Hi, my name is Ira Mellman. I'm a scientist at Genentech, which is a biotechnology company here in San Francisco. I study cancer, but I also study the immune system, so I'm happy to be here today to tell you something about the immune system, what it is, and how it works. It is really not as complicated as a lot of us fear. Now, what is the function of the immune system? Now, it turns out that in our daily lives, we are surrounded by a wide variety of pathogens. Bacteria, viruses, other little organisms that cause an almost limitless number of infections in us, in humans, and we need to be protected against these environmental pathogens and toxins that they make on an almost continuous basis. Every time we breathe, we take in bacteria or viruses, every time we drink or eat something also, we have the potential of taking in viruses and bacteria, and obviously we don't get infected and sick as a consequence of just daily life on a routine basis.

And the reason that happens is because we have immune systems to protect us against all of these pathogens and toxins. Now, the immune system has to work in a very special way though. Although it's very powerful at being able to rid us of all sorts of noxious organisms, it has to be able to understand who is foreign. In other words, who are the pathogens that are trying to infect us, and distinguish those pathogens from our own cells. So, all of this has to occur without avoiding injury to the host, which is us. To do that, what the immune system has to do, and this is the complicated part, is to distinguish self from non-self. In other words, distinguish the invaders from that which it is trying to protect, which, again, is us. So this is a very, very important feature of the immune system, and means that it's actually really highly specialized. And in many ways, really smart to be able to tell the differences. And I'll touch on some of the ways in which the immune system does this.

Now, it turns out that all multicellular organisms have immune systems, whether they are animals, humans, fish, insects, or plants. The degree of complexity of the immune system, as you go through different types of organisms that you find on earth, is entirely different. Where, you know, humans and dogs and cats have much more complicated ways of protecting themselves than do plants and insects. But nevertheless, the same basic principle is conserved throughout evolution, and in fact, you can find even the most primitive types of immune responses and immune systems that one can see in even organisms as simple as insects, and also playing a very, very important role in protecting us against the very same pathogens that insects have to be protected against. Now, as I said, immune response is complicated, yep, that's true, but it's really not that much more complicated than anything else in biology. And if you break it down in terms of the cells that are involved, that actually make it work.

it's a lot easier to understand. Now, it is important to understand, not only because, as I already told you, on a day-to-day basis, we have to protect ourselves against invading pathogens, but also many, many important diseases, such as infectious disease, as we've already been discussing, or AIDS, or asthma, or lupus, autoimmune disorders, or even cancer, and various allergies, are caused by breakdowns, or at least are aided by breakdowns of the immune system, and as a result, in order to really understand the basis for these diseases and understand their biology, we have to know something about how the immune system works. So, what is the immune system anyway? It's very, very simple. In very, very simple terms, it's a system of specialized cell types that are mostly derived from the bone marrow. I'm sure all of you know what the bone marrow is, especially in long bones, such as shown here. You find a factory of cells that produce many, many types of cells that are found throughout the body.

These are called, in the first instance, the most popular and populous of them are called lymphocytes. Which come in two basic flavors, T cells and B cells. There are also cells known as macrophages, and dendritic cells and monocytes, and K cells, granulocytes. Each one of them has a very, very specific function in helping us to protect ourselves against invading pathogens. All of these cells together are called the immune system, and they're found all over the place. So, they may form themselves in the bone marrow, but they then span out through the blood and into virtually every tissue that we find in the body. Here, what you're looking at is a picture of skin, which has one type of immune cell in it, called a dendritic cell, which basically sits in the skin waiting for invading pathogens to come. For example, after you cut your finger or something like that, a bacteria will enter into the cut, and that bacteria will be detected and recognized by the dendritic cells.

