1 00:00:15 --> 00:00:20 So we're going to start by talking about this story. 2 00:00:20 --> 00:00:25 This is a famous moment in the treatment of infectious diseases and 3 00:00:25 --> 00:00:30 the prevention of infectious diseases. 4 00:00:30 --> 00:00:34 This is the first human vaccination, at least the first purposeful human 5 00:00:34 --> 00:00:39 vaccination where the famous British doctor, Edward Jenner, 6 00:00:39 --> 00:00:44 is vaccinating a child for the prevention of smallpox, 7 00:00:44 --> 00:00:49 a devastating disease at that time and for centuries before that time 8 00:00:49 --> 00:00:54 which would wipe out literally millions of people due to its very 9 00:00:54 --> 00:00:59 aggressive nature. Not everybody who died or was 10 00:00:59 --> 00:01:05 infected by smallpox would die from it, but a lot of people did. 11 00:01:05 --> 00:01:11 And it was an important infectious agent throughout the world, 12 00:01:11 --> 00:01:16 actually brought, for example, by colonizing troops in Mexico and 13 00:01:16 --> 00:01:22 wiped out Native peoples there, used purposely as a biological agent 14 00:01:22 --> 00:01:28 in warfare. Smallpox was used by the British to suppress Native 15 00:01:28 --> 00:01:33 Americans in warfare. In fact, the town of Amherst, 16 00:01:33 --> 00:01:38 Massachusetts was named after Jeffrey Amherst, 17 00:01:38 --> 00:01:43 I think, who was an officer in the British Army whom ordered that 18 00:01:43 --> 00:01:47 smallpox infected blankets, or blankets from smallpox infected 19 00:01:47 --> 00:01:52 individuals be sent as a gift to Indian tribes in the region so as to 20 00:01:52 --> 00:01:57 spread the disease to them thereby limiting their ability to fight in 21 00:01:57 --> 00:02:02 an oncoming war. So this is an important agent, 22 00:02:02 --> 00:02:07 and this is an important moment in the treatment and prevention of this 23 00:02:07 --> 00:02:12 particular agent. So I want to tell you this story 24 00:02:12 --> 00:02:17 because it illustrates some important points about immunology. 25 00:02:17 --> 00:02:22 Edward Jenner, who as you see, was doing this work in the late 1700s, 26 00:02:22 --> 00:02:27 made two important observations. One was that milkmaids, 27 00:02:27 --> 00:02:33 people who got milk from cows, milkmaids had smooth skin. 28 00:02:33 --> 00:02:40 And that was unusual in the time, 29 00:02:40 --> 00:02:44 because most people had been infected by this agent smallpox, 30 00:02:44 --> 00:02:48 developed the smallpox disease which led to a pocking of their skin if 31 00:02:48 --> 00:02:52 they survived. So most people did not have smooth 32 00:02:52 --> 00:02:56 skin, but milkmaids had surprisingly smooth skin. One wonders what was 33 00:02:56 --> 00:03:00 behind this observation by Jenner, but it doesn't really matter. 34 00:03:00 --> 00:03:05 He also noticed that milkmaids had previously been exposed, 35 00:03:05 --> 00:03:11 in many instances, to a related disease of cows called cowpox. 36 00:03:11 --> 00:03:17 And this was manifested on their hands, they developed sores on their 37 00:03:17 --> 00:03:23 hands, but it didn't progress into a disease that looked 38 00:03:23 --> 00:03:30 like smallpox. And so Jenner made a hypothesis that 39 00:03:30 --> 00:03:39 prior exposure to cowpox, whatever the agent was that caused 40 00:03:39 --> 00:03:49 cowpox, prior exposure to cowpox protected against smallpox. 41 00:03:49 --> 00:03:58 And this was the suggestion of a phenomenon known as immunological 42 00:03:58 --> 00:04:10 memory. 43 00:04:10 --> 00:04:13 And it was well known by then that you only got a disease once. 44 00:04:13 --> 00:04:16 You only got exposed, if you got exposed to a disease and developed 45 00:04:16 --> 00:04:19 symptoms and recovered, you were protected against getting 46 00:04:19 --> 00:04:23 that disease in the future. And this is a phenomenon of 47 00:04:23 --> 00:04:26 immunological memory, which we now understand in some 48 00:04:26 --> 00:04:30 detail, and I'll tell you how it all works. 49 00:04:30 --> 00:04:33 But that was known already by then. And so what Jenner said was that 50 00:04:33 --> 00:04:37 maybe you develop immunological memory to your cowpox exposure which 51 00:04:37 --> 00:04:40 then protects you against smallpox. Well, so that was the hypothesis. 52 00:04:40 --> 00:04:44 He needed to do an experiment. And the experiment is illustrated 53 00:04:44 --> 00:05:00 up there. 54 00:05:00 --> 00:05:06 He started with a milkmaid by the name of Sarah Nelms who had a cowpox 55 00:05:06 --> 00:05:15 sore on her hand. 56 00:05:15 --> 00:05:20 He took that cowpox sore from her hand and injected it into 57 00:05:20 --> 00:05:29 James Phipps -- 58 00:05:29 --> 00:05:33 -- who was a clueless neighbor's boy. He just happened to live in the 59 00:05:33 --> 00:05:38 neighborhood wandering by one day and where Jenner invited him in for 60 00:05:38 --> 00:05:43 some cocoa or something and said, by the way, since you're here, let 61 00:05:43 --> 00:05:48 me just inject you with some of this stuff. [LAUGHTER] And that's 62 00:05:48 --> 00:05:53 exactly what's depicted here. Sarah Nelms is holding the boy and 63 00:05:53 --> 00:05:58 Jenner is injecting him with some cowpox stuff. 64 00:05:58 --> 00:06:12 He then waited three weeks, and he injected him with smallpox. 65 00:06:12 --> 00:06:22 A known lethal agent. 66 00:06:22 --> 00:06:34 He then waited six weeks and injected him again. [LAUGHTER] 67 00:06:34 --> 00:06:41 Then he waited and waited and waited. And the kid was disease-free. 68 00:06:41 --> 00:06:49 He had, in fact, protected the boy against the development of smallpox. 69 00:06:49 --> 00:06:58 The first purposeful vaccination. 