Biological Sciences M121. Immunology with Hematology. Lecture 01. Course Introduction.

okay according to my watch it's noon that clock in the back seems to be slow but we'll go by my watch welcome to BIOS I 121 immunology I'm Professor David Freeman my co-instructor will be Professor Craig Walsh and I'd like to start by going through the syllabus and talking a little bit about enrollments then there'll be an announcement from a tutor and then we'll jump right into the lecture so I projected the syllabus up here we actually have three teaching assistants we've added a third one Warren place Ted but we won't be interacting with them because there's no discussion section that teaching assistants are really just here to Proctor exams and to do grading and so that brings me that noise to another announcement which I always make which is please turn off all electronic devices or silence them during the lectures and if you're going to use your computer please use it for course materials and not for other things that movies distract those around you okay so the textbook shown here we were little late in ordering but I think it should be in the bookstore by now but it also comes as an e-book which is what I use and it has all the information that you need there and you can um it you know don't have to carry around the textbook everywhere and so that's a choice for you and then what I want to talk about next is the examinations there are only two ways to earn or lose points in this in this course it's just the midterm in the final exam so you got to be ready for those the midterm is 100 points the finals 200 points the midterm is is a 50-minute exam on the final is a two-hour exam and I scheduled the midterm this year to be about one third of the way through the course the final will cover mainly the last two thirds we consider a comprehensive because the information you learn in the first third is important to understand to apply to the second half but we won't ask you detailed questions about the first part so it's a little bit different than some other core classes where what you learn before the first midterm or before the second midterm is really separate from what you learn later on it's a comprehensive exam yet it really focuses on the material after the mid-to our grading system is a little unusual in that we don't we don't use the mean and the standard deviation we basically use the median and we break down into the grades into eight divisions so 12 1/8 or 12.5% of the class will get an A 12.5 a - so 12.5 each of the half grades down to a C and then anything below is C C minus D and F will represent the last 12 and a half percent so when you look at the midterm and the final you'll be looking at the median and seeing where you are relative to that and relative to the graph so we show the standard deviation is not taken into account and what this means is that half the class will get a B or better half will get a B - or below and so it's a little more generous than in many of the core classes where they set them the mean at the border between the B - and the C+ now everybody does really well spectacularly well we don't have to give so many grades low grades but in general things sort themselves out so this is the breakdown that we get alright so be aware that the midterm takes place in class on October 21st the final will be at a different time one-third to 3:30 p.m. I'm going to have at least for my part of this course some optional quizzes that I'll post on EEE that you can take and then I'll post the answers about a week later so you can check your work so to keep up and see how you're doing and see the format of questions that will appear on the exams later on I will have a review session we will have one along with dr. Walsh on the Friday before the final exam if there's time I'll have I'll answer a few questions before the midterm as well I I also take questions during the lectures and I can usually stick around for about five or ten minutes after the lectures to answer questions but other than those times that the time to meet with me would be during my office hour which is Monday I've set it from 2:30 to 3:30 p.m. so that people have two o'clock classes or three o'clock classes we'll still have a chance to squeeze in some time if you can't make if every week you're booked for this entire time and you need to schedule time with me send me an email and we'll see if we can work something but I would prefer to have you uh preparing questions in meet with me after class I have a lot of other teaching duties and research administrative responsibilities so I also will have a message board where you can post questions that I'll try to answer that may be frequently asked by other students as well and sometimes other students will try to answer the question on the message board and we can and we can deal with difficult problems that way as well or commonly occurring questions now I just want to go through the syllabus the lectures itself you can see that I've listed the titles of the lectures the textbook chapter that they're associated with and the lecturer over here and for the most part we go in order and the first half or so of the course deals with basic mechanisms of the immune system this the cells and the molecules that do the work in the immune system how they're put together their general functions and then this the second half of the course really puts this in motion and applies it to problems of host defense to infection autoimmune disease and transplantation and so forth so the first half was really mechanistic you might think of it as a fair amount of memorization of parts that are going to later be put together into some sort of whole and sometimes students complain that there's really no not enough context in the first half of the course so what I've done this year so I've moved up a lecture on the function of antibodies from chapter 9 to follow the lectures on any body structure and generation