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0:01
This program is a presentation of UCTV for educational and non-commercial use only. I'm very excited to introduce to this week Tony DeFranco. After spending significant time going back and forth between East and West coast I've learned tonight, he very wisely settled on the West Coast in 1983, coming to UCSF. But he spent undergraduate time at Harvard, and then he was at Berkeley for graduate school, and then was at NIH, and then came back out to UCSF.
1:22
When I asked him how he wanted to be introduced, he mostly very modestly said, please introduce me as a teacher of immunology. Well, that is certainly an understatement because he has been absolutely core to the teaching programs not only of medical students, but of everyone here learning immunology. Compared to my basic overview that you got last week of clinical immunology with a little bit of basic thrown in with just mostly introduction and terminology. Tonight, you're set for the nuts
1:53
and bolts of immunology so that you can learn a little bit more in depth and more precisely about the immune system. I feel very privileged that he's here tonight, and I'm going to turn you over to Dr. DeFranco. Thanks, Dr. Gundling, and thanks for that fine introduction. It's great to see everybody here tonight. I gave a very similar talk about two weeks ago to another group of medical students. That group is really busily studying for a really big exam. That's our second year medical students
2:33
and you all don't look nearly as nervous as that group. Nuts and bolts are in the title and I hope you don't get too afraid by that. I'm going to give you a few nuts and a few bolts. But what I'm going to try to mostly do is give you the principles and use those nuts and bolts to illustrate the key principles for how our immune system helps protect us. Of course, I think most people, even before last week's lecture, knew that the immune system is
3:08
to protect us from scary things that want to eat us. No, not these scary things. These scary things. On the left, we have an electron micrograph of a virus particles. This is the virus that causes AIDS, Acquired Immunodeficiency Syndrome. This is a bacterium here. That's the bacterium that causes tuberculosis. Over here, we have a red blood cell that's got some parasites inside. Those are the parasites that cause malaria. Those, of course, are the three big killers worldwide.
3:48
Infectious disease killers of people worldwide along with influenza, we probably should include that to be the big four. We're going to hear something today about how the immune system protects us about these kinds of threats. Now, these are numbers from the US Centers for Disease Control, the CDC, who keep track of this thing. This is the number of types of viruses and bacteria and fungi and worms and parasitic protozoa such as the one that causes malaria. These are the number that cause
4:23
serious disease in people. You can see, it's not just a few things, but the immune system has got to protect us from a continual barrage of things that want to eat us. They don't eat us the way a lion or an alligator would, but they want to make use of our goodies and grow in us. That really should be in the very big type, and then some other functions of the immune system I've listed here should be a much smaller type. The immune system also promotes the normal functioning of the body
4:56
by helping clean up our tissues and repair wounds. It helps remove abnormal cells, including the beginnings of some cancers. This is now well established that the immune system does cure cancer. To some extent, it prevents cancers from coming up, and it's also in some clinical settings does cure cancer. I'll talk about that toward the end. Then this is the good. This is why we need our immune system, and this is why individuals who are born with a big malfunction in their immune system,
5:30
really are going to die in a very short time unless we do some really drastic treatment. We have a lecture coming up on bone marrow transplantation, which is one way that some of those diseases can be completely cured. Which I think is very exciting and some of that really was pioneered here at UCSF. Some of those therapies. I don't know if anybody saw the Chronicle, I think it was on Saturday. There was an article about the pediatrics department here is working on getting faster diagnosis of
6:01
those kinds of individuals because the therapies, the bone marrow transplantation works better if you catch the people before they have serious infections. This is an ongoing area that UCSF is a leader in. But then there's also the bad part of the immune system and a couple of the lectures are going to touch on that. Our immune system sometimes confuses all of these bad guys for things that are not so bad, like hay fever pollen and cat dander and things like that, and can cause allergies,
6:29
which is Dr. Gundling's specialty. Even worse, it can mistake some of our own components for foreign invaders and cause auto-immune diseases. We're going to have a lecture from Dr. Andrew Gross in our rheumatology division about some of the exciting new therapies that are coming online that make use of this information, the understanding of the immune system that I'm going to talk about today, to develop new therapies for some of these very nasty diseases where we really
6:55
need a really strong intervention. Then of course, another example would be transplantation. If somebody needs a new kidney, or a new lung, or a new heart, or a new liver, we have immunological rejection as one of the problems.
7:13
Those procedures only became feasible when we learned how to suppress immune responses enough to allow those organs to remain and not get destroyed by the immune system.
7:27
A slider to remind you of some of the things that Dr. Gundling covered last week. First off, I just want to remind you of the players. The Giants have pitchers and in fielders and outfielders and a great catcher, what does the immune system have? The immune system has sentinel cells that are sitting in the tissues waiting for an infection to come along, and there's really three types of immune cells sitting out there. A cell called the dendritic cells, and I'll talk a little bit more about them.
7:58
This is a type of cell that immunologists are really excited about right now. We're learning about these dendritic cells as being very important players. There's the macrophage, which is also an important player out in the tissues, and there's a cell called a mast cell, which is important for allergies and asthma, and also for protecting us from worms and blood-sucking insects like mosquitoes and ticks and things like that. Then these cells that are in
8:26
the tissues waiting for an infection to come along, when they find one, they call out for help from their friends which are circulating around in the bloodstream, and they come in two flavors. The cells that are good at killing things, the phagocytes are good at eating things and the granules are good for killing things. You saw some movies of neutrophils last week. Neutrophils monocytes and eosinophils would be the three types of cells in this category. They're circulating around in
8:57
the blood waiting for an infection, and then they're going to go into the infected tissue and help get rid of that infection. Then we have our lymphocytes. These are what we call our adaptive immune system. They are the B cells that make antibodies, T cells that do cell-mediated immunity. You heard a little about these last time, and I'm going to go into these in a little bit more detail today. Some of these immunodeficiency patients that really need a bone marrow transplantation are
9:24
because they're missing these components here. Although that therapy is also being considered for defects in these kinds of cells as well, genetic defects. Then finally, I heard that you had some questions last week about a type of cell called the natural killer cell, and it's really good at killing virus infected cells. It is more in this category than in this category. But morphologically, it's a lymphocyte, which is what does it look like in a light microscope type of definition.
9:53
Anyway, you'll hear a little bit about this. One of the world's experts on natural killer cells is Lewis Lanier, and he's going to be part of that bone marrow transplantation lecture coming up in a couple of weeks. Those are the players. Let's then look at what happens when we get an infection. Again, this is something that we heard a little bit about, we're going to go into some more detail about it tonight. The sentinel cells in the tissues, and that would be
10:23
the macrophages and dendritic cells in this case, if we're talking about a new infection. They would recognize the microorganism that's coming in. Let's say you get a cut in your finger and you get some bacteria in there, or you breathe in something and it gets past the barriers in the lung and gets into the tissue, then we would be having an infection, and then our cells in the tissue would be recognizing that. This process of recognition by these types of cells as opposed to the lymphocytes,
10:56
we call that innate immunity, and they utilize evolved receptors that recognize broad classes of microbes. They would recognize that this is a virus, or this is a bacteria, or this is a worm. They recognize broad classes. They recognize molecules that are characteristic of broad classes of organisms. Not necessarily pathogens, but any bacteria, or any yeast, or any worm. Some small fraction of the bacteria in the world are pathogens of people. Most of them are benign and live in the soil,
11:32
and help decompose dead organisms, and so forth, they provide a very beneficial role. Most of the bacteria are good, but then occasionally they are really ones that come after us and are bad. These sentinel cells in the tissue, the dendritic cells and the macrophage, what happens when they see these agents? Well, they realize that they are in limited number and they won't be able to really take care of the problem all by themselves, they got to call out to their friends in the bloodstream.
