Good DVT prophylaxis running over here. All right, so let's just do this. So this is why I wanted to be late because I got impossible task to explain immunology in 15 minutes. Like if any of you studied for the USMLE and most of us did, you can understand the magnitude of my problem. I got already introduced. I have conflicts which are not really relevant to my talk. So let's talk about immunology. What we're going to talk about is, well, let's start understanding how the immunology works. Then the purpose of the talk is also to know how this relates to the ICU. And then maybe you can sort of talk about how we can change the landscape of the immunology. And actually, my subsequent speaker, we're going to talk much more about that. So what is the immune system, right? We start from the definition. And this is the definition that I pulled from the National Cancer Institute. And it pretty much says it's a complex network of the cells, tissues, organs, substances that helps body fight infectious and other disease, right? Sounds like a good definition. I think we all feel that this should be right. Well, except that this is the definition from 2013. Actually, that's when the website got updated, OK? In 10 years, a lot of things changed in medicine. And thinking about the immunology that only fights your infections is a very, very old thinking. And probably, it's not current. So if there's no good definition of the immune system, how should we define it? Should we use the structure? Should we use the function? The problem is that both of those axiomats of definitions are very, very diverse and heterogeneous. Second thing is immune system does not work in the vacuum. We do study often immune system this way. But it intersects with the metabolomics, intersects with the hormonal system, and intersects with the biome. So again, immune system cannot be isolated, like some of the organs probably can be, from surroundings and all the interactions. Now, one thing about the immunology is that everybody likes definition and calls something whatever creative name. So in preparation for this talk, and I was literally horrified to see that I'm the speaker for this, I was like, okay, let's just see what the people call what. So you have immune system, which is the system. You have immunity. Well, what's the difference between those two? Is it function, structure? How did they redefine? Then you have inflammation, another term that we throw all around during the rants hundreds of time. Well, what is precisely inflammation, right? So again, we use these words in almost inter-exchangeable format. I think most of the PhD immunologists would probably be a little bit horrified. Then I found something called idiosyncratic inflammation. There is also allergologists, which is always funny when I ask, can we define the immune system? And my fellow tells me, oh, let's call the allergology hematology. I don't know how often you guys call those consult for the problem with the complement, but they just look at you like we do cancer, or we do the desensitization, but we don't do your ICU stuff. So there's really no specialist over there, and the overlap is very, very illusoric. The next thing is there's something called a translational medicine. Well, whatever we do is supposed to be related to the patients. Translational from what? Mice, humanized mice, other healthcare problems. Again, big open thing. And then the one that I like most is, I find in one of the book, acute immunology. I guess it's acute and the chronic. Again, although definitions are imprecise, they add to the noise because you don't know the definition. So let's talk about the immune system function because that's the one way you can try to define it. So immune system maintains your homeostasis, and one of the function of that homeostatic balance is actually defense against the pathogens, but this is the one of many homeostatic function of the immune system. It has autocrine functions, all the cytokines that we produce, not only fight the bacteria, but also regulate our system. They have an influence over the hormones. So again, it's very, very precise system to regulate how we maintain our body together. It regulates, it induce the tolerance. Some of us in this room got sometimes pregnant. That means that you have actual allotransplant in your body, and your immune system was able to suppress immune system response to the foreign body de facto. Well, we don't think about that immune system actually plays role in that, but situation when someone is pregnant in NCU do happen. But again, is that immune system? Well, immune system has to make it happen. It induce the tolerance, and then it still is able to fight the infection at the same time. Then what else does immune system do? There's a lot of evidence right now that it actually helps with organogenesis, when you're being born and when you grow from the baby, but it's also critical for repair. Every time you get yourself cut and you have to grow the scars, you rely on the fact that the monocytes will go in that place, clean all the debris, secretes bunch of the cytokines, which will induce the fibroblast to produce the actual scar. Well, that's a tissue repair. Again, was