1 00:00:05,698 --> 00:00:08,668 IT'S MY GREAT PLEASURE TO 2 00:00:08,668 --> 00:00:09,435 INTRODUCE THE BEAUTIFUL LECTURE 3 00:00:09,435 --> 00:00:09,769 TODAY. 4 00:00:09,769 --> 00:00:17,977 FOR THOSE OF YOU MAYBE YOUNGER 5 00:00:17,977 --> 00:00:22,949 GENERATION, NIH COMMUNITY, AT 6 00:00:22,949 --> 00:00:25,018 NIH 45 YEARS, HIS CONTRIBUTION, 7 00:00:25,018 --> 00:00:27,820 BILL WAS TRAINED AT NYU, MOVED 8 00:00:27,820 --> 00:00:30,256 IN THE '70s HERE TO START HIS 9 00:00:30,256 --> 00:00:32,659 OWN LAB, HEADING THE LABORATORY 10 00:00:32,659 --> 00:00:33,626 FOR MANY YEARS. 11 00:00:33,626 --> 00:00:35,495 OF COURSE HE'S REMEMBERED FOR 12 00:00:35,495 --> 00:00:41,534 MANY, MANY, MANY SEMINAL 13 00:00:41,534 --> 00:00:43,736 CONTRIBUTIONS IN NATION, 14 00:00:43,736 --> 00:00:46,806 ESPECIALLY DISCOVERY OF IL-4, 15 00:00:46,806 --> 00:00:49,842 ENTER PLAY BETWEEN T CELLS, B 16 00:00:49,842 --> 00:00:55,248 CELLS, MAST CELLS, YOU NAME IT. 17 00:00:55,248 --> 00:01:03,323 AND I WAS STRIKED TO SEE THE 18 00:01:03,323 --> 00:01:04,757 FIRST PAPER, 1982, 19 00:01:04,757 --> 00:01:07,293 IDENTIFICATION OF T CELL DERIVED 20 00:01:07,293 --> 00:01:10,930 B CELL GROWTH FACTORS, DISTINCT 21 00:01:10,930 --> 00:01:11,230 FROM IL-2. 22 00:01:11,230 --> 00:01:13,366 AT THAT TIME WE DIDN'T CALL IT 23 00:01:13,366 --> 00:01:15,635 IL-4 YET, BUT IT WAS CLEARLY 24 00:01:15,635 --> 00:01:16,703 SOMETHING SEMINAL. 25 00:01:16,703 --> 00:01:23,476 OF COURSE, BILL WAS SO CREATIVE, 26 00:01:23,476 --> 00:01:24,210 FUNDAMENTAL IMMUNOLOGY, THE 27 00:01:24,210 --> 00:01:29,716 GIGANTIC BOOK ON OUR DESKS, 28 00:01:29,716 --> 00:01:32,819 FIRST EDITION 1984, AND ONE OF 29 00:01:32,819 --> 00:01:34,420 THE EDITIONS HE REPORTS AT THAT 30 00:01:34,420 --> 00:01:36,589 TIME WANTED TO ACKNOWLEDGE 31 00:01:36,589 --> 00:01:38,591 EXPLOSION OF FIELD OF 32 00:01:38,591 --> 00:01:39,892 IMMUNOLOGY, CONSOLIDATE THE 33 00:01:39,892 --> 00:01:43,730 KNOWLEDGE IN THE FIELD. 34 00:01:43,730 --> 00:01:45,698 1984, 800 PAGES, THOUGHT THAT 35 00:01:45,698 --> 00:01:52,505 WOULD BE ENOUGH, RIGHT? 36 00:01:52,505 --> 00:01:54,374 SO MOVE FORWARD, 2022, THE 37 00:01:54,374 --> 00:01:57,110 EIGHTH EDITION OF FUNDAMENTAL 38 00:01:57,110 --> 00:01:59,645 IMMUNOLOGY, NOW 1800. 39 00:01:59,645 --> 00:02:00,613 WE'RE STILL IN EXPLOSIVE GROWTH 40 00:02:00,613 --> 00:02:02,782 OF THE FIELD AND STILL NEED TO 41 00:02:02,782 --> 00:02:03,983 CONSOLIDATE AND IT'S GREAT THAT 42 00:02:03,983 --> 00:02:08,921 THE NAME OF BILL IS STILL IN THE 43 00:02:08,921 --> 00:02:11,524 BIBLE OF THE FIELD. 44 00:02:11,524 --> 00:02:12,959 BILL MOVED FROM THE FUNDAMENTAL 45 00:02:12,959 --> 00:02:14,694 IMMUNOLOGY, BASIC IMMUNOLOGY TO 46 00:02:14,694 --> 00:02:15,695 MORE CLINICAL. 47 00:02:15,695 --> 00:02:16,929 OF COURSE, HE MANAGED THE OFFICE 48 00:02:16,929 --> 00:02:19,632 OF AIDS RESEARCH IN THE '90s 49 00:02:19,632 --> 00:02:22,035 WHEN A LOT OF THERAPIES WERE 50 00:02:22,035 --> 00:02:22,902 BEING DEVELOPED. 51 00:02:22,902 --> 00:02:28,374 ALSO FOUNDED THE VACCINE 52 00:02:28,374 --> 00:02:29,008 RESEARCH CENTER, CONTRIBUTION 53 00:02:29,008 --> 00:02:29,809 FOR PUBLIC HEALTH. 54 00:02:29,809 --> 00:02:32,545 BILL WAS A MENTOR TO MANY, MANY, 55 00:02:32,545 --> 00:02:37,116 MANY GREAT SCIENTISTS, TO NAME A 56 00:02:37,116 --> 00:02:40,520 FEW TO INSPIRE PEOPLE, MAUREEN 57 00:02:40,520 --> 00:02:43,156 HOWARD, FIRST AUTHOR. 58 00:02:43,156 --> 00:02:50,830 MELISSA BROWN, BOB, MATT DAVIS, 59 00:02:50,830 --> 00:02:52,231 AND MANY OTHERS. 60 00:02:52,231 --> 00:02:54,434 MORE PERSONAL LIVE, I WAS NOT A 61 00:02:54,434 --> 00:03:01,874 MENTEE PER SE BUT I JOINED RON 62 00:03:01,874 --> 00:03:03,609 GERMAIN'S LAB IN 2000, MY DESK 63 00:03:03,609 --> 00:03:05,578 WAY AS CROSS THE STORE FROM 64 00:03:05,578 --> 00:03:06,446 BILL'S OFFICE. 65 00:03:06,446 --> 00:03:08,414 I I WOULD BUMP INTO HIM AND 66 00:03:08,414 --> 00:03:12,819 BENEFIT FROM HIS WISDOM AND 67 00:03:12,819 --> 00:03:14,454 KINDNESS, AND HIS ABILITY TO 68 00:03:14,454 --> 00:03:15,755 DISCUSS, I'M A THEORETICAL 69 00:03:15,755 --> 00:03:16,989 PHYSICIST BY TRAINING, BILL 70 00:03:16,989 --> 00:03:18,291 WOULD LISTEN TO MY CRAZY IDEAS, 71 00:03:18,291 --> 00:03:22,095 WHAT WE'RE TRYING TO PUSH 72 00:03:22,095 --> 00:03:23,463 FORWARD WITH RON, ASKING PROBING 73 00:03:23,463 --> 00:03:26,265 QUESTIONS IN A KIND WAY, TELLING 74 00:03:26,265 --> 00:03:28,034 ME LIKE, NO, CALM DOWN. 75 00:03:28,034 --> 00:03:28,301 [LAUGHTER] 76 00:03:28,301 --> 00:03:30,903 TRY TO LOOK AT THIS, SO ON AND 77 00:03:30,903 --> 00:03:34,006 SO FORTH. 78 00:03:34,006 --> 00:03:35,942 ESPECIALLY AT THIS TIME A LOT OF 79 00:03:35,942 --> 00:03:37,009 DISCUSSION, AND BILL KEPT 80 00:03:37,009 --> 00:03:39,946 HELPING ME EVEN WHEN I MOVED TO 81 00:03:39,946 --> 00:03:41,013 SLOAN-KETTERING PUSHED ME TO DO 82 00:03:41,013 --> 00:03:43,449 INFLAMMATORY WORK, IT WAS GREAT. 83 00:03:43,449 --> 00:03:45,585 FOR THE YOUNG GENERATION, THE 84 00:03:45,585 --> 00:03:49,122 LABORATORY OF IMMUNOLOGY AT THAT 85 00:03:49,122 --> 00:03:53,626 TIME, SEMINAL SERIES, YOU HAD 86 00:03:53,626 --> 00:03:55,828 RON AND BILL, A BIT 87 00:03:55,828 --> 00:03:57,897 INTIMIDATING. 88 00:03:57,897 --> 00:04:02,502 TO ME REMINDS ME OF LAW AND 89 00:04:02,502 --> 00:04:04,170 ORDER, A GOOD COP AND BAD COP. 90 00:04:04,170 --> 00:04:05,872 I'LL LET YOU GUESS WHO THE BAD 91 00:04:05,872 --> 00:04:06,973 COP IS. 92 00:04:06,973 --> 00:04:07,640 RON. 93 00:04:07,640 --> 00:04:08,174 [LAUGHTER] 94 00:04:08,174 --> 00:04:09,609 BILL'S MEMORY SHINES OVER ALL OF 95 00:04:09,609 --> 00:04:09,909 US. 96 00:04:09,909 --> 00:04:12,445 WE HOPE WE'RE FOLLOWING IN HIS 97 00:04:12,445 --> 00:04:13,446 FOOTSTEPS, GREAT SCIENCE, THAT'S 98 00:04:13,446 --> 00:04:16,282 WHAT WE'RE GOING TO DO TODAY SO 99 00:04:16,282 --> 00:04:17,583 I'LL MOVE TO INTRODUCE RUSLAN 100 00:04:17,583 --> 00:04:20,153 MEDZHITOV, SPEAKER FOR TODAY. 101 00:04:20,153 --> 00:04:22,188 WE GREATLY APPRECIATE THAT YOU 102 00:04:22,188 --> 00:04:23,523 ANSWERED THE INVITATION TO 103 00:04:23,523 --> 00:04:25,892 DELIVER THIS LECTURE. 104 00:04:25,892 --> 00:04:30,163 EVERY YEAR WHEN IMMUNOLOGY 105 00:04:30,163 --> 00:04:30,830 INTEREST GROUP STARTS NOMINATING 106 00:04:30,830 --> 00:04:36,402 PEOPLE FOR AWARDS OF BEAUTIFUL 107 00:04:36,402 --> 00:04:38,037 LECTURE, WE CANNOT INVITE RUSLAN 108 00:04:38,037 --> 00:04:39,906 EVERY MONTH, WE HAVE TO WAIT. 109 00:04:39,906 --> 00:04:41,274 HE DELIVERED A LECTURE A FEW 110 00:04:41,274 --> 00:04:43,109 YEARS AGO, SO WELCOME BACK. 111 00:04:43,109 --> 00:04:51,083 TO INTRODUCE RUSLAN, TRAINED IN 112 00:04:51,083 --> 00:04:54,687 BIOCHEMISTRY IN MOSCOW, 113 00:04:54,687 --> 00:04:58,257 EVOLUTIONARY BIOLOGY. 114 00:04:58,257 --> 00:05:00,860 THEN MOST IMPORTANTLY RUSLAN 115 00:05:00,860 --> 00:05:03,362 MOVED IN 1994, IN THE LAB OF 116 00:05:03,362 --> 00:05:04,630 CHARLES JANEWAY, NO PRESSURE ON 117 00:05:04,630 --> 00:05:09,602 THE TRAINEES BUT I THINK RUSLAN 118 00:05:09,602 --> 00:05:12,538 FIRST AUTHOR PAPER WAS A 119 00:05:12,538 --> 00:05:15,508 BOMBSHELL FOR THE FIELD. 120 00:05:15,508 --> 00:05:18,377 RUSLAN AND CHARLIE FIRST 121 00:05:18,377 --> 00:05:20,680 REPORTED CLONING OF HUMAN 122 00:05:20,680 --> 00:05:23,082 HOMOLOG OF TLR FLY RECEPTORS 123 00:05:23,082 --> 00:05:25,251 IDENTIFIED AS KEY RECEPTORS TO 124 00:05:25,251 --> 00:05:28,554 BUILT INNATE RESPONSE. 125 00:05:28,554 --> 00:05:30,823 AGAIN, 1994. 126 00:05:30,823 --> 00:05:32,725 THERE HAD BEEN SOME STATEMENT, 127 00:05:32,725 --> 00:05:34,327 WE NEEDED SOMETHING TO REALLY 128 00:05:34,327 --> 00:05:38,064 ACTIVATE THE IMMUNE SYSTEM, AND 129 00:05:38,064 --> 00:05:42,435 THIS PAPER WAS ABSOLUTELY 130 00:05:42,435 --> 00:05:43,402 REVOLUTIONIZED THE FIELD, THE 131 00:05:43,402 --> 00:05:44,971 REST IS HISTORY. 132 00:05:44,971 --> 00:05:46,072 NO PRESSURE ON TRAINEES, BUT TRY 133 00:05:46,072 --> 00:05:48,774 TO FOLLOW UP ON THAT. 134 00:05:48,774 --> 00:05:49,408 [LAUGHTER] 135 00:05:49,408 --> 00:05:52,011 RUSLAN OF COURSE DIDN'T STOP 136 00:05:52,011 --> 00:05:58,985 THERE, WENT ON TO MAKE 137 00:05:58,985 --> 00:05:59,685 DISCOVERY, INFLAMMATION, 138 00:05:59,685 --> 00:06:02,255 PROCESSING, INNATE SYSTEM SPEAK 139 00:06:02,255 --> 00:06:03,256 WITH IMMUNE RESPONSE, AND SILVER 140 00:06:03,256 --> 00:06:05,992 LINING OF ALL OF RUSLAN'S PAPER 141 00:06:05,992 --> 00:06:07,093 FROM PERSONAL LEVEL IS THAT 142 00:06:07,093 --> 00:06:09,929 SOMETIMES A BIT LIGHT ON DATA, 143 00:06:09,929 --> 00:06:16,502 AGAIN GREAT, BUT CONCEPT IS VERY 144 00:06:16,502 --> 00:06:18,271 CLEAR AND VERY CHALLENGING, 145 00:06:18,271 --> 00:06:22,842 BETTER TO MAKE A POINT CLEARLY 146 00:06:22,842 --> 00:06:25,811 WITH FEWER DATA, THE RATIO OF 147 00:06:25,811 --> 00:06:27,446 IDEAS TO DATA IS IN THE RIGHT 148 00:06:27,446 --> 00:06:28,214 PLACE. 149 00:06:28,214 --> 00:06:35,755 ONE OF MY FAVORITE PAPERS FROM 150 00:06:35,755 --> 00:06:37,523 2012, I THINK WE HAVE THE 151 00:06:37,523 --> 00:06:43,562 ROADMAP FOR MANY YEARS TO TRY TO 152 00:06:43,562 --> 00:06:45,631 UNDERSTAND IMMUNOLOGY, AGAIN 153 00:06:45,631 --> 00:06:46,932 VERY BROAD VISTA, A LOT OF 154 00:06:46,932 --> 00:06:48,167 PEOPLE IN THE FIELD. 155 00:06:48,167 --> 00:06:51,103 AND I THINK IT'S A VERY GOOD 156 00:06:51,103 --> 00:06:55,274 SETTING TO HAVE RUSLAN DELIVER 157 00:06:55,274 --> 00:06:56,909 THE LECTURE TODAY BECAUSE IT'S A 158 00:06:56,909 --> 00:07:01,847 GLOBAL VIEW OF IMMUNOLOGY WHICH 159 00:07:01,847 --> 00:07:02,948 IS GREAT. 160 00:07:02,948 --> 00:07:06,319 CME LECTURE, THE CODE ON THE 161 00:07:06,319 --> 00:07:07,219 SCREEN, 57689, FOR PEOPLE ONLINE 162 00:07:07,219 --> 00:07:10,056 IF YOU WANT TO ASK QUESTIONS 163 00:07:10,056 --> 00:07:11,791 PLEASE DO TYPE YOUR QUESTIONS IN 164 00:07:11,791 --> 00:07:13,326 LIVE FEEDBACK AND WE'LL TYPE IN 165 00:07:13,326 --> 00:07:16,095 THE QUESTIONS AT THE END OF THE 166 00:07:16,095 --> 00:07:16,329 SEMINAR. 167 00:07:16,329 --> 00:07:18,264 AGAIN, GREAT TO HAVE RUSLAN 168 00:07:18,264 --> 00:07:19,165 HERE. 169 00:07:19,165 --> 00:07:28,774 THE FLOOR IS YOURS. 170 00:07:28,774 --> 00:07:29,642 [APPLAUSE] 171 00:07:29,642 --> 00:07:30,609 >> THANK YOU FOR THE 172 00:07:30,609 --> 00:07:30,943 INTRODUCTION. 173 00:07:30,943 --> 00:07:32,511 THANK YOU FOR INVITING ME. 174 00:07:32,511 --> 00:07:37,750 IT'S A GREAT HONOR TO GIVE THE 175 00:07:37,750 --> 00:07:37,983 LECTURE. 176 00:07:37,983 --> 00:07:43,989 VERY SIMILAR KIND OF MEMORIES OF 177 00:07:43,989 --> 00:07:45,591 BILL BEING THIS NICE GOOD COP, 178 00:07:45,591 --> 00:07:51,697 KIND, WITH A LOT OF WISDOM. 179 00:07:51,697 --> 00:07:56,302 HE WAS REALLY MONUMENTAL FIGURE 180 00:07:56,302 --> 00:07:57,103 IN IMMUNOLOGY. 181 00:07:57,103 --> 00:07:59,939 SO, I HAVE TO EXPLAIN THE TITLE, 182 00:07:59,939 --> 00:08:01,140 WHICH IS SCHIZOPHRENIC. 183 00:08:01,140 --> 00:08:02,808 THE REASON FOR THAT IS THAT WHEN 184 00:08:02,808 --> 00:08:06,212 I WAS ASKED TO GIVE A TITLE, AS 185 00:08:06,212 --> 00:08:08,814 IT HAPPENS YOU FORGET TO 186 00:08:08,814 --> 00:08:09,715 RESPOND, FORGET TO RESPOND, 187 00:08:09,715 --> 00:08:13,753 THERE'S E-MAIL NEEDED TODAY, I 188 00:08:13,753 --> 00:08:15,054 PANICKED AND SENT THIS, JUST 189 00:08:15,054 --> 00:08:17,223 POPPED IN MY HEAD. 190 00:08:17,223 --> 00:08:18,657 I HAD SOME THOUGHT RELATED TO 191 00:08:18,657 --> 00:08:21,527 THAT BUT WHEN ASKED TO SEND 192 00:08:21,527 --> 00:08:23,629 ABSTRACT, WHAT I WAS LEARNING, 193 00:08:23,629 --> 00:08:24,463 OBJECTIVES OR SOMETHING, I 194 00:08:24,463 --> 00:08:28,200 FORGOT WHAT I SENT AND I THOUGHT 195 00:08:28,200 --> 00:08:29,735 -- 196 00:08:29,735 --> 00:08:30,069 [LAUGHTER] 197 00:08:30,069 --> 00:08:32,571 WELL, BILL PAUL LECTURE, I 198 00:08:32,571 --> 00:08:34,206 THOUGHT TALK ABOUT ALLERGY, IT'S 199 00:08:34,206 --> 00:08:35,775 HIS FIELD, I SENT THE ABSTRACT. 200 00:08:35,775 --> 00:08:37,443 THIS MORNING WAS TRYING TO 201 00:08:37,443 --> 00:08:39,011 FIGURE OUT HOW DO I GET OUT OF 202 00:08:39,011 --> 00:08:39,745 IT. 203 00:08:39,745 --> 00:08:40,446 [LAUGHTER] 204 00:08:40,446 --> 00:08:41,247 AND I CAN'T. 205 00:08:41,247 --> 00:08:45,251 SO IT WILL BE ABOUT ALLERGY BUT 206 00:08:45,251 --> 00:08:50,289 IT'S NOT GOING TO BE THE TALK 207 00:08:50,289 --> 00:08:51,624 ABOUT IMMUNOLOGY FROM FIRST 208 00:08:51,624 --> 00:08:56,195 PRINCIPLES BUT I WILL TRY TO 209 00:08:56,195 --> 00:08:58,964 CONNECT IT TO SOME COUPLE OF 210 00:08:58,964 --> 00:09:02,067 POINTS THAT ARE MORE GENERAL. 211 00:09:02,067 --> 00:09:07,306 SO, SORRY FOR THAT TYPE OF TITLE 212 00:09:07,306 --> 00:09:08,374 THAT'S A LITTLE MISLEADING. 213 00:09:08,374 --> 00:09:13,078 I PUT THEM BOTH HERE, MAKES NO 214 00:09:13,078 --> 00:09:14,613 SENSE. 215 00:09:14,613 --> 00:09:19,118 ANYWAY, I'LL TALK ABOUT ALLERGIC 216 00:09:19,118 --> 00:09:22,188 DISEASES AND A COUPLE 217 00:09:22,188 --> 00:09:25,157 PERSPECTIVES ON IT. 218 00:09:25,157 --> 00:09:26,325 AND THE MAIN POINT WOULD BE 219 00:09:26,325 --> 00:09:27,460 ABOUT, YOU KNOW, THE QUESTION ON 220 00:09:27,460 --> 00:09:29,094 THE MIND OF MANY PEOPLE HAVE 221 00:09:29,094 --> 00:09:32,698 ALLERGIES, WHY DO WE HAVE 222 00:09:32,698 --> 00:09:35,434 ALLERGIES, WHY DO WE HAVE TO 223 00:09:35,434 --> 00:09:37,136 SUFFER FROM IT? 224 00:09:37,136 --> 00:09:41,774 AND WHY IS IT BECOMING SO 225 00:09:41,774 --> 00:09:42,374 COMMON. 