hi my name is iron Melman 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 um bacteria viruses other little organisms that cause a almost Limitless number of infections in in us and in humans and we need to be protected against these environmental pathogens and toxins that they make uh on an almost continuous basis every time we breathe we take in bacteria or viruses every time we drink or eat something uh also we have the potential of taking in um uh 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 um 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 um from that which it is trying to protect which again is us so this is a a very very important feature of the immune system and means that it's actually really uh highly specialized and in many ways really smart to be able to tell the differences and I'll a touch on some of the ways in which the immune system does this now turns out that all multicellular organisms have immune systems whether they are animals humans fish an insects or plants um the degree of complexity of the immune system as you go through different types of organisms that you find on Earth is entirely different um where um you know humans and and dogs and cats um have much more complicated uh ways of protecting themselves than do uh plants and insects but nevertheless um the same basic principle is conserved throughout Evolution and in fact you can find even the most primitive type YP of immune responses and immune systems that one can see in even organisms as uh simple as insects as 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 um the immon 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 um many many important diseases um such as infectious disease as we've already been discussing or AIDS or asthma or lupus autoimmune disorders even cancer and various allergies are caused by breakdowns or at least are aided by breakdowns of the immune system and as a result uh in order to really understand uh the basis for these diseases and understand their biology we have to know something about um how the immune system works so what is the immune system anyway um 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 uh you find a a factory of of cells that produce many many types of cells that are found um throughout the body um these are called in the first instance the most popular and populous of them are called lymphocytes which come in two basic flavors um t- cells and B cells uh they're also cells known as macrofagos and dendritic cells and monocytes NK 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 uh called the immune system and they're found all over the place um 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 uh which has one type of um immune cell in it called the dendritic cell which basically sits in the skin waiting for invading pathogens to come for example after when 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 uh little tubes and vessels totally separate from your blood vessels but basically doing the same sort of thing and this is called um the lymphatic system or or lymphatic vessels um these are small tubes as I said that are found literally everywhere uh lymphoid cells enter into lymphatics uh and start migrating where do they go U they migrate and then congregate in a series of small lympho organs well some of them are not so small like the spleen which is found in your abdomen um but the small ones and in fact probably the most important ones are called lymph nodes now lymph nodes are um are little Aggregates and I'll show you this in a minute of uh of cells of the immune system that have very very special uh functions and very very important activities to perform but you can find them on yourself uh throughout your body on your arms legs um uh chest everywhere else but probably most uh typically if you just feel on your neck particularly uh after you have any type of an infection such as a sore throat you can find these little bumps uh that are there and I'm sure you probably many of you know that these are lymph nodes but this is basically what they 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 uh so they really exist only to transport cells of the immune system from your peripheral tissues from your fingers um back to uh the lymph nodes where they can find other uh types of immune cells now this is a a blow up of what actually happens u in a lymph node precisely what happens here at the moment is not really important but what I want you to to look at is the fact that you see a great and high concentration of all different types of cells of the immune system uh particularly lymphocytes and dendritic cells um that all are talking to each other and basically what they do is they they are communicating uh and trading information on what they encountered encountered in the tissue in the tissues uh what types of pathogens were there uh and decide among themselves essentially what to do about them so uh these are centralized processing uh centers uh in which uh information about invading pathogens uh is communicated to different cells that have different functions in uh then actually mounting a protective response against a particular pathogen type now the immune system cons consists of two interconnected arms that we call um the innate immune system and the Adaptive immune system um innate immunity is the most evolutionarily ancient uh and is found in insects in fact it was first found in insects and uh 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 rec recognize those things that are fundamentally the same from one bacteria to another or from one virus to another or one protozoan parasite um to to another regardless of of of what their species actually is the Adaptive immune system though recognizes those things that are really very specific and very special um to an individual pathogen and requires a greatly uh more Amplified and uh complex uh 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 uh with each other hand and glove U and how they connect one to the next uh has only recently been worked out and uh turns out uh to to reveal yet another fundamental part of the immune system which is the missing link between uh the Adaptive and the innate immune responses and we'll get to that just in a minute uh but uh just to give you a hint uh that's what dendritic cells do now um our understanding of how the immune system works really uh dates back into the 19th century um really to the work of two scientists the first of whom is shown here this is Ellie mechnikov uh who really made a very very important conceptual understanding which is that when you see an infection uh particularly infection that would occur in the skin um the swelling and the redness and the Heat and the pain and and all of this um stuff that occurs that that you know is characteristic of infections is not really an indication of tissue being destroyed but is an indication of the immune