BENG 100: Frontiers of Biomedical Engineering

Lecture 8

 - Cell Communication and Immunology (cont.)


Professor Saltzman continues his discussion of cell communication in the body, extending the description to the nervous and immune system. Professor Saltzman describes the mode of signal transmission in neurons: action potential in the axon, and neurotransmitter release at the synaptic cleft. He also introduces elements of the innate and adaptive immune system. The adaptive immune system is presented as a host/foreign antigen recognition system involving immune cells (T, B, and macrophages), antibodies, and the major histocompatibility complex 1 and 2. Immune response by cytotoxic T cells, T helper cells, and B cells to antigen recognition are discussed in detail.

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Frontiers of Biomedical Engineering

BENG 100 - Lecture 8 - Cell Communication and Immunology (cont.)

Chapter 1. Overview of the Nervous System [00:00:00]

Professor Mark Saltzman: Okay, today we’re going to continue to talk about cell communication. I’m going to talk about - take sort of the general concepts that we talked about last time and talk about how they apply in two physiological systems, the nervous system first and then the immune system. This is a lead in to what we’ll talk about next week. We’re going to start talking about vaccines which is really sort of applied immunology: trying to take immunological concepts and put them into action or to engineer them in some way. So, we’ll talk about that next time.

I want to start with the nervous system. This is a picture of a neuron, this particular neuron has been filled with a fluorescent dye so that it’s colored green. I’m using it just to make the point, which you already know about; that the nervous system is complex in it performs a complex set of functions. It’s able to do that because there are cells like this particular cell that have shapes that are suited to their function. In this case the shape is - there’s a cell body in the center here so this is where the nucleus is and where all the transcription, production of proteins take place here. Then around this cell body there’s an elaborate set of processes which extend out from the cell body, and they go in various directions.

If you look throughout the nervous system you would find cells that look different in different regions, because of where they’re situated in the brain. But they’d all have some of these same features, that is a cell body with many processes that meet in the cell body. Now, what this enables these cells to do is to communicate with very specific other regions of the nervous system. So this cell, wherever it’s setting, wherever it is positioned within the nervous system - let’s say in the cortex somewhere or the outside surface of the brain - is able to communicate with a region of the brain that’s in this direction, a region in this direction, a region in this direction, a region in this direction. So one way that neurons, in particular, are able to communicate with other cells in the nervous system, share information, integrate information, decide what to do next is that they are physically connected to other different cells. Part of the complexity of the nervous system is the complexity of this interconnection of cells.

Now, if we look at this schematically and so again this is a schematic. It doesn’t represent any particular neuron in the body, but just meant to represent functions that all of them have. Here is the cell body up at the top of the diagram here. You could distinguish between some properties of these processes that extend out, in that most of them are what are called dendrites. One of these processes, a special one is called the axon. The way this cell works as an information processing unit is that the dendrites, which extend out in all these different directions, are receiving information from other cells which is integrated at the position of the cell body. Then that information - that integrated information - is passed onto another cell through the axon. Information flows from the dendrites, through the cell body, down the axon. That’s what this arrow at the right shows, the direction of the flow of information. We’re going to talk in some detail, not a very high level of detail, but in some detail about how this communication takes place between cells and how the information is passed down one of these cells today.

Some terminology, some of which I’ve already given you: cell body, dendrites, axons. If this is the particular kind of axon that is ‘myelinated’, then it might have a layer of a special substance called myelin in sheathing the axon. That just allows information to move more quickly from one end of the cell to the other. That can be important because in some cases these processes are very long. There are processes that go from my nervous system, from my brain and spinal cord out to the tips of my fingers that allow me to move muscles there, or down to your toes. So, these cells can be many, many feet long, these processes can.

Chapter 2. Cell Communication in the Nervous System [00:05:29]

Well, the mechanism that the cell uses to transmit information along itself, along this process which goes from my brain to my fingers, for example, is through an electrical signal called an action potential. We’re not going to talk about this is in great detail, there’s some detail in your book. If you go on to take, particularly the course that’s offered here called Physiological Systems, you’ll learn a lot about action potentials and what the mechanisms for generating them are, but I’m only going to say a few words here to sort of orient you in the subject. All membranes are electrically charged. They carry a potential, that is, if you could - if you had a tiny, tiny electrical meter, you could one put one electrode on one side of the cell membrane, on the extracellular side and one on the intracellular side and measure, you would measure a potential difference; just like a battery you would measure a potential difference. That potential difference is generated by the movement of ions, principally sodium and potassium across the membrane. Now, sodium and potassium don’t ordinarily move across membranes, they’re charged molecules, they can’t dissolve, they can’t permeate through a cell membrane, but they go through because there are channels that allow them to pass through in the membrane.

