know, your history lectures and stuff like that because the question will often be framed like this talking about the histology and stuff rather than just focusing on them, you know, aspects. So really the only immuno thing they mentioned here is that there are no auto antibodies detected that should naturally point you towards the fact that is an auto inflammatory condition. But then to actually come up with the diagnosis, you need to pay attention to the histology because it's a continuous inflammation that's confined to the rectum. And the colon that indicates that it's all sort of colitis as opposed to crone's disease, which would be more sporadic and can go all the way from the mouth down to the rectum. Uh Well, don't anyone who said all sorts of colitis and finally, we'll finish with hypersensitivity. Um And good, we're nearly done because I'm hungry. Uh This will be pretty great because it's pretty easy and there's not a great deal to learn about it. Um So hypersensitivity as a word is quite a broad on relative, which describes the immune system going into overdrive. And so this is going to encompass some of these autoimmune conditions that we've already talked about, which tend to fall within this type two category of hypersensitivity. But it's also going to include other situations where the immune system isn't attacking ourselves, but it's still overreacting to harmless antigen, for example, like an analogy. So, yeah, there is a bit of overlap between hypersensitivity and you know, these autoimmune autoinflammatory conditions that we've already talked about. This table, pretty much covers everything you need to know for um the different types of, of hypersensitivity. Uh But I'll just go through each one step by step um briefly anyway, so um type one hypersensitivity is referring to a two P and anaphylaxis. So this is where you have IgE antibodies being produced by plasma cells, they will bind to an antigen. And in the case of analogy, a harmless antigen, the IgE then cross links with either mast cells or basophils and triggers the d granulations of these cells. The release of histamine then causes absolute mayhem which I'm sure you will know uh from, from knowing about anaphylaxis. So that's all you really need to about type one hypersensitivity in exam questions they're talking about I G then instantly that should make you think about type one hypersensitivity with type two hypersensitivity. The idea is that antibodies are going to bind to antigens on the cell surface and then activate other immune cells like faga sites and natural killer cells through the FC portion. So in this case, as I said earlier, autoimmune conditions are usually a form of type two hypersensitivity where you've got these auto antibodies targeting our own cells binding to antigens on the cell surface and then causing those cells to die. You know, whether it's Goodpasture syndrome where you're targeting cells on the kidney and you're, you're causing them to die. Um you know, you know, quite a lot of other autoimmune diseases as well. So yeah, it's kind of um hopefully type two hypersensitive to make sense. Sometimes it can be confused with type three hypersensitivity in that both of these will involve activation of complement and inflammatory cells. But the key difference between the two is that in type three hypersensitivity, the antibodies are binding to antigens in the blood to form immune complexes. And then these immune complexes will deposit in blood vessels in various locations to trigger the inflammation. So for example, in sle which is the most famous example of type four hypersensitivity, you get these immune complexes forming, they can then deposit in the skin or in the kidneys and trigger inflammation there. And then that obviously causes all sorts of issues whether it's kidney failure, whether it's skin rashes and so on. So yeah, that's the key different type two hypersensitivity is about antibodies driving cell breakdown. Whereas type three hypersensitivity is all about antibodies forming the immune forming immune complexes by binding to soluble antigens. And then these immune complexes depositing in different parts of the body and triggering inflammation and causing causing damage like that. And then finally, type four hypersensitivity is also known as the delay type. So this takes longer to occur and it's the only one that's actually driven by T cells. So the main examples of this are going to be type one, diabetes, contact dermatitis and multiple sclerosis. And as you can imagine with all of these, these conditions progress over a period of time rather than use having this sort of sudden inflammatory response taking place. So yeah, just to quickly summarize, we go back to this table type one, if they mentioned I G E and mass cell degranulation and stuff like that, that that should point you towards type one, both type two and type three. They might mention activation of complement and faga sites and stuff. But the difference between the two is that in type two hypersensitivity, the antibody is binding to surface cell surface antigens and causing cell death. We type three, your antibodies are binding to soluble antigens in the bloodstream. Former mean immune complexes which then deposit in different parts of the body and trigger inflammation and then type four hypersensitivity one, it will be delayed to, they'll mention how it's t cell driven. Um So