1 00:00:06,735 --> 00:00:09,204 NOKAY, WE ARE NOW 2 MINUTES 2 00:00:09,204 --> 00:00:10,472 OFFICIALLY INTO IT SO I THINK 3 00:00:10,472 --> 00:00:13,208 IT'S TIME TO START. 4 00:00:13,208 --> 00:00:17,746 IT'S MY PLEASURE TO INTRODUCE 5 00:00:17,746 --> 00:00:19,648 BETTY DIAMOND TODAY. 6 00:00:19,648 --> 00:00:21,616 BETTY RECEIVED AN M. D. FROM 7 00:00:21,616 --> 00:00:23,385 HARVARD MEDICAL SCHOOL AND SHE 8 00:00:23,385 --> 00:00:26,922 DID HER RESIDENCY IN INTERNAL 9 00:00:26,922 --> 00:00:28,757 MEDICINE AT COLUMBIA PRES BI 10 00:00:28,757 --> 00:00:30,826 TERRIAN MEDICAL CENTER AND A 11 00:00:30,826 --> 00:00:32,361 POST DOCTORAL FELLOWSHIP IN 12 00:00:32,361 --> 00:00:34,563 IMMUNOLOGY WITH MATTHEW SHARP AT 13 00:00:34,563 --> 00:00:36,398 THE ALBERT EINSTEIN. 14 00:00:36,398 --> 00:00:39,701 NOW BETTY IS THE HEAD OF THE 15 00:00:39,701 --> 00:00:40,635 AUTOIMMUNE DISEASE CENTER AND 16 00:00:40,635 --> 00:00:43,472 DIRECTOR OF THE INSTITUTE FOR 17 00:00:43,472 --> 00:00:45,874 MOLECULAR MEDICINE AT THE 18 00:00:45,874 --> 00:00:47,042 FEINSTEIN INSTITUTE FOR MEDICAL 19 00:00:47,042 --> 00:00:47,309 RESEARCH. 20 00:00:47,309 --> 00:00:48,944 AND HER RESEARCH FOR THOSE 21 00:00:48,944 --> 00:00:53,582 MANYIERS HAS FOCUSED ON THE 22 00:00:53,582 --> 00:00:56,451 INDUCTION AND PATHOGENICITY OF 23 00:00:56,451 --> 00:01:04,059 ANTIDNA ANTIBODIES IN SYSTEMIC 24 00:01:04,059 --> 00:01:06,561 LUPUS HEMAITOSEIS, SLE FOR 25 00:01:06,561 --> 00:01:07,028 SHORT. 26 00:01:07,028 --> 00:01:09,197 HER RESEARCH FOCUSED MAINLY ON 27 00:01:09,197 --> 00:01:11,633 THE ANTIBODIES BUT IS PART OF 28 00:01:11,633 --> 00:01:14,469 THE BROAD AND VERY PROLIFIC 29 00:01:14,469 --> 00:01:16,204 RESEARCH PORTFOLIO THAT SHE HAS 30 00:01:16,204 --> 00:01:20,242 AND HER CV LISTS ABOUT 300 31 00:01:20,242 --> 00:01:20,609 PUBLICATIONS. 32 00:01:20,609 --> 00:01:24,513 SHE SHOWED THAT SOMATIC MUTATION 33 00:01:24,513 --> 00:01:28,750 OF IMMUNOGLOBULIN GENES CAN 34 00:01:28,750 --> 00:01:30,886 GENERATE AUTOIMMUNO ANTIBODIES, 35 00:01:30,886 --> 00:01:32,421 AND PARTICULARLY C1 Q, SHE 36 00:01:32,421 --> 00:01:35,323 STUDIED THE IMPACT OF SEX 37 00:01:35,323 --> 00:01:37,726 HORMONES ON B-CELL SELECTION AND 38 00:01:37,726 --> 00:01:41,630 DEFINED FUNCTIONALITY OF SEVERAL 39 00:01:41,630 --> 00:01:42,531 SLE RISK ALLELES. 40 00:01:42,531 --> 00:01:46,668 HER LAB ALSO DEMONSTRATED THAT A 41 00:01:46,668 --> 00:01:50,238 SUBSET OF THE NTD AND ANTIBODIES 42 00:01:50,238 --> 00:01:51,106 CAN CAUSE NEUROPSYCHIATRIC LUPUS 43 00:01:51,106 --> 00:01:52,407 AND THIS IS GOING TO BE THE 44 00:01:52,407 --> 00:01:56,611 SUBJECT OF TODAY'S TALK. 45 00:01:56,611 --> 00:01:59,948 I DON'T NEED TO SAY THAT SHE 46 00:01:59,948 --> 00:02:00,882 RECEIVED A GAZILLION AWARDS AND 47 00:02:00,882 --> 00:02:02,451 I HAVE A LIST HERE IF I READ ALL 48 00:02:02,451 --> 00:02:04,052 OF THEM IT WILL TAKE PROBABLY 49 00:02:04,052 --> 00:02:05,120 HALF OF OUR TIME. 50 00:02:05,120 --> 00:02:09,825 SO I WILL JUST MENTION THAT HE 51 00:02:09,825 --> 00:02:11,092 HAS BEEN ELECKED TO THE 52 00:02:11,092 --> 00:02:12,594 INSTITUTE OF MEDICINE, IS A PAST 53 00:02:12,594 --> 00:02:14,930 PRESIDENT OF THE AMERICAN 54 00:02:14,930 --> 00:02:17,399 ASSOCIATION OF IMMUNOLOGISTS, 55 00:02:17,399 --> 00:02:19,334 AND JUST A COUPLE OF YEARS AGO, 56 00:02:19,334 --> 00:02:22,103 SHE WAS ELECTED TO THE NATIONAL 57 00:02:22,103 --> 00:02:22,704 ACADEMY OF SCIENCES. 58 00:02:22,704 --> 00:02:27,342 I THINK THAT NEXT IS THE LASKER, 59 00:02:27,342 --> 00:02:32,848 SO WITHOUT FURTHER ADO, BETTY I? 60 00:02:32,848 --> 00:02:35,784 [ APPLAUSE ] 61 00:02:35,784 --> 00:02:39,354 NSO IT'S A PLEASURE TO BE HERE 62 00:02:39,354 --> 00:02:39,554 TODAY. 63 00:02:39,554 --> 00:02:50,098 AND OBVIOUSLY I WILL TALK ABOUT 64 00:02:50,699 --> 00:02:51,800 NEUROPSYCHIATRIC LUPUS, WELL, 65 00:02:51,800 --> 00:02:52,934 IT'S OBVIOUSLY IMPORTANT FOR 66 00:02:52,934 --> 00:02:54,970 PATIENT WHO IS HAVE LUPUS BUT IN 67 00:02:54,970 --> 00:02:56,571 ADDITION THE PARADIGM THAT I'M 68 00:02:56,571 --> 00:02:59,107 GOING TO PRECEPT TO YOU I THINK 69 00:02:59,107 --> 00:03:03,044 IS PROBABLY SOMETHING THAT 70 00:03:03,044 --> 00:03:04,246 EXISTS IN MANY BRAIN DISEASES 71 00:03:04,246 --> 00:03:06,948 AND THEREFORE WHAT WE LEARN IN 72 00:03:06,948 --> 00:03:10,585 TODAYING LUPUS MAY HAVE MUCH 73 00:03:10,585 --> 00:03:11,286 BROADER APPLICATION. 74 00:03:11,286 --> 00:03:12,821 SO THESE ARE DISCLOSURES EMPLOY 75 00:03:12,821 --> 00:03:14,322 I JUST THINK IT'S VERY FUNNY 76 00:03:14,322 --> 00:03:18,360 THAT ALMOST ALL OF THESE ARE CAR 77 00:03:18,360 --> 00:03:22,397 T-CELL COMPANIES. 78 00:03:22,397 --> 00:03:25,000 YOU PROBABLY KNOW THAT CAR 79 00:03:25,000 --> 00:03:28,069 T-CELLS ARE NOW THE NEW PANACEA 80 00:03:28,069 --> 00:03:29,137 FOR LUPUS SO WE'LL SEE. 81 00:03:29,137 --> 00:03:31,673 I THINK EVERYBODY KNOWS THAT 82 00:03:31,673 --> 00:03:38,813 LUPUS IS AN AUTOIMMUNE DEC THAT 83 00:03:38,813 --> 00:03:39,347 PRIMARILY AFFECTS WOMEN. 84 00:03:39,347 --> 00:03:40,916 AND WHAT YOU NEED TO KNOW ABOUT 85 00:03:40,916 --> 00:03:42,817 LUPUS FOR THE PURPOSES OF WHAT I 86 00:03:42,817 --> 00:03:46,688 WILL TALK ABOUT TODAY IS THAT 87 00:03:46,688 --> 00:03:51,726 THERE--I'LL TRY THIS 1--THAT 88 00:03:51,726 --> 00:03:52,894 THERE ARE NEUROPSYCHIATRIC 89 00:03:52,894 --> 00:03:53,495 MANIFESTATIONS OF THE DISEASE 90 00:03:53,495 --> 00:03:55,664 AND THE OTHER THING YOU HAVE TO 91 00:03:55,664 --> 00:03:59,568 KNOW IS THAT ANTIDNA ANTIBODIES 92 00:03:59,568 --> 00:04:02,037 ARE REALLY DIAGNOSTIC OF THE 93 00:04:02,037 --> 00:04:03,405 STEEZ AND THEY CAUSE TISSUE 94 00:04:03,405 --> 00:04:06,841 INJURY IN SKIN AND IN KIDNEY AND 95 00:04:06,841 --> 00:04:09,377 ARE CLEARLY IMPORTANT IN 96 00:04:09,377 --> 00:04:10,178 PATHOGENESIS. 97 00:04:10,178 --> 00:04:14,249 AND INDEED, WITH THE EXCEPTION 98 00:04:14,249 --> 00:04:15,717 OF ACCELERATED ABNORMAL GLUCOSE 99 00:04:15,717 --> 00:04:16,351 TOLERANCELER O SCLEROSIS, MOST 100 00:04:16,351 --> 00:04:18,620 OF WHAT WE KNOW ABOUT TISSUE 101 00:04:18,620 --> 00:04:25,327 INJURY IN LUPUS BEGINS WITH 102 00:04:25,327 --> 00:04:26,027 AUTOANTIBODIES. 103 00:04:26,027 --> 00:04:27,629 SO THESE ARE 19 DIFFERENT 104 00:04:27,629 --> 00:04:30,865 SYNDROMES THAT BE ATTRIBUTED TO 105 00:04:30,865 --> 00:04:32,500 LUPUS, IN THE ABSENCE OF ANY 106 00:04:32,500 --> 00:04:36,438 OTHER REASON FOR HAVING THEM AND 107 00:04:36,438 --> 00:04:39,641 AS YOU CAN SEE SOME AFFECT THE 108 00:04:39,641 --> 00:04:41,009 PERIPHERAL NERVOUS SYSTEM AND 109 00:04:41,009 --> 00:04:43,645 THOSE THAT AFFECT THE CENTRAL 110 00:04:43,645 --> 00:04:45,347 NERVOUS SYSTEM CAN EITHER BE 111 00:04:45,347 --> 00:04:47,115 FOCUS MANIFESTATIONS OF THE 112 00:04:47,115 --> 00:04:50,719 DISEASE WHICH INCLUDE VASCULAR 113 00:04:50,719 --> 00:04:56,691 DISEASE IN THE BRAIN OR DIFFUSE 114 00:04:56,691 --> 00:04:58,393 MANIFESTATIONS OF DISEASE. 115 00:04:58,393 --> 00:05:00,495 THE PREVALENCE OF 116 00:05:00,495 --> 00:05:01,896 NEUROPSYCHIATRIC MANIFESTATIONS 117 00:05:01,896 --> 00:05:03,632 IN LUPUS IS REALLY BEEN VERY, 118 00:05:03,632 --> 00:05:07,936 VERY GREAT, AND IN COHORTS FROM 119 00:05:07,936 --> 00:05:13,208 MANY DIFFERENT PLACES, IT'S 120 00:05:13,208 --> 00:05:16,878 REALLY, YOU KNOW OVER 50% OF 121 00:05:16,878 --> 00:05:19,781 PATIENTS WILL HAVE SOME 122 00:05:19,781 --> 00:05:20,682 MANIFESTATION OF 123 00:05:20,682 --> 00:05:21,950 NEUROPSYCHIATRIC LUPUS, THE ONLY 124 00:05:21,950 --> 00:05:23,818 COHORT IN WHICH THAT'S NOT TRUE 125 00:05:23,818 --> 00:05:28,023 IS A COHORT IN WHICH COGNITIVE 126 00:05:28,023 --> 00:05:30,558 IMPAIRMENT HAD TO BE ACTUAL 127 00:05:30,558 --> 00:05:32,027 DEMENTIA AND WHILE COGNITIVE 128 00:05:32,027 --> 00:05:35,563 IMPAIRMENT AS YOU CAN SEE IS 129 00:05:35,563 --> 00:05:39,768 FREQUENT IN PATIENTS WITH LUPUS, 130 00:05:39,768 --> 00:05:45,640 DEMENTIA IS REALLY QUITE, QUITE 131 00:05:45,640 --> 00:05:45,840 RARE. 132 00:05:45,840 --> 00:05:48,510 COGNITIVE DYSFUNCTION AND MOOD 133 00:05:48,510 --> 00:05:51,713 DISORDERS ARE BOTH NONFOCAL CNS 134 00:05:51,713 --> 00:05:53,648 MANIFESTATIONS OF DEC, ARE 2 OF 135 00:05:53,648 --> 00:05:56,084 THE MOST COMMON MANIFESTATIONS 136 00:05:56,084 --> 00:06:01,156 OF DEC AND IN FACT, PATIENTS 137 00:06:01,156 --> 00:06:05,160 WITH LUPUS WHEN ASKED TO 138 00:06:05,160 --> 00:06:06,661 IDENTIFY THOSE MANIFESTATIONS OF 139 00:06:06,661 --> 00:06:09,064 DEC THAT MOST INTERFERE WITH 140 00:06:09,064 --> 00:06:14,936 QUALITY OF LIFE, HAVE SAID, PAIN 141 00:06:14,936 --> 00:06:15,503 FATIGUE AND COGNITIVE 142 00:06:15,503 --> 00:06:19,741 IMPAIRMENT, SO IT'S A COMMON 143 00:06:19,741 --> 00:06:21,976 MANIFESTATION AND 1 THAT IS 144 00:06:21,976 --> 00:06:26,481 IMPORTANT TO THE PATIENTS 145 00:06:26,481 --> 00:06:26,781 THEMSELVES. 146 00:06:26,781 --> 00:06:31,886 SO HOW DID WE GET INVOLVED IN 147 00:06:31,886 --> 00:06:32,854 STUDYING NEUROPSYCHIATRIC LUPUS 148 00:06:32,854 --> 00:06:36,357 BECAUSE WE NEVER REALLY SET OUT 149 00:06:36,357 --> 00:06:37,392 TO STUDY NEUROPSYCHIATRIC LUPUS. 150 00:06:37,392 --> 00:06:40,428 WHAT WE WERE LOOKING AT WAS THE 151 00:06:40,428 --> 00:06:42,097 STRUCTURAL CORRELATES OF DMA 152 00:06:42,097 --> 00:06:46,267 BINDING, SO WE WILL BUSY 153 00:06:46,267 --> 00:06:47,902 PERFORMING SIGHT DIRECTED MUTE O 154 00:06:47,902 --> 00:06:49,571 GENESIS OF AN ANTIDNA ANTIBODY 155 00:06:49,571 --> 00:06:56,010 THAT WE HAD CLONED FROM A MOUSE 156 00:06:56,010 --> 00:06:59,080 R4A AND LOOKING AT THE BINDING 157 00:06:59,080 --> 00:07:01,182 OF THE ANTIBODY OF THE MUTANTS 158 00:07:01,182 --> 00:07:04,352 TO DNA AND WHAT WE ACTUALLY 159 00:07:04,352 --> 00:07:09,424 FOUND WAS A MUTANT THAT HAD A 10 160 00:07:09,424 --> 00:07:11,593 FOLD HIGHER APPARENT AFFINITY 161 00:07:11,593 --> 00:07:15,263 FOR DNA BUT DID NOT DEPOSIT INTO 162 00:07:15,263 --> 00:07:16,564 KIDNEYS LIKE THE PARENTAL 163 00:07:16,564 --> 00:07:19,200 ANTIBODY DID AND SO WE SAID WELL 164 00:07:19,200 --> 00:07:22,237 THAT ANTIBODY MUST HAVE A 165 00:07:22,237 --> 00:07:23,071 DIFFERENT FINE SPECIFICITY, AND 166 00:07:23,071 --> 00:07:29,210 SO WE WENT TO A PEPTIDE LIBRARY, 167 00:07:29,210 --> 00:07:31,579 A PHAGE DISPLAY LIBRARY AND 168 00:07:31,579 --> 00:07:40,421 LOOKED FOR WHAT THE PARENT R4A 169 00:07:40,421 --> 00:07:42,023 ANTIBODY WOULD BIND AND MUTANT 170 00:07:42,023 --> 00:07:43,892 WOULD BOUND AND INDEED THEY 171 00:07:43,892 --> 00:07:45,493 BOUND DIFFERENT PEPTIDES BUT 172 00:07:45,493 --> 00:07:47,796 WHAT WAS MOST AMAZING IS THAT 173 00:07:47,796 --> 00:07:50,365 THE PARENT ANTIBODY BOUND TO A 174 00:07:50,365 --> 00:07:54,302 CONSENSUS SEQUENCE, PRESENT IN 175 00:07:54,302 --> 00:08:00,441 THE GLUE N2A AND GLUN2 B 176 00:08:00,441 --> 00:08:02,310 SUBUNITS OF THE NMDA VECTOR 177 00:08:02,310 --> 00:08:03,945 EMPLOY SO THAT WAS EXSEATING TO 178 00:08:03,945 --> 00:08:05,547 US AND SUGGESTED WE MIGHT HAVE 179 00:08:05,547 --> 00:08:07,882 THE FIRST ACTUAL MECHANISTIC 180 00:08:07,882 --> 00:08:10,318 CLUE ABOUT NONFOCAL 181 00:08:10,318 --> 00:08:12,020 MANIFESTATIONS OF 182 00:08:12,020 --> 00:08:13,521 NEUROPSYCHIATRIC LUPUS, BUT 183 00:08:13,521 --> 00:08:15,056 BEFORE WE WENT FURTHER, WE 184 00:08:15,056 --> 00:08:18,026 WANTED TO MAKE SURE THAT 185 00:08:18,026 --> 00:08:20,728 ANTIBODIES WITH THIS SPECIFICITY 186 00:08:20,728 --> 00:08:23,398 ACTUALLY EXISTED IN INDIVIDUALS 187 00:08:23,398 --> 00:08:25,667 WHO HAD LUPUS, BECAUSE IF THIS 188 00:08:25,667 --> 00:08:28,002 WAS JUST 1 MOUSE MONOCLONAL THAT 189 00:08:28,002 --> 00:08:31,005 HAD THIS CROSS REACTIVITY, IT 190 00:08:31,005 --> 00:08:32,373 WASN'T GOING BE OF INTEREST TO 191 00:08:32,373 --> 00:08:35,577 US, BUT IF IT WAS A SPECIFICITY 192 00:08:35,577 --> 00:08:37,011 THAT WAS PRESENT IN PATIENTS, 193 00:08:37,011 --> 00:08:40,715 THEN ALL OF A SUDDEN IT BECAME 194 00:08:40,715 --> 00:08:41,149 VERY INTERESTING. 