The Necessity of the Immune System

[Music] Stanford University good evening everybody wonderful to see you again let me just get a quick show of hands how many of you are new for the first time for this quarter all right well welcome my name is Phil Pisa I'm the Dean of the School of Medicine and this is our third quarter so for those of you who are just joining you've missed 20 incredible presentations but don't worry we have 10 more to go and they're all going to be wonderful as well I should say in passing that as you if you are coming for the first time you're going to be leaping into new fields that are really quite exciting and interesting and each one of them in a sense is sort of self-contained but for those of you who have had an opportunity to be with us either from the beginning or from the winter quarter I think as we get a little bit further you're going to begin to see some connections which is often what begins to happen in medicine I often tell our first-year students when they're beginning that it's like parachuting right in the middle of a knowledge field and you have to kind of look forward and backward and around before you begin to get some of the intersections of the information that really brings what we deal with alive and well so a couple of practical things first we will be meeting here each Tuesday for the next ten weeks we'll start pretty promptly at 6:30 we'll end pretty promptly at 8:20 and respect your time they'll always be an opportunity David for any of you who have questions that aren't answered during the presentation to come forward at the end and have an opportunity for some additional dialogue we want to foster obviously your knowledge and hope that you will be great ambassadors this has turned out to be we're told the most popular continuing education course in Stanford's history at least measured at least measured by the number of you now the way you rate it at the end of the day can have a different nuance on that but we're pleased to be part of this the reasons that we're doing this began because we were last year celebrating our fiftieth anniversary from the time that the medical school moved here from San Francisco and it was a seminal time for us but I must tell you that this course also began thanks to a Stanford undergrad who came to my office one day Eric lifer and said he had heard about mini med schools and why weren't we doing one true undergrad stimulus and I reckoned and told him that I'd actually participated in one of these programs decades ago and was well aware of how significant important they could be and we decided to go from what is often the kind of minimal response that many medical schools do where they'll have a handful of lectures and call it a mini medical school to a three quarter event so I think we've covered the waterscape on this one I'll also tell you that if you're interested in going backwards and looking at what we've done the first quarter is all online and it's on YouTube and I think an iTunes and really quite doable I've looked at some of them so you can enjoy those and last quarters will be up relatively soon we purposefully delay a bit just to keep the action live before you in addition Cathy Gilliam who I'd like to have stand up and acknowledge who has been literally my partner in crime she is the senior adviser to the Dean but we work very collaboratively and when this idea arose I asked her to work with me on it and she's done a splendid job in helping to keep everything together and moving forward and she tells me that the syllabus for the rest of the this quarter will be online tomorrow and as you likely know we'll be covering a variety of different selected topics this quarter we're going to start out with immunology and I'll come back to that in in a moment and then we're going to move in a couple of directions actually move is the correct term because we're going to have a session on movement and then we're going to talk about what happens if you don't move enough which is obesity a real problem in this country in fact it's been forecast that the two things that could change longevity in the United States from the current projections are one [Music] unreconciled here this evening and the second is obesity so these are real issues and we'll want to talk about them and then we'll go to something that I'm particularly concerned about which is aging and all of the science that relates to it and for those of you who are here last quarter you'll remember the very interesting presentation that we had about memory that relates also to to that process and then we'll kind of end with a trilogy of topics that relate to cancer cancer biology and some new innovations and we'll finalize the the quarter with the fusion product that has been quite characteristic at Stanford which is the connection between stem cells and cancer so you'll have a pot pourri of presentations again each contained within themselves but you'll begin to see the intersections between them now I have to tell you with regard to our presentation tonight that when I was in medical school decades ago immunology was a to lecture course there wasn't very much known and the reason it was to lectures is one was on b-cells and the other was on so-called t-cells and they actually had names associated with them but this has been an area that has evolved enormous ly and is perhaps one of the most complicated areas in all of medicine because the immune system may rival the nervous system for its intrinsic complexity but as you'll hear tonight it really it really stands at the center piece of what protects us what defines us it's what gives us our own personal identity protects us from all the organisms around us you'll remember from the first quarter that while you may be comprised of around 10 to the what 13th or 12th cells you've got at least a log more bacteria and germs living inside and outside you and it's the immune system that creates the balance of power within them if the immune system gets out of whack it leads to autoimmune disease if the immune system is altered it doesn't only increase the risk for infection but in my world it also increases the risk for cancer so these connections are important and you'll see how much the immune system discussions are going to play into our subsequent presentations next week on autoimmune disease and the one that follows on vaccines nomen vaccines has probably been one of the things that has so transformed human history in the last last many decades and I can't think of a better person to lead off this presentation than my friend and colleague David Lewis and I say that because he's a pediatrician and you know I come from that ilk and so that's always a good sign at least he'll be nice I don't know how smart he'll be we'll see how that goes but nice-nice is the usual term that goes with Pediatrics David grew up in California he told me to say he grew up in a log cabin but I don't really believe that but he did migrate east as many have as I've done these introductions there was a kind of phenotype that he merges he was at Yale for his undergraduate work and then moved back here to do his MD degree at UCSF and then moved a bit north to Seattle to do his training in pediatrics and immunology one of the great fonts of pediatric immunology is at Seattle Children's Hospital and I think David was well mentored there he now directs the immunology program in Pediatrics both at Stanford and Lucile Packard Children's Hospital and is really an expert on congenital immunodeficiencies meaning when you're born with a risk for not having a completely formed immune system and there are many consequences that unfold from that but I also have the pleasure of interacting and working with David on the infectious disease service so he kind of crosses that line between the immune system and infectious diseases and I think that's going to be where he starts his saga I'm with you tonight so let me introduce David Lewis well thanks for the kind introduction I think I'd like to start with a joke about how a lot of non immunologist medical people view immunologist so this guy is robbing a bank he sees these two really well-dressed gentlemen he says I'm taking you hostage and they go into this getaway car and it's up this very steep hill with a very sheer escarpment on one side and it's an old car and it's kind of underpowered and they can hear the sirens getting louder and louder he says I hate to tell you guys this I'm going to have to throw one of you out of the car and I don't know how to decide how to do it maybe I'll base it on what you do for society so he points the gun at the first guy and he says what do you do with this is I'm a cardiologist he says what's a cardiologist he says well like if your baby is born with a hole in his heart I make sure that the surgeons patch him up or if your grandmother has a heart attack I make sure she leaves the the ICU he says that sounds pretty important he says what do you do he points the gun at the next guy who guy says I'm an immunologist he says what's an immunologist well and then the cardiologist says just shoot me I don't want to hear any more of us so so you are now for warm if anyone wants to leave now it's fine okay so what I'd like to do is is really provide an overview first why do we need an immune system then talk a little bit about innate immunity and some historical observations that then led to the thought over a thousand years ago that there was a special form of immunity that we call adaptive immunity and then how innate an adaptive immunity worked together to protect us and and really properly integrate the immune response and then a little bit about how things can go wrong and how we might fix it so kind of a tall order but we're going to try and do that so immunity really is a biologic term that describes a state of having defenses against infection so the focus really of why the immune system came into being is to protect us from some bad pathogens that are out there and we really live in a microbial world we may not believe it as much now because of modern society but our immune system has had to deal with all kinds of potential pathogens and I'm going to briefly because I think it's so important to understand the immune system I'm going to actually introduce the bad actors if you will first and though I'm a peace-loving person and I've been accused of being a war monger if you really look at the best metaphor for the for the immune system it is a defensive strategy and a lot of military strategy that is independently evolved in society once civilization reached the point of being relatively complicated and you had a city-state that you needed to defend against these Marauders very simple what we've really done in humanity is come up with in parallel the same strategies that the immune system has been using for hundreds of millions of the big decisions have to be if there is a microbe out there is it a friend or a foe or something that you can ignore if it's a foe how do you best mobilize defenses to contain it and the immune system makes a lot of distinctions about whether the foe is inside cells of the body or in the outside in the humors you know the circulating fluids of the