226 00:09:42,374 --> 00:09:46,045 AND SO IT HAS TO DO WITH THIS 227 00:09:46,045 --> 00:09:48,147 TRADEOFFS WE DEAL WITH ANY TYPE 228 00:09:48,147 --> 00:09:49,682 OF DEFENSE SYSTEMS, SO JUST TO 229 00:09:49,682 --> 00:09:53,352 PUT IT A LITTLE BIT OF 230 00:09:53,352 --> 00:09:53,953 INTRODUCTORY PERSPECTIVE, SO 231 00:09:53,953 --> 00:09:59,758 THIS IS HOW WE CAN THINK OF 232 00:09:59,758 --> 00:10:00,893 DIFFERENT TYPES OF INFLAMMATION, 233 00:10:00,893 --> 00:10:04,196 AND THEIR INTENDED CAUSES AND 234 00:10:04,196 --> 00:10:05,998 UNINTENDED SORT OF CONSEQUENCES, 235 00:10:05,998 --> 00:10:07,666 BIOLOGICAL CONSEQUENCES. 236 00:10:07,666 --> 00:10:10,169 WE NOW APPRECIATE THAT THERE ARE 237 00:10:10,169 --> 00:10:13,339 SEVERAL DIFFERENT TYPES OF 238 00:10:13,339 --> 00:10:15,975 INFLAMMATION SO FOR NOW I THINK 239 00:10:15,975 --> 00:10:19,178 WE CAN DISTINGUISH FOUR, 240 00:10:19,178 --> 00:10:21,080 INFECTION, A CLEAR INTENDED 241 00:10:21,080 --> 00:10:23,616 PURPOSE TO PROTECT FROM 242 00:10:23,616 --> 00:10:23,983 PATHOGENS. 243 00:10:23,983 --> 00:10:25,684 AND EXAGGERATED RESPONSES LEAD 244 00:10:25,684 --> 00:10:30,689 TO COLLATERAL DAMAGE AND SEPSIS 245 00:10:30,689 --> 00:10:32,591 WITH TISSUE DAMAGE INTENDED 246 00:10:32,591 --> 00:10:36,829 RESPONSE IS TISSUE REPAIR, WHEN 247 00:10:36,829 --> 00:10:39,999 EXAGGERATED CAN LEAD TO 248 00:10:39,999 --> 00:10:40,900 FIBROSIS, PROMOTE TUMOR GROWTH, 249 00:10:40,900 --> 00:10:42,368 THEN INFECTION AND DAMAGE IS NOT 250 00:10:42,368 --> 00:10:45,271 THE ONLY PROBLEMS IN THE WORLD 251 00:10:45,271 --> 00:10:48,440 OF ANIMALS. 252 00:10:48,440 --> 00:10:54,580 SO NOXIOUS SUBSTANCES, TOXINS, 253 00:10:54,580 --> 00:10:57,983 NOXIOUS CHEMICALS, COMING WITH 254 00:10:57,983 --> 00:10:59,084 FOOD, METABOLITES, VENOMS. 255 00:10:59,084 --> 00:11:00,185 WE DON'T APPRECIATE THEM AS MUCH 256 00:11:00,185 --> 00:11:01,820 NOW BECAUSE WE'RE NOT GENERALLY 257 00:11:01,820 --> 00:11:03,222 EXPOSED TO THEM IN THE 258 00:11:03,222 --> 00:11:03,923 INDUSTRIALIZED WORLD BUT IT 259 00:11:03,923 --> 00:11:07,626 PLAYED AN IMPORTANT ROLE IN 260 00:11:07,626 --> 00:11:08,127 EVOLUTION. 261 00:11:08,127 --> 00:11:12,097 I THINK THE DEFENSE FROM THEM IF 262 00:11:12,097 --> 00:11:13,966 IT'S METABOLIC DEFENSE, 263 00:11:13,966 --> 00:11:14,700 DETOXIFICATION, OTHERWISE 264 00:11:14,700 --> 00:11:15,301 EXPULSION, NEUTRALIZATION, SO 265 00:11:15,301 --> 00:11:15,935 ON. 266 00:11:15,935 --> 00:11:17,703 THAT'S THE PART THAT I THINK 267 00:11:17,703 --> 00:11:19,238 LEADS TO WHEN EXAGGERATED LEADS 268 00:11:19,238 --> 00:11:21,874 TO WHAT WE CALL ALLERGIES. 269 00:11:21,874 --> 00:11:23,909 THE NORMAL COUNTERPART OF 270 00:11:23,909 --> 00:11:25,578 ALLERGIES IS DIFFERENCE FROM 271 00:11:25,578 --> 00:11:27,112 NOXIOUS ENVIRONMENTAL 272 00:11:27,112 --> 00:11:30,282 SUBSTANCES. 273 00:11:30,282 --> 00:11:31,817 FINALLY THE FOURTH DOESN'T 274 00:11:31,817 --> 00:11:33,552 HAPPEN, INTENDED PURPOSE, 275 00:11:33,552 --> 00:11:38,157 BECAUSE IT'S A CONSEQUENCE OF 276 00:11:38,157 --> 00:11:39,925 MISMATCH BETWEEN EVOLUTIONARY 277 00:11:39,925 --> 00:11:41,660 HISTORY AND MODERN ENVIRONMENT, 278 00:11:41,660 --> 00:11:45,230 MODERN LIFESTYLE AS WE KNOW CAN 279 00:11:45,230 --> 00:11:49,034 BE GREAT BUT HAVE COSTS, VARIOUS 280 00:11:49,034 --> 00:11:51,203 MODERN DISEASES, METABOLIC, 281 00:11:51,203 --> 00:11:51,971 CARDIOVASCULAR, AGING-ASSOCIATED 282 00:11:51,971 --> 00:11:52,338 DISEASES. 283 00:11:52,338 --> 00:11:59,078 BUT THE POINT HERE IS THAT FOR 284 00:11:59,078 --> 00:12:00,746 ALLERGIES IN PARTICULAR, WE CAN 285 00:12:00,746 --> 00:12:02,915 DRAW THE SAME PARALLELS IN THE 286 00:12:02,915 --> 00:12:04,116 MORE SIMPLER BETTER UNDERSTOOD 287 00:12:04,116 --> 00:12:07,186 CASE OF INFECTIONS THAT YOU 288 00:12:07,186 --> 00:12:07,519 HAVE. 289 00:12:07,519 --> 00:12:08,954 IMMUNE PROTECTION BUT IT COMES 290 00:12:08,954 --> 00:12:10,723 WITH THE COST. 291 00:12:10,723 --> 00:12:12,257 AND IF IT'S EXAGGERATED THEN WE 292 00:12:12,257 --> 00:12:13,359 CALL IT DISEASE. 293 00:12:13,359 --> 00:12:14,627 AND MORE GENERALLY IF YOU THINK 294 00:12:14,627 --> 00:12:19,665 ABOUT THE COST OF DEFENSES, 295 00:12:19,665 --> 00:12:20,766 WHICH ARE HISTORICALLY ALWAYS 296 00:12:20,766 --> 00:12:23,669 FIRST WERE THOUGHT OF AS 297 00:12:23,669 --> 00:12:25,004 DISEASES, BUT WE NEED TO 298 00:12:25,004 --> 00:12:27,206 DISTINGUISH TWO VERY DIFFERENT 299 00:12:27,206 --> 00:12:30,075 TYPES OF COSTS OF DEFENSES, AND 300 00:12:30,075 --> 00:12:33,112 TRUE FOR ANY DEFENSES, AND IT'S 301 00:12:33,112 --> 00:12:34,980 VERY MUCH TRUE FOR INFLAMMATORY 302 00:12:34,980 --> 00:12:38,384 DEFENSES, TWO TYPES OF COSTS OF 303 00:12:38,384 --> 00:12:38,984 INFLAMMATION. 304 00:12:38,984 --> 00:12:42,221 ONE IS ON THE RIGHT SIDE THAT'S 305 00:12:42,221 --> 00:12:46,258 THE MORE FAMILIAR ONE, IT'S 306 00:12:46,258 --> 00:12:46,859 UNINTENTIONAL BUT UNAVOIDABLE 307 00:12:46,859 --> 00:12:48,560 LOSS OF FUNCTION AT THE EXTREME 308 00:12:48,560 --> 00:12:50,029 WILL BE COLLATERAL DAMAGE. 309 00:12:50,029 --> 00:12:52,498 THAT'S JUST SOMETHING WE CAN'T 310 00:12:52,498 --> 00:12:55,234 AVOID. 311 00:12:55,234 --> 00:12:59,638 BUT IT'S PART OF THE COST WE 312 00:12:59,638 --> 00:12:59,905 PAY. 313 00:12:59,905 --> 00:13:02,141 THE OTHER IS MORE INTERESTING, 314 00:13:02,141 --> 00:13:03,909 THAT IS INTENTIONAL SUPPRESSION 315 00:13:03,909 --> 00:13:05,344 OF LOW PRIORITY FUNCTIONS. 316 00:13:05,344 --> 00:13:09,048 THAT NEEDS TO HAPPEN IN ORDER 317 00:13:09,048 --> 00:13:09,682 FOR THE IMMUNOINFLAMMATORY 318 00:13:09,682 --> 00:13:11,784 RESPONSE TO DO ITS JOB, THANKED 319 00:13:11,784 --> 00:13:13,752 IS MORE BY DESIGN, BUT OF COURSE 320 00:13:13,752 --> 00:13:17,623 IF IT'S -- IT COMES WITH A COST 321 00:13:17,623 --> 00:13:19,458 BECAUSE YOU SUPPRESS SOME OTHER 322 00:13:19,458 --> 00:13:20,092 FUNCTIONS. 323 00:13:20,092 --> 00:13:21,460 WHEN IT'S EXAGGERATED ALSO CAN 324 00:13:21,460 --> 00:13:22,861 BECOME PROBLEMATIC AND CAN LEAD 325 00:13:22,861 --> 00:13:25,597 TO DISEASE. 326 00:13:25,597 --> 00:13:27,900 AND BOTH OF THESE CONTRIBUTE TO 327 00:13:27,900 --> 00:13:29,535 ULTIMATE SORT OF CAUSE OF 328 00:13:29,535 --> 00:13:31,937 INFLAMMATORY RESPONSE AND CAN 329 00:13:31,937 --> 00:13:33,072 CONTRIBUTE TO INFLAMMATORY 330 00:13:33,072 --> 00:13:34,473 DISEASES, BUT THESE ARE VERY 331 00:13:34,473 --> 00:13:36,875 DIFFERENT TYPES. 332 00:13:36,875 --> 00:13:39,378 ONE IS INTENDED AND WELL 333 00:13:39,378 --> 00:13:43,449 ORCHESTRATED, JUST CAN BECOME 334 00:13:43,449 --> 00:13:49,154 ACKNOWLEDGE RATED -- 335 00:13:49,154 --> 00:13:51,023 EXAGGERATED, THE OTHER IS 336 00:13:51,023 --> 00:13:51,557 COLLATERAL DAMAGE. 337 00:13:51,557 --> 00:13:56,395 BOTH AT A COST TO FITNESS, 338 00:13:56,395 --> 00:13:57,996 IMPORTANT FOR SURVIVAL, COMING 339 00:13:57,996 --> 00:13:58,530 WITH A COST. 340 00:13:58,530 --> 00:14:01,567 LIKE ANY TRAITS IN ORDER TO BE 341 00:14:01,567 --> 00:14:02,334 EVOLUTIONARY STABLE BENEFITS 342 00:14:02,334 --> 00:14:04,803 SHOULD BE HIGHER THAN THE COST 343 00:14:04,803 --> 00:14:08,974 AND AS WE CAN SEE HERE ANYTHING 344 00:14:08,974 --> 00:14:12,611 IN THE GREEN PART OF THE SQUARE 345 00:14:12,611 --> 00:14:16,381 BENEFIT HIGHER THAN COST WOULD 346 00:14:16,381 --> 00:14:17,716 BE EVOLUTIONARILY SELECTED FOR. 347 00:14:17,716 --> 00:14:20,686 ANYTHING IN THE RED SIDE WOULD 348 00:14:20,686 --> 00:14:21,987 BE SELECTED AGAINST, COSTS MORE 349 00:14:21,987 --> 00:14:24,957 THAN BENEFIT. 350 00:14:24,957 --> 00:14:26,458 IN THIS AREA WHERE BENEFIT 351 00:14:26,458 --> 00:14:29,528 HIGHER THAN COST YOU CAN 352 00:14:29,528 --> 00:14:31,196 APPRECIATE THAT IF BENEFIT IS 353 00:14:31,196 --> 00:14:32,498 VERY HIGH, ACCEPTABLE COST CAN 354 00:14:32,498 --> 00:14:35,234 BE HIGH AS WELL. 355 00:14:35,234 --> 00:14:37,569 AND THIS IS EVOLUTIONARY SORT OF 356 00:14:37,569 --> 00:14:39,404 POINT OF VIEW, AND PATIENT OR 357 00:14:39,404 --> 00:14:41,306 DOCTOR POINT OF VIEW OF THE SAME 358 00:14:41,306 --> 00:14:43,142 EXACT PLOT WOULD BE LIKE THIS. 359 00:14:43,142 --> 00:14:45,778 SO ANYTHING ON THE RIGHT SIDE OF 360 00:14:45,778 --> 00:14:48,280 THE SQUARE WOULD BE CONSIDERED 361 00:14:48,280 --> 00:14:49,848 TO BE DISEASE. 362 00:14:49,848 --> 00:14:51,083 EVEN THOUGH IT'S EVOLUTIONARILY 363 00:14:51,083 --> 00:14:52,951 STABLE, AND THESE ARE THE 364 00:14:52,951 --> 00:14:55,854 CONDITIONS WE EXPERIENCE, FOR 365 00:14:55,854 --> 00:15:00,225 EXAMPLE, IN ACUTE ILLNESS, WITH 366 00:15:00,225 --> 00:15:04,363 VERY SEVERE SEQUENCES OF HIGH 367 00:15:04,363 --> 00:15:05,631 MAGNITUDE DEFENSE RESPONSES, 368 00:15:05,631 --> 00:15:06,865 INFLAMMATORY RESPONSE, OR 369 00:15:06,865 --> 00:15:09,668 ANAPHYLACTIC RESPONSE, AND THE 370 00:15:09,668 --> 00:15:10,669 REASON THEY EXIST IS BECAUSE -- 371 00:15:10,669 --> 00:15:12,204 NOT BECAUSE THEY ARE GOOD FOR 372 00:15:12,204 --> 00:15:14,840 THAT PARTICULAR PERSON AND THAT 373 00:15:14,840 --> 00:15:15,641 PARTICULAR SITUATION BUT BECAUSE 374 00:15:15,641 --> 00:15:17,776 OF AVERAGE IN THE COURSE OF 375 00:15:17,776 --> 00:15:20,512 EVOLUTION IN VERY DIFFERENT 376 00:15:20,512 --> 00:15:22,347 ENVIRONMENTS ON AVERAGE THAT 377 00:15:22,347 --> 00:15:24,449 PROVIDED BETTER BENEFIT THAN NOT 378 00:15:24,449 --> 00:15:27,853 HAVING THAT TYPE OF RESPONSE. 379 00:15:27,853 --> 00:15:29,021 AND INCIDENTALLY WHAT'S 380 00:15:29,021 --> 00:15:31,023 INTERESTING IS MOST OF THE 381 00:15:31,023 --> 00:15:34,092 STUDIES OF VARIOUS TYPES OF 382 00:15:34,092 --> 00:15:36,595 EXPERIMENTAL MODELS OF DISEASES, 383 00:15:36,595 --> 00:15:37,930 THEY -- BASICALLY WE DRAW THE 384 00:15:37,930 --> 00:15:41,867 LINE SOMEWHERE, WHERE WE JUST 385 00:15:41,867 --> 00:15:43,435 SAY, WELL, ANIMALS DIE, BUT IN 386 00:15:43,435 --> 00:15:45,370 THIS WAY THERE'S A LOT OF 387 00:15:45,370 --> 00:15:46,839 INTERESTING BIOLOGY THAT'S 388 00:15:46,839 --> 00:15:48,006 HIDDEN THAT LIVES OVER HERE. 389 00:15:48,006 --> 00:15:49,842 AND THIS IS BECAUSE WE DON'T 390 00:15:49,842 --> 00:15:52,244 KNOW THAT BIOLOGY WELL, THAT'S 391 00:15:52,244 --> 00:15:55,314 WHY CRITICAL CARE MEDICINE IS 392 00:15:55,314 --> 00:15:56,949 ALSO NOT WHERE OTHER BRANCHES OF 393 00:15:56,949 --> 00:15:59,017 MEDICINE ARE IN TERMS OF 394 00:15:59,017 --> 00:16:01,253 UNDERSTANDING HOW TO HELP 395 00:16:01,253 --> 00:16:01,753 PATIENTS. 396 00:16:01,753 --> 00:16:02,955 BECAUSE UNDERLYING BIOLOGY IS 397 00:16:02,955 --> 00:16:04,489 NOT WELL STUDIED. 398 00:16:04,489 --> 00:16:05,691 AND THAT'S ONE AREA WE'RE 399 00:16:05,691 --> 00:16:06,358 INTERESTED IN. 400 00:16:06,358 --> 00:16:09,628 BOUGH -- BUT IN THE CONTEXT OF 401 00:16:09,628 --> 00:16:12,030 THIS TALK I'M BRINGING IT UP 402 00:16:12,030 --> 00:16:13,065 BECAUSE IN SEVERE ALLERGIC 403 00:16:13,065 --> 00:16:15,367 REACTIONS CAN BE A NUISANCE, 404 00:16:15,367 --> 00:16:20,005 THEY CAN BE LIFE-THREATENING, 405 00:16:20,005 --> 00:16:21,006 ANAPHYLACTIC REACTIONS CAN BE 406 00:16:21,006 --> 00:16:21,540 LIFE-THREATENING, AND THE 407 00:16:21,540 --> 00:16:23,775 QUESTION IS WHAT TYPES OF 408 00:16:23,775 --> 00:16:25,944 MECHANISMS ENABLE IT AND WHAT 409 00:16:25,944 --> 00:16:27,913 CAN WE DO ABOUT IT. 410 00:16:27,913 --> 00:16:31,650 SO, TO QUICKLY REMIND YOU WHAT I 411 00:16:31,650 --> 00:16:34,319 WILL TALK ABOUT IS ALLERGIC 412 00:16:34,319 --> 00:16:36,655 IMMUNITY, TYPE 2 IMMUNITY FOR 413 00:16:36,655 --> 00:16:38,423 SIMPLICITY TO REMIND YOU WE HAVE 414 00:16:38,423 --> 00:16:42,728 TWO TYPES OF IMMUNE RESPONSES TO 415 00:16:42,728 --> 00:16:45,397 MICROBIAL PATHOGENS, TYPE 1 416 00:16:45,397 --> 00:16:50,669 RESPONSE AND MACRO PARASITES AS 417 00:16:50,669 --> 00:16:52,537 WELL AS ALLERGENS, WHETHER WE 418 00:16:52,537 --> 00:16:55,374 HAVE TYPE 2 RESPONSEN BOTH CASE 419 00:16:55,374 --> 00:16:56,008 EXAGGERATION, EXAGGERATED 420 00:16:56,008 --> 00:17:02,147 RESPONSE CAN LEAD TO SEPSIS AND 421 00:17:02,147 --> 00:17:04,216 ANAPHYLAXICS, AND FOR TYPE 1 422 00:17:04,216 --> 00:17:05,851 IMMUNITY WE KNOW BASIC 423 00:17:05,851 --> 00:17:07,519 PRINCIPLES THAT THERE'S 424 00:17:07,519 --> 00:17:10,589 COMBINATION OF ANTIGEN WITH SOME 425 00:17:10,589 --> 00:17:12,224 IMMUNOGENIC STIMULUS, TYPICALLY 426 00:17:12,224 --> 00:17:15,594 SOMETHING DERIVED FROM CONSERVED 427 00:17:15,594 --> 00:17:17,696 MICROBIAL STRUCTURES DETECTED BY 428 00:17:17,696 --> 00:17:18,730 INNATE RECOGNITION RECEPTORS, 429 00:17:18,730 --> 00:17:19,765 THAT'S WHAT DRIVES TYPE 1 430 00:17:19,765 --> 00:17:23,702 RESPONSE . 431 00:17:23,702 --> 00:17:26,905 IN THE CASE OF TYPE 2 RESPONSE 432 00:17:26,905 --> 00:17:29,608 WE DON'T HAVE GOOD UNDERSTANDING 433 00:17:29,608 --> 00:17:31,243 WHAT THE ADJUVANT RESPONSE WILL 434 00:17:31,243 --> 00:17:35,514 BE, SOME FUNCTIONAL RECOGNITION 435 00:17:35,514 --> 00:17:37,149 IN SOME CASE, ENZYMATIC ACTIVITY 436 00:17:37,149 --> 00:17:40,852 LIKE VENOMS AND OTHER TYPES OF 437 00:17:40,852 --> 00:17:42,254 ENZYMES, PROTEASES, LIPASES, SO 438 00:17:42,254 --> 00:17:44,022 FORTH, AND SOMETIMES OTHER 439 00:17:44,022 --> 00:17:47,426 FEATURES STILL ILL DEFINED. 