12:02
The way they do that is by secreting proteins. They secrete proteins that then go and diffuse over to the neighboring cells and to the neighboring blood vessels and cause those cells to now bring in the cells from the blood. These proteins that are made by immune cells and act on other cells, we call cytokines. Cyto for cell, and kine because it induces an action on the part of the cell that it's acting on, so cytokines. The cytokines are really important in immunology.
12:36
I'm going to mention them again and again in this lecture. I'm not going to give you the names of too many of them, the actual nuts and bolts. We know of about 50 cytokines. We don't even make our second-year medical students, and the people who write the board exam questions, don't make them learn the names of all 50 of those cytokines. They have to learn about a dozen of them. I'm going to mention about three or four or five tonight, so you're not going to get quite as many as
13:01
our second year medical students. But you're going to hear about some more from Andrew Gross because some of them are targets of new therapeutics. We'll talk about cytokines and what they do. These cytokines go over to the neighboring blood vessel, the blood vessel cells then respond to that. What do they do? They put adhesion molecules, sticky molecules, on their surface that's facing the bloodstream for this white blood cells in the bloodstream to attach and then come into the tissue.
13:31
I'll explain how that works in just a minute. They're going to attract circulating immune cells to the site of the tissue. This is a very efficient system. The cells recognize the infection, they say to the neighboring blood cells, "Bring in some help." The blood vessels bring in some help, and here it comes. The blood vessels also allow fluid from the blood. This is the cellular help. They also allow the fluid to come in with proteins that are put directly protective as well,
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such as antibody molecules that you heard about last time. I'll talk in a lot more detail tonight about antibody molecules. In general, this response of bringing in immune cells and bringing in fluid from the blood, we call this inflammation. Everybody is familiar with inflammation. You'd get a cut in your skin, you get bacteria in there, it swells up, it's red, it hurts. The definition of an inflammation was made by the ancient Romans. We've known for many years.
14:26
You've all experienced inflammation. What I'm telling you is inflammation is good. We think of inflammation as bad, in this context, inflammation is good. It's doing what it's supposed to. It's getting the immune system there to fight the infection. When inflammation is bad, however, is when it's prolonged and chronic then you get tissue damage. Those immune cells that are coming in, their goal is to kill the bacteria, kill the fungi, kill these other things that are trying to eat us,
14:55
and they're going to cause some damage to the underlying tissue if we give them the chance. That's where inflammation is bad, is when it's prolonged and chronic. This is just an illustration of the process I just went through. This is the tissue side. This is the layer of cells that line the blood vessel called the endothelium. This is the bloodstream here. We've got our white blood cells flowing through here. On the interstate, they're going through it 70 miles an hour.
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Out here in the tissue we got these bacteria. Our sentinel cells are recognizing those bacteria, they're secreting cytokines, and I've listed two cytokines on this diagram, interleukin-1, IL-1 and TNF. Among about the 50 cytokines, about 35 of them or so have a systematic name called the interleukin-1, interleukin-2 all the way up to interleukin-35. That's good for being systematic, but it's hard to remember them. What does interleukin-22 do again? We immunologists struggle with that.
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They originally named interleukin because it was thought that they're being secreted by one immune cell and acting on another immune cell. We now know it's more complicated that they can act on non-immune cells, like blood vessel cells as shown here. That's when the name was changed from interleukin to cytokine. But instead of calling them cytokine-1, cytokine-2, cytokine-3, we've stayed with the interleukin 1, 2, 3, etc. About the other 15 all have names that were too popular to give up.
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This one, for example, the TNF, that stands for tumor necrosis factor. Now, put yourself in the place of the scientist who discovered tumor necrosis factor. He had this thing that he found that he injected into a mouse that had a tumor, and the tumor cells all died rapidly by a process of cell death called necrosis, which is what happens if you starve the blood supply. The cells don't get any blood then they die by necrosis. It's a violent death. It's also what would happen if you
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take blood cells and stick them in a glass of water and they would blow up because there's no salt around. He had dollar signs and visions of fame flash before his eyes when he gave this molecule this name. Turns out, you can't use it to treat cancer. You cannot give people TNF. The reason you can't give them TNF is because this happens too much and you get inflammation too much, you go into shock, very bad news. However, somebody is making money from TNF,
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but by doing the opposite, by blocking it. This is really good for some nasty inflammatory diseases such as rheumatoid arthritis, then blocking TNF can be a very good therapeutic. You're going to hear more about that from Dr. Gross in a couple of weeks. IL-1 and TNF. It turns out we have therapeutics that block TNF, they are good for some diseases. Therapeutics that block IL-1, they're good for some other diseases, not quite as many diseases, so they're not making as much money from that.
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Somebody got the bright idea. What if we block both of them at once? That clinical trial stopped really fast because the people got severe infections. These two cytokines have overlapping functions and if you block them both, you have bad news, but you can block one of them and there's a therapeutic value that you can get from that.
18:28
Our host sentinel cell sees the bacteria, secretes TNF and IL-1 that acts on these blood vessels, they put up several adhesion molecules. This one here grabs the leukocytes as they're coming by and they start rolling on the endothelium instead of zipping by 70 miles an hour, they get on the off-ramp and say, "Do I want to exit or not?" Whether they want to exit or not is determined by this little green ball here, which we call a chemokine, because it's a kine means that the cells respond to it.
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The kine refers to the cells responding, and the chemo is referring to the fact that there's a chemical that it's attracting cells. Basically, what the chemokine does is it controls which immune cells come into that site of inflammation. The reaction started here is determining which chemokine, which is determining which blood cell is coming in. The immune system has the ability to customize the response, and we'll talk a little bit more about how that happens a little bit later in the talk.
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You can customize the response to fight the type of infection that is being sensed here. The type of chemokine determines what blood cell comes in. If this cell sees the right chemokine that it can respond to, then its other sticky molecules, adhesion molecules become more sticky. It then stops, instead of rolling along, it stops and then it squeezes through between the endothelial cells and comes in here and then helps fight the infection.
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That's that sequence of events to get inflammation going. As I indicated there, the neutrophil is the immune system's first responder. If we have an infection with bacteria or fungus, yeast type a cell, it's the neutrophil that's going to come in and do the heavy lifting. Neutrophils are typically the first cells that come in, they are really good at killing things. They make a lot of nasty chemicals, including bleach molecule. Basically, what we use as
20:38
bleach is one thing that the neutrophil makes. They're very good at killing microbes. They can also damage tissue in the process. If you get an infection, you'll probably notice you get some pus, and a lot of that is due to the dead neutrophils that are coming there. The neutrophils make nasty chemicals. They're very short-lived cells, because they make these nasty chemicals it's not good for their own health, but they come in and they fight the infection. Because they don't live very long,
21:09
they need to be continually replenished from our bone marrow. This is, again, another medical correlation here, is that, if we have a situation where the bone marrow is not putting out blood cells adequately, the first place we feel that would be two things, the red blood cells and anemia, and the other thing would be the neutrophils and getting more infections or more severe infections, if we don't have enough neutrophils, because the neutrophils have got do
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this all the time because we're always getting some bacteria or fungus getting in there whether we got to kill off. Some chemotherapies for cancer treatment have this problem, and luckily, we have a couple of cytokines that make the bone marrow produce more neutrophils, and so since they've come online as therapeutics, that's helped cancer patients getting chemotherapy to do better that we can boost their neutrophils back up to where they should be.