195 00:08:41,149 --> 00:08:43,218 AND WHAT YOU CAN SEE HERE IS 196 00:08:43,218 --> 00:08:46,955 THAT PATIENTS WITH LUPUS HAVE AN 197 00:08:46,955 --> 00:08:47,922 ELEVATED TITERS OF THESE 198 00:08:47,922 --> 00:08:50,491 ANTIBODY ANDS THOSE WITH 199 00:08:50,491 --> 00:08:52,193 NEUROPSYCHIATRIC MANIFESTATIONS, 200 00:08:52,193 --> 00:08:53,795 MORE SO, AND IT'S PRESENT NOT 201 00:08:53,795 --> 00:08:55,897 JUST IN THE SERUM OF PATIENTS 202 00:08:55,897 --> 00:08:58,533 WITH LUPUS, BUT IT'S ALSO 203 00:08:58,533 --> 00:09:00,735 PRESENT IN THE CEREBRAL SPINAL 204 00:09:00,735 --> 00:09:03,304 FLUID, SO THIS IS CEREBRAL 205 00:09:03,304 --> 00:09:08,176 SPINAL FLUID IN RED, PATIENTS 206 00:09:08,176 --> 00:09:10,578 WITH NONFOCAL CNS 207 00:09:10,578 --> 00:09:13,114 MANIFESTATIONS, PNS IS 208 00:09:13,114 --> 00:09:14,249 PERIPHERAL MANIFESTATIONS OF 209 00:09:14,249 --> 00:09:17,418 LUPUS AND S IS A GROUP OF 210 00:09:17,418 --> 00:09:19,020 PATIENT WHO IS WERE UNDERGOING 211 00:09:19,020 --> 00:09:24,893 SURGERY FOR OTHER REASONS AND 212 00:09:24,893 --> 00:09:26,027 PATIENTS WITH LUPUS UNDERGOING 213 00:09:26,027 --> 00:09:28,029 SURGERY FOR OTHER REASONS AND 214 00:09:28,029 --> 00:09:29,464 CONSENTED TO HAVE AN LP DONE AND 215 00:09:29,464 --> 00:09:32,433 YOU CAN SEE THAT IT'S THEREFORE 216 00:09:32,433 --> 00:09:34,636 BOTH IN SERUM AND CSF OR ABOUT 217 00:09:34,636 --> 00:09:36,971 30% OF THE PASHTS. 218 00:09:36,971 --> 00:09:39,073 SO I'M NOT A NEUROSCIENTIST, SO 219 00:09:39,073 --> 00:09:40,942 THIS SLIDE INCLUDES EVERYTHING I 220 00:09:40,942 --> 00:09:44,245 KNOW ABOUT THE NMDA RECEPTOR 221 00:09:44,245 --> 00:09:50,418 WHICH IS THAT IT'S MADE UP OF 2 222 00:09:50,418 --> 00:09:59,360 GL U AND 1 SUBUNITS AND GLUN2 223 00:09:59,360 --> 00:10:00,361 SUBUNITS AND AGONIST IS FLUTE 224 00:10:00,361 --> 00:10:02,664 MATE AND THIS CAUSES CALCIUM 225 00:10:02,664 --> 00:10:04,732 INFLUX INTO THE CELL, IT'S 226 00:10:04,732 --> 00:10:06,834 CRITICAL IN LEARNING AND MEMORY 227 00:10:06,834 --> 00:10:08,569 AND TOO MUCH CALCIUM INFLUX 228 00:10:08,569 --> 00:10:15,243 RESULTS IN WHAT IS CALLED FLUTA 229 00:10:15,243 --> 00:10:15,843 MITTERGIC OR CYTOTOXIC CELL 230 00:10:15,843 --> 00:10:17,578 DEATH EMPLOY I SHOULD ALSO SAY 231 00:10:17,578 --> 00:10:22,984 RIGHT AWAY THAT THIS IS NOT THE 232 00:10:22,984 --> 00:10:25,086 ANTIBODY TO THE NMDA RECEPTOR 233 00:10:25,086 --> 00:10:31,726 THAT HAS BEEN IDENTIFIED IN 234 00:10:31,726 --> 00:10:32,527 PATIENTS WITH LIMBIC 235 00:10:32,527 --> 00:10:34,062 ENCEPHALITIS OR BREAN ON FIRE, 236 00:10:34,062 --> 00:10:37,966 THOSE ANTIBODIES ARE DIRECTED TO 237 00:10:37,966 --> 00:10:38,766 THE GLUN1 SUBUNIT. 238 00:10:38,766 --> 00:10:41,302 THEY CAUSE AN INTERNALIZATION OF 239 00:10:41,302 --> 00:10:44,238 THE RECEPTOR AS SOON AS 240 00:10:44,238 --> 00:10:45,974 ANTIBODIES DISAPPEAR, THE 241 00:10:45,974 --> 00:10:47,642 RECEPTOR IS EXPRESSED ON THE 242 00:10:47,642 --> 00:10:52,380 SURFACE AGAIN AND SYMPTOMS LAST 243 00:10:52,380 --> 00:10:56,651 ONLY AS LONG AS THE ANTIBODY IS 244 00:10:56,651 --> 00:10:58,052 PRESENT AND THEN MOST 245 00:10:58,052 --> 00:11:00,355 INDIVIDUALS RETURN TO NORMAL 246 00:11:00,355 --> 00:11:05,293 BRAIN FUNCHES AND YOU WILL SEE 247 00:11:05,293 --> 00:11:08,663 THAT IS NOT TRUE IN LUPUS. 248 00:11:08,663 --> 00:11:11,265 SO WE WANTED TO DEVELOP A MODEL 249 00:11:11,265 --> 00:11:13,901 WHERE WE COULD STUDY THESE 250 00:11:13,901 --> 00:11:16,804 ANTIBODIES AND I SHOULD SAY THAT 251 00:11:16,804 --> 00:11:19,407 THESE ANTIBODIES, ANTIBODIES 252 00:11:19,407 --> 00:11:22,110 WITH THIS CROSS REACTIVITY 253 00:11:22,110 --> 00:11:25,079 COMPRISE 60% OF THE ANTIDNA 254 00:11:25,079 --> 00:11:27,515 ANTIBODIES, SEEN IN THE MRL, 255 00:11:27,515 --> 00:11:29,951 LPR, MOUSE, WHICH IS A MUCH 256 00:11:29,951 --> 00:11:33,921 STUDIED MODEL FOR LUPUS, AND 257 00:11:33,921 --> 00:11:37,392 ABOUT 60% OF THE ANTIDNA 258 00:11:37,392 --> 00:11:40,895 ANTIBODIES THAT ARE SEEN IN NZBW 259 00:11:40,895 --> 00:11:42,296 MICE, THE ORGT MOST STUDIED 260 00:11:42,296 --> 00:11:46,300 MOUSE MODEL OF LUPUS, BUT THOSE 261 00:11:46,300 --> 00:11:48,503 MODELS HAVE OTHER AUTOANTIBODIES 262 00:11:48,503 --> 00:11:53,007 AND LOTS OF CYTOKINE 263 00:11:53,007 --> 00:11:56,778 PROTURBATIONS, PLUS IF THEY WERE 264 00:11:56,778 --> 00:11:59,714 BORN TO DAMS THAT ALREADY HAD 265 00:11:59,714 --> 00:12:01,082 IMMUNOLOGIC ABNORMALITIES, THEY 266 00:12:01,082 --> 00:12:03,584 COULD HAVE ABNORMAL BRAIN 267 00:12:03,584 --> 00:12:06,554 FUNCTION FROM THE VERY 268 00:12:06,554 --> 00:12:08,489 BEGINNING, BRAIN DEVELOPMENT, SO 269 00:12:08,489 --> 00:12:11,325 WE WANTED TO TAKE 270 00:12:11,325 --> 00:12:12,260 NONSPONTANEOUSLY AUTOIMMUNE MICE 271 00:12:12,260 --> 00:12:14,862 AND MAKE THEM MAKE THIS ANTIBODY 272 00:12:14,862 --> 00:12:21,202 AND THEN BE ABLE TO ASK WHAT IS 273 00:12:21,202 --> 00:12:23,171 THIS ANTIBODY DO. 274 00:12:23,171 --> 00:12:27,175 SO WE IMMUNIZED NORMAL MICE WITH 275 00:12:27,175 --> 00:12:28,810 THE WEPTIDE, MULTIMERRIZED DOWN 276 00:12:28,810 --> 00:12:31,345 A POLYSIGNIFY SEEN BACKBONE OR 277 00:12:31,345 --> 00:12:33,214 IMMUNIZED WITH THE POLYLYSINE 278 00:12:33,214 --> 00:12:34,615 BACKBONE ALONE AND WHAT YOU CAN 279 00:12:34,615 --> 00:12:38,719 SEE IS THAT MICE IMMUNIZED WITH 280 00:12:38,719 --> 00:12:40,855 THE PEPTIDE MAKE ANTIBODIES, 281 00:12:40,855 --> 00:12:42,757 ANTIPEPTIDE O TIDE ANTIBODIES 282 00:12:42,757 --> 00:12:45,760 AND ANTIDNA ANTIBODIES AND IN 283 00:12:45,760 --> 00:12:49,263 THE ANTIDNA ANTIBODIES, ARE AT 284 00:12:49,263 --> 00:12:52,834 THE SAME TITER AS THOSE YOU SEE 285 00:12:52,834 --> 00:12:55,036 IN NCBW MICE AND THEY DEPOSIT IN 286 00:12:55,036 --> 00:13:00,942 KIDNEY SO THEY WERE A GOOD LUPUS 287 00:13:00,942 --> 00:13:01,375 PATHOGENIC ANTIBODY. 288 00:13:01,375 --> 00:13:05,113 AND WE CALL THESE ANTIBODIES DNR 289 00:13:05,113 --> 00:13:06,681 ABs AND YOU WILL SEE THAT 290 00:13:06,681 --> 00:13:08,082 THROUGH THE REST OF THE TALK 291 00:13:08,082 --> 00:13:10,084 EMPLOY BUT WHEN WE WENT TO LOOK 292 00:13:10,084 --> 00:13:11,886 IN THE BRAINS OF THESE MICE, 293 00:13:11,886 --> 00:13:13,254 THEIR BRAINS WERE PERFECTLY 294 00:13:13,254 --> 00:13:15,690 NORMAL AND SO, WE THOUGHT, WELL, 295 00:13:15,690 --> 00:13:17,091 THAT'S BECAUSE THERE'S A BLOOD 296 00:13:17,091 --> 00:13:21,262 BRAIN BARRIER THAT WORKS NOT 297 00:13:21,262 --> 00:13:24,832 JUST TO PROTECT THE BRAIN FROM 298 00:13:24,832 --> 00:13:28,236 IMMUNO GLOBUE LINE BUT ACTUALLY 299 00:13:28,236 --> 00:13:30,404 FCRN HAS AN ABNORMALITIES 300 00:13:30,404 --> 00:13:31,172 LUMINAL LOCALIZATION IN 301 00:13:31,172 --> 00:13:34,475 ENDOTHELIAL CELLS IN THE BRAIN 302 00:13:34,475 --> 00:13:35,109 AND TRANSPORTS IMMUNOGLOBULIN 303 00:13:35,109 --> 00:13:37,044 OUT OF THE BRAIN BUT THERE ARE 304 00:13:37,044 --> 00:13:39,680 MANY INSULTS TO THE INTEGRITY OF 305 00:13:39,680 --> 00:13:43,351 THE BLOOD BRAIN BARRIER AND WE 306 00:13:43,351 --> 00:13:45,753 DECIDED TO USE LPS TO DISRUPT 307 00:13:45,753 --> 00:13:50,658 THE BLOOD BRAIN BARRIER TO MODEL 308 00:13:50,658 --> 00:13:52,493 INFECTION WHICH IS COMMON IN 309 00:13:52,493 --> 00:13:55,496 PEASHTS WITH LUPUS, BY VIRTUE OF 310 00:13:55,496 --> 00:13:59,033 THE IMMUNOSUPPRESSION THERE ON, 311 00:13:59,033 --> 00:14:03,037 AND IT ALSO LPS ALSO GIVES RISE 312 00:14:03,037 --> 00:14:05,439 TO INCREASED TITERS OF MANY OF 313 00:14:05,439 --> 00:14:09,310 THE SAME CYTOKINES, THE 314 00:14:09,310 --> 00:14:11,679 CHARACTERIZE LUPUS FLAIRS. 315 00:14:11,679 --> 00:14:13,981 SO WE IMMUNIZE MICE WITH THE 316 00:14:13,981 --> 00:14:16,384 PEPTIDE OR JUST WITH THE 317 00:14:16,384 --> 00:14:17,785 POLYLYSINE BACKBONE AND THEN WE 318 00:14:17,785 --> 00:14:20,254 GIVE LPS AND THE MICE THAT IMET 319 00:14:20,254 --> 00:14:24,225 THE PEPTIDE IN LPS, ARE DNR AB 320 00:14:24,225 --> 00:14:26,994 POSITIVE MICE AND THE MICE THAT 321 00:14:26,994 --> 00:14:36,237 GET THE POLYLYSINE BACKBONE IN 322 00:14:36,237 --> 00:14:37,371 LPS, ARE DNABRNEGGATIVE MICE. 323 00:14:37,371 --> 00:14:39,941 AND WHAT WE FOUND WERE 2 STAGES 324 00:14:39,941 --> 00:14:42,009 OF PATHOLOGY, 1 IS ACUTE 325 00:14:42,009 --> 00:14:45,179 NEURONAL DEATH, AND YOU SEE THAT 326 00:14:45,179 --> 00:14:48,616 HERE WHERE YOU CAN COUNT THE 327 00:14:48,616 --> 00:14:50,585 PARAMETRAL NEURONS IN THE 328 00:14:50,585 --> 00:14:52,153 HIPPOCAMPUS BECAUSE LPS OPENS 329 00:14:52,153 --> 00:14:54,055 THE BLOOD BRAIN BARRIER 330 00:14:54,055 --> 00:14:56,991 SELECTIVELY IN THE HIPPOCAMPUS, 331 00:14:56,991 --> 00:14:59,860 AND WHAT WE FOUND WAS EXCITE O 332 00:14:59,860 --> 00:15:03,231 TOXIC DEATH BUT THERE'S NO 333 00:15:03,231 --> 00:15:05,900 INFILTRATION OF BLOOD BORN 334 00:15:05,900 --> 00:15:13,541 INFLAMMATORY CELLS, IT'S A BLAND 335 00:15:13,541 --> 00:15:14,208 PATHOLOGY. 336 00:15:14,208 --> 00:15:17,478 AND THEN, NOT AT 2 WEEKS AFTER 337 00:15:17,478 --> 00:15:21,549 GIVING LPS, BUT STARTING AROUND 338 00:15:21,549 --> 00:15:24,685 4-6 WEEKS, AND CLEARLY PRESENTED 339 00:15:24,685 --> 00:15:31,392 8 WEEKS AFTER LPS, WE SEE A LOSS 340 00:15:31,392 --> 00:15:32,593 OF DENDRITIC HARBORRIZATION IN 341 00:15:32,593 --> 00:15:37,431 THE REMAINING NEURONS AND WHAT 342 00:15:37,431 --> 00:15:39,367 YOU SEE ON THE--OVER HERE IS 343 00:15:39,367 --> 00:15:43,104 THAT BY 2 WEEKS AFTER LPS, 344 00:15:43,104 --> 00:15:46,741 THERE'S NO MORE ANTIBODY IN THE 345 00:15:46,741 --> 00:15:46,974 BRAIN. 346 00:15:46,974 --> 00:15:49,944 SO THIS IS OCCURRING, THIS 347 00:15:49,944 --> 00:15:55,616 DAMAGE IS ACUING CUING--ACCRUINN 348 00:15:55,616 --> 00:15:57,218 THE ABSENCE OF ANTIBODIES STILL 349 00:15:57,218 --> 00:15:58,586 BEING IN THE BRAIN. 