body different strategies are needed for these two locations and then finally once the foe is eliminated you have to just like with the military somehow get them to demobilize so you're not using all your resources inappropriately and becoming just a giant lymph node at the end of the day so bacteria are some of the most important pathogens so I'm showing you here these round Staphylococcus aureus this is a form of this is called mr si that's that's highly resistant to a commonly used antibiotic this bacteria forms these pus containing infections frequently a less frequent infection but one that we've unfortunately had some encounters with in in this millennium is the anthrax bacillus which is this sort of long as they're called Boxcar like bacteria they can form these ulcers where there's a lot of dead cells that are forming this crater as they're being eliminated some some bacteria have really had a disproportionate influence on the evolution of the immune system meaning that they're so important that the immune system has really had to tie up a lot of its major defense mechanisms just to keep them at bay one example is Mycobacterium tuberculosis which is the cause of tuberculosis and you can see the bacteria they stain what a lot of the infectious disease people call little red snappers they're inside cells these are bacteria they can cause these cavitary lung disease particularly at the tops apices of the lung the bacteria are very smart like to hide out inside cells of the immune system they particularly like cells that are called mononuclear phagocytes and they actually live very happily in these cells and these cells live for a fairly long time so this is actually a way of evading the immune system so you need to get other components of the immune system to wake this cell up to eliminate this pathogen and even today with all of our therapies almost 2 million people are dying every year from tuberculosis and 30% of the entire world is infected another example of a of a disease that's not gone that that at least historically even in the United States and and more developed countries used to be a really big problem and it still strikes terror I think into the hearts of many of us as clinicians is something called Neisseria meningitidis or the also called the meningococcal so this is also around sort of bacteria in parts of Africa it still is causing probably one out of a hundred infections in in the population in certain countries and the mortality even the United States with all of our technology can still be as high as 10% but as but as dr. piso mentioned we are also awash in bacteria that are in our guts you heard that there's at least tenfold more bacteria than there ourselves in the human body and some of these are actually quite helpful they're helping us digest foods or helping produce vitamins and we call these these bacteria commensals in that the relationship is that we get something out of these bacteria being in our body they don't get too much other than it's sort of a free ride but commensal comes from the sharing of food but the important thing is that you don't want the immune system to inappropriately attack these these bacteria and that's actually one of the things that I think we really have a long way to go in in fully understanding I'll give you a little bit of Vince that's recently come from a few studies as to how the immune system tries to distinguish between these commensals that are harmless and true pathogens in the gut okay so we've dealt with bacteria but there are other kinds of organisms there are fungi which are more closely related to us than bacteria in that they have a nucleus in their cells that makes them a little bit harder to treat because the kinds of antimicrobial therapy tends to overlap somewhat in side effects on ourselves with with those that inhibit them this is an example of one that we see mainly in in patients who have a problem with their immune system particularly with t-cells not working which we'll talk about called Pneumocystis this is what was one of the major causes of death from HIV infection and still is unfortunately in many parts of the world where there's limited access to therapy to prevent this infection so this is a very important infection in terms of human mortality even now then we can move up a little bit in evolution to parasites that are a little more complicated than the fungi there are some that are single cells in this case malaria you can see that malaria is still endemic in much of the tropics and amazingly enough there are still about almost half a billion cases per year in the in the world and it kills between 1 to 3 million people a year unfortunately most of these people are children that live in sub-saharan Africa that die from falciparum malaria so this is one of the reasons that there's really a push by the Bill and Melinda Gates Foundation to try and get a a malaria vaccine if you look at all the things that we could do to improve humanity's lot this would probably be at the very top in terms of just the impact on the on the total number of people now some parasites as you know I guess this is a nice Pleasant after-dinner conversation is that is that they can be actually quite large and become these worms that like to inhabit the gut and sometimes a respiratory tract I'm using for an example a worm that's called schistosomiasis again this is particularly prevalent in Africa some parts of Asia as well this shows you a little larvae of schistosomiasis and what I want you to notice are all these little white blood cells that are attempting to eliminate this larvae and you can see how large these worms are relative to white cells so the immune system for some pathogens that are so large has to come up with a completely separate strategy to get them out of the body if possible which we'll talk about finally viruses I'm sure Harry Greenberg when he talks about vaccines because he and I are both very interested in viral next things are going to talk in more detail but viruses are kind of like software viruses and the in fact that they're just an incredible diversity they can be small they can be large but unfortunately just like computer viruses are almost never beneficial they replicate inside cells you can have a acute viral infections such as influenza where in relatively short order the body is able to rid itself completely of the virus until the next time that you get a brand new infection say for example a year later these are obviously very important for example influenza probably kills about up to five hundred thousand people a year in the world in a typical epidemic but when we have a pandemic that it affects a larger number of people in the population it can be substantially higher thankfully the current pandemic that we're finally seeing light at the end of the tunnel in most parts of the world is probably not going to be that bad compared to some of the others that for example cost three million deaths or the 1918 pandemic that caused its estimate between 30 to 50 million deaths but unfortunately these pandemics caused a disproportionate number of deaths in otherwise healthy people particularly children so it's always a concern that we don't have better ways of controlling these pathogens there are many viruses that have a very different kind of history once you're infected with them you never get rid of them so the herpes viruses are kind of the classic example of this and I guess there's the joke about what's the difference between true love and herpes viruses and the answer is herpes viruses are forever so cytomegalovirus for example affects probably if you look at the world population overall in this country it's not quite so high but probably on average about 85 to 90% of humans by the time they die will be infected with this virus and it can cause serious problems in pregnant women by causing the fetus to be born with a number of congenital anomalies particularly deafness and possibly can can cause a mental retardation so what's going on here in terms of what led to the development the need for the development of an immune response well probably when organisms were only living for a brief period of time it wasn't a big deal but once you have a multicellular organism that needs to be around for a while to reproduce it needs the protection from invasion with these microbes because from the point of view of the microbe a big multicellular organism is like a bunch of goodies that they can just grow on and and themselves reproduce and in the case of mammals or homeo therms the thermostat is on and that makes it even more attractive for them to grow that much faster so the innate immune system developed first and it was poised to act immediately in the event that an intruder came into this multicellular organism and innate immunity goes back to the very beginning of multicellular organisms you can see it in sponges sea urchins insects as well as ourselves the characteristic thing about the innate immune system it's ready to go all the time but it's a stereotyped response so the response it gives the first time it sees a particular pattern will be the response it gives the second third or fourth time it doesn't really learn or adapt its immune response to to the to the organism and it uses clues that that there is a pathogen around by having receptors that are able to detect the difference between pathogen derived products and things that are normally produced by the own host cells what's interesting is that in many cases trauma or damage just by itself will it will activate these innate immune mechanisms and the way I look at this teleologically is that in the past during evolution most of most of the time during human development when trauma almost always occurred in a non sterile setting you might get bitten on the arm by the saber-toothed tiger you might have been wounded in battle with a spear or whatever but there's going to be dirt associated with it it's only very recently that you might actually have trauma that might actually be a sterile thing where it's not introducing microbes so I think a lot of the parts of the body that deal with trauma for example clotting to protect you there's been a linkage to at the same time turn on the innate immune system because you're really most likely are going to need it so innate immunity includes just the barriers of the body for example the skin is a barrier for entry of micros for example and many of these what we call epithelial linings of these of these tissues that have to be crossed for the organism to get into the deeper tissues actually produce natural antimicrobial peptides these are small chains of amino acids that are very potent at actually inhibiting both bacteria and fungi and this is really a field of immunology that still I think somewhat in its infancy and could be much more exploited for therapeutic purposes one of the oldest cells again goes back you can see these in sponges and other multicellular fairly primitive organism is the phagocyte and what the phagocyte does is it takes up the microbe puts it into a compartment that's shown here as the phagosome and then has ways of killing i in a neat and clean way inside the cell so it doesn't cause a