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The neutrophils, now, because they're pretty nasty, this basic inflammation generally doesn't bring in neutrophils for very long, maybe about a day, and then it switches, and the next cell up is the monocyte. The neutrophil comes in first and then we start making different chemokines on the blood vessel that attract now the monocytes instead of the neutrophils. The beauty of the monocyte is it's bipotential. It can either be a good killer like a neutrophil, not quite as good as a neutrophil,
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but it can still be pretty good, or it can clean up the mess and help us repair the damage and get back to normal healthy tissue and not being all red and swollen anymore. What controls whether the monocyte is going to fight or going to clean up? Cytokines. Whatever cytokines are getting made when the monocyte gets in there, if we've already gotten rid of the infection, the cytokines shift over and we get the ones that promote wound healing. If the bacteria are still multiplying,
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we haven't gotten them all yet, then the cytokines are getting produced by the other cells in the tissue are going to be the ones to tell the monocyte to keep fighting. The monocytes comes in, it's sort of, "What's going on guys? Tell me what to do." It can respond to cytokines to do what we want it to do. Now, as I said, the neutrophils make a lot of nasty things. Another important principle about how we kill microbes is that we eat them. Our neutrophils, and our monocytes,
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and our macrophages, and our dendritic cells are really good at eating things. That's a process that we call phagocytosis. Phagocytosis means one cell eating something, in this case, eating something big. The definition of phagocytosis is something big, at least a bacteria size. That would be eating a microbe. The neutrophils and the monocytes can do this to some extent on their own but it's really greatly helped along if we make antibodies against
24:15
that bacteria or that virus or that fungus particle. If we coat that microbe with some soluble immune components, can be some innate components work this way, but for sure, antibodies are really, really good at this. Now, our phagocytes really will eat them much faster and much better and kill them much better. That's the cooperation of the circulating phagocytes that act early with antibodies which are going to get produced a little bit later against things that we don't kill off right away.
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Now, I think this is a pretty important point here. Those things I gave you from the list, I just gave you the numbers, I didn't give you the names. Those things that cause human disease, mostly, and I think there's probably very few exceptions to this. Almost all of them cause disease because they're good at evading the immune system killing them. They have figured out ways to avoid getting killed by the immune system. Microbes that cause illness in healthy people either resist phagocytosis or
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resist killing inside the phagocytes or have some other related strategies to get by. Some good examples of the latter, some of them get taken up by the phagocytes, but then they keep the phagocyte from killing them somehow. A couple of good examples of that are Salmonella, which is a common cause of food poisoning, and also causes Typhoid fever if you have a breakdown in the water supply. Another great example would be Mycobacterium tuberculosis, the organism that causes TB.
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Tuberculosis, as I said, it's one of the big four. It's a huge threat to human health in many parts of the world. Although it's not a terrible problem in this country, there are people who get infected in this country as well. It's just much less, but in many parts of the world, it's a big threat. An example of an organism that evades this principle here of the antibodies coating it and making it really easy for our phagocytes to eat them up and kill them, an example of one that evades
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that is Streptococcus pneumoniae, which is a bacteria that is important cause of severe bacterial pneumonia. This one, it changes its outer surface so that if you make antibodies against Streptococcus pneumoniae, it's got a lot of very close cousins that your antibodies won't recognize that slight variant. There's lots and lots of really close cousins of Streptococcus pneumoniae. We've tried to help this along because we have a vaccine. One of the main vaccines for this takes 23 of
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these different variants and puts them all together and immunizes people. That takes care of about 90 percent of the cases, there's still about 10 percent that are relatives that are enough different that these antibodies don't help. But it does help about 90 percent of the time. Now, other examples of common organisms that change their coat so that the antibodies don't work again and protect us from a second infection, influenza virus is another flu, is another example of that.
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Another common example would be the common cold, rhinoviruses. Again, come in about 100 different varieties. Eventually, you will have had almost all of them, but it takes a while before you've had that many colds. Unfortunately. Yeah. Our adaptive immunity is good, but the bugs can figure out ways to evade it. That's a good transition for me now to talk about the B cells and antibodies and the T cells and cell-mediated immunity. They're part of what we call adaptive immunity.
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We've been talking so far mostly about innate immunity, the ability of our neutrophils and monocytes and dendritic cells and macrophages to directly recognize infectious agents. Adaptive immunity uses a completely different strategy. Innate immunity, those innate cells, they just have a bunch of different receptors that recognize very conserved elements of whole classes of organisms and are hard for those organisms to change because it's part of their lifestyle,
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certain aspects of their cell wall, if it's a virus, most viruses have RNA as their genetic material and when they replicate their RNA, they make a double-stranded RNA that the two strands paired against each other, we can detect that double-stranded RNA. It's hard for the virus to change how it replicates its genetic material. There aren't very many viruses that can directly avoid doing that. There are a few viruses that have switched to using DNA as
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their genetic material but most of them use RNA. Anyway, that's how the innate immunity does. Adaptive immunity uses a completely different strategy. Here now instead of all of the cells having a dozen different receptors, each of which it recognizes broad classes of organisms, our T cells and B cells, each one uses a similar molecule but slightly different. So it can recognize a different pathogen. We'll have one cell in 10,000 that will recognize influenza virus, one cell in 10,000 that will
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recognize rhinovirus that causes colds, one in 10,000 that will recognize the organism that causes tuberculosis, etc. That's all before we get infected. When we get infected, those ones that can respond, they expand up and we get more of them so that there's now enough to help fight the infection. Adaptive immunity uses a very different strategy. It starts out with each cell having one receptor and being able to recognize one type of thing, one individual rather than a broad
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class but then you have to expand those up to make them useful. Now, there are some other points here which I'm going to come to in a minute. The way in which this works for the B cells and the T cells, is that they do it at the DNA level. They start out with their ability to recognize these pathogen molecules. The gene encoding, those recognition elements exist in pieces spread out across the DNA of one chromosome. Then as part of the development of each individual B-cell, it picks one of these
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several 100 elements, and sticks them next to one of these, in this example, four elements. Some of the genes have three different types that come together, some of them have two that come together. I'm just trying to be very schematic here, but any given individual B-cell as it develops, it picks at random one of these 1, 2, 3 up to several 100. It puts it next to one of these four, you're getting a multiplication to give you the number of possibilities.
31:27
This example I have given you only get up to a few 100 different possibilities, but it turns out, there are various mechanisms that are a little more complicated than I want to get into, but we can get up to millions and billions of possibilities for our B-cells and T-cells. Really, our B-cells and T-cells can recognize almost anything. There were studies done by an American by the name of Landsteiner in the 1930s. He made lots of organic chemicals and tested the immune system's ability
31:58
to make antibodies against them. Really, whatever he made, he was able to get antibodies against pretty much.
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The B-cells and the T-cells, they can recognize whatever we throw at them.
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As I mentioned, these cells start out pretty rare because we've got each of which recognize different things. The principle here is that once we get an infection, those B-cells and those T-cells, which can recognize with their receptors, can recognize molecules of the infectious agent, they multiply many times to expand their number, and then some fight the infection, others are left in reserve as memory, and that's one of the main reasons that we don't get nearly as sick the second
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time around is that we have more of those lymphocytes. Instead of one in 10,000, we have one in a 100 or several in a 1,000, we have a lot more. That's what vaccines do, vaccines give us a fake infection that gives us more of that immunological memory and antibodies so that if we get the real infection, we're more prepared, our adaptive immunity doesn't take as long to get going, it gets going faster, it beats back the infection faster before we get as sick.