The dendritic cells, as I'll show you in a minute, will leave the skin and then migrate elsewhere, through a system of little tubes and vessels, totally separate from your blood vessels, but basically doing the same sort of thing. And this is called the lymphatic system, or lymphatic vessels. These are small tubes, as I said, that are found literally everywhere. Lymphoid cells enter into the lymphatics and start migrating. Where do they go? They migrate and then congregate in a series of small lymphoid organs. Well, some of them are not so small, like the spleen, which is found in your abdomen, but the small ones, and in fact probably the most important ones, are called lymph nodes. Now, lymph nodes are little aggregates, and I'll show you this in a minute, of cells of the immune system that have very, very special functions and very, very important activities to perform, but you can find them on yourself throughout your body.

on your arms, legs, chest, everywhere else. But probably most typically, if you just feel on your neck, particularly after you have any type of an infection, such as a sore throat, you can find these little bumps that are there. And I'm sure you probably many of you know that these are lymph nodes, but this is basically what they do. They're just not there sitting there. They're actually all connected together in a very complex system that is again totally parallel to what's going on in the blood. So, they really exist only to transport cells of the immune system from your peripheral tissues, from your fingers, back to the lymph nodes where they can find other types of immune cells. Now, this is a blow-up of what actually happens in a lymph node. Precisely what happens here at the moment is not really important, but I want you to look at is the fact that you see a great and high concentration of all different types of cells of the immune system, particularly lymphocytes and dendritic cells.

that all are talking to each other, and basically what they do is they are communicating and trading information on what they encountered in the tissues: what types of pathogens were there, and decide among themselves essentially what to do about them. So, these are centralized processing centers in which information about invading pathogens is communicated to different cells that have different functions than actually mounting a protective response against a particular pathogen type. Now, the immune system system consists of two interconnected arms that we call the innate immune system and the adaptive immune system. Innate immunity is the most evolutionarily ancient and is found in insects. In fact, it was first found in insects and is responsible for detecting components that are shared by virtually all pathogens. So, although there are many, many different types of bacteria, they do have a lot of very fundamental things in common, and the innate immune system evolved to be able to recognize those things that are fundamentally the same from one bacteria to another or from one virus to another or one protozoan parasite to another.

Regardless of what their species actually is, the adaptive immune system, though, recognizes those things that are really very specific and very special to an individual pathogen, and requires a greatly more amplified and complex series of events to take place at the cellular level in order to allow that type of specificity to take place. These two systems work very, very closely with each other, hand in glove, and how they connect one to the next has only recently been worked out. It turns out to reveal yet another fundamental part of the immune system, which is the missing link between the adaptive and the innate immune responses, and we'll get to that just in a minute. But just to give you a hint, that's what dendritic cells do. Now, our understanding of how the immune system works really dates back into the 19th century, really to the work of two scientists. The first of whom is shown here. This is Ellie Metchnikoff, who really made a very, very important conceptual understanding.

which is that when you see an infection, particularly infection that would occur in the skin, the swelling, and the redness, and the heat, and the pain, and all of this stuff that occurs, that we know is characteristic of infections, is not really an indication of tissue being destroyed, but actually is an indication of the immune system, particularly the innate immune system, trying to do its job, and trying to kill of the invading bacteria. One of the cells, and perhaps the most important one, that Metchnikoff found is the cell called a macrophage, and this is one of his original drawings showing what a macrophage looks like. You can see a cell with these long tentacles hanging off the ends of it, plus a lot of structures inside the cell, some of which are colored red, which are actually the intracellular destructive bodies that are to a very large extent responsible for killing and then destroying invading bacteria. And all of this Metchnikoff found out just with very, very crude microscopes.

and very, very simple techniques. In fact, probably a lot simpler than what's available now in even junior high schools and high schools everywhere, he was still able to work this out. As I said, microorganisms such as bacteria are recognized by macrophages and they are killed. They are taken up, they're ingested by macrophages, and this process all enhances the protective immune aspect of what macrophages do and starts the process of inflammation. Inflammation is really the process whereby one cell, after detecting a pathogen, signals to its neighbors that there's something going on, and as a consequence, more cells come in to help out. Part of the reason that inflammation takes place is because the act of killing bacteria involves a lot of agents that really serve as signals that attract other cells of the immune system. So, I've listed some of the more important ones here. Cytotoxic agents occur so that macrophages can make large amounts of hydrogen peroxide, which actually is quite effective at killing most bacteria.