that in the definition of the NCI? No, it wasn't. And then we have to think about the immune system as a source of the pathology. So we heard about autoimmune diseases. Everybody who has a TV opens the TV and hear the things about the anti-TNF antibody or anti-IL-3 antibodies. This is immunology in action. That also means that immunology in that particular diseases is the underlying source. We know all about the hypersensitivity. We talk about the allergy. Those are two different phenomena immunologically. They operate on the different levels and they rely on the different mechanism. And there's something called the immunosuppression, which sometimes called the allergy, and again, this is when immune system shows a different face of the performance that we don't really know how to interpret. When you think about the function, and this is one of the oldest things, we only think that immune system get either activated or suppressed. It's like one of the, I'm going to show you one of the old graphs. And there's a systemic inflammatory response that we're not supposed to use the term and then you have a curse, which is rebound. Well, that's a two-definition, that's a two-dimensional, so this is two opposite dimensions of the one thing. Well, the immune system is not one dimension, it's multiple the dimensions. And as I told you, so you can be pregnant, immunosuppressed, yet effectively respond to the bacteria. Because almost none of the pregnant woman gets sepsis. So when you think about the function performance, it's not only the direction, it's also which way and what do you define by the activation or suppression. Now, the other problem of the immune system is that it's extremely variable. So one thing, there's a difference between the species. If somebody does the research over here in mice, they discover around 2000, 2010, that whatever we do in mice works, whatever we try to do with these experiments in humans, it doesn't work. And I apologize, I exaggerated, that's not true. But we discover that there's a difference between those two. And we're very good vets, but we're not such a good doctors, right? So it's a question of the translation. Second thing, there's a genetic determinants. All of us are slightly different. Those genetic determinants actually describe how your immune system will perform. We have almost no way to translate that in the clinical realm. And the second thing is, even though we have the same genome, this genome or its activity evolve over the time depends on the different factors. And that makes us different from one day to another. You get the vaccine, this is not genetic mechanism, you just change your immune system performance. And we got just educated quite extensively about the COVID-19 vaccines. One thing we discovered, the R side effects, which means that immune system works slightly different than we expected, and that may happen if you do X amount of the vaccination. The second thing is there's a time dependent viability. Okay, I just ran from the third floor because I actually have a wrong room number over here. So my granulocytes are probably going crazy right now. In half an hour, they will be a little bit better, but also means that how do you measure that? And the variability is kind of interesting. This is a graph from one of the paper that we published many years ago. It shows something which we call potential of the monocyte to became dendritic cells. And this is an in vitro experiment. And I utilize for the experiment my nurses. They would draw the blood three months apart. And as you see, this CD1A is the marker that we use. So if you look at my nurses on the baseline, the variability, like average is what? 60 plus minus 40, right? That's a huge variability. You cannot do anything with that if you're trying to show something. But if you look at the time, that variability is much less. What does it mean that the nurse whose dendritic cells, monocytes can became dendritic cells are 30% worse than 75? We don't know. None of these people is, by the way, sick. So you see how redundant system works and can compensate each other. Now, let's talk about the organization. That's another way we can look at the immune system, right? So there are, of course, leukocytes. There are all those molecules that we talk about, the cytokines, chemokines, prostaglandin. They have all the numbers from one to, at this point, probably infinity or close to that. But we do not have a good concept how to figure out how those system interact with each other. And then if you go back to the NCI, the definition they talk about, the peripheral system. You can look, and I'm sorry for the font being small, but one of the problem is that there is 28 different monocytes types, like at least seven different T cells, helpers, and there's a bunch of the granulocytes. We do not know what to do with this data. But we do produce the paper who say that if you knock out TH17, your response to the gram-negative bacteria is better. I don't know how to translate this. So what I'm saying is that it's difficult to find the clinical relevance because we know very little about immune system because it's extremely complex. There's a bone marrow, there