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Adaptive immunity is very important in a first infection and it's even better in a second, it learns from the experience of the first. It changes how many cells there are waiting around for the infection to give us more of those to be able to respond faster. I've illustrated that a little bit in this slide here. This is now lymphocytes, these happen to be T-cells, based on the shape of this molecule, but they're each a different color here, and that is supposed to
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represent the fact that they each have a little bit different shape and they can recognize a different pathogen. We start out with many different possibilities, now, because of the way this is generated, the B-cells and the T-cells, they are randomly bringing these gene segments together. It turns out, not only can they recognize any molecule we can synthesize, or any molecule that a pathogen can throw at us, but they also recognize our own molecules as well.
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That is the downside that comes with the good side, the bad with the good. That's the reason when we have an autoimmune disease or an allergy against food or against cat dander or against pollen, our immune system, our B-cells and T-cells have made a mistake, they've made an immune response when they shouldn't have. In most of us, we make that decision correct so often that we don't notice that we ever make any mistakes, we do make mistakes at small levels, all of us do, certainly, not rare,
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but only in a few percent of people do those mistakes get made badly enough that it becomes a disease or a really bad nuisance. Now, I guess probably, for allergies, it would be higher than the few percent, that would be probably, many of us experience allergies in springtime and things like that, but the point is that we randomly generate these lymphocytes. We then have to have a way of trying to get rid of the ones that are bad. Part of that is done during their development,
35:27
they go through a phase in their development where if they contact their antigen, they're inactivated. That's illustrated here, some of the colors have dropped out,
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the point of that is that our self molecules are always there, whereas infections are not there and then appear. We have a timing device. The cells are developing all the time, the ones that develop before the infection, well, if we're going to see that infection in the future, they could just develop, they wouldn't see our self molecules, they would make it to the mature stage, and now when we get the infection, they can respond. The ones that saw ourselves, our self is there all the time,
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it would be there during the immature phase, and a lot of those cells would die off. That is one of the mechanisms which we get rid of the self reactive cells, it's not the complete mechanism, and I'll come back later in the talk to other mechanisms that the immune system uses. This is one of the important mechanisms, but there's also a subsequent mechanism that occurs. Some cells sneak past that checkpoint and then we have to silence them later to avoid auto-immune disease.
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If we get an infection, in this example, we're getting an infection with a virus that is seen by this cell here with the orange receptor, and so those cells expand. The other colors don't expand, they stay the same in number, but we give more of these. Now, at this state, if we get infected again with this orange pathogen, well, we've got a lot more cells to deal with it. We call that clonal selection. This would be referred to as a clone of cells that came from the original mother cell
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divided many times and gave rise to a clone of cells. They're all identical or nearly so. Again, vaccination works by generating memory T-cells and memory B-cells. Also, the cells that make antibodies, the B-cells during an immune response, some of them become antibody secreting factories and make large amounts of antibody, during an immune response, some of those can become very long lived cells, and continue to make antibody for many years, certainly, up to a decade, if not longer.
37:51
We don't know completely how long they live, but certainly, for a decade, they slowly go down over time. We have antibody right there, right at the beginning when the pathogen comes back to deal with it right away. I've been talking about antibodies. What I want to do for the next five or so minutes is, probably, more like ten minutes, I want to tell you a little bit more in detail about antibodies. You all have heard about antibodies, but let's talk about some details so you
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understand a little bit better how they work and how we can use them in therapeutics. As a person, I can make millions or billions of different antibodies, but any one B-cell is only going to make one antibody. That's because it rearranged its DNA, each B-cell did that individually. Now, the molecule, I want to define another term here that immunologists always use, antigen. Antigen is what an antibody recognizes. That's an easy way, we have to have a word for what does an antibody binds to,
39:00
it binds to the antigen. The name antigen comes from the fact that the antigen generates the production of the antibody. We inject an antigen into ourselves or into an animal, our immune systems produce the antibody against that molecule, they generate an antibody response. It's a circular definition. An antigen is something that causes you to make an antibody that recognizes it, that's where the name comes from. Then by analogy, we call it when a T cell recognizes also an antigen,
39:30
although T cells don't make antibodies, but by analogy, we call that antigen as well. Now, as I mentioned, we have many B cells in our body and each B cell is making a little bit different antibody. But when we have, let say, a flu virus come in, we have different B cells that will make an antibody recognize different parts of that flu virus. It's not just one B cell that's getting activated, it's a handful or 100 or maybe even 1,000 B cells are getting activated and each expanding
40:05
in number and then each making antibody. Each of those is a clone, but it's many clones because there were many different B cells to start with, each of which made a different antibody. We call that antibody polyclonal, and I'm going to distinguish that in a minute from a monoclonal antibody which we use in therapy, so this is a clone. Now, another important principle here is that B cells are often helped by T cells. Although T cells do cell-mediated immunity and B cells make antibody,
40:40
they also work together and I believe you've got a movie of that last week from Dr. Gundling. That's the T cells helping the B cells to make antibodies. When that happens, the B cells make a higher quality antibody. What will happen in an immune response is actually some B cells will go off and make some antibody quickly on their own and that's an antibody that sticks a little bit to the pathogen, but not really well, sticks a little bit, so we want to get some of that out there fast,
41:11
just to help right away. But some of those B cells, they're going to take the more long-term investing strategy, they're going to collaborate with the T cells, and they're going to make better antibody. They're going to go through a process in which they introduce mutations and then pick out the one, the mutants that have the highest affinity for the antigen. There's a slow, but ultimately useful process in which we make higher-quality antibodies that bind more strongly to the pathogen
41:45
and therefore are more protective. We make some lower-quality antibody quickly, they help out right away and then we take some of our B cells and we invest them in a long-term bond and at the end of the day, we have higher-quality product. The B cells and the T cells see antigen in a fundamentally different way, as I'm going to explain. But yes, the way this works is that T cell has to see the same virus or bacteria or whatever that the B cells sees and only if they both are against
42:14
the same molecular antigen, perfect, the same particle or, it doesn't have to be exact, immunologists would usually use antigen to refer to a single molecule. But in a virus particle, there are several types of molecules in there, and this will work for two different molecules in the same particle as well. Now, we call this the germinal center response and you don't need to remember that. But the key point is that this gives you these long-lasting antibodies secreting cells
42:53
that go to the bone marrow and they secrete antibody for years and years and years. This makes sense if you think about it, that B cells that make the quick response, that's not as sticky, but it's going to help a little bit, we don't worry about, we just make that those cells only make antibody for a short time, but the ones that get the T cell help and make the really high-quality antibody, those are the ones we want, those antibody secreting cells to last a long time and to
43:21
really help us over time so that when that pathogen comes back, we've got the best quality antibody to fight it. Almost all the vaccines work by this principle of producing this high-quality antibody that you're cranking out all the time. At least 25 of the 27 licensed vaccines work by that mechanisms, there is a little bit of argument about the last two, but almost all the vaccines work by this mechanism here, this is what we know how to do.
43:50
Now, I want to say that actually this understanding of immunology was put to use in the 1990s to develop improved vaccines. It turned out some of the vaccines against some bacteria were using a type of antigen which could not engage the helper T cells, and so you only got the quick low affinity response that was only protective for a short period of time because you didn't keep making those antibodies six months later. It was found that those vaccines in very young children were not protective,
44:29
it was only protecting against half, when the trials were done, the number of cases of that disease only went down by about half, not more as you would see with other good vaccines. They said, "Well, wait a minute, this vaccine doesn't have any way to activate the helper T cell, let's add that in there." That's a type of vaccine called the conjugate vaccine. Those came into being in the 1990s. Those are a case where this basic understanding of immunology has been applied to making new vaccines.