70 00:06:58 --> 00:07:03 It's called vaccination, by the way, because cowpox, 71 00:07:03 --> 00:07:08 which is the agent used to vaccinate the boy, is caused by a virus known 72 00:07:08 --> 00:07:13 as vaccinia. So in honor of that, the whole field, the whole approach 73 00:07:13 --> 00:07:18 is called vaccination. So this is an example of 74 00:07:18 --> 00:07:23 introducing an agent which the body then responds to. 75 00:07:23 --> 00:07:28 And based on the body's response to that agent, the body is protected 76 00:07:28 --> 00:07:32 against further disease. Now, this works because the agent 77 00:07:32 --> 00:07:36 that was used to vaccinate the boy, vaccinia is very similar to the 78 00:07:36 --> 00:07:40 agent that causes smallpox. It's not identical but it's 79 00:07:40 --> 00:07:44 sufficiently similar that the body's response to that agent is compatible 80 00:07:44 --> 00:07:48 with a response to the dangerous agent. This is called a 81 00:07:48 --> 00:07:52 heterologous vaccine. And I'll briefly mention other 82 00:07:52 --> 00:07:56 vaccine strategies towards the end. Jenner succeeded in doing this with 83 00:07:56 --> 00:08:00 a number of patients directly after that. 84 00:08:00 --> 00:08:04 And he actually published his paper, or he tried to publish a paper on 85 00:08:04 --> 00:08:08 this finding in the early 1800s. He was actually blocked from doing 86 00:08:08 --> 00:08:12 so. People didn't want to believe it. People were extremely nervous 87 00:08:12 --> 00:08:16 about this approach. It lead to editorials in local 88 00:08:16 --> 00:08:21 magazines such as shown here. This is a cartoon of Jenner with 89 00:08:21 --> 00:08:25 young James Phipps and a bunch of people getting vaccinated with this 90 00:08:25 --> 00:08:29 cow thing. And the consequence, as you might be able to see, is that 91 00:08:29 --> 00:08:33 these people are sprouting cows out of their arms, 92 00:08:33 --> 00:08:38 out of their faces, out of their butts. 93 00:08:38 --> 00:08:41 And there was general nervousness about tinkering with the natural 94 00:08:41 --> 00:08:45 species in the world in this deliberate way. 95 00:08:45 --> 00:08:49 But it was generally accepted, used extensively in Europe and 96 00:08:49 --> 00:08:53 actually in the United States. And now it's sufficiently 97 00:08:53 --> 00:08:57 successful, has been sufficiently successful over the last couple of 98 00:08:57 --> 00:09:01 centuries that smallpox is no longer a problem. 99 00:09:01 --> 00:09:05 It's been eradicated through proper vaccination using this approach. 100 00:09:05 --> 00:09:09 So there is no longer smallpox out there, although there are vials of 101 00:09:09 --> 00:09:14 smallpox sitting in freezers which have been a concern to governments 102 00:09:14 --> 00:09:18 in the sense that bioterrorists might get their hands on it. 103 00:09:18 --> 00:09:23 And there have actually been efforts to bring back smallpox 104 00:09:23 --> 00:09:27 vaccination as a protective against the potential use of the smallpox 105 00:09:27 --> 00:09:32 agent for some sort of bioterrorism. 106 00:09:32 --> 00:09:36 Do you have a question? OK. Now, as you know, vaccinations 107 00:09:36 --> 00:09:40 against viral agents and other pathogens are commonplace. 108 00:09:40 --> 00:09:44 You've all been vaccinated against lots of things. 109 00:09:44 --> 00:09:49 They've changed the course of human history in a dramatic way. 110 00:09:49 --> 00:09:53 This was not very long ago, 1952, a bunch of children who were 111 00:09:53 --> 00:09:57 infected with polio virus. It led to deaths of many kids and 112 00:09:57 --> 00:10:02 paralysis of many more. And this is a picture in a hospital 113 00:10:02 --> 00:10:06 ward of children in iron lungs, which is how they were kept alive 114 00:10:06 --> 00:10:10 because of their paralysis. Many of them survived this early 115 00:10:10 --> 00:10:14 phase but then went on to develop paralysis in their extremities. 116 00:10:14 --> 00:10:19 And it was a very devastating disease. Fortunately, 117 00:10:19 --> 00:10:23 both Drs. Sabin and Salk in the early 1950s developed vaccines using 118 00:10:23 --> 00:10:27 the principles laid out by Jenner 150 years before. And these 119 00:10:27 --> 00:10:31 were successful. And so kids were treated with polio 120 00:10:31 --> 00:10:35 vaccines for the next 30 or so years. And polio itself was wiped out. 121 00:10:35 --> 00:10:39 So there are no, or very, very few examples of active polio outbreaks 122 00:10:39 --> 00:10:43 these days. And, in fact, kids are not vaccinated 123 00:10:43 --> 00:10:46 with polio vaccines in this country because it's not a threat. 124 00:10:46 --> 00:10:50 It's not that it's not a threat worldwide. In fact, 125 00:10:50 --> 00:10:54 last year when I was teaching this course we read that there were some 126 00:10:54 --> 00:10:58 new outbreaks of polio. So it's not that the virus is gone. 127 00:10:58 --> 00:11:02 It hasn't been fully eradicated. But it's very, 128 00:11:02 --> 00:11:06 very uncommon thanks to these kinds of efforts. And we think about this 129 00:11:06 --> 00:11:10 also again to protect against deliberate use of pathogens. 130 00:11:10 --> 00:11:14 Here, Anthrax, I've shown you this slide before. So there are now 131 00:11:14 --> 00:11:18 efforts to develop vaccines against Anthrax. In case somebody were to 132 00:11:18 --> 00:11:22 use it as an agent, you could protect people from 133 00:11:22 --> 00:11:26 getting exposed to Anthrax. And pathogens are important out 134 00:11:26 --> 00:11:30 there. Many of the diseases that have been 135 00:11:30 --> 00:11:34 scourges of humanity over the millennia are due to pathogens. 136 00:11:34 --> 00:11:39 It's been a constant battle between humans and pathogens, 137 00:11:39 --> 00:11:43 viruses, bacteria, other single-cell organisms. And our greatest hope 138 00:11:43 --> 00:11:47 against controlling these infections is to protect them through 139 00:11:47 --> 00:11:52 vaccination. Where that's worked it's been extremely successful. 140 00:11:52 --> 00:11:56 Where it hasn't worked, like in the case of HIV, it's been much 141 00:11:56 --> 00:12:01 more problematic. So vaccination in general, 142 00:12:01 --> 00:12:06 immunological response, immunological memory are extremely 143 00:12:06 --> 00:12:11 important. OK. So to understand what's happening 144 00:12:11 --> 00:12:16 with respect to vaccination and immunological memory, 145 00:12:16 --> 00:12:21 you have to think about what happens in an infection and how your body 146 00:12:21 --> 00:12:26 responds to it. So if you plot a time course of 147 00:12:26 --> 00:12:31 infection where this might be the very earliest stages. 148 00:12:31 --> 00:12:42 When you get exposed to a pathogen, 149 00:12:42 --> 00:12:46 virus, bacterium, it enters your body and it begins to 150 00:12:46 --> 00:12:59 reproduce itself. 