system particularly the imate innate immune system uh trying to do its job and trying to kill off the invading bacteria one of the cells and perhaps the most important one that mechnikov found is a cell called a maccrage and this is one of his original drawings showing what a maccrage looks like you can see a cell with with these long tentacles uh uh hanging off the ends of it plus a lot of uh structures inside the cell uh some of which are colored red which are actually the intracellular destructive bodies uh that are to a very large extent responsible for killing and then destroying uh invading bacteria and all of this metov found out just with very very crude microscopes and very very very very simple techniques in fact probably a lot uh simpler uh than than what's available uh now in uh even junior high schools and high schools everywhere he was still able to work this out as I said micro organisms such as bacteria are recognized by macrophages and they are killed they're taken up or ingested by macras and uh this process all enhances the protective immune aspect of um of what macrofagos do and starts the process of inflammation uh and inflammation is really the process whereby one cell after detecting a pathogen signals to its uh its neighbors that there's something going on and as a consequence more cells should come in uh to help out um part of the reason that inflammation takes place uh is because the Act of Killing bacteria involves a lot of agents that really serve as signals uh to attract other cells of the immune system so I've listed some of the more important ones here cytotoxic agents occur uh so that macras can make large amounts of hydrogen peroxide which actually is quite effective at killing most bacteria um they uh secrete uh enzymes uh or or expose the bacteria to enzymes that will degrade U the bacteria themselves and then also finally they will release U these inflammatory components uh which in uh the business we call cyto Mines uh that are um small proteins or hormones that are released by the back by the maccrage rather uh that attract other immune cells to the site now why is it that macras and in fact other similar immune cells are able to do all of this uh how can they even know when a bacterium is present so is 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 um on the surface that are really very specialized for being able to understand uh when bacteria are present these are called tolllike receptors um 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 uh some images of just what a developing embryo of dropo looks like uh that has mutations in uh toll receptors and you can see a normal one in panel a up on uh the left uh showing what a normal embryo should look like at this stage and here down in the lower right um You can see a mutant embryo that is not able to form because it's absent of uh this toll receptor but by performing genetic tricks you can actually get uh these embryos to form uh real flies and uh 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 dropa um blown up at a very high magnification uh using something called a scanning electron microscope and uh dropa don't normally have hair or beards in in quite this way what you're looking at here is a um very um serious fungal infection uh that this uh uh fruit fly could not fend off off against because um the fly is defective in one of these toll receptors this is one of the earliest indications uh that um toll receptors are important uh in fly uh for being able to protect them against fungal infections and indeed as it turns out other infections as well turns out um that total receptors this is just a molecular diagram of what they look like the details are not important uh these are the ones that are found in fly which is D melanogaster is dropa melanogaster these are the similar ones that are found in human and uh as soon as they were found uh just by scanning The genome uh it became uh a very very uh clear that uh that maybe they were performing a very similar type of function and in fact uh a series of laboratory studies over the years all fairly recent by the way um has really Illustrated that indeed these toll like receptors that one finds in humans and mice and and dogs and cats and everything else uh really perform um not so much an important function in development of of the human embryo or or fetus but rather in protecting the human adult and in fact all animals um against bacteria and indeed all sorts of pathogens how Again by serving as the sensor that macras 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 um the immune immune response uh the innate immune response or when to activate um inflammation now um again the way these work is that they're many many different types of to toll receptors maybe as many as 14 of them now um and they as a consequence of being so many they they really can bracket the entire universe of different types of pathogens and bacteria um shown here a bacterium is releasing a a a portion of its cell wall which it can't avoid doing and there's specific toll like receptors that can actually detect those those components things with 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 um but I just wanted to indicate that that something that happens outside the cell stimulates a toll like receptor that then generates an event that occurs inside the cell that they basically then licenses the cell in this case a maccrage to start the inflammatory process and start protection now here what you're looking at is macras is in action um these are cells that detect bacteria uh actually what they're detecting is a small yeast particles such as the A and that you can see very quickly that maccrage as soon as I pointed at it came and ate it uh 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 maccrage attract the maccrage towards uh in this case the yeast particle um and then uh the maccrage both eats and kills the yeast particle at the same time now what you're not seeing in that movie is that um the maccrage also was releasing all sorts of cyto kindes that would stimulate the surrounding macrofagos uh but nevertheless U 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 three macras that that have been stained with fluorescent dyes the green Dy stains the surface or plasma membrane of the maccrage and the red Dy stains of these intracellular digestive elements exactly the same ones that mechnikov colored red in his early diagrams a hundred or so years earlier these are the lomes which are responsible for both killing and digesting uh in uh the bacteria that are being eaten so the cell on the on your left um you can see this little crescent shaped thing there um that's where a a particle has has bound and I just want you to watch what happens when that particle is uh is 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 maccrage and that uh intracellular vacu then fuses physically coalesces with