All cell membranes have these channels within them, and under their resting conditions sodium is moving from outside to inside, potassium’s moving from inside to outside. Because there are ions moving back and forth, there’s a current that flows and there’s a electrical potential that’s generated. Now, this is in the resting state of all cells, there’s some membrane potential and neurons have this resting membrane potential also. If you measured it for most cells it’s about between -60 and -90 millivolts. For this particular cell here it looks like it’s about -75 millivolts, so the inside of the cell is a little bit more negative than the outside. Now, what happens during an action potential is that that membrane potential changes rapidly and it changes from being negative to being more positive. That change happens because something gets triggered in the membrane, and what gets triggered is a voltage gated sodium channel, which is shown here.

Now, remember we talked about these last time, voltage-gated channels are channels that would allow the passage of sodium, in this case, but they can exist in two states, a closed state and an open state. When an action potential is initiated these ion channels go from their closed state to their open state, when they open sodium can now pass through. The balance of sodium movement relative to potassium movement changes because there’s this resting movement of all these molecules anyway, but that balance changes dramatically when these ion - when these gated ion channels open. That results in a dramatic change in the membrane voltage; the potential across the membrane and that’s shown here by this rapid rise in membrane potential.

Now, that rapid rise is called depolarization and the membrane is said to be in a depolarized state because it’s less polarized or less negatively charged - repolarized as negatively charged. It’s less negatively charged than it is in its resting state. That happens, and if I was looking at a region of membrane that was experiencing an action potential I would see voltage change in just the way it’s shown in this graph here. Now, if that potential changed and it stayed changed forever, then the cell would never go back to its resting state. That would be - you could have a cell that did that but that would be cell that could only send one signal. It sends it’s signal, it’s signal - the signal that it sends is this change in voltage, and once it changes, maybe it’s all done. That would be a bad design for our nervous system where we want to use cells over and over again, so they’re able to recover from this change in potential. That’s shown functionally here but recovery means that this sodium channel becomes closed again.

Now, it’s more complicated than that because it’s not just sodium channels that are involved, there are potassium channels also, and the interplay between sodium channels opening and potassium channels opening, this is described in some detail in your book. We’re not going to talk about those details in the class here; I want you to sort of understand this really at the level that I’ve described it here. There’s a local change in the membrane, that local change involves opening of channels that allow ions to pass through regions where they couldn’t pass through before, that results in a change in voltage. That voltage moves from one end of the cell to the other. That action potential is initiated here up in this region. This part of the cell becomes depolarized because it gets the message that it’s supposed to depolarize because of all the inputs that impinge on these dendrites. It’s collecting information from all these dendrites under the right series of signals the cell body integrates all that information, says time for me to fire an action potential. That happens, the membrane potential changes here, and the change in membrane potential here is so dramatic that it changes the membrane potential here, and here, and here, and that change of potential flows down the surface of the axon, eventually reaching this output region.

The flow of information is really a flow of electrical potential and it goes in one direction only. It goes from the region of the cell where the dendrites are down through the axon. We’re going to come back and talk about the action potential a little bit more when we talk about how the heart works, because the heart when its contracting, the muscle cells also use action potentials to initiate contraction. When we measure EKG’s, what we’re measuring is the activity of all these cells within our heart performing action potentials. Now, in the heart action potential is moving from one heart muscle cell to another over the surface of the heart. In the brain, action potentials are moving down processes, down a single cell process for example. So action potentials are used by tissues in different ways to send signals from one cell to another or from one end of one cell to another end of the cell. Does that make sense? We’ll come back to this in our example in the cardiovascular system when we’re talking about the heart and we’ll talk about how to measure the collective group of action potentials using EKG’s. You’ll actually get to measure EKG’s on each other during section the week we talk about that.