350 00:15:58,586 --> 00:16:02,757 AND WHAT WE ALSO FOUND WAS 351 00:16:02,757 --> 00:16:05,526 MICROGLIAL ACTIVATION AND A 352 00:16:05,526 --> 00:16:08,529 QUIESCENT MICROGLIA IS A LACY 353 00:16:08,529 --> 00:16:11,098 LOVELY STRUCTURE AND AN 354 00:16:11,098 --> 00:16:13,167 ACTIVATED MICROGLIA IS A MUCH 355 00:16:13,167 --> 00:16:18,205 MORE ROBUST TRUCTURE WITH 356 00:16:18,205 --> 00:16:21,108 EXPRESSION OF CD69 AND BETH 357 00:16:21,108 --> 00:16:24,645 STEPHENS LAB HAS WORKED OUT A 358 00:16:24,645 --> 00:16:25,680 CORING SYSTEM FOR MICROTBLEEL 359 00:16:25,680 --> 00:16:28,249 ACTIVATION AND YOU START SEEING 360 00:16:28,249 --> 00:16:29,717 THEY BECOME ACTIVATED 2 WEEKS 361 00:16:29,717 --> 00:16:32,753 BUT BY 8 WEEKS THEY ARE VERY 362 00:16:32,753 --> 00:16:35,589 ACTIVATED EMPLOY AND THIS IS A 363 00:16:35,589 --> 00:16:41,662 BET SCAN USING PBR 28 WHICH WILL 364 00:16:41,662 --> 00:16:49,437 BIND TO ACTIVATED GLIAL CELLS 365 00:16:49,437 --> 00:16:50,638 BOTH MICROGLIA AND DENDRITIC 366 00:16:50,638 --> 00:16:52,573 CELLROCYTES, BUT WHAT YOU CAN 367 00:16:52,573 --> 00:16:54,442 SEE IS GLIAL CELLS IN THE 368 00:16:54,442 --> 00:16:58,412 HIPPOCAMPUS OF THE MICE THAT 369 00:16:58,412 --> 00:17:00,848 HAVE THE LUPUS AND BRAIN, AND WE 370 00:17:00,848 --> 00:17:02,249 FOCUSED OUR ATTENTION TO SPATIAL 371 00:17:02,249 --> 00:17:03,617 MEMORY IN THESE MICE AND WHAT 372 00:17:03,617 --> 00:17:05,086 YOU SEE HERE IS AN OBLIGATIONS 373 00:17:05,086 --> 00:17:07,221 YECT MEMORY TEST WHERE YOU PUT A 374 00:17:07,221 --> 00:17:13,327 MOUSE IN A CHAMBER WITH 2 375 00:17:13,327 --> 00:17:14,395 OBJECTS, YOU REPLACE THE MOUTH 376 00:17:14,395 --> 00:17:15,696 WITH THE DIFFERENT OBJECT, PUT 377 00:17:15,696 --> 00:17:17,765 IT BACK IN A NORMAL MOUSE WILL 378 00:17:17,765 --> 00:17:19,734 SPEND MOST TIME STUDYING THE 379 00:17:19,734 --> 00:17:21,202 NOVEL OBLIGATIONS YECT AND 380 00:17:21,202 --> 00:17:23,170 INDEED, THESE MICE WITH THE 381 00:17:23,170 --> 00:17:28,209 LUPUS LIKE ANTIBODY PENETRATING 382 00:17:28,209 --> 00:17:30,344 THE BRAIN HAVE NORMAL OBJECT 383 00:17:30,344 --> 00:17:32,513 MEMORY, TEST IS YOU PUT THE 384 00:17:32,513 --> 00:17:34,248 MOUSE IN THE CHAMBER WITH 2 385 00:17:34,248 --> 00:17:41,856 OBLIGATIONS JEKS, TAKE THE MOUSE 386 00:17:41,856 --> 00:17:44,024 OUT AND A NORMAL MOUSE WILL 387 00:17:44,024 --> 00:17:45,693 SPEND NORMAL TIME IN THE CHAMBER 388 00:17:45,693 --> 00:17:47,428 EXPLORING THE OBJECT IN THE NEW 389 00:17:47,428 --> 00:17:48,496 LOCATION, BUT WHAT YOU SEE HERE 390 00:17:48,496 --> 00:17:53,834 IS THAT THE LUPUS MICE DID NOT 391 00:17:53,834 --> 00:17:55,870 AND THIS FOCUS ON SPATIAL MEMORY 392 00:17:55,870 --> 00:17:57,238 WAS SUGGESTED TO US BY A PATIENT 393 00:17:57,238 --> 00:18:01,342 WHO CAME TO CLINIC 1 DAY AND 394 00:18:01,342 --> 00:18:03,511 SAID IT WAS THE WE'RED THING, 395 00:18:03,511 --> 00:18:05,713 BUT WHEN SHE GOT OFF THE BUS TO 396 00:18:05,713 --> 00:18:16,223 GO HOME, SHE COULDN'T REMEMBER 397 00:18:20,227 --> 00:18:21,429 BUT THIS EPITOMIZED THAT 398 00:18:21,429 --> 00:18:22,530 PROBLEM. 399 00:18:22,530 --> 00:18:24,498 SO HIPPOCAMPAL CELLS ARE THE 400 00:18:24,498 --> 00:18:26,000 CELLS THAT ARE RESPONSIBLE FOR 401 00:18:26,000 --> 00:18:28,202 THE SPATIAL MAPS WE MAKE, 402 00:18:28,202 --> 00:18:30,838 THEY'RE CALLED PLACE CELLS AND 403 00:18:30,838 --> 00:18:36,377 THEY FIRE IN A PARTICULAR 404 00:18:36,377 --> 00:18:37,077 LOCATION. 405 00:18:37,077 --> 00:18:38,379 EACH NEURON WILL FIRE IN A 406 00:18:38,379 --> 00:18:40,014 PARTICULAR LOCATION AND THE SAME 407 00:18:40,014 --> 00:18:40,815 LOCATION EVERY TIME. 408 00:18:40,815 --> 00:18:42,416 AND THE AREA OVER WHICH THAT 409 00:18:42,416 --> 00:18:45,219 NEURON WILL FIRE IS CALLED THE 410 00:18:45,219 --> 00:18:45,653 PLACE FIELD. 411 00:18:45,653 --> 00:18:52,059 AND YOU CAN SEE THAT BEFORE LPS 412 00:18:52,059 --> 00:18:55,329 AND AFTER LPS, THE PLACE FIELD 413 00:18:55,329 --> 00:18:57,298 SIZE IS THE SAME IN THE 414 00:18:57,298 --> 00:18:59,467 PENETRATION OF THOSE WHAT HAD 415 00:18:59,467 --> 00:19:00,334 NONLUPUS SERIES POINTSOLOGY IN 416 00:19:00,334 --> 00:19:02,703 THEIR BRAIN BUT IN THE MICE THAT 417 00:19:02,703 --> 00:19:05,473 HAD THE LUPUS LIKE ANTIBODY BEN 418 00:19:05,473 --> 00:19:07,641 TRAIT THE BRAIN, THE--EACH 419 00:19:07,641 --> 00:19:10,978 NEURON HAS A BIGGER PLACE FIELD. 420 00:19:10,978 --> 00:19:13,080 SO FIRES OVER A WIDER AREA AND 421 00:19:13,080 --> 00:19:15,149 TO ME IT'S THAT PLACE CELL 422 00:19:15,149 --> 00:19:18,419 FIRING ON 2 BLOCKS INSTEAD OF 423 00:19:18,419 --> 00:19:23,991 JUST ON 1 BLOCK. 424 00:19:23,991 --> 00:19:26,560 AND SO WHAT WE LEARNED IS THAT 425 00:19:26,560 --> 00:19:30,297 MICROGLIA ARE REQUIRED FOR THE 426 00:19:30,297 --> 00:19:32,299 LOSS OF DENDRITICAR BORRIZATION 427 00:19:32,299 --> 00:19:34,568 IN THE RESIDUAL NEURONS AND C1 Q 428 00:19:34,568 --> 00:19:38,572 IS REQUIRED FOR THE LOSS OF 429 00:19:38,572 --> 00:19:40,007 ARBORIZATION ON THE RESIDUAL 430 00:19:40,007 --> 00:19:43,410 YOU'REONS IN THE DNA AB POSITIVE 431 00:19:43,410 --> 00:19:44,945 MICE AND THIS SUGGIESTED TO US 432 00:19:44,945 --> 00:19:48,916 THAT WHAT WE WERE SEEING WAS 433 00:19:48,916 --> 00:19:49,617 ACTUAL PRUNING. 434 00:19:49,617 --> 00:19:54,688 SO THAT THE SYNAPSES WERE BEING 435 00:19:54,688 --> 00:19:57,358 EATEN BY THE ACTIVATED MICROGLIA 436 00:19:57,358 --> 00:20:00,160 AND WHEN THE SYNAPSES ARE EATEN 437 00:20:00,160 --> 00:20:02,062 OFF A DENDRITE, THERE'S 438 00:20:02,062 --> 00:20:07,735 RETRACTION OF THAT DENDRITE AND 439 00:20:07,735 --> 00:20:09,136 HENCE DECREASED DENDRITIC 440 00:20:09,136 --> 00:20:09,470 ARBORIZATION. 441 00:20:09,470 --> 00:20:13,240 AND INDEED, YOU CAN SEE C1 Q 442 00:20:13,240 --> 00:20:17,077 SITTING ON THE SYNAPSES, SO WE 443 00:20:17,077 --> 00:20:21,215 ASKED HOW DOES C1 Q GET TO THE 444 00:20:21,215 --> 00:20:21,515 SYNAPSES. 445 00:20:21,515 --> 00:20:23,951 WHAT TARGETS IT THERE AND 1 OF 446 00:20:23,951 --> 00:20:25,886 THE OBSERVATIONS THAT WE MADE 447 00:20:25,886 --> 00:20:29,757 WAS THAT IN THE MICE THAT HAD 448 00:20:29,757 --> 00:20:33,260 THE LUPUS, ANTIBODY, PENETRATE 449 00:20:33,260 --> 00:20:36,730 THEIR BRAIN, THERE WAS EVIDENCE 450 00:20:36,730 --> 00:20:38,599 FOR SECRETION OF HMGB1. 451 00:20:38,599 --> 00:20:42,736 SO IT WAS KNOWN FROM OTHERS THAT 452 00:20:42,736 --> 00:20:46,407 AS YOU ACTIVATE THE NMDA 453 00:20:46,407 --> 00:20:48,475 RECEPTOR, IN A DOSE DEPENDENT 454 00:20:48,475 --> 00:20:52,446 FASHION, WELL IS SECRETION OF 455 00:20:52,446 --> 00:20:55,516 HMGB1 WHICH IS NORMALLY A 456 00:20:55,516 --> 00:20:59,520 NUCLEAR PROTEIN INVOLVED IN 457 00:20:59,520 --> 00:21:02,156 PROAMA TIN STRUCTURE BUT IS 458 00:21:02,156 --> 00:21:04,925 ACTIVELY ACETALATED AND SECRETED 459 00:21:04,925 --> 00:21:10,831 BY STRESS CELLS, AND ACTIVATED 460 00:21:10,831 --> 00:21:13,634 CELLS AND AS I SAID HAS BEEN 461 00:21:13,634 --> 00:21:17,137 KNOWN TO BE SECRETING NEURONS TO 462 00:21:17,137 --> 00:21:19,073 THE NMDA RECEPTOR. 463 00:21:19,073 --> 00:21:25,045 SO OUR HYPOTHESIS WAS THAT HMGB1 464 00:21:25,045 --> 00:21:28,349 WHICH HAD ALSO PREVIOUSLY TO OUR 465 00:21:28,349 --> 00:21:31,685 WORK BEEN SHOWN TO BIND TO 466 00:21:31,685 --> 00:21:35,322 GASHING WELL, UN2 SUBUNITS OF 467 00:21:35,322 --> 00:21:36,323 THE NMDA RECEPTOR ACTUALLY 468 00:21:36,323 --> 00:21:39,126 SERVED AS A BRIMMING TO BRING C1 469 00:21:39,126 --> 00:21:43,330 Q TO THIS SYNAPSE BECAUSE IN OUR 470 00:21:43,330 --> 00:21:45,099 STUDIES OF C1 Q, SOME OF YOU MAY 471 00:21:45,099 --> 00:21:47,768 KNOW THAT C1 Q IS THE BIGGEST 472 00:21:47,768 --> 00:21:51,171 RISK FACTOR FOR LUPUS AND OVER 473 00:21:51,171 --> 00:21:54,742 90% OF INDIVIDUALS WHO HAVE C1 Q 474 00:21:54,742 --> 00:21:58,278 DEFICIENCY HAVE LUPUS SO WE 475 00:21:58,278 --> 00:22:02,249 WERE--ARE INTERESTED IN HOW C1 Q 476 00:22:02,249 --> 00:22:03,651 MAINTAINS'MUNE HOMEOSTASIS. 477 00:22:03,651 --> 00:22:09,323 BUT WE HAD SHOWN THAT C1 Q BINDS 478 00:22:09,323 --> 00:22:09,590 HMGB 1. 479 00:22:09,590 --> 00:22:13,260 SO WHAT YOU SLEEP APNEA SLEEP D 480 00:22:13,260 --> 00:22:16,797 OBESITY--WHAT YOU SEE HERE IS IN 481 00:22:16,797 --> 00:22:19,533 FACT THAT HMGB1 WILL BIND TO 482 00:22:19,533 --> 00:22:22,736 SYNAPSES AND THAT C1 Q WILL BIND 483 00:22:22,736 --> 00:22:27,107 TO THE HMGB 1 ON SYNAPSES. 484 00:22:27,107 --> 00:22:28,809 SO, INDEED, THERE IS A BRIDGE 485 00:22:28,809 --> 00:22:33,714 FORMED BY THE SECRETED HMGB1 486 00:22:33,714 --> 00:22:37,251 THAT BRINGS C1 Q TO THE SYNAPSE 487 00:22:37,251 --> 00:22:41,922 TO ALLOW THE SYNAPSE TO BE EATEN 488 00:22:41,922 --> 00:22:45,426 BY ACTIVATED MICROGLIAL CELLS. 489 00:22:45,426 --> 00:22:48,362 SO 1 OF THE QUESTIONS WE THEN 490 00:22:48,362 --> 00:22:51,365 ASKED IS WHETHER THIS HMGB1 HAS 491 00:22:51,365 --> 00:22:56,336 TO COME FROM NEURONS. 492 00:22:56,336 --> 00:23:00,040 AND SO WE ACTUALLY DELETED HMGB1 493 00:23:00,040 --> 00:23:04,011 IN NEURONS AND WHAT YOU 494 00:23:04,011 --> 00:23:07,214 CAN--WHAT WE FIND IS THAT THESE 495 00:23:07,214 --> 00:23:11,985 MICE HAVE THE SAME INITIAL LOSS 496 00:23:11,985 --> 00:23:14,922 OF PARAMETRAL NEURONS BUT 497 00:23:14,922 --> 00:23:15,656 THERE'S NO MICROGLIAL 498 00:23:15,656 --> 00:23:16,457 ACTIVATION. 499 00:23:16,457 --> 00:23:22,062 AND WHEN YOU DO THIS SAME STUDY, 500 00:23:22,062 --> 00:23:26,200 WHERE YOU DELETE THE HMGB1 FROM 501 00:23:26,200 --> 00:23:29,303 MICROGLIA, YOU DON'T HAVE THIS 502 00:23:29,303 --> 00:23:29,570 PHENOTYPE. 503 00:23:29,570 --> 00:23:32,573 THEY DEVELOP DISEASE JUST LIKE 504 00:23:32,573 --> 00:23:33,941 THE WILD-TYPE MICE DO. 505 00:23:33,941 --> 00:23:38,445 SO WHY YOU NEED THE HMGB1 TO BE 506 00:23:38,445 --> 00:23:40,080 SECRETED BY NEURONS AND IF IT'S 507 00:23:40,080 --> 00:23:41,682 REALLY JUST A MATTER OF 508 00:23:41,682 --> 00:23:51,658 PROXIMITY TO BE ABLE TO GET THE 509 00:23:51,658 --> 00:23:57,564 HMGB1 TO THE SYNAPSE, I'M NOT 510 00:23:57,564 --> 00:23:57,998 SURE. 511 00:23:57,998 --> 00:24:05,372 SO, HAVING SHOWN THAT HMGB1 IS 512 00:24:05,372 --> 00:24:07,207 CRITICAL FOR SYNAPTIC PRUNING, 513 00:24:07,207 --> 00:24:11,779 WE ALSO ASKED WHETHER HMGB1 IS 514 00:24:11,779 --> 00:24:13,514 CRITICAL TO THE MICROGLIAL 515 00:24:13,514 --> 00:24:14,882 ACTIVATION. 516 00:24:14,882 --> 00:24:20,788 BECAUSE EXTRA CELLULAR HMGB1 IS 517 00:24:20,788 --> 00:24:23,090 A DAM, A DAMP ASSOCIATED PAT 518 00:24:23,090 --> 00:24:25,425 EXPERN IT BINDS TO RAGE AND 519 00:24:25,425 --> 00:24:25,626 TLR4. 