45:00
Just to step back a little bit, I would say that where we stand with vaccines right now is we have some really good ones, some ones that are sore cells, and some ones that just don't work. The three big ones that I mentioned, AIDS, tuberculosis, and malaria, we don't have their vaccines there obviously. There's a lot of thinking that we need to really apply, we need to learn more about the immune system and apply it to our vaccines because what we've learned to do is this kind of
45:32
immunology and what we need to do is to learn, probably to boost the cell-mediated component of immunology better in order to get vaccines against the things where we don't have them now. I'm an apple guy, but I have to give credit to Bill and Melinda Gates Foundation is really spearheading the effort to develop these new vaccines, particularly for things like malaria, which are problems in third-world countries. Now, I want to show you some molecules here. This is what an antibody looks like
46:07
if we look at the actual structure.
46:12
I've got one version on the left, and one version on the right. The version on the left shows all of the atoms in the antibody, the antibody is in purple and the antigen, which is a viral protein is here in red. In this diagram here, every atom is shown by a little ball, and the size of the ball depends on which atom it is, whether it's a carbon or a nitrogen or a hydrogen. Anyway, what you can see here very clearly, I think, is how close the fit is between the antibody and the antigen.
46:45
The antibody mimics the antigen in its shape and that allows it to stick to it tightly, like a hand in a glove or a key in a lock, those are some analogies people like to use. Now, that's what we will learn from looking at this picture. What we learn from looking at this picture, now, what this shows is not all of the atoms, but just the traces, the path of the protein molecule. Protein molecule is a long thin molecule with amino acids stuck together, many, many, many.
47:22
Two protein parts stuck together here, there are about 200 amino acids each. This is tracing out from the beginning to the end. It's a linear molecule in terms of the sequence, but it folds up into a compact shape. Now, what I want to illustrate here is that this part of the antibody and this part of the antibody, they are very similar from one antibody to the next, so the shape of antibodies is very similar from one antibody to the next. What is different is these little loops
47:54
up here at the end that make the part that actually contacts the antigen. We get all of them, not all, but almost all of the variation occurs out in these loops. The structure is very similar, but the actual part that touches the antigen varies a lot from one antibody to the next because the variation goes into those loops. This is a case where the detailed structure lets us see the principle of how the whole system works. Yes, each B cell makes a different antibody,
48:26
but they're not that different from each other, they're very similar to each other, except in those loops. Only the loops are different and it's the loops that give a very exquisite hand-in-glove type of fit. Now, actually, this is just a piece of the antibody molecule, it's about a third. It corresponds to this part here in this diagram. An antibody has two equal parts that each bind the same antigen because one antibody molecules made by one cell and one cell just makes one antibody,
48:59
so the two halves are identical and can each bind to the antigen. Then this back-end is going to help the antibody be useful to the immune system, it's a tag for the other cells in the immune system. Then in the middle, we have a flexible part, this allows the antibody, if you can imagine my two hands of the part that grab onto the antigen, and my shoulders are the flexible part we call the hinge, the value of that is that my two hands can grab on to that virus particle regardless
49:31
of its geometry because if I have to, I can do like this or I can do like this or I can do like this. I have a lot of flexibility in my ability to latch on with both hands. Again, that makes for a tighter binding, I can grab on more tightly if I use both hands than if I just use one. Now, the other point I want to make from this slide is that we make actually five types of antibodies that differ primarily down here, which is the part that the immune system uses to latch on
50:00
to help do other business such as phagocytosis, the phagocyte taking up the antibody coated bacteria. That's illustrated here. Antibodies can help in several ways. They can help by just gumming up the works. This is called neutralization, where we have a virus particle, the antibody binds to the virus particle and now that virus can't get into the cell anymore because we've grabbed onto the part that it needs to get into the cell. Now, that virus particle we can destroy it,
50:34
our phagocytes can eat it up and chop to pieces, but it can't even infect our cells in the meantime. This is the holy grail if you're trying to make a vaccine against the virus, you'd love to make a vaccine that makes an antibody that neutralizes, that can really just directly prevent the virus from entering. However, an important part of antibodies, as I said, is connect to the phagocytes. If the antibodies in this case they're coating of bacterial particle, that lets
51:02
the phagocyte eat it up much more easily. Here, we've got an eosinophil which is good against defense against parasitic worms. Here's a worm, it should be much bigger than that, this is obviously a worm that's got to say, a few thousand cells compared to one cell here, so it should be 1,000 times bigger but if you'll ignore the artistic license there, if it's got antibodies on it, then the eosinophil is going to secrete its granule contents, which make nasty things that are going
51:29
to kill that worm if we do that up and down its length. Then there's some other mechanisms as well. But you can see that the antibodies can work directly or they can work together with our immune cells to help protect us. Few other quick comments about antibodies. Vaccines cause us to make our own antibodies, we call that active immunity. That is good because it's going to last a very long time. The tetanus vaccine, we're supposed to get boosted every 10 years, so slowly your amount of
52:07
antibodies go down over a 10-year period, you want to boost them up every 10 years. Now, the disadvantages it takes a week or two weeks to make some good antibodies. If I may needs some antibodies right away, they just got bit by a snake. What are we going to do? We can give them antibody, we can inject the antibodies into them so that the antibodies can just float around and grab the snake venom and inactivate it. That's the alternative then, we call that passive immunity.
52:37
The advantages is fast. The disadvantage is not going to last very long. Antibodies in the blood have a half-life of about three weeks so within a couple months they're pretty much gone. Examples where we would use that would be if somebody gets exposed to tetanus and has not been immunized, hepatitis A, there's now use of vaccine. But about 10 years ago I got a hepatitis A shot when I was visiting India, for example, that was antibody against hepatitis A, that was passive immunity.
53:07
Protection against snake venom, and also the mother imparts this type of immunity to newborn. When in utero, there is transfer of antibody across the placenta. That's our most important passive immunity is what we get from our mother and help us through those first few months of life. Finally, I want to mention that as we said, that the antibodies taken from a person or an animal, such as these examples, those would be polyclonal antibodies. They would be made by the progeny
53:40
of a number of different B cells. But we can also make monoclonal antibodies. We can take a single B cell, we can immortalize it and then have it turn into antibody secreting factories in the laboratory and make lots of antibody. Then the advantage of that, we can use that for as a therapeutic or diagnostic. The advantage is that they're all identical, enhance very standardized, and we can, know what they're going to do time after time. Whereas these products really have to be
54:10
carefully tested and make sure it's good in that kind of thing. One, I think really big change is that in the last 10 years, we're getting new therapeutics based on monoclonal antibodies that are coming and getting approved by the FDA and it's I would say on the order of 3-5 new ones every year and I don't mean me too types of therapies. I mean novel therapies where it's a new target is a new indication and so I think this is a really exciting time for the field of immunology.
54:37
We're seeing it translated into new therapeutics. The key to this was the monoclonal antibody technology got discovered in around 1970. But this really is taken hold in the last 10 or 15 years and that's because we've learned in the meantime to make those antibodies as similar to human antibodies as possible, they were originally made in mice. The problem was if you injected a mouse monoclonal antibody into a person, our immune system would see that as foreign and make an antibody and then
55:10
we'd get rid of that as a therapeutic. That still happens with these new generation, but in a much smaller percentage now, less than one percent typically. That was the key breakthrough and that's why we now have a lot of these coming online. This is just a very short representative list. These are two molecules here that are used in cancer immunotherapy for breast cancer and for B cell lymphomas. These are made by Genentech, which is in South San Francisco, and I don't own any Genentech stock.
55:44
I should say happy to say, but probably would have made a lot of money on it. But these are two that are made by a local company that was started by a UCSF faculty member, Herbert Boyer.