of diverse antibodies and when I looked at this lecture and the content I realized that it really doesn't require any of the material in between chapters you know five to eight so it's possible to give this lecture I up here and all the question burning burning questions you have when you're learning about any body structure and diversity will start to be answered and even before the midterm so you'll get a little bit of application in the first half of the course on the other point I want to make is that the other part of chapter 9 I've giving that lecture on November 1st which is before dr. Walsh will present chapter 8 and again the B cell immunity lecture not require prior knowledge of the material in this chapter eight and this is done based on the schedules of myself and professor Walsh okay any questions about the syllabus so far I want to go back for a second and talk about the book I you don't absolutely have to buy the book or read the book I recommend it but the first and most important thing that you should do to prepare for exams in this course is to is to really understand the lecture notes myself and professor Walsh both provide notes and slides and if we do not ask you any questions based on material that's not presented in class and summarized in these lecture notes our lecture notes are fairly detailed so if you read and understand everything in these lecture notes that is sufficient now the reason for the book is that often the material is not exactly clear or you want to put it in the context of some of the human diseases that they talk about in the textbook or restate the information and probably the other important reason to get the book is because the pictures I'm going to show you the slides I'm going to project will not have the figure legends or captions with them so sometimes when you go back and look at the slides during your review you will really remember exactly what the what it was trying to say even if you can refer to the notes so if you actually have the book or the e-book you could look at the captions with the figures and it'll remind you exactly what's there and the other really important reason to get the book is that the beginnings and ends of the chapters have some reads that really put everything big-picture in context the important facts and concepts for you to remember and we really try to be concept driven in this class there is a lot to memorize but if you don't understand the big picture of how cells work together and how the immune response happens and what goes wrong in different diseases then you're not going to do well on the exam especially the short answer free answer parts so by reading those more broad summary material and also looking at the the sample questions in the back you put yourself in a better position to do well but the but just to return to the first point the very first thing and the second thing you should do is review the note because we will choose our questions based on what we present in the class and we will never I promise you have a question based on material that's in the book that's not covered in class so if you're reading in the book and there's something that's unfamiliar and you don't understand it don't worry about it if it was not in class don't spend your time your valuable study time trying to understand everything in the book if it wasn't presented here and every year we have people who come after midterm and say I did really badly I read the book and and I did badly and I'll say well how well did you study the notes and they'll say well I looked at them but I really read the book and for some reason the message doesn't always get through but focus your study time on the notes and use the book as a secondary study tool okay now everybody who's going to be here probably here I can talk about enrollment you can see this room has extra space but we limit the class to 160 some of you may be here waiting to get into the class I can assure you that you will get into the class because I'm teaching this class for 12 years now and we've never had an undergraduate student who hasn't got into the course and that's because within the first two weeks we have a large turnover a lot of students will drop the course will choose something else they find my lectures boring or challenging I don't know what it is but I scare them away so you will get into this class the reason we don't open it up to 250 or whatever the capacity is we used to be in a smaller room this class is designed to be a reasonable size we have a limited number of TAS and used to be 135 we only raise it to 160 this year because we got 1/3 TA it's just impossible to teach the course in the kind of interactive way that we want and with the amount of grading help that we get in a larger size we want to be able to do short answer questions instead of scantrons so that's why we keep the class in a manageable size if you are an extension student usually extension students also get spaces but you need to hang on for two weeks and wait I can't sign paperwork until we know their spaces if you are an extension student you will I would appreciate it if you come up after class and bring me and write down your email address so I can keep you in the loop about course announcements before you enroll any questions alright now the last thing has to do with the podcasts in previous years I've used UCI replay to record my voice and pictures that I'm projecting this year the course is being filmed you'll see if fellow in the back who is recording this and he will and the goal is eventually I might be able to use the lectures in a more flipped course way to have more time to discuss in class and also potentially offer components of the course in a distance learning online format so we're taping the class this year and Sean back there is going to provide me with a with videos that will be posted on a private youtube link and that those I will provide to you as opposed to a UC I replay