these lomes exposing the internalized bacterium to the uh cytotoxic and digestive enzymes that are found within the lomes that are responsible for killing the internalized bacteria okay just to summarize inate immunity discovered by Ellie mechnikov he got a Nobel Prize for this work in 1908 um and what inate immunity does is to remember to recognize shared pathogen derived components that are recognized by toik receptors and related receptors but the most important ones for today are tolik receptors um the main cell of the innate immune system are fago sites in other words cells that eat the bacteria that are recognized uh these are cell such as macrofagos and another cell type closely related that we didn't talk about called neutrophils uh these are the cells that are the main effectors as we say of the innate immune response by uh protecting us against bacteria and other uh types of organisms uh by eating them and killing them okay so let's go on to the next system this is adaptive immunity or the Adaptive immune system uh which was really discovered about the same time as mechnikov discovered the inate immune system um the individual really responsible for this uh was Paul Erick who also won a Nobel Prize for his work together with mechnikov in 1908 here he is in his office uh and what um Erick found was that uh when you immunize people with foreign proteins such as a bacterial toxin or a protein from a cow or a sheep um those individuals make what erck called protective antibodies in the blood and you could actually confer protection from one individual um to the the next these antibodies um were very specific to the individual pathogen or the individual protein that was added and unlike the uh innate immune system uh you just any protein wouldn't do but it had to be a very specific protein um that would be recognized by a given antibody and um finally uh also in this realm although this really was beyond what what Erik himself did turns out that um the antibodies um are not made by the macras but they're rather made by antigen specific lymphocytes which are the other major cell type that I told you about at the very beginning that really comprise the immune system so um the lymphocytes figure out how to make antibodies against these individual um proteins against these individual pathogens and use those antibodies um to help kill the infected cells now this is what an antibody molecule looks like um in a three-dimensional structure it really consists of two major parts on top you can see the so-called fa region and on the bottom you can see the FC region now both have different functions the Fab region um which actually consists of two arms uh are is really where the specificity lies uh in antibody molecules so it's this portion of the antibody that is capable of recognizing and binding to uh any one of the thousands if not millions of different um uh proteins uh that are pathogen derived that can come into our bloodstream uh at a moment's notice as a con consequence of breathing in the wrong stuff um or cutting ourselves uh in the presence of the wrong bacteria now this is just a diagram of what this looks like again uh on the top you can see these Fab domains um or Fab regions uh which are responsible for um the specificity of the antibodies and the FC regions uh which have a different function we'll come to just in a moment I think it's important to to understand this a bit this illustrates what the different functions of the Fab and FC regions are um so here in green is a bacterium uh it's being recognized by an antibody that's specific uh 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 compliment what compliment does is B basically bind to the FC portion of an antibody molecule and stick a hole in the surface of the bacteria uh 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 uh antibody molecules all by themselves uh can help kill bacteria another thing that can happen though is that these antibodies can work in conjunction with metov maccrage um so that the FC regions that fixed comp ment to put holes in bacteria also will bind to specific receptors that are present on the surface of macras and related cells called FC receptors and these um 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 in the two videos we looked at but also like to receptors binding of bacteria that are coated with antibody to these FC receptors will also help aid the process of inflammation by enabling the maccrage and related cells um to secrete the the hormones and the inflammatory cyto kindes and other components that will basically indicate to the rest of the immune system that an infection is taking place and help is needed uh at the site where the macras has detected these bacteria where do antibodies come from as I already mentioned they come from lymphocytes but they come from a very specific lymy which is called the B lymp it or simp more simply B cell um these are cells that have the capacity to be able to actually molecularly generate this incredibly uh uh broad specificity uh array of antibodies that one finds in in fact that one needs in order to maintain proper immunity in in the bloodstream um B cells will continuously mutate the genes that encode for antibodies and these are called imunoglobulin genes and as a consequence quence of this continuous process of mutation which is very very carefully controlled um B cells can generate the type of diversity that they need uh in in terms of recognition to be able to provide and secrete antibodies or release antibodies uh that can interact with virtually any type of pathogen that we are exposed to in life now um 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 when they are as we say helped by a second major type of lymy and these are called the te- cell so t- cells interact with B cells while B cells are interacting with the specific uh proteins derived from a given pathogen and um help the B cells do a better job making even better antibodies than they could possibly have done on their own now uh how do they do this uh Well turns out that te- cells have their own receptor they don't make an bodies 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 um the the pathogen or the pathogenic Protein that's come in and use another receptor uh which not surprisingly is called a te- cell receptor to recognize that small bit uh 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 uh more clear fashion I think so you uh see over here the antigen or the bacterium coming in it binding to a a receptor on B cells which is actually an antibody molecule it's embedded in the B cell um 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 uh that then turns on the te- cells allowing uh these hormones or cyto kindes to be secreted by the t- cell basically telling the B cell what to do at least to do its job better finally I'd just like to address the problem of where do te- cells come from and