lot of disruption of normal bodily processes one of the things that the phagocyte also does is it puts out little proteins that we call cytokines that are sort of an alarm to bring in other cells that are even better at killing than it might be the so-called professional killers and to cause what we call inflammation so inflammation is basically just an accumulation of white blood cells at a site of infection or some kind of damage now the key discovery I think for innate immunity was really made not until 1997 by Charlie Janeway jr. and and meds etaf when they discovered that there are these special receptors that innate immune cells have called toll-like receptors toll has nothing to do with like a toll road toll means cool or far out in German and it's just the name that these receptors have this interesting effect in fruit flies so a guy who's a postdoc said well I'll call them Toru and so now these receptors are similar to the toll receptors of Drosophila but that we call them toll-like but they're very important because they recognize specific products that are unique to two pathogens but not to the body's own cells so for example there are these things there's something called LPS that's made by a kind of bacteria that's called a gram-negative bacteria and this tells the body that there's been an infection with this particular bacteria triggering it and triggers the cells to release some of the same meteors that I talked about with mononuclear phagocytes or phagocytes that is helps set the alarm off to bring in pathogens to I'm sorry to bring in white cells to control pathogens so there are a number of these toll-like receptors some are specialized for recognizing the nucleic acid of viruses many are on the cell surface are specialized for recognizing bacterial and fungal derived products but once they set off the alarm with these inflammatory cytokines they bring the white blood cells that are normally just circulating around in the bloodstream and bring them across into the tissue to form collections of white blood cells that you may have experienced if you've had an infection as pus where you have this collection of intense collection of white blood cells these white blood cells called neutrophils are particularly professional killers for eliminating bacteria and fungi compared to just a generic phagocyte they are really about a hundred to a thousand fold more effective at killing now there's another system of the innate immunity that's that's very old and important and just to show you the diversity of mechanisms so this one involves tagging the pathogen for destruction by the phagocyte so the way this works is that there are proteins in your blood called complement proteins so this is a we all have substantial levels of these proteins all of time and they're constantly slowly being cleaved into smaller proteins that tend to stick to the surfaces of cells it can either be the pathogen if it happens to be around or your own cells if it happens to be on a pathogen there will be this amplification reaction to make more and more of these cleaves products and this also helps attract phagocytes to the site of where this is being generated and at the same time you also get the ability of the phagocyte to take up the pathogen much more effectively so this is called opsonization and the way I like to remember it is opposite this is quoting directly from George Bernard Shaw the doctors dilemma obstinate is what you butter the disease germs with to make your white blood corpuscles eat them and that in fact is what compliment does this compliment protein when it's tagged on the pathogen there are receptors for it that make it much more efficiently taken up by this phagocyte leading to the end of the pathogen and again another piece of the complement proteins that are cleaved helped attract more of these profession or killers to the site of the infection so you get both of these effects working together to help control infection there's a also a nifty thing that the complement system can do it can actually make holes in bacteria that where if the reaction is allowed to go to completion and these holes will actually cause the bacteria to swell up and burst now why doesn't this happen to your own cells the reason is that your all of your cells they do get tagged by the same complement proteins but you have multiple proteins on the cell surface that actually are there for one purpose and one purpose only which is to inactivate the complement system most pathogens haven't figured out a way of doing that so this is one of the most primitive ways of distinguishing between yourself and something that's not yourself that might be a pathogen there's also recently discovered something called an inflammasome so there are certain pathogen derived products that may get inside cells and this is another alarm system similar to the taluk receptors that will produce inflammatory cytokines that will help bring in more white blood cells in this case these also are very potent at inducing fever which is characteristic as you know of infection okay so that's all I'm going to say today about innate immunity though I think when you really look at clinical medicine probably our patients suffer infectious consequences from problems with it with an eighth immunity that we unfortunately in this country have the luxury of inducing with things like chemotherapy but adaptive immunity of course is really captured immunologists attention for a long time we've known since 430 BC that there was a funny phenomenon that sometimes occurred with very serious inflect infections so in the plague of Athens people were dying right and left but it was noticed at that time that if someone was lucky enough to recover from the plague they could then go into the population of people who were already you know were afflicted and not worry about getting the infection again so there was something about there was some process that was allowing there to be long term protection if you survived the initial infection and then of course more recently was discovered that you could use vaccination where you vaccinated with cow pox a relatively mild disease found on cow udders and you could then protect people from smallpox and again the the protection seemed to be for a best one could tell close to life long so one of the key things about adaptive immunity is that there's a learning process but once the lesson is learned there's durability of the immunity and durability of the protection and we now know that there really are striking differences between adaptive immunity and innate immunity so first of all innate immunity as I told you is ready to go right away it's on all the time unfortunately for adaptive immunity it takes probably about five days for you to develop the kinds of responses that are characteristic of adaptive immunity and unfortunately certain infections may win the upper hand you may die of Ebola virus infection or of meningococcemia before your adaptive immune system gets a chance to protect you the adaptive immune system unlike the innate immune system where I told you that it's going to be the same the first second third enth time it actually changes with repeated exposure it gets better and better if you get repeated exposure and the innate immune response is pretty much limited to the number of receptors you have of these total number toll-like receptors flam is ohm receptors and it's still a finite number it might be a hundred different tricks total in the body in terms of dealing with infection yeah is it is it constant throughout our life or does it sounds good so the question is innate immunity constant throughout your life are there differences with age there are some subtle differences with age but they're they're important ones so in newborns it seems to be somewhat slow to get started and then you kind of go through this honeymoon period where probably from childhood well into being elderly it's pretty constant at the extremes of age you may actually see again some decline in in innate immune function but again it's relatively subtle yeah the people who survive during the plague that would describe condition for what would be featuring about them to survive were diagnosed well it would be great to know but I think part of the problem with the plague of Athens is we don't even know what the actual microbe was that caused it so we really would only be speculating so that the question was what allowed some people during the plague of Athens to survive and others not but even if even in in current if you will modern plagues like Ebola virus outbreaks in Africa we often don't understand why there's such variable courses there are some immunologists that that like to believe everything can be explained by genetics perhaps but I think we still have to you know prove that I think the thing that's amazing yeah go ahead what about the so called immune enhancing things like vitamin C and echinacea first of all you know they work and secondly what do they do okay so the question is whether there are do these so-called immune enhancing agents like vitamin C echinacea work well all I can tell you is that most of them have very subtle effects in if you if you look at the evidence kind of based medicine and do immune ology I think they have a fairly modest impact on innate immunity they may have some moderate benefit but probably not in the in the bigger scheme of things anything like for example the impact for example of whether you're on an immunosuppressive drug or nice nothing like that that level of impact is true David that control trials of vitamin C and akinesia have showed no benefit yeah control trials so dr. B's was asking what's seen in control trials I have not seen any you know evidence that that there there's a significant effect statistically so so the important thing though about a DAP of immunity is it's highly tailored to the specific pathogen so if you get encounter if you're one of those unlucky people you travel to Africa you get Ebola virus it will come up with an Ebola virus specific immune response if you never encounter a bolivars it will come up with something else depending on what you encounter and one of the great mysteries for a long time was how is this specificity achieved so I'm going to try and I get to that and I think again one of the reasons that you really needed the development of adaptive immunity as multicellular organisms live longer and longer there was a greater chance that you're going to have repeated infectious threats that it would be an advantage to respond to and then in the event that you got second bout of this infection you could deal with it much more effectively so particularly with vertebrates we're now lifespans were now approaching you know years to decades you could see that there would be a clear advantage so the adaptive immune system involves the generation of many more receptors that are specific for what we call antigen that is that these are things that turn on the immune system that are derived from the pathogens literally millions of receptors to deal with any possibility of any kind of infection that you're going to encounter the adaptive immune system doesn't know tomorrow what