link and he'll be able to capture me the screen and everything going on with the pointer as as we give this and I have a mic here which is recording seems like it slid down a little bit so I'll bring it back up if there any problems with the recordings or accessing them we'll work on that but it they've done this a lot with other courses and so we're going to try that this year okay is it too dark I think 75 might be better it's not better or do you like to have it lower to see the screen let me know okay let me tell you about what you're going to learn in this course before we jump into the actual content you'll learn how the immune system functions to protect the host meaning the person or the animal and in some cases to cause damage to the host and why is this exciting it's because I think that this is a really fun course an exciting course because really you can apply all that you've learned for more basic courses in genetics molecular biology cell biology to a complex biological system that affects our lives every day we've all been sick we all know people who are sick whose immune systems are not fighting off viruses and bacteria or causing problems so understanding how this works is a really exciting process and I would recommend to enjoy this course into better in this course try to get beyond what do I need to know on the exam and try to think about what can I learn in this class about how life really works most of the students who stick with this class find it to be one of the most interesting courses they take even though they usually say it's one of the most challenging so again there's a lot of material and some very complex concepts I will go fairly quickly through much of the material which is written down carefully in the notes for you to review later but from experience I know the areas that the concepts get difficult and then I'll slow down nevertheless at any point if there's if there's something that you don't understand I would welcome questions and I try to break during the class to answer questions at various points to wake people up and to sort of break the monotony also not in the first lecture but in later lectures I always take a one to two minute break to just leave the lecture drop the pencils and talk about something topical and in the news or in in our lives that relates to the lecture material so that's our little break from the class that we'll have again to try to wake people up and put this more in the context of something more interesting now I recommend that you read chapter one as soon as possible when I was in college I would often wait weeks to start you know studying and reading and that do not recommend you do that in this class you should read the notes and the lecture and the start reading chapter one if you do read the book you should start reading that right away okay here are some pictures of pathogens just to get us started and we all know that the immune system protects us from pathogens and we'll talk more about what pathogens are in a minute but the immune system also protects us from cancer and one way we know that is that HIV patients whose immune systems aren't working very well tend to have many cancers appear that don't appear in otherwise healthy people so in this course you're going to learn how the human immune system has evolved mechanisms to recognize a nearly limitless array of foreign invaders some of we're showing here as well as subtle differences between cancer cells and normal cells you'll learn how the immune system eliminates the dangerous invaders and cancer cells but keep in mind as we move along that many people still die of infectious diseases in cancer so the mean system doesn't work perfectly and our task as immunologists is to bring in other human advantages like intelligence and creativity to bolster the remarkable immune system we already have it's worth keeping in mind that really the immune system doesn't work as well as many other organ systems in the absence of vaccines and antibiotics and all the other things we do to help us survive in this world of microbes you know a large fraction people die before they even make it to adulthood that was the history of humanity death from infection on the battlefield death of children and young adults whereas it's rare that somebody's born with a heart that doesn't work or lungs that don't work or kidneys that don't function those things happen but they're they're very rare it's almost anybody can die of an infectious disease if they don't have the right antibiotics handy or they didn't have the right vaccine so really our immune systems are playing catch-up with these diverse microbes and it's amazing that they do a job as well as they do but we'd like to help them do better it's also important to remember that the immune system is not always protective the immune system can cause severe inflammation if the response is too strong or it's not turned off properly you can get tissue damage like all the scarring that you get from the acne the response to innocuous bacteria in your skin or you can even get death from septic shock or anaphylactic shock so the immune system isn't always your friend it's also responsible for allergy I have allergies many of you have allergies and these again allergies our immune responses against harmless substances that really don't pose any danger to us yet we're trying to sneeze them out and and you know cop them out and other immune reactions that are really dangerous and can lead to death life-threatening anaphylactic shock for example to some peanut allergies and so forth then you have autoimmunity if the response occurs against one's own tissue then you get autoimmune disease and it's this is really a very common set of diseases a lot of people in the community don't realize it but autoimmune disease include multiple sclerosis juvenile diabetes rheumatoid arthritis and lupus and I'm sure many of you know people with these diseases and others like Crohn's