PL1003 Topic 4: Introduction to the Immune System PDF

**[Introduction to the Immune System]** Slide 1 ------- In this lecture, I'm going to give you a basic overview of the immune system, a useful framework to return to as you learn more detail about different individual components of the immune system in subsequent lectures. Slide 2 ------- These...

**[Introduction to the Immune System]** Slide 1 ------- In this lecture, I'm going to give you a basic overview of the immune system, a useful framework to return to as you learn more detail about different individual components of the immune system in subsequent lectures. Slide 2 ------- These are your Learning objectives. What I'm going to do in this lecture is incorporate these concepts into a broad overview of how an immune response is generated from the first point of infection, to elimination of the infection by the adaptive immune system. Slide 3 ------- Before we start, I think it's worth acknowledging a couple of issues that students commonly encounter when studying immunology. The first issue is represented well by this image -- each component of the immune response is interconnected with a wide range of other components, and we need to know about each of them to understand the immune response as a whole. The second issue is the jargon.... It often feels as if we are talking in a series of incomprehensible letters and numbers! Slide 4 ------- So what am I going to do to try and help you with this? I'm going to start by giving you a broad overview of how an immune response develops, to give you a big picture overview. Then, in subsequent lectures, I'll start to fill in some of the details that will be relevant to you as pharmacy students, but will aim to stay relatively light on the molecular detail. It is the broad concepts that I want you to understand here. In the final lecture of the series, we will talk about the growing field of immunotherapeutics, which is likely to be an ever expanding part of your professional life as pharmacists. You'll have access to plenty of quiz questions to test your understanding, but please, if you start to feel lost, just ask! Either on the Padlet, during the lecture, or by email. Slide 5 ------- Often the first thing we think of when we consider the function of the immune system is protection of the host from pathogenic microbes. Those might be bacteria, viruses, fungi or parasites. And the immune system has evolved a variety of different mechanisms to deal with each different type of infectious threat. Also important are the ability of the immune system to remove cancerous cells and to maintain tissue homeostasis by removing dead or damaged cells, and promoting tissue repair. Slide 6 ------- Let's consider the role of the immune system in protecting against infection. The host has three main layers of protection. Physical/Chemical barriers, the innate immune system, and the adaptive immune system. Each of these barriers consist of both cells, and molecules released by those cells into the extracellular space. First there are the physical and chemical barriers that line the body's surfaces. So the skin, the respiratory tract, the urogenital tract, the gastrointestinal tract - all of those are lined by an epithelium. These epithelial barriers take different forms. The example here is of the epithelium in the gut. That\'s just a single layer of cells all held together by tight junctions that form seals between the cells, providing a physical barrier against the external environment, and against microbes in that external environment entering the tissue underneath.Epithelial cells also secrete host protective factors into the extracellular space. For example, specialised epithelial cells produce mucus that forms a sticky barrier to prevent microbes coming into close contact with the epithelium, leaving it vulnerable to infection. Epithelial cells will also produce a variety of factors that have direct antimicrobial function. If that physical barrier is breached - so you have some damage to the skin or maybe you encounter an invasive pathogen like *Salmonella* - then you\'re going to need to evoke the innate immune response. The innate immune response is very rapidly acting but quite non-specific. Some of the key cellular mediators of the innate immune system that you may have come across before are macrophages, neutrophils, dendritic cells. Again we\'ve got more soluble mediators. So things like cytokines, complement, acute phase proteins and antimicrobial factors. We\'ll talk about each of those in more detail in this lecture, and the following lecture on innate immunity. What if the innate immune system can\'t cope on its own? Then we need the development of an adaptive immune response to bring the infection under control. The cells that make up the adaptive immune system are the T cells and B cells. Again there are soluble mediators of protection, B cells and T cells can produce cytokines -- these are just small protein messengers between immune cells - and B cells produce antibodies. Slide 7 ------- This table compares the innate and adaptive immune responses. Why do we need both of them and how are they different? So the innate immune system is always poised and ready for an immediate response. Cells of the innate immune system are always present at the body surfaces ready to detect an invading pathogen, and so it can respond to infection rapidly - within minutes to hours. And that\'s what you want. You don\'t want to give a pathogen time to spread from the initial site an infection or to replicate too much and start to use up the body\'s resources or damage tissues. To achieve that rapid response the innate immune system is by nature relatively non-specific. All the innate immune system is recognizing is common molecular patterns among classes of microbes. So for example, it might recognise molecular patterns that are common to bacteria that you