that infection is going to be so it's approach has been generate receptors for everything receptors so receptor is something that can bind on the surface of a of a adaptive immune cell there's two kinds called t-cells and b-cells and I'm going to talk about both of them this can actually bind the antigen which is again some kind of product from the pathogen and turn that cell on it delivers a signal to the inside of the cell telling it it's time to get activated it's time to divide and it's time to carry out an immune response so to generate these receptors there's a unique pathway that's called vdj recombination the names kind of a lousy name but we're stuck with it it stands for variable diversity in joining but those are just the name of the segments that are used to make up these receptors and this is unique this system only works in two kinds of cells T cells and B cells it has no other role in the body other than to generate the adaptive immune system and what happens and you're going to learn more about stem cells I guess at the end of this quarter they can give rise to these early T cells or these early B cells the t-cells developed are called t-cells because they develop in an organ called the thymus which is in the neck and they undergo this this process of vdj recombination to generate literally millions of different receptors each cell has a different receptor the b-cells do the same thing but they're called B cells because they differentiate into the mature B cells in the bone marrow so B for bone marrow but the same process is used to create literally millions of different receptors that can see anything that the immune system is going to be thrown at it how does this happen so what these receptors do is you can think of them as sort of a lock and key thus getting a fills question in that a receptor will happen to have the right shape if you will to bind something from a pathogen to trigger that path to trigger that cell to divide and to become active in the immune system so because this is one kind of cell that has a unique receptor we call it a clone so so all descendants of this clone have the identical receptor okay and this is actually very important part of how the adaptive immune system works you start with a very rare cell that has a particular kind of receptor and you select that one to become much more prevalent to deal with the infection in response to it being able to recognize the infection so the thymus a lot of us are very interested in the thymus because it turns out that of the T cells and the B cells the T cells are kind of the master regulators of the whole show they kind of boss the B cells around so cells from your bone marrow enter into this gland called the thymus where they where they become mature T cells and then they leave the thymus and move out to the rest of the body where they can do surveillance for infection so we call these when they're outside of the thymus peripheral t-cells because they're now in the periphery of the body not in the in the thymus t-cells are very important for sensing infection inside cells B cells mainly function against pathogens that are outside cells and we'll see how that how that works in a second T cells are odd though they don't what they actually detect is they don't go inside cells to recognize pathogens what has to happen is that the infected cell or a cell that's taken up the pathogen derived material in the case of T cells they really only see one thing they see proteins and actually just fragments of proteins from pathogens that are taken up by these cells or that infect these cells these are ground up into little hotdogs like small pieces that we call peptides that are placed on these particular molecules whose only function is to present these things to T cells so T cells are only able to see little fragments of protein from pathogens in the context if you want to use that term together with these these MHC molecules I don't have enough time to tell you why they're called MHC molecules but if you want to come afterwards I'll explain it but we're stuck with the nomenclature so this is really very different that as we'll see of what B cell see but this is what T cells see and what they do is they will sort of do surveillance of all of your cells and if they come across a peptide with an MHC molecule that their particular receptor called the T cell receptor that's made by this VD j recombination if it can bind this with a high affinity triggers the T cell to become activated and a trigger adaptive immunity the last thing I'll do with Delmon cloture then hopefully we'll be done for the night with the with the bad stuff more or less is that there are two other molecules on the surface of the t cell that divide them into two kinds two major flavors we'll have to talk a little bit about some other flavors of cd4 T cell but for the purposes of tonight I'm only going to talk about one flavor of something called the cd8 T cell so you'll hear that a lot that their cd4 and cd8 T cells these are the two major subsets of T cells and I'll talk a little bit in a second about what they do but the cd4 T cells are really the master regulators of of the immune system they carry out a whole variety and orchestrate a whole variety of immune responses and they also boss around the B cells as well to some extent the cd8 T cells the only thing you really need to remember about the cd8 T cells is that they're licensed to kill they are professional killers and they kill one thing well which is viruses they are able to do that quite well cd4 T cells have a lot of other functions that they have to do so again it's this T cell receptor that both the cd4 T cells and the cd8 T cells have that recognize these little peptides sort of like hot dogs in a bun on the MHC molecule that's what is determining whether the T cell is going to get turned on or not so you can think of it as sort of a lock and key mechanism it's that shape formed by that particular peptide on that particular it makes a molecule that determines whether or not the T cell it's turned on so here's the problem if you've got say on the order of 10 million different kinds of T cell receptors so each each T cell is going to have or B cell for is going to have one unique receptor and there's 10 million of them and then like probably each one of those there might be 10 copies so 10 cells with that particular t-cell receptors circulating in the body how do you generate all of that when there's we know that there's only 20,000 genes in the entire human genome if we use the genome to encode each one of those receptors we'd run out of the genome pretty quickly so how does that happen and that is the is the mystery of vdj recombination that's now been solved and what's done is that you take little fragments of the of a gene that could become a t-cell receptor in this case and you select randomly from among all these different little segments in a particular in an individual t-cell it's sort of like a the menu at a restaurant you're going to select one of these segments one of these yellow segments one of these blue segments and in that cell you're only going to put together those three to form the final t-cell receptor so it's like a total deck of cards where you're selecting randomly and this is a totally random process now that's going to get you some a number of different kinds of t-cell receptors if you look at probability theory but it's not going to be enough to give you ten million so how does that happen I'll get to that in a second so what actually has to happen in order for you to piece together these genes is you actually have to make cuts in the DNA of the gene these little segments and stitch them together so there are special proteins called recombination activating gene or rag proteins that do this now this is a really radical solution to this problem because you never want to mess with your your genome unless you absolutely have to so there has to be a pretty darn good reason that this is evolved and the adaptive immune system apparently is worth it to actually mess around with your genome by doing these doubles stranded cuts and as part of the joining process more randomness it's it's almost like a random number generator you just put in random you have four nucleotides that you can piece together add on to these these cuts and this actually allows you to generate more than ten million potentially up to ten to the eighteenth possible different kinds of t-cell receptors or V cell receptors so it's this randomness that's inherently built into the system that's allowed to generate what we call this highly diverse t-cell receptor repertoire where you have all of these different cells expressing this this incredible array of receptors and I'll briefly mention that these cell receptors do the same thing so I'm not going to spend a lot of time same kind of randomness they just happen to do it for slightly different genes but it's exactly the same process now this this pattern of random recombination from little fragments must be important because it's actually we now know as of two years ago it's happened at least twice in the evolution of vertebrates people like us with backbones other animals with backbones so if you happen to be a jawless vertebrates like a hagfish you've done it with a completely different set of segments but nevertheless it's independently evolved at least twice same thing you've stitched together this highly diverse set of receptors we use the vdj recombination system from everything from sharks on up and all all all jawed vertebrates use the vdj resist system to make both t-cells and b-cells so one of the downsides that I have to mention in passing is that when you do these double-stranded breaks of DNA there's always the risk that there might happen to be another double-stranded break of DNA somewhere else on another chromosome and you can actually get a what we call a translocation where you have an inappropriate joining between one chromosome and another and this is actually an important cause of certain kinds of tumors but again this is relatively rare so for the species overall the advantages of having an adaptive immune system outweigh the risk of cancer the other problem though is that remember that the T cells don't know really they don't intrinsically know what they're saying in terms of they can't tell whether that little peptide in a hotdog bun it could be from anything it could be a protein from your own body it could be a protein from a pathogen and remember they're randomly generated so there's no control over what their particular binding affinity is going to be for so you could for example just generate by chance a t-cell receptor that's going to bind insulin from the pancreas and cause diabetes if that T cell gets activated and starts attacking your tissue so there has to be a way of purging the body of T cells that have this reactivity with your own tissues in other words with peptides that are derived from your own proteins like insulin and other proteins and how is that done so this is really I think one of the most remarkable findings in the last ten years of immunology it turns out that in the thymus gland that that a part of the thymus actually