hopefully that comes up in exams, you've kind of got uh an easy way of distinguishing these four. Um So uh we've got a question here. Um This is literally like a past paper questions. So it should show you really how um straightforward the hypersensitive to your questions tend to be. I think it's the only hypersensitivity related question I've seen. So, um yeah, let's see what you guys come up with. Do you have a few more seconds? All right, good. Uh I'll show you the answer now. Uh Yeah. So all of you've got the right answers well done. Um And yeah, like say it's from past paper. So it shows that it's pretty straightforward what you need to know for this. Just have a general overview of um how to distinguish the four main types. Um So just going through them step by step. So binding to a cellular antigen, that's type two hypersensitivity. If you mentioned T cell T cell driven disease, then it's type four, it talks about I G E, then it's gonna be type one forming these immune complexes or in this case antibody antigen complexes, these complexes depositing and triggered inflammation that is type three hypersensitivities. That's correct answer. And then the last one is an interesting one where um that sometimes this is known as type five hypersensitivity or you can think of it as a specific form of type two hypersensitivity. So, again, the antibody's binding to a cell surface receptor, which is why you can think of it as type two. But instead of just causing the cell to be broken down or or killed, it's going to end up changing how the cell works. So the obvious examples of this would be grave's disease where you've got these auto antibodies stimulating um the TSH receptor in causing hypothyroidism. You're not destroying the thyroid gland uh but you are changing how it functions. Uh It's an alternative is myasthenia gravis where you've got these auto antibodies that are blocking your acetylcholine receptors and causing that neurological diseases result. So again, you're not destroying your, your, you know, your muscle muscle cells or anything, but you are changing how those muscle cells work. Um So that's what he's referring to. They don't really talk about it a great deal. Uh But anyway, importantly, all of you guys have got the right, the right answer there. So that is the end of the lecture, but I do have one more question left. Um So if you guys could fill in the feedback from now, I'll move onto the last question, but just uh before if any of you guys need to leave quickly or whatever, please fill this in or at least get it up and have it ready to fill out later on. I'll just give you like a minute to fill it out and then we'll do the last question also. If you guys have had any questions during the lectures and feel free to pop them in the child, I'll try and answer them all at the end. Uh Okay, just a few more seconds, then I'll move on. Um What? All right. So let's do this last question. Um So I'll give you a minute for another VSA so just, all right, what you think is this is a pretty tough question, but it is also very path in that. It's, it's all buzzwords and this is how like a lot of it will be. So I have some good answers coming in. Um, so you've had this, I think if this came up in the exam, it would probably be an S B A because it's a bit wooly to, to write out a clear answer for this, but just give it your best shot. Uh Yeah, thanks. Give you a few more seconds. Okay. All right. Um Cool. So, um, the correct answer is c three deficiency, the nephritic factors just um, some of you got this. So, so well done. Um We'll just go through it systematically. So, uh the first thing that's kind of, you know, quite important, um That should give you a clue is that the patient's had severe meningococcal septicaemia. So, as you said, manager coccus is one of those encapsulated organisms. So clearly, they've got this increased susceptibility to that. That could mean that they've had a splenectomy, but they probably mentioned that in the history as well. So, otherwise, if you have this susceptibility to encapsulated organisms specifically, that should point you towards a compliment, efficiency. That's the first thing. Um The next thing is hem a tree and protein you here. So just using 30 knowledge that suggests a nephritic syndrome. Um so we can think of glomerulonephritis. So we've got glomerulonephritis and for some reason, a compliment efficiency as well. And then we've got this abnormal fat distribution which is effectively describing something called a partial lipodystrophy. So, the combination of all of these things points towards this particular complement deficiency which is C three deficiency with nephritic factor. So it's a bit and ask the question and it will be easier if it came up as an SBA, which is probably what he'll be like in the exam just going through some of the other answers some people have put. So yeah, secondary complement efficiency is good, you know, when it's a VSA it can, you might not always be specific and they usually accepted range of answers. Um So yeah, this is a secondary complement efficiency. It's the nephritic factor causing excessive complement activation which then causes over consumption of C three. Um What else do people put C seven deficiency? I mean, it would probably end up in C seven deficiency and see some deficiency itself would cause severe manager cockle septicemia, but the addition of glomerulonephritis