They secrete enzymes or expose the bacteria to enzymes that will degrade the bacteria themselves, and then also, finally, they will release these inflammatory components. Which in the business we call cytokines, that are small proteins or hormones that are released by the macrophage, rather, that attract other immune cells to the site. Now, why is it that macrophages and in fact other similar immune cells are able to do all of this? How can they even know when a bacterium is present, so as not to turn on all of this inflammatory activity when only normal host cells are around? Well, that's because they have a series of receptors on the surface that are really very specialized for being able to understand when bacteria are present. These are called Toll-like receptors, which, rather interestingly, were first discovered not because they had anything to do with bacteria, but because they had something very important to do with the earliest stages of fruit fly development. And so these are some images of just what a developing embryo of Drosophila looks like.

that has mutations in Toll receptors, and you can see a normal one in panel A, up on the left, showing what a normal embryo should look like at this stage. And here, down in the lower right, you can see a mutant embryo that is not able to form because it's absent of this Toll receptor. But by performing genetic tricks, you can actually get these embryos to form real flies, and these real flies are defective in Toll receptors. And what you see when those real flies grow up is something like this. So, here you have a Drosophila blown up at a very high magnification using something called a scanning electron microscope. And Drosophila don't normally have hair or beards in quite this way. What you're looking at here is a very serious fungal infection that this fruit fly could not fend off against because the fly is defective in one of these Toll receptors. This is one of the earliest indications that Toll receptors are important in fly for being able to protect them against fungal infections. And indeed, as it turns out, other infections as well.

Turns out that Toll receptors. This is just a molecular diagram of what they look like. The details are not important. These are the ones that are found in fly, which is D. melanogaster, is Drosophila melanogaster. These are the similar ones that are found in human. And as soon as they were found, just by scanning the genome, it became very, very clear that maybe they were performing a very similar type of function. And in fact, a series of laboratory studies over the years, all fairly recent, by the way, has really illustrated that these Toll-like receptors that one finds in humans and mice and dogs and cats and everything else really perform not so much of an important function in development of the human embryo or fetus, but rather in protecting the human adult, and in fact all animals, against bacteria and indeed all sorts of pathogens. How, again, by serving as the sensor that macrophages and other similar cells in the immune system use.

in order to detect when a bacterium is present, and in order to allow those cells to know when to activate the immune response, the innate immune response, and when to activate inflammation. Now, again, the way these work is that there are many, many different types of Toll receptors, maybe as many as 14 of them now, and they as a consequence of being so many, they really can bracket the entire universe of different types of pathogens and bacteria. I'm showing here a bacterium is releasing a portion of its cell wall, which it can't avoid doing, and there's specific Toll-like receptors that can actually detect those components, things with names like LPS, or lipopolysaccharide. So, these activate the receptors, which then turn on a typical signaling cascade, again, the details of this are not important, but I just wanted to indicate that something that happens outside the cell stimulates a Toll-like receptor, that then generates an event that occurs inside the cell.

that basically then licenses the cell. In this case, a macrophage, to start the inflammatory process and start protection. Now, here what you're looking at is macrophages in action. These are cells that detect bacteria; actually, what they're detecting is a small yeast particle, such as there, and what you can see very quickly, that macrophage, as soon as I pointed at it, came and ate it. The reason it was able to do that was because there are molecules that yeast make, like bacteria, that can bind to specific Toll-like receptors present on the macrophage and track the macrophage towards, in this case, the yeast particle, and then the macrophage both eats and kills the yeast particle at the same time. Now, what you're not seeing in that movie is that the macrophage also was releasing all sorts of cytokines that would stimulate the surrounding macrophages, but nevertheless, it's a pretty clear indication of exactly what happens.

I'd like to show you one more video of just what this process looks like in a bit more resolution. So, here you're looking at 3 macrophages that have been stained with fluorescent dyes. The green dye stains the surface of the plasma membrane with the macrophage, and the red dye stains these intracellular digestive elements, exactly the same ones the Metchnikoff colored red in his early diagrams, a hundred or so years earlier. These are the lysozomes, which are responsible for both killing and digesting the bacteria that are being eaten. So, the cell on your left, you can see this little crescent-shaped thing there, that's where a particle has bound, and I just want you to watch what happens when that particle is internalized. You'll see it first surrounded by green, then rapidly, the green turns red. So, what that means is the bacterium is eaten in a piece of membrane that is derived from the cell surface of the macrophage.