Well, what happens when the signal gets to the end of the axon? How do cells pass the signal from themselves to the next cell? In the heart it turns out that the cells of the heart are electrically coupled together, so if an action potential moves down this cell it directly moves into the next cell. So, there’s a continuum of electrical connection in the heart that allows an action potential to sweep across the surface of the heart and for the heart to beat in a coordinated fashion. In the nervous system it doesn’t work that way. It doesn’t work that way for a variety of reasons, but the main reason is that you want some decisions to be made at each space between two cells. You want decisions to be made there so you need some additional mechanism for decision making at the point of contact between the axon of one cell and the dendrite of another.

Well, that specialized region - now in this diagram here, this is the axon of one cell, the first cell in a sequence and that axon meets the dendrite of another cell at a special region called a synapse. The synapse is just this anatomical region of contact between two adjacent cells in the nervous system. It varies in its structure among cells of the nervous system but all synapses have some properties in common. One is that there’s a physical space in between the two cells, so the axon of what’s called the pre-synaptic neuron, or the neuron that’s bringing a signal into the synapse, the axon terminal is physically separated from the dendrite of the next cell. That space is about 20 to 40 nanometers, it’s not a very big space, but it’s a significant space. It’s called the synaptic cleft and it’s filled with extracellular fluid.

Now, another thing that you’d find if you looked inside the axon terminals of any of these pre-synaptic membranes, you’d find lots of vesicles or some membrane bound compartments that contain special chemicals called neurotransmitters. Neurotransmitters are molecules you’ve heard of like acetylcholine, like dopamine, like serotonin. They’re small molecules that - whose principal function in the body is to carry signals from one cell in the nervous system to another. Now, how they carry signals is that these neurotransmitters act as ligands. When an action potential comes down this pre-synaptic axon, when it reaches this point here, it sets off the process of these vesicles dumping their content into the synaptic cleft.

This process, which is shown schematically here, as a vesicle fusing with the cell membrane and then dropping its neurotransmitter only happens when an action potential reaches the end of the axon. Neurotransmitter release is stimulated by the electrical activity that reaches the end of the axon. When these vesicles dump their contents into the synaptic cleft, the concentration of these ligands rise. Another characteristic of the synapse is that the post-synaptic membrane, the membrane of the cell which is going to receive the signal has receptors on it. Those receptors, some fraction of them, are specific for the ligand that the pre-synaptic cell releases. There’s a lot of words here, long words, pre-synaptic, post-synpatic, but pre, post, you get the idea. Caitlin?

Student: Just curious; before the ligand perimeter [inaudible] where are they stored?

Mark Saltzman: They’re actually stored in these vesicles and so–and they get into the vesicles in a variety of different ways. In some cells they’re recycled, that is the cell is able to take up the neurotransmitter after it’s released and restore it, but most often there are enzyme systems inside the pre-synaptic membrane where those neurotransmitters are synthesized. They’re synthesized, they’re packaged into vesicles, and then they’re just waiting. If you could look inside a pre-synaptic axon terminal, you would find one of the characteristics is that it’s loaded with these vesicles and they’re just sitting there waiting to receive an action potential so that they can immediately dump their contents.

One of the things you know about the nervous system is its fast. I decided to move, I can move right away. So, in order to have fast transmission you do that by transmitting electrical signals; that happens pretty quickly. You turn on your lamp, it happens pretty fast because current can flow very quickly through wire or through a charged - a solution of ions. So, that process happens fast but you also need this neurotransmitter release and activation to happen fast so that you can have rapid activity.

Now, in this cartoon here I’ve shown a variety of different receptors just to show - just to remind you of the different families of receptor molecules that could be involved in receiving and translating a signal. But in general, for each neurotransmitter that released it there would only be one population of receptors that’s ready to receive it. In some cases it might be a ligand-gated ion channel. Wouldn’t that be convenient? Because if it was a neurotransmitter activated ion channel, what would happen when the neurotransmitter bound here? It would generate an electrical signal because it would - you’d open the ion channel and you would ion fluxes and you would change the membrane potential in just the way I described for the action potential. This is a mechanism by which an electrical signal comes here, it gets translated into a chemical signal, the chemical diffuses across the gap and reinitiates a - an electrical signal in the next cell and that’s one way that it happens. It can also happen in other ways, it could be a G-protein coupled receptor which we talked about last time, which indirectly activates another ion channel to start the electrical signal.