520 00:24:25,626 --> 00:24:30,063 SO WE THOUGHT THAT THIS SECRETED 521 00:24:30,063 --> 00:24:35,369 HMGB1 MIGHT HAVE THE FUNCTION OF 522 00:24:35,369 --> 00:24:38,572 ALSO ACTIVATING THE MICROGLIA TO 523 00:24:38,572 --> 00:24:39,940 MOVE THEM TO THIS STATE WHERE 524 00:24:39,940 --> 00:24:42,042 THEY ENGAGE IN PRUNING AND WHAT 525 00:24:42,042 --> 00:24:52,486 YOU CAN SEE HERE IS IF YOU 526 00:24:55,255 --> 00:24:57,691 INCUBATE HMGB1 ISOLATED FROM THE 527 00:24:57,691 --> 00:24:59,927 BRAIN, EITHER WILD-TYPE OR RAGE 528 00:24:59,927 --> 00:25:01,395 DEFICIENT MICROGLIA, YOU CAN SEE 529 00:25:01,395 --> 00:25:08,869 THERE'S MUCH LESS ACTIVATION OF 530 00:25:08,869 --> 00:25:12,739 THE DEFICIENT MICROGLIA IN TERMS 531 00:25:12,739 --> 00:25:15,642 OF TNF SECRETION AND PRODUCTION 532 00:25:15,642 --> 00:25:18,045 IN TERMS OF INTERFERON, TYPE 1 533 00:25:18,045 --> 00:25:22,149 PRODUCTION AND SECRETION IL1, ON 534 00:25:22,149 --> 00:25:26,587 THE RIGHT HAND SIDE, YOU SEE THE 535 00:25:26,587 --> 00:25:31,358 RESULTS OF THE INTERFERON 536 00:25:31,358 --> 00:25:32,526 ACTIVATION IN INCREASED 537 00:25:32,526 --> 00:25:37,130 INTERFERON STIMMULED GENES AND 538 00:25:37,130 --> 00:25:39,600 ALSO INCREASED C1 Q. 539 00:25:39,600 --> 00:25:42,803 SO WE DID THE EXPERIMENT TO LOOK 540 00:25:42,803 --> 00:25:45,973 AT THIS MODEL IN MICE THAT 541 00:25:45,973 --> 00:25:51,778 LACKED RAGE. 542 00:25:51,778 --> 00:25:54,848 SO, WE ACTUALLY WERE NOT ABLE TO 543 00:25:54,848 --> 00:26:01,088 MAKE MICE THAT LACKED--THAT WE 544 00:26:01,088 --> 00:26:02,055 WERE ABLE TO--RAGE DEFICIENT 545 00:26:02,055 --> 00:26:04,892 MICE THAT WE WERE ACTUALLY ABLE 546 00:26:04,892 --> 00:26:07,060 TO DEVELOP THE IMMUNIZATION 547 00:26:07,060 --> 00:26:10,130 MODEL IN, BECAUSE RAGE IS ON THE 548 00:26:10,130 --> 00:26:12,666 SAME CHROMOSOME AS MHC, AND THE 549 00:26:12,666 --> 00:26:16,570 MICE HAVE TO BE H2 D IN ORDER TO 550 00:26:16,570 --> 00:26:19,740 MOUNT AN IMMUNE RESPONSE TO THE 551 00:26:19,740 --> 00:26:23,310 PEPTIDE, AND WE WERE NOT ABLE TO 552 00:26:23,310 --> 00:26:26,747 GET A RECOMBINATION EVENT 553 00:26:26,747 --> 00:26:29,850 BETWEEN THE RAGE AND THE MHC. 554 00:26:29,850 --> 00:26:33,954 SO WE USED A MONOCLONAL 555 00:26:33,954 --> 00:26:36,323 ANTIBODY, EITHER A CONTROL 556 00:26:36,323 --> 00:26:39,426 ANTIBODY, THAT DID NOT, CROSS 557 00:26:39,426 --> 00:26:43,597 REACT WITH DNA AND THE NMDA 558 00:26:43,597 --> 00:26:47,534 RECEPTOR, OR AN ANTIBODY THAT 559 00:26:47,534 --> 00:26:50,804 CROSS REACTS WITH THE NMDA 560 00:26:50,804 --> 00:26:51,672 RECEPTOR AND DNA. 561 00:26:51,672 --> 00:26:55,409 AND WHAT YOU CAN SEE, IS THAT IN 562 00:26:55,409 --> 00:26:58,045 THE RAGE KNOCKOUT MICE, WE DID 563 00:26:58,045 --> 00:27:03,884 NOT HAVE MICROGLIAL ACTIVATION 564 00:27:03,884 --> 00:27:06,320 WHEN WE USED THE LUPUS LIKE 565 00:27:06,320 --> 00:27:07,387 ANTIBODY, IT WAS NO DIFFERENT 566 00:27:07,387 --> 00:27:10,123 THAN WHEN WE GAME THE MOUSE THE 567 00:27:10,123 --> 00:27:13,060 NONLUPUS LIKE ANTIBODY AND THEN 568 00:27:13,060 --> 00:27:15,395 LPS, AND IN THE RAGE KNOCKOUT 569 00:27:15,395 --> 00:27:19,700 MICE WE DID NOT GET A LOSS OF 570 00:27:19,700 --> 00:27:22,769 DENDRITIC ARBORIZATION, SO 571 00:27:22,769 --> 00:27:28,308 CLEARLY THE HMGB1 CAN ACTIVATE 572 00:27:28,308 --> 00:27:35,816 MICROGLIA THROUGH BINDING TO 573 00:27:35,816 --> 00:27:37,884 RAGE. 574 00:27:37,884 --> 00:27:40,053 SO OUR INTEREST IS ALWAYS IN THE 575 00:27:40,053 --> 00:27:40,287 PATIENT. 576 00:27:40,287 --> 00:27:43,523 SO WE WERE WONDERING IF THE NEED 577 00:27:43,523 --> 00:27:45,559 FOR MICROGLIAL ACTIVATION GAVE 578 00:27:45,559 --> 00:27:56,069 US A CLUE AS TO A THERAPEUTIC 579 00:27:59,172 --> 00:28:00,574 INTERVENTION. 580 00:28:00,574 --> 00:28:04,011 AND ANGIO TENSEIN ENZYME 581 00:28:04,011 --> 00:28:07,547 INHIBITORS CAN BLOCK ACTIVATION 582 00:28:07,547 --> 00:28:09,616 OF MYELOID CELLS IN THE 583 00:28:09,616 --> 00:28:10,017 PERIPHERY. 584 00:28:10,017 --> 00:28:16,390 THEY ARE USED ALL THE TIME IN 585 00:28:16,390 --> 00:28:17,591 INDIVIDUALS WITH LUPUS BECAUSE 586 00:28:17,591 --> 00:28:20,560 THEY'RE USED TO MANAGE THE RENAL 587 00:28:20,560 --> 00:28:23,296 DEC AND HYPERTENSION, THEY'RE 588 00:28:23,296 --> 00:28:26,800 SAFE, THEY'RE RELATIVELY 589 00:28:26,800 --> 00:28:28,935 INEXPENSIVE COMPARED TO MOST 590 00:28:28,935 --> 00:28:31,505 DRUGS WE USE IN LUPUS, THEY HAVE 591 00:28:31,505 --> 00:28:35,709 BEEN SHOWN TO HAVE SOME BENEFIT 592 00:28:35,709 --> 00:28:40,781 IN ALZHEIMER'S DISEASE, WHICH IS 593 00:28:40,781 --> 00:28:42,816 ALSO CHARACTERIZED BY 594 00:28:42,816 --> 00:28:48,555 MICROTBLEEL PRUNING OF NEURONS, 595 00:28:48,555 --> 00:28:51,958 AND SO, WE DECIDED THAT WE WERE 596 00:28:51,958 --> 00:28:55,595 GOING TO STUDY ACE INHIBITORS. 597 00:28:55,595 --> 00:28:58,598 AND 1 OF THE OTHER OBSERVATIONS 598 00:28:58,598 --> 00:29:03,270 WE MADE IS NEURONS ACTUALLY 599 00:29:03,270 --> 00:29:07,307 PRODUCE ACE ANGIO TENSEIN 600 00:29:07,307 --> 00:29:09,676 CONVERTING ENZYME AND THERE WAS 601 00:29:09,676 --> 00:29:16,149 LOTS MORE ACE IN THE 602 00:29:16,149 --> 00:29:17,250 DNR AB POSITIVE MICE THAN THE 603 00:29:17,250 --> 00:29:21,721 NEGATIVE MICE, AND THERE'S A 604 00:29:21,721 --> 00:29:25,492 RISK ALLELE FOR LUPUS THAT LEADS 605 00:29:25,492 --> 00:29:30,430 TO HIGH PRODUCTION OF ACE. 606 00:29:30,430 --> 00:29:33,967 THE OTHER THING THAT'S IMPORTANT 607 00:29:33,967 --> 00:29:36,736 TO KNOW IS THAT INTERFERON WHICH 608 00:29:36,736 --> 00:29:40,440 IS PRODUCED BY THESE ACTIVATED 609 00:29:40,440 --> 00:29:47,414 MICROTBLEEL CELLS, LEADS TO 610 00:29:47,414 --> 00:29:49,549 INCREASED PRODUCTION OF THE 611 00:29:49,549 --> 00:29:53,887 RECEPTOR 1 FOR ANGIO TENSEIN 2 612 00:29:53,887 --> 00:29:59,993 WHICH TRIGGERS PRO INFLAMMATORY 613 00:29:59,993 --> 00:30:00,360 PATHWAY. 614 00:30:00,360 --> 00:30:02,529 SO WE DECIDED TO USE ACE 615 00:30:02,529 --> 00:30:04,498 INHIBITORS IN BOTH THE 616 00:30:04,498 --> 00:30:09,803 PREVENTION AND THE TREATMENT 617 00:30:09,803 --> 00:30:12,973 MODEL AND CAPP A TRIL IS AN ACE 618 00:30:12,973 --> 00:30:18,478 INHIBITOR THAT CROSSES THE BLOOD 619 00:30:18,478 --> 00:30:20,780 BRAIN BARRIER AND NOW 620 00:30:20,780 --> 00:30:21,948 [INDISCERNIBLE] IS AN INHIBITOR 621 00:30:21,948 --> 00:30:25,685 THAT DOES NOT CROSS THE BLOOD 622 00:30:25,685 --> 00:30:26,987 BRAIN BARRIER AND WHAT YOU CAN 623 00:30:26,987 --> 00:30:31,525 SEE IS THAT IN THE SCORE BELOW 624 00:30:31,525 --> 00:30:35,395 IS THAT CAPTOPRIL LED TO A 625 00:30:35,395 --> 00:30:36,296 DECREASE IN MICROGLIAL 626 00:30:36,296 --> 00:30:38,598 ACTIVATION IN BOTH THE 627 00:30:38,598 --> 00:30:40,667 PREVENTION TRIAL AND ENALAPRIL 628 00:30:40,667 --> 00:30:41,568 DID NOT. 629 00:30:41,568 --> 00:30:48,275 AND IN FACT, CAPTOPRIL RESTORED 630 00:30:48,275 --> 00:30:49,476 NORMAL DENDRITIC NORMALIZE IN 631 00:30:49,476 --> 00:30:53,313 THE IN THE NEURONS AND ENALAPRIL 632 00:30:53,313 --> 00:30:56,783 DID NOT IN BOTH THE PREVENTION 633 00:30:56,783 --> 00:31:01,021 AND TREATMENT MODEL AND IN 634 00:31:01,021 --> 00:31:02,856 THE--IN BOTH MODELS, SPATIAL 635 00:31:02,856 --> 00:31:06,626 MEMORY WAS EITHER PROTECTED OR 636 00:31:06,626 --> 00:31:06,993 RESTORED. 637 00:31:06,993 --> 00:31:09,396 SO THIS WAS A VERY EFFECTIVE 638 00:31:09,396 --> 00:31:09,729 TREATMENT. 639 00:31:09,729 --> 00:31:15,802 SO HOW DOES IT WORK? 640 00:31:15,802 --> 00:31:17,871 WELL WE THOUGHT THAT IT MIGHT 641 00:31:17,871 --> 00:31:18,872 WORK THROUGH UPREGULATION OF 642 00:31:18,872 --> 00:31:21,875 LAYER, IN OUR STUDIES OF C1 Q, 643 00:31:21,875 --> 00:31:24,444 WE IDENTIFIED LAYER 1 AS AN 644 00:31:24,444 --> 00:31:30,183 INHIBITORY RECEPTOR FOR C1 Q. 645 00:31:30,183 --> 00:31:33,820 AND IT WILL BLOCK ENGAGING LAYER 646 00:31:33,820 --> 00:31:36,423 1 WILL BLOCK MONOCYTE ACTIVATION 647 00:31:36,423 --> 00:31:37,357 IN THE PERIPHERY. 648 00:31:37,357 --> 00:31:42,295 AND SO WHAT OUR MODEL WAS WAS 649 00:31:42,295 --> 00:31:44,264 THAT A QUIESCENT MICROGLIA HAS A 650 00:31:44,264 --> 00:31:45,932 CERTAIN NUMBER OF SCAVENGER 651 00:31:45,932 --> 00:31:48,001 RECEPTORS AND A CERTAIN NUMBER 652 00:31:48,001 --> 00:31:50,937 OF LAYER 1 MOLECULES. 653 00:31:50,937 --> 00:31:53,006 AND THEY'RE IN SOME KIND OF 654 00:31:53,006 --> 00:31:56,109 BALANCE AND THE ACTIVATED 655 00:31:56,109 --> 00:31:59,679 MICRODPLIA, WE THOUGHT HAD MORE 656 00:31:59,679 --> 00:32:03,883 SCAVENGER RECEPTORS, FEWER LAYER 657 00:32:03,883 --> 00:32:06,519 1 MOLECULES, SO C1 Q WILL 658 00:32:06,519 --> 00:32:08,388 PREFERENTIALLY BIND THE 659 00:32:08,388 --> 00:32:09,889 SCAVENGER RECEPTORS LEADING TO 660 00:32:09,889 --> 00:32:15,795 PRUNING, AND WHEN WE USE THE ACE 661 00:32:15,795 --> 00:32:17,530 INHIBITOR, THERE IS REEXPRESSION 662 00:32:17,530 --> 00:32:24,638 OF MORE LAYER 1, AND SO NOW, 663 00:32:24,638 --> 00:32:26,673 THERE'S NO LONGER PREFERENTIAL 664 00:32:26,673 --> 00:32:29,109 ACTIVATION OF THE SCAVENGER 665 00:32:29,109 --> 00:32:32,112 RECEPTORS AND SO 1 OF THE 666 00:32:32,112 --> 00:32:34,247 PREDICTIONS, WELL I SHOULD FIRST 667 00:32:34,247 --> 00:32:38,084 SAY THAT IF WE LOOK AT LAYER 1 668 00:32:38,084 --> 00:32:40,020 EXPRESSION ON MICROGLIA, 669 00:32:40,020 --> 00:32:43,023 ISOLATED FROM THE DNRAB POSITIVE 670 00:32:43,023 --> 00:32:48,495 MICE, THERE'S LESS LAYER 1 THAN 671 00:32:48,495 --> 00:32:49,462 FROM DNRA B-NEGATIVE MICE AND IF 672 00:32:49,462 --> 00:32:58,571 YOU LOOK AT THE ENALOPRIL MICE 673 00:32:58,571 --> 00:33:01,141 VERSUS CAPTOPRIL TREATMENT MICE, 674 00:33:01,141 --> 00:33:02,375 THERE'S HIGHER LAYER OF 675 00:33:02,375 --> 00:33:07,814 EXPRESSION LAYER 1 IN THE 676 00:33:07,814 --> 00:33:10,183 CAPTOPRIL, QUIESCENT NOW 677 00:33:10,183 --> 00:33:12,619 QUIESCENT MICRO FLI COLSISSA. 678 00:33:12,619 --> 00:33:14,454 AND 1 OF THE PREDICTIONS IS THAT 679 00:33:14,454 --> 00:33:15,989 ACE INHIBITION WILL NOT BE OF 680 00:33:15,989 --> 00:33:21,394 ANY BENEFIT IN LAYER 1 DEFICIENT 681 00:33:21,394 --> 00:33:23,730 MICE AND INDEED THAT'S THE CASE. 682 00:33:23,730 --> 00:33:27,467 SO THERE'S NO DECREASE IN 683 00:33:27,467 --> 00:33:30,070 MICROTBLEEL ACTIVATION WITH ACE 684 00:33:30,070 --> 00:33:32,772 INHIBITION IN THE LAIR 1 685 00:33:32,772 --> 00:33:36,476 DEFICIENT MICE AND THE LAIR 1 686 00:33:36,476 --> 00:33:41,715 DEFICIENT MICE DO NOT HAVE THEIR 687 00:33:41,715 --> 00:33:43,083 DENDRITIC ARBORIZATION RESTORED 688 00:33:43,083 --> 00:33:48,688 TO NORMAL IN THE PRESENCE OF AN 689 00:33:48,688 --> 00:33:50,724 ACE INHIBITOR. 690 00:33:50,724 --> 00:33:53,259 SO WHAT REGULATES LAYER 1 IN THE 691 00:33:53,259 --> 00:33:53,526 MICROGLIA. 692 00:33:53,526 --> 00:33:56,363 SO I'M SURE THERE ARE MANY, MANY 693 00:33:56,363 --> 00:34:00,333 FACTORS THAT DO THAT, BUT WHAT 694 00:34:00,333 --> 00:34:04,437 WE FOUND IS THAT MICROGLIA 695 00:34:04,437 --> 00:34:06,005 TREATED WITH HMGB1 MAKE 696 00:34:06,005 --> 00:34:08,007 INCREASED IL10 AND IL10 CAN 697 00:34:08,007 --> 00:34:10,410 DECREASE LAYER 1 EXPRESSION IN 698 00:34:10,410 --> 00:34:16,015 MICROGLIA, SO THAT'S AT LEAST 1 699 00:34:16,015 --> 00:34:16,383 MECHANISM. 