expresses all kinds of proteins that are found in the rest of the body and there's a particular time and place where the T cells are put through whether they're reactive with your own proteins so in other words you can find evidence of insulin protein being made in the thymus it's not that insulin a role for the thymus it's just to get rid of t-cells that can react with that particular protein and you literally express probably thousands of genes that you ordinarily wouldn't Express in the thymus except for one reason which is to purge the t-cells before they leave the thymus and start acting in the rest of the body so that they don't cause autoimmune disease and I'll show you an example what can go wrong when that doesn't happen and just in passing if you look at what the thymus really looks like where we talk about thymic epithelial cells these are cells that form this kind of meshwork that the developing t-cells have to kind of they have to go through like a sim so they have to interact with them and this is how they actually get interrogated for whether they have a self reactive t-cell for a particular peptide and they get rid of them we think about 25% of the t-cells and otherwise would be released from the thymus just get eliminated at the very end and we and we use the term tolerance because this is allows the the t-cells to be in tolerance with the your own tissues of the body so it's called a tolerance mechanism and this just shows you a little schematic of what actually happens the developing t-cell if it happens to have a very strong reaction with a peptide on a thymic epithelial cell it's triggered to die and it never leaves the thymus if it doesn't have that reactivity it's allowed to live and it can go out and be ready to deal with a pathogen so if all of this happens so there's a lot of quality control in making T cells most T cells that develop in the thymus very few of them actually ever leave because of all these things that have to be just so but if they do get out they can now form what we call the Nighy antigenically naive to our it's a fancy word but what it basically means is these cells are now sitting outside in the periphery waiting they've never actually encountered a foreign antigen but they're now waiting and to encounter they're ready to go if you happen to get that Ebola virus infection tomorrow now there's another problem you've got say maybe 10 T cells that can recognize that Ebola virus peptide and you don't know let's say that the Ebola virus enters into your body in your great toe but most of your t-cells happen to be at the top of your head at that time how are they ever going to find each other it really is a true needle in a haystack so there is an amazing system that has evolved to allow the T cell and the the antigenic peptide the thing that will turn it on to find each other you have specialized cells called dendritic cells because they have these things that look like dendrites but they're really a special kind of white cell and these are really the sentinels of the immune system they sit in all the tissues quietly waiting for danger or infection to turn them on if they get that danger or infection signal some of the same pathways we talked about with the innate immune system like the toll-like receptors turn them on they will be very effective at taking up that the these foreign proteins grinding them up into peptides and putting them on the surface of the cell and at the same time they go to specialized train stations if you will called lymph nodes where they now have a better chance of meeting t-cells because these lymph nodes are places that t-cells like to hang out so a Tisa will enter into a particular length node and and interrogate all these dendritic cells see if it's antigen happens to be around if the antigen is there the t-cell recognizes it it stays put it starts dividing it becomes what we call an effector cell well it carries out an immune response and now you have adaptive immunity but if within 24 hours or so it hasn't encountered it it actually moves it'll just randomly leave that lymph node go into the blood go to another lymph node so it's this elaborate shell game that allows your whole repertoire to it's constantly undergoing surveillance of your body for foreign proteins this is part of the reason that there may be a lag with the adaptive immune response as opposed to the innate immune response because they still have to find each other and it can take some days sometimes for that to happen so the immunologist view of cardiology getting back to my joke is that really the heart is the pump for lymphocytes to kind of move them around from one place to another so it is location location location just like real-estate again if there's not the encounter the diesel says I'm out of here and it goes to another site and we call this lymphocyte recirculation so this obviously is a very important part of the immune system but it's amazing when you think about how much energy is spent just being poised for the t-cell to find the antigen so again it must have an enormous adaptive advantage to evolve this way it may seem incredibly wasteful but such as the the nature of some of our most intricate defenses as we know in military terms so this is what we would call a pretty high-end expensive defense mechanism so the other thing that is characteristic of adaptive immunity as opposed to eight immunity is the memory recall the plague of Athens so once you've gotten over it you're able to have an enhanced immune response that can that can maybe save your life or give you a milder infection how does that work well as part of the expansion of these cells so so when a t-cell gets activated by its by its particular antigen that it sees let's say the Ebola virus peptide the numbers of that cell expand enormous Li and then after the pathogen is dealt with there will be a contraction back down to lower numbers but it will never be as low as when you start it and it's that persistent higher frequency of cells to it to a pathogen that allows you to have a memory response so you can actually use this to determine what people have actually been infected with if you can show that there's more cells that react with a particular pathogen than is characteristic of what we call a naive T cell repertoire you know that they've already been exposed to that pathogen and we use this all the time and immunology to characterize it this is shows you in diagrammatic terms you get the initial big expansion of the number of T cells or the number of B cells and then when with the resolution of the infection hopefully you get a very slow decline but it can take years or decades in some cases memory really is that durable a five year old that has for example smallpox at 80 years of age will still have detectable T cell immunity and B cell immunity to smallpox so it's quite remarkable yeah could you use this for prime identification so you just take a person's blood find everything uses - and say that's the person just as well as the fingerprint or a DNA you'd have to know what they actually have been exposed to but I suppose you could you could determine where they might have grown up or some of their infectious history right is there enough unique that you can say that this person when you go I see yes so I think the question is more of a sort of forensic thing can you use is it is each person's if I may rephrase it for you if each person's sort of adaptive immune repertoire unique so that you can say this this drop of blood came from that that individual it theoretically you could do it it's just that it's so much easier just to use straight DNA but you could theoretically work yes active visit the immune system defined with the agent of saliva it does yet so the question is does the effectiveness of the immune system decline with age absolutely does one of the problems is that the thymus eventually becomes lazy fat filled and probably what happened is that from an evolutionary point of view we used to not live so long so there probably wasn't any need to have an immune system after age 50 because nobody lived to 50s so there actually is a problem now with what we call immuno senescence so for example after age 50 you make very few new T cells by the thymus and that probably is an important factor for example of why the elderly don't respond well to new infections that come on the scene like pandemic influenza diseases developed within this immune system so the question is how to autoimmune diseases valve in the immune system I could always just say stay tuned next week I will talk a little bit about it one of the problems is that I'll talk a little bit about defects in this negative selection process causing autoimmune disease but I think the a fair answer is that we really don't understand the pathogenesis of most autoimmune diseases in the kind of detail I think you're probably after one thing that's true is that you can have inappropriate triggers by infections what we call molecular mimicry where the T cells will be triggered by a pathogen say for example a streptococcal infection and it will trigger the immune system to attack related antigens that are found on the body like in the heart so that would be the cause of rheumatic heart disease but to be honest for most Ottoman diseases we don't even have that level of understanding but I'll be happy to tell you some theories if you want to afterwards they're fairly complicated yes they really what they see what they so in a person receives a bone marrow transplant they receive stem cells what we call metabolic stem cells from the donor and those have to give rise to an entirely new immune system so they give rise to new T cells and B cells and that's one of the reasons that as your thymus gets older it's difficult to do bone-marrow transplants and get good t-cell recall t-cell reconstitution if you're over 50 because you still are depending not just on that bone marrow but on the bone marrow going to the thymus to make those new T cells and that's one of the limitations of bone marrow transplant yes are you going to get into the effective stress on the immune system and its ability am I going to get into the the impact of stress on the immune system probably not tonight but if that was covered last quarter god help us that's great because that's a whole there's a lot of interesting things I'm not going to get into tonight one is stress the other as phil was mentioning that there's some very interesting impacts of obesity on being pro-inflammatory it actually turns out that obesity is interpreted in a way by the innate immune system as sort of a danger as something that's gone amiss so it's actually a very inflammatory and that's one of the reasons that obesity is associated with things like heart disease and atherosclerosis because those are those are linked but I unfortunately could cover everything so but I do want to give you some idea about the importance of what the immune system can do against pathogens so let me just give you some examples so your cd4 T cells I think are the most remarkable example of what of how the immune system has evolved to deal with all these nasty critters out there so it turns out that you have