55:58
Then some of these are used for inflammatory diseases blocking immune responses and here's one that's used for coronary disease just as some examples. I wanted to say a few words about cell-mediated immunity and then I want to finish off by the news you can use, some thoughts about what do we know about the immune system that we can apply to our everyday lives? I've got a few slides on that at the end. I want to switch over to cell-mediated immunity. The T cells recognize,
56:32
instead of recognizing an antigen in its normal form, the way it would be sitting in a virus particle, the way it would be sitting on a bacterial cell cell surface. Instead of that, the T cell recognizes a piece of a pathogen the immune system is extracted out of that pathogen and displays. A piece, and we call it a peptide, which means it's a short piece of a protein. The advantage of that is that the T cell can do what an antibody can't do. An antibody can only see
57:03
a pathogen when it's outside of cells. Antibodies are secreted from cells, they float around on the outside of our cells. However, T cells can see those pathogens when they're hiding inside our cells. Those bacteria that get into the phagocytes and keep the phagocytes from killing them, the T cell can see that. The virus, when it infects a cell and the cell is now producing virus particles, well our antibody can act against the virus particles that get released. But the T cells can see
57:31
this infected cell and they can kill the infected cell. The T cells are very complimentary to the B cells. They see the antigen or pathogen when it's inside our own cells and they can root it out and get rid of it. The way they do that is they see little pieces of the antigen that our immune cells extract from antigen and put it onto our own proteins that display it. Now our T cells come in two types. The T cells to recognize antigen, which is up at this peptide,
58:03
bound to one of our own proteins, they use a molecule very similar, to the antibody molecule. We call it the T cell antigen receptor, or TCR for short. It's very similar type of molecule that's got the loops and it's very parallel system, it looks very similar. However, it's never secreted, it's always on the surface of the T cell, the T cell never secretes it. It doesn't float around. It's always stuck to the T cell and that's because the T cell is always acting locally.
58:34
The antibody can act all over the body. The T cells only acting locally because it's going after the infected cell so it doesn't want to get away from the fact that I'm here and you're here and I'm going to attack you. That's the idea of the T cell.
58:51
There are two types of T cells. There are the killer T cells, their purpose is to kill virus infected cells, and there are the helper T cells, and their purpose is to secrete cytokines to direct the action of other immune cells.
59:12
The helper T cells are the cells that are infected by HIV and get depleted, and that's when we get the immunodeficiency for the acquired immunodeficiency syndrome, is when our CD4 T cells get too few to protect us anymore. If you know anybody with AIDS who is on antiretroviral therapy, their doctor will take some of their blood, send it to the lab, and measure the number of helper T cells in the blood. If that's falling instead of rising, then that means the virus is
59:46
getting resistant to that drug and I better switch them to another drug because once that number falls below a certain level, they're going to start getting all sorts of infections, and that's when life becomes threatened in those individuals. The helper T cells are needed to protect us by secreting cytokines and boosting our immune responses from other cells. The cytotoxic or killer T cells instead of CD4, they have a molecule called CD8. The CD4 and CD8 are molecules on the surface.
1:00:19
They play important roles in the function and that allows us to distinguish cytotoxic T cells from helper T cells. This is just a picture of what I just told you. The killer T cell kills the virus infected cell. It sees a peptide from the virus that is displayed by a protein of the infected cell. In other words, the infected cell take some of these proteins of the virus that it's making inside, chops them into pieces, sticks them onto this protein, sticks the protein on the surface.
1:00:51
Even though the virus is not putting its own proteins on the surface, this cell is putting that piece of the virus on the surface, the killer cells sees that and it kills. It secretes toxic molecules that make holes and induces cell to die. This won't necessarily kill the viruses that have already assembled and haven't yet been released. But the point is that you want to cut off the factory that is producing new virus, they block the virus that's already been released with antibodies.
1:01:21
The killer cells and the antibody work in a complementary fashion. Helper cell is a little more complicated. Here what happens is that instead of the pathogen molecule being made inside the cell, now the immune cell is taking it up from the outside by phagocytosis or endocytosis, so related process with smaller molecules, and then that cell chops it into bits, takes those peptides, sticks them on a very similar molecule but a slightly different molecule that binds those peptides.
1:01:58
This type of molecule takes peptides that the cell brought in from outside. This type of peptide binding molecule takes peptides that were made inside the cell. Some elaborate cell biology that matches the peptide to the type of binding molecule that's going to bind it. That's illustrated here that we have two types of peptide binding molecules, and they look like hot dog bun. It's got this part, this part, and it's hard to see the three-dimensionality.
1:02:30
This is sticking out and this is in the back. It's a table with two sausages on the surface here, and then the peptide goes in the middle. We have two of these types. The red type, what we call class 1, is going to pick up the peptide that's made by the virus inside the cell and stick that on the surface, and the blue one we call class 2, it's going to take a peptide that was brought into the cell from outside by phagocytosis, then we chop that pathogen into pieces, load the peptide on,
1:03:07
and then stick it back on the surface. The T cell is interacting with cells that are displaying peptides for it to see. There's a cooperation between the cell, it's got the peptide and the T cell that can then visualize that because it's displayed outside for it. That's very different than antibody. The antibody just binds directly to the pathogen molecule. Here we have elaborate process for finding these, not letting the virus hide it inside. We're not going to let it hide it.
1:03:36
We're going to show it out there so that it can be seen. Now, one more point before I go to the immunology you can use is that immune responses are tailored to the type of infection. I already mentioned this a little bit. We can have a microbe infection or we can have a virus infection. We can have an extracellular microbe or an extracellular microbe like the TB microbe or the Salmonella food poisoning microbe. We can have the location. The immune system can specialize
1:04:07
to immune response in the lung versus in the gut. There's some different properties to the immune responses. Worms and biting insects versus microbes would make a different type of immune response against the worms and the biting insects, then against the microbes. Defense against most microbes is antibodies and the phagocytes. We've already gone over that in a bit of detail. We get a neutrophil rich inflammation, and that can be prolonged by the helper T cells. Normally, I said that you get
1:04:35
neutrophils first and then monocytes. Some circumstances, the helper T cells will prolong the neutrophils and keep bringing them in. That's of course a more destructive type of inflammation. But sometimes, that's what happens. Normally, it would switch over to monocytes within a day. Defense against the microbes that can survive and replicate inside phagosomes. Now, here it's mostly the monocytes and macrophages they're surviving in. Because remember, the neutrophils came in for the first day,
1:05:04
after that, the monocytes came in. A lot of times what happens is these things gain a foothold in the monocyte or the macrophage. It doesn't really do them any good to get a foothold in the neutrophil, because a neutrophil dies in a day or two anyway. They're not going to stay there very long. But the macrophages are long lived cell. If you can establish an infection in a macrophage, it can stay there for quite a while. That's what happens with tuberculosis and salmonella.
1:05:28
The defense against this type of infection is what we call type 1 immunity, and the helper T cells then specialize to detect these infected cells, they release cytokines that promote killing by the macrophages. Defense against viruses, I think we've already covered this, the early defenses, the innate mechanisms that restrict the replication of the virus that would be primarily a cytokine called interferon, one of the first cytokines that was discovered, interferon, and it's called
1:06:02
interferon because it interferes with virus growth. It makes cells able to resist the replication of viruses to some extent. That's our early defense and that's really critical, and then adaptive immune defense comes in and we make neutralizing antibodies, and we have the killer T cells. I think we've covered that. Then finally what we haven't really covered very much is defense against worms and biting insects. This is a different type of immunity called type 2 immunity.
1:06:29
Here the helper T cells, do two types of things, they promote a different type of antibody called IgE, which works together with a mast cells, and another type of cell called the basophil to strengthen our barriers at the scan and in the gut and in the lungs. At the barrier between the outside and the inside, the epithelial layers, will strengthen that barrier. Also these type 2 helper T cells, they attract eosinophils to the site of infection which are very good at attacking worms.