440 00:17:47,426 --> 00:17:49,695 THAT MAKES THIS AREA STILL NOT 441 00:17:49,695 --> 00:17:51,463 WELL DEVELOPED, NOT NEARLY AS 442 00:17:51,463 --> 00:17:53,732 WELL AS UNDERSTANDING OF 443 00:17:53,732 --> 00:17:55,100 INITIATION TYPE 1 IMMUNITY, 444 00:17:55,100 --> 00:17:56,802 ONGOING QUESTIONS IN THE FIELD, 445 00:17:56,802 --> 00:17:58,337 BUT GENERALLY THE IDEA WOULD BE 446 00:17:58,337 --> 00:18:00,739 SOME KIND OF NOXIOUS ACTIVITY 447 00:18:00,739 --> 00:18:02,674 WHEN COMBINED WITH ANTIGEN IS 448 00:18:02,674 --> 00:18:05,243 WHAT DRIVES TYPE 2 RESPONSE. 449 00:18:05,243 --> 00:18:07,312 AND THE POINT OF IT IS THAT THE 450 00:18:07,312 --> 00:18:08,647 SUBSEQUENT EXECUTION OF THIS 451 00:18:08,647 --> 00:18:10,082 RESPONSE WILL BE PROTECTIVE. 452 00:18:10,082 --> 00:18:13,352 AND THAT'S WHAT BRINGS ME TO 453 00:18:13,352 --> 00:18:15,954 THIS POINT THAT WHEN WE THINK OF 454 00:18:15,954 --> 00:18:17,856 ALLERGIES WE TYPICALLY THINK OF 455 00:18:17,856 --> 00:18:19,624 IT AS A DISEASE STATE. 456 00:18:19,624 --> 00:18:21,426 BUT I THINK WE NEED TO 457 00:18:21,426 --> 00:18:23,128 DISTINGUISH BETWEEN ALLERGIC 458 00:18:23,128 --> 00:18:24,396 DISEASES AND ALLERGIC DEFENSES. 459 00:18:24,396 --> 00:18:28,467 WHAT'S THE NORMAL COUNTERPART OF 460 00:18:28,467 --> 00:18:29,534 ALLERGIC RESPONSES? 461 00:18:29,534 --> 00:18:32,170 FOR A WHILE, THE DOMINATING 462 00:18:32,170 --> 00:18:34,373 THOUGHT WAS THAT, WELL, ALLERGY 463 00:18:34,373 --> 00:18:37,142 IS JUST A MISTAKE THE IMMUNE 464 00:18:37,142 --> 00:18:38,877 SYSTEM MAKES AND NORMAL 465 00:18:38,877 --> 00:18:40,012 COUNTERPART DEFENSE FROM 466 00:18:40,012 --> 00:18:40,545 PARASITES. 467 00:18:40,545 --> 00:18:42,314 I THINK THAT'S NOT ENTIRELY 468 00:18:42,314 --> 00:18:43,281 CORRECT. 469 00:18:43,281 --> 00:18:45,384 I THINK THE NORMAL COUNTERPART 470 00:18:45,384 --> 00:18:47,452 IS DEFENSE FROM NOXIOUS 471 00:18:47,452 --> 00:18:51,623 SUBSTANCES, AND MANY REASONS TO 472 00:18:51,623 --> 00:18:53,291 THINK THAT, THAT THE RESPONSE, 473 00:18:53,291 --> 00:18:56,628 ALLERGIC RESPONSE IS NOT JUST A 474 00:18:56,628 --> 00:18:57,062 MISTAKE. 475 00:18:57,062 --> 00:18:57,729 THERE'S ONE NUANCE I'LL CAMPAIGN 476 00:18:57,729 --> 00:19:00,732 AT THE -- EXPLAIN AT THE END. 477 00:19:00,732 --> 00:19:03,035 IT'S NOT JUST A MISTAKE, IN THE 478 00:19:03,035 --> 00:19:04,970 CASE OF FOOD ALLERGIES IN 479 00:19:04,970 --> 00:19:07,172 PARTICULAR, PEOPLE WHO ARE 480 00:19:07,172 --> 00:19:10,442 ALLERGIC TO CERTAIN FOODS, THEY 481 00:19:10,442 --> 00:19:12,010 ARE RESPONDING TO THE SAME 482 00:19:12,010 --> 00:19:13,445 ALLERGEN FROM THE SAME FOOD 483 00:19:13,445 --> 00:19:14,012 SOURCES. 484 00:19:14,012 --> 00:19:16,515 IF IT'S A MISTAKE OF THE IMMUNE 485 00:19:16,515 --> 00:19:17,916 SYSTEM IT'S MAKING THE SAME 486 00:19:17,916 --> 00:19:19,017 MISTAKE AGAIN AND AGAIN, CAN'T 487 00:19:19,017 --> 00:19:20,652 BE JUST RANDOM MISSIC THAT. 488 00:19:20,652 --> 00:19:23,388 ALL ALLERGIES SYMPTOMS ALL HAVE 489 00:19:23,388 --> 00:19:24,022 TO DO WITH EXPELLING SOMETHING 490 00:19:24,022 --> 00:19:26,224 KNOCK SHOULD GOES FROM THE BODY, 491 00:19:26,224 --> 00:19:28,093 AND MOREOVER EXACT SAME 492 00:19:28,093 --> 00:19:32,297 REACTIONS OCCUR IN PEOPLE 493 00:19:32,297 --> 00:19:36,068 WITHOUT ALLERGIES, IF YOU 494 00:19:36,068 --> 00:19:38,270 SNEEZE, COUGH, TOUCH IRRITANTS 495 00:19:38,270 --> 00:19:44,509 IT WILL CAUSE ITCHING, FOOD 496 00:19:44,509 --> 00:19:45,377 POISONING DIARRHEA, PROMOTING 497 00:19:45,377 --> 00:19:49,214 ELIMINATION FROM THE BODY. 498 00:19:49,214 --> 00:19:50,882 ALLERGIC IMMUNITY, THOSE 499 00:19:50,882 --> 00:19:54,186 DEFENSES ARE MOSTLY OPERATED BY 500 00:19:54,186 --> 00:20:01,293 NEURONAL REFLEXES, AND ALLERGIC 501 00:20:01,293 --> 00:20:02,227 RESPONSES SUPERIMPOSED, MORE 502 00:20:02,227 --> 00:20:03,829 PROBLEMATIC POTENTIALLY. 503 00:20:03,829 --> 00:20:06,098 FROM THAT PERSPECTIVE WE CAN 504 00:20:06,098 --> 00:20:08,433 THINK OF ALLERGIC DEFENSES AS 505 00:20:08,433 --> 00:20:10,702 OPTIMAL EXECUTION OF TYPE 2 506 00:20:10,702 --> 00:20:12,471 RESPONSE, WHEN EXAGGERATED 507 00:20:12,471 --> 00:20:15,273 RESULTS IN ALLERGIC DISEASES, 508 00:20:15,273 --> 00:20:19,444 AND THEN WE CAN PREDICT THERE'S 509 00:20:19,444 --> 00:20:21,980 ANOTHER AREA OF PATHOLOGY WHERE 510 00:20:21,980 --> 00:20:23,281 DIFFERENCES ARE INEFFICIENT. 511 00:20:23,281 --> 00:20:25,684 SO THIS IS VERY MUCH 512 00:20:25,684 --> 00:20:28,553 PARALLELLING WHAT WE KNOW ABOUT 513 00:20:28,553 --> 00:20:30,722 IMMUNITY TO MICROBES, CAN HAVE 514 00:20:30,722 --> 00:20:32,791 IMMUNE PATHOLOGY, CAN HAVE 515 00:20:32,791 --> 00:20:33,558 IMMUNODEFICIENCY. 516 00:20:33,558 --> 00:20:36,094 IN THE CASE OF ALLERGIC DEFENSES 517 00:20:36,094 --> 00:20:37,529 WE DON'T KNOW WHAT THAT IN THE 518 00:20:37,529 --> 00:20:39,197 LEFT CORNER IS, QUESTION MARK, 519 00:20:39,197 --> 00:20:40,799 BUT THIS WOULD BE JUST 520 00:20:40,799 --> 00:20:43,435 PREDICTION THAT THERE MAY BE A 521 00:20:43,435 --> 00:20:46,171 CLASS OF CONDITIONS WHICH MAY 522 00:20:46,171 --> 00:20:48,006 NOT KNOWN TO BE CAUSED BY THAT 523 00:20:48,006 --> 00:20:51,309 BUT PREDICTED TO BE CAUSE BY 524 00:20:51,309 --> 00:20:54,713 INSUFFICIENT ALLERGIC DEFENSES, 525 00:20:54,713 --> 00:20:56,781 AGAINST NOXIOUS SUBSTANCES. 526 00:20:56,781 --> 00:21:02,721 SO, THE QUESTION THEN WE ARE 527 00:21:02,721 --> 00:21:03,421 INTERESTED IN, RESPONSE 528 00:21:03,421 --> 00:21:08,326 INITIATED, WHAT I WILL FOCUS ON 529 00:21:08,326 --> 00:21:12,330 NOW IS A BIG ENIGMA IN THE FIELD 530 00:21:12,330 --> 00:21:16,067 WHAT MAKES SOMEBODY ALLERGIC OR 531 00:21:16,067 --> 00:21:19,271 HYPERSENSITIVE? 532 00:21:19,271 --> 00:21:22,440 EVERYBODY HAS IGE RESPONSES, 533 00:21:22,440 --> 00:21:23,742 TRIGGERED BY APPROPRIATE 534 00:21:23,742 --> 00:21:27,245 STIMULI, BUT ONLY A SUBSET 535 00:21:27,245 --> 00:21:28,613 BECOME HYPERSENSITIVE OR WHAT WE 536 00:21:28,613 --> 00:21:31,950 CALL ALLERGIC. 537 00:21:31,950 --> 00:21:34,586 THIS IS NOT ALL OR NONE TYPE OF 538 00:21:34,586 --> 00:21:36,221 DISTINCTION, PEOPLE CAN BE 539 00:21:36,221 --> 00:21:41,059 ALLERGIC TO DIFFERENT DEGREES, 540 00:21:41,059 --> 00:21:45,130 BUT WHAT MAKES SOMEBODY ALLERGIC 541 00:21:45,130 --> 00:21:47,732 OR HYPER DEFENSE IS THE 542 00:21:47,732 --> 00:21:49,467 QUESTION. 543 00:21:49,467 --> 00:21:50,468 ANTIBODIES OF HIGH AFFINITY ARE 544 00:21:50,468 --> 00:21:52,003 REQUIRED BUT BEYOND THAT IT'S 545 00:21:52,003 --> 00:21:56,041 NOT CLEAR WHAT EXACTLY DEFINES 546 00:21:56,041 --> 00:21:57,943 HYPERSENSITIVE STATE. 547 00:21:57,943 --> 00:21:59,244 AND SO THAT'S ONE OF THE BIGGEST 548 00:21:59,244 --> 00:22:00,412 QUESTIONS IN THE FIELD BECAUSE 549 00:22:00,412 --> 00:22:03,748 WE WOULD WANT TO BE IDEALLY ABLE 550 00:22:03,748 --> 00:22:05,283 TO REVERSE THAT STATE. 551 00:22:05,283 --> 00:22:06,952 BUT THE QUESTION THAT I WILL 552 00:22:06,952 --> 00:22:09,221 FOCUS ON IN THE FIRST PART, MY 553 00:22:09,221 --> 00:22:10,622 TALK WOULD HAVE TWO PARTS. 554 00:22:10,622 --> 00:22:14,793 THEY DEAL WITH TWO ASPECTS OF 555 00:22:14,793 --> 00:22:17,762 THE ENVIRONMENT THAT FROM 556 00:22:17,762 --> 00:22:20,632 DIFFERENT PERSPECTIVES THAT MAKE 557 00:22:20,632 --> 00:22:25,503 ALLERGY PROBLEMATIC IN MODERN 558 00:22:25,503 --> 00:22:26,071 WORLD. 559 00:22:26,071 --> 00:22:30,609 THE FIRST ONE, SO WHY INCIDENCE 560 00:22:30,609 --> 00:22:31,977 OF ALLERGIC DISEASE IS 561 00:22:31,977 --> 00:22:35,280 INCREASING, OVER THE PAST FEW 562 00:22:35,280 --> 00:22:37,015 DECADES DRAMATICALLY, THE WAY TO 563 00:22:37,015 --> 00:22:38,483 EXPLAIN IS ENVIRONMENTAL 564 00:22:38,483 --> 00:22:39,551 INFLUENCES, CANNOT BE GENETIC IN 565 00:22:39,551 --> 00:22:41,086 THAT TIME SCALE. 566 00:22:41,086 --> 00:22:42,187 WE'RE INTERESTED IN WHAT IS IT 567 00:22:42,187 --> 00:22:43,188 IN THE ENVIRONMENT. 568 00:22:43,188 --> 00:22:44,589 IT'S A VERY HARD QUESTION 569 00:22:44,589 --> 00:22:45,690 BECAUSE SO MANY THING IN THE 570 00:22:45,690 --> 00:22:47,025 ENVIRONMENT IN THE LAST 30 571 00:22:47,025 --> 00:22:47,892 YEARS, RIGHT? 572 00:22:47,892 --> 00:22:51,730 IT'S EASY TO FIND SOMETHING THAT 573 00:22:51,730 --> 00:22:53,265 HAS PERFECT CORRELATION, AND 574 00:22:53,265 --> 00:22:57,035 THERE ARE SOME USUAL SUSPECTS, 575 00:22:57,035 --> 00:23:04,542 LIKE CLEANER WORLD, MORE SORT OF 576 00:23:04,542 --> 00:23:05,744 CHANGED DIETS, CHANGED 577 00:23:05,744 --> 00:23:06,711 MICROBIOTA, WHATEVER THE 578 00:23:06,711 --> 00:23:07,646 ENVIRONMENTAL FACTOR IS. 579 00:23:07,646 --> 00:23:08,913 THEY PROBABLY ALL CONTRIBUTE TO 580 00:23:08,913 --> 00:23:09,614 VARIOUS DEGREES. 581 00:23:09,614 --> 00:23:15,420 THIS IS JUST A PICTURE SHOWING 582 00:23:15,420 --> 00:23:17,289 HOW ENVIRONMENT CONTRIBUTES TO 583 00:23:17,289 --> 00:23:22,093 INCIDENCE OF ALLERGIES AND HOW 584 00:23:22,093 --> 00:23:25,563 IT VERY MUCH RELATES TO 585 00:23:25,563 --> 00:23:27,465 INDUSTRIALIZATION, EATING FOODS 586 00:23:27,465 --> 00:23:28,566 THAT ARE HIGHLY PROCESSED, 587 00:23:28,566 --> 00:23:31,970 LIVING IN A CLEAN ENVIRONMENT, 588 00:23:31,970 --> 00:23:34,506 USE OF ANTIBIOTICS, HYGIENE 589 00:23:34,506 --> 00:23:35,473 PRODUCTS, SO FORTH. 590 00:23:35,473 --> 00:23:37,876 AND SO CLEARLY SOMETHING ABOUT 591 00:23:37,876 --> 00:23:39,644 THE ENVIRONMENT HAS BEEN 592 00:23:39,644 --> 00:23:40,945 LONGSTANDING SORT OF HYPOTHESIS 593 00:23:40,945 --> 00:23:43,114 THAT CLEAN ENVIRONMENTS ARE THE 594 00:23:43,114 --> 00:23:45,216 ONES THAT PROMOTE DEVELOPMENT OF 595 00:23:45,216 --> 00:23:45,984 ALLERGIES. 596 00:23:45,984 --> 00:23:49,688 WHY THAT IS IS WHAT -- THAT'S 597 00:23:49,688 --> 00:23:51,756 THE QUESTION THAT IS -- THAT 598 00:23:51,756 --> 00:23:53,792 WE'VE BEEN INTERESTED IN. 599 00:23:53,792 --> 00:23:56,461 SO, BASIC PREMISE WOULD BE THAT 600 00:23:56,461 --> 00:24:02,701 IMMUNE SYSTEM EVOLVED UNDER 601 00:24:02,701 --> 00:24:04,936 CONDITIONS THAT -- ENVIRONMENTAL 602 00:24:04,936 --> 00:24:07,005 CONDITIONS DIFFERENT THAN WHAT 603 00:24:07,005 --> 00:24:10,775 WE ENJOY CURRENTLY, NORMAL 604 00:24:10,775 --> 00:24:11,509 EVOLUTIONARILY, NORMAL 605 00:24:11,509 --> 00:24:14,913 CONDITIONS WOULD BE HIGH 606 00:24:14,913 --> 00:24:16,648 MICROBIAL EXPOSURE AND 100% 607 00:24:16,648 --> 00:24:17,182 PARASITIC INFECTION, EVERY 608 00:24:17,182 --> 00:24:19,250 ANIMAL IN THE WILD HAS 609 00:24:19,250 --> 00:24:19,684 PARASITES. 610 00:24:19,684 --> 00:24:21,353 AND THAT WOULD BE THE NORMAL 611 00:24:21,353 --> 00:24:21,586 STATE. 612 00:24:21,586 --> 00:24:24,422 BUT THE REASON IT'S IMPORTANT IS 613 00:24:24,422 --> 00:24:25,724 BECAUSE THAT'S WHAT IMMUNE 614 00:24:25,724 --> 00:24:27,625 SYSTEM NORMALLY DEALS WITH. 615 00:24:27,625 --> 00:24:29,160 THAT'S WHAT IT EVOLVED TO DEAL 616 00:24:29,160 --> 00:24:31,529 WITH, TO OPERATE UNDER THOSE 617 00:24:31,529 --> 00:24:32,130 CONDITIONS. 618 00:24:32,130 --> 00:24:35,266 AND IN THE MODERN ENVIRONMENT 619 00:24:35,266 --> 00:24:36,267 THOSE CONDITIONS CHANGE 620 00:24:36,267 --> 00:24:37,902 DRAMATICALLY, CHARACTERIZED BY 621 00:24:37,902 --> 00:24:40,205 REDUCED EXPOSURE TO MICROBES, 622 00:24:40,205 --> 00:24:42,173 PARASITES, FOREIGN ANTIGENS IN 623 00:24:42,173 --> 00:24:42,507 GENERAL. 624 00:24:42,507 --> 00:24:46,211 SO, WE WANTED TO ASK TO WHAT 625 00:24:46,211 --> 00:24:49,047 DEGREE THAT CONTRIBUTES TO 626 00:24:49,047 --> 00:24:54,753 PREDISPOSITION TO ALLERGIES. 627 00:24:54,753 --> 00:24:58,390 HOW ENVIRONMENTAL FACTORS 628 00:24:58,390 --> 00:24:59,124 INFLUENCE SENSEIZATION. 629 00:24:59,124 --> 00:25:02,627 IN THE FIRST PART OF THE TALK WE 630 00:25:02,627 --> 00:25:03,628 USED SO-CALLED PET SHOP MICE, 631 00:25:03,628 --> 00:25:07,432 THAT YOU BUY IN A PET SHOP, BRED 632 00:25:07,432 --> 00:25:10,201 NOT AS PETS BY THE WAY BUT FOOD 633 00:25:10,201 --> 00:25:12,070 FOR SNAKES, PET SHOP MICE IS A 634 00:25:12,070 --> 00:25:13,905 BETTER NAME. 635 00:25:13,905 --> 00:25:15,540 THESE ARE BASICALLY WILD MICE 636 00:25:15,540 --> 00:25:19,411 THAT ARE CAUGHT SOMEWHERE IN THE 637 00:25:19,411 --> 00:25:21,079 BARN, AND GENETICALLY DIVERSE, 638 00:25:21,079 --> 00:25:23,882 VERY DIRTY WITH ALL KINDS OF 639 00:25:23,882 --> 00:25:24,282 MICROBES. 640 00:25:24,282 --> 00:25:26,718 AND WE -- THE GOAL WAS TO 641 00:25:26,718 --> 00:25:30,088 INVESTIGATE THEIR IMMUNE SYSTEM 642 00:25:30,088 --> 00:25:32,624 AS COMPARED TO SPF MICE, 643 00:25:32,624 --> 00:25:35,260 PATHOGEN FREE THAT LIVES IN 644 00:25:35,260 --> 00:25:36,594 ENVIRONMENTS, DESCRIBED THE 645 00:25:36,594 --> 00:25:39,597 MODEL AS PET SHOP MICE A FEW 646 00:25:39,597 --> 00:25:42,033 YEARS AGO, CHARACTERIZED BASIC 647 00:25:42,033 --> 00:25:42,801 IMMUNOLOGICAL CHARACTERISTICS OF 648 00:25:42,801 --> 00:25:44,769 THESE MICE AND WHY THEY COULD BE 649 00:25:44,769 --> 00:25:46,304 GOOD MODEL FOR VARIOUS 650 00:25:46,304 --> 00:25:46,871 QUESTIONS. 651 00:25:46,871 --> 00:25:49,774 SO THIS IS WHAT THESE GUYS LOOK 652 00:25:49,774 --> 00:25:50,809 LIKE. 653 00:25:50,809 --> 00:25:52,210 ON THE RIGHT, CLEAN, SPF MICE. 654 00:25:52,210 --> 00:25:55,613 ON THE LEFT PET SHOP MICE, YOU 655 00:25:55,613 --> 00:25:58,583 SEE THEY CLEARLY GENETICALLY ARE 656 00:25:58,583 --> 00:26:01,085 VERY DIVERSE, LOOK DIFFERENT, 657 00:26:01,085 --> 00:26:01,753 BEHAVE DIFFERENTLY, FULL OF 658 00:26:01,753 --> 00:26:03,421 STUFF ON THE RIGHT. 