are specialized immune organs, and there's also local immune organs. We, right now, appreciate that there is a gut, which is probably one-third of the immune system sits there. We don't know what to do with that in the context of the clinical care. We're just discovering that. So the field is wide open. Now, when you think about the immune system, how it evolved in the individual over the time, you have a genetics, obviously, but it's environmental influences. We do know that the pollution affect the immune system to the greater degree. There's a lot of research about the diesel fumes and the diesel exhaustion, what it does with the immune system. So it's probably great to live in California and not so great to live in Italy when diesel is allowed. There's a diet, right, which has a huge impact of the performance of the immune system. There's a sleep and there's physical exercises. If you take all those determinants, at least three of them are profoundly perturbed when you're in the ICU. And how does it impact the immune system? Again, unknown. So then let's talk about what does the immune system do, and the way I did it is to decide to show a process, what happened when you're being invited by the bacteria. So let's just make it simple. Let's not test all the viruses or God knows what. You have a simple E. coli invaded you. So first of all, the bacteria has to invade you, and there's a bunch of the mechanisms which protect that. Skin integrity, pH of your stomach, epithelium movement in your airway, mucus, all of these things are the immunity defects. They prevent you from this NCA definition, which is I don't want to get infected. Well, some of them are going to be affected by the ICU's environment, actually most of them. And we do know that giving PPI nullify the acidic contents of the stomach with subsequent increase of the infection rates. Why is that? Because your acid is not more acid. That means the bacteria can grow, and then you have an infection in the airway. There are a bunch of the non-specific molecules. Again, field is wide open. People think how to apply this, but we always focus on only one or two variables at the same time. So let's just assume that your bacteria broke through our defenses. Well, you have to know that you actually have a bacteria in the bloodstream. If you don't see it, you don't know it's there. And we all heard about the toll-like system, right? It's a system which was discovered in the Drosophila originally. And people who did that discovery got a Nobel Prize or should get a Nobel Prize. But that's not the only system, which is the early warning system. There's a knot system, there's a rick-like receptor, there's a sea gas thing, all this and that. You don't have to memorize all of this. This is just show you that when you read some of the critical care review about the immunology, the landscape is much more richer. That also means it's much harder to actually study. Now, once you have a, when you have an invasion, what your body will do with this, right? Of course, you can have a defense and you'll get the inflammation, let's call it this way. But inflammation is the immune system response when you produce the second prostaglandins and you muster all the responses. That's what we call the inflammation. But you will have a pyroptosis. It means that your immune system actually is induced towards dying. And that's a little bit different ways of dealing with the bacteria. But pyroptosis is as, I would say, a legit way to respond to bacteria as possible. Now, you may be tolerant to the bacteria. How many of us have a patient in the ICU who has a bacteremia and doesn't have a fever? Well, there's some kind of interaction between those two system and suddenly we can live, live happily sometimes for a couple weeks and it is what it is. So not always you respond with the pyroptosis. You do not always respond to the inflammation. There's something which determines that. It's actually not really well understood. All right, but you will decide to respond. So the first response of the immune system is this response based on the innate immune system. And that's a term that you will hear here and there and it's a more definition what happened, not how it happened. Most of the time definition is done because something binds to the toll-like receptors which recognize a common motif of the bacteria like LPS or flagellin or CPG, which is the viral molecule. And it happens that all those patterns looks the same across variety of the pathogens, which means I don't know what this is E. coli, but I do know it's a gram-negative bacteria. So what happened now, once I see that, I can respond very, very quickly. I don't need to do any recognition. I just need to know that there is somebody trying to steal my food from the house. Okay, and that's how these responses work. They're fast, they're non-specific, they're robust. However, they only are scalable in the linear fashion. You can get twice, four times, six times, eight times, but that's pretty much what you get from those. Okay, they're also inflexible. If invasion is done by viral particle, the toll-like four receptors will not see it. Okay, so the recognition of the molecule and