151 00:12:59 --> 00:13:02 It will build up. And it might peak in its 152 00:13:02 --> 00:13:08 concentrations at about a week or so, maybe two weeks. 153 00:13:08 --> 00:13:14 And it's at this stage where you're developing symptoms. 154 00:13:14 --> 00:13:19 And those symptoms might be sufficiently severe that it can 155 00:13:19 --> 00:13:25 cause death. But if you live then you observe typically that the 156 00:13:25 --> 00:13:31 pathogen concentrations drop and can be eliminated all together within 157 00:13:31 --> 00:13:36 two or three weeks. The reason that they drop is because 158 00:13:36 --> 00:13:41 your body is making defense mechanisms against it in two forms, 159 00:13:41 --> 00:13:47 antibodies and specialized cells called T cells that are built to 160 00:13:47 --> 00:13:52 eradicate the agent. And so if you plot the 161 00:13:52 --> 00:13:57 concentration of antibodies and T cells that are active against this 162 00:13:57 --> 00:14:03 agent, you find that initially there's a delay. 163 00:14:03 --> 00:14:07 And then the concentrations of these antibodies and T cells rises. 164 00:14:07 --> 00:14:11 And as they do they are acting on either the agent itself or the cells 165 00:14:11 --> 00:14:16 that the agent has infected. And a combined activity then leads 166 00:14:16 --> 00:14:20 to the elimination of those agents. Concentrations stay up and then 167 00:14:20 --> 00:14:25 they fall, but they don't go to zero. They stay around. 168 00:14:25 --> 00:14:30 You have low levels of these specific antibody-producing cells or 169 00:14:30 --> 00:14:35 T cells that are directed against this agent that stay in your blood 170 00:14:35 --> 00:14:40 forever such that if you get a second infection, 171 00:14:40 --> 00:14:45 even years later, these cells are already there set aside such that 172 00:14:45 --> 00:14:50 the response to that agent is very rapid and the concentrations of the 173 00:14:50 --> 00:14:55 agent never rise very high. So you're able to control it before 174 00:14:55 --> 00:15:01 the amounts of the agents build up and cause symptoms or death. 175 00:15:01 --> 00:15:06 And that's why you don't develop secondary infection. 176 00:15:06 --> 00:15:12 This process is called immunological memory. 177 00:15:12 --> 00:15:20 And, as I said, 178 00:15:20 --> 00:15:25 it's the setting aside of cells that are specific to the thing that's 179 00:15:25 --> 00:15:30 causing the disease. And we'll talk about how that 180 00:15:30 --> 00:15:35 happens in a moment. So this phase, I should have said, 181 00:15:35 --> 00:15:43 is called recovery. OK. 182 00:15:43 --> 00:15:49 Now, I mentioned two cell types that are important in this process. 183 00:15:49 --> 00:15:55 There are B cells and T cells, and they are the ones that I'm going 184 00:15:55 --> 00:16:01 to focus on. But it's important for you to know 185 00:16:01 --> 00:16:05 that they are not the only cells of your immune system. 186 00:16:05 --> 00:16:09 The body produces a whole series of cells shown here in addition to B 187 00:16:09 --> 00:16:13 cells and T cells and a specialized form of B cells called plasma cells. 188 00:16:13 --> 00:16:17 And these cells also contribute to your immune response. 189 00:16:17 --> 00:16:22 They're part of what's called the innate immune response. 190 00:16:22 --> 00:16:31 And they act in a way that is 191 00:16:31 --> 00:16:35 nonspecific. So they recognize classes of agents, 192 00:16:35 --> 00:16:40 viruses as a class or bacteria as a class. They recognize things that 193 00:16:40 --> 00:16:44 are common to all viruses or most or all bacteria or most. 194 00:16:44 --> 00:16:49 And they're very important in the early phases of an infection. 195 00:16:49 --> 00:16:53 And, in fact, in this first phase where you're ramping up the antibody 196 00:16:53 --> 00:16:58 producing cells in the T cells, it's those cells that are acting to 197 00:16:58 --> 00:17:03 help suppress the proliferation of the agent. 198 00:17:03 --> 00:17:07 And so this is where the innate immune response is taking place. 199 00:17:07 --> 00:17:12 And Claudette will review for you some of those cell types in the next 200 00:17:12 --> 00:17:16 lecture. We're going to focus on B cells and T cells. 201 00:17:16 --> 00:17:21 And they fall into what's called the adaptive or specific 202 00:17:21 --> 00:17:38 immune response. 203 00:17:38 --> 00:17:42 And that can be broken down, as I said, into these two cell types. 204 00:17:42 --> 00:17:47 There are T cells which are T lymphocytes. And the T lymphocytes 205 00:17:47 --> 00:17:52 constitute what's called cell-based immunity. 206 00:17:52 --> 00:18:01 It's the cells themselves that are 207 00:18:01 --> 00:18:08 participating in the eradication of the agent. And then there are B 208 00:18:08 --> 00:18:15 lymphocytes, and they participate in what's called humoral which is also 209 00:18:15 --> 00:18:22 liquid phase immunity. And what that means is that they're 210 00:18:22 --> 00:18:29 producing something that gets secreted into the bodily fluids, 211 00:18:29 --> 00:18:34 blood or whatever. And it's that which is participating 212 00:18:34 --> 00:18:38 in the eradication of the agent. In particular, what that is, is 213 00:18:38 --> 00:18:59 antibodies, as we'll talk about. 214 00:18:59 --> 00:19:05 These cells have these names, B cells and T cells, because where 215 00:19:05 --> 00:19:11 they mature. So both B lymphocytes and T lymphocytes start off in the 216 00:19:11 --> 00:19:17 bone marrow, or I should say the precursors of these cells start off 217 00:19:17 --> 00:19:25 in the bone marrow. The precursors to B lymphocytes make 218 00:19:25 --> 00:19:34 their way either to the spleen or they stay in the bone marrow, 219 00:19:34 --> 00:19:44 and that's why they're called B cells. And they go on to make B 220 00:19:44 --> 00:19:53 lymphocytes, including these cells called plasma cells, which 221 00:19:53 --> 00:20:05 produce antibodies. 222 00:20:05 --> 00:20:17 A separate precursor called the T cell precursor makes its way to the 223 00:20:17 --> 00:20:29 thymus which is a lymphoid organ in your chest, and there the cells 224 00:20:29 --> 00:20:41 mature into two types of T cells, cytotoxic T cells, otherwise known 225 00:20:41 --> 00:20:53 as CTLs, or TC cells, and helper T cells or TH cells. 