659 00:26:03,421 --> 00:26:05,156 THIS IS NOT EVEN COMPLETE LIST 660 00:26:05,156 --> 00:26:13,465 BUT THEY GOT IT ALL. 661 00:26:13,465 --> 00:26:15,433 THEY GOT PROTOZOA, PARASITES, 662 00:26:15,433 --> 00:26:16,501 BACTERIA, FUNGI, VIRUSES OF ALL 663 00:26:16,501 --> 00:26:16,734 KINDS. 664 00:26:16,734 --> 00:26:18,903 THEY ARE FULL OF THAT. 665 00:26:18,903 --> 00:26:22,874 YOU GIVE ANY ONE OF THIS TO SPF 666 00:26:22,874 --> 00:26:24,309 MICE YOU INFECT THEM AND SEE 667 00:26:24,309 --> 00:26:24,976 WHETHER THEY GUY. 668 00:26:24,976 --> 00:26:26,744 THESE DIES HAVE IT ALL. 669 00:26:26,744 --> 00:26:29,147 THAT'S THEIR NORMAL STATE. 670 00:26:29,147 --> 00:26:31,649 THAT'S ONE KIND OF -- ACTUALLY 671 00:26:31,649 --> 00:26:33,284 PRETTY AMAZING FACT, RIGHT? 672 00:26:33,284 --> 00:26:35,687 THEY HAVE ALL THIS. 673 00:26:35,687 --> 00:26:36,187 COLONIZATION. 674 00:26:36,187 --> 00:26:37,155 YOU CAN'T EVEN CALL IT INFECTION 675 00:26:37,155 --> 00:26:39,891 BECAUSE THEY ARE NOT SICK. 676 00:26:39,891 --> 00:26:41,626 IT'S JUST THEIR NORMAL STATE. 677 00:26:41,626 --> 00:26:43,895 AND THAT SHOULD TELL US 678 00:26:43,895 --> 00:26:46,564 SOMETHING ABOUT WHAT THE NORMAL 679 00:26:46,564 --> 00:26:48,666 STATE OF THE IMMUNE SYSTEM OF 680 00:26:48,666 --> 00:26:50,668 THE ORGANISM HAS TO DEAL WITH. 681 00:26:50,668 --> 00:26:52,537 WE USE THESE MICE. 682 00:26:52,537 --> 00:26:56,841 WHAT THIS ALLOWS, WE ARE LOOKING 683 00:26:56,841 --> 00:26:57,675 AT GENETICALLY VERY 684 00:26:57,675 --> 00:26:59,344 HETEROGENEOUS GROUP OF MICE FULL 685 00:26:59,344 --> 00:27:03,047 OF NORMAL SORT OF EXPOSURE TO 686 00:27:03,047 --> 00:27:04,148 MICROBES OF ALL KINDS AND 687 00:27:04,148 --> 00:27:08,319 COMPARING TO WHAT WE NORMALLY 688 00:27:08,319 --> 00:27:10,355 USE IN THE LABS, SPF CONDITION 689 00:27:10,355 --> 00:27:12,690 IN BRED MICE OF A PARTICULAR 690 00:27:12,690 --> 00:27:13,625 STRAIN. 691 00:27:13,625 --> 00:27:18,096 WHEN WE SUBJECT THEM TO EXACT 692 00:27:18,096 --> 00:27:18,897 SAME PROTOCOL FOR SENSITIZATION, 693 00:27:18,897 --> 00:27:29,374 THIS IS A MODEL WHERE WE USE 694 00:27:30,174 --> 00:27:30,975 SUBCUTANEOUS ALBUMIN, IF YOU 695 00:27:30,975 --> 00:27:32,644 CHALLENGE THEM THIS IS 696 00:27:32,644 --> 00:27:34,846 TEMPERATURE DROP, THIS IS RESULT 697 00:27:34,846 --> 00:27:36,381 OF ANAPHYLACTIC REACTION. 698 00:27:36,381 --> 00:27:39,684 IF IT'S SEVERE, IT WILL KILL 699 00:27:39,684 --> 00:27:40,351 MILES. -- MICE. 700 00:27:40,351 --> 00:27:42,620 PET SHOP MICE ARE REALLY 701 00:27:42,620 --> 00:27:43,621 PROTECTED FROM IT. 702 00:27:43,621 --> 00:27:45,790 THIS TYPE OF GRAPH I'LL SHOW 703 00:27:45,790 --> 00:27:47,091 SEVERAL TIMES, DELTA IN 704 00:27:47,091 --> 00:27:48,293 TEMPERATURE. 705 00:27:48,293 --> 00:27:49,627 HIGHER THE GRAPH, STRONGER 706 00:27:49,627 --> 00:27:50,962 ANAPHYLACTIC REACTION, AS YOU 707 00:27:50,962 --> 00:27:53,498 CAN SEE THESE MICE ARE 708 00:27:53,498 --> 00:27:53,998 PROTECTED. 709 00:27:53,998 --> 00:27:56,668 EVEN THOUGH THEY MAKE 710 00:27:56,668 --> 00:27:57,769 ANTIGEN-SPECIFIC IGE. 711 00:27:57,769 --> 00:27:59,537 THAT'S THE PART THAT I THINK IS 712 00:27:59,537 --> 00:28:02,140 REALLY IMPORTANT THAT THEY DO 713 00:28:02,140 --> 00:28:04,242 MAKE IGE JUST FINE. 714 00:28:04,242 --> 00:28:05,543 ANTIGEN-SPECIFIC IGE. 715 00:28:05,543 --> 00:28:10,715 BUT IT DOESN'T RESULT IN 716 00:28:10,715 --> 00:28:11,149 ANAPHYLAXIS. 717 00:28:11,149 --> 00:28:13,451 AND SO THEN WE ASKED WHETHER IF 718 00:28:13,451 --> 00:28:19,123 WE TAKE OUR CLEAN MICE TO RULE 719 00:28:19,123 --> 00:28:22,927 OUT THIS IS JUST SOMETHING LIKE 720 00:28:22,927 --> 00:28:26,230 REALLY WEIRD RANDOM GENETIC 721 00:28:26,230 --> 00:28:26,998 EFFECT. 722 00:28:26,998 --> 00:28:29,734 AND WE CROSS-FOSTER THEM WITH 723 00:28:29,734 --> 00:28:33,438 PET SHOP MICE, SO THIS IS 724 00:28:33,438 --> 00:28:37,642 ANAPHYLACTIC REACTION IN CONTROL 725 00:28:37,642 --> 00:28:39,243 SPF MICE, IF CO-HOUSED WITH 726 00:28:39,243 --> 00:28:41,179 DIRTY MICE ACQUIRE SOME 727 00:28:41,179 --> 00:28:44,849 MICROBES, BECOME MORE PROTECTED. 728 00:28:44,849 --> 00:28:46,517 IF FOSTERED BY PET SHOP MICE 729 00:28:46,517 --> 00:28:48,119 THEY ARE COMPLETELY PROTECTED. 730 00:28:48,119 --> 00:28:50,688 JUST ACQUIRING MICROBES FROM THE 731 00:28:50,688 --> 00:28:54,859 DIRTY MICE MAKES THEM PROTECTED. 732 00:28:54,859 --> 00:28:55,860 THAT'S CONSISTENT WITH 733 00:28:55,860 --> 00:28:57,061 EPIDEMIOLOGICAL STUDIES IN 734 00:28:57,061 --> 00:28:58,696 HUMANS LIVING IN A MORE NATURAL 735 00:28:58,696 --> 00:29:01,666 SORT OF DIRTY ENVIRONMENT, 736 00:29:01,666 --> 00:29:03,067 PROTECTIVE GROWING UP ON THE 737 00:29:03,067 --> 00:29:05,803 FARM IS PROTECTIVE, SO FORTH. 738 00:29:05,803 --> 00:29:06,804 AND THEY ARE PROTECTED NOT 739 00:29:06,804 --> 00:29:10,274 BECAUSE THERE'S ANY KIND OF 740 00:29:10,274 --> 00:29:11,709 DEFECT IN THE ALLERGIC 741 00:29:11,709 --> 00:29:14,112 INFLAMMATION BECAUSE IF WE 742 00:29:14,112 --> 00:29:17,081 BYPASS THE SENSITIZATION STATE 743 00:29:17,081 --> 00:29:18,049 AND GIVE PASSIVE SYSTEMIC 744 00:29:18,049 --> 00:29:22,453 ANAPHYLAXICS ON THE LEFT THEY 745 00:29:22,453 --> 00:29:31,763 WOULD AN A TAMPA LACKS AS WELL. 746 00:29:31,763 --> 00:29:38,503 IF WE GIVE COMPOUND, INDUCE HIS 747 00:29:38,503 --> 00:29:42,707 THAT MEAN THEY WOULD ANAPHYLAX 748 00:29:42,707 --> 00:29:48,246 AS WELL. 749 00:29:48,246 --> 00:29:51,215 THERE'S A COMMON TREND, SO T 750 00:29:51,215 --> 00:29:53,084 DEPENDENT ANTIBODIES ELEVATED 751 00:29:53,084 --> 00:29:59,223 COMPARED TO SPF MICE SHOWN HERE 752 00:29:59,223 --> 00:30:00,525 WITH IgGs AND NIGA, 753 00:30:00,525 --> 00:30:03,061 DEPENDENT ANTIBODIES SEEM TO BE 754 00:30:03,061 --> 00:30:05,363 OPPOSITE TREND, PROBABLY THE 755 00:30:05,363 --> 00:30:08,433 CONSEQUENCE OF THEM MOSTLY 756 00:30:08,433 --> 00:30:08,900 SWITCHING. 757 00:30:08,900 --> 00:30:12,470 SO THEY HAVE HIGH ANTIBODY 758 00:30:12,470 --> 00:30:18,943 LEVELS, AND WE TOOK ABOUT 20+ 759 00:30:18,943 --> 00:30:20,144 VERY DIFFERENT GENETICALLY 760 00:30:20,144 --> 00:30:22,046 DISTANT MOUSE STRAINS FROM 761 00:30:22,046 --> 00:30:25,650 JACKSON LAB, WE CHOSE THEM BASED 762 00:30:25,650 --> 00:30:27,285 ON BEING MAXIMALLY DIFFERENT 763 00:30:27,285 --> 00:30:29,187 GENETICALLY, SHOWN HERE. 764 00:30:29,187 --> 00:30:30,388 WE COMPARED SENSITIZATION IN ALL 765 00:30:30,388 --> 00:30:32,256 OF THEM TO PET SHOP MICE, WHICH 766 00:30:32,256 --> 00:30:33,991 ARE IN THE RED. 767 00:30:33,991 --> 00:30:37,195 AND AS YOU CAN SEE, THE RESPONSE 768 00:30:37,195 --> 00:30:40,231 IS VARIED, THIS IS FOR GENETIC 769 00:30:40,231 --> 00:30:42,967 REASONS, ALL SPF, BUT DIFFERENT 770 00:30:42,967 --> 00:30:45,136 GENETIC BACKGROUNDS. 771 00:30:45,136 --> 00:30:46,170 COMPARING TO GENETICALLY 772 00:30:46,170 --> 00:30:47,505 HETEROGENEOUS PET SHOP MICE, 773 00:30:47,505 --> 00:30:48,539 WHICH ARE RED. 774 00:30:48,539 --> 00:30:49,874 THEY HAVE MUCH -- THIS IS, 775 00:30:49,874 --> 00:30:53,077 AGAIN, THE SAME TYPE OF 776 00:30:53,077 --> 00:30:55,379 IMMUNIZATION AND ALUM, THEY 777 00:30:55,379 --> 00:31:03,588 DEVELOP VERY ROBUST IgG 778 00:31:03,588 --> 00:31:06,858 RESPONSE, WHICH IN SPF MICE IT'S 779 00:31:06,858 --> 00:31:10,027 ALMOST NOT THERE, BUT PET SHOP 780 00:31:10,027 --> 00:31:11,329 MICE DEVELOP STRONG IgG TO 781 00:31:11,329 --> 00:31:15,399 RESPONSE. 782 00:31:15,399 --> 00:31:21,839 THIS BY THE WAY, ALUM IS AN 783 00:31:21,839 --> 00:31:25,510 ADJUVANT USED IN HUMANS, CAN 784 00:31:25,510 --> 00:31:27,812 INDUCE APPROPRIATE RESPONSE FOR 785 00:31:27,812 --> 00:31:30,948 VACCINATION AGAINST MICROBIAL 786 00:31:30,948 --> 00:31:32,483 ANTIGENS, IT WILL INDUCE IgG, 787 00:31:32,483 --> 00:31:32,784 FOR EXAMPLE. 788 00:31:32,784 --> 00:31:34,919 THAT'S NOT THE CASE IN SPF MICE 789 00:31:34,919 --> 00:31:39,190 BUT IT IS THE CASE IN MORE 790 00:31:39,190 --> 00:31:41,692 NATURALLY EXPOSED PET SHOP MICE. 791 00:31:41,692 --> 00:31:44,162 SO THEY HAVE ELEVATED 792 00:31:44,162 --> 00:31:46,230 ANTIBODIES, AND PROTECT FROM 793 00:31:46,230 --> 00:31:47,999 ALLERGY, THEY GENERATE BOTH IGE 794 00:31:47,999 --> 00:31:53,437 AND IgG IN RESPONSE TO 795 00:31:53,437 --> 00:31:56,240 ALLERGIC SENSITIZATION, MEANING 796 00:31:56,240 --> 00:31:59,043 USE OF ALUM, SIMILAR TO ADULT 797 00:31:59,043 --> 00:32:00,645 HUMANS. 798 00:32:00,645 --> 00:32:02,046 ADULT HUMANS WILL INDUCE BOTH 799 00:32:02,046 --> 00:32:03,514 TYPE I AND TYPE II RESPONSE. 800 00:32:03,514 --> 00:32:06,350 YOU MAY REMEMBER WHEN Th1 AND 801 00:32:06,350 --> 00:32:07,218 Th2 SUBSETS WERE DISCOVERED 802 00:32:07,218 --> 00:32:10,087 FOR A LONG TIME IN THE HUMAN 803 00:32:10,087 --> 00:32:11,856 FIELD IT WAS ARGUED THEY DON'T 804 00:32:11,856 --> 00:32:13,724 HAVE THE CLEAR DISTINCTION 805 00:32:13,724 --> 00:32:16,227 BETWEEN Th1 AND Th2. 806 00:32:16,227 --> 00:32:22,800 THAT'S GENERALLY TRUE FOR ADULT 807 00:32:22,800 --> 00:32:23,067 HUMANS. 808 00:32:23,067 --> 00:32:29,507 AND SO ALLERGY-SPECIFIC 809 00:32:29,507 --> 00:32:30,107 ANTIBODIES PROTECTIVE FROM 810 00:32:30,107 --> 00:32:31,375 ALLERGIES, WHY IS THE ANTIBODY 811 00:32:31,375 --> 00:32:34,545 RESPONSE TO THE SAME 812 00:32:34,545 --> 00:32:43,321 IMMUNIZATION DIFFERENT IN PET OF 813 00:32:43,321 --> 00:32:47,458 PET SHOP MICE AND SPF. 814 00:32:47,458 --> 00:32:49,393 WHEN WE LOOKED AT RESPONSE IN 815 00:32:49,393 --> 00:32:53,364 SPF AND PET SHOP MICE WITHOUT 816 00:32:53,364 --> 00:32:58,836 IMMUNIZATION, NEITHER OF THOSE 817 00:32:58,836 --> 00:33:01,539 MICE WERE NOT EXPOSED TO IT, IN 818 00:33:01,539 --> 00:33:03,407 SPF THERE'S NO RESPONSE BUT IN 819 00:33:03,407 --> 00:33:04,742 PET SHOP MICE THERE'S A 820 00:33:04,742 --> 00:33:05,176 RESPONSE. 821 00:33:05,176 --> 00:33:10,715 IT'S NOT A VERY HIGH TITER BUT 822 00:33:10,715 --> 00:33:14,685 IT'S THERE. 823 00:33:14,685 --> 00:33:24,462 AND IF WE TAKE -- SORRY, THE SPF 824 00:33:24,462 --> 00:33:29,934 MICE, I'M SORRY, IF WE TAKE PET 825 00:33:29,934 --> 00:33:32,336 SHOP MICE, PUT THEM IN SPF 826 00:33:32,336 --> 00:33:33,304 CONDITIONS, THEY LOSE IT. 827 00:33:33,304 --> 00:33:35,206 GROW UP IN CLEAN ENVIRONMENT, 828 00:33:35,206 --> 00:33:39,810 THEN THEY DON'T HAVE THE 829 00:33:39,810 --> 00:33:41,012 ANTIBODY RESPONSE REAVE SO THEY 830 00:33:41,012 --> 00:33:45,182 HAVE TO BE DUTY TO HAVE IT EVEN 831 00:33:45,182 --> 00:33:48,119 THOUGH THEY DIDN'T SEE IT. 832 00:33:48,119 --> 00:33:50,855 WHEN WE LOOKED AT -- NORTH TO 833 00:33:50,855 --> 00:33:52,957 CHARACTERIZE THAT FURTHER WE 834 00:33:52,957 --> 00:33:54,725 DEVELOPED THIS ANTIBODY 835 00:33:54,725 --> 00:33:56,060 SCREENING PLATFORM, THAT ALLOWS 836 00:33:56,060 --> 00:33:59,063 YOU US TO LOOK AT EPITOPE 837 00:33:59,063 --> 00:34:00,298 RESPONSE, LINEAR BUT 838 00:34:00,298 --> 00:34:01,465 NEVERTHELESS THAT WAS 839 00:34:01,465 --> 00:34:04,201 INFORMATIVE SO WE USED THIS 840 00:34:04,201 --> 00:34:06,504 SYSTEM WHERE IT'S A BACTERIAL 841 00:34:06,504 --> 00:34:07,705 DISPLAY ESSENTIALLY OF EPITOPES, 842 00:34:07,705 --> 00:34:10,374 AND THEN THIS IS SHOWING THAT IT 843 00:34:10,374 --> 00:34:13,177 WORKS, WHEN WE INDUCE EXPRESSION 844 00:34:13,177 --> 00:34:16,781 OF THE ANTIGEN AND THEN 845 00:34:16,781 --> 00:34:18,649 ANTIBODIES WILL RECOGNIZE THE 846 00:34:18,649 --> 00:34:21,452 APPROPRIATE EPITOPE AND THEN IF 847 00:34:21,452 --> 00:34:22,920 WE USE MONOCLONAL ANTIBODIES AS 848 00:34:22,920 --> 00:34:24,255 CONTROL IT SHOWS EXACTLY IN 849 00:34:24,255 --> 00:34:25,756 WHICH POSITION THEY EPITOPES 850 00:34:25,756 --> 00:34:30,561 ARE, AND ON THIS GRAPH THIS IS 851 00:34:30,561 --> 00:34:32,463 THE POSITION ON X-AXIS, TWO 852 00:34:32,463 --> 00:34:33,531 EPITOPES RECOGNIZED BY THE 853 00:34:33,531 --> 00:34:35,066 MONOCLONAL ANTIBODIES, TO SHOW 854 00:34:35,066 --> 00:34:36,300 THE SYSTEM WORKS. 855 00:34:36,300 --> 00:34:40,871 WE USE THAT SYSTEM AND COMPARED 856 00:34:40,871 --> 00:34:42,740 ANTIBODY REACTIVITIES TOWARDS 857 00:34:42,740 --> 00:34:44,575 DIFFERENT EPITOPES, FROM PET 858 00:34:44,575 --> 00:34:48,446 SHOP MICE VERSUS SPF MICE, 859 00:34:48,446 --> 00:34:49,213 WITHOUT AND WITH IMMUNIZATION, 860 00:34:49,213 --> 00:34:51,749 AND THIS IS WHAT HAPPENS. 861 00:34:51,749 --> 00:34:54,485 THE TOP IS SPF MICE. 862 00:34:54,485 --> 00:34:56,887 AS EXPECTED WITHOUT IMMUNIZATION 863 00:34:56,887 --> 00:34:59,056 THERE'S NO ANTIBODIES REACTIVE 864 00:34:59,056 --> 00:35:00,391 TO OVA. 865 00:35:00,391 --> 00:35:05,396 AFTER IMNATION YOU SEE REACTION 866 00:35:05,396 --> 00:35:07,631 TO EPITOPES, IN PET SHOP MICE 867 00:35:07,631 --> 00:35:10,701 PLENTY OF ACTIVITIES TOWARDS 868 00:35:10,701 --> 00:35:15,039 EPITOPES OF ALBUMIN. 869 00:35:15,039 --> 00:35:16,974 WITH IMMUNIZATION IT CHANGES, 870 00:35:16,974 --> 00:35:17,675 EVEN WITHOUT IMMUNIZATION 871 00:35:17,675 --> 00:35:18,943 THERE'S PLENTY OF RESPONSES. 872 00:35:18,943 --> 00:35:20,411 SAME TRUE WITH T CELLS. 873 00:35:20,411 --> 00:35:25,983 IF YOU TAKE T CELLS FROM SPF 874 00:35:25,983 --> 00:35:27,818 UNIMMUNIZED, THERE'S NO RESPONSE 875 00:35:27,818 --> 00:35:28,319 TO EITHER. 