um and this partial lipodystrophy, that's what points us towards this nephritic factor um driven condition. Um And yes, C one Q inhibitor deficiency. So, C one Q deficiency would they probably present with lupus? So, a classical pathway deficiency um I think probably mixed, you've kind of mixed C one esterase inhibitor as well. C one esterase inhibitor deficiency. That's what causes are hereditary angioedema. Um But yeah, well done. Um most of you guys have got given really good answers throughout the lecture. Uh So hopefully some of that made sense. It's one of those things, you might just need to watch it back a bit slower later on um If you could fill in the feedback, that would be great. Um And thank you very much for coming. And if you have any questions, either you can email me after or you can put them in the chat and I'll try and answer them now. Okay. Here we go. Uh OK. So I'll just go back to that in Lupus. Okay. Yeah. So, um so the question is um explain the C three and C four, C four decrease um in Lupus. Okay. So basically, um there are two ways in which Lupus is related to complement deficiencies. First is if we have a primary deficiency of complement, a primary deficiency of um components of the classical pathway, then that can cause lupus. So, deficiency of complement can cause Lupus. So that's like one direction. And the reason for this is having the accumulation of immune complexes, having the accumulation of self antigens. So all of this um drives all of this, it makes you increase us more susceptible to sle in this case, if we look at the flow chart because we've got this deficiency of the classical pathway, um we're not actually gonna reach C four and C three in the complement cascade. So in this form of Lupus, the patient should have normal C three and C four levels because the classical pathway itself isn't going to happen. So you're not going to reach the, you're not kind of going to go all the way down the domino cascade to the point of consuming the C three and C four components. So that's the first way in which Lupus and complement are related. The flipside is if you have, if you have Lupus to begin with, lupus itself can cause a deficiency of complement and specifically, it can cause over consumption of C three and C four. So in this way, um you've got Lupus, you're producing loads and loads of immune complexes. All of those immune complexes are triggering are classical pathway causing the cascade to go into overdrive. And then you're going to end up over consuming the different uh complement components, especially C three and C four. So if you have a secondary complement deficiency, because you have lupus to begin with, then you can have low C three and C four levels. But if you have a compliment, a primary complement deficiency, which is causing lupus, then these patient's will probably just have normal C three and C four levels because the complement cascade is stopped kind of earlier on in the chain. Um It is a bit of a bullet to understand, but you don't really need to understand it for exams. I think the main thing is just going if it's a primary complement deficiency and they have Lupus C three and C four, be normal. If it's Lupus, that's then causing a secondary complement efficiency, it will cause low C three and C four. Okay. Next question. Um okay with, I'll 12 and gamma interfere on. Um, well, I need to check. Actually, I think I generally learned it as just I'll 12. I think it was more just if you have this failure of communication between macrophages and t cells then you're susceptible to both of those. But I'll just double check. Um, but yeah, you might just need to google it afterwards. Um, so interleukin 12 definitely makes you more susceptible to micro bacteria. Uh Yeah, I think salmonella infection is also associated with. I think it's both of them make you susceptible to both, both infections but to fair, they probably won't be that specific in the exam. I don't think they ever really refer to salmonella in the exam. It will usually be patient has normal cell counts and stuff normal pass but they have TB and you'll think, okay. This is probably a cytokine deficiency. Okay. Next question. Um The niche cytokines involved in case are maturation. Okay. So, yeah, so there's like a whole list of cytokines that what's the name? The the main immunology? Margaret Callan kind of puts on a slide. And you're supposed to technically know all the cytokines that trigger T cell development and all the sightings that T cells produce. I mean, I never learned them and it didn't really have any effect on my example from it's I don't think so. It's one of those ones you can just like cram the night before if you want, but I wouldn't spend too much time on it. Allergies, allergies comes up. Um Then we had questions on like specific I G uh skin prick testing and specific I G testing and things like that come up in the exam. Um So I think that that was gonna be covered in the next lecture. So things like immune modulating drugs and alert and hyper since like anaphylaxis and stuff, I think that's gonna be covered later on. Mine was just more to give a brief overview of hypersensitivity. But I think they go into more detail on allergies in the next lecture. Um Yeah, I'll hang on for a couple of minutes if anyone has any questions. But otherwise, um if you could just fill out the feedback and then you're free to go. Uh.