226 00:20:53 --> 00:20:57 OK? And because they go to the thymus they're called T cells. 227 00:20:57 --> 00:21:02 Now, these cells are distinguishable based on the types 228 00:21:02 --> 00:21:07 of protective molecules that they produce. 229 00:21:07 --> 00:21:11 This slide just shows you an overview of the lymphoid system in 230 00:21:11 --> 00:21:15 your body emphasizing the points I just made. The bone marrow is 231 00:21:15 --> 00:21:20 important based on the origin of the cells, as well as it's where B cells 232 00:21:20 --> 00:21:24 mature. B cells also mature in the spleen. And here's the thymus where 233 00:21:24 --> 00:21:28 T cells mature. And in green here you see the 234 00:21:28 --> 00:21:32 lymphatic system. These are the vessels that carry 235 00:21:32 --> 00:21:36 your lymph fluids where many of these cells move to get to the sites 236 00:21:36 --> 00:21:40 of infection. And what's not so obvious to see are lymph nodes, 237 00:21:40 --> 00:21:43 which is again where many of these cells mature and turn into fully 238 00:21:43 --> 00:21:47 blown antibody producing cells or matured T cells. 239 00:21:47 --> 00:21:51 I also want to point out that the handout that you have has the wrong 240 00:21:51 --> 00:21:55 numbers. I was looking at least year's book when I took 241 00:21:55 --> 00:21:59 these numbers down. So the figures are what I'm showing 242 00:21:59 --> 00:22:03 you here. And on the Web, the version that's on the Web has 243 00:22:03 --> 00:22:07 been corrected, so you might want to pay attention 244 00:22:07 --> 00:22:12 to that. Now, what the antibodies that are 245 00:22:12 --> 00:22:16 produced by B cells and the molecules on the surface of T cells 246 00:22:16 --> 00:22:21 are recognizing are things called antigens. 247 00:22:21 --> 00:22:36 Antigens are one of a number of 248 00:22:36 --> 00:22:46 different types of molecules, lipids, carbohydrates, proteins, 249 00:22:46 --> 00:22:59 that are specific to the pathogen. 250 00:22:59 --> 00:23:02 And your body makes antibodies produced by T cells, 251 00:23:02 --> 00:23:06 produced by B cells, as well as proteins on the surface of T cells 252 00:23:06 --> 00:23:10 that will specifically recognize these antigens. 253 00:23:10 --> 00:23:14 And that's why it's called a specific immune response, 254 00:23:14 --> 00:23:17 because the protein that the lymphocytes are producing 255 00:23:17 --> 00:23:21 specifically recognizes the antigen, whether it be a lipid antigen, a 256 00:23:21 --> 00:23:25 carbohydrate antigen or a protein antigen. And that's illustrated on 257 00:23:25 --> 00:23:29 this side where you have a virus particle here or a secreted protein 258 00:23:29 --> 00:23:33 that might be floating around in the blood. 259 00:23:33 --> 00:23:37 And you can see that there are bound to it these colored structures. 260 00:23:37 --> 00:23:41 These are antibodies. And the different colors are recognizing 261 00:23:41 --> 00:23:45 different antigens. So this orange colored antigen is 262 00:23:45 --> 00:23:49 being recognized by that orange colored antibody. 263 00:23:49 --> 00:23:53 The purple colored antigen is being recognized by the purple antibody. 264 00:23:53 --> 00:23:57 Your body has an amazing ability to generate tremendous diversity in the 265 00:23:57 --> 00:24:01 structures, these antibodies or T cell receptors that recognize 266 00:24:01 --> 00:24:08 particular antigens. 267 00:24:08 --> 00:24:15 B cells, B lymphocytes start off by producing on their surface antibody 268 00:24:15 --> 00:24:23 molecules. These antibody molecules are heterotetromers. 269 00:24:23 --> 00:24:32 They have two heavy chains and two 270 00:24:32 --> 00:24:41 light chains. And we'll talk about how those produced in a moment. 271 00:24:41 --> 00:24:50 B cells mature and they turn into plasma cells. And plasma cells 272 00:24:50 --> 00:25:00 secrete the antibody into the bodily fluids. OK? 273 00:25:00 --> 00:25:13 T cells have on their surface a protein called the T cell receptor. 274 00:25:13 --> 00:25:20 And likewise it is very specific. 275 00:25:20 --> 00:25:24 Just like antibodies, as depicted up here, have a particular sequence 276 00:25:24 --> 00:25:28 at the end, which is the antigen binding site. 277 00:25:28 --> 00:25:36 And no two antibodies produced by 278 00:25:36 --> 00:25:40 different B cells would be the same with respect to their antigen 279 00:25:40 --> 00:25:44 binding site. Likewise, this region of the T cell receptor 280 00:25:44 --> 00:25:54 is unique. 281 00:25:54 --> 00:25:57 And, again, that's what gives specificity to the immune system. 282 00:25:57 --> 00:26:01 There are B cells that produce particular antibodies that recognize 283 00:26:01 --> 00:26:04 particular antigens. And T cells that have on their 284 00:26:04 --> 00:26:08 surface T cell receptors that are specific to particular antigens 285 00:26:08 --> 00:26:12 compared to other T cells. This is a detail from your book 286 00:26:12 --> 00:26:16 which shows again an antibody molecule. You can see that it's a 287 00:26:16 --> 00:26:20 heterotetromer, two heavy chains, 288 00:26:20 --> 00:26:24 two light chains, and at the very tips, both of these arms are these 289 00:26:24 --> 00:26:28 antigen binding sites. And, again, this is where the 290 00:26:28 --> 00:26:32 diversity comes from. This antibody, 291 00:26:32 --> 00:26:36 with its particular structure, will bind to this particular antigen 292 00:26:36 --> 00:26:40 because that antigen fits into the pocket formed by that antigen 293 00:26:40 --> 00:26:44 binding site specifically. Likewise, on the surface of T cells 294 00:26:44 --> 00:26:48 there are T cell receptor proteins. They're composed of two chains, an 295 00:26:48 --> 00:26:52 alpha chain and a beta chain. And the coming together of the 296 00:26:52 --> 00:26:56 alpha chain and the beta chain produces, again, 297 00:26:56 --> 00:27:00 an antigen binding site that is unique to that particular 298 00:27:00 --> 00:27:04 T cell receptor. OK. So this is interesting. 299 00:27:04 --> 00:27:10 And it raises an important question, an important problem. 