don\'t usually find in the host. Things like Lipopolysaccharide in the outer membrane of gram negative bacteria, or bacterial flagellin -- these are things we wouldn't normally expect to see in a host tissue, and your innate immune system can immediately recognise that and response. It has little or no memory. So the second time it encounters the same pathogen it is going to respond in broadly the same way. Because of that it doesn\'t get any more effective upon second exposure. The adaptive immune system functions quite differently. That requires priming by antigens. What do I mean when I refer to antigens? I'm going to define that for you now, but will come back to the concept in a bit more detail later on. So an antigen is basically a molecule, usually a protein or peptide, that can be recognised or detected by T and B cells, leading to the generation of an immune response. It is important to understand that each T or B cell will have a receptor on its surface that recognises only one antigen. In other words, the adaptive immune response is highly specific. Your adaptive immune system requires priming or activation by these antigens. There are billions of different antigens that our immune systems could encounter, and it takes time to find the right T or B cell, specific for that particular antigen, and for that T or B cell to proliferate and generate multiple copies of itself. Because of that, the adaptive immune system responds a lot more slowly -- in the order of days to weeks. It is however highly specific. While the innate immune system just recognises broad molecular patterns that occur across whole classes of microbes, the adaptive immune system recognizes unique antigens. For example a short peptide in the spike protein of SARS-CoV2. The adaptive immune system has a memory response, so it can remember the previous antigens that it\'s seen. And because of that it becomes more effective with repeated exposures to the same pathogen. And that memory response is the basis of vaccination, which I'll return to later in the topic. Slide 8 ------- I'm now going to introduce you to some of the key players in the immune system, before I take you through the generation of an immune response. These are your main categories of innate immune cells. So first we have the sentinel cells. They include mast cells, dendritic cells and macrophages. These are tissue resident meaning they\'re present in the body\'s tissues -- so the skin, or the intestine - at all times. Even in the absence of infection. And their job there is to recognize invading pathogens as soon as they invade that tissue and then to alert the rest of the immune system that that has happened. Next we have the phagocytes, including neutrophils, macrophages and dendritic cells. These can be either tissue resident - already present in the tissue before infection -- or they can be called in from the blood in large numbers after an infection has taken place. And their job is to then engulf and kill the invading pathogens - we call that process phagocytosis. Dendritic cells have a particularly important role to play here - they will then process the antigens from that pathogen and display them on their cell surface. And that helps to alert the adaptive immune system. So the dendritic cells form the bridge between the innate and adaptive systems. And then over there on the right you\'ve got your innate lymphoid cells or ILCs. They can be tissue resident or recruited from the blood in response to infection. They have got a number of different jobs. You have your natural killer or NK cells. Their job is to kill infected or cancerous host cells. And the other ILC populations produce cytokines -- small protein messengers -- that allow them to communicate with other cells of the immune system and dictate what type of immune response develops. Slide 9 ------- The main cells of the adaptive immune system you might be more familiar with. So we have two types of T-cells. You\'ve got the helper T-cells and the killer T-cells. The way that we identify them is by expression of these proteins on the cell surface. So helper T cells express a protein called CD4, so you might hear them referred to as CD4 T cells, and killer or cytotoxic T cells express a protein called CD8. Helper T cells as the name suggests can help other immune cells to do their jobs - help B cells to produce antibodies, help macrophages to kill ingested pathogens. Cytotoxic T cells can kill host cells that are infected with intracellular pathogens, so for example viruses. On the other side you have your B cells. Their job is to produce antibodies, and as we\'ll see as we go on those antibodies have a variety of different protective functions. Slide 10 -------- Here are the soluble or extracellular mediators of the innate and adaptive immune systems. Some of these are shared by both the innate and adaptive systems, in particular the cytokines. Slide 11 -------- What are cytokines? Cytokines are a family of small proteins used for communication in the immune system. So we\'ve got lots of different types of immune cells. They all need to talk to each other to tell each other what the nature of the threat is. Are we responding to a bacteria? Are we responding to a virus? And cytokines are the way that they do that. So they\'re basically the language of the immune system. So when one immune cell receives a stimulus -- for example it might detect a bacterial molecule -- it begins to produce cytokines and release them into the extracellular space. Other cells have receptors for these cytokines, allowing them to respond to the cytokine, and change its own activity or function to deal with the infection. So, in this way, this cell that senses infection, can communicate the presence of the infection to a variety of other cell types in the body, allowing them to respond accordingly. Slide 12 -------- The innate immune system relies heavily on the