and that intracellular vacuole then fuses, physically, coalesces with these lysosomes, exposing the internalized bacterium to the cytotoxic and digestive enzymes that are found within the lysosomes that are responsible for killing the internalized bacteria. Ok, just to summarize: innate immunity, discovered by Ellie Metchnikoff, he got a Nobel prize for this work in 1908, and what innate immunity does, is to, remember, to recognize shared pathogen-derived components that are recognized by Toll-like receptors, and related receptors, but the most important ones for today are Toll-like receptors. The main cell of the innate immune system are phagocytes, are the cells that eat the bacteria that are recognized. These are cells such as macrophages, and another cell type closely related that we didn't talk about, called neutrophils. These are the cells that are the main effectors, as we say, of the innate immune response by protecting us against bacteria and other types of organisms by eating them and killing them.

Ok, so let's go on to the next system. This is adaptive immunity, or the adaptive immune system, which was really discovered about the same time as Metchnikoff discovered the innate immune system. The individual really responsible for this was Paul Ehrlich, who also won a Nobel prize for his work, together with Metchnikoff, in 1908. Here he is in his office. And what Ehrlich found was that when you immunize people with foreign proteins, such as a bacterial toxin, or a protein from a cow or a sheep, those individuals make what Ehrlich called protective antibodies in the blood. And you could actually confer protection from individual to the next. These antibodies were very specific to the individual pathogen or the individual protein that was added and, unlike the innate immune system, you just, any protein wouldn't do, but had to be a very specific protein that would be recognized by a different antibody and finally, also, in this realm, although this really was beyond what Ehrlich himself did.

it turns out that the antibodies are not made by the macrophages, but they're rather made by antigen-specific lymphocytes, which were the other major cell type that I told you about at the very beginning that really comprise the immune system. So, lymphocytes figure out how to make antibodies against these individual proteins, against these individual pathogens, and use those antibodies to help kill the infected cells. Now, this is what an antibody molecule looks like in a 3-dimensional structure. It really consists of two major parts: on top, you can see the so-called Fab region, and on the bottom you can see the Fc region. Now, both have different functions. The Fab region, which actually consists of two arms, is really where the specificity lies in antibody molecules, so it's this portion of the antibody that is capable of recognizing and binding to any one of the thousands, if not millions, of different proteins that are pathogen-derived that can come into our bloodstream at a moment's notice.

as a consequence of breathing in the wrong stuff or cutting ourselves in the presence of the wrong bacteria. Now, this is just a diagram of what this looks like. Again, on the top, you can see these Fab domains or Fab regions, which are responsible for the specificity of the antibodies, and the Fc regions, which have a different function that we'll come to just in a moment. And I think it's important to understand this a bit. This illustrates what the different functions of the Fab and Fc regions are. So, here, in green, is a bacterium. It's being recognized by an antibody that's specific to a protein on that bacterium, and you can see here we've drawn that the Fab regions are up, attached to the bacteria, because it's the Fab regions that are responsible for understanding and decoding the specificity in the process. The Fc regions are waving off in the breeze, but they have a very specific function. The first instance they'll recruit another protein that one finds in the blood.

called complement. What complement does is basically bind to the Fc portion of an antibody molecule and stick a hole in the surface of the bacteria. It's very hard to live, if you're a cell, if you've got holes stuck in you, so as a consequence, this is one way in which antibody molecules all by themselves can help kill bacteria. Another thing that can happen though is that these antibodies can work in conjunction with Metchnikoff's macrophages so that the Fc regions, that fixed complement to put holes in bacteria also will bind to specific receptors that are present on the surface of macrophages and related cells, called Fc receptors, and these Fc receptors have two functions. One is that they will help mediate the uptake of the bacteria by this process of phagocytosis that I've already shown you in the two videos that we looked at, but also, like Toll receptors, binding of bacteria that are coated with antibody to these Fc receptors

will also help aid the process of inflammation by enabling the macrophage and related cells to secrete the hormones and the inflammatory cytokines, and other components that will basically indicate to the rest of the immune system that an infection is taking place and help is needed at the site where the macrophages detected these bacteria. Where do antibodies come from? As I already mentioned, they come from lymphocytes, but they come from a very specific lymphocyte, which is called the B-lymphocyte, or more simply, B-cell. These are cells that have the capacity to be able to actually molecularly generate this incredibly broad specificity array of antibodies that one finds, and in fact, that one needs, in order to maintain proper immunity in the bloodstream. B-cells will continuously mutate the genes that encode for antibodies, and these are called immunoglobulin genes, and as a consequence of this continuous process of mutation, which is very, very carefully controlled, B-cells can generate the type of diversity that they need.