Why do this? Well, one reason to do this is because on each post-synaptic neuron there might be many axons coming together at once, and each one might be generating a different kind of signal, through maybe even different neurotransmitters. Because this post-synaptic neuron is going to be receiving different signals from different cells, it’s decision about what to do next, and the what to do next is either create an actual potential or not create an action potential. So, it makes a binary decision, either I create an action potential or I don’t, but that decision could be based on many inputs, not just on input from one cell. It could be the integration of many different chemical signals. Because of that, because they’re not directly wired together but because there is - are decisions and integrations occurring at each junction, the potential operation of the nervous system becomes diverse. So, you have both the diversity in the physical connections, any one cell is potentially contacting lots of other cells. You have a diversity in the chemical changes that occur as a result of any of those connections. That’s what leads to some of the complexity of function of the nervous system.

Chapter 3. Overview of the Immune System [00:22:20]

I want to talk about the immune system for the rest of the time here. Again, the point today is not for you to understand in detail all these mechanisms but to understand how those basic concepts we talked about last time, basic concepts of cell communication if arranged in the right kinds of ways can lead to complex outcomes. That was the point I was trying to illustrate in the nervous system. In the immune system you could think of it as an even more complex set of outcomes that occur. The outcomes that occur are protective outcomes in general. Our immune system’s function is to keep us healthy in the face of an environment where there are lots of things that could potentially harm us. The study of immunology is the study of mechanisms that your body uses to protect itself from - mainly from foreign pathogens like viruses and bacteria.

Some words that are useful in this discussion, a ‘host’. A host is the organism that you’re interested in defending and it could be you or me or some typical person. ‘Foreign’ is, then, any molecule or set of molecules or substances that are foreign to the host, they don’t belong there; it could be foreign proteins from a virus, could be foreign elements from a bacterium, it could be that one of your cells has become mutated, is now abnormal and so doesn’t belong in you anymore. It’s foreign, it’s not part of the host or not a normal part of the host. So, all those things would be considered foreign.

We’re going to use this special word “antigen,” and antigen has a very particular meaning. Its molecules are pieces of molecules often derived from foreign pathogens which stimulate an immune response. So, antigens are molecules or pieces of molecules that stimulate an immune response. Any molecule can be an antigen; the food that you eat is full of antigens, microbes that try to live in your body are full of antigens. Pieces of your own cells are antigens as well. They’re just antigens that belong to you and so you don’t normally mount an immune response to antigens that are part of you. We’ll talk about how that happens a little bit as we go through here.

Generally, you think about the immune system protecting against different classes of pathogens and several classes of pathogens are shown on this table. So, you’re familiar with some of these bacteria like salmonella, or the micro bacterium that causes tuberculosis are shown here. Viruses, you know about viruses; variola, we’re going to talk about next week which causes smallpox, influenza, which causes the flu and HIV of course which cause AIDS are some examples. Fungi which don’t often cause infections in people with healthy immune systems but can under some circumstances, and can be tremendous problems in patients that have weakened immune systems. Parasitic organisms like protozoa and worms which are - which can cause terrible diseases. Malaria is one that causes much disease worldwide. Schistomiosis, which is a worm that lives in river waters, causes terrible diseases that are still prevalent in many parts of the world.

So, just an introduction to the classes of potential foreign invaders that our immune system tries to defend us against. Because it’s working to defend us against many different kinds of potential assaults, the immune system has a diverse repertoire of responses that it uses in the face of these assaults. One kind of response is called the innate response and innate means that it’s present from the beginning. So, this is an immune response that doesn’t have to be activated and we’re used to thinking about immune responses that have to be activated. You get a vaccine for chicken pox, it gets injected, and sometime later you’re going to be protected against it. Or you get a cold, the cold virus takes hold, the viruses start replicating inside of you and it takes some time for immune system to gear up to eliminate it, so we’re used to thinking about responses that take some time. But innate responses are there from the very beginning and they can fight foreign–against foreign pathogens immediately.

It’s mainly–these functions are mainly performed by a set of cells called macrophages, neutrophils and natural killer cells, which are circulating throughout your body all the time, ready to destroy anything that they recognized as not part of you. So, that’s the innate response. We’re not really going to say much about that here, there’s a little bit about in the book. If you go onto study immunology you’ll learn that this is one of the most important and rapidly evolving areas of the study of immunology. In fact, the people who have been most important in understanding how the innate immune system works are people here at Yale.