700 00:34:16,383 --> 00:34:20,120 SO HAVING FOLLOWED SORT OF 701 00:34:20,120 --> 00:34:22,856 CANDIDATE YEENS THAT CAME FROM 702 00:34:22,856 --> 00:34:25,525 OUR OWN EXPERIMENTS OR OUR 703 00:34:25,525 --> 00:34:26,426 READING LITERATURE, WE DECIDED 704 00:34:26,426 --> 00:34:28,862 TO TAKE A MORE UNBIASED APPROACH 705 00:34:28,862 --> 00:34:32,766 AND LIKE EVERYBODY ELSE WE DID 706 00:34:32,766 --> 00:34:35,668 RNASEQ SINGLE CELL RNASEQ ON 707 00:34:35,668 --> 00:34:39,672 MICROGLIA FROM MICE THAT WERE 708 00:34:39,672 --> 00:34:46,045 DNR ABNEGGATIVE, MICE THAT WERE 709 00:34:46,045 --> 00:34:49,716 DNRAB+, AND DNRAB+ MICE TREATED 710 00:34:49,716 --> 00:34:50,683 WITH CAPTOPRIL, AND THE FIRST 711 00:34:50,683 --> 00:34:52,585 THING YOU CAN SEE IS THERE 712 00:34:52,585 --> 00:34:54,120 THERE'S 2 CLUSTERS OF MICROGLIA 713 00:34:54,120 --> 00:34:59,058 AND 1 THAT IS HOMEOSTATIC AND 1 714 00:34:59,058 --> 00:34:59,626 THAT IS REACTIVE. 715 00:34:59,626 --> 00:35:01,961 AND WHAT YOU CAN ALSO SEE IS THE 716 00:35:01,961 --> 00:35:05,064 FREQUENCY OF THE REACTIVE CELLS 717 00:35:05,064 --> 00:35:09,769 IS INCREASED IN THE DNETWORK R 718 00:35:09,769 --> 00:35:12,572 AB-POSITIVE MICE AND DECREASED 719 00:35:12,572 --> 00:35:15,809 BY TREATMENT WITH CAPTOPRIL. 720 00:35:15,809 --> 00:35:18,611 THIS IS A SET OF VOLCANO PLOTS, 721 00:35:18,611 --> 00:35:23,383 AND WHAT YOU CAN SEE IS IN THE 722 00:35:23,383 --> 00:35:25,318 HOMEOSTATIC CLUSTER, THERE'S NOT 723 00:35:25,318 --> 00:35:29,522 ALL THAT MUCH DIFFERENCE IN THE 724 00:35:29,522 --> 00:35:32,992 DNR AB POSITIVE MICE AND 725 00:35:32,992 --> 00:35:35,528 DNR ABNEGGATIVE MICE AND THERE'S 726 00:35:35,528 --> 00:35:39,365 NOT THAT MUCH DIFFERENCE INDUCED 727 00:35:39,365 --> 00:35:41,501 BY CAPTOPRIL TREATMENT. 728 00:35:41,501 --> 00:35:45,238 BUT IN THE REACTIVE POPULATION 729 00:35:45,238 --> 00:35:47,440 WHAT YOU CAN SEE IS THAT THERE'S 730 00:35:47,440 --> 00:35:50,777 A BIG DIFFERENCE BETWEEN DNR 731 00:35:50,777 --> 00:35:54,981 AB-+ AND NEGATIVE, AND ALMOST NO 732 00:35:54,981 --> 00:35:56,382 DIFFERENCE BETWEEN DNR 733 00:35:56,382 --> 00:36:02,722 AB NEGATIVE AND THE CAP TO PRIL 734 00:36:02,722 --> 00:36:06,025 TREATED DNR AB + MICROGLIA. 735 00:36:06,025 --> 00:36:09,696 AND WHEN WE LOOKEDDA THE OUR 736 00:36:09,696 --> 00:36:12,232 CANDIDATE GENES WITHIN THE 737 00:36:12,232 --> 00:36:17,370 SINGLE CELL RNASEQ DATA, IN THIS 738 00:36:17,370 --> 00:36:22,942 REACTIVE POPULATION, WHAT WE SEE 739 00:36:22,942 --> 00:36:26,513 IS THE SAME TRENDS THAT WE 740 00:36:26,513 --> 00:36:29,215 SHOWED WITH HMGB1 INCREASING 741 00:36:29,215 --> 00:36:33,052 EXPRESSION OF INFLAMMATORY 742 00:36:33,052 --> 00:36:35,989 CYTOKINES AND INTERFERON, AND 743 00:36:35,989 --> 00:36:41,628 CAPTOPRIL RESTORING EXPRESSION 744 00:36:41,628 --> 00:36:42,295 MORE TOWARDS NORMAL. 745 00:36:42,295 --> 00:36:45,598 AND I SHOULD JUST SAY THAT ACE 746 00:36:45,598 --> 00:36:48,468 INHIBITORS CAN WORK BY 747 00:36:48,468 --> 00:36:50,136 PREVENTING THE PRODUCTION OF 748 00:36:50,136 --> 00:36:51,938 ANGIO TENSEIN 2 WHICH I TOLD YOU 749 00:36:51,938 --> 00:36:57,610 CAN BIEN TO A PRO INFLAMMATORY 750 00:36:57,610 --> 00:37:00,246 RECEPTOR, AT1 R, BUT THEY CAN 751 00:37:00,246 --> 00:37:09,656 ALSO WORK BY DECREASING THE 752 00:37:09,656 --> 00:37:10,957 DEGRADATION OF BETA KINEIN AND 753 00:37:10,957 --> 00:37:15,361 IT HAS BEEN SHOWN TO SUPPRESS 754 00:37:15,361 --> 00:37:15,795 MONOCYTE ACTIVATION. 755 00:37:15,795 --> 00:37:17,897 SO WE WERE INTERESTED IN WHETHER 756 00:37:17,897 --> 00:37:19,966 THE ACE INHIBITION WAS WORKING 757 00:37:19,966 --> 00:37:23,536 BY PREVENTING THE ACTIVATION OF 758 00:37:23,536 --> 00:37:26,506 THE ANGIO TENSEIN 2 RECEPTOR, OR 759 00:37:26,506 --> 00:37:31,477 WAS WORKING BY INCREASING THE 760 00:37:31,477 --> 00:37:33,613 AMOUNT OF BRAIDA KINEIN PRESENCE 761 00:37:33,613 --> 00:37:34,981 AND WHAT CAN YOU SEE HERE IS 762 00:37:34,981 --> 00:37:41,087 THAT IT CLEARLY CAN WORK BY 763 00:37:41,087 --> 00:37:45,758 DECREASING THE ENGAGEMENT OF THE 764 00:37:45,758 --> 00:37:47,226 ANGIO TENSEIN RECEPTOR BECAUSE 765 00:37:47,226 --> 00:37:51,764 [INDISCERNIBLE] IS AN ANGIO 766 00:37:51,764 --> 00:37:53,199 TENSEIN RECEPTOR BLOCKER AND 767 00:37:53,199 --> 00:37:54,000 [INDISCERNIBLE] THAT'S USED 768 00:37:54,000 --> 00:37:55,034 CLINICALLY IN MANY SITUATIONS 769 00:37:55,034 --> 00:37:58,938 AND WHAT YOU CAN SEE IS THAT 770 00:37:58,938 --> 00:38:06,446 THAT WORKED LIKE CAPTOPRIL TO 771 00:38:06,446 --> 00:38:08,414 RESTORE A NORMAL MICROGLIAL 772 00:38:08,414 --> 00:38:09,849 NEURONAL HOMEOSTASIS IN THE 773 00:38:09,849 --> 00:38:11,818 BLOOD AND THE BRAIN. 774 00:38:11,818 --> 00:38:13,586 SO WHAT'S OUR MODEL, WELL, OUR 775 00:38:13,586 --> 00:38:17,657 MODEL IS THAT THE FIRST STAGE IS 776 00:38:17,657 --> 00:38:19,692 CAUSED BY EXCITE O TOXICITY. 777 00:38:19,692 --> 00:38:24,364 THAT THERE IS LOTS OF HMGB1 THAT 778 00:38:24,364 --> 00:38:27,133 IS BEING SECRETED BY NEURONS 779 00:38:27,133 --> 00:38:30,603 THAT ACTUALLY DON'T DIE BUT GET 780 00:38:30,603 --> 00:38:33,439 ENORMOUS NMDA RECEPTOR 781 00:38:33,439 --> 00:38:36,142 ACTIVATION BY THE PRESENCE OF 782 00:38:36,142 --> 00:38:37,677 THE ANTIBODY. 783 00:38:37,677 --> 00:38:41,681 THAT THAT BOTH TARGETS, HELPS 784 00:38:41,681 --> 00:38:46,219 TARGET SYNAPSES FOR PRUNING AND 785 00:38:46,219 --> 00:38:48,821 ACTIVATES THE MICROGLIA TO 786 00:38:48,821 --> 00:38:54,093 ENGAGE IN PRUNING AND WHEN ACE 787 00:38:54,093 --> 00:38:56,496 INHIBITORS OR ARBs COME ALONG 788 00:38:56,496 --> 00:38:58,665 WE INCREASE LAIR 1 EXPRESSION, 789 00:38:58,665 --> 00:39:02,235 SO THE C1 Q CAN PREFERENTIALLY 790 00:39:02,235 --> 00:39:05,972 BIND TO LAYER 1 AS OPPOSE TO 791 00:39:05,972 --> 00:39:08,107 SCAVENGER RECEPTORS AND WE END 792 00:39:08,107 --> 00:39:12,345 UP WITH MICROFLEEL QUIESCENCE 793 00:39:12,345 --> 00:39:14,013 AND RECONSTITUTION OF THE 794 00:39:14,013 --> 00:39:18,284 DENDRITIC PROCESSES IN THE 795 00:39:18,284 --> 00:39:18,651 NEURONS. 796 00:39:18,651 --> 00:39:20,353 WHAT WAS REALLY MOST SURPRISING 797 00:39:20,353 --> 00:39:24,323 TO US AND I'M GOING TO GET BACK 798 00:39:24,323 --> 00:39:26,426 TO THIS, IS THAT THIS PATHOLOGY 799 00:39:26,426 --> 00:39:30,863 IS SUSTAINED AS FAR AS WE CAN 800 00:39:30,863 --> 00:39:34,734 TELL INDEFINITELY AFTER THE 801 00:39:34,734 --> 00:39:37,603 INITIAL ADMINITRATION OF LPS, SO 802 00:39:37,603 --> 00:39:40,773 12 MONTHS LATER, THERE IS NO 803 00:39:40,773 --> 00:39:45,745 RESOLUTION OF THE INFLAMMATION 804 00:39:45,745 --> 00:39:46,312 IN THE BRAIN. 805 00:39:46,312 --> 00:39:49,048 SO HOW DOES THIS RELATE TO 806 00:39:49,048 --> 00:39:49,315 PATIENTS. 807 00:39:49,315 --> 00:39:54,520 SO THIS IS LOOKING AT BLOOD 808 00:39:54,520 --> 00:39:58,858 BRAIN BARRIER INTEGRITY IN 809 00:39:58,858 --> 00:39:59,492 PATIENTS WITH LUPUS. 810 00:39:59,492 --> 00:40:07,433 AND THESE ARE PATIENTS WHO HAVE 811 00:40:07,433 --> 00:40:09,502 ABNORMAL PERFORMANCE ON 812 00:40:09,502 --> 00:40:13,673 NEUROCOGNITIVE EXAMS, BUT NO 813 00:40:13,673 --> 00:40:14,173 ACUTE CNS DISEASE. 814 00:40:14,173 --> 00:40:18,377 AND WHAT YOU CAN SEE IS THERE IS 815 00:40:18,377 --> 00:40:19,645 SELECTIVE IMPAIRMENT OF BLOOD 816 00:40:19,645 --> 00:40:20,947 BRAIN BIRRIER SURFACESSIER 817 00:40:20,947 --> 00:40:25,017 INTEGRITY IN THE HYPOCAMPUS. 818 00:40:25,017 --> 00:40:28,020 IF YOU TAKE LUPUS SERUM THAT HAS 819 00:40:28,020 --> 00:40:34,193 THESE ANTIBODIES IN IT, AND GIVE 820 00:40:34,193 --> 00:40:34,994 IT INTRAVENOUSLY, THE 821 00:40:34,994 --> 00:40:36,429 IMMUNOGLOBULIN TO A MOUSE OR 822 00:40:36,429 --> 00:40:38,965 GIVE NORMAL SERUM TO A MOUSE OR 823 00:40:38,965 --> 00:40:41,634 FRANKLY GIVE THIS LUPUS IMMUNO 824 00:40:41,634 --> 00:40:43,236 DPLOBUE LYNN DEPLETED OF THIS 825 00:40:43,236 --> 00:40:45,438 ANTIBODY, ON A PEPTIDE AFFINITY 826 00:40:45,438 --> 00:40:50,877 COLUMN TO A MOUSE, AND THEN GIVE 827 00:40:50,877 --> 00:40:53,012 LPS, AND TEST FOR SPATIAL MEMORY 828 00:40:53,012 --> 00:40:54,280 IN A PADDLING MAZE, THE MICE 829 00:40:54,280 --> 00:40:56,582 THAT HAVE THE LUPUS ANTIBODY 830 00:40:56,582 --> 00:41:01,587 PENETRATE THE BRAIN AND BIND THE 831 00:41:01,587 --> 00:41:08,127 HIPPOCAMPAL NEURONS HAVE 832 00:41:08,127 --> 00:41:10,196 IMPAIRED MEMORY FUNCTION. 833 00:41:10,196 --> 00:41:14,033 IF YOU LOOK AT LUPUS PATIENTS 834 00:41:14,033 --> 00:41:16,803 AND YOU ASK WHETHER THEY HAVE 835 00:41:16,803 --> 00:41:20,706 NORMAL OBJECT MEMORY AND NORM AT 836 00:41:20,706 --> 00:41:24,644 SPATIAL MEMORY, WHAT YOU CAN 837 00:41:24,644 --> 00:41:26,946 SEE, IS THAT OUR TEST FOR--WELL, 838 00:41:26,946 --> 00:41:30,883 I SHOULD FIRST SAY, THAT MOST 839 00:41:30,883 --> 00:41:32,518 NEUROPSYCHIATRIC BATTERIES THAT 840 00:41:32,518 --> 00:41:38,024 ARE USED IN THE CLINIC AND THAT 841 00:41:38,024 --> 00:41:39,759 ARE RECOMMENDED FOR USE WITH 842 00:41:39,759 --> 00:41:42,628 PATIENTS WITH LUPUS, DO NOT 843 00:41:42,628 --> 00:41:43,996 DISTINGUISH BETWEEN OBLIGATIONS 844 00:41:43,996 --> 00:41:48,100 YECT MEMORY, AND SPATIAL MEMORY. 845 00:41:48,100 --> 00:41:49,869 SO WE DEVICED A VERY SIMPLE TEST 846 00:41:49,869 --> 00:41:53,339 OR USED A VERY SIMPLE TEST WHERE 847 00:41:53,339 --> 00:41:54,440 THERE ARE 4 OBLIGATIONS YECTS ON 848 00:41:54,440 --> 00:41:57,977 A CARD AND AN OBJECT MEMORY 849 00:41:57,977 --> 00:42:00,613 TEST, IS IF YOU ASK IF THERE WAS 850 00:42:00,613 --> 00:42:03,950 A DOG ON THE CARD, AND THEY SAY 851 00:42:03,950 --> 00:42:06,586 YES OR NO, AND A SPATIAL MEMORY 852 00:42:06,586 --> 00:42:08,354 TEST IS WHETHER THE BANANA WAS 853 00:42:08,354 --> 00:42:12,725 NEXT TO THE LION, AND THEY SAY, 854 00:42:12,725 --> 00:42:13,192 YES OR NO. 855 00:42:13,192 --> 00:42:18,564 AND WHAT YOU CAN SEE, HC IS 856 00:42:18,564 --> 00:42:19,465 HEALTHY CONTROLS, DNRB 857 00:42:19,465 --> 00:42:20,333 ABNEGGATIVE AND PATIENTS WITH 858 00:42:20,333 --> 00:42:26,105 LUPUS WHO DO NOT HAVE THIS 859 00:42:26,105 --> 00:42:28,207 ANTIBODY, AND DNRAB+ IS PATIENTS 860 00:42:28,207 --> 00:42:29,675 WITH LUPUS WHO DO HAVE THIS 861 00:42:29,675 --> 00:42:33,212 ANTIBODY AND WHAT YOU CAN SEE IS 862 00:42:33,212 --> 00:42:35,481 THAT THEY ALL PERFORM 863 00:42:35,481 --> 00:42:37,450 SIMILARLY ON AN OBLIGATIONS YECT 864 00:42:37,450 --> 00:42:40,753 RECOGNITION TASK BUT ON A 865 00:42:40,753 --> 00:42:44,156 SPATIAL MEMORY TEST, THOSE WHO 866 00:42:44,156 --> 00:42:45,625 HAVE THE--THOSE PATIENTS WITH 867 00:42:45,625 --> 00:42:48,728 LUPUS WHO HAVE THIS ANTIBODY, 868 00:42:48,728 --> 00:42:52,431 HAVE AN IMPAIRMENT IN THEIR 869 00:42:52,431 --> 00:42:53,699 SPATIAL MEMORY. 