disease so I improper activation of the immune system against your own tissue is very very common I had a student in the class a few years ago who had juvenile rheumatoid arthritis it's not just a disease of elderly people and lastly the immune system limits our ability to transplant organs because it wants to reject organs that from somebody else so at the same time we're trying to boost immune responses to these bugs we're trying to limit immune responses to our own bodies so I'm going to try to keep the arrow on here alright so a pathogen is defined as any organism that has potential to cause disease to the host it's usually a microorganism or parasite here are some pictures and figure 1.4 comes in three parts and it just is a long list of the different types of human pathogens now I don't expect you to memorize this this is just for your interest to you know why are we sitting here talking about immunology because there's a lot of dangerous bugs out there and these are some of them many of them you've heard of some of you haven't some of them cause diseases you are aware of but didn't realize that that there they had a microorganism involved one thing you should do especially if you haven't taken the microbiology course yet is to review bacteria vs viruses vs fungi vs protozoa and general aspects of their lifecycle you need to understand viruses as intracellular parasites that replicate in cells and bacteria as either extracellular intracellular those sorts of distinctions of pathogen likes life cycles become important as we talk about how they mean system deals with them now some of these pathogens are called opportunistic pathogens because they only cause disease in hosts that are immunological weakened or compromised in some way like HIV infected people or patients can undergoing immunosuppressive therapy after organ transplantation or cancer treatment and then there are many many microorganisms that are not pathogens even though they coexist in our body there the normal flora of the gut on the skin and in some cases they actually help you and I'm sure you've all heard about helpful bacteria and microbiome and by a probiotic therapies and so forth and the term for normal gut flora is commensal species in fact we have more non-human cells in our body than human cells because bacteria are so small a lot of them don't add up to a lot of space but we have more of them than we have of ourselves now even among pathogens most of them don't kill the host it's actually a better strategy to survive to allow the host to survive and to transmit the disease by being really sick and coughing and sneezing or having diarrhea and then recovering too and so that the person doesn't die right away and they infect as many people as possible not gives the immune system chance to deal with it in allow recovery even severe diseases like influenza don't usually kill the patient at the immune system eventually eliminates the virus now all of these pathogens have molecules on their surface or inside of them that are different than our own molecules and those are called antigens an antigen really is defined as any substance that can induce an immune response okay so before I get into the next slides I just want to talk generally about some of the body's defenses and give you some definitions in this course we're going to talk about innate immunity versus adaptive immunity innate immunity is defined as mechanisms that recognize and control or eliminate pathogens without requiring any prior exposure to that pathogen it's like the first line of defense its pre-existing in the host and it's relatively nonspecific you've probably heard about this if you've taken microbiology and virology just to remind you that's innate immunity adaptive immunity are mechanisms that are not pre-existing they develop over time after exposure to a pathogen and they're mediated mainly by cells called lymphocytes and two main classes of lymphocytes t-cells and b-cells and also adaptive immunity is antigen specific and finally it provides memory provides lifelong immunity to reinfection that's just the introduction we'll come back at the end of this lecture to little more details about an eight and adapt immunity and then of course detailed lectures on each of them later on so some definitions I want to start with the term leukocyte is a from greek words that mean white cell so leukocyte is a white blood cell and that includes just about all the cells that we're going to talk about in this course or generally termed leukocytes within that group the lymphocytes are subtype that includes the T cells and B cells as well as another cell type called natural killer cells or NK cells and while they're lymphocytes and K cells are really more part of the innate immune system and we'll see how that works later on an antibody is a protein that binds antigens and is produced by D cells anybody's found in the plasma and other body fluids what is plasma plasma is the liquid component in the blood if you can imagine blood just removing all the cells from it what's left is plasma and plasma is constantly leaking out of the blood vessels into tissues where it mixes with other fluids that are in those in those tissues outside the cells together this material is called lymph we've heard of lymph nodes I'm sure lymph is this material that is partly composed of blood plasma and other secretion and everything that's existing inside the tissues now how do you obtain plasma from a person or from an animal you can do it by removing the blood in a in a in a weighted prevents clotting and then centrifuging to remove all of the cells so it's basically doing an experiment similar to what I just imagined which is removing all the cells but in order to do that you have to take them out of the body and spin down the cells but you have to do it in a way that prevents clotting once the blood clots things change and if you let the blood clot first before you do the centrifugation now