complement pathway. That\'s just a system of plasma proteins that can be activated in response to a pathogen entering the body. And once that system of proteins is activated they have a number of different jobs such as direct lysis of bacteria, recruitment of immune cells, or they can decorate the surface of bacteria to help them be taken up (eaten) by phagocytes and destroyed. Antibodies are the other key secreted component of the adaptive immune system. Slide 13 -------- So that's a very quick tour of the key components of an immune response. Don't worry! We'll come back to them all in more detail over the next few lectures. What I want to do now is fit all these things together for you, to form a story of how a protective adaptive immune response is generated from the moment the pathogen enters the body. Slide 14 -------- You'll hear my version of events, but I think it\'s useful for you to go and look at some of these animations too. It\'s always nice to hear things presented in a few different ways and something here might resonate more with you. The first animation in particular is really useful because it gives you a very accurate description of how an immune response is generated without using too much jargon or terminology. So that could be a very useful revision tool for you, if you go back and try and write a new voice over for that animation, that DOES use all of the correct terminology. Can you use the knowledge acquired during this lecture to figure out which processes, cells and molecules are being referred to in the animation? Slide 15 -------- Let's use the intestine as an example. Here you\'ve got the epithelial cell layer that forms a physical barrier between the external environment -- the lumen of the intestine where you have food, microbiota, waste -- and the internal environment -- the host cells and tissues. These are the epithelial cells. They\'re all held together by tight junctions and they\'re producing things like antimicrobial peptides and mucus which help maintain this physical separation between bacteria living in the intestine and the immune system underneath. We want to maintain that physical separation because if we were constantly activating the immune system at high levels, we\'d use a lot of energy and pretty soon get exhausted and very damaged tissues. Let\'s just assume that we have a bacteria ingested in contaminated food that is particularly invasive and can cause some damage to the host epithelium and access the tissue underneath. Sitting under the epithelium you have your sentinel cells -- macrophages, dendritic cells, mast cells - and these are present in the tissues all of the time ready to sense immediately when an infection has taken place. Slide 16 -------- How do they recognize that that an infection has taken place? On the surface of each of these sentinel cells there are lots of different receptor molecules, and we call these receptors pattern recognition receptors or PRR. And what they can recognize are pathogen associated molecular patterns or PAMPS. Those are molecular patterns that are common to groups of bacteria or fungi or viruses, but which are NOT commonly found on host cells. So things like LPS, or flagellum or viral genomes. The other thing that they can recognize are *damage* associated molecular patterns, or DAMPS. These are host molecules that are released from dying host cells or as a result of damage to host tissue. So they\'re normal molecules that are always present in the human host, but the immune system wouldn\'t normally be able to *see* them because they would be hidden in a cell nucleus or in the cell cytoplasm. When these are released in large quantities, the immune system knows there is damage to the tissue, and responds. This is really helpful for pathogens that look more similar to the host, or hide well from the host. Each individual sentinel cell expresses a variety of different pattern recognition receptors. So this one macrophage might be able to recognize bacterial LPS, bacterial flagellum, viral double standard RNA, and an array of host DAMPS. Recognition of PAMPs or DAMPs by PRR leads to activation of immune cells. This includes things like inflammatory cytokine production to alert the rest of the immune system, enhanced ability to "present" or show antigens to the adaptive immune system, and the internalisation and destruction of pathogens. Slide 18 -------- Once the sentinel cells recognize that an infection is present, they become activated, and they have two main jobs. The first is to directly destroy that pathogen. And the second is to initiate an inflammatory response and alert the rest of the immune system. Slide 19 -------- So the first thing that can happen is the macrophages and also the dendritic cells can ingest and destroy the pathogens through the process of phagocytosis. So this is a very general overview of the process of phagocytosis. It\'s initiated when cell surface receptors bind to components of the pathogen surface directly or to opsonins. So opsonins are host molecules, for example antibodies, that coat the surface of the pathogen, and allow it to be more easily recognized and taken up by phagocytes. So once that initial recognition event takes place, the pathogen is then surrounded by the plasma membrane and internalized into a large vesicle called the phagosome. And the phagosome becomes acidified and it will fuse with lysosomes (these red dots here) to generate a phagolysosome. Then the contents of the lysosome will result in destruction of the pathogen. And once the pathogen is destroyed, then spits out, or exocytoses, the soluble debris. Slide 20 -------- This video shows macrophages phagocytosing bacteria. The small rod shaped things are the bacteria. These are the macrophages. What you\'ll see is that the macrophages are probing their environment and sampling what\'s around them when they make contact with the bacteria they\'re going