1:07:03
Some manifestations of type 2 immunity, which you probably don't like, would be things like sneezing, coughing itching, diarrhea tears. What these things all have in common is we're trying to get rid of stuff. We're trying to blow it out. We're trying to wash it out. Diarrhea, were trying to wash it out that end. Coughing, we're trying to blow it out by coughing. We just had somebody coughs. That's your immune system trying to get rid of something.
1:07:29
Now, the reason we don't like that is because we live in a world that doesn't have very many parasitic worms, and so our immune system, the one theory that you're going to hear about from Dr. Boucher in one of the other lectures in this mini Med school is that one of the theories that has a lot of support is that our immune system gets bored with not having enough worms to deal with. It goes after pollen and cat dander and things like that, which if we had worms and other nasty stuff,
1:08:03
we would just ignore that stuff, we would concentrate on the important stuff. That's called the hygiene hypothesis. You're going to hear about that from Dr. Boucher.
1:08:15
I've left you with a big problem, actually is a big problem that immunologist don't fully understand. This is one of the really active areas in immunology research right now, including at UCSF, and that is how did the B cells and T cells know what's an infection and what's pollen and cat dander and the food you ate that you had never eaten before? The answer is that, that's a very complicated thing, but I can give you at least some of what we understand.
1:08:45
One thing is that endorse innate recognition mechanisms, the dendritic cells and macrophages, the sentinel cells recognizing bacterial cell walls and things like that. They then put molecules on their surface that promote T cell activation, so that innate recognition of microbe is translated into promoting the T cell activation by putting molecules on the surface of those innate cells, particularly the dendritic cells. We call this process something called co-stimulation.
1:09:16
The co being, the stimulation would be the antigen, and this molecule that the dendritic cell is making in response to it recognizing an infection. It's saying I see an infection, I'm going to tell a T cell I've seen an infection. I know this is an infection. That's one of the most important principles. We now have a therapeutic that directly attacks that co-stimulation, directly blocks that co-stimulation to try to suppress T cell in some nasty immune diseases. Another mechanism we have is
1:09:49
something called the regulatory T cells. Some of those CD4 T cells make cytokines that promote immune responses. Some of them are now going to be the stop T cells instead of the go T cells. They're going to make cytokines that slowdown immune responses, that inhibit immune responses. We call that type of cell a regulatory T cell. The rare individuals have defects in the ability can't make any regulatory T cells. They get horrible autoimmune disease of all their organs at a very young age,
1:10:21
is a very horrible disease. Luckily, only a very few people ever experienced that. But we really need these regulatory T cells. Again, they arise during development. When they see self-antigen during development, instead of being gotten rid of, they actually stay around and suppress the immune responses later. Then finally, that's what I just said, the defects in making regulatory T cells is very bad. This is another area that's a research area that we have some people at UCSF doing,
1:10:52
can we harness regulatory T cells for therapies? Can we take a person's regulatory T cells, expand them in the laboratory, and then put back where there's now more of them, and now maybe they can block an immune response in a very specific way? Instead of just blocking all immune responses, maybe we can block just the rejection of that kidney transplant. That's a very exciting area for the future. Quick couple of comments about chronic inflammation. Sterile inflammation, we mostly talked about
1:11:26
the innate immune system responding to actual microbes, but it also responds to just tissue damage. That really, I think, is a strategy that we use because some pathogens have figured out how to not be seen by the recognition of bacterial cell wall components, etc. Just if we have tissue damage, that will induce some inflammation on its own. Many of you probably experienced this with sore knees and sore elbows after doing too much basketball or something like that.
1:11:58
Chronic inflammation, if an antigen persists, then you can get chronic inflammation because it's driven by the T cells. This is true in autoimmune diseases and some allergic diseases as well. There is speculation and I think there's some evidence is becoming now very well accepted in atherosclerosis field that inflammatory processes participate in the progression of atherosclerosis, and I can talk about that more if people are interested afterwards, and then this is now more speculative.
1:12:32
There's something in the Alzheimer's disease may also probably not be initiated by inflammation, but propagated and made worse by inflammation. There's a lot of hope that maybe we could learn to ameliorate these things a little bit and hold off some of these diseases and not let them progress as much. That's an exciting thing for the future. The immune system in cancer, as I mentioned before, there's good evidence that the immune system removes early cancerous cells in
1:13:00
many cases and reduces cancer incidence. The immune system is actually used to cure some leukemias together with chemotherapy, and this is a process called the graft versus leukemia effect. When bone marrow transplantation is done, we use bone marrow from a different individual, and then they leave the T cells in there, and then they can attack the residual cancer cells. There are some side effects to that, but this is very commonly used, including at UCSF now because it really does work
1:13:30
and that is the immune system killing off the residual cancer cells. We have some man-made killing cancer cells with monoclonal antibodies. I mentioned that before. Then there are ongoing efforts to boost the patient's own T cells to react against their cancer, and there's been some real progress in recent clinical trials on that front, but there's still a long way to go for that, I think. Anti-inflammatory therapies, some of you may have, well, probably all of you
1:14:00
are involved with this one way or another, or maybe many of you anyway. Many of you probably have taken aspirin and ibuprofen. They're good painkillers, but they're also anti-inflammatories. They're used to inhibit inflammation as well as pain. Now, they'll work when the inflammation is not too strong. If it's too strong, then you got to go with the bigger guns, the glucocorticoids steroids like cortisone, and the more potent versions of that. They were developed originally in the 1950s,
1:14:28
and they were really life-changing for people who had severe inflammatory diseases like rheumatoid arthritis. They're very effective immunosuppressive drugs and anti-inflammatory drugs, but the problem is they have very significant side effects of long-term use. We've been trying to find better agents, and then you're going to get a whole lecture on the newer biologics, monoclonal antibodies, and related molecules to block the inflammatory cytokines. These are really very effective,
1:14:56
not every patient, but in the patients that they work in. They worked really quite well. You'll hear about that in another lecture. Last three slides. Keeping your immune system in good working order. Now, we're getting into the areas where the immunologists have, it's more speculation and less hard fact, but let me give you a few things. Nutrition and the immune system, you'll hear a lot about nutrition and the immune system. I'll tell you my opinion. It's very clear that real malnutrition,
1:15:28
if you're really so poor that you're not getting enough calories or not getting enough protein, your immune system will suffer from that. That's what we call macronutrients. If you don't getting enough calories or enough protein, your immune system won't function as well as it should. There are some micronutrients that are important, some of the vitamins are important. A normal, diverse diet would do that fine. You don't need to take vitamin supplements unless there's something about your diet.