300 00:27:10 --> 00:27:16 There are lots of pathogens. There are lots and lots and lots of 301 00:27:16 --> 00:27:22 things out there that can get into your body and cause you harm. 302 00:27:22 --> 00:27:28 And, therefore, in order to effectively fight those things you 303 00:27:28 --> 00:27:41 need many different antibodies -- 304 00:27:41 --> 00:27:50 -- and many different T cell receptors. It's actually estimated 305 00:27:50 --> 00:27:59 that there are ten to the seventh distinct B cells and T cells in your 306 00:27:59 --> 00:28:06 body at any time. So you've got ten million different 307 00:28:06 --> 00:28:11 B cells and T cells that make different antibodies or different T 308 00:28:11 --> 00:28:16 cell receptors on the surface. So where does that diversity come 309 00:28:16 --> 00:28:21 from? How do you get ten million different B cells or T cells in your 310 00:28:21 --> 00:28:26 body? Well, one possibility would be that there are ten million 311 00:28:26 --> 00:28:34 different genes. 312 00:28:34 --> 00:28:37 That there are ten million different antibody genes or ten million 313 00:28:37 --> 00:28:41 different alpha genes and beta genes in the T cell receptor. 314 00:28:41 --> 00:28:45 Is that the likely explanation? How do you know it's not true? 315 00:28:45 --> 00:28:48 Because I've already told you that there are only 30, 316 00:28:48 --> 00:28:52 00 genes total throughout your genome. So there sure as hell 317 00:28:52 --> 00:28:56 aren't ten to the seventh different antibody genes. So that 318 00:28:56 --> 00:28:59 answer is wrong. It could have been from 319 00:28:59 --> 00:29:08 alternative splicing. 320 00:29:08 --> 00:29:12 Maybe there are genes with many, many exons. And depending on how 321 00:29:12 --> 00:29:16 those exons get joined together, through a process of alternative 322 00:29:16 --> 00:29:21 splicing, you could produce diverse antibodies or T cell receptors. 323 00:29:21 --> 00:29:25 That could be true. And we actually think a lot of diversity in 324 00:29:25 --> 00:29:29 biology does come from alternative splicing of complex genes, 325 00:29:29 --> 00:29:34 but that's not the answer here. Instead, the answer has to do with a 326 00:29:34 --> 00:29:43 process known as DNA rearrangement. 327 00:29:43 --> 00:29:46 This is a process that was discovered, in the context of the 328 00:29:46 --> 00:29:49 immune system, by Susumu Tonegawa who was a 329 00:29:49 --> 00:29:53 professor in the Cancer Center at MIT. And, actually, 330 00:29:53 --> 00:29:56 he won the Nobel Prize for that discovery some years ago. 331 00:29:56 --> 00:30:00 We now know that the generation of all of these different antibodies 332 00:30:00 --> 00:30:03 and all of these different T cells is due to complex rearrangements of 333 00:30:03 --> 00:30:07 a very small number of complex genes. 334 00:30:07 --> 00:30:11 And I want to go through that with you now. And it is a little 335 00:30:11 --> 00:30:16 complicated. And so I warn you that I'm going to show you slides which 336 00:30:16 --> 00:30:20 come directly out of your book. And we'll walk through them. But 337 00:30:20 --> 00:30:25 then I advise you to read your book which I think does a good job 338 00:30:25 --> 00:30:30 explaining how this rearrangement process takes place. 339 00:30:30 --> 00:30:34 And hopefully together that will solidify the concepts for you. 340 00:30:34 --> 00:30:38 So, again, immunological diversity means that each B cell produces 341 00:30:38 --> 00:30:43 particular antibodies, as I've said. And these are the 342 00:30:43 --> 00:30:47 product of uniquely rearranged heavy chain genes and a uniquely 343 00:30:47 --> 00:30:51 rearranged light chain gene. And, likewise, each T cell, each 344 00:30:51 --> 00:30:56 distinct T cell has a specific T cell receptor on its surface which 345 00:30:56 --> 00:31:00 is the product of a uniquely rearranged T cell alpha genes and a 346 00:31:00 --> 00:31:05 uniquely rearranged T cell beta gene. 347 00:31:05 --> 00:31:08 And you can kind of think about the process that we're going to talk 348 00:31:08 --> 00:31:11 about like a roulette wheel that in roulette, as you know, 349 00:31:11 --> 00:31:14 one wheel spins and a particular object shows up and the next wheel 350 00:31:14 --> 00:31:17 spins and a different object shows up or the same one, 351 00:31:17 --> 00:31:20 and likewise the third way. And you end up with a unique 352 00:31:20 --> 00:31:23 combination of objects. The same is true is here. 353 00:31:23 --> 00:31:27 And there are lots of different combinations that can come up. 354 00:31:27 --> 00:31:30 Actually, last year when I was talking about this, 355 00:31:30 --> 00:31:33 I realized that an even better analogy is Mr. 356 00:31:33 --> 00:31:36 Potato Head. And I thought to bring this morning the Mr. 357 00:31:36 --> 00:31:39 Potato Head thing from my three-year-old daughter, 358 00:31:39 --> 00:31:42 but she threw herself across the door. So I actually was unable to 359 00:31:42 --> 00:31:45 bring Mr. Potato Head with me, but hopefully you remember Mr. 360 00:31:45 --> 00:31:48 Potato Head. It's a bland head, and you can put a different mouth or 361 00:31:48 --> 00:31:52 a different nose or a different pair of eyes or hair. 362 00:31:52 --> 00:31:55 And based on the combination that you choose you get a very different 363 00:31:55 --> 00:31:58 looking face. The same thing is true in the generation of antibodies 364 00:31:58 --> 00:32:02 and T cell receptors. It's a choice at different positions, 365 00:32:02 --> 00:32:06 and based on the choice that's made you make a unique looking antibody 366 00:32:06 --> 00:32:11 or T cell receptor. So this is illustrated here. 367 00:32:11 --> 00:32:16 What we're looking at is a piece of DNA that constitutes the 368 00:32:16 --> 00:32:20 un-rearranged heavy chain gene of antibodies. And you can see that 369 00:32:20 --> 00:32:25 there are different regions colored differently. There's a region 370 00:32:25 --> 00:32:30 called the V region which has several segments, 371 00:32:30 --> 00:32:35 several bits, which are similar but a little bit different. 372 00:32:35 --> 00:32:39 There might be a hundred or so of these V segment exons clustered 373 00:32:39 --> 00:32:43 together here. Next door is another set of 374 00:32:43 --> 00:32:47 segments called the D segments, and there are about 30 of those. 