870 00:42:53,699 --> 00:42:56,802 SO THE PATIENT WHO CAME TO US IN 871 00:42:56,802 --> 00:43:00,439 CLINIC AND MADE US THINK ABOUT 872 00:43:00,439 --> 00:43:06,812 SPATIAL MEMORY, WAS ACTUALLY 873 00:43:06,812 --> 00:43:09,148 ENORMOUSLY INSTRUCTIVE. 874 00:43:09,148 --> 00:43:11,817 IF YOU PERFORM FDG PET SCANS 875 00:43:11,817 --> 00:43:14,220 ON PATIENTS WITH TO LOOK WITH 876 00:43:14,220 --> 00:43:16,422 LUPUS TO LOOK AT TBLUICOSE 877 00:43:16,422 --> 00:43:19,025 UPTAKE, WHAT YOU SEE IS 878 00:43:19,025 --> 00:43:20,626 INCREASED GLUCOSE UPTAKE IN THE 879 00:43:20,626 --> 00:43:23,729 PIP O CAMPUS THAT CORRELATES 880 00:43:23,729 --> 00:43:25,898 WITH MEMORY DYSFUNCTION AND IF 881 00:43:25,898 --> 00:43:29,502 THEY HAVE THE ANTIBODY AS WELL 882 00:43:29,502 --> 00:43:34,073 THERE'S EVEN A GREATER 883 00:43:34,073 --> 00:43:37,143 CORRELATION WITH MEMORY 884 00:43:37,143 --> 00:43:37,443 DYSFUNCTION. 885 00:43:37,443 --> 00:43:42,148 AND THEN IF YOU LOOK AT 886 00:43:42,148 --> 00:43:44,016 FRACTIONAL AND ISOTROPY WHICH IS 887 00:43:44,016 --> 00:43:48,587 REALLY LOOKING AT 888 00:43:48,587 --> 00:43:49,422 MICROSTRUCTURAL INTEGRITY IN THE 889 00:43:49,422 --> 00:43:57,163 BRAIN, WHAT YOU CAN SEE IS THAT 890 00:43:57,163 --> 00:43:58,998 THE GOOD MICROSTRUCTURAL 891 00:43:58,998 --> 00:44:01,400 INTEGRITY, CORRELATES WITH GOOD 892 00:44:01,400 --> 00:44:07,440 PERFORMANCE ON SPATIAL MEMORY, 893 00:44:07,440 --> 00:44:12,144 AND THE GOOD MICROSTRUCTURAL 894 00:44:12,144 --> 00:44:14,613 INTEGRITY CORRELATES WITH NOT 895 00:44:14,613 --> 00:44:19,218 HAVING THE ANTIBODY PRESENT IN 896 00:44:19,218 --> 00:44:20,019 THE SERUM. 897 00:44:20,019 --> 00:44:24,357 SO THOSE WITH POOR 898 00:44:24,357 --> 00:44:25,291 MICROSTRUCTURAL INTEGRITY. 899 00:44:25,291 --> 00:44:28,260 ARE POSITIVE FOR THIS CROSS 900 00:44:28,260 --> 00:44:30,229 REACTIVE ASPECT BODY AND HAVE 901 00:44:30,229 --> 00:44:31,964 IMPAIRED SPATIAL MEMORY AND THIS 902 00:44:31,964 --> 00:44:35,568 IS JUST LOOKING AT THE 903 00:44:35,568 --> 00:44:36,702 MICROSTRUCTURAL INTEGRITY AND 904 00:44:36,702 --> 00:44:39,805 YOU CAN SEE, ARK ROUND THE 905 00:44:39,805 --> 00:44:43,843 HIPPOCAMPUS, THAT THERE'S 906 00:44:43,843 --> 00:44:44,510 REDUCED STRUCTURAL INTEGRITY. 907 00:44:44,510 --> 00:44:54,186 IF YOU LOOK AT PATIENTS FOR 908 00:44:54,186 --> 00:44:55,788 GLIAL CELL ACTIVATION USING THE 909 00:44:55,788 --> 00:44:57,223 SAME PET LIGAND AS WE USED IN 910 00:44:57,223 --> 00:45:01,093 MICE, CAN YOU SEE THAT PATIENTS 911 00:45:01,093 --> 00:45:06,298 WITH LUPUS HAD INCREASED 912 00:45:06,298 --> 00:45:07,400 MICROTBLEEL ACTIVATION IN THE 913 00:45:07,400 --> 00:45:08,667 HIPPOCAMPUS AND I SHOULD JUST 914 00:45:08,667 --> 00:45:16,208 SAY THAT THE BLOOD BRAIN BARRIER 915 00:45:16,208 --> 00:45:18,177 CAN BE IMPAIRED, THE INTEGRITY 916 00:45:18,177 --> 00:45:20,946 OF THE BLOOD BRAIN BARRIER CAN 917 00:45:20,946 --> 00:45:22,915 BE IMPAIRED BY SOLUBLE FACTORS 918 00:45:22,915 --> 00:45:25,651 THAT ARE IN THE CIRCULATION BUT 919 00:45:25,651 --> 00:45:30,356 IT CAN ALSO BE IMPAIRED BY 920 00:45:30,356 --> 00:45:32,858 SOLUBLE FACTORS SECRETED BY 921 00:45:32,858 --> 00:45:37,930 MICROGLIA WITHIN THE CENTRAL 922 00:45:37,930 --> 00:45:38,397 NERVOUS SYSTEM. 923 00:45:38,397 --> 00:45:41,767 AND WHAT YOU SEE, WHEN YOU 924 00:45:41,767 --> 00:45:49,141 FOLLOW PATIENTS OVER TIME, AND 925 00:45:49,141 --> 00:45:50,676 SO, WE'VE DONE LONGITUDINAL 926 00:45:50,676 --> 00:45:54,847 KAN--KANAS AND ASSESSMENTS OF 927 00:45:54,847 --> 00:45:55,815 PATIENTS WITH COGNITIVE 928 00:45:55,815 --> 00:45:57,883 IMPAIRMENT AND LUPUS, AND WHAT 929 00:45:57,883 --> 00:46:03,255 YOU CAN SEE IS THAT THOSE WHO 930 00:46:03,255 --> 00:46:05,825 HAVE BEEN GIVEN AN ACE 931 00:46:05,825 --> 00:46:09,161 ESSENTIALLY ACTING ACE 932 00:46:09,161 --> 00:46:11,030 INHIBITOR, CAPTOPRIL IS NOT THE 933 00:46:11,030 --> 00:46:13,799 1 USED CLINICALLY SO MUCH 934 00:46:13,799 --> 00:46:14,934 ANYMORE, BUT ESSENTIALLYACKING 935 00:46:14,934 --> 00:46:17,570 ACE INHIBITOR HAVE A DECREASE IN 936 00:46:17,570 --> 00:46:21,540 THE HYPER METABOLISM AND THOSE 937 00:46:21,540 --> 00:46:24,043 WHO DID NOT GET CENTRALLY ACTING 938 00:46:24,043 --> 00:46:25,978 ACE INHIBITOR HAVE NO ACE 939 00:46:25,978 --> 00:46:27,847 INHIBITOR OR ACE INHIBITOR THAT 940 00:46:27,847 --> 00:46:33,352 DOESN'T CROSS THE BLOOD BRAIN 941 00:46:33,352 --> 00:46:37,156 BARRIER HAD IN FACT AN INCREASE 942 00:46:37,156 --> 00:46:38,090 IN HYPER METABOLISM IN THE 943 00:46:38,090 --> 00:46:38,290 BRAIN. 944 00:46:38,290 --> 00:46:41,293 SO THAT HAS LED TO A CLINICAL 945 00:46:41,293 --> 00:46:44,163 TRIAL THAT IS ONGOING, TO LOOK 946 00:46:44,163 --> 00:46:47,967 AT A CENTRALLY ACTING, VERSUS A 947 00:46:47,967 --> 00:46:50,469 NONCENTRALLY ACTING ACE 948 00:46:50,469 --> 00:46:56,242 INHIBITOR IN PEOPLE WITH LUPUS, 949 00:46:56,242 --> 00:47:03,983 WHO HAVE INCREASED METABOLISM IN 950 00:47:03,983 --> 00:47:06,785 THEIR HIPPOCAMPUS, ABNORMAL 951 00:47:06,785 --> 00:47:10,322 MEMORY FUNCTION ON 952 00:47:10,322 --> 00:47:12,491 NEUROPSYCHIATRIC TESTING, AND 953 00:47:12,491 --> 00:47:15,895 IT'S REALLY THE CLINICAL TRIAL 954 00:47:15,895 --> 00:47:18,397 MADE IN HEAVEN BECAUSE EVERYBODY 955 00:47:18,397 --> 00:47:20,633 GETS AN ACE INHIBITOR AND SO 956 00:47:20,633 --> 00:47:23,802 EVERYBODY GETS THE BENEFITS OF 957 00:47:23,802 --> 00:47:26,972 THE ACE INHIBITOR FOR BLOOD 958 00:47:26,972 --> 00:47:28,807 PRESSURE CONTROL AND RENAL 959 00:47:28,807 --> 00:47:32,545 PROTECTION, BUT SOME GET AN ACE 960 00:47:32,545 --> 00:47:35,314 INHIBITOR THAT WILL ACTUALLY WE 961 00:47:35,314 --> 00:47:36,348 HOPE SEPRESS MICROFLEEL 962 00:47:36,348 --> 00:47:39,018 ACTIVATION AND SOME GET AN ACE 963 00:47:39,018 --> 00:47:41,187 INHIBITOR THAT WILL NOT 964 00:47:41,187 --> 00:47:41,754 PENETRATE THE BRAIN. 965 00:47:41,754 --> 00:47:47,226 OUR READ OUT FOR THIS CLINICAL 966 00:47:47,226 --> 00:47:50,629 TRIAL IS NEUROIMAGING, BECAUSE 967 00:47:50,629 --> 00:47:51,730 NEUROIMAGING IS BASICALLY 968 00:47:51,730 --> 00:48:02,208 INDEPENDENT OF TIME OF DAY, 969 00:48:04,343 --> 00:48:06,445 INDEPENDENT OF MOOD, AND 970 00:48:06,445 --> 00:48:07,179 NEUROPSYCHIATRIC TESTING. 971 00:48:07,179 --> 00:48:09,181 YOU WOULD HAVE TO HAVE INFINITLY 972 00:48:09,181 --> 00:48:11,483 MORE PATIENTS TO DO THIS KIND OF 973 00:48:11,483 --> 00:48:13,852 STUDY AND USE NEUROPSYCHIATRIC 974 00:48:13,852 --> 00:48:16,355 TESTING AS YOUR END POINT AND WE 975 00:48:16,355 --> 00:48:17,156 FINISHED ENROLLMENT THIS MONTH 976 00:48:17,156 --> 00:48:20,693 AND WE WILL FIND OUT. 977 00:48:20,693 --> 00:48:22,561 SO WE'RE ROWBSLY DOING COGNITIVE 978 00:48:22,561 --> 00:48:24,463 TESTING BUT THAT'S NOT A PRIMARY 979 00:48:24,463 --> 00:48:24,997 END POINT. 980 00:48:24,997 --> 00:48:29,802 ONE OF OUR OTHER END POINTS IS 981 00:48:29,802 --> 00:48:38,143 MICRODPLEEL ACTIVATION. 982 00:48:38,143 --> 00:48:39,878 AND THIS IS WHERE WE COME BACK 983 00:48:39,878 --> 00:48:43,582 TO THE FACT THAT IN MICE THERE'S 984 00:48:43,582 --> 00:48:48,854 NO SPONTANEOUS RESOLUTION OF 985 00:48:48,854 --> 00:48:49,588 THIS INFLAMMATORY PATHOLOGY OVER 986 00:48:49,588 --> 00:48:55,394 TIME SO IN THE MICE, THERE IS 1 987 00:48:55,394 --> 00:48:57,229 TRIGGERING EPISODE AND THEN 988 00:48:57,229 --> 00:49:01,967 THERE IS A POGHT O LOGIC 989 00:49:01,967 --> 00:49:06,205 HOMEOSTASIS THAT STAYS AND STAYS 990 00:49:06,205 --> 00:49:06,472 AND STAYS. 991 00:49:06,472 --> 00:49:08,641 SO WE'VE BEEN STUDYING PATIENTS 992 00:49:08,641 --> 00:49:11,977 WHO WERE IN LONG-TERM REMISSION, 993 00:49:11,977 --> 00:49:13,679 MEANING THEY'VE BEEN IN CLINICAL 994 00:49:13,679 --> 00:49:17,516 REMISSION FOR 3 YEARS OR MORE, 995 00:49:17,516 --> 00:49:19,585 ON NO DRUGS, EXCEPT MAYBE 996 00:49:19,585 --> 00:49:23,422 HYDROXY CHLOR O QUIN, MAYBE NOT, 997 00:49:23,422 --> 00:49:30,195 WHO ALL HAD VERY ACTIVE DEC AT 998 00:49:30,195 --> 00:49:31,130 SOME POINT. 999 00:49:31,130 --> 00:49:34,366 SO THEY HAD ALL PREVIOUSLY 1000 00:49:34,366 --> 00:49:34,967 REQUIRED IMMUNOSUPPRESSIVE 1001 00:49:34,967 --> 00:49:37,603 THERAPY AND AT LEAST 1002 00:49:37,603 --> 00:49:39,238 20-MILLIGRAMS OF COTTERRIC O 1003 00:49:39,238 --> 00:49:41,740 STEROIDS BUT THEY'RE NOW ALL 1004 00:49:41,740 --> 00:49:42,374 CLINICALLY QUIESCENT. 1005 00:49:42,374 --> 00:49:45,744 WE A THEY'RE IN REMISSION, 1006 00:49:45,744 --> 00:49:48,514 THERE'S NO EVIDENCE OF 1007 00:49:48,514 --> 00:49:49,014 PERIPHERAL INFLAMMATION, 1008 00:49:49,014 --> 00:49:49,248 ANYMORE. 1009 00:49:49,248 --> 00:49:59,058 AND WHAT YOU CAN SEE, THAT THEY 1010 00:49:59,058 --> 00:50:02,861 STILL HAVE INCREASED FDGPET, 1011 00:50:02,861 --> 00:50:04,129 INCREASED METABOLISM, GLUCOSE 1012 00:50:04,129 --> 00:50:05,631 UPTAKE IN THE HIPPOCAMPUS, THE 1013 00:50:05,631 --> 00:50:06,865 PATIENTS IN REMISSION OR IN 1014 00:50:06,865 --> 00:50:12,504 BLUE, THE PATES WHO ARE--WHO 1015 00:50:12,504 --> 00:50:15,607 STILL HAVE ACTIVE DISEASE AND 1016 00:50:15,607 --> 00:50:17,176 ARE ON IMMUNOSUPPRESSIVE THERAPY 1017 00:50:17,176 --> 00:50:18,010 ARE IN GREEN. 1018 00:50:18,010 --> 00:50:22,481 THEY STILL HAVE BLOOD BRAIN 1019 00:50:22,481 --> 00:50:25,851 BARRIER ABNORMALITIES, AND THEY 1020 00:50:25,851 --> 00:50:27,920 TILL HAVE EVIDENCE FOR 1021 00:50:27,920 --> 00:50:30,322 MICRODPLEEL ACTIVATION. 1022 00:50:30,322 --> 00:50:33,859 SO, WE THINK THAT THIS IS A 1023 00:50:33,859 --> 00:50:40,666 NONRESOLVING INFLAMMATION IN THE 1024 00:50:40,666 --> 00:50:43,469 BRAIN AS WELL WHILE THE NO 1025 00:50:43,469 --> 00:50:45,304 INFLAMMATION IS NO LONGER 1026 00:50:45,304 --> 00:50:46,238 DETECTABLE, THE BRAIN 1027 00:50:46,238 --> 00:50:47,406 INFLAMMATION IS STILL THERE AND 1028 00:50:47,406 --> 00:50:51,844 OBVIOUSLY WE THINK THERE ARE BIG 1029 00:50:51,844 --> 00:50:55,447 CLINICAL IMPLICATIONS OF THIS 1030 00:50:55,447 --> 00:50:55,748 OBSERVATION. 1031 00:50:55,748 --> 00:50:59,084 SO WHAT ARE OUR CONCLUSIONS? 1032 00:50:59,084 --> 00:51:02,821 WE THINK THESE ANTIBODIES 1033 00:51:02,821 --> 00:51:03,856 CONTRIBUTE TO COGNITIVE 1034 00:51:03,856 --> 00:51:09,161 IMPAIRMENT IN LUPUS, BUT I DON'T 1035 00:51:09,161 --> 00:51:10,562 FOR A MOMENT, WANT YOU TO THINK 1036 00:51:10,562 --> 00:51:13,399 THIS IS THE ONLY MECHANISM, THE 1037 00:51:13,399 --> 00:51:15,401 ONLY TRIGGER FOR COGNITIVE 1038 00:51:15,401 --> 00:51:20,839 IMPAIRMENT IN LUPUS, THERE ARE 1039 00:51:20,839 --> 00:51:22,641 OTHER ANTIBRAIN ANTIBODIES. 