876 00:35:28,319 --> 00:35:30,921 WHEN THEY ARE IMMUNIZED YOU 877 00:35:30,921 --> 00:35:35,226 START SEEING RESPONSE TO TL 8 878 00:35:35,226 --> 00:35:36,827 BUT NOT ALBUMIN, PET SHOP MICE 879 00:35:36,827 --> 00:35:38,462 THERE'S PLENTY OF RESPONSE TO 880 00:35:38,462 --> 00:35:40,765 BOTH EVEN THOUGH THEY HAVEN'T 881 00:35:40,765 --> 00:35:41,866 SEEN EITHER ONE. 882 00:35:41,866 --> 00:35:43,601 THIS IS REMINISCENT OF WHAT 883 00:35:43,601 --> 00:35:49,640 HAPPENS, WHAT'S REPORTED IN 884 00:35:49,640 --> 00:35:51,742 HUMANS, IT WAS DEMONSTRATED WHEN 885 00:35:51,742 --> 00:35:54,979 THEY LOOK FOR SPECIFIC 886 00:35:54,979 --> 00:35:55,746 ANTI-VIRAL EPITOPES, RESPONSES 887 00:35:55,746 --> 00:35:58,049 IN T CELLS, THEY SEE THAT THEY 888 00:35:58,049 --> 00:36:00,684 HAVE T CELLS REACTIVE TO 889 00:36:00,684 --> 00:36:01,352 PARTICULAR EPITOPES EVEN THOUGH 890 00:36:01,352 --> 00:36:05,956 FOR EXAMPLE HIV AT THE TOP THEY 891 00:36:05,956 --> 00:36:07,892 WERE NOT INFECTED OR VACCINATED, 892 00:36:07,892 --> 00:36:11,195 THAT SEEMS TO BE THE GENERAL 893 00:36:11,195 --> 00:36:21,739 RULE, ONLY NOT THE CASE WITH SPF 894 00:36:22,773 --> 00:36:26,210 MICE THAT DON'T HAVE THAT. 895 00:36:26,210 --> 00:36:28,746 SPF MICE LAST LIKE HUMANS, DIRTY 896 00:36:28,746 --> 00:36:31,449 MICE ARE MORE -- SO THIS IS JUST 897 00:36:31,449 --> 00:36:33,451 TO SHOW THAT THERE IS THIS 898 00:36:33,451 --> 00:36:36,954 REACTIVITY OF T CELLS IN BOTTOM 899 00:36:36,954 --> 00:36:38,489 CD4 T CELLS, WITH Th2 900 00:36:38,489 --> 00:36:40,891 RESPONSES THE SITUATION IS 901 00:36:40,891 --> 00:36:42,660 DIFFERENT, THERE'S NOT MUCH OF 902 00:36:42,660 --> 00:36:44,862 TYPE 2 MEMORY RECALL RESPONSE, 903 00:36:44,862 --> 00:36:48,299 BUT IT'S VERY STRONG WITH TYPE 1 904 00:36:48,299 --> 00:36:48,566 RESPONSE. 905 00:36:48,566 --> 00:36:50,801 SO, CONCLUSION FROM THAT PART IS 906 00:36:50,801 --> 00:36:54,071 THAT PET SHOP MICE FROM 907 00:36:54,071 --> 00:36:55,840 PREEXISTING RESPONSES, BOTH 908 00:36:55,840 --> 00:36:58,576 IgG AND T CELLS, AND THIS MUST 909 00:36:58,576 --> 00:37:02,646 BE SPECIFIC TO SOMETHING BECAUSE 910 00:37:02,646 --> 00:37:03,981 WE HAVEN'T SEEN THIS, MUST BE 911 00:37:03,981 --> 00:37:04,849 CROSS-REACTIVE TO SOMETHING THEY 912 00:37:04,849 --> 00:37:08,419 HAVE BEEN EXPOSED TO. 913 00:37:08,419 --> 00:37:11,322 THIS CROSS REACTIVITY IS WHAT WE 914 00:37:11,322 --> 00:37:14,058 DETECT WHEN WE DO THESE 915 00:37:14,058 --> 00:37:15,593 EXPERIMENTS. 916 00:37:15,593 --> 00:37:21,065 AND THEY GENERATE THIS MIXED 917 00:37:21,065 --> 00:37:22,233 Th1/Th2 RESPONSE, UNLIKE SPF 918 00:37:22,233 --> 00:37:24,201 MICE BUT SIMILAR TO ADULT 919 00:37:24,201 --> 00:37:27,171 HUMANS, IMMUNE SYSTEM IS IN A 920 00:37:27,171 --> 00:37:27,838 DIFFERENT STATE. 921 00:37:27,838 --> 00:37:30,574 WE CAN LOOK AT IT THIS WAY IN 922 00:37:30,574 --> 00:37:33,844 TRUE NAIVE STATE, MIMICKED BY 923 00:37:33,844 --> 00:37:38,682 SPF MICE, IN GRAY NAIVE T CELLS, 924 00:37:38,682 --> 00:37:41,852 THEN YOU PERFORM ALLERGIC 925 00:37:41,852 --> 00:37:43,454 SENSITIZATION, GENERATE Th2 926 00:37:43,454 --> 00:37:46,957 AND IgG RESPONSE, THEY WILL 927 00:37:46,957 --> 00:37:47,992 BECOME ALLERGIC. 928 00:37:47,992 --> 00:37:55,099 IF YOU DO ORAL TOLERANCE, EXPAND 929 00:37:55,099 --> 00:37:57,201 T REGSES, PROTECTED, THERE'S 930 00:37:57,201 --> 00:37:58,569 ALREADY PREEXISTING NATURAL TYPE 931 00:37:58,569 --> 00:38:04,708 1 RESPONSE IN THE NATURAL CASE, 932 00:38:04,708 --> 00:38:06,477 THAT PROTECTS THEM FROM 933 00:38:06,477 --> 00:38:08,245 DEVELOPING ALLERGY, EVEN THOUGH 934 00:38:08,245 --> 00:38:10,748 WOULD HAVE TYPE 2 RESPONSE, JUST 935 00:38:10,748 --> 00:38:12,650 THEY WILL NOT BE HYPERSENSITIVE, 936 00:38:12,650 --> 00:38:15,452 THAT'S WHAT NATURAL STATE S 937 00:38:15,452 --> 00:38:17,655 EVERYONE HAS IGE RESPONSE, NOT 938 00:38:17,655 --> 00:38:18,789 EVERYONE IS HYPERSENSITIVE. 939 00:38:18,789 --> 00:38:20,591 PREDICTION IS PET SHOP MICE 940 00:38:20,591 --> 00:38:22,526 SHOULD BE SUSCEPTIBLE TO 941 00:38:22,526 --> 00:38:24,995 DEVELOPING ALLERGY IF THEY ARE 942 00:38:24,995 --> 00:38:25,596 SENSITIZED BEFORE THEY DEVELOP 943 00:38:25,596 --> 00:38:30,267 THAT STATE OF THE IMMUNE SYSTEM. 944 00:38:30,267 --> 00:38:32,102 BEFORE THEY DEVELOP THAT 945 00:38:32,102 --> 00:38:33,204 ANTIGENIC EXPERIENCE, WHERE THEY 946 00:38:33,204 --> 00:38:37,708 NOW CROSS-REACT TO ALL SORTS OF 947 00:38:37,708 --> 00:38:38,676 ANTIGENS. 948 00:38:38,676 --> 00:38:40,578 AND SPF MICE CONVERSELY SHOULD 949 00:38:40,578 --> 00:38:42,713 BE PROTECTED BY PRIOR 950 00:38:42,713 --> 00:38:43,247 CROSS-REACTIVE EXPOSURES. 951 00:38:43,247 --> 00:38:46,150 THIS IS THE EXPERIMENT ABOUT THE 952 00:38:46,150 --> 00:38:49,220 FIRST PART, WHERE WE TOOK PET 953 00:38:49,220 --> 00:38:50,588 SHOP MICE, SO IF YOU SENSITIZE 954 00:38:50,588 --> 00:38:53,591 AS ADULTS THEY ARE PROTECTED, 955 00:38:53,591 --> 00:38:55,659 SHOWN IN GREEN. 956 00:38:55,659 --> 00:38:58,395 THEN WE SENSITIZE THEM AT 957 00:38:58,395 --> 00:39:00,998 POSTNATAL DAY 7, BEFORE THEY 958 00:39:00,998 --> 00:39:02,600 DEVELOPED ALL THIS STATE OF THE 959 00:39:02,600 --> 00:39:08,172 IMMUNE SYSTEM, EXPOSED TO ALL 960 00:39:08,172 --> 00:39:10,908 THE ALLERGENS, DAY 58, 65, WE 961 00:39:10,908 --> 00:39:15,713 CHALLENGE THEM AND NOW THEY ARE 962 00:39:15,713 --> 00:39:17,915 ALLERGIC AND THEY ANAPHYLAX. 963 00:39:17,915 --> 00:39:20,784 IF THEY ARE EXPOSED PRIOR TO 964 00:39:20,784 --> 00:39:21,852 DEVELOPING ALL THE ANTIGENIC 965 00:39:21,852 --> 00:39:22,953 EXPERIENCE THEN THEY ARE 966 00:39:22,953 --> 00:39:23,921 SENSITIVE. 967 00:39:23,921 --> 00:39:25,022 THAT'S THE WINDOW OF 968 00:39:25,022 --> 00:39:26,223 VULNERABILITY, ALSO FITS WITH 969 00:39:26,223 --> 00:39:29,960 WHAT WE KNOW IN HUMANS WHERE IN 970 00:39:29,960 --> 00:39:34,131 BABIES ARE MUCH MORE SENSITIVE 971 00:39:34,131 --> 00:39:41,805 TO DEVELOPING ALLERGIC 972 00:39:41,805 --> 00:39:42,139 REACTIVITY. 973 00:39:42,139 --> 00:39:42,339 OKAY. 974 00:39:42,339 --> 00:39:52,216 TO LOOK AT IT IN A DIFFERENT WAY 975 00:39:52,216 --> 00:39:54,952 WE TOOK THIS, TO SEE WHETHER 976 00:39:54,952 --> 00:39:56,687 THERE WOULD BE CROSS-REACTIVITY, 977 00:39:56,687 --> 00:40:00,324 WE COULD MIMIC THAT IN SPF MICE. 978 00:40:00,324 --> 00:40:04,161 WE SENSITIZED THEM WITH AL UM 979 00:40:04,161 --> 00:40:06,697 OVA BUT CHALLENGED WITH CHICKEN 980 00:40:06,697 --> 00:40:09,333 ALBUMIN OR DUCK OR EVEN TURTLE. 981 00:40:09,333 --> 00:40:13,037 AND THESE ALL HAVE DIFFERENT 982 00:40:13,037 --> 00:40:14,672 DISTANCES IN TERMS OF SEQUENCES. 983 00:40:14,672 --> 00:40:17,641 EVEN AS YOU GO DOWN IN DISTANCE 984 00:40:17,641 --> 00:40:19,610 FROM LEFT TO RIGHT, REACTIVITY 985 00:40:19,610 --> 00:40:21,145 GOES DOWN BUT REACTIVITY IS 986 00:40:21,145 --> 00:40:26,617 THERE EVEN TO THIS 987 00:40:26,617 --> 00:40:28,452 CROSS-REACTIVE NON-IDENTICAL 988 00:40:28,452 --> 00:40:28,852 ANTIGENS. 989 00:40:28,852 --> 00:40:30,988 MORE CLEARLY SEEN WITH OUR 990 00:40:30,988 --> 00:40:32,289 ANTIGEN SCREENING SYSTEM WHERE 991 00:40:32,289 --> 00:40:36,026 CHICKEN OVA IS THE ONE THAT IS 992 00:40:36,026 --> 00:40:37,227 HUNDRED PERCENT MATCH AND GOES 993 00:40:37,227 --> 00:40:39,430 DOWN BUT YOU STILL SEE THIS 994 00:40:39,430 --> 00:40:39,797 REACTIVITY. 995 00:40:39,797 --> 00:40:45,269 THIS IS JUST TO SAY THAT THERE 996 00:40:45,269 --> 00:40:46,704 IS THIS CROSS-REACTIVE IMMUNITY 997 00:40:46,704 --> 00:40:48,138 THAT CAN BE EVEN ARTIFICIALLY 998 00:40:48,138 --> 00:40:51,842 DEVELOPED HERE WITH JUST USING 999 00:40:51,842 --> 00:40:52,142 ONE ANTIGEN. 1000 00:40:52,142 --> 00:40:55,446 THIS LEADS US TO THE MODEL WHERE 1001 00:40:55,446 --> 00:40:58,682 WE THINK OF ONE AFFECT OF 1002 00:40:58,682 --> 00:41:00,784 VULNERABILITY TO ALLERGIES, 1003 00:41:00,784 --> 00:41:01,919 ASSOCIATED WITH MORE THAN CLEAN 1004 00:41:01,919 --> 00:41:05,289 ENVIRONMENT IS THE FOLLOWING. 1005 00:41:05,289 --> 00:41:06,924 THAT NEONATAL STATE THE ONLY 1006 00:41:06,924 --> 00:41:10,661 ANTIGENS THE ANIMAL WOULD SEE IS 1007 00:41:10,661 --> 00:41:16,333 SELF-ANTIGENS, IF THEY DEVELOPED 1008 00:41:16,333 --> 00:41:19,403 IN CLEAN ENVIRONMENTSPF 1009 00:41:19,403 --> 00:41:21,372 COMMENSALS WOULD BE EXPOSED TO 1010 00:41:21,372 --> 00:41:23,240 DIETARY, THERE ARE MANY OTHER 1011 00:41:23,240 --> 00:41:25,309 ANTIGENS THAT ARE NOT EXPOSED 1012 00:41:25,309 --> 00:41:25,709 TO. 1013 00:41:25,709 --> 00:41:29,480 IN THE PET SHOP MICE AND ALSO IN 1014 00:41:29,480 --> 00:41:30,247 NATURAL CONDITIONS FOR HUMANS, 1015 00:41:30,247 --> 00:41:32,549 WHEN YOU GO FROM THIS NEONATAL 1016 00:41:32,549 --> 00:41:36,387 STATE AND GET EXPOSED TO THIS 1017 00:41:36,387 --> 00:41:38,789 HUGELY DIVERSE ANTIGENIC 1018 00:41:38,789 --> 00:41:40,224 ENVIRONMENT, YOU DEVELOP 1019 00:41:40,224 --> 00:41:41,325 RESPONSES THAT THROUGH 1020 00:41:41,325 --> 00:41:43,160 CROSS-REACTIVITY WILL COVER THE 1021 00:41:43,160 --> 00:41:44,595 ENTIRE ANTIGENIC SPACE. 1022 00:41:44,595 --> 00:41:49,933 AND THAT'S WHAT MAKES THEM 1023 00:41:49,933 --> 00:41:50,501 PROTECTED FROM DEVELOPING 1024 00:41:50,501 --> 00:41:52,136 ALLERGIC REACTIVITY AFTER THAT 1025 00:41:52,136 --> 00:41:52,803 STATE IS ESTABLISHED. 1026 00:41:52,803 --> 00:41:55,773 OVER THERE ON THE RIGHT THERE 1027 00:41:55,773 --> 00:41:58,175 WOULD BE GAPS IN WHAT'S COVERED 1028 00:41:58,175 --> 00:42:04,314 BY ANTIGENIC SPACE AND IF 1029 00:42:04,314 --> 00:42:10,120 ALLERGY 1030 00:42:10,120 --> 00:42:12,423 ALLERGIN FITS IN, YOU WOULD BE 1031 00:42:12,423 --> 00:42:13,290 PROTECTED. 1032 00:42:13,290 --> 00:42:15,359 IN TERMS OF LIFE HISTORY COURSE 1033 00:42:15,359 --> 00:42:18,095 HERE THE PET SHOP MICE AT THE 1034 00:42:18,095 --> 00:42:20,831 TOP WOULD SHOW SITUATIONS 1035 00:42:20,831 --> 00:42:24,334 SIMILAR TO HUMANS IN NATURAL 1036 00:42:24,334 --> 00:42:27,604 ENVIRONMENTS WHERE THIS WINDOW 1037 00:42:27,604 --> 00:42:28,372 OF SUSCEPTIBILITY IS SHORT IN 1038 00:42:28,372 --> 00:42:29,773 THE EARLY STAGES OF LIFE, 1039 00:42:29,773 --> 00:42:30,808 THERE'S A SHORT WINDOW BEFORE 1040 00:42:30,808 --> 00:42:37,147 YOU ARE EXPOSED TO THE 1041 00:42:37,147 --> 00:42:38,649 ALLERGENS, THAT'S WHEN YOU'RE 1042 00:42:38,649 --> 00:42:40,184 VULNERABLE. 1043 00:42:40,184 --> 00:42:41,885 IT QUICKLY CLOSES DOWN BY 1044 00:42:41,885 --> 00:42:44,688 DEVELOPING ALL THE OTHER 1045 00:42:44,688 --> 00:42:46,323 REACTIVITIES, FILLING ANTIGENIC 1046 00:42:46,323 --> 00:42:52,463 SPACE BY VARIOUS ANTIBODY AND T 1047 00:42:52,463 --> 00:42:53,230 CELL REACTIVITIES. 1048 00:42:53,230 --> 00:42:55,399 SPF MICE IT'S NOT CLEARED AS 1049 00:42:55,399 --> 00:43:02,105 MUCH, AND THEY CAN MAINTAIN 1050 00:43:02,105 --> 00:43:02,473 SUSCEPTIBILITY. 1051 00:43:02,473 --> 00:43:07,377 HUMANS IN INDUSTRIALIZED 1052 00:43:07,377 --> 00:43:14,918 ENVIRONMENT SOMEWHAT SIMILAR TO 1053 00:43:14,918 --> 00:43:16,186 SPF MICE THE WINDOW IS EXTENDED, 1054 00:43:16,186 --> 00:43:17,554 THEY ARE MORE PRONE. 1055 00:43:17,554 --> 00:43:20,290 IT HAS TO DO WITH THE ABILITY OF 1056 00:43:20,290 --> 00:43:21,959 THE SYSTEM TO COVER AS MUCH AS 1057 00:43:21,959 --> 00:43:23,927 ANTIGENIC SPACE DUE TO NATURAL 1058 00:43:23,927 --> 00:43:25,462 EXPOSURE TO ANTIGENIC 1059 00:43:25,462 --> 00:43:26,530 ENVIRONMENT, AND THAT'S WHAT 1060 00:43:26,530 --> 00:43:27,631 PROVIDES PROTECTION. 1061 00:43:27,631 --> 00:43:30,167 THAT'S ONE ASPECT OF PROVIDING 1062 00:43:30,167 --> 00:43:30,467 PROTECTION. 1063 00:43:30,467 --> 00:43:31,902 THE SECOND PART THAT I WILL 1064 00:43:31,902 --> 00:43:34,204 QUICKLY GO THROUGH HAS TO DO 1065 00:43:34,204 --> 00:43:39,476 WITH ANOTHER ASPECT OF THE 1066 00:43:39,476 --> 00:43:41,411 ENVIRONMENTAL FACTOR THAT MAKES 1067 00:43:41,411 --> 00:43:42,312 ALLERGIES PROBLEMATIC, NOT ABOUT 1068 00:43:42,312 --> 00:43:44,381 DEVELOPING THEM OR NOT BUT WHAT 1069 00:43:44,381 --> 00:43:45,482 MAKES THEM PROBLEMATIC. 1070 00:43:45,482 --> 00:43:51,388 AND THAT HAS TO DO WITH 1071 00:43:51,388 --> 00:43:52,923 BASICALLY EVOLUTIONARY TRAP, 1072 00:43:52,923 --> 00:43:54,892 WHEN ANIMALS OR HUMANS EVOLVE 1073 00:43:54,892 --> 00:43:56,560 UNDER CERTAIN CONDITIONS, AND 1074 00:43:56,560 --> 00:43:58,061 THEN IN ENVIRONMENT CHANGE THEY 1075 00:43:58,061 --> 00:43:59,496 STILL REACT THE SAME WAY, AND 1076 00:43:59,496 --> 00:44:07,271 THAT LEADS TO THEIR DEMISE OR 1077 00:44:07,271 --> 00:44:07,738 DISEASE. 1078 00:44:07,738 --> 00:44:11,208 SO, FOR EXAMPLE, TURTLES TRYING 1079 00:44:11,208 --> 00:44:12,743 TO CROSS THE ROAD, YOU TURN THEM 1080 00:44:12,743 --> 00:44:14,912 AROUND THEY STILL CROSS THE ROAD 1081 00:44:14,912 --> 00:44:16,780 BECAUSE THEY DIDN'T EVOLVE WITH 1082 00:44:16,780 --> 00:44:18,115 CARS RUNNING AROUND, THIS SORT 1083 00:44:18,115 --> 00:44:18,649 OF THING. 1084 00:44:18,649 --> 00:44:20,284 IN THE CONTEXT OF ALLERGIES, 1085 00:44:20,284 --> 00:44:22,252 WHAT THAT MEANS IS IF IT IS 1086 00:44:22,252 --> 00:44:24,555 INDEED THE WAY WE THINK BIT THAT 1087 00:44:24,555 --> 00:44:27,124 IT'S A PROTECTIVE RESPONSE 1088 00:44:27,124 --> 00:44:28,058 AGAINST NOXIOUS SUBSTANCES, ONCE 1089 00:44:28,058 --> 00:44:30,060 YOU ARE EXPOSED TO SOMETHING 1090 00:44:30,060 --> 00:44:34,197 THAT CAUSES ALLERGY, LET'S SAY 1091 00:44:34,197 --> 00:44:35,933 HOUSE DUST MITE, IN -- WELL, IN 1092 00:44:35,933 --> 00:44:38,135 THE WILD IT WON'T BE HOUSE DUST 1093 00:44:38,135 --> 00:44:39,670 MITE BUT SOMETHING SIMILAR, 1094 00:44:39,670 --> 00:44:42,072 LET'S SAY POLLEN UNDER A TREE, 1095 00:44:42,072 --> 00:44:43,840 FROM SOME TREE, SO BASICALLY ALL 1096 00:44:43,840 --> 00:44:46,543 YOU DO IS DON'T SLEEP UNDER THAT 1097 00:44:46,543 --> 00:44:46,743 TREE. 1098 00:44:46,743 --> 00:44:48,745 GO TO THE OTHER SIDE OF THE 1099 00:44:48,745 --> 00:44:52,115 RIVER AND YOU'RE FINE. 1100 00:44:52,115 --> 00:44:55,519 IF THERE'S A PLANT THAT MAKES 1101 00:44:55,519 --> 00:44:56,386 YOUR STOMACH UPSET, REMEMBER 1102 00:44:56,386 --> 00:45:01,892 WHAT IT IS AND DON'T EAT THE 1103 00:45:01,892 --> 00:45:03,327 PLANT, JUST AVOID THEM. 1104 00:45:03,327 --> 00:45:07,197 IN MODERN ENVIRONMENT IF YOU'RE 1105 00:45:07,197 --> 00:45:08,599 ALLERGIC TO HOUSE DUST MITE THE 1106 00:45:08,599 --> 00:45:10,133 ONLY WAY TO MIMIC WHAT NATURE 1107 00:45:10,133 --> 00:45:11,868 INTENDED IS NOT TO LIVE INDOORS 1108 00:45:11,868 --> 00:45:14,838 WHICH IS NOT AN OPTION. 