in terms of recognition, to be able to provide and secrete antibodies, or release antibodies, that can interact with virtually any type of pathogen that we are exposed to in life. Now, although B-cells can make antibodies on their own, it turns out, of course, the system is more complicated than that because the best antibodies that B-cells can make are only made are only made when they are, as we say, helped by a second major type of lymphocyte, and these are called the T-cell. So, T-cells interact with B-cells, while B-cells are interacting with the specific proteins derived from a given pathogen and help the B-cells do a better job making even better antibodies than they could possibly have done on their own. Now, how do they do this? Well, turns out that T-cells have their own receptor, they don't make antibodies. In fact, they make nothing that will go into the bloodstream and directly kill a pathogen like this.

under normal circumstances. But they will see another, a little bit of the pathogen, or the pathogenic protein that's come in and use another receptor, which not surprisingly is called the T-cell receptor, to recognize that small bit, and then, as a consequence of that, release its own hormones that then help the B-cell do its job at making antibodies. This just shows this process in a little bit more clear fashion, I think, so you see over here, the antigen, or the bacterium coming in, it binding to a receptor on B-cells, which is actually antibody molecule that's embedded in the B-cell. A small piece of that antigen is broken off and put on another receptor on the surface of the B-cell, which interacts with this so-called T-cell receptor that then turns on the T-cells, allowing these hormones, or cytokines, to be secreted by the T-cell, basically telling the B-cell what to do, or at least to do its job better.

Finally, I'd just like to address the problem of where do T-cells come from? And how do they know what to do? Turns out, of course, that T-cells come in multiple components, or multiple types. The two basic flavors of T-cell are called CD4 and CD8. It's not really important to be able to distinguish between the two. One of them, the CD4 T-cell, is actually the one that's actually responsible for helping B-cells. CD8 T-cells, which we won't talk about today, have an additional property to that, which is that they can actually kill stuff on their own and form a very important component of anti-viral immunity. But we can take that up another time. Now, the way that T-cells develop their own ability to recognize these small pieces of antigen that are derived from various bacteria or other pathogens, is not because they interact with the B-cells, necessarily, but because they interact with another cell type, which I mentioned early on, called the dendritic cell.

Dendritic cells have the special property of being able to also take up bacteria, and they don't really kill the bacteria. They analyze the bacteria and ask, What type of bacterium is it? and then display small bits of that bacterium on their surfaces on molecules here that are called MHC class I or class II molecules that have the very, very special property of being able to detect the appropriate recognition sequences on T-cells such that the right T-cells are generated for the right type of bacterial infection that's taking place. Now, the way this actually works is shown in this little cartoon, and so, once again, you maybe can understand it a little bit better. In the left, you see a happy dendritic cell taking up a not-so-happy bacteria. Parts of that bacteria are then generated as a consequence of the dendritic cell having the ability to break it down, placing some parts of small little bits of the bacterium on the surface, small peptides derived from bacterial proteins, for those of you who know what a peptide is.

bound to these MHC class I or class II molecules. T-cells will recognize this. The dendritic cell will make additional cytokines, and that T-cell, if it sees its right little bit, it becomes activated, very happy, as you can see here, and then runs off to find B-cells that it can help in the antibody generation process. So, it's all a nicely closed loop. I would like to show you a video that tries to put all of this together. So, here you're looking at an animation of someone who's just gotten a sore throat, so you can see the sore throat. What happens in a sore throat, of course, is you have, in most cases, a bacterial infection. So, here, you see a bunch of green bacteria that are colonizing, that have infected the throat and are colonizing the surface of it. Now, those bacteria are covered with specific proteins, and that's what's shown in green, and the proteins then are sloughed off, or released from the bacteria.