to attach to using specific cell surface receptors. Then they\'re going to engulf the bacteria take it up into the cell and start to destroy it. Eventually, they will just spit out all of the digested debris from the bacteria into the tissue. Slide 21 -------- Their second job is to alert the rest of the immune system. When a sentinel cell becomes activated following recognition of a PAMP or DMAP, they will start to produce cytokines, chemokines (small molecules that attract immune cells to the site of infection), and vasoactive molecules (molecules that act of the blood vessels). And they start to secrete these molecules into the extracellular space. Slide 22 -------- What happens next? The cytokines will act on other immune cells locally, activating them. They will also leak into the blood stream and act systemically to produce fever, and to drive the production of acute phase proteins in the liver. They act on the blood vessel endothelium to make it more permissive to entry of immune cells into the infected tissue. The chemokines help with this to, directing recruited immune cells to the site of infection. Finally, the vasoactive molecules act on blood vessel endothelium leading to dilation or widening of the blood vessels and increased vascular permeability. And that allows fluid, proteins and inflammatory cells to leave the blood and to enter the tissue to deal with the infection. Slide 23/24 ----------- The result of all this is what you\'ll recognize as the cardinal signs of inflammation: heat, redness, swelling, pain and loss of function. Slide 25 -------- I mentioned that one result of the activation of sentinel cells is the recruitment of more immune cells from the blood to the site of infection. The first immune cells to arrive in large numbers are the neutrophils. You can see this process happening in real time in this video. This red and blue structure is a blood vessel in the muscle of a living mouse. The green cells are neutrophils -- the mouse has been genetically engineered so that the neutrophils express a green fluorescent protein and can be visualised on a microscope. Out here is the muscle. That\'s not empty space, its very tightly packed with cells, but they haven't been labelled so we can't see them. What the researchers have done is to inject an inflammatory stimulus into the muscle of this animal and we\'re going to watch what happens. Normally your neutrophils are just flowing through the blood in large numbers. After injection of the inflammatory stimulus you can start to see them squeezed between the blood vessel endothelial cells and out into the tissue. You have a few pioneer neutrophils and then they start to migrate out in large numbers ready to deal with whatever infectious threat is present in the tissue. Once the neutrophils arrive in the tissue they\'ve got three main jobs to do. They also get involved in phagocytosis and destruction of pathogens. They can also degranulate. They have these pre-formed granules that are full of antimicrobial, cytotoxic, proteolytic and other molecules, and they can release the contents of these molecules into the extracellular space to kill microbes. But that\'s quite a dangerous move. It\'s quite destructive to our own host tissues as well and must be tightly regulated. They can also form NETs or neutrophil extracellular traps. Those are just webs of DNA fibers decorated with all of these antimicrobial molecules from the granules. The NETS have two functions: to physically trap the pathogens and then to use the concentrated antimicrobial mediators to destroy and kill them. Slide 26 -------- We brought in large numbers of neutrophils and together with the macrophages they're doing a pretty good job of containing the pathogen. But it\'s quite non-specific. It\'s quite destructive. We need to also alert the adaptive immune system. The key bridge between the innate and adaptive immune systems is the Dendritic cell. Dendritic cells can also recognise take-up and degrade pathogens through the process of phagocytosis, but they degrade protein antigens into short peptides, and then takes those peptides and displays them on its surface. The dendritic cell then leaves the site of infection, and travels through lymphatic vessels to the nearest draining lymph node, where they can present these peptide antigens to T cells. So you will hear dendritic cells referred to as "Antigen Presenting Cells" or APC. Slide 27 -------- Here you can see the dendritic cell arriving in the lymph node from the infected tissue. Each T cell will recognise a different antigen -- we'll talk about that in more detail a bit later. T cells are constantly passing through the lymph nodes looking to see if the antigen that they recognise is present. If a T cell sees its antigen presented by a dendritic cell, it will become activated and start to proliferate, generating thousands of T cells specific for that same antigen, so all useful for fighting the same infection. Slide 28 -------- What do the T cells do next? If it is a helper T cell it might go and help a B cell to start producing antibody. Slide 29 -------- Then the T cells and the antibodies are going to return from the lymph node to the site an infection to eliminate the pathogen or infected cells. If you\'re a helper T cell, you\'re going to release cytokines that activate other immune cells. And the most important thing here is to activate the macrophages further to help them do a better job of killing the pathogens they phagocytose. If you are a cytotoxic T cell you might directly kill host cells that being infected with viruses. If you're are a B cell you\'re going to start producing buckets of antibodies. And those antibodies can do a number of things: they can bind to and neutralise pathogens, they can enhance phagocytosis of pathogens, and they can activate the complement cascade, which we'll hear about in the next lecture. Slide 30 -------- Summary