375 00:32:47 --> 00:32:51 And then next to them are the J segments, and there are about six of 376 00:32:51 --> 00:32:55 those. Next door is another set of segments called the constant region 377 00:32:55 --> 00:33:00 exons. These actually get used in a slightly different way. 378 00:33:00 --> 00:33:04 They don't come together by DNA rearrangement but rather by splicing, 379 00:33:04 --> 00:33:08 but this also adds to the diversity. When this rearrangement process is 380 00:33:08 --> 00:33:12 done you can choose a different exon down here by alternative splicing. 381 00:33:12 --> 00:33:17 So you can maybe get a sense, if we're going to pick one of these and 382 00:33:17 --> 00:33:21 then randomly one of these and then randomly one of these we can 383 00:33:21 --> 00:33:25 generate a lot of diversity. This happens, as I said, through an 384 00:33:25 --> 00:33:30 ordered process of DNA rearrangement. 385 00:33:30 --> 00:33:34 Our goal is to take an immature B cell, B cell precursor and then 386 00:33:34 --> 00:33:39 sequentially rearrange the heavy chain gene and the light chain gene. 387 00:33:39 --> 00:33:44 And then finally, when that's all done, that mature B cell is going to 388 00:33:44 --> 00:33:48 be sticking on its surface a specific antibody molecule which 389 00:33:48 --> 00:33:53 will have this structure here. And the region of the antigen 390 00:33:53 --> 00:33:58 binding site will be the unique product of the coming together of 391 00:33:58 --> 00:34:03 those V segments, D segments and J segments. 392 00:34:03 --> 00:34:07 So the first step that happens is, with respect to the heavy chain gene, 393 00:34:07 --> 00:34:11 rearrangements take place. There are enzymes that get turned 394 00:34:11 --> 00:34:16 on in the immature B cell which specifically recognizes sequences 395 00:34:16 --> 00:34:20 next door to these segments. The first segments that recombine 396 00:34:20 --> 00:34:25 together involve the D region and the J region. 397 00:34:25 --> 00:34:29 So randomly one of the D region segments and one of the J region 398 00:34:29 --> 00:34:34 segments gets chosen, and the enzyme comes along and clips 399 00:34:34 --> 00:34:39 the DNA right next door to that segment and right upstream of that 400 00:34:39 --> 00:34:43 segment looping out the stuff in the middle, getting rid of it and 401 00:34:43 --> 00:34:48 joining together that particular pair of segments. 402 00:34:48 --> 00:34:53 So now you have a unique new piece of DNA which joins one of the D 403 00:34:53 --> 00:34:58 segments with one of the J segments. Next, one of the V segments is 404 00:34:58 --> 00:35:02 chosen which then gets clipped, and this region up here also gets 405 00:35:02 --> 00:35:07 clipped such that the middle piece gets taken away and the two pieces 406 00:35:07 --> 00:35:12 get joined together. And the product of that is a new 407 00:35:12 --> 00:35:16 piece of DNA that has a unique V region joined to a D region joined 408 00:35:16 --> 00:35:21 to a J region. OK? So there's a series of cut and 409 00:35:21 --> 00:35:26 paste reactions that produces a unique combination of V, 410 00:35:26 --> 00:35:30 D and J. Once that process is done then an RNA is produced 411 00:35:30 --> 00:35:35 from that locus. The RNA gets spliced, 412 00:35:35 --> 00:35:40 as I said, to allow the VDJ segment to get joined to one of the constant 413 00:35:40 --> 00:35:44 region segments. That mRNA product then gets 414 00:35:44 --> 00:35:49 translated into the heavy chain. Once you make the heavy chain you 415 00:35:49 --> 00:35:54 more or less go ahead and do the exact same thing with the light 416 00:35:54 --> 00:35:59 chain. You do a VDJ recombination. Join it up with a constant region. 417 00:35:59 --> 00:36:03 Now that cell is able to produce both a heavy chain and a light chain 418 00:36:03 --> 00:36:08 which is unique. Those come together to form a 419 00:36:08 --> 00:36:12 unique specific antibody molecule. So, again, that's complicated stuff. 420 00:36:12 --> 00:36:16 I don't expect that those of you who haven't heard it before will 421 00:36:16 --> 00:36:19 understand it from what I've just said, but all of what I told you is 422 00:36:19 --> 00:36:23 in the book. And there's an animation, which is where this comes 423 00:36:23 --> 00:36:27 from. So I advise you to read your textbook. OK? 424 00:36:27 --> 00:36:30 The important point is that recombination of these individual 425 00:36:30 --> 00:36:34 segments, random joining together of these distinct segments gives 426 00:36:34 --> 00:36:38 tremendous diversity. It allows you to produce ten to the 427 00:36:38 --> 00:36:42 seventh different T cells, sorry, B cells. The exact same 428 00:36:42 --> 00:36:46 process happens in the rearrangement of the alpha genes and the beta 429 00:36:46 --> 00:36:50 genes in the T cell receptor. So you get, again, tremendous 430 00:36:50 --> 00:36:54 diversity in that way. Now, I'm just going to mention this 431 00:36:54 --> 00:36:58 but I don't expect you to know it for life. Well, 432 00:36:58 --> 00:37:02 you might know it for life but you don't need to know it for a test. 433 00:37:02 --> 00:37:06 There are still other mechanisms that the body uses to add even more 434 00:37:06 --> 00:37:10 diversity. It turns out that this process of joining is actually 435 00:37:10 --> 00:37:14 intentionally messy so that the joints that occur between these 436 00:37:14 --> 00:37:19 segments are not all the same from one cell to another. 