and enter the circulation, and then also enter into the lymphatics. So, these, remember, are these small conduits that cells in the immune system travel through in order to go from the peripheral tissues into lymph nodes. So, cells of the immune system, such as dendritic cells, have taken up these proteins. B-cells have taken up these proteins, and then come back to these central congregating sites that are connected to all of these lymphatic vessels called lymph nodes. We talked about these in the very beginning. So, here, you see, in this particular video, not the cells, but the bacterial protein entering into the lymph nodes, where it encounters all of these lymphocytes and dendritic cells that begin to take up the bacterial protein and whatever bacteria that come in and begin to interrogate what has happened, respond via Toll-like receptors to these proteins and other components, and start to be activated. So here you see, now, a blow-up of the surface of the B-cell.

these are the receptors on the surface of the B-cell. This one seems to be specific for this particular bacterial protein because you can see as these proteins come down, they bind to these receptors, one and then a second and a third and a fourth. And as a consequence of all of these receptors accumulating together, particularly if a T-cell is around, these B-cells will then generate a signal, as you can see here, that then tells the B-cell it has recognized the right antigen, the one that it was born to recognize, and it basically gets activated. And as a consequence of getting activated, it not only starts moving, but as you'll see in a second, it starts to grow. There, it's dividing two and four and eight, 16, et cetera, et cetera. You wind up with a clone of B-cells, in other words, they're all identical to the first one, they just expand, make more and more of themselves.

and the reason for that is so that the immune system can then generate a large amount of the antibody that it already had. That can then neutralize the bacteria. So, here you see these B-cells after they've grown up and replicated themselves. Now secreting large quantities of these antibodies that enter not only back into the lymphatics, but now also permeate into the bloodstream. And can circulate throughout the body, including going back to the original bacteria that had colonized the throat. Creating the sore throat in the first place. Binding to it, complement will fix to it at that point. And here, in this last image, a macrophage or something similar to that is coming in. And as a consequence of recognizing the antibody bound to the bacterium. Being attracted by the bacterium itself. You can see this macrophage eating these cells and kill them. And eventually, we get better as a consequence of all this. Ok, just one last word just to make sure that you at least get the basic concept.

of how the immune system works, what its logic is, what its function is. I want you to remember that the immune system consists of two basic components: the innate immune system, discovered by Metchnikoff, and the adaptive immune system, discovered by Ehrlich. The innate immune system exists, and it's a very primitive form of the immune response. It exists to recognize components that are found on virtually all pathogens, without really distinguishing so well one pathogen from the next. The adaptive immune system, on the other hand, is highly specific and makes antibodies through the activity of T-cells and B-cells that can specifically identify very, very highly individual pathogens and very highly individual viruses and help, working together with the innate immune system, killing them off. Now, as I mentioned, one of the big problems that we've had until fairly recently, just really within the last 15 years or so, is really understanding how the innate and the adaptive immune system work together. In fact, Metchnikoff or Ehrlich didn't really understand this either.

but this is a realization that was achieved by another scientist. Just in 2011, received a Nobel prize. Tragically, died just days before learning of the award. This is Ralph Steinman, who worked at the Rockefeller University in New York, and Ralph was really the person who is responsible for our understanding that dendritic cells exist and that dendritic cells provide this missing link. They are like macrophages in the sense that they have all of the Toll-like receptors macrophages have. They have the capacity of taking up bacteria and other pathogens, and to some extent killing them. But that's not really what their major role in the immune system is. What their role is, is to carry the information, small pieces of the bacteria that are preserved on the surface of the dendritic cell. They take that information from the periphery, where the dendritic cell first encountered the bacterium, into lymph nodes and into the lymphoid organs, basically instructing the cells of the adaptive immune response, the B-cells, and the T-cells.

as to exactly what type of bacterium is present, stimulating their activities, stimulating their growth, and ultimately leading to the protective antibody responses that you saw in the video. Ok, I hope you enjoy understanding something about the immune system because it really is very important, and there are a lot of resources, both online and in print, that you can go to in order to be able to learn more and test your own knowledge of this very, very important and very elemental part of biology. Thank you.

The Immune System - Ira Mellman (Genentech)

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