how do they know what to do um turns out of course the te cells come in multiple uh components or multiple types um the two basic flavors of te- cell are called CD4 and cd8 um the it's not really important at the moment to be able to distinguish between the two uh one of them uh the CD4 T cell is actually the one that's 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 uh form a very important component of antiviral immunity but we can take that up another time now the way that uh tea cells develop their own ability to recognize these small pieces of uh of of antigen that are derived from various bacteria or other pathogens is uh not because they interact with the B cells necessarily but because they interact with another cell type uh which I mentioned early on called the dendritic cell um 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 they ask what type of bacterium it is and then display small bits of that per bacterium on their surfaces on molecules here that are called MHC class one or class two molecules that have the very very special property of being able to um detect uh the appropriate uh recognition U sequences on te- cells such that the right te- cells are generated uh for the right type of bacterial uh infection that's taking place now the way this actually works is shown in this little cartoon um so once again you maybe can understand it a little bit better um in the left uh you see a happy dendritic cell taking up um a not so happy bacteria um parts of that bacteria are then gener ated as a consequence of the dendritic Cel having the ability to break it down um 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 one or Class 2 molecules uh te- cells will recognize this uh the Ma dendritic cell will make additional cyto kindes and that t- cell if it sees its right little bit um it becomes uh activated very happy as you can see here and then runs off to find um B cells that it can help uh in the antibody generation process so it's all a nicely closed loop I'd 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 the sore throat so you can see the sore throat and um what 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 um and are colonizing the surface of it now those bacteria um are covered with specific uh proteins and that's what's shown in green and and the proteins then uh are sloughed off or or released from from the bacteria um and enter the um uh the circulation and then also enter into the lymphatics um so these remember are these small conduits uh that cells in the immune system travel through in order to go from the peripheral tissues into lymph nodes um so cells of the immune system such as dendritic cells have taken up um these um proteins B cells have taken up these proteins and then come back to these Central congregating sites that are connected um to all of these lymphatic vessels uh called uh lymph nodes we talked about these at the very beginning so here you see in this particular video uh not the cells but the bacterial protein entering into lymph nodes where it encounters all of these lymphocytes and dendritic cells uh that begin to take up the bacterial protein and whatever bacteria that come in um and begin to interrogate what has happened respond via toll like receptors um to to these uh proteins and other components and start to be activated so here you see now a blow up of the surface of a B cell these are the receptors on the surface of a B cell um this one seems to be specific for this particular bacterial protein because you can see as these um proteins come down uh they bind um to these recept c s uh one and then a second and a third and a fourth and as a consequence of all of these receptors accumulating together um particularly if a t- cell is around um these B cells uh 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 um and it basically gets activated um and as a consequence of getting activated um it not only starts moving but as you'll see in a second it starts to grow there is dividing two and four and eight and 16 etc etc and you wind up with a clone of B cells 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 uh 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 and replicated themselves uh now uh secreting uh large quantities of of these antibodies that enter not only back into the lymphatics but now also uh permeate into the bloodstream and can circulate throughout the body including going back um to the original bacteria that had colonized um the throat um creating the sore throat in the first place uh binding to it a compliment will fix to it at that point and uh here in this last image um a maccrage or something similar to that is coming in is a consequence of recognizing the antibody bound to the bacterium being attracted by the bacterium itself uh you can see this maccrage eating these cells and kill them and um eventually we get better as a consequence of all this okay just one last word just to make sure that you uh at least get the uh basic concept of how the immune system works what it's 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 metov and the Adaptive immune system discovered by erck the innate immune system exists and it's a very primitive uh form of the immune response it exists to recognize components that are found on virtually all pathogens Without Really distinguishing so well one pathogen for 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 uh and and help U and working together with the innate immune system killing them off now um as I mentioned uh one of of the uh big problems that we've had until fairly recently just really within the last uh 15 years or so is really understanding how the innate and the Adaptive immune system work together uh in fact metov or erck didn't really understand this either but this was a realization that was um achieved by um another scientist who very recently just in 2011 uh received a Nobel Prize tragically died uh just uh days before learning of the award this say um Ralph Steinman uh who worked at the Rockefeller University in New York and Ralph uh 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 macro in the sense that they have all of the toll like receptors macres have they have the capacity of taking up bacteria and other pathogens and um 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 uh that are preserved on the surface of the dendritic cell to take those that information from the periphery where the dentritic cell first encountered the bacterium into lymph nodes into the lymph oid organs basically instructing the cells of the Adaptive immune response the p 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 okay um I hope uh you enjoy understanding something about the immune system because it really is very important and uh 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 uh and test your own knowledge of this very very important and very Elemental part of biology thank you