the resulting liquid is called serum why is plasma different than serum during the blood clotting process many of the proteins in plasma get broken down and changed as part of the clotting process in addition platelets which are involved in blood clotting secrete a bunch of other proteins that are involved in wound healing for example and so the protein content of the blood changes during the process of clotting and depending on what analysis you're going to do for clinic clinical analysis or if you're going to use the liquid for some you know biological or biomedical application in the lab you might use plasma you might use serum but I just wanted you to be aware that they're they're actually two different things they're both a liquid component of the blood the plasma is just really is a liquid component of the blood the serum is a liquid after clotting has occurred and you'll run into both terms as you read through the text and I wanted you to be aware of the difference any questions about plasma vs. serum so now to return to innate immunity here is a picture of many of the surfaces that are places that pathogens could gain entry you can breathe them in you can eat them they can try to get in through your skin once you breathe them in they'll try to get across your lungs they can come in through the genital urinary tract if they make it past the the stomach they can take take up residence the intestines so all these places are areas that pathogens as well as symbiotic organisms can live an innate immunity is often concentrated in those areas in fact the anatomical barriers themselves are considered part of an eighth immunity skin is part of your innate immune system by preventing access of pathogens to your body all the time in Figure 1.6 you can see some of the other properties of the innate immune system and mechanical properties for example the mucus and cilia that we have in our lungs trachea esophagus and etc this traps a lot of the microbes and it gets them out as you caught and helps you cut to comp them out so the then you have these epithelial cells that are joined together by tight junctions in your skin in all those surfaces that I mentioned over here epithelial cells is the type of cell that has tight junctions to prove it it really serve as a barrier to the access of any potential pathogen that's trying to get across so I mentioned earlier battlefield wounds you watch a movie about some battle that took place in 1500 or 1700 they always show people getting their you know getting impaled by a sword or getting a head chopped off or something like that but far more common was you know a some sort of deep wound or a gunshot wound to the stomach where the person didn't die right away they with the reason that that most people died on the battlefield until the advent of antibiotics was through infection so they would linger for a few days and then get these horrible infections and eventually die and that's because the barrier function of the skin was broken so it's a really powerful component of the innate immune system our skin it's it's what you avoid having broken when when you're in battle and it's as they would clean up the battlefield afterwards a lot of those people are still alive and they would just go back to the medical tents and died a few days later okay so going back to this slide here some other aspects of the innate immune system that are sort of nonspecific it's hard to even think with them as a as an organ or anything like that is that the low pH the acidity of the the stomach takes care of a huge fraction of any pathogens that we take in through our food and drink there's also proteases like lysozyme which is present in our nasal secretions that's present in tears its present in saliva and lysozyme breaks down the cell walls of bacteria and then there also a whole class of peptides short peptides known as defensins which are secreted by epithelial cells all over the place and they can poke holes in the membranes of bacteria now not shown on this slide but something we'll talk about is a process known as phagocytosis in which cells internalize and break down foreign cells and macromolecules but we will talk about this process known as inflammation inflammation is defined as tissue damage and leakage of vascular fluids and cells in response to I and it's all initiated to try to help fight the infection but of course if there's too much inflammation that can cause damage the innate immune system plays a critical role in the in the inflammatory process by secretion of proteins known as as cytokines and among cytokines there's a subset called chemokines which actually attract other cells and lead to permeability of the membrane so here we go in healthy skin there's these effector cells which is a general term will just use now to describe cells of the innate immune system here's the capillary or the blood vessel with some white blood cells and red blood cells and here's the epithelial layer of or the endothelial layer of the capillary and epithelial skin you fall down you get some dirt and some bacteria get in the effector cell of the native mewn system takes up the bacteria releases cytokines this leads to openings in the endothelial wall allowing fluid plasma to leak in allowing cells white blood cells to squeeze across and and then these additional cells through the process of phagocytosis taking up the bacteria can eliminate the any remaining pathogens so the four cardinal signs of inflammation are heat pain redness and swelling and for those of you going to medical school you don't need to write this down but you may hear the Latin terms for these which are Kahlo or dole or rubra and two more again heat pain redness and swelling and the reason you have heat is because of the increased blood flow normally the surface of your skin is more close closer to the surface of the the temperature of the air your Bloods at body temperature as you get more blood in that area it warms up