Chapter 4. Immune System Responses against Foreign Hosts [00:28:26]

The immune system that we’re used to thinking about is called the adaptive immune system, and the adaptive immune system does just that. It changes or adapts in response to an insult or a threat. So, this is the kind of immune response that gets activated only when it’s needed. Then it will stay activated for some period of time, and eventually disappear again. There are two types of adaptive immune responses and they’re called humoral immune responses. Humoral comes from the term humours and it used to be that we thought about disease as being caused by the balance of humours in our blood. You could have good humours and you could have bad humours and if those humours, whatever they are, got out of balance then you got sick if you had too many bad ones compared to good ones.

Humoral refers to immunity in the blood and it’s immunity that’s in the blood in the form of antibodies. We’re going to talk a lot about antibodies over the next week or so, but antibodies are specialized proteins that, as you know, are designed to bind to antigens or foreign molecules inside the body. I’ll say more about that in a minute. The humoral immune response involves antibody production and antibodies are made by a subset of cells called B-cells.

The other part of the adaptive immune system is the cell mediated immune system and this is an immune where - that doesn’t involve antibodies but involves cells that are activated in response to a foreign antigen and that utilize cellular means to get rid of it. Usually the cellular means that they get rid of is that instead of an antibody being produced, you activate a population of cells that will specifically go and hunt down the foreign antigen, or more commonly, cells that contain the foreign antigen. Now, why do you need a cell mediated immune response if you have an antibody response? We’ll talk about that in a few minutes.

We’re going to - one of the reasons why you’ll see why cell mediated responses are important is because antigens can appear in your body in different ways. The way that they appear in your body tells the immune system something about where they came from. We’ll learn more about that in a moment, but basically it allows the immune system to distinguish between viral and bacterial pathogens, and respond appropriately depending on the type of pathogen that’s there.

The main effector cells in cell mediated immunity, the cells that do the main business are called T-cells. Now, T-cells are also involved in humoral immunity but they’re not the end result. The end result in humoral immunity is B-cells producing antibodies, the end result, or the molecules that carry out the function in cell mediated immunity are T-cells, either - let me talk about different types of T-cells in a moment, but either cells that are called CD4+ cells or CD8+ cells. Why do you have these different kinds of responses? The reason is that because of the ways that different microorganisms take - the ways the different microorganisms reproduce and damage cells and tissue within your body, you need different ways to respond to them effectively.

Think for a minute about what happens if you get infected with a virus. Now, a virus is not capable of reproducing on its own, so if you got a virus into your body somehow and it didn’t enter any of your cells, it would cause no damage because it could not reproduce. It’s reproduction of the virus and passage of that virus onto new cells which causes the problems with disease that we associate. They often kill the cells that they infect, and that’s a problem with viruses. A virus isn’t troublesome until it infects a host cell and when it infects a host cell it becomes troublesome because it takes over some of the host machinery for DNA synthesis, transcription, and translation and starts making more viruses and this happens largely in the cytoplasm of the cell.

How is your immune system going to recognize that this virus is there causing bad results if it’s living inside of a cell and doing all its business inside a cell where antibodies can’t get to it? Antibodies are outside of cells circulating in your extracellular fluid. Well, the way that your immune system recognizes it is that all the cells of our body express a molecule on their surface, a membrane protein called the MHC1 complex. MHC1 is a word, MHC stands for major histocompatibility complex and it’s one of the things that distinguishes my cells from your cells, from your parents cells, from your roommates cells. Each one of our cells - one of the things that distinguishes them is the kind of MHC molecules that all of my cells make. It’s what makes my cells my cells, and your cells your cells. It’s the reason why you can’t do organ transplants between people that aren’t immunologically matched. If you take an organ from one person and put it in another, if their MHC molecules don’t match then the immune system recognizes - the immune system of the host recognizes ‘this is not the right MHC for me’ and the immune tries to destroy those cells. One of the functions of MHC is to indicate which cells belong inside your body, which cells don’t.

The other thing that it does is that when a virus is inside these cells making its proteins, some of those proteins get processed or digested into small fragments that are themselves antigens. Those antigens get expressed together with MHC1. One of the other things that MHC1 does, in addition to marking yourselves as your own, is that it’s capable of making combinations with all the different molecules that are present inside the cell and expressing them on the surface, and sort of showing them to the outside world. It’s showing them to the outside world in combination with MHC1. The immune system, some cells of the immune system, in particular this class of T-cells called CD8 cells have receptors which recognize MHC1.