flexibility is going to be limited. And because they're also inflexible and a little bit blind, there's also this potential for the collateral damage. Right, so again, there's somebody in my house who's trying to steal the food. I'm going to flip all the lights. My grandma will wake up as a side effect, right? That's how this system works. Okay, mechanism, well, it's based on the very primitive or very conservative mechanism. Conservative means that me and shark and the plants may actually share it. Okay, but those mechanisms are very effective. And by the way, one of the most common mechanism, NF-kappa-B and if you ever work in the ICU, you did use the steroids. That's what the actual steroids do. They turn off the NF-kappa-B, one of the most potent system to respond to the bacteria. But let's move on. So we have this innate immune responses ongoing and your immune system at the same time is trying to learn because there is a two actual part of the immune system, innate and acquired. Acquired means that I'm trying to actually figure out who precisely is in my house so I can call him by name and maybe he will pay attention. And there's a whole process behind it when we as a body, we look for the peptides which circulate, we grab those peptides. Those peptides are part or particles are part of the bacteria or the pathogen. We very skillfully process them and then what we do, we expose them back. Okay, this is magical mechanism because this is what we share from the shark app but nobody else has. That means we produce millions of the keys trying to find this one key which will feed the bacteria. This is called acquired immunity, all right? Benefit of that is that it's logarithmic response. It's extremely precise. It turns off the innate immunity limiting damage but it does takes a time. The way we shorten that time is by giving the people vaccines. All right, we're almost done. So what happen after all this response roll for you in the three days when you have a flu or the UTI? Well, you have to deactivate the system. If your immune system keep being activated, it will eventually kill you. HLH is the disease when you don't have a deactivation. Then what happen is you may have repair your body. That's the next thing you see. You might have a memory of how you should, it's good to remember who was in my house but then you can have abnormal resolution of that process and some of our patients have this perpetual inflammation or some kind of process that is difficult to define but their immune system does not want to switch. So that's how you response to the bacteria. Taking this together, that's how it looks like. You're vulnerable, you have invasion, there's a first stop by the innate immunity. Innate immunity gives the time for your body to learn what it should be done precisely. Acquired immunity emerges and switch everything off and hopefully we all come by after that. That happens a lot of time but in the ICU not so often. This is the most common graphs that you will see. I just redid it. That means there's activation, deactivation, three different fields that this can land. What I would suggest on this graph, it's a unidimensional graph and the immune system response is not unidimensional. It can go in all different direction. And by the way, this description what I tell you is only applied to the bacteria. How we respond to the viral, protozoa, foreign bodies, autoantigens, dampened vaccines is different and we don't know very well how to apply that knowledge. Almost done. Taking to this new level, all of this, what you need to remember from that quick talk is that immune system is extremely redundant. It's very, very diverse and because of those two features, it's very, very robust. What makes us, what makes this complicated for us, we do not understand immune system because you have a two very complex system. All right, we're not going to talk about dysfunctional immune system. This is for you guys to know that the other functions do exist. Again, I have 15 minutes. I was already being told that I should shut it up. Okay. But what you should leave this lecture with is immune system is problematic. It's difficult to wrap your hand, to what is happening when there's a patient immune system. Okay, there's only few absolutes. If you measure the IL-6 levels in the ICU, please tell me what is the normal level. Two, 12, it's almost sounds like a steroids situation. By the way, IL-6 is critical for you to make the B cells produce immunoglobulins. So every time you give the antibodies, you just make less immunoglobulins technically. Okay, understanding is very immature and application is point of care for procalcitonin or some other markers. How this translate to anything, I'm not exactly sure. So very complex issue. The good thing is you can pick up any of these elements and do your PhD and career out of it. The field is wide open. Okay, I would like to thank you, people who invited me over here. Also, you see the staff of my lab. The youngest one is my kid. I have no problem using him in the lab. And thank you very much for all the sponsor of my research. Thank you very much.

immune system

intensive care units

complexity

homeostasis

terminology

research