1040 00:51:22,641 --> 00:51:32,017 A GROUP IN CHILE HAS SHOWN THAT 1041 00:51:32,017 --> 00:51:33,519 THERE ARE GROUP OF ASPECT BODIES 1042 00:51:33,519 --> 00:51:35,053 THAT ARE HONE IN A SMALLER 1043 00:51:35,053 --> 00:51:37,723 SUBSET OF PATIENTS AND DNA 1044 00:51:37,723 --> 00:51:38,791 ANTIBODIES THAT THOSE CROSS 1045 00:51:38,791 --> 00:51:44,563 REACT WITH A CELL SURFACE 1046 00:51:44,563 --> 00:51:47,132 MOLECULE ON NEURONS THAT 1047 00:51:47,132 --> 00:51:49,568 REGULATE AMPORECEPTOR 1048 00:51:49,568 --> 00:51:51,270 TRAFFICKING AND THAT THE 1049 00:51:51,270 --> 00:51:53,572 PENETRATION OF THOSE ANTIBODIES 1050 00:51:53,572 --> 00:51:58,777 INTO THE BRAIN WILL ALSO CAUSE A 1051 00:51:58,777 --> 00:52:00,846 MEMORY IMPAIRMENT AND A 1052 00:52:00,846 --> 00:52:01,880 COGNITIVE PHENOTYPE AND I'M SURE 1053 00:52:01,880 --> 00:52:06,919 THERE ARE MANY OTHERS. 1054 00:52:06,919 --> 00:52:10,022 THAT MICROTBLEEL ACTIVATION WITH 1055 00:52:10,022 --> 00:52:11,190 INCREASED C1 Q SECRETION WE 1056 00:52:11,190 --> 00:52:16,528 THINK IS A KEY COMPONENT OF THE 1057 00:52:16,528 --> 00:52:17,362 COGNITIVE IMPAIRMENT BECAUSE WE 1058 00:52:17,362 --> 00:52:20,432 THINK THAT THE NEURONAL HMGB1 1059 00:52:20,432 --> 00:52:25,871 WHICH CAN LEAD TO INCREASED C1 1060 00:52:25,871 --> 00:52:31,477 Q, SECRETION BY MICROFLEEL CELS 1061 00:52:31,477 --> 00:52:34,947 AND THE C1 Q LEAD TO THIS 1062 00:52:34,947 --> 00:52:39,017 MALADAPTIVE HOMEOSTASIS WHICH IS 1063 00:52:39,017 --> 00:52:39,785 NONRESOLVING WITHOUT AN 1064 00:52:39,785 --> 00:52:41,153 INTERVENTION. 1065 00:52:41,153 --> 00:52:46,191 SO WE THINK THAT ACE INHIBITORS 1066 00:52:46,191 --> 00:52:47,826 AND ANGIO TENSEIN RECEPTOR 1067 00:52:47,826 --> 00:52:49,461 BLOCKERS CAN SUPPRESS THE 1068 00:52:49,461 --> 00:52:51,363 MICROTBLEEL ACTIVATION AND THEY 1069 00:52:51,363 --> 00:52:54,800 DO THIS IN PART BY INCREASING 1070 00:52:54,800 --> 00:52:55,934 LAYER 1 EXPRESSION. 1071 00:52:55,934 --> 00:53:01,173 SO C1 Q IS A PIVOTAL MOLECULE 1072 00:53:01,173 --> 00:53:04,676 HERE, IT CAN EITHER EXACERBATE, 1073 00:53:04,676 --> 00:53:08,013 SUSTAIN THE INJURY, BY BINDING 1074 00:53:08,013 --> 00:53:13,285 SCAVENGER RECEPTORS AND 1075 00:53:13,285 --> 00:53:16,588 MEDIATING PRUNING OF NEURONAL 1076 00:53:16,588 --> 00:53:19,324 DENDRITES OR IT CAN BIND TO 1077 00:53:19,324 --> 00:53:21,627 LAYER AND SUPPRESS THE 1078 00:53:21,627 --> 00:53:24,696 MICROGLIAL ACTIVATION AND ALLOW 1079 00:53:24,696 --> 00:53:29,468 THE NEURON TO RESTORE NORMAL 1080 00:53:29,468 --> 00:53:30,536 DENDRITIC ARBORIZATION EMPLOY WE 1081 00:53:30,536 --> 00:53:32,604 THINK THIS PARADIGM MAY BE 1082 00:53:32,604 --> 00:53:33,906 PRESENT IN MANY DISEASES, WE 1083 00:53:33,906 --> 00:53:37,109 THINK IN FACT IT IS THE PRESENT 1084 00:53:37,109 --> 00:53:46,151 IN ALZHEIMER'S DISEASE AND CAN 1085 00:53:46,151 --> 00:53:47,586 CONTRIBUTE TO CHANGES IN 1086 00:53:47,586 --> 00:53:48,086 COGNITION AND BEHAVIOR. 1087 00:53:48,086 --> 00:53:49,988 AND 1 OF THE THINGS THAT IS MOST 1088 00:53:49,988 --> 00:53:53,292 CURIOUS TO ME THAT THE PHENOTYPE 1089 00:53:53,292 --> 00:54:01,567 OF OF THE MICROGLIAL CELL THAT 1090 00:54:01,567 --> 00:54:05,070 IS RESPONSIBLE IN PART FOR THIS 1091 00:54:05,070 --> 00:54:07,139 BRAIN INJURY IS HIGH PRODUCTION 1092 00:54:07,139 --> 00:54:15,147 OF C1 Q, HIGH PRODUCTION OF 1093 00:54:15,147 --> 00:54:24,189 IL10, AND INCREASED CREASED CREC 1094 00:54:24,189 --> 00:54:24,623 POTENTIAL. 1095 00:54:24,623 --> 00:54:27,392 I THINK IT WAS ON 1 OF THE 1096 00:54:27,392 --> 00:54:29,161 SLIDES INCREASED EXPRESSION OF 1097 00:54:29,161 --> 00:54:36,234 AXLE WHICH IS 1 OF THE PH 1098 00:54:36,234 --> 00:54:36,969 AGOSITIC RECEPTORS ON 1099 00:54:36,969 --> 00:54:37,269 MACROIFIESS. 1100 00:54:37,269 --> 00:54:41,440 SO IF YOU THINK ABOUT THAT, 1101 00:54:41,440 --> 00:54:46,345 THAT'S THE PHENOTYPE OF THE PRO 1102 00:54:46,345 --> 00:54:47,879 RESOLVING MACROPHAGE IN THE 1103 00:54:47,879 --> 00:54:48,447 PERIPHERY. 1104 00:54:48,447 --> 00:54:51,316 AND IN FACT, AN M2 LIKE 1105 00:54:51,316 --> 00:54:57,556 MACROPHAGE WHICH WE THINK OF AS 1106 00:54:57,556 --> 00:54:59,925 ANTIINFLAMMATORY PRO 1107 00:54:59,925 --> 00:55:03,095 INFLAMMATION RESOLUTION HAS 1108 00:55:03,095 --> 00:55:06,898 INCREASED C1 Q PRODUCTION, 1109 00:55:06,898 --> 00:55:11,770 INCREASED IL10, AND INCREASED PH 1110 00:55:11,770 --> 00:55:12,437 AGOSITIERK C POTENTIAL. 1111 00:55:12,437 --> 00:55:18,010 SO I'M NOT SURE EXACTLY HOW TO 1112 00:55:18,010 --> 00:55:19,945 UNDERSTAND HOW 1 IS 1113 00:55:19,945 --> 00:55:21,680 ANTIINFLAMMATORY IN THE 1114 00:55:21,680 --> 00:55:24,549 PERIPHERY, AND PRO INFLAMMATORY 1115 00:55:24,549 --> 00:55:28,387 IN THE BRAIN, BUT I THINK IT 1116 00:55:28,387 --> 00:55:30,656 RAISES A VERY IMPORTANT CAVEAT 1117 00:55:30,656 --> 00:55:32,557 AS WE THINK ABOUT THERAPEUTICS 1118 00:55:32,557 --> 00:55:35,193 THAT FOCUS ON THE MYELOID CELL 1119 00:55:35,193 --> 00:55:38,830 BECAUSE WHAT YOU WOULD WANT TO 1120 00:55:38,830 --> 00:55:40,532 ENIENDER IN THE PERIPHERY MAY 1121 00:55:40,532 --> 00:55:43,969 ACTUALLY NOT BE GOOD FOR THE 1122 00:55:43,969 --> 00:55:44,403 BRAIN. 1123 00:55:44,403 --> 00:55:49,074 SO I'M GOING TO END THERE AND 1124 00:55:49,074 --> 00:55:50,275 JUST ACKNOWLEDGE THAT AS ALWAYS 1125 00:55:50,275 --> 00:55:52,010 IT TAKES A VILLAGE AND THERE 1126 00:55:52,010 --> 00:55:53,578 HAVE BEEN MANY WONDERFUL PEOPLE 1127 00:55:53,578 --> 00:55:58,984 BOTH FROM WITHIN MY OWN LAB, 1128 00:55:58,984 --> 00:56:00,052 MOST RECENTLY MARK AND KATE 1129 00:56:00,052 --> 00:56:03,588 WORKING ON THIS AND MANY 1130 00:56:03,588 --> 00:56:06,091 COLLABORATORS AT THE FINE STEIN, 1131 00:56:06,091 --> 00:56:07,125 DAVID, AND [INDISCERNIBLE] AND 1132 00:56:07,125 --> 00:56:11,897 CHRIS IN THE IMAGING STUDYING 1133 00:56:11,897 --> 00:56:14,433 AND BRUCE VOLPE AND TRUTH IN 1134 00:56:14,433 --> 00:56:16,501 ADVERTISING THESE MY HUSBAND IN 1135 00:56:16,501 --> 00:56:20,539 SOME OF THE HISTOLOGY OF THE 1136 00:56:20,539 --> 00:56:20,906 BRAIN. 1137 00:56:20,906 --> 00:56:29,247 CINDY AND MEGAN SEE THE PATIENTS 1138 00:56:29,247 --> 00:56:30,749 AND PAT O DOES THE PHYSIOLOGY 1139 00:56:30,749 --> 00:56:32,284 FOR US AND THEN WE HAD 1140 00:56:32,284 --> 00:56:35,320 COLLABORATORS AT OTHER 1141 00:56:35,320 --> 00:56:36,788 INSTITUTIONS WHO HAVE EITHER 1142 00:56:36,788 --> 00:56:38,523 HELPED US WITH EXPERIMENTS, 1143 00:56:38,523 --> 00:56:40,158 TAUGHT US SOMETHING OR GIVEN US 1144 00:56:40,158 --> 00:56:40,392 IDEAS. 1145 00:56:40,392 --> 00:56:49,301 I'M FLAD TO --GLAD TO ANSWER AY 1146 00:56:49,301 --> 00:56:49,568 QUESTIONS. 1147 00:56:49,568 --> 00:56:50,235 [ APPLAUSE ] 1148 00:56:50,235 --> 00:56:50,836 NWONDERFUL SEMINAR. 1149 00:56:50,836 --> 00:56:54,473 I WAS CURIOUS FOR THE CLINICAL 1150 00:56:54,473 --> 00:56:58,110 TRIAL WHY YOU CHOSE THE FDG PET 1151 00:56:58,110 --> 00:57:00,178 OVER THE ALLELE ACTIVATION? 1152 00:57:00,178 --> 00:57:01,613 >> YOU KNOW YOU HAVE TO CHOOSE 1 1153 00:57:01,613 --> 00:57:06,318 THING, AND WE HAD THE DATA THAT 1154 00:57:06,318 --> 00:57:09,020 PEOPLE WHO WERE ON CENTRALLY 1155 00:57:09,020 --> 00:57:10,188 ACTING ACE INHIBITORS OVER TIME 1156 00:57:10,188 --> 00:57:12,657 HAD A DECREASE IN THEIR HYPER 1157 00:57:12,657 --> 00:57:14,326 METABOLISM. 1158 00:57:14,326 --> 00:57:15,627 SO WE KNEW THAT. 1159 00:57:15,627 --> 00:57:17,929 I BELIEVE THEY WILL ALSO HAVE A 1160 00:57:17,929 --> 00:57:19,264 DECREASE IN MICROFLEEL 1161 00:57:19,264 --> 00:57:21,833 ACTIVATION, BUT WE DIDN'T HAVE 1162 00:57:21,833 --> 00:57:23,101 LONGITUDINAL STUDIES AT THE TIME 1163 00:57:23,101 --> 00:57:26,171 THAT WE WROTE FOR FUNDING FOR 1164 00:57:26,171 --> 00:57:29,241 THE TRIAL TO SHOW THAT THERE WAS 1165 00:57:29,241 --> 00:57:33,411 A DECREASE IN THOSE INDIVIDUALS 1166 00:57:33,411 --> 00:57:34,646 WITH THE MICROFLEEL ACTIVATION 1167 00:57:34,646 --> 00:57:38,083 BECAUSE WE JUST STARTED USING 1168 00:57:38,083 --> 00:57:39,618 THAT PET LIGAND LATER IN THE 1169 00:57:39,618 --> 00:57:42,354 COURSE OF OUR STUDIES. 1170 00:57:42,354 --> 00:57:43,321 SO I ACTUALLY THINK THAT YOU 1171 00:57:43,321 --> 00:57:46,091 WANT TO GO FOR THE TARGET RIGHT? 1172 00:57:46,091 --> 00:57:47,959 YOU WANT TO SHOW YOU HAD AN 1173 00:57:47,959 --> 00:57:50,695 EFFECT ON YOUR PRESUMED TARGET 1174 00:57:50,695 --> 00:57:56,468 AND HOPE THAT THE MICRODPLEEL 1175 00:57:56,468 --> 00:57:57,202 ACTIVATION WILL SURELY CHANGE 1176 00:57:57,202 --> 00:58:00,806 AND IF I WERE DESIGNING IT NOW 1177 00:58:00,806 --> 00:58:02,207 AND WE HAD LONGITUDINAL DATA 1178 00:58:02,207 --> 00:58:05,544 THAT WOULD BE THE PRIMARY END 1179 00:58:05,544 --> 00:58:07,078 POINT. 1180 00:58:07,078 --> 00:58:10,148 >> ALSO YOU MENTIONED THE C1 Q 1181 00:58:10,148 --> 00:58:13,185 LOSS OF FUNCTION IS A MAJOR 1182 00:58:13,185 --> 00:58:14,352 SUSCEPTIBILITY FOR SLE, IT SEEMS 1183 00:58:14,352 --> 00:58:17,122 LIKE THAT'S THE OPPOSITE OF WHAT 1184 00:58:17,122 --> 00:58:19,491 YOU JUST SHOWED US. 1185 00:58:19,491 --> 00:58:20,926 >> SO I'M ONLY SHOWING YOU IN 1186 00:58:20,926 --> 00:58:25,463 THE BRAIN, RIGHT AND BECAUSE IN 1187 00:58:25,463 --> 00:58:28,700 FACT, C1 Q IS CRITICAL TO 1188 00:58:28,700 --> 00:58:31,436 DECREASING MYELOID CELL 1189 00:58:31,436 --> 00:58:34,272 ACTIVATION IN THE PERIPHERY, AND 1190 00:58:34,272 --> 00:58:36,508 YOU GET ACTIVATED DENDRITIC 1191 00:58:36,508 --> 00:58:39,511 CELLS, ACTIVATED MYELOID CELLS, 1192 00:58:39,511 --> 00:58:42,147 MORE T-CELL ACTIVATION, MORE 1193 00:58:42,147 --> 00:58:45,750 B-CELL ACTIVATION AND YOU END UP 1194 00:58:45,750 --> 00:58:47,652 WITH A LUPUS LIKE PHENOTYPE, I 1195 00:58:47,652 --> 00:58:49,588 THOUGHT YOU WERE GOING TO ASK ME 1196 00:58:49,588 --> 00:58:52,224 WHAT THOSE PEOPLE LOOK LIKE IN 1197 00:58:52,224 --> 00:58:56,228 TERMS OF BRAIN FUNCTION AND I 1198 00:58:56,228 --> 00:58:59,264 WISH I KNEW. 1199 00:58:59,264 --> 00:59:00,899 KEITH ELCON AT THE UNIVERSITY OF 1200 00:59:00,899 --> 00:59:02,000 WASHINGTON IN SEATTLE HAS A 1201 00:59:02,000 --> 00:59:03,902 COHORT OF THEM AND I KEEP ASKING 1202 00:59:03,902 --> 00:59:06,571 HIM TO STUDY THE BRAIN. 1203 00:59:06,571 --> 00:59:11,643 >> THANK YOU . 1204 00:59:11,643 --> 00:59:13,011 >> SO I DON'T KNOW. 1205 00:59:13,011 --> 00:59:13,311 >> YES. 1206 00:59:13,311 --> 00:59:15,547 >> GREAT TALK BOO I THE WAY, IN 1207 00:59:15,547 --> 00:59:17,415 YOUR TALK YOU KEEP MENTIONING C1 1208 00:59:17,415 --> 00:59:20,518 Q BUT IN THE BRAIN IS C1 Q 1209 00:59:20,518 --> 00:59:24,823 COMPLEXED WITH C1 R AND C1 S AS 1210 00:59:24,823 --> 00:59:29,060 A COMPLEX OR IS IT STAND ALONE 1211 00:59:29,060 --> 00:59:32,597 NYES AND INFACT HGMGB1 INCREASES 1212 00:59:32,597 --> 00:59:33,598 PRODUCTION IN ALL OF THIS. 1213 00:59:33,598 --> 00:59:36,268 >> SO IN THE BRAIN IT WILL 1214 00:59:36,268 --> 00:59:36,735 ALWAYS-- 1215 00:59:36,735 --> 00:59:38,136 >> OH, ALWAYS, --I DON'T KNOW. 1216 00:59:38,136 --> 00:59:43,041 >> I CAN TELL YOU THEY'RE THERE. 1217 00:59:43,041 --> 00:59:47,445 I CAN'T TELL YOU THAT THEY'RE 1218 00:59:47,445 --> 00:59:48,013 ALWAYS COMPLEXED TOGETHER. 