They’re capable of recognizing MHC1 together with foreign antigens. When these CD8 T-cells see your MHC1 together with an antigen that doesn’t belong in you, it creates an immune response. The immune response is directed at killing this cell. The notion is, if there’s something foreign that’s being produced inside this cell, then that cell must have been corrupted in some way and it has to be gotten rid of. It could have been corrupted because a virus was inside of it so it was making foreign proteins. That’s making the cell look foreign because some of that foreign protein is on the surface with MHC1. It could be foreign because it’s become malignant. Maybe it got mutated and its making the wrong kinds of proteins; cancer cells often do that. So, those wrong proteins get presented on MHC1 and your immune system can kill the cell because it’s a tumor cell. This is a way for the immune system to recognize things that are going wrong inside the cell protected from antibodies.

Other kinds of microorganisms reproduce and cause tissue damage in a different way. If you get bacteria under your skin, if you get a cut and somehow that cut gets - bacteria gets inside there, the bacteria can reproduce on their own. They’re fully functional organisms that can reproduce on their own, and they can start growing outside of any cell and that’s what they do, they live extracellularly. Well, your innate immune system tries to get rid of them. The innate immune system composed of neutrophils and macrophages; these are cells that are crawling around your body all the time ready to eat bacteria. When they do that they can actually engulf the bacteria in a process called phagocytosis and break the bacteria down into antigens. Then those antigens get expressed with MHC just like they did in all the other cells inside the host, but particular cells of the innate immune system have a different kind of MHC called MHC2. When T-cells recognize a foreign antigen that’s combined with MHC2, they know that that antigen must have come from one of these professional phagocytic cells digesting bacteria or some other extracellular invader. Because this antigen gets expressed in the context of MHC2, your immune system responds differently.

Now, there’s a lot of words here, I mean there’s a lot of words, there’s a lot of abbreviations, there’s a lot of players. The details are not particularly important to us. Some of them are in your book and I hope you read about them because it’s really interesting, but the main points are that for us here that this is a very elaborate of cell communication that is - has the same essential characteristics that we talked about last time in that there are receptors that are presenting signals which now other cells receive. Those receptors are more complicated than the ones we thought about before. The ligands are more complicated than the ones we thought about before. The reason for that complexity is because your immune system needs to be able to respond to all the potential foreign invaders that we could encounter. It’s not just a limited number of things that might happen, and so it’s evolved these sort of mechanisms in order to allow it to respond to a wide variety of potential molecules, and to respond in the same way - in a coordinated way that somehow knows where those foreign molecules came from. Importantly, is able to distinguish foreign molecules from your own molecules. So, read about this but please don’t worry about all of the details because the details aren’t so important for what we’re going to talk about.

Chapter 5. Cytotoxic T-cells and Antibodies [00:40:24]

He says that and then he shows an even more detailed picture, but what I want to show you on this slide is just the simple part of it. I talked last time about MHC - on the last slide about MHC1. So, this is a cell that’s infected with a microorganism, it’s infected with a virus, let’s say it’s infected with influenza virus. That virus is reproducing inside cells of your respiratory tract. You’ve got the flu, you’ve got influenza in your upper respiratory tract, your cells are making more influenza. That gets presented in the context of MHC1 on cells within your body. Immune cells recognize it, and they recognize it by a very special form of receptor-ligand interaction where the ligand is MHC1 with the foreign antigen and the receptor is a receptor called the T-cell receptor complex. T-cell receptor complex is able to recognize on one population of T-cells, able to recognize MHC1, together with foreign peptides, on another type of T-cell able to recognize MHC2 with other types of foreign antigens.

What happens when that recognition takes place is that your immune system gets activated, and the activation that happens usually involves two things. It involves proliferation, which we talked about last week. So, when the right signal is received, the right T-cell finds your host cell with a foreign virus in it, the first thing that happens is that this T-cell becomes activated and it starts reproducing, making more copies of itself. So, reproduction, proliferation, cell growth happens and then those cells become more differentiated. They become more mature and they mature into, in this case, they mature into cytotoxic cells, and cytotoxic means ‘cyto’ - cell, ‘toxic’ - killing, they mature into cells that are capable of killing other cells. You don’t want to generate a lot of cells that just start killing every cell inside your body. Here’s where the intelligence of the immune system comes in, is that these cytotoxic T-cells that are generated only kill cells that have this signal on it. They only kill cells that have the signal which stimulated them. So, they don’t start killing all the cells in your respiratory system; they only kill the cells that are harboring the virus. They know that these cells are harboring the virus because those cells have foreign antigens on their MHC1. Does that make sense?