it also causes redness because you have more blood there the pain is because of pressure that's exerted on your nerve endings by the increased fluid flow and then the swelling of course is because of the increased presence of platon blood plasma and cells in that area so we're going to learn a lot in this class about cytokines which are small proteins that direct other cells and tissues what to do and among the cytokines a sub group called chemokines which are specifically involved in attracting or repelling other cells to get them to move in different directions the point is not staying I don't know why all right so any questions about inflammation all right it's I think it's it's partly it's society kinds in general but among the cytokines that chemokines are particularly important actually there I would say both chemokines and other types of cytokines that are not involved in interacting cells are both acting on the cells of the blood vessel to make them more permeable and we'll come back to some of the names of those proteins in the later lecture now let's return to the question of how the innate immune system recognizes the danger because before you do anything about it you need to recognize that there's something wrong so there are two phases of the innate immune response the recognition phase and the destruction phase which involves which is also known as effector mechanisms and as an example I'll use a part of the innate immune system known as the complement system complement system are a group of proteins in plasma that bind to pathogen surfaces and mark them as dangerous so here's a bacteria here's complement proteins they have a way of recognizing bacteria which we'll talk about later and forming a covalent bond and covering the surface of the bacteria with bits of these complement proteins once you have this coating of the bacteria there are receptors on the surface of innate immune cells that can recognize the complement fragment and that leads to binding an internalization of the complement coded pathogen in fact a cytosis and destruction of the back of this bacteria inside this cell now cells of the innate immune system can also directly recognize pathogens surfaces they have common structures that are that do not vary from one bacteria to another so we call these pathogen associated molecular patterns or Pam's an example would be gram-negative bacteria have a structure called lipopolysaccharide gram positive bacteria have other cell wall structures and all bacteria of those classes have those in variant conserved structures and we have evolved receptors that basically stick to them and when that recognition event happens that tells the cell to spring into action to do phagocytosis over these cytokines or whatever their job is so again one way is through these complement proteins that are in plasma and lymph and extracellular fluids which tag the bacteria or pathogen for recognition another is directly through not shown on this slide pathogen PAMP recognition receptors which can directly recognize that there's a pathogen associated molecular pattern okay we're moving along pretty well now I want to give you a brief introduction to adaptive immunity when I was a graduate student in the early 90s studying immunology this is all anybody wanted to talk about it's really fascinating and people didn't appreciate the importance of the innate immune system and now the pendulum has swung back a little bit so that a large fraction of the immunology research community is focused on the innate immune system and how we can harness that to improve vaccines or to reduce inflammation or deal with certain types of infections and autoimmune disease nevertheless the adaptive immune system remains fascinating and it will be the really the focus of much of the first half of the of the class and much of the material that I'm going to present so I'll do a little bit of a preview today and be prepared for a lot more details later on adaptive immunity as I said it's an urgent specific and that means it can distinguish one strain of bacteria or a virus from another where I said that all gram-negative bacteria have the same structure that is recognized by an eighth immune receptor the innate the adaptive immune system the T cells and the D cells can distinguish one strain of E coli from another that just can't be done by the innate immune system but only by the adaptive immune system it can distinguish closely related viruses and mount a response against one and not the other but in order to do this it requires a delayed period of four to ten days and we'll see why that is in a moment adaptive immunity provides this long-lasting immunological memory so that a second encounter with the antigen produces a much stronger response and also a much faster response this is the basis for vaccines this is why vaccines work it's because it's basically educating your body and giving it a memory of a pathogen so that if you ever are exposed to the real thing you have a fast and strong response and you never feel sick again the memory is specific so that a vaccine for one virus doesn't protect from another a vaccine from one bacterial toxin doesn't protect you from another this memory and the any aspect of adaptive immunity is mediated by lymphocytes t-cells and b-cells and in the case of b-cells it's mainly mediated by the antibodies that they secrete t-cells have a very diverse set of jobs that they do b-cells their main job is to secrete antibodies it's also important to realize that innate immunity and adapt to immunity talk to each other we'll see how innate immunity signals the adaptive immune system to get get into gear but it's also true that adaptive immunity the effector mechanisms or sorry the adaptive immune system helps to increase the efficacy of the innate immune system by focusing its effective elements at the site of invasion and enhancing responses such as a phagocytosis so they really work hand in hand innate