1109 00:45:14,838 --> 00:45:17,240 THAT SORT OF -- THAT'S THE 1110 00:45:17,240 --> 00:45:20,544 PRINCIPLE OF EVOLUTIONARY TRAP. 1111 00:45:20,544 --> 00:45:21,878 WITH ALLERGIES, WE THINK AND 1112 00:45:21,878 --> 00:45:23,480 THERE'S PLENTY OF EVIDENCE WITH 1113 00:45:23,480 --> 00:45:25,482 HUMANS THAT ONE IMPORTANT ASPECT 1114 00:45:25,482 --> 00:45:28,418 OF ALLERGIC DEFENSE IS 1115 00:45:28,418 --> 00:45:30,387 BEHAVIORAL DEFENSE, AVOIDING 1116 00:45:30,387 --> 00:45:31,154 EXPOSURE. 1117 00:45:31,154 --> 00:45:33,023 ONCE THE SYSTEM DETECTED 1118 00:45:33,023 --> 00:45:34,024 SOMETHING IS PROBLEMATIC, TRIES 1119 00:45:34,024 --> 00:45:37,961 TO REMEMBER IT AND AVOID IT. 1120 00:45:37,961 --> 00:45:39,062 THAT'S BEHAVIORAL DEFENSE. 1121 00:45:39,062 --> 00:45:40,697 THAT'S WHAT WE STUDIED. 1122 00:45:40,697 --> 00:45:43,667 I'LL GO QUICKLY THROUGH THIS 1123 00:45:43,667 --> 00:45:44,134 PART. 1124 00:45:44,134 --> 00:45:47,504 BUT I WANT TO GET TO THE FINAL 1125 00:45:47,504 --> 00:45:47,704 POINT. 1126 00:45:47,704 --> 00:45:49,439 BUT THE HISTORY OF THAT IS 1127 00:45:49,439 --> 00:45:50,874 ACTUALLY THERE'S BEEN STUDIES 1128 00:45:50,874 --> 00:45:53,243 ABOUT 30 YEARS AGO IN BRAZIL 1129 00:45:53,243 --> 00:45:55,012 FROM A GROUP WHERE THEY LOOKED 1130 00:45:55,012 --> 00:45:57,547 IT THE QUESTION WHETHER 1131 00:45:57,547 --> 00:45:59,716 ALLERGIES WOULD PROMOTE AVERSE 1132 00:45:59,716 --> 00:46:00,884 BEHAVIORS, MADE MICE ALLERGIC TO 1133 00:46:00,884 --> 00:46:05,856 CORN OR PEA PEANUTS, GAVE THEM 1134 00:46:05,856 --> 00:46:06,957 CHOICE TO EAT BOTH, THEY CHOOSE 1135 00:46:06,957 --> 00:46:08,191 ONE OTHER THE OTHER, OVER 30 1136 00:46:08,191 --> 00:46:09,059 YEARS AGO. 1137 00:46:09,059 --> 00:46:12,462 WE WANTED TO STUDY WITH MODERN 1138 00:46:12,462 --> 00:46:14,965 APPROACHES TO LOOK IN MORE 1139 00:46:14,965 --> 00:46:15,732 DETAIL. 1140 00:46:15,732 --> 00:46:17,934 WE USE THIS PREFERENCE TEST, 1141 00:46:17,934 --> 00:46:19,236 EITHER MAKE MICE ALLERGIC OR 1142 00:46:19,236 --> 00:46:21,304 NOT, AND THEN WE GIVE THEM A 1143 00:46:21,304 --> 00:46:24,474 CHOICE TO DRINK CLEAN WATER, 1144 00:46:24,474 --> 00:46:26,677 REGULAR WATER, OR WATER OF THE 1145 00:46:26,677 --> 00:46:29,279 ALLERGEN THEY ARE SENSITIVE TO. 1146 00:46:29,279 --> 00:46:31,281 AND IT'S SO HAPPENS WHICH WAS 1147 00:46:31,281 --> 00:46:33,016 GOOD FOR EXPERIMENTAL PURPOSES 1148 00:46:33,016 --> 00:46:34,751 THEY ACTUALLY -- IF THEY ARE NOT 1149 00:46:34,751 --> 00:46:36,420 ALLERGIC THEY PREFER THE WATER 1150 00:46:36,420 --> 00:46:38,689 WITH ALBUMIN FOR SOME REASON BUT 1151 00:46:38,689 --> 00:46:41,224 GOOD FOR US, MADE RESULTS MORE 1152 00:46:41,224 --> 00:46:41,825 CLEAR. 1153 00:46:41,825 --> 00:46:45,062 IN CONTROL MILES THEY PREFER 1154 00:46:45,062 --> 00:46:47,798 ALBUMIN WATER, IF ALLERGIC THREE 1155 00:46:47,798 --> 00:46:51,635 LOSE PREFERENCE, OVER TIME START 1156 00:46:51,635 --> 00:46:51,968 AVOIDING. 1157 00:46:51,968 --> 00:46:55,806 48 WEEKS PAST THEY NOW PREFER 1158 00:46:55,806 --> 00:46:59,943 DRINKING CLEAN WATER AND AVOID 1159 00:46:59,943 --> 00:47:02,245 OVALBUMIN WATER. 1160 00:47:02,245 --> 00:47:04,414 IF YOU USE BSA THEY ARE FINE. 1161 00:47:04,414 --> 00:47:07,951 THEY WILL CONTINUE DRINKING IT. 1162 00:47:07,951 --> 00:47:12,189 ANTIGEN SPECIFIC RESPONSE, 1163 00:47:12,189 --> 00:47:15,926 BEHAVIORAL RESPONSE, AND THE 1164 00:47:15,926 --> 00:47:17,294 NEUROBIOLOGICAL ASPECTS OF 1165 00:47:17,294 --> 00:47:21,364 AVOIDANCE BEHAVIOR, IN THE 1166 00:47:21,364 --> 00:47:22,399 CONTEXT OF SICKNESS, CIRCUITS 1167 00:47:22,399 --> 00:47:24,367 THAT ARE INVOLVED IN INDUCING, 1168 00:47:24,367 --> 00:47:28,071 FOR EXAMPLE, ANOREXIA AND 1169 00:47:28,071 --> 00:47:31,675 AVOIDING FOOD CONSUMPTION, 1170 00:47:31,675 --> 00:47:33,210 INCLUDES INFORMATION COLLECTED 1171 00:47:33,210 --> 00:47:37,848 THAT COMES FROM VISCERAL SENSORY 1172 00:47:37,848 --> 00:47:41,618 NEURONS AND COMMUNICATES WITH A 1173 00:47:41,618 --> 00:47:43,420 MAJOR BREAK ON BEHAVIORS LIKE 1174 00:47:43,420 --> 00:47:47,257 FOOD CONSUMPTION. 1175 00:47:47,257 --> 00:47:49,226 THAT INFORMATION ALSO THEN 1176 00:47:49,226 --> 00:47:51,528 PASSED ON TO AMYGDALA TO 1177 00:47:51,528 --> 00:47:52,729 GENERATE MEMORIES ABOUT THE 1178 00:47:52,729 --> 00:47:54,064 NEGATIVE EXPERIENCES TO AVOID IT 1179 00:47:54,064 --> 00:47:54,698 IN THE FUTURE. 1180 00:47:54,698 --> 00:47:57,033 WE FOUND THAT IF WE MAKE MICE 1181 00:47:57,033 --> 00:48:06,343 ALLERGIC AND THEN EXPOSE THEM TO 1182 00:48:06,343 --> 00:48:08,779 ALLERGEN, ALL THESE BECOME 1183 00:48:08,779 --> 00:48:10,981 ACTIVATED WHEN MICE EXPERIENCE 1184 00:48:10,981 --> 00:48:12,582 NEGATIVE STIMULI THAT INDUCE 1185 00:48:12,582 --> 00:48:14,684 AVOIDANCE BEHAVIOR, THEY WILL 1186 00:48:14,684 --> 00:48:16,419 BECOME ACTIVATED, AND THAT 1187 00:48:16,419 --> 00:48:22,025 RESPONSE IN THE BRAIN IS 1188 00:48:22,025 --> 00:48:23,326 DEPENDENT ON IG ANTIBODIES, 1189 00:48:23,326 --> 00:48:24,561 WITHOUT THEM AVOIDANCE GOES AWAY 1190 00:48:24,561 --> 00:48:26,196 AND ACTIVATION OF THE BRAIN 1191 00:48:26,196 --> 00:48:29,032 AREAS GOES AWAY. 1192 00:48:29,032 --> 00:48:30,467 SO IT'S ANTIGEN-SPECIFIC 1193 00:48:30,467 --> 00:48:33,503 BEHAVIORAL RESPONSE. 1194 00:48:33,503 --> 00:48:35,138 AND BECAUSE IGE ALSO DEPENDS ON 1195 00:48:35,138 --> 00:48:36,439 CELLS SHOWN HERE. 1196 00:48:36,439 --> 00:48:39,609 THE QUESTION IS HOW DO MUST 1197 00:48:39,609 --> 00:48:41,845 CELLS COMMUNICATE WITH THE 1198 00:48:41,845 --> 00:48:43,513 NERVOUS SYSTEM, CENTRAL NERVOUS 1199 00:48:43,513 --> 00:48:44,815 SYSTEM TO PROMOTE AVERSIVE 1200 00:48:44,815 --> 00:48:45,882 BEHAVIORS. 1201 00:48:45,882 --> 00:48:48,185 THERE ARE TWO MECHANISMS, FAST 1202 00:48:48,185 --> 00:48:50,387 AND SLOW, VERY MUCH SIMILAR TO 1203 00:48:50,387 --> 00:48:52,122 SOME OTHER TIMES OF AVERSIVE 1204 00:48:52,122 --> 00:48:53,890 BEHAVIORS, FOR EXAMPLE PAIN. 1205 00:48:53,890 --> 00:48:57,727 THERE'S A FAST PAIN, WHICH IS 1206 00:48:57,727 --> 00:48:59,029 MEDIATED BY A-BETA FIBERS, FAST 1207 00:48:59,029 --> 00:49:01,431 RESPONSE WHEN YOU WITHDRAW FROM 1208 00:49:01,431 --> 00:49:03,099 TOUCHING SOMETHING PAINFUL, AND 1209 00:49:03,099 --> 00:49:06,069 THERE'S SLOW PAIN MEDIATED BY C 1210 00:49:06,069 --> 00:49:07,504 FIBERS, MUCH MORE PROLONGED. 1211 00:49:07,504 --> 00:49:10,073 WE THINK THERE'S SOMETHING 1212 00:49:10,073 --> 00:49:10,540 SIMILAR. 1213 00:49:10,540 --> 00:49:11,508 MECHANISTICALLY IT'S NOT THROUGH 1214 00:49:11,508 --> 00:49:12,943 DIFFERENT TYPES OF FIBERS BUT 1215 00:49:12,943 --> 00:49:16,880 IT'S DIFFERENT TYPES OF SIGNALS. 1216 00:49:16,880 --> 00:49:20,617 THE FIRST THING WE FOUND THERE 1217 00:49:20,617 --> 00:49:22,052 IS THIS HORMONE EXTREMELY 1218 00:49:22,052 --> 00:49:23,253 INTERESTING INDUCED WHEN THERE'S 1219 00:49:23,253 --> 00:49:28,491 SOMETHING OFF. 1220 00:49:28,491 --> 00:49:30,560 IT PATHOGENS, TOXINS, DNA 1221 00:49:30,560 --> 00:49:33,730 DAMAGE, SO FORTH, INDUCES 1222 00:49:33,730 --> 00:49:36,166 PROTECTIVE RESPONSE LIKE NAUSEA, 1223 00:49:36,166 --> 00:49:40,670 ANOREXIA, CAN BE PROBLEMATIC IN 1224 00:49:40,670 --> 00:49:41,004 CACHEXIA. 1225 00:49:41,004 --> 00:49:42,072 RECEPTOR IS EXPRESSED IN THE 1226 00:49:42,072 --> 00:49:43,940 BRAIN AREA RESPONSIBLE FOR 1227 00:49:43,940 --> 00:49:47,210 VOMITING, NAUSEA, THESE TYPES OF 1228 00:49:47,210 --> 00:49:48,745 PROTECTIVE RESPONSES FROM 1229 00:49:48,745 --> 00:49:48,979 TOXINS. 1230 00:49:48,979 --> 00:49:52,916 AND SO WHAT WE FOUND IS THAT GDF 1231 00:49:52,916 --> 00:49:54,885 15 IS ROBUSTLY INFUSED WHEN 1232 00:49:54,885 --> 00:50:05,395 SENSITIZED MICE ARE EXPOSED TO 1233 00:50:06,763 --> 00:50:07,063 ALLERGEN. 1234 00:50:07,063 --> 00:50:10,934 AND, YEAH, THIS IS JUST I THINK 1235 00:50:10,934 --> 00:50:12,035 TIME COURSE THERE. 1236 00:50:12,035 --> 00:50:15,105 AND THIS PRODUCTION IS DEPENDS 1237 00:50:15,105 --> 00:50:17,641 ON IgG AND MAST CELLS. 1238 00:50:17,641 --> 00:50:23,313 IT IS KNOWN TO ACT AND INDUCE 1239 00:50:23,313 --> 00:50:26,483 NAUSEA AND AVERSION, THAT'S ONE 1240 00:50:26,483 --> 00:50:27,050 MECHANISM. 1241 00:50:27,050 --> 00:50:30,020 WHEN WE BLOCK GDF 15 AVOIDANCE 1242 00:50:30,020 --> 00:50:37,560 BEHAVIOR GOES AWAY AND THEY KEEP 1243 00:50:37,560 --> 00:50:38,328 CONSUMING OVALBUMIN THAT THEY 1244 00:50:38,328 --> 00:50:39,629 ARE ALLERGIC TOO. 1245 00:50:39,629 --> 00:50:41,298 HOW DO MUST CELLS TURN ON THE 1246 00:50:41,298 --> 00:50:41,698 PRODUCTION? 1247 00:50:41,698 --> 00:50:44,668 IT WAS NOT COMING FROM MUST 1248 00:50:44,668 --> 00:50:47,971 CELLS, TURNS OUT IT WAS COMING 1249 00:50:47,971 --> 00:50:49,472 FROM -- IT REQUIRED A DIFFERENT 1250 00:50:49,472 --> 00:50:56,813 PATHWAY THAT OPERATES IN MAST 1251 00:50:56,813 --> 00:50:59,215 CELLS, THESE LEUKOTRIENES, THE 1252 00:50:59,215 --> 00:51:02,285 TARGET DRUGS CAN INHIBIT THEM OR 1253 00:51:02,285 --> 00:51:03,053 GENETIC KNOCKOUTS, THAT'S WHAT 1254 00:51:03,053 --> 00:51:04,454 WE USED. 1255 00:51:04,454 --> 00:51:13,563 AND FOUND THAT IF WE BLOCKED 1256 00:51:13,563 --> 00:51:15,165 LEUKOTRIENE, BY DIFFERENT STEPS 1257 00:51:15,165 --> 00:51:18,368 OF SYNTHESIS, ON THE LEFT YOU 1258 00:51:18,368 --> 00:51:19,903 SEE AVOIDANCE IS ABLATED. 1259 00:51:19,903 --> 00:51:24,774 AND IF WE USE THE KNOCKOUT IT 1260 00:51:24,774 --> 00:51:27,277 GOES AWAY COMPLETELY SO THE MICE 1261 00:51:27,277 --> 00:51:28,912 NOW DON'T DISTINGUISH AND THEY 1262 00:51:28,912 --> 00:51:30,347 CONTINUE CONSUMING EVEN THOUGH 1263 00:51:30,347 --> 00:51:33,717 THE REST OF THE ALLERGIC 1264 00:51:33,717 --> 00:51:41,057 RESPONSE IS THERE, INTESTINAL 1265 00:51:41,057 --> 00:51:42,058 INFLAMMATION, DIARRHEA, BUT THEY 1266 00:51:42,058 --> 00:51:44,294 KEEP EATING SOMETHING THAT'S BAD 1267 00:51:44,294 --> 00:51:45,662 FOR THEM. 1268 00:51:45,662 --> 00:51:47,731 AND SO, BASICALLY WHAT WE FOUND 1269 00:51:47,731 --> 00:51:53,169 IS THAT TWO PATHWAYS, BOTH 1270 00:51:53,169 --> 00:51:58,908 INITIATED BY ANTIGEN RECOGNITION 1271 00:51:58,908 --> 00:52:02,245 OF ALLERGEN, ACTS ON TWO 1272 00:52:02,245 --> 00:52:06,249 PATHWAYS, EPITHELIAL CELLS IN 1273 00:52:06,249 --> 00:52:07,450 THE LARGE INTESTINE INCLUESES 1274 00:52:07,450 --> 00:52:12,355 PRODUCTION, REPORTED IN THE 1275 00:52:12,355 --> 00:52:15,792 CONTEXT OF KIEM THERAPEUTIC 1276 00:52:15,792 --> 00:52:17,427 DRUGS, HOW LTC INDUCES WE STILL 1277 00:52:17,427 --> 00:52:21,264 ARE WORKING OUT SOME DETAILS BUT 1278 00:52:21,264 --> 00:52:25,635 SEEMS LIKE IT'S DOWNSTREAM OF 1279 00:52:25,635 --> 00:52:25,869 LTC4. 1280 00:52:25,869 --> 00:52:29,272 FOR FAST RESPONSE THROUGH VAGUS 1281 00:52:29,272 --> 00:52:31,141 POPULATION OF VAGAL NEURONS 1282 00:52:31,141 --> 00:52:31,941 STIMULATED AND GO INDUCE THE 1283 00:52:31,941 --> 00:52:34,344 SAME CIRCUMSTANCES THAT I SHOWED 1284 00:52:34,344 --> 00:52:34,878 BEFORE. 1285 00:52:34,878 --> 00:52:36,379 THERE'S TWO PATHWAYS LEADING TO 1286 00:52:36,379 --> 00:52:36,646 AVERSION. 1287 00:52:36,646 --> 00:52:38,715 AND THAT BIOLOGY WE THINK IS A 1288 00:52:38,715 --> 00:52:42,652 VERY IMPORTANT PART OF ALLERGIES 1289 00:52:42,652 --> 00:52:45,955 WE ABUSE IN THE MODERN WORLD 1290 00:52:45,955 --> 00:52:47,490 BECAUSE AVOIDANCE ALTHOUGH IT'S 1291 00:52:47,490 --> 00:52:49,025 THE MOST EFFECTIVE WAY AND 1292 00:52:49,025 --> 00:52:50,527 SOMETIMES POSSIBLE IN MANY 1293 00:52:50,527 --> 00:52:54,998 SITUATIONS NOT POSSIBLE TO 1294 00:52:54,998 --> 00:52:56,099 COMPLETELY AVOID SOMETHING. 1295 00:52:56,099 --> 00:52:57,534 LIKE I DESCRIBED WITH HOUSE DUST 1296 00:52:57,534 --> 00:52:58,635 MITE. 1297 00:52:58,635 --> 00:53:02,572 EVEN WITH FOOD ALLERGIES WHERE 1298 00:53:02,572 --> 00:53:06,309 YOU THINK, WELL, AVOIDING 1299 00:53:06,309 --> 00:53:06,876 PEANUTS ALLERGIES ARE 1300 00:53:06,876 --> 00:53:09,579 PROBLEMATIC IN THE NATURAL 1301 00:53:09,579 --> 00:53:11,548 WORLD, YOU HAVE 150 SOURCES OF 1302 00:53:11,548 --> 00:53:14,717 FOOD, WE REDUCED EVERYTHING TO 1303 00:53:14,717 --> 00:53:16,719 JUST FEW, PEANUTS-BASED FOODS 1304 00:53:16,719 --> 00:53:18,788 BECOME VERY DOMINANT AND HARD TO 1305 00:53:18,788 --> 00:53:19,355 AVOID. 