In the same way cells get activated but these are different cells, these are T helper cells that get activated by MHC2. Helper cells don’t become cytotoxic cells but they help B cells become antigen producing - antibody producing cells. So, this kind of recognition leads to an effect. What’s the effect? Cell killing. This kind of recognition leads to another effect, what’s the effect? Antibody production. Why are antibodies useful for bacteria? Because bacteria are outside of cells and when antibodies bind to them they can neutralize them. They can’t always neutralize viruses because the viruses are predominantly inside cells. That’s why you need two kinds of immune responses.

We’re going to talk a lot about antibodies, we’re going to talk about antibodies in section, and at the end of the course, our last section meeting every year we get together and we talk about which sections did you think were useful and which parts - which sections were not so useful. The section when you do today is always the most popular section of the year, you’ll know why after the section, and you can tell me afterwards if you think you figured out why. It involves thinking about antibodies and how to use antibodies and technology.

Well, let me just say for the rest of time where do antibodies come from naturally? They come from B-cells, they come from B-cells that are activated with a specific antigen. The antibodies that are produced from these B-cells are also specific for the antigen. An antigen expressed in the context of MHC stimulates your immune system. One of the results of that stimulation is that B-cells - a particular subset of B-cells - gets activated. What happens when they’re activated is they start to reproduce, they make more and more, and more B-cells. Those B-cells also mature, they differentiate and that’s what’s shown on this slide here is the differentiation of those immature B-cells into mature B-cells. What do immature B-cells do? They just wait, they wait for their time, they wait until you are in danger from a particular antigen. When you get exposed to that particular antigen they say, ‘I’m on, it’s my time’. They differentiate, they make many copies of themselves - I’m sorry they proliferate, they make many copies of themselves, and then they differentiate into antibody production machines. The antibodies they make are all specific to the antigen that stimulated them.

That’s shown here, a B-cell gets stimulated, matures into an antibody producing factory. Antibodies look like this, they’re big proteins, if you looked at them under a microscope or if you looked at them in cartoons they’re shaped like the letter Y. One part of them is all common. The parts at the end of the Y’s are variable. What’s variable about them is that they bind to a specific antigen. They bind to the antigen that stimulated their production. So, I have a bacteria infection, stimulates my immune system, I start making antibodies that bind to an antigen specific to that bacteria. Won’t help me against other bacteria, but only against the one that I’ve got. How do they recognize it? Because at the end of the Y, there’s a special region of the antibody, the antigen-binding region, that is highly tuned for binding to the antigen that stimulated them.

We’re going to talk more about now how to use antibodies in section today. One of the beautiful things about antibodies is that one your immune system is able to make antibodies against all the thousands, ten thousand, hundred thousand different pathogens that you’ll come into contact with in your lifetime. So, our bodies are capable of making antibodies that are tuned for all the potential antigens that we come into contact with, That’s amazing that we have this capacity to respond and you respond only when needed. From a technological perspective, antibodies are incredible tools because antibodies are molecules that are specifically designed to bind to a particular antigen or a particular chemical. What if you could manufacture antibodies? Don’t worry about how they work in the immune system, but what if you could manufacture antibodies then you could make a chemical, an antibody, that is capable of binding to a specific other chemical and you could use that for things.

It turns out you can use that for lots of things, you can use it to detect the presence of small amounts of chemicals anywhere. We’ll talk about how to use antibodies in that fashion later today in section. Questions? One last word of encouragement, I’ll say it again, there’s a lot of words in this chapter, there’s a lot of concepts, focus on the things that I talked about in class not the details, the basic concepts. Focus on the concepts of receptors and ligands. I wanted to show you this slide here on the homework. I realize that this thinking about antigen, antibody combinations and the mathematics of how strongly an antibody binds to a specific antigen, is maybe something that’s new to you. There’s - this diagram comes directly from your book, from one of the boxes in the book which describe how you analyze antibody interactions. If you have questions about this I hope that you’ve already taken advantage of the teaching fellows or come up after class, I’d be happy to try to answer your questions now if you have time as well. See you in section.

[end of transcript]

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