these funny named cells at the bottom here T helper one cells or th 1 cells T helper 2 cells th17 cells what are these things each one of these are a type of cd4 T cell that has evolved really to deal with different types of pathogens and each one involves a process where it secretes these proteins called cytokines that orchestrate other non T cells other kinds of cells in the immune system to carry out the immune response and this is really I think one of the more important achievements of understanding of the immune system that wasn't probably known when Phil was in medical school or even even there wasn't any inkling that any of this stuff is going on so there's unique cytokine profiles as shown here and what's also interesting is that these cells sort of have this these marching orders to become you know to carry out all this stuff where maybe one or two proteins in the cell that we call master transcription factors once they get activated everything is stereotyped the cell knows what to do it's quite remarkable one protein regulating fifty to a hundred protein so that it's done just the right way and all this is now known so let's start with T helper one or th one effector cells these really have one important purpose they deal with organisms like tuberculosis that love to hide out inside these these what we call mono nuclear phagocytes so these cells are great places to hide out because they're very wimpy at actually killing things that that get inside these little compartments called the phagosome they actually need signals from the T helper one cell to get revved up to kill tuberculosis and in the rare patients that have defects in just these two helper one cells this is the infection we see over and over again mycobacteria infection they also help orchestrate kind of a holding action to keep these bacteria from running amok so they may not be able to completely eliminate tuberculosis as many of you know once you get exposed to tuberculosis and get what we call latent infection where it may not cause disease it's really hard to be sure that you ever get rid of the bacteria but you can do things that the body can do things to contain this infection sure the bacteria try to get the upper hand and they form these sort of little forts where they have all these cells around the site of infection called granulomas and these granulomas are characteristic if you see this when you take a piece of tissue look under the microscope you know that there's been a t-helper one response and there's likely to be an organism like tuberculosis t-helper two cells even though they're just one number different completely different strategy they're really here for one reason to deal with those nasty big worms I talked about so the nasty big worms they're so big you can't really put them inside a phagocyte they're dwarf they dwarf the phagocyte they can't be taken up you have to use mechanisms to get rid of them that are quite different so what these cells do is there's their cd4 T cells but they make other cytokines that have a very different program they bring they make your gut contract so that it helps expel the worm or cough it up in the case of if it's in your lung they put a lot of mucus into your gut so that if that worm is trying to hold on to the to the gut wall it's harder for it to do it and they bring some special cells called eosinophils and these are Naevia Sinha fills because he goes was the goddess of the dawn and the histologies thought gee this kind of looks like this nice pink color you see when the Sun is coming ups we're going to call them eosinophils and that's the dye that stains the ESN dye that stains these cells they may look kind of pretty but they're actually the suicide bombers of the immune system what they do is they fling themselves on parasites and even though they're small they gather in large numbers in it and they are chock-full of very nasty toxic things that will tend to make that parasite unhappy and either try and leave the body or if they're lucky they may kill it so all these things are coordinated by a single type of cd4 T cell called the T helper - cell then there's another one called th17 cells this one's kind of a funny name it's it's mainly named because it makes us cytokine called interleukin 17 or il 17 and this is an important cytokine for bringing neutrophils remember neutrophils are really good killers of things like bacteria and this is an example of where a t-cell is helping orchestrate a response against bacteria that unlike TB these bacteria are found outside the cell most bacteria like to live outside cells and these these cells these th17 cells help orchestrate the the production of more neutrophils by the bone marrow bring them into the site of infection so that they they can help eliminate the pathogen now the you have to have appropriate control of the immune system each one of these mechanisms is kind of like a bomb going off in the body potentially if it's allowed to run amok and in particular in your guts as you've heard already you have literally millions and billions of bacteria probably all of us have about 50 species of bacteria in enormous numbers in our guts that are actually commensals so they're helping us they're making vitamins they're helping us digest and yet each one of these potentially encodes all of these proteins that are not our own proteins that have never been expressed in the thymus so you have not purged your body of potentially of T cells that would react with with the proteins from these bacteria so one of the I think outstanding issues with the immune system is why is the immune system so good at ignoring all this noise when it could be going after all these bacteria inappropriately and causing things like inflammatory bowel disease so we don't know the answer to it except that it seems that in the gut the default path wave for the cd4 T cells is if they counter a uninflated state where these these peptides are floating around taken up by these dendritic cells they actually are converted to what we call a regulatory cell that suppresses turns off the immune system so this is the normal pathway it's only in the exception of where that dendritic cell gets a danger signal that there's actually a serious pathogen around say that the pathogen is associated with tissue destruction that the cd4 T cell gets a different signal it becomes for example a T helper 17 cell but I think this is going to be a very fruitful area of study and it's still to me one of the most amazing things about the immune system of how good it is it's starting out friend from foe yes yeah so in so the so the question is what's the involved in the immunology of pregnancy so there probably are multiple mechanisms by which pregnancy is maintained because the the father is encoding the father's chromosomes but the baby inherits are going to potentially encode things that could lead to the rejection of the baby turns out that these regulatory cells are induced during pregnancy it turns out that one of the most interesting things I think in the last two years that's come out is that mother's cells almost routinely enter into the fetus at these these are the blood cells and they induce what we call regulatory t-cells of the baby as a fetus to turn off response to the mother cells and what's interesting is that persists for at least 18 years after you're born so it's a quite remarkable system and this was work that was performed by Joseph McCune at UCSF so so yes some of the same Meccan are involved in in keeping the mother and baby from rejecting each other okay so again some of the key signals for which of these cd4 T cells you become if you're at if you're what we call a naive cd4 T cell you're an undifferentiated t cell you don't know what you're need to do how does the immune system make that decision for you what it uses again are these proteins called cytokines there are many different types of cytokines but these particular cytokines come from cells like dendritic cells and other cells of the innate immune system and for example in a parasitic infection there will be particular cytokines that are induced by having that parasite around that will direct the cd4 T cell to become a T helper to cell there will be particular cytokines that mononuclear phagocytes when they get parasitized by TB they will make cytokines that help direct the cd4 T cell to become the T helper one so this is an example of where you have the linkage between the innate immune system and the appropriate outcome in terms of the adaptive immune system but sometimes there's a mismatch and this can be real trouble between the signals that are made and what actually is needed to deal with the infection and the outstanding example is in a disease that's related to Bourke ulos is called leprosy it's caused by the same gener a bacterium Mycobacterium so in leprosy you'll have examples of where though the best thing that you could have to control this infection just like with TB would be a T helper one response for some reason and we still don't know that exactly why in some individuals instead the cd4 T cells are guided to become T helper to cells which is if you've heard helps you deal with large parasitic worms but don't help you deal with these these bacteria that are inside your phagocytes and when you get this mismatch it's a disaster these patients have huge numbers of bacteria running amok and again it's another mystery where despite many years of study we still don't quite understand why in particular individuals there's the the crossing of signals that are inappropriate but probably a very important thing to figure out okay a little bit about the killer the killer T cells cd8 T cells are truly double-oh-seven they're licensed to kill so what they do is they have special granule contents so these are little proteins inside their cell that they release when they get triggered when they detect a virally infected cell so they detect it just the same way that cd4 t-cells do they only see in this case viral from viruses little peptides on hot dog buns if they happen to get the signal they will release these proteins that poke holes in in that what we call the target cell that they're trying to eliminate and then they bring in other proteins that trigger that cell to undergo something called programmed cell death or apoptosis so the cell suddenly shuts down and dies but it's done in a very clean manner the virus isn't allowed to escape it gets destroyed at the same time the nice thing about apoptosis is it doesn't cause a lot of collateral damage you don't get a lot of inflammation at the site of where it's happening it's like a surgical strike and you need in a typical viral infection as all of us that have had influenza are where you feel like your whole body is coming to an end you've got all this virus and this huge numbers you may need a lot of these foot soldiers to actually go out and check out all of your tissues to get rid of virus and for example in mononucleosis which is due to a virus called epstein-barr virus half of the cd8 T cells in your blood may actually just be seeing one kind of protein from that virus so you may need enormous numbers of these cells to control the the viral infection