1306 00:53:19,355 --> 00:53:21,524 BASICALLY THE IDEA THAT NORMALLY 1307 00:53:21,524 --> 00:53:25,495 INDUCTION OF THIS RESPONSE IS 1308 00:53:25,495 --> 00:53:27,897 AVERSION, UNPLEASANT FEELINGS IN 1309 00:53:27,897 --> 00:53:29,299 ADDITION TO EXPELLING SOMETHING 1310 00:53:29,299 --> 00:53:30,733 INDUCES AVOIDANCE A NATURAL AND 1311 00:53:30,733 --> 00:53:38,074 EFFECTIVE WAY IN THE WILD. 1312 00:53:38,074 --> 00:53:39,742 IN THE MODERN ENVIRONMENT IT'S 1313 00:53:39,742 --> 00:53:42,378 HARD TO DO THAT. 1314 00:53:42,378 --> 00:53:45,215 SO THIS PART, WHAT IT SUGGESTS, 1315 00:53:45,215 --> 00:53:49,285 IT EXTENDS THIS IDEA THAT 1316 00:53:49,285 --> 00:53:50,453 NEURONS, IN THE SENSORY 1317 00:53:50,453 --> 00:53:52,889 PHYSIOLOGY NEURONS CAN SENSE 1318 00:53:52,889 --> 00:53:54,724 SOMETHING DIRECTLY LIKE 1319 00:53:54,724 --> 00:53:56,593 OLFACTORY NEURONS OR INDIRECTLY 1320 00:53:56,593 --> 00:53:58,061 THROUGH SPECIALIZED SENSORY 1321 00:53:58,061 --> 00:54:00,330 CELLS, USUALLY EPITHELIAL CELLS 1322 00:54:00,330 --> 00:54:01,998 THAT DETECT SOMETHING FOR 1323 00:54:01,998 --> 00:54:02,966 EXAMPLE TASTE BUD CELLS DETECT 1324 00:54:02,966 --> 00:54:06,469 TASTE IN THE TONGUE AND 1325 00:54:06,469 --> 00:54:09,105 COMMUNICATE TO SENSORY NEURONS, 1326 00:54:09,105 --> 00:54:11,174 HERE CELLS DETECT VIBRATIONS, 1327 00:54:11,174 --> 00:54:12,108 COMMUNICATE TO NEURONS, ENTERING 1328 00:54:12,108 --> 00:54:14,777 THE CELLS IN THE GUT DETECT 1329 00:54:14,777 --> 00:54:16,546 NUTRIENTS, COMMUNICATE TO 1330 00:54:16,546 --> 00:54:16,980 NEURONS. 1331 00:54:16,980 --> 00:54:23,119 WHAT WE'RE ADDING MAST CELLS 1332 00:54:23,119 --> 00:54:24,420 WHEN DETECT ALLERGENS DETECT 1333 00:54:24,420 --> 00:54:24,888 NEURONS. 1334 00:54:24,888 --> 00:54:29,025 WHAT CAN BE DETECTED IS NOW 1335 00:54:29,025 --> 00:54:32,195 BECAUSE IT'S IGE, EXPANDING THIS 1336 00:54:32,195 --> 00:54:33,997 SCOPE OF SENSORY MODALITY, 1337 00:54:33,997 --> 00:54:36,499 ALMOST TO INFINITY, OF COURSE 1338 00:54:36,499 --> 00:54:38,768 ANYTHING COULD BE AN ALLERGEN 1339 00:54:38,768 --> 00:54:40,737 POTENTIALLY, YOU CAN MAKE 1340 00:54:40,737 --> 00:54:42,705 ANTIBODIES TO ALMOST ANYTHING. 1341 00:54:42,705 --> 00:54:45,108 IT'S A WAY FOR THE IMMUNE SYSTEM 1342 00:54:45,108 --> 00:54:46,242 TO EXPAND SENSORY CAPABILITIES 1343 00:54:46,242 --> 00:54:51,281 OF THE NERVOUS SYSTEM OF THE 1344 00:54:51,281 --> 00:54:53,883 SENSORY PATHWAYS, AND MOREOVER 1345 00:54:53,883 --> 00:54:56,486 THAT EXPANSION CAN BE FOR ANY 1346 00:54:56,486 --> 00:54:57,720 PARTICULAR CONTEXT WOULD BE 1347 00:54:57,720 --> 00:54:59,789 ANTIGEN SPECIFIC. 1348 00:54:59,789 --> 00:55:01,191 IN PRINCIPLE ONE CAN MANIPULATE 1349 00:55:01,191 --> 00:55:02,859 THESE TYPES OF BEHAVIORS AT 1350 00:55:02,859 --> 00:55:04,827 LEAST THROUGH SPECIFIC ANTIGENS. 1351 00:55:04,827 --> 00:55:07,497 AND TO FINISH I WANT TO PUT IT 1352 00:55:07,497 --> 00:55:12,835 IN THE OTHER CONTEXT WHY THESE 1353 00:55:12,835 --> 00:55:14,837 FINDINGS WITH AVOIDANCE AND 1354 00:55:14,837 --> 00:55:17,307 COMMUNICATION BETWEEN NERVOUS 1355 00:55:17,307 --> 00:55:23,346 SYSTEM, IT'S INTERESTING TO US, 1356 00:55:23,346 --> 00:55:25,882 ILLUSTRATES THIS IS AN EXAMPLE 1357 00:55:25,882 --> 00:55:29,852 OF ASSOCIATIVE LEARNING. 1358 00:55:29,852 --> 00:55:32,589 CLASSICAL EXAMPLE IS PAVLOV'S 1359 00:55:32,589 --> 00:55:34,224 DOGS, TO TYPES OF STIMULI, 1360 00:55:34,224 --> 00:55:36,726 ANIMAL IS HARD WIRED TO RESPOND 1361 00:55:36,726 --> 00:55:38,595 IN A STEREOTYPIC WAY. 1362 00:55:38,595 --> 00:55:39,929 MEAT HERE INDUCES PRE-PROGRAMMED 1363 00:55:39,929 --> 00:55:44,500 RESPONSE LIKE SALVATION, SO ON. 1364 00:55:44,500 --> 00:55:45,635 CONDITIONED STIMULUS LIKE RING 1365 00:55:45,635 --> 00:55:47,437 OF A BELL DOESN'T INDUCE THAT 1366 00:55:47,437 --> 00:55:50,540 RESPONSE, IF THEY ARE COMBINED, 1367 00:55:50,540 --> 00:55:52,041 BY ASSOCIATION, CONDITIONED 1368 00:55:52,041 --> 00:55:54,811 STIMULUS INDUCE CONDITIONED 1369 00:55:54,811 --> 00:55:55,078 RESPONSE. 1370 00:55:55,078 --> 00:55:56,446 THAT'S CLASSICAL CONDITIONING. 1371 00:55:56,446 --> 00:55:58,715 IN THE IMMUNE SYSTEM EXACT SAME 1372 00:55:58,715 --> 00:56:00,650 SITUATION WHERE WE HAVE SIMPLER 1373 00:56:00,650 --> 00:56:03,386 EXAMPLE WITH TYPE 1 IMMUNITY, 1374 00:56:03,386 --> 00:56:05,188 UNCONDITIONED STIMULUS WHICH 1375 00:56:05,188 --> 00:56:07,156 WOULD BE MICROBIAL STRUCTURES 1376 00:56:07,156 --> 00:56:11,227 THAT ARE DETECTED BY PATTERN 1377 00:56:11,227 --> 00:56:13,196 RECOGNITION RECEPTORS LIKE LPS, 1378 00:56:13,196 --> 00:56:14,063 TLR, PRE-PROGRAMMED RESPONSE 1379 00:56:14,063 --> 00:56:14,964 NOTHING TO LEARNED, LEARNED 1380 00:56:14,964 --> 00:56:16,065 THROUGH EVOLUTION. 1381 00:56:16,065 --> 00:56:17,700 IF WE HAVE CONDITIONED STIMULUS 1382 00:56:17,700 --> 00:56:20,570 WHICH WOULD BE ANTIGEN, DETECTED 1383 00:56:20,570 --> 00:56:21,638 BY ANTIGEN RECEPTORS THAT 1384 00:56:21,638 --> 00:56:23,306 GENERATE, DON'T KNOW WHAT THAT 1385 00:56:23,306 --> 00:56:24,707 MEANS, NO RESPONSE, IF YOU 1386 00:56:24,707 --> 00:56:25,341 COMBINE THEM HAVE YOU 1387 00:56:25,341 --> 00:56:27,343 ASSOCIATION AND YOU HAVE 1388 00:56:27,343 --> 00:56:30,179 ADAPTIVE IMMUNE RESPONSE. 1389 00:56:30,179 --> 00:56:31,414 NOW CONDITIONED STIMULUS, 1390 00:56:31,414 --> 00:56:32,915 ANTIGEN ALONE WILL INDUCE 1391 00:56:32,915 --> 00:56:35,084 CONDITIONED RESPONSE, THE SAME 1392 00:56:35,084 --> 00:56:37,487 PRINCIPLE IN BOTH CASES. 1393 00:56:37,487 --> 00:56:40,256 THEN A PHENOMENON MAKES A 1394 00:56:40,256 --> 00:56:42,558 CONNECTION TO THE ASSOCIATED 1395 00:56:42,558 --> 00:56:43,559 LEARNING IN ALLERGIES, 1396 00:56:43,559 --> 00:56:46,162 PHENOMENON IS KNOWN AS 1397 00:56:46,162 --> 00:56:47,297 CONDITIONED FLAVOR AVERSION, 1398 00:56:47,297 --> 00:56:49,132 WHEN YOU EAT SOMETHING THAT 1399 00:56:49,132 --> 00:56:51,200 DOESN'T AGREE WITH YOU, AND THEN 1400 00:56:51,200 --> 00:56:52,535 THAT FLAVOR OF THAT FOOD THAT 1401 00:56:52,535 --> 00:56:53,936 MADE YOU SICK YOU REMEMBER IT 1402 00:56:53,936 --> 00:56:56,372 AND CAN NEVER EAT IT AGAIN, 1403 00:56:56,372 --> 00:56:56,606 RIGHT? 1404 00:56:56,606 --> 00:56:59,108 SO OFTEN IT COMES FROM SEAFOOD, 1405 00:56:59,108 --> 00:57:00,209 PROBABLY NOROVIRUS INFECTION OR 1406 00:57:00,209 --> 00:57:02,312 SOMETHING LIKE THAT MAKES YOU 1407 00:57:02,312 --> 00:57:04,947 VERY BAD FOOD POISONING, AND 1408 00:57:04,947 --> 00:57:07,317 THEN YOU CAN'T STAND SMELL FOR 1409 00:57:07,317 --> 00:57:08,084 DECADES, RIGHT? 1410 00:57:08,084 --> 00:57:09,952 ALMOST ALL THE PEOPLE HAVE SOME 1411 00:57:09,952 --> 00:57:11,587 EXPERIENCE OF THAT SORT. 1412 00:57:11,587 --> 00:57:13,156 WHAT HAPPENS HERE IS THAT 1413 00:57:13,156 --> 00:57:14,557 THERE'S SOME TOXIN THERE. 1414 00:57:14,557 --> 00:57:17,827 WE DON'T HAVE SPECIAL SENSES 1415 00:57:17,827 --> 00:57:19,696 LIKE THROUGH SMELL OR TASTE TO 1416 00:57:19,696 --> 00:57:20,663 DETECT THE TOXIN. 1417 00:57:20,663 --> 00:57:22,532 THE ONLY WAY WE CAN DETECT IS 1418 00:57:22,532 --> 00:57:23,933 BECAUSE IT MADE US SICK. 1419 00:57:23,933 --> 00:57:25,935 BUT WE WANT TO AVOID IT IN THE 1420 00:57:25,935 --> 00:57:27,670 FUTURE. 1421 00:57:27,670 --> 00:57:30,106 SO WHAT WE DO, WE MEANING 1422 00:57:30,106 --> 00:57:31,407 ANIMALS, ASSOCIATE WITH 1423 00:57:31,407 --> 00:57:33,876 SOMETHING THEY CAN DETECT, IN 1424 00:57:33,876 --> 00:57:37,880 THIS CASE FLAVOR, TASTE, AND 1425 00:57:37,880 --> 00:57:38,214 SMELL. 1426 00:57:38,214 --> 00:57:39,549 NEXT TIME THEY TASTE OR SMELL, 1427 00:57:39,549 --> 00:57:41,250 THEY SAY I WON'T EAT IT, LAST 1428 00:57:41,250 --> 00:57:43,252 TIME I ATE IT I WAS SICK. 1429 00:57:43,252 --> 00:57:44,454 THAT'S WHAT CONDITIONED FLAVOR 1430 00:57:44,454 --> 00:57:48,825 AVERSIONS ONE OF THE MOST POTENT 1431 00:57:48,825 --> 00:57:50,093 PARADIGMS IN ASSOCIATIVE 1432 00:57:50,093 --> 00:57:52,995 LEARNING, IT WORKS WITH ONE TRY. 1433 00:57:52,995 --> 00:57:55,631 AND SO IN THIS CASE WHAT WE HAVE 1434 00:57:55,631 --> 00:57:57,600 SOMETHING WE CANNOT DETECT, 1435 00:57:57,600 --> 00:57:58,034 TOXIN. 1436 00:57:58,034 --> 00:57:59,802 WE DON'T HAVE ANY SENSORS FOR 1437 00:57:59,802 --> 00:58:00,069 IT. 1438 00:58:00,069 --> 00:58:01,637 IT MAKES US SICK. 1439 00:58:01,637 --> 00:58:02,638 AND THERE'S SOMETHING WE CAN 1440 00:58:02,638 --> 00:58:04,841 DETECT, WHICH IS FLAVOR. 1441 00:58:04,841 --> 00:58:05,808 WE ASSOCIATE THEM. 1442 00:58:05,808 --> 00:58:08,778 WHAT IF THERE IS NO FLAVOR? 1443 00:58:08,778 --> 00:58:12,915 AND THAT'S THE CASE OF ALLERGIC 1444 00:58:12,915 --> 00:58:13,583 CONDITIONED RESPONSES. 1445 00:58:13,583 --> 00:58:16,185 SO AGAIN IF YOU HAVE LET'S SAY 1446 00:58:16,185 --> 00:58:19,255 SOME FOOD ANTIGENS, AND THERE'S 1447 00:58:19,255 --> 00:58:20,723 NOTHING NOXIOUS, NOTHING CAUSING 1448 00:58:20,723 --> 00:58:22,558 MALAISE, JUST NORMAL RESPONSE TO 1449 00:58:22,558 --> 00:58:23,993 FOOD, IF THERE'S SOMETHING 1450 00:58:23,993 --> 00:58:26,496 NOXIOUS THERE THAT CANNOT BE 1451 00:58:26,496 --> 00:58:28,498 DETECTED BY ANY OF THE SYSTEMS, 1452 00:58:28,498 --> 00:58:30,166 BUT WOULD MAKE YOU SICK, YOU 1453 00:58:30,166 --> 00:58:31,901 WANT TO ASSOCIATE WITH SOMETHING 1454 00:58:31,901 --> 00:58:33,202 YOU CAN DETECT. 1455 00:58:33,202 --> 00:58:34,837 IF IT'S FLAVOR, FINE. 1456 00:58:34,837 --> 00:58:35,638 YOU DEFECT FLAVOR. 1457 00:58:35,638 --> 00:58:37,707 IF IT'S NOT THEN WHAT DO YOU DO? 1458 00:58:37,707 --> 00:58:42,512 THAT'S WHERE WHERE THIS COMES , 1459 00:58:42,512 --> 00:58:46,549 PROTEIN ANTIGENS, IT WILL DETECT 1460 00:58:46,549 --> 00:58:50,853 THEM, WHATEVER MADE YOU SICK, 1461 00:58:50,853 --> 00:58:53,756 NEXT TIME YOU SEE THIS ANTIGEN 1462 00:58:53,756 --> 00:58:54,991 DON'T EAT IT, THAT'S WHAT I 1463 00:58:54,991 --> 00:58:55,858 THINK IS THERE. 1464 00:58:55,858 --> 00:58:59,829 THE PURPOSE OF THIS RESPONSE. 1465 00:58:59,829 --> 00:59:01,564 BOTH CONDITIONED FLAVOR AVERSION 1466 00:59:01,564 --> 00:59:02,865 AND ANTIGEN SPECIFIC AVERSION, 1467 00:59:02,865 --> 00:59:04,634 YOU CAN THINK, WELL, THIS IS 1468 00:59:04,634 --> 00:59:05,735 KIND OF SILLY SYSTEM BECAUSE 1469 00:59:05,735 --> 00:59:08,237 MOST OF THE TIME THINGS WILL NOT 1470 00:59:08,237 --> 00:59:09,238 HAVE TOXINS. 1471 00:59:09,238 --> 00:59:12,809 AND WE KNOW THAT ALLERGIC 1472 00:59:12,809 --> 00:59:15,144 IMMUNITY IS ERROR PRONE. 1473 00:59:15,144 --> 00:59:18,314 IT'S NOT THAT IT MAKES -- 1474 00:59:18,314 --> 00:59:19,382 DOESN'T MAKE MISTAKES, IT DOES 1475 00:59:19,382 --> 00:59:21,918 BUT IT'S SPECIFIC TIMES OF 1476 00:59:21,918 --> 00:59:22,285 MISTAKES. 1477 00:59:22,285 --> 00:59:23,553 BASICALLY MAKES FALSE POSITIVE 1478 00:59:23,553 --> 00:59:24,287 ERRORS. 1479 00:59:24,287 --> 00:59:27,723 THE REASON FOR THAT IS, THAT'S 1480 00:59:27,723 --> 00:59:30,326 MY LAST SLIDE, EVERY SENSORY 1481 00:59:30,326 --> 00:59:33,062 SYSTEM HAS TO OPTIMIZE 1482 00:59:33,062 --> 00:59:34,163 SPECIFICITIES, THERE'S A 1483 00:59:34,163 --> 00:59:35,164 TRADEOFF, YOU CANNOT OPTIMIZE 1484 00:59:35,164 --> 00:59:35,598 BOTH. 1485 00:59:35,598 --> 00:59:40,736 WHICH ONE DO YOU OPTIMIZE? 1486 00:59:40,736 --> 00:59:42,271 THAT DEPENDS ON THE VALENCE OF 1487 00:59:42,271 --> 00:59:43,372 THE STIMULUS. 1488 00:59:43,372 --> 00:59:44,674 IF IT'S POSITIVE, SOMETHING 1489 00:59:44,674 --> 00:59:48,177 GOOD, LIKE FOOD OR WHATEVER, 1490 00:59:48,177 --> 00:59:49,278 THEN MAXIMIZE SPECIFICITY AND 1491 00:59:49,278 --> 00:59:51,581 THAT'S PRONE TO FALSE NEGATIVE 1492 00:59:51,581 --> 00:59:52,114 ERRORS. 1493 00:59:52,114 --> 00:59:53,883 THAT BASICALLY MEANS THAT WE 1494 00:59:53,883 --> 00:59:55,952 ALWAYS WANT SOMETHING BETTER, 1495 00:59:55,952 --> 00:59:58,154 RIGHT? 1496 00:59:58,154 --> 00:59:59,455 IF IT'S NEGATIVE VALENCE, FALSE 1497 00:59:59,455 --> 01:00:00,756 NEGATIVE ERROR WOULD BE COSTLY 1498 01:00:00,756 --> 01:00:02,525 BECAUSE THAT CAN KILL YOU, 1499 01:00:02,525 --> 01:00:03,292 CAUSES ILLNESS. 1500 01:00:03,292 --> 01:00:05,928 WHAT YOU DO INSTEAD MAXIMIZE 1501 01:00:05,928 --> 01:00:08,431 SENSITIVITY, AND THAT IS MAKING 1502 01:00:08,431 --> 01:00:10,733 IT PRONE TO FALSE POSITIVE 1503 01:00:10,733 --> 01:00:11,067 ERROR. 1504 01:00:11,067 --> 01:00:13,336 SO IT'S BETTER SAFE THAN SORRY. 1505 01:00:13,336 --> 01:00:14,570 YOU REACT TO SOMETHING, YOU 1506 01:00:14,570 --> 01:00:18,174 DIDN'T HAVE TO, BUT IT'S BETTER 1507 01:00:18,174 --> 01:00:19,175 THAN NOT REACTING. 1508 01:00:19,175 --> 01:00:21,777 THAT'S THE IDEA. 1509 01:00:21,777 --> 01:00:24,013 SO ALLERGIC IMMUNITY IS 1510 01:00:24,013 --> 01:00:25,114 ILLUSTRATING THAT PRINCIPLE IT'S 1511 01:00:25,114 --> 01:00:27,149 VERY PRONE TO FALSE POSITIVE 1512 01:00:27,149 --> 01:00:28,684 ERRORS BECAUSE IT MAXIMIZED 1513 01:00:28,684 --> 01:00:39,195 SENSITIVITY OVER SPECIFICITY. 1514 01:00:39,395 --> 01:00:43,366 I'LL RECOGNIZE THESE PEOPLE THAT 1515 01:00:43,366 --> 01:00:51,007 DID THE WORK. 1516 01:00:51,007 --> 01:00:57,914 THANK YOU VERY MUCH, AGAIN, FOR 1517 01:00:57,914 --> 01:00:58,281 YOUR ATTENTION. 