1:15:56
You're not getting your vegetables or what have you. Then finally, you'll sometimes see a lot in the news about fish oils. Fish oil is anti-inflammatory, that is pretty well established. You have to take a fairly high amount of it to achieve that effect. But fish oil is one of those things that will be anti-inflammatory. That has to do with the fact that inflammation is regulated by a variety of lipids, and we're now changing the lipids that are present. So we're changing a little bit
1:16:29
the balance between pro-inflammatory lipids, which would be blocked also by ibuprofen and aspirin to some extent. Again, if you take enough of them and which again, speak to your doctor about that. I'm not telling you how much to take. But there's also anti-inflammatory lipids, so the thinking is the fish oil helps boost the anti-inflammatory lipids and protects us in that way. It reduces the chronic inflammation in that way. Again, if it's fair, this would be a case where it's relatively mild,
1:17:01
I think not a really strong inflammation. Stress and the immune system is another popular topic. We actually have a lecture for this, for our medical students. What I can tell you is that chronic stress and I really mean, over several year period being stressed, a caregiver for a spouse who has Alzheimer's disease or for a child who has leukemia, something like that where you're really stressed a lot for a substantial period of time, that has detrimental effects
1:17:34
on immune function, but it's complex. It really depends, and again, these things will correct. There are some circumstances where chronic stress will affect your ability to fight infections. Mind over matter is a very popular topic. What I can tell you is there is some science that relates to this. There is a nerve that controls the heart beat, the vagus nerve. It also enervates many of the immune organs, and it does modulate immune responses up and down to some extent,
1:18:06
it won't totally shut off an immune response, but it can influence it up or down. When people do clinical trials, you really want to do something to account for something called the placebo effect, and that is if somebody is getting a pill that they think is going to help them, they actually will get better with some diseases. That's called a placebo effect. If you're doing a clinical trial for a new therapy, you have to give half the people something that's the same pill, but one of them has
1:18:36
got the real pill and one of them is not the real pill and neither the patient nor the doctor really knows. That's called a double-blind placebo-controlled, and you really need to do that with immune system diseases because they have a substantial placebo effect in some cases. I think there is some mind over matter when it comes to the mind and the immune system. It's not something you can necessarily use except that maybe try to be less stressed. Aging and the immune system,
1:19:03
I think this is something where a good diet and trying to keep yourself healthy is going to help your immune system. It is well established that as people get old, they don't respond as well to vaccines, but it's quite variable from person to person. Some people show that immune aging, other people not so much. We don't really know all the details, but it would be a good guess that a healthy lifestyle is good there and then vaccination. I want to say a few words about vaccination.
1:19:30
I really appreciate your willingness to stand around. But I should have put this in earlier because this is maybe the most important thing I want to say today and that is in terms of keeping your immune system in good working order, there's one thing that we for sure no works and that is vaccination. Not every vaccine works, but a lot of the vaccines we have work really, really quite well. What we don't have, we need new vaccines for some things,
1:20:00
but the ones that we have that work really do work. Childhood vaccination, again, get the advice of your doctor, but I really think vaccinating children is the right answer, and I think there's a lot of fears being spread on the Internet, which really just are not true. There are British physician claimed, this as more than a decade ago that mercury preservatives in vaccines caused autism. This has been completely disproven. There's even people who think that this was fraud to start with,
1:20:30
and it wasn't just bad science, but he may have had an extra grind. But in any case, it's clearly not true. The one that had a little bit of truth was there was a small incidence of side effects from the old DPT, which is the diphtheria, tetanus, and pertussis. Pertussis is whooping cough. That vaccine, the formula used prior to 2002, did have high fever. It's uncommon, but not really all that rare side effect. It really had to be monitored. The new formulation has much less problem there.
1:21:07
It's a more purified version of the pertussis that does not cause nearly as much fever. This is something that's gotten quite a bit better, but nonetheless, there's a lot of fear surrounding this, and whooping cough has been making a comeback among unvaccinated children. It's a very nasty disease. If you have any little children at home or grandchildren, this is my advice. Don't believe the fears on the Internet about these vaccines. Finally, vaccines aren't just for children,
1:21:39
they're for us as well. Few things, tetanus booster, you should get a tetanus booster every 10 years. The best advice is that, do it when your birthday has a zero. So 40, 50, 60, then it's easy to remember when the 10 years comes up. Because who can remember when you had that tetanus vaccine last? Every 10 years really, that's great advice. You don't want to get tetanus, I guarantee you. Flu vaccine. Yes, for most people, influenza can be life threatening,
1:22:12
particularly as people get older in life. Most of the guidelines say 50 and older really should get vaccinated every year. Then it changes its coat so that the antibodies that we make against this year's influenza won't help us very much against some of the strains that are circulating the next year. Each year, they try to figure out what the most important flu that's circulating is, make the antibody against that. They're all very close cousins of each other.
1:22:40
Those of you traveling to foreign countries, vaccination may be helpful. Plan ahead and I can recommend from personal experience, the city of San Francisco Health Department has an adult immunization and travel clinic, which is really excellent. Also, you can check out the Center for Disease Control website that will tell you what part of the world you're going to, what vaccines you should be thinking about maybe to help you there. Then as we get older, even if we don't travel,
1:23:07
there's two vaccines that are specifically aimed at people getting near retirement age or after retirement age. That would be the shingles vaccine, which is basically, if you had chicken pox as a young child, that can come back as you get older and your immune system wanes a little bit. It never went away completely and you can get a very painful condition called shingles. This vaccine's been shown to ameliorate that greatly. There's another one called Pneumovax.
1:23:35
That's against that Streptococcus pneumoniae that you had. It's got 23 different cousins stuck in that vaccine and it protects really quite well. Again, this is something. Ask your doctor, but if you're 60 and older, you might want to consider these things. I really thank you for your patience, and I will stay, and take your questions. The question is, how do we immortalize an antibody producing cell to make monoclonal antibodies? There's two ways. The way that was discovered in early 1970s
1:24:14
and for which the Nobel Prize was awarded to a man in England, Cesar Milstein and George Kohler, two men in England. That was they would take a cell that came originally from a cancer of an antibody producing cell in which they had manipulated in the laboratory to lose its own antibody producing genes, and then they would fuse it with a B cell so that the B cell in the fusion part though, the one cell gave you immortal growth, the other cell gave you the antibody genes
1:24:47
to make the antibody you wanted. That was the original method and then more recently, there's direct DNA cloning method of pulling out antibodies and screening through to find the ones that you want. There's two methods now. There's the fusing two cells or just going straight in and pulling out the DNA and expressing it in a new cell. The question has to do with autoimmune disease called lupus. The long form is systemic lupus erythematosus. That's an autoimmune disease that preferentially hits
1:25:21
women usually in their 20s, and 30s, and 40s when it starts and then it's never really goes away. You just try to keep it at bay as best you can. I understand there's a new therapeutic that was just approved for this last week and we're going to get Dr. Andrew Gross in one of the future lectures, and that is he sees lupus patients. He'll give you all the up-to-date thing. What I will tell you is that for most of the autoimmune disease, we don't know what triggers it. There's a generally thought,
1:25:53
and you're going to hear this for allergies as well, is that there's a genetic susceptibility which is complex and we all have lots of genes that influence our immune response, it's a little bit this way and a little bit that way. If we get the wrong combination, then we would be susceptible to a particular autoimmune disease, and then there's some trigger. The trigger is thought to be probably some infection or another. It's a combination of genetics and some trigger.
1:26:17
That would apply to all the autoimmune diseases. In the case of lupus, the disease manifestations are primarily due to antibodies. Bacterial spores. Does immune system recognize bacterial spores? Yes, it does. Now, so the outside of that is a really thick carbohydrate and so the antibodies can recognize it, but the T cells really can't recognize it very well. Again, that what I was mentioning, the conjugate vaccines, what was done was to take those, that coat of a bacteria
1:26:52
and the original vaccine was just to use the carbohydrate part. Because it was known that the antibody to the carbohydrate was protective, but by coupling it to something that T cell could see some protein component, you can then get this higher quality. Question's why would the virus in a virus infected cell allow the immune system to take a peptide and stick it onto that MHC molecule, the HLA molecule? That's because that's what we're trying to do, it's not what the virus is trying to do.
1:27:20
We have a machinery that's doing this all the time with our own peptides. But then that we're already tolerant to those because we've developed in the presence of those peptides all along. It's when the new peptides show up that the killer T cells can get activated and can come and kill. Now, there are some viruses that do block that process. I don't know if people have heard of cytomegalovirus. Cytomegalovirus is a virus that specifically blocks that process. CMV exactly.
1:27:51
CMV is a virus that blocks that process. Most viruses can't block it, but that's one that does.
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