but again once the virus is under control you're going to demobilize these cd8 t-cells and you can see that you need more foot soldiers you need more killers to go out in the field and you need the generals the cd4 T cells so you don't have as many of these getting expanded you have an enormous number of the cd8 t-cells typically to deal with a viral infection and this is just a cartoon showing the kind of surgical strike I'm talking about the cd8 t-cell will march along let's say this is a group of cells in a thing called an epithelium and it says AHA t-cell receptor gets recognizes that there's a little foreign viral peptide on this MHC molecule gets the appropriate trigger kills the cell then it goes to the next cell sees if it has the same infection and so on so these cd8 t-cells can actually what we call recycle where they can Rev themselves up to kill again and again and again in a relatively short period of time and they're very efficient now the problem with viruses is they can infect virtually any tissue you don't know what virus is going to come along ten years from now we hope not but there might be a virus that has a completely new kind of tissue that it's attacking that we don't even know about so the immune system has got that covered as well because the particular kind of MHC molecules that display these viral peptides these are found on all the tissues of the body so the viruses can infect whatever they want but the cd8 T cells will eventually be able to find them and get rid of them and that's what one of the interesting things about these MHC molecules they really are very versatile and are there to be able to present these peptides from viruses in they may occur do you have a question it is a virus that's correct is the question was epstein-barr virus or her preserves it is or preserves and like all herpes viruses it is forever once you get it okay the other thing that cd8 t-cells illustrate is that I that part of memory is the fact that you after you've had an infection you always have for the rest of your life more of the cells that have that specificity for that particular infection ready to go the other thing about memory is that once a cd8 t-cell has you've generated response of cd8 t-cells you get these cells that are what we call memory cells that when they if they let's say that you happen to get influenza one year expand your influenza specific cd8 t-cells the next year you get another case of influenza and it's very similar you will have the cd8 t-cells that that come from the memory cells the ones that become licensed to kill again they're better they have better function each cell has the ability to do more things than the first time the cd8 T cell gets its license to kill so there's there's a difference in the quality of the of the immune response from what we call memory cells as opposed to from naive cells and that accounts for also why you're better protected the second or third time around now we think that cd8 T cells mainly are there as antiviral mechanisms but they do have the ability to kill tumors if a tumor in particular comes up with something that is not found for example in the thymus so that the T cell wasn't purged of that particular you know that particular T so wasn't purchase of reaction with that something new it will be interpreted by the T cell as as something foreign like a virus and they can potentially kill tumors and this is something that had that is being attempted to be exploited for for therapy and I actually think that there's very promising approaches by which to really unleash cd8 T cells in cancer I think there was a lot of skepticism but I think that there's growing evidence that even naturally with many tumors you can find seagate t-cells that are going to be too more reactive they often are suppressed by the tumor but if you can figure out how to bypass that they can actually be potentially potent weapons against the tumor I'll probably leave that for the lectures on on tumors so of course I have to talk about b-cells even though some may mean I'll just think the B stands for boring I actually think they're kind of interesting so B cells are also mediators of adaptive immunity but they have a very different role so remember T cells have this very unusual process where they recognize peptides bound to MHC molecules so very very strange and sort of counterintuitive B cells are very intuitive you can grasp right away how they work they secrete these proteins they have from the cell and they float around in all the fluids of the body and like the complement system they can tag the pathogen for destruction so it's much much simpler but again you have tens of millions of different kinds of potential antibodies are also called immunoglobulins it means the same thing and so you have to go through the same process of making these by this process of vdj recombination but the process is the same other than the fact that the genes are slightly different they are still put together exactly the same way where you kind of cut select from column a column B column C stitch them together with the same enzymes that are used for the teas cells you have the same double-stranded breaks by the rag proteins you have the same random nucleotide generator at the ends to make them even more diverse it's just that that these these genes encode immunoglobulin and not t-cell receptors so these have the ability unlike the t-cell receptor which is always stuck on the surface of the t-cell it's never secreted these can be both in a form in which there on the surface of the B cell and then they can also become secreted into the fluids of the body the other big difference between antibody and t-cell receptors antibody does not see peptide MHC complexes it actually sees 3-dimensional shapes also more intuitive so kind of like a lock-and-key system as shown here so it has this nice triangular shape that mat that complements the antigen then it's going to bind but it's not going to bind to this this shape over here because it's not a good match with its complementary shape the other thing about antibodies they're they're not limited to seeing proteins they can see any molecule any three-dimensional molecule shape so they're much more versatile in that sense of it's a sugar molecule on the surface of the pathogen they can bind it most of the antibody is actually produced these cells get activated in the same way that t-cells do where first the antigen binds to the surface triggers the B cell to get activated to divide and to start carrying out its immune function but but the immune function of the B so really is to just make lots of antibody and put it out in the fluids and it does it in the form of a special cell called the plasma cell shown here so b-cell immunity is also called humoral immunity because in Latin the humors are the body fluids and and that's that's app so you'll often hear that term humoral immunity but all it really means is that it's B cells and plasma cells that are secreting at bodies into the fluids so just like the complement system antibody can help tag bacteria and fungi for destruction so you have special receptors on on the professional phagocytes like the neutrophils that are the good killers that help optimize using the George Bernard Shaw terminology bring in the pathogen into the inside of the cell where you can now kill it and it turns out that antibody binding to these pathogens can also activate the complement system so you get a double whammy you get both antibody and complement both tagging the pathogen to help bring it in for destruction make it even more efficient as shown here so where do you really need the system to deal with what kind of pathogens are really the bad actors where B cell immunity is essential probably the single species of bacteria where you really need it the most is something called streptococcus pneumoniae also called the pneumococcus you may hear it as pneumococcal pneumonia so these bacteria this is the part of the bacteria that actually has all the met metabolism going on so these bacteria can live this way but in in the actual body when they invade as a pathogen they have this enormous goo you can see how much larger they are this is all an outer capsule that surrounds the bacteria proper and its main purpose is to help the bacteria evade the immune system this stuff is extremely slippery these capsules and complement really cannot tag it effectively the only way to effectively tag these so these bacteria for Destruction is to have an antibody that can bind the capsule then the neutrophils can take these things up and kill them so what we see is that in people that have problems with their bee cells they're going to have recurrent problems in dealing with these bacteria they're going to have pneumonia and sinusitis and other kinds of infections and this bacteria is going to count for 90 percent of the problems that they have so this also illustrates I like in this slide just looking at the specificity of antibody cell receptors they're exquisitely specific so if you for example get infected with measles virus you will make antibodies that are able to bind to the surface of that virus and prevent it from infecting a cell but this is not going to have any help if you get infected with an unrelated virus so the specificity is a great thing but unfortunately what it means is that you have to either get vaccinated or actually get the infection to have that great specificity and those of us that are parents know full well what that really means getting infected over and over again with the latest cold virus is part of the job description now the exquisite specificity though can be exploited you can make in the laboratory specific antibodies to almost anything if you want to and in large quantity and these can be used for therapies these are called monoclonal antibodies because they come from one clone so it's one type of antibiotic 'el molecularly and i think an outstanding example is using these for example to treat lymphoma b-cell lymphomas you can make an antibody against a protein that's on most b-cells and use this to eliminate the b-cells with the same mechanisms that would normally be involved with eliminating pathogens so this is a very promising way of for example cancer therapy and there are now literally dozens of monacle antibodies for various kinds of tumors but of course we'd like to be able to boost the immune response and this is what Harry greenberg is going to talk about I've been interested in using a particular technology to fool the immune system if you well into thinking that it's actually been invaded by a serious pathogen it makes sense to me anyway that that if the immune system interprets the vaccine is actually a real threat to it the same thing is like a natural infection it's going to do everything it can to put up a good fight and so we've come up with tricks ways of mimicking infections to fool the immune system into putting out putting out its best defense so for example you can make things that look like viruses to the immune system in that they rapidly enter into cells such as dendritic cells and they activate the toll-like receptors and the other receptors and turn on the immune