immune system is the first line of defense it also signals the adaptive immune system and once the adopt immune system has gotten into gear it will help the innate immune system do its job better and in the right place so why is it that you can recognize the subtle differences and in using adaptive immune system and why does it take so long for it to develop and that's illustrated on mainly on Figure 110 which talks about clonal selection but first I want to define a couple of terms first is proliferation we probably understand this but it's basically refers to cell division that leads to expansion of a single parent cell into a population of clonal daughter cells this happens during embryonic development it happens in many tissues in your body that need to regenerate themselves but many tissues in the body are not regenerating and not proliferating and lymphocytes the vast majority of them are not proliferating either but in response to recognizing antigen they prefer they like praising and you've got a huge population of clonal daughter cells of the original parental clone differentiation refers to a change in the phenotype and function of the cell it's often irreversible so what we'll see is that during the process by which ki b-cells LIF rate they also differentiate and change their functions and become related cells but with new or different functions now the T and B cells the reason that they're so specific is because each one has a single antigen receptor and the sequences unique to that cell and that this kind of sequence diversity is unprecedented in biology and it's generated through a process of DNA recombination that involves the random cutting and splicing and modification of small gene segments and we'll cover this in some of the later lectures the outcome of all this is that East lymphocyte has a different antigen specificity and you can sort of see that illustrated in Figure 110 this just shows seven different cells each of the different color and each with a different slightly different structure of its antigen receptor pointing here remember there's thousands of copies of these receptors on on each cell but the structure of the receptor on one cell is slightly different from the structure of the receptor on another cell it's illustrated in two dimensions here as little bumps or or caves or you know different kind of subtle features to that to the the surface of the engine recognition molecule and that differs from this the receptors of the innate immune system if you look at ten effector cells and an example is a macrophage that will learn a lot about or a neutrophil they have ten or fifteen different pattern recognition receptors that are useful for recognizing gram positive gram-negative fungi viruses etc but the sequence of those receptors is the same on all the macrophages and all the neutrophils in contrast the sequence and the fine structure of these antigen receptors is different on every t-cell from each other and on every b-cell from each other and you have billions of these t-cells and billions of these b-cells and when you get infected with any one pathogen only a very small number of these will actually have a receptor that makes a good fit with Anjan that that is presented or present on the surface of that pathogen its these clones that are selected to fight the invader from the huge pool of potential t-cells and b-cells only those clones whose antigen receptor fits well with the antigen are selected the clonal selection refers to the proliferation of these antigen specific clones that are going to be the ones that are useful to combat the infection so that allows your immune system to be prepared to respond to an infinite array of antigens through this huge diverse repertoire of cells but ii 'the path each pathogen selects only a few cells that then make many many copies of themselves so here the pathogen is illustrated as a little round antigen here and it seems to fit nicely with this yellow cell of course it wouldn't fit nice as nicely with these others and that clone is selected and make to proliferate and take many copies shown here are five copies but typically there might be 100 or more daughter cells that are produced during this process of clonal selection and that process takes time it takes several days to make hundreds of copies of the original cell and that's why adapt immunity is slow all the cells of the innate immune system are already there they have the receptors already expressed you have a lot of the cells in your tissues they can respond immediately but they're limited in how well they can differentiate one cell type one pathogen from another here innate immune system immune system you have billions of different specificities one or two are selected to expand and after several days now you have your little army ready to fight the infection during this process the cells differentiate to acquire effector functions for example the resting b-cell can't secrete antibodies only during the clonal expansion phase that they differentiate into a type of cell that can really secrete antibodies that are useful in the infection and we'll discuss the functions of effector T cells and effector b-cells in great detail later now figure 1.9 compares some of the concepts I've just gone through in the native unity versus a deaf community again innate immunity responds rapidly in hours or even minutes but it's a fixed response that doesn't differ between cells or even between individuals and there's a limited number of specificities we've evolved receptors that can recognize general features of different classes of pathogens but there's a finite number of those available to us and it doesn't really change much in the during the response there's no there's no alteration in the army that's being used to fight the battle as a difference in adapt immunity is it's a very slow can take days two weeks the response is variable only those that are useful for the infection are selected