1219 00:59:48,013 --> 00:59:53,051 AND I CAN TELL YOU C1 Q, ALONE 1220 00:59:53,051 --> 00:59:55,353 CAN BIND LAYER 1 AND THE WHOLE 1221 00:59:55,353 --> 00:59:57,989 COMPLEX CAN BIND LAYER 1 NSO THE 1222 00:59:57,989 --> 01:00:00,325 WHOLE COMPLEX IS NOT NECESSARY 1223 01:00:00,325 --> 01:00:03,795 FOR THIS PATTERN? 1224 01:00:03,795 --> 01:00:05,730 >> FOR ENGAGING LAIR 1 AND 1225 01:00:05,730 --> 01:00:07,799 SUPPRESSING MACROPHAGES IN THE 1226 01:00:07,799 --> 01:00:08,633 PERIPHERY, NO. 1227 01:00:08,633 --> 01:00:11,703 THE WHOLE COMPLEX IS NOT 1228 01:00:11,703 --> 01:00:12,604 NECESSARY. 1229 01:00:12,604 --> 01:00:14,039 >> DOES ANYTHING HAPPEN DOWN 1230 01:00:14,039 --> 01:00:14,806 STREAM OF THAT? 1231 01:00:14,806 --> 01:00:16,875 OR DOES IT END THERE? 1232 01:00:16,875 --> 01:00:18,977 >> YOU MEAN WHAT'S DOWN TREME OF 1233 01:00:18,977 --> 01:00:24,115 LAIR 1 IN LAIR 1 HAS 2 ITEM 1234 01:00:24,115 --> 01:00:25,150 MOTIFS. 1235 01:00:25,150 --> 01:00:26,418 >> NO, C1 Q? 1236 01:00:26,418 --> 01:00:27,686 >> WHAT? 1237 01:00:27,686 --> 01:00:29,921 >> IN THE NORMALY COMPLEMENT 1238 01:00:29,921 --> 01:00:30,655 ACTIVATION, DOES ANYTHING HAPPEN 1239 01:00:30,655 --> 01:00:32,524 AFTER THAT OR DOES THIS PATHWAY 1240 01:00:32,524 --> 01:00:35,627 JUST SORT OF END AT C1 Q AND 1241 01:00:35,627 --> 01:00:39,197 THEN ACTIVATING ON LAIR 1 NWELL, 1242 01:00:39,197 --> 01:00:44,502 C1 Q HAS MANY RECEPTORS THAT 1243 01:00:44,502 --> 01:00:47,372 REQUIRE ONLY C1 Q FOR ENGAGEMENT 1244 01:00:47,372 --> 01:00:50,976 AND DOWN STREAM PATHWAY 1245 01:00:50,976 --> 01:00:51,776 ACTIVATION. 1246 01:00:51,776 --> 01:00:55,080 C1 Q IS ALSO PART OF THE 1247 01:00:55,080 --> 01:00:56,147 COMPLEMENT CASCADE THAT CAN END 1248 01:00:56,147 --> 01:01:00,618 UP WITH THE MEMBRANE ATTACK 1249 01:01:00,618 --> 01:01:01,753 COMPLEX, RIGHT? 1250 01:01:01,753 --> 01:01:05,523 SO, I HONESTLY THINK OF HMGB1 1251 01:01:05,523 --> 01:01:10,895 AND C1 Q, AS THE PRIMORDIAL 1252 01:01:10,895 --> 01:01:11,629 CYTOKINES. 1253 01:01:11,629 --> 01:01:12,864 THEY'RE EVOLUTIONAR VERY 1254 01:01:12,864 --> 01:01:15,200 CONSERVED, THEY PRECEDE ADAPTIVE 1255 01:01:15,200 --> 01:01:18,737 IMMUNITY BY A GAZILLION YEARS 1256 01:01:18,737 --> 01:01:20,872 AND HMGB1 IS PRO INFLAMMATORY 1257 01:01:20,872 --> 01:01:24,776 AND AT LEAST IN THE PERIPHERY C1 1258 01:01:24,776 --> 01:01:26,644 Q IS ANTIINFLAMMATORY BUT C1 Q 1259 01:01:26,644 --> 01:01:31,516 CAN FUNCTION AS PART OF THE--AND 1260 01:01:31,516 --> 01:01:33,218 THEY BOTH HAVE NUMEROUS 1261 01:01:33,218 --> 01:01:35,620 RECEPTORS, SO IT'S BEFORE YOU 1262 01:01:35,620 --> 01:01:40,992 GOT 1 CYTOKINE, 1 RECEPTOR AND 1263 01:01:40,992 --> 01:01:44,195 IT CAN FUNCTION INDEPENDENTLY OF 1264 01:01:44,195 --> 01:01:46,264 THE COMPLEMENT CASCADE BINDING 1265 01:01:46,264 --> 01:01:49,167 MANY DIFFERENT RECEPTORS ON 1266 01:01:49,167 --> 01:01:49,567 CELLS. 1267 01:01:49,567 --> 01:01:50,935 >> AWESOME. 1268 01:01:50,935 --> 01:01:57,776 AND THEN MY SECOND QUESTION IS-- 1269 01:01:57,776 --> 01:02:07,485 >> CAN YOU JUST STAY THERE 1270 01:02:07,485 --> 01:02:08,053 AND--OKAY, SORRY. 1271 01:02:08,053 --> 01:02:11,056 >> SO DID I GET IT RIGHT THAT 1272 01:02:11,056 --> 01:02:12,824 THE ANTIBODY INCREASES 10 FOLD 1273 01:02:12,824 --> 01:02:14,793 AFENNITY FOR DNA, AFTER IT GETS 1274 01:02:14,793 --> 01:02:18,396 THE MUTATION WHICH BINDS THE 1275 01:02:18,396 --> 01:02:20,231 RECEPTOR? 1276 01:02:20,231 --> 01:02:22,901 >> THE ANTIBODY WITH 10 FOLD 1277 01:02:22,901 --> 01:02:24,636 INCREASED AFFINITY FOR DNA IN 1278 01:02:24,636 --> 01:02:27,439 FACT DOES NOT CROSS REACT WITH 1279 01:02:27,439 --> 01:02:28,039 THE NMDA RECEPTOR. 1280 01:02:28,039 --> 01:02:30,241 IT'S THE LOWER AFFINITY AND THE 1281 01:02:30,241 --> 01:02:33,778 ANTIBODY WHICH WE GOT TO, WE GOT 1282 01:02:33,778 --> 01:02:34,646 TO THE PEPTIDE LIBRARY BECAUSE 1283 01:02:34,646 --> 01:02:37,982 WE WANTED TO KNOW THE DIFFERENCE 1284 01:02:37,982 --> 01:02:40,685 THEEN THOSE ANTIBODIES, BUT THE 1285 01:02:40,685 --> 01:02:42,921 ANTIBODY, THIS IS THE LOWER 1286 01:02:42,921 --> 01:02:44,422 AFFINITY ANTIBODY AND THIS IS 1287 01:02:44,422 --> 01:02:47,292 THE ANTIBODY THAT IS PRESENT IN 1288 01:02:47,292 --> 01:02:47,559 PATIENTS. 1289 01:02:47,559 --> 01:02:51,496 >> YEAH, SO DO YOU SEE IN THE 1290 01:02:51,496 --> 01:02:55,166 BRAIN, DO YOU SEE DNA RELEASE BY 1291 01:02:55,166 --> 01:02:57,035 DAMAGE CELLS WHICH THEN CAN 1292 01:02:57,035 --> 01:02:58,503 POTENTIALLY CUT OFF LINK AND 1293 01:02:58,503 --> 01:03:01,473 LEAD TO THIS SUSTAINING 1294 01:03:01,473 --> 01:03:03,541 INFLAMMATION AND CASCADE IN. 1295 01:03:03,541 --> 01:03:08,379 >> SO WE DON'T SEE INCREASE-- 1296 01:03:08,379 --> 01:03:09,214 >> EXCUSE ME? 1297 01:03:09,214 --> 01:03:11,649 >> TALK TO THE MICROPHONE. 1298 01:03:11,649 --> 01:03:12,817 >> OH SORRY. 1299 01:03:12,817 --> 01:03:14,452 >> SORRY. 1300 01:03:14,452 --> 01:03:16,154 NWE DON'T SEE CONTINUAL LOSS OF 1301 01:03:16,154 --> 01:03:17,789 NEURONS IN THE BRAIN. 1302 01:03:17,789 --> 01:03:21,526 WE SEE LOSS OF NEURONS OVER THE 1303 01:03:21,526 --> 01:03:23,761 FIRST 48, 72 HOURS, AND THEN 1304 01:03:23,761 --> 01:03:28,199 WHEN WE GO COUNT NEURONS, WE 1305 01:03:28,199 --> 01:03:31,603 DON'T SEE ANY CONTINUOUS LOSS 1306 01:03:31,603 --> 01:03:34,372 AND WHEN WE LOOK AT THE BRAINS A 1307 01:03:34,372 --> 01:03:36,674 YEAR LATER, WE DON'T SEE THAT 1308 01:03:36,674 --> 01:03:41,112 THEY'RE MORE NEURONS LOST THAN 1309 01:03:41,112 --> 01:03:42,013 THERE WERE IMMEDIATELY. 1310 01:03:42,013 --> 01:03:44,582 SO WE CAN'T TELL THAT YOU 1311 01:03:44,582 --> 01:03:48,353 THERE'S NO DEATH IN RELEASE OF 1312 01:03:48,353 --> 01:03:52,323 DNA, BUT I DON'T THINK IT'S AN 1313 01:03:52,323 --> 01:03:52,790 ONGOING BIG EVENT. 1314 01:03:52,790 --> 01:03:55,627 YOU KNOW THERE'S SUPPOSED TO BE 1315 01:03:55,627 --> 01:03:56,427 NEURONAL NEOGENESIS AND WE 1316 01:03:56,427 --> 01:03:58,530 LOOKED FOR THAT AND WE DON'T SEE 1317 01:03:58,530 --> 01:04:02,867 THAT SO IT'S NOT AS IF NEW 1S, 1318 01:04:02,867 --> 01:04:05,703 IT'S NOT OBVIOUS TO US OR NOT 1319 01:04:05,703 --> 01:04:11,643 DETECTABLE BY US THAT NEW 1S ARE 1320 01:04:11,643 --> 01:04:13,178 BEING GENERATED AND OTHERS 1321 01:04:13,178 --> 01:04:14,879 CONTINUE TO DIE. 1322 01:04:14,879 --> 01:04:17,949 >> AND THE RECEPTOR IS IT 1323 01:04:17,949 --> 01:04:21,352 SPECIFIC FOR HYPOCAMPICAL 1324 01:04:21,352 --> 01:04:23,054 RECEPTOR OR NOT? 1325 01:04:23,054 --> 01:04:24,255 >> IS THE NMDA, IT'S ALL OVER 1326 01:04:24,255 --> 01:04:27,358 AND IF YOU INYECT, IT'S 1327 01:04:27,358 --> 01:04:29,294 WHERE--SO WE'VE DONE THE STUDY 1328 01:04:29,294 --> 01:04:31,462 WHERE WE GIVE MICE EPINEPHRINE 1329 01:04:31,462 --> 01:04:33,064 AND AT THE TIME OF THE FIRST 1330 01:04:33,064 --> 01:04:35,833 GULF WAR THEY DORPHED THAT 1331 01:04:35,833 --> 01:04:40,538 EPINEPHRINE OPENS THE BLOOD 1332 01:04:40,538 --> 01:04:41,806 BRAIN BARRIER AND BECAUSE OF ALL 1333 01:04:41,806 --> 01:04:46,077 OF THE TROOPS WHO GOT SOME YOU 1334 01:04:46,077 --> 01:04:49,314 KNOW DRUG TO PROTECT YOU AGAINST 1335 01:04:49,314 --> 01:04:51,616 GERM WARFARE AT BASE CAMP THEN 1336 01:04:51,616 --> 01:04:53,451 GOT PSYCHOTIC WHEN THEY GOT THE 1337 01:04:53,451 --> 01:04:58,690 DRUGS IN TANKS ON THE DESERTS OF 1338 01:04:58,690 --> 01:05:00,758 KUWAIT AND YOU GIVE EPINEPHRINE, 1339 01:05:00,758 --> 01:05:02,126 YOU OPEN UP THE BLOOD BRAIN 1340 01:05:02,126 --> 01:05:03,127 BARRIER IN THE ARK MIG DUALA 1341 01:05:03,127 --> 01:05:06,331 DUALA AND YOU GET AN ALTERATION 1342 01:05:06,331 --> 01:05:07,031 IN FEAR CONDITIONING. 1343 01:05:07,031 --> 01:05:09,834 >> SO WHY DO YOU THINK THEN IT 1344 01:05:09,834 --> 01:05:11,469 JUST TRIGGER THIS IS SPECIFIC 1345 01:05:11,469 --> 01:05:14,038 NEURONS IN THIS DEC, DO YOU HAVE 1346 01:05:14,038 --> 01:05:15,206 A HYPOTHESIS FOR THAT? 1347 01:05:15,206 --> 01:05:19,210 >> I THINK WHERE IT ENTERS THE 1348 01:05:19,210 --> 01:05:21,379 BRAIN IT CAUSES EXCITE O 1349 01:05:21,379 --> 01:05:24,816 TOXICITY OF THE NEURONS IN THAT 1350 01:05:24,816 --> 01:05:25,049 REGION. 1351 01:05:25,049 --> 01:05:31,322 IF YOU INYECT --INJECT IT INTO 1352 01:05:31,322 --> 01:05:33,124 THE CORTEXSTER O PATHICALLY YOU 1353 01:05:33,124 --> 01:05:34,158 GET DEATH IN THE CORTEX. 1354 01:05:34,158 --> 01:05:36,594 SO I THINK WE HAVE NOT AT ALL 1355 01:05:36,594 --> 01:05:42,233 SEEN EVERYWHERE IT MAY ENTER THE 1356 01:05:42,233 --> 01:05:42,567 BRAIN. 1357 01:05:42,567 --> 01:05:45,436 >> SO IN YOUR TALK YOU SAID THAT 1358 01:05:45,436 --> 01:05:49,107 LIKE PATIENTS ARE AT INCREASED 1359 01:05:49,107 --> 01:05:50,108 RISK OF NEUROPSYCHIATRIC 1360 01:05:50,108 --> 01:05:51,909 SYMPTOMS IF THEY HAVE SOME KIND 1361 01:05:51,909 --> 01:05:54,012 OF DISRUPTION TO THE BLOOD BRAIN 1362 01:05:54,012 --> 01:05:56,648 BARRIERS SO I WOULD AT LEAST 1363 01:05:56,648 --> 01:06:01,653 MEAN SOMETHING LIKE INFECTION OR 1364 01:06:01,653 --> 01:06:02,020 LIKE, YOU KNOW? 1365 01:06:02,020 --> 01:06:04,856 >> WELL, SO, IT CAN BE 1366 01:06:04,856 --> 01:06:08,993 INFECTION, THAT'S FOR SURE. 1367 01:06:08,993 --> 01:06:10,828 IT CAN BE VERY GREAT STRESS. 1368 01:06:10,828 --> 01:06:12,597 I DON'T KNOW THE DEGREE OF 1369 01:06:12,597 --> 01:06:18,403 STRESS BUT IT CAN BE THAT. 1370 01:06:18,403 --> 01:06:20,672 SMOKING, AGING, HYPERTENSION ALL 1371 01:06:20,672 --> 01:06:22,740 DISRUPT THE AT THE BLOOD BRAIN 1372 01:06:22,740 --> 01:06:24,909 BARRIER AND 1 OF THE THINGS THAT 1373 01:06:24,909 --> 01:06:31,149 I WORRY ABOUT A LOT IN ALL OF US 1374 01:06:31,149 --> 01:06:34,018 IS THAT THE GUT MICROBI OTA 1375 01:06:34,018 --> 01:06:38,156 MAINTAINED THE BLOOD BRAIN 1376 01:06:38,156 --> 01:06:40,725 BARRIER, AND WE SHOWED WITH 1377 01:06:40,725 --> 01:06:41,993 PATTERSON YEARS AGO THAT 1378 01:06:41,993 --> 01:06:43,394 GERM-FREE MICE DON'T HAVE A 1379 01:06:43,394 --> 01:06:46,998 BLOOD BRAIN BARRIER AND THAT IF 1380 01:06:46,998 --> 01:06:49,867 YOU IMIF MICE, ADULT MICE 1381 01:06:49,867 --> 01:06:51,703 ANTIBIOTICS THEY LOSE THEIR 1382 01:06:51,703 --> 01:06:53,871 BLOOD BRAIN BARRIER, THEY LOSE 1383 01:06:53,871 --> 01:06:56,074 THEIR BLOOD BRAIN BARRIER IN THE 1384 01:06:56,074 --> 01:06:58,476 HIPPOCAMPUS AND THE INTERRHINAL 1385 01:06:58,476 --> 01:07:00,144 CORTEX, SO, YOU KNOW IF YOU HAVE 1386 01:07:00,144 --> 01:07:05,316 MORE INFECTIONS YOU GET MORE 1387 01:07:05,316 --> 01:07:07,085 ANTIBIOTICS, AND SO I DON'T KNOW 1388 01:07:07,085 --> 01:07:09,587 WHAT'S CAUSING IT IN INDIVIDUAL 1389 01:07:09,587 --> 01:07:11,889 PATIENTS BUT THERE ARE LOTS OF 1390 01:07:11,889 --> 01:07:13,291 INSULTS THAT COULD COMPROMISE 1391 01:07:13,291 --> 01:07:15,593 THE BLOOD BRAIN BARRIER. 1392 01:07:15,593 --> 01:07:18,696 >> DOES IT MATTER THE TIMING