system and to get these these walloping immune responses and I think we're just really in the infancy of developing these approaches to to enhance the immune response so when we talk about adjuvant these are really additions to vaccines to make them work even better comes from the Latin same Latin root for rejuvenation or juvenile you want that youthful vigor of the immune response in dealing with pathogens so health vs. disease so I often I obviously can't go into all the things that can go wrong with the immune system but just like Tolstoy said all happy families resemble one another but each unhappy family is unhappy in its own way the same thing with immunodeficiency each one is a special story we know of a hundred and forty genetic defects and each one is a story but they do illustrate the importance of the immune system and normal a function so for example you can have a problem where the only problem is that there's one protein missing that helps the neutrophil get across from the bloodstream into the tissue to form pus and to help kill bacteria and fungi and this protein is also when it's missing as part of your normal health of your mouth your gums are always a potentially going to be invaded by bacteria and the only thing that keeps them healthy is that the neutrophils have the ability to also go into the tissue and help control them so these patients lose their teeth prematurely this is a patient with this at 16 years of age and they have all kinds of recurrent infections but they never like pus you can have a complete lack of the adaptive immune system from a single gene defect remember that in order to make the t-cell receptors and the B cell receptors immunoglobulin molecules you needed to do these double stranded DNA cuts by these rag proteins there are rare individuals where there's a problem with the rag proteins they have a mutation in the genes encoding them they completely lack a thymus that's functional this is a normal thing as showing all these nice developing t-cells and this is all the the few t-cells that can be made in someone who has the deficiency of these rag proteins you can have much more selective problems so it turns out that there are certain genes whose sole function is to help the thymus express all of these proteins of the body as part of the purging process of what we call autoreactive t-cells so for example helping the thymic epithelial cells Express the insulin protein so that those can be used to purge the the developing T cells of the T cells that react with insulin so in fact what happens is if you lack this one gene that process is impaired the patients tend to get diabetes because the t-cells get out the thymus they find the insulin peptide in the in the islets of langerhans and they and they attack the whole tissue and they cause diabetes so quite remarkable single gene can do that so I want to end with this because i Richard vitamin though he's a physicist I think I like this using this quote with medical students because I like to teach immunology not just for its pragmatic purpose but I what he says here is what people are poets who can speak of Jupiter as if he were a man but if he is an immense spinning sphere of methane and ammonia must be silent so I have really tried to provide you with as accurate as I can the real immune system in with some scientific rigor because I think that really reveals its elegance more than anthropomorphizing about it so I hope you've found it interesting in that way and I'd like to oh yeah go ahead I'm Astrid the question is do these thymus transplants there is one center that does thymus transplants it's still in the early stages they've had some reasonable results it's for a particular disease called complete to gorge syndrome but it's not it's not something that's been reduced to clinical practice all over the world Gavin I see the blood transfusion you're deso deso mmunity if so the question is if you get a blood transfusion for me do you get potentially my t-cells as part of it if you get a whole blood transfusion the answer is yes and in individuals that don't have a normal immune system what's typically done is that that is irradiated with radiation to paralyze and kill the t-cells so that they can't potentially try and set up shop inside your body there is a phenomenon where that can happen called graph versus host disease where the t-cells will actually sit in your body and will start rejecting every tissue they encounter but if you're a healthy individual what will happen is your t-cells your t-cells will be able to get rid of the t-cells that are attempting to enter into the body because they will recognize them as foreign I didn't really have time to get into transplantation immunology that's a whole probably at least worth an hour our immune or not sensitive to their mother's immune but I understood that that babies who are breastfed and when they're first born and have their mothers immunities services well what what so the question is what kind of immunity do babies get from their mother so I didn't have time to get into it but during the last trimester of pregnancy there is a transfer from the mother of antibody across the placenta so that the baby is actually born with as high a level of antibody to anything the mothers had in her life and it's a wonderful protective mechanism it's one of the reasons that you may have noticed many of us may have noticed that the first six months are kind of like the holiday from infections that then suddenly start appearing with the babies and it's because these antibodies last for about that long the mother does not transfer T cell immunity however so it's pretty much just antibody the tolerance mechanism is probably very durable where the mothers some of her blood cells do get into the fetus and do induce this tolerance mechanism but it doesn't again doesn't have anything helpful in terms of T cell immunity it's really just to prevent there from being a rejection of the mother by the fetus now what's interesting is that if you get a transplant from the mother to the baby compared to the father in general the mother is better tolerated for that reason because of that that and again this wasn't even known until two years ago the mechanism so it's quite more yeah theory that our homes in a way are too clean and that children [Music] see y know what the mechanism with so that so the question is there's this hypothesis it's usually called the hygiene hypothesis and it's used to account the question is why is allergic diseases such as asthma eczema increasing in in developed countries first thing you have to know is that that I don't think we really know the answer and I think that that whether hygiene itself is really the cause is still controversial I've been accused of being kind of a naysayer of that hypothesis but I can talk to you about why I've been accused of that just publish what I see but but I think what's interesting is that allergy can really be seen as a mistaken q so what the immune system is doing is it's turning on the t helper to response all the mechanisms that I mentioned that help you deal with worms are being targeted against allergens dust mite cockroach allergen ragweed whatever all these things are triggering inappropriately these are otherwise completely innocuous compounds but they are triggering the same response as you get with a worm we now think we understand some of the things that they do they trick a cell that helps direct the T helper to response called the basal fill it misinterprets the cue but it leads to the to the production of allergy it doesn't answer your question but I think now that we understand really what fundamentally triggers allergy we may have a chance to see why having a lack of dirt and certain kinds of infections around might be leading to increased allergy I think until that observation last year we really weren't any position to put it all together one more yes fire so the question is what what is why is aids so causing such profound immunodeficiency what happens in AIDS is that the the virus very early on starts destroying cd4 T cells all kinds not just T helper one T helper to all of them and as well as ones that are freshly produced from the thymus and it's particularly good at doing this in the gut and even though your numbers in the blood may not look that low initially the total body number of cd4 T cells starts declining almost within two weeks of infection and it just goes downhill from there the virus also in addition to reducing the numbers has some other immunosuppressive effects on cells such as dendritic cells but essentially you're taking away the master regulators of the immune system all of these mechanisms that cd4 t-cells can do they're all taken away at the same time this would be two weeks of actual replication of the virus in detectable amounts so people now feel that the gut is probably the major site within about two weeks of it entering into the body you start to see the virus probably disseminates from the initial site of entry and then in the gut you have the smoldering infection again the blood really doesn't give you a real window on what's going on in the gut when people have actually been able to look more directly a lot of the immune destruction is happening in that tissue so and as you will remember for those who are here for the talk on the GI tract you'll remember those peyer's patches and the fact is the GI tract is actually on a surface area level one of the largest parts of the immune system in its own right so it's amazing to think about this so I think while you've been sitting here your own immune systems have been producing interesting things some cells responding others dying some to your neighbor some to yourself but it's been an active event I really wanted David to do what he did this evening this is not easy stuff I began by saying that when I was a medical student immunology was almost one or two lecture course and you had a compression of this the differences the level of sophistication that has taken place and continues to take place about the intricacies that this system is just unbelievable and by thinking about now some of the issues and lessons that you've had tonight I think it will make more relevant the discussion that you'll hear next week on autoimmunity or the one that follows on how vaccines work it will relate to aging in some ways and you heard some forecasts of that and then when we get to cancer it'll be quite clear how it relates to that both in terms of impact as well as in terms of therapy so I want to thank dr. Lewis for are getting us off to a great start making wonderful lecture and if you have immune fortitude and abilities you can come forward just don't get too close to him okay tonight see you next week for more please visit us at stanford.edu

Channel: Stanford

Views: 282,826

Rating: 4.6248479 out of 5

Keywords: medicine, human health, immunology, immune system, biology, science, microbe, cells, bacteria, pathogen, fungi, parasites, white, blood, virus, pandemic, innate, epithelial, peptides, phagocyte, toll-like, receptor, tlr, protein, complement system, adapti

Id: xDvQI9ynl1Q

Length: 113min 54sec (6834 seconds)

Published: Thu Jul 15 2010