437 00:37:19 --> 00:37:23 Even if the cells were to rearrange the same two or three segments, 438 00:37:23 --> 00:37:27 they wouldn't necessarily produce the exact same antigen binding site 439 00:37:27 --> 00:37:31 because the process is inherently sloppy in order to even 440 00:37:31 --> 00:37:37 make more diversity. OK? But you don't really need to 441 00:37:37 --> 00:37:44 know about that specific aspect of it. OK. So through this process of 442 00:37:44 --> 00:37:51 rearrangement, through this process of 443 00:37:51 --> 00:37:58 rearrangement we are able to make, in the case of B cells, lots and 444 00:37:58 --> 00:38:05 lots and lots of distinct unique B cells that are circulating 445 00:38:05 --> 00:38:11 throughout your body. They're different from one another 446 00:38:11 --> 00:38:15 because they have on their surface, initially in the case of B cells 447 00:38:15 --> 00:38:19 they have on their surface these antibody molecules which are 448 00:38:19 --> 00:38:23 different from one another in these regions. So these antigen 449 00:38:23 --> 00:38:31 binding sites -- 450 00:38:31 --> 00:38:35 -- are unique. This one is different from this one. 451 00:38:35 --> 00:38:39 And I should have mentioned I wanted to emphasize that because of 452 00:38:39 --> 00:38:43 this rearrangement process the DNA of this cell is different from the 453 00:38:43 --> 00:38:47 DNA of that cell. I point that out because we've 454 00:38:47 --> 00:38:51 emphasized in the past that the genome that you get when you're 455 00:38:51 --> 00:38:55 first fertilized is stable and exactly the same in 456 00:38:55 --> 00:38:59 all of your cells. That's actually clearly not true in 457 00:38:59 --> 00:39:03 the case of B cells and T cells because they purposely rearranged 458 00:39:03 --> 00:39:07 the genome in the production of antibodies in T cell receptor genes. 459 00:39:07 --> 00:39:10 So the genome actually is a little bit different, 460 00:39:10 --> 00:39:14 at least in the case of the lymphoid cells. So these cells then are 461 00:39:14 --> 00:39:18 produced and they're quietly circulating in your blood. 462 00:39:18 --> 00:39:22 So how do you mount an immune response? 463 00:39:22 --> 00:39:31 You're now infected by some pathogen. 464 00:39:31 --> 00:39:35 How do you build up the concentrations of one of these 465 00:39:35 --> 00:39:39 particular B cells or T cells that can recognize that pathogen? 466 00:39:39 --> 00:39:43 How do you mount an immune response? Well, the way you do it through a 467 00:39:43 --> 00:39:48 process of clonal selection. And, again, this comes right out of 468 00:39:48 --> 00:39:52 your book. These cells which are floating around in the blood and not 469 00:39:52 --> 00:39:56 doing very much in terms of making more of themselves, 470 00:39:56 --> 00:40:00 they're not proliferating, can respond through the exposure to 471 00:40:00 --> 00:40:04 the antigen. So if floating around the blood 472 00:40:04 --> 00:40:08 along with these cells is a particular antigen, 473 00:40:08 --> 00:40:12 and it's able to bind to that antibody molecule which is sitting 474 00:40:12 --> 00:40:16 on the surface, that sends a signal to that cell 475 00:40:16 --> 00:40:20 it's time to divide. There's something in the 476 00:40:20 --> 00:40:24 environment that we like so that we need to make more of ourselves in 477 00:40:24 --> 00:40:28 order to fight off whatever that thing is. 478 00:40:28 --> 00:40:31 This induces a rapid and impressive proliferation. 479 00:40:31 --> 00:40:35 So you go from one or a small number of these cells to many, 480 00:40:35 --> 00:40:39 many of these cells, particularly these cells. These cells don't 481 00:40:39 --> 00:40:43 proliferate because they're not binding to the antigen. 482 00:40:43 --> 00:40:47 These cells do proliferate. They make many, many more of 483 00:40:47 --> 00:40:51 themselves, and when they get to a certain point they differentiate. 484 00:40:51 --> 00:40:55 They begin to make the material they need to secrete really well. 485 00:40:55 --> 00:40:59 They actually change their shape dramatically. They become very 486 00:40:59 --> 00:41:03 efficient secretory cells. And so these B cells that have the 487 00:41:03 --> 00:41:07 antibody on their surface then become secretory cells, 488 00:41:07 --> 00:41:11 these plasma cells. And the plasma cells then secrete the antibody into 489 00:41:11 --> 00:41:16 the bodily fluids allowing the antibody to then go off and bind to 490 00:41:16 --> 00:41:20 the antigen whether it is itself circulating or it's on the surface 491 00:41:20 --> 00:41:25 of the pathogen like a virus or a bacterium. So this process of 492 00:41:25 --> 00:41:29 clonal selection then allows for the cells to build up and, 493 00:41:29 --> 00:41:34 in this case, to differentiate into antibody-secreting cells. 494 00:41:34 --> 00:41:38 Now, these are the cells and the antibodies that are going to fight 495 00:41:38 --> 00:41:42 the infection. These are the cells that are 496 00:41:42 --> 00:41:46 building up right here producing, in this case, the antibody. The 497 00:41:46 --> 00:41:51 same exact thing happens with respect to T cells which you'll 498 00:41:51 --> 00:41:55 learn about in detail next time. However, after the infection is 499 00:41:55 --> 00:41:59 cleared most of those cells go away. They're no longer being stimulated 500 00:41:59 --> 00:42:04 and they actually die off. But importantly not all of them go 501 00:42:04 --> 00:42:08 away. Some of them are set aside as these memory cells. 502 00:42:08 --> 00:42:12 And if these memory cells that just kind of hang around in higher 503 00:42:12 --> 00:42:16 concentrations than they were at the very beginning of this process but 504 00:42:16 --> 00:42:20 it's still relatively low concentrations, 505 00:42:20 --> 00:42:24 and it's the presence of those memory cells that when you're 506 00:42:24 --> 00:42:28 infected again they kick into action quickly. They've already matured to 507 00:42:28 --> 00:42:33 a very great extent, as you can see here. 508 00:42:33 --> 00:42:37 They're on the edge. They're poised to make a lot of 509 00:42:37 --> 00:42:42 antibody or be an effective T cell. They build up very quickly and they 510 00:42:42 --> 00:42:46 suppress the immune response, they suppress the infection. So 511 00:42:46 --> 00:42:51 this process of clonal expansion is the early phase. 512 00:42:51 --> 00:42:55 The setting aside of the memory cells is the late phase. 513 00:42:55 --> 00:43:00 And it allows us to effectively respond in a second infection. 514 00:43:00 --> 00:43:04 And it's also the reason that you can respond once vaccinated. 515 00:43:04 --> 00:43:08 Vaccination is the exact same process except you're exposed to 516 00:43:08 --> 00:43:12 something that is not inherently dangerous. In the case of an active 517 00:43:12 --> 00:43:17 infection, you're infected with the pathogen, the active pathogen, 518 00:43:17 --> 00:43:21 and it builds up and then you respond to it. 519 00:43:21 --> 00:43:25 But there's this dangerous phase where you might actually die. 520 00:43:25 --> 00:43:29 In the case of vaccination, you get exposed to something that is like 521 00:43:29 --> 00:43:34 the antigen, like the pathogen, but it's not otherwise dangerous. 