1518 01:00:58,281 --> 01:00:58,548 [APPLAUSE] 1519 01:00:58,548 --> 01:01:00,650 >> WE'RE PAST THE HOUR BUT THIS 1520 01:01:00,650 --> 01:01:03,619 GROUP IS CONDITIONED TO HAVE 1521 01:01:03,619 --> 01:01:06,188 LECTURES UNTIL 5:00, SO PROBABLY 1522 01:01:06,188 --> 01:01:08,758 CAN'T HANG OUT TOO LONG. 1523 01:01:08,758 --> 01:01:10,726 A HANDFUL OF QUESTIONS, MAYBE 1524 01:01:10,726 --> 01:01:13,396 YOU OVER THERE FIRST, MAYBE FOUR 1525 01:01:13,396 --> 01:01:15,264 QUESTIONS WE CAN DO. 1526 01:01:15,264 --> 01:01:18,200 >> FIRST, THIS WAS I THOUGHT A 1527 01:01:18,200 --> 01:01:20,703 PERFECT BILL PAUL LECTURE, THE 1528 01:01:20,703 --> 01:01:22,705 CONTRIBUTIONS TO TYPE 2 IMMUNITY 1529 01:01:22,705 --> 01:01:24,674 THAT WERE DISCUSSED HERE. 1530 01:01:24,674 --> 01:01:27,944 WITH REGARD TO THE PET SHOP 1531 01:01:27,944 --> 01:01:33,316 MICE, AND THE HYPOTHESIS OF 1532 01:01:33,316 --> 01:01:33,883 REPEATED -- HIGH MICROBIAL 1533 01:01:33,883 --> 01:01:35,184 ANTIGEN EXPOSURE, I WOULD THINK 1534 01:01:35,184 --> 01:01:39,789 ONE OF THE CONSEQUENCES OF THAT 1535 01:01:39,789 --> 01:01:42,525 WOULD BE DEVELOPMENT OF A MUCH 1536 01:01:42,525 --> 01:01:44,093 MORE ROBUST PERIPHERAL POWERING 1537 01:01:44,093 --> 01:01:46,596 SYSTEM LIKE ABILITY TO PRODUCE 1538 01:01:46,596 --> 01:01:48,030 IL-10 AND B CELLS OR TREGS AND 1539 01:01:48,030 --> 01:01:50,299 SO ON. 1540 01:01:50,299 --> 01:01:52,702 SO I WAS WONDERING IF YOU 1541 01:01:52,702 --> 01:01:57,039 BLOCKED IL-10 IN THE SETTING, 1542 01:01:57,039 --> 01:02:01,143 DID - YOU -- COULD YOU REVERSE? 1543 01:02:01,143 --> 01:02:04,413 >> CAN YOU REMOVE THE BREAKS IN 1544 01:02:04,413 --> 01:02:05,514 ALLERGIC -- YEAH, WE DON'T KNOW. 1545 01:02:05,514 --> 01:02:07,149 WE HAVEN'T DONE THAT EXPERIMENT. 1546 01:02:07,149 --> 01:02:08,784 WE'VE DONE EXPERIMENTS WITH 1547 01:02:08,784 --> 01:02:09,986 INDUCING TOLERANCE IN THE MICE 1548 01:02:09,986 --> 01:02:11,420 BUT I MEAN I SEE WHAT YOU MEAN 1549 01:02:11,420 --> 01:02:13,923 AND I AGREE WITH YOU COMPLETELY 1550 01:02:13,923 --> 01:02:15,891 THAT THEY ALSO HAVE OF COURSE 1551 01:02:15,891 --> 01:02:20,162 NOT JUST INCREASED REACTIVITY TO 1552 01:02:20,162 --> 01:02:24,300 EVERYTHING BUT MUCH INCREASED 1553 01:02:24,300 --> 01:02:25,201 COMPORTMENT THAT PROBABLY 1554 01:02:25,201 --> 01:02:31,140 CONTRIBUTES BUT WE CAN SEE THE 1555 01:02:31,140 --> 01:02:31,874 CROSS-REACTIVITY IS SUFFICIENT 1556 01:02:31,874 --> 01:02:32,975 WE'VE DONE EXPERIENCE WITH 1557 01:02:32,975 --> 01:02:35,177 TRANSFERS AND SO ON BUT I AGREE 1558 01:02:35,177 --> 01:02:41,017 TREGS WOULD BE -- THERE'S 1559 01:02:41,017 --> 01:02:42,718 SOMETHING WE COULD TRY IF IT'S 1560 01:02:42,718 --> 01:02:43,052 BLOCKING. 1561 01:02:43,052 --> 01:02:46,422 >> JUST BECAUSE IN THE CONTEXT 1562 01:02:46,422 --> 01:02:48,424 OF HELMINTH INFECTION IN PEOPLE, 1563 01:02:48,424 --> 01:02:51,260 IL-10 IS ALWAYS LIKE THE KEY, 1564 01:02:51,260 --> 01:02:53,663 ONE OF THE KEY CYTOKINES. 1565 01:02:53,663 --> 01:02:54,730 >> WE HAVEN'T DONE SPECIFIC 1566 01:02:54,730 --> 01:02:56,999 EXPERIMENT BUT IT WOULD BE GOOD 1567 01:02:56,999 --> 01:02:58,968 TO TRY IT, YEAH. 1568 01:02:58,968 --> 01:02:59,435 >> HI. 1569 01:02:59,435 --> 01:03:02,505 SO, YOU MADE A POINT THAT IT'S 1570 01:03:02,505 --> 01:03:05,341 THE EARLY EXPOSURE TO ANTIGENS 1571 01:03:05,341 --> 01:03:07,309 THAT SOMEHOW FILL OUT A 1572 01:03:07,309 --> 01:03:09,278 REPERTOIRE AND THAT'S MISSING IN 1573 01:03:09,278 --> 01:03:11,614 THE SPF. 1574 01:03:11,614 --> 01:03:13,883 BUT SINCE THE ANTIBODY 1575 01:03:13,883 --> 01:03:16,218 REPERTOIRE T-CELL RECEPTOR IS 1576 01:03:16,218 --> 01:03:19,088 ALMOST INFINITE, HOW DO YOU -- 1577 01:03:19,088 --> 01:03:20,890 WHAT'S THE HOLE, AND HOW DO YOU 1578 01:03:20,890 --> 01:03:24,960 FILL IT? 1579 01:03:24,960 --> 01:03:27,296 THAT IS, ARE THERE PARTICULAR 1580 01:03:27,296 --> 01:03:31,200 SPECIFICITIES, OR IS IT THAT 1581 01:03:31,200 --> 01:03:33,269 YOU'RE GENERATING BROADLY 1582 01:03:33,269 --> 01:03:35,371 CROSS-REACTING ANTIBODIES EARLY 1583 01:03:35,371 --> 01:03:38,774 THAT ARE FILLING OUT LARGE 1584 01:03:38,774 --> 01:03:39,408 THINGS? 1585 01:03:39,408 --> 01:03:42,478 OR ARE THERE -- COULD ONE 1586 01:03:42,478 --> 01:03:43,679 IDENTIFY SPECIFIC ANTIGENS WITH 1587 01:03:43,679 --> 01:03:46,348 SOME CAREFUL WORK THAT COULD 1588 01:03:46,348 --> 01:03:49,852 PLUG THESE HOLES MOST OPTIMALLY 1589 01:03:49,852 --> 01:03:51,253 AND THEN PREVENT ALLERGY? 1590 01:03:51,253 --> 01:03:53,122 >> YEAH, THE SECOND PART IS 1591 01:03:53,122 --> 01:03:55,891 EXACTLY WHAT WE'RE THINKING 1592 01:03:55,891 --> 01:03:57,727 ABOUT TRYING TO EXPORT LIKE FOR 1593 01:03:57,727 --> 01:03:59,829 THERAPEUTIC PURPOSE ALSO. 1594 01:03:59,829 --> 01:04:02,131 THE FIRST PART IS THE HARDER 1595 01:04:02,131 --> 01:04:02,565 QUESTION. 1596 01:04:02,565 --> 01:04:04,300 WE DON'T KNOW BECAUSE WHAT WE'VE 1597 01:04:04,300 --> 01:04:06,936 TRIED SO FAR IS LIMITED. 1598 01:04:06,936 --> 01:04:08,904 JUST EXTRAPOLATING WITH THAT 1599 01:04:08,904 --> 01:04:09,205 MODEL. 1600 01:04:09,205 --> 01:04:12,408 BUT I THINK THE NOTION THAT WE 1601 01:04:12,408 --> 01:04:15,277 KIND OF ARE GETTING CONVERTED TO 1602 01:04:15,277 --> 01:04:21,050 IS THAT THE IDEA OF ANTIGEN 1603 01:04:21,050 --> 01:04:22,818 SPECIFICITY, IT MAY BE BETTER OR 1604 01:04:22,818 --> 01:04:24,420 AT LEAST ALTERNATIVE WAY TO 1605 01:04:24,420 --> 01:04:28,491 THINK BIT, NOT SPECIFICITY BUT 1606 01:04:28,491 --> 01:04:28,791 REACTIVITY. 1607 01:04:28,791 --> 01:04:32,061 SPECIFICITY IS VERY RELATIVE 1608 01:04:32,061 --> 01:04:33,629 TERM, RIGHT? 1609 01:04:33,629 --> 01:04:34,864 AND REACTIVITY IS MORE NEUTRAL 1610 01:04:34,864 --> 01:04:36,499 AND I THINK MORE CORRECT WAY TO 1611 01:04:36,499 --> 01:04:39,135 TALK ABOUT IT, THAT YOU CAN 1612 01:04:39,135 --> 01:04:42,404 REACT TO SOMETHING, THAT MAY NOT 1613 01:04:42,404 --> 01:04:44,840 HAVE BEEN ANTIGEN SPECIFIC BUT 1614 01:04:44,840 --> 01:04:45,808 THE QUESTION QUANTITATIVELY IS 1615 01:04:45,808 --> 01:04:46,809 HOW MUCH YOU COVER, HOW MUCH 1616 01:04:46,809 --> 01:04:48,444 SPACE YOU COVER. 1617 01:04:48,444 --> 01:04:51,947 AND WE HYPOTHESIZE THAT YOU 1618 01:04:51,947 --> 01:04:56,852 COVER ON AVERAGE MAYBE ENOUGH, 1619 01:04:56,852 --> 01:04:58,087 AND THAT WOULD ON AVERAGE 1620 01:04:58,087 --> 01:05:00,823 PROVIDE THE STATE WHEN IMMUNE 1621 01:05:00,823 --> 01:05:03,225 SYSTEM IN ADULT IS NEVER LIKE 1622 01:05:03,225 --> 01:05:05,394 TRULY NAIVE, BUT THERE'S ALWAYS 1623 01:05:05,394 --> 01:05:06,195 SOME REACTIVITY. 1624 01:05:06,195 --> 01:05:08,430 BUT IT MAY BE BIASED TO THINK 1625 01:05:08,430 --> 01:05:10,966 MAYBE MORE COMMON IN THE 1626 01:05:10,966 --> 01:05:11,500 ENVIRONMENT. 1627 01:05:11,500 --> 01:05:13,269 THAT WOULD MAKE SENSE, 1628 01:05:13,269 --> 01:05:14,703 BIOLOGICALLY, BUT WE DON'T KNOW 1629 01:05:14,703 --> 01:05:15,604 THAT. 1630 01:05:15,604 --> 01:05:17,173 THAT'S THE QUESTION THAT'S 1631 01:05:17,173 --> 01:05:20,509 DEFINITELY WE NEED TO EXPLORE 1632 01:05:20,509 --> 01:05:22,378 FURTHER TO SEE WHETHER WE CAN 1633 01:05:22,378 --> 01:05:25,347 SEE IF THERE ARE STILL GAPS IN 1634 01:05:25,347 --> 01:05:25,481 -- 1635 01:05:25,481 --> 01:05:28,551 >> RIGHT, BEING ABLE TO BE 1636 01:05:28,551 --> 01:05:30,719 TOLERANT TO PROTEIN-LIKE 1637 01:05:30,719 --> 01:05:32,021 STRUCTURES VERSUS SOME WEIRD 1638 01:05:32,021 --> 01:05:32,888 CHEMICAL STRUCTURE THAT WOULD 1639 01:05:32,888 --> 01:05:33,989 NOT BE THERE. 1640 01:05:33,989 --> 01:05:35,424 >> RIGHT, EXACTLY. 1641 01:05:35,424 --> 01:05:37,059 SO THAT'S THE QUESTION. 1642 01:05:37,059 --> 01:05:42,431 ONE CAN THINK OF DIFFERENT TYPES 1643 01:05:42,431 --> 01:05:44,667 OF REACTIVITY PROFILES, SO CAN 1644 01:05:44,667 --> 01:05:46,802 IMAGINE SOMETHING SHALLOW LIKE 1645 01:05:46,802 --> 01:05:51,507 THIS WHERE IN THE MIDDLE HIGHEST 1646 01:05:51,507 --> 01:05:52,741 AFFINITY, DEVIATIONS ARE HIGH, 1647 01:05:52,741 --> 01:05:56,345 SURFACES MAY BE SMOOTHER SORT OF 1648 01:05:56,345 --> 01:06:02,618 SURFACE, YOU MAKE TEN VERSUS 1649 01:06:02,618 --> 01:06:06,889 EIGHT HYDROGEN BONDS, THE PEAK 1650 01:06:06,889 --> 01:06:09,391 WOULD BE SHARP. 1651 01:06:09,391 --> 01:06:10,693 PARTICULAR IN STRUCTURE TO 1652 01:06:10,693 --> 01:06:11,493 DETECT IT. 1653 01:06:11,493 --> 01:06:13,762 WONDERFUL SYSTEM BUT MAYBE 1654 01:06:13,762 --> 01:06:17,933 BIASED, THINKING ABOUT 1655 01:06:17,933 --> 01:06:18,801 SPECIFICITY. 1656 01:06:18,801 --> 01:06:19,368 >> THANK YOU. 1657 01:06:19,368 --> 01:06:20,135 >> FASCINATING. 1658 01:06:20,135 --> 01:06:23,205 I HAVE A QUESTION ABOUT THIS 1659 01:06:23,205 --> 01:06:25,341 EARLY EXPOSURE SENSITIZATION. 1660 01:06:25,341 --> 01:06:29,478 SO WHAT YOU DESCRIBED LARGELY 1661 01:06:29,478 --> 01:06:33,749 FITS WITH SO-CALLED HYGIENE 1662 01:06:33,749 --> 01:06:34,149 HYPOTHESIS. 1663 01:06:34,149 --> 01:06:35,718 BUT ONE VARIATION I'M NOT SURE 1664 01:06:35,718 --> 01:06:38,654 IF YOU WERE SAYING THIS IS THAT 1665 01:06:38,654 --> 01:06:40,656 IT DEPENDS ON THE SKEWING OF THE 1666 01:06:40,656 --> 01:06:43,926 IMMUNE SYSTEM AT THE TIME OF 1667 01:06:43,926 --> 01:06:44,293 FIRST EXPOSURE. 1668 01:06:44,293 --> 01:06:48,430 SO, IF YOU'RE EXPOSED TO A LOT 1669 01:06:48,430 --> 01:06:50,299 OF ENVIRONMENTAL MICROBES, AT AN 1670 01:06:50,299 --> 01:06:52,468 EARLY AGE, THAT SKEWS YOU MORE 1671 01:06:52,468 --> 01:06:54,069 TOWARD A Th1 TYPE RESPONSE AND 1672 01:06:54,069 --> 01:06:56,872 THEN WHEN YOU'RE EXPOSED YOU 1673 01:06:56,872 --> 01:06:58,641 MAKE AN IgG RESPONSE RATHER 1674 01:06:58,641 --> 01:07:01,777 THAN AN IGE RESPONSE, WHEREAS IF 1675 01:07:01,777 --> 01:07:04,947 AN INFANT IS MORE Th2 SKEWED 1676 01:07:04,947 --> 01:07:08,751 THAN EXPOSURE MIGHT LEAD TO AN 1677 01:07:08,751 --> 01:07:10,219 ALLERGIC SENSITIVITY. 1678 01:07:10,219 --> 01:07:11,387 AND THINKING IN THAT WAY I 1679 01:07:11,387 --> 01:07:13,722 WANTED TO ASK A PRACTICAL 1680 01:07:13,722 --> 01:07:16,592 QUESTION, WHICH IS, FOR A LONG 1681 01:07:16,592 --> 01:07:18,994 TIME PEDIATRICIANS RECOMMENDED 1682 01:07:18,994 --> 01:07:27,002 NOT EXPOSING INFANTS AND YOUNG 1683 01:07:27,002 --> 01:07:29,104 CHILDREN TO PEANUTS TO AVOID 1684 01:07:29,104 --> 01:07:29,738 DEVELOPING ALLERGIES BUT THAT 1685 01:07:29,738 --> 01:07:32,341 FLIPPED IN THE LAST FIVE OR TEN 1686 01:07:32,341 --> 01:07:33,442 YEARS, THE RECOMMENDATION IS 1687 01:07:33,442 --> 01:07:36,512 EXPOSURE KIDS VERY EARLY TO 1688 01:07:36,512 --> 01:07:43,319 PEANUTS AND OTHER POTENTIAL 1689 01:07:43,319 --> 01:07:44,753 ALLERGENS. 1690 01:07:44,753 --> 01:07:50,459 HOW DOES THAT FIT AND WHERE IS 1691 01:07:50,459 --> 01:07:51,126 THE CUTOFF BETWEEN SENSITIZATION 1692 01:07:51,126 --> 01:07:52,194 AND -- 1693 01:07:52,194 --> 01:07:52,494 >> THANKS. 1694 01:07:52,494 --> 01:07:53,896 THIS IS AN IMPORTANT 1695 01:07:53,896 --> 01:07:54,997 DISTINCTION. 1696 01:07:54,997 --> 01:07:58,767 HOW MUCH THE COVERAGE, ANTIGEN 1697 01:07:58,767 --> 01:08:06,475 COVERAGE CONTRIBUTES VERSUS 1698 01:08:06,475 --> 01:08:07,543 EFFECTOR TYPE VERSUS 1699 01:08:07,543 --> 01:08:08,043 TOLERIZATION. 1700 01:08:08,043 --> 01:08:10,713 IN THE CASE OF THE PEANUT 1701 01:08:10,713 --> 01:08:16,218 FEEDING TO BABIES IT'S ALL ABOUT 1702 01:08:16,218 --> 01:08:17,052 INDUCING THIS TOLERANCE, 1703 01:08:17,052 --> 01:08:18,821 EXTENDING TREGS SPECIFIC FOR 1704 01:08:18,821 --> 01:08:21,423 PEANUT ANTIGENS. 1705 01:08:21,423 --> 01:08:22,224 THERE'S THAT CONTRIBUTION. 1706 01:08:22,224 --> 01:08:24,426 AND IN THAT CASE I THINK 1707 01:08:24,426 --> 01:08:27,262 PROTECTION PROBABLY WORKS 1708 01:08:27,262 --> 01:08:30,199 THROUGH THAT MECHANISM, AS YOU 1709 01:08:30,199 --> 01:08:31,433 IMPLY, INDUCING TOLERANCE 1710 01:08:31,433 --> 01:08:35,471 TOWARDS THE PARTICULAR ANTIGEN. 1711 01:08:35,471 --> 01:08:38,307 IN THE CASE OF DEVIATING 1712 01:08:38,307 --> 01:08:42,077 RESPONSE TO OPPOSITE TYPE OF 1713 01:08:42,077 --> 01:08:43,379 RESPONSE, VERSUS ANTIGEN 1714 01:08:43,379 --> 01:08:46,348 COVERAGE, IT'S HARDER TO 1715 01:08:46,348 --> 01:08:50,386 DISASSOCIATE FOR US, DEVIATED 1716 01:08:50,386 --> 01:08:52,154 IgG TYPES OF ANTIBODIES 1717 01:08:52,154 --> 01:08:56,525 PROVIDE PROTECTION, IT'S BOTH, 1718 01:08:56,525 --> 01:08:58,260 HAVING ANTIBODIES AND OF THAT 1719 01:08:58,260 --> 01:08:59,795 PARTICULAR TYPE. 1720 01:08:59,795 --> 01:09:03,399 IT'S HARDER TO DISTINGUISH, AND 1721 01:09:03,399 --> 01:09:05,467 I THINK THEY PROBABLY SHOULD BE 1722 01:09:05,467 --> 01:09:07,136 DISTINGUISHED OUT OF INTEREST 1723 01:09:07,136 --> 01:09:10,639 BUT I THINK GENERALLY WOULD 1724 01:09:10,639 --> 01:09:12,041 OPERATE TOGETHER. 1725 01:09:12,041 --> 01:09:13,475 BUT DISTINGUISHING FROM THE 1726 01:09:13,475 --> 01:09:15,110 PATHWAY THAT LEADS TO THE 1727 01:09:15,110 --> 01:09:18,580 TOLERANCE TO TREG EXPANSION 1728 01:09:18,580 --> 01:09:21,784 VERSUS ANTIGENIC COVERAGE I 1729 01:09:21,784 --> 01:09:24,153 THINK THESE OPERATE ON DIFFERENT 1730 01:09:24,153 --> 01:09:26,922 TIME SCALES, DISCRETE EVENT IN 1731 01:09:26,922 --> 01:09:30,826 EARLY LIFE DEVELOPING TREGS 1732 01:09:30,826 --> 01:09:32,761 VERSUS CONTINUOUS ACCUMULATION 1733 01:09:32,761 --> 01:09:34,296 OF SPECIFICITIES OR REACTIVITIES 1734 01:09:34,296 --> 01:09:35,931 TOWARDS DIFFERENT ANTIGENS THAT 1735 01:09:35,931 --> 01:09:39,001 TAKES MAYBE YEARS IN HUMANS TO 1736 01:09:39,001 --> 01:09:41,370 DEVELOP. 1737 01:09:41,370 --> 01:09:41,637 >> OKAY. 1738 01:09:41,637 --> 01:09:42,938 THANK YOU. 1739 01:09:42,938 --> 01:09:46,975 >> LET ME REPEAT THE CME CODE, 1740 01:09:46,975 --> 01:09:47,276 57689. 1741 01:09:47,276 --> 01:09:49,745 WE'LL HAVE A RECEPTION I BELIEVE 1742 01:09:49,745 --> 01:09:51,613 WITH PEANUTS AND FRIED CALAMARI 1743 01:09:51,613 --> 01:09:52,214 OUT THERE. 1744 01:09:52,214 --> 01:09:52,514 [LAUGHTER] 1745 01:09:52,514 --> 01:09:53,449 HURRY UP. 1746 01:09:53,449 --> 01:09:55,617 LET'S THANK OUR SPEAKER ONE LAST 1747 01:09:55,617 --> 01:09:56,218 TIME. 1748 01:09:56,218 --> 01:10:03,258 [APPLAUSE] 1749 01:10:03,258 --> 01:10:13,302