and then you have a lot of these specificities billions of different t-cells and b-cells and over the course of the response the the immune response the adopt immune response improves you get more and better cells with increased ability to detect and destroy the antigen eventually though they both converge on a similar set of effector mechanisms that actually destroy the pathogen so we need to remember that that eventually there's only limited numbers of ways you can destroy pathogen phagocytosis as one direct lysis is another and so we'll learn about the ways that we actually destroy the pathogens and how innate immunity and adapter immunity control those effector mechanisms so I said that when I was a graduate student everybody seemed to be interested in adaptive immunity but this graph really makes it clear that if anything innate immunity is more important so if you do an experiment with an animal that lacks innate immunity or a human who's had their bone marrow eliminated through radiation or chemotherapy so they can't make any cells of the innate immune system or a doubt from unum and then they get infected the microorganisms just replicate superfast exponentially there's no first line of defense and if you genetically remove certain you know genes and cells of innate immunity in a mouse even leaving adop community intact this happens that the microorganisms will outpace any adaptive immune response if you only are lacking adaptive immunity compared to normal humans the early phase of the wreath up is fine you control the expansion of these microorganisms but there's a point normally where the adaptive immune system kicks in to destroy the remaining cells if you don't have a doubt community those microorganisms will now slowly overwhelm you so this would be an example of somebody with HIV they're lacking certain types of T cells but it might take months years or decades to reach the point where the immune system can no longer deal with infections but somebody who's had radiation or has it been a burn victim so that their skin is largely removed and they're the barrier to micro releases is removed they can die within hours or days from from massive infection and the last slide is just the last two slides are just to illustrate that the concept of in illogical memory and met the secondary response to the antigen is faster and stronger now in this example an animal or a human is getting two vaccines once again one against Amgen a one against engine B and then you're measuring the antibodies in the serum on a log scale here that are specific either to vaccine a or vaccine B what you can see is the person's vaccinated just with a here takes a little less than a week to start measuring antibodies this is a DAF immune system lag phase and then the antibody response goes up and after a couple weeks it reaches a plateau and then slowly starts to go away as the antibodies are degraded but remember this is a log scale so you still have quite a lot of antibodies left now here the person is vaccinated with a mixture of a and B and you can see that the secondary response has a very much shorter lag phase it's almost immediate and you get many logs of increase in antibodies so it's faster and it's stronger and then the plateau is much higher so you know you may have had booster shots you can imagine the booster shot is giving you a very large and rapid huge increase in the amount of antibodies to whatever that antigen is but in the same vaccine the response to vaccine B is just the same as it was for a and the primary response so just because your body is responding faster to antigen a doesn't make it respond better to vaccine B because this is a primary response to vaccine B at this point the patient would have protective immunity to any pathogen that had a in it but probably would need a booster shot to get a really strong protective immunity to be and lastly just to illustrate the power of vaccines diphtheria is a is a bacteria that produces a toxin that's very deadly and in the first half of the century it actually was very common my father who was born in 1923 nearly bought died of diphtheria toxin the vaccine came in around World War two and then within a decade the frequency of diphtheria cases was almost reduced to zero polio was a disease it only was became prominent in the middle of the 20th century and you could see it became very common and was very it could be life-threatening and disabling disease and then the the Salk Jonas Salk vaccine and then disable saving vaccine came in and you could see the dramatic effects they had to reduce the cases and eventually eliminate polio largely from our world and interestingly enough with measles again the vaccine came in measles went away but there's a disease that occurs 20-30 years later that is a neurological disease that you could see followed in the same course it occurred in these people who had had measles early on in the 20th century later on they got this disease and then there was a lag phase for after the vaccine eliminated the primary infection later on you stopped getting people with this disease so you're going to hear me advocate for vaccines a lot in this class and we can refer to this this figure it just shows you the power of the adaptive immune system immune illogical memory in vaccines okay I'll see you Monday last announcement I put this into email yesterday but I will always post the lecture notes and slides ahead of time yet I still think there's value in coming to class as questions and hearing about the context all right you

Channel: UCI Open

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Keywords: UCI, UC Irvine, OCW, OpenCourseWare, David, Fruman, Bio, Biology, Biological, Sciences, Immunology (Medical Specialty), Hematology, Lecture, Disease, Virus, Mechanical, Chemical, Microbiological, Lymphocytes, Rapid Response, Slow Response, Introduction

Id: gVCfC8WW4eU

Length: 51min 45sec (3105 seconds)

Published: Thu Oct 03 2013