522 00:43:34 --> 00:43:38 But, still, the same stuff happens. You build up antibody producing 523 00:43:38 --> 00:43:43 cells. You build up T cells. They then get set aside in the 524 00:43:43 --> 00:43:47 process of immunological memory. And when you're exposed to the real 525 00:43:47 --> 00:43:52 thing, if you're exposed to the real thing later on, 526 00:43:52 --> 00:43:57 like James Phipps was exposed to smallpox, you already have those 527 00:43:57 --> 00:44:02 cells set aside and you can respond effectively to the agent. 528 00:44:02 --> 00:44:08 So I want to now just mention in closing the various vaccine 529 00:44:08 --> 00:44:14 strategies that are used. And they all rely on this same 530 00:44:14 --> 00:44:20 phenomenon of exposing you to a related agent or antigen allowing 531 00:44:20 --> 00:44:26 you to make T cells or B cells and then fight them effectively. 532 00:44:26 --> 00:44:32 So the first one that I mentioned is cowpox for smallpox and I used 533 00:44:32 --> 00:44:37 the term heterologous vaccine. A heterologous vaccine is an 534 00:44:37 --> 00:44:42 organism which is very similar to the organism that causes the disease 535 00:44:42 --> 00:44:48 cowpox virus versus smallpox virus. And it's so similar that the 536 00:44:48 --> 00:44:53 antigens that it produces direct the development of antibodies or T cells 537 00:44:53 --> 00:44:59 that will also work against the dangerous pathogen. 538 00:44:59 --> 00:45:02 That's a great one if you can have it, but there aren't very many of 539 00:45:02 --> 00:45:06 them. There are very few examples of heterologous vaccines. 540 00:45:06 --> 00:45:10 It's just coincidence or luck that it worked in the case of 541 00:45:10 --> 00:45:19 cowpox and smallpox. 542 00:45:19 --> 00:45:23 A more common one is the attenuated vaccine. In this case, 543 00:45:23 --> 00:45:28 you take the active agent like polio virus and the Sabin polio vaccine is. 544 00:45:28 --> 00:45:32 You take that active agent and you grow it in the laboratory for a long 545 00:45:32 --> 00:45:37 time under conditions in which it changes. 546 00:45:37 --> 00:45:41 It adapts to the laboratory conditions and it's no longer 547 00:45:41 --> 00:45:45 dangerous to a person. If infected with this you will not 548 00:45:45 --> 00:45:49 get polio, but it's sufficiently similar to the original virulent 549 00:45:49 --> 00:45:53 pathogen but it has the same antigens so you mount a proper 550 00:45:53 --> 00:45:57 immune response. This is an effective strategy. 551 00:45:57 --> 00:46:01 It's used all the time. It's a little bit dangerous because 552 00:46:01 --> 00:46:05 if the attenuation process isn't good enough and there's still a 553 00:46:05 --> 00:46:08 little bit of active pathogen in there it could cause disease. 554 00:46:08 --> 00:46:12 And this happens every once in a while with attenuated vaccines. 555 00:46:12 --> 00:46:19 Another way is to just take the 556 00:46:19 --> 00:46:23 agent, whatever it is, and kill it. Mix it with a chemical 557 00:46:23 --> 00:46:26 that will crosslink its genome or heat it up really high so its DNA 558 00:46:26 --> 00:46:30 will be destroyed. That's an agent which cannot 559 00:46:30 --> 00:46:34 reproduce itself in your body. Its genome has been destroyed, 560 00:46:34 --> 00:46:38 but it still has in it the antigens. It still has on its surface the 561 00:46:38 --> 00:46:42 antigens. Your body will still recognize it, make antibodies and, 562 00:46:42 --> 00:46:46 therefore, if you were ever exposed to the live thing you will be 563 00:46:46 --> 00:46:51 protected. This is also very effective. This is the Salk polio 564 00:46:51 --> 00:46:55 vaccine. But every once in a while the killing process isn't perfectly 565 00:46:55 --> 00:46:59 effective. And so there's a little bit of live virus or whatever in 566 00:46:59 --> 00:47:08 there and people get disease. 567 00:47:08 --> 00:47:12 Another strategy is component vaccines. Nowadays, 568 00:47:12 --> 00:47:16 we can purify from the pathogen virus or bacteria a piece of it. 569 00:47:16 --> 00:47:20 You can purify some protein from the virus or from the bacterium and 570 00:47:20 --> 00:47:24 just use that as the antigen. That's not dangerous because it 571 00:47:24 --> 00:47:28 cannot replicate on its own inside you, but your body makes antibodies 572 00:47:28 --> 00:47:32 against it. And, therefore, you'll be protected at 573 00:47:32 --> 00:47:36 some later time against the real thing. 574 00:47:36 --> 00:47:46 And, increasingly, 575 00:47:46 --> 00:47:52 we're using recombinant vaccines. Using molecular biology, genetic 576 00:47:52 --> 00:47:58 engineering, we can actually build new agents that carry the genes of 577 00:47:58 --> 00:48:03 dangerous pathogens. And, actually, 578 00:48:03 --> 00:48:07 a commonly used one is vaccinia itself. So if you take vaccinia, 579 00:48:07 --> 00:48:11 the cowpox virus, take some of its genes out and put in the genes of a 580 00:48:11 --> 00:48:16 dangerous virus like polio virus, now that cowpox virus will get into 581 00:48:16 --> 00:48:20 you. It will replicate a little bit and it will start making those 582 00:48:20 --> 00:48:24 antigens. Your body will recognize that with antibodies and T cells. 583 00:48:24 --> 00:48:29 You'll clear up that infection because it's not a dangerous agent. 584 00:48:29 --> 00:48:32 But you will have made antibodies and T cells that can recognize those 585 00:48:32 --> 00:48:36 other antigens such that if you were infected at a later time you would 586 00:48:36 --> 00:48:40 be protected. So these are examples of vaccines, again extremely 587 00:48:40 --> 00:48:44 effective. They rely entirely on immunological memory, 588 00:48:44 --> 00:48:47 the generation of immunological diversity. Now, 589 00:48:47 --> 00:48:51 importantly, and this is something that you'll pay attention to next 590 00:48:51 --> 00:48:55 time, not all of these vaccines are created equal when it comes to 591 00:48:55 --> 00:48:59 producing a B cell or a T cell response. 592 00:48:59 --> 00:49:03 Some will produce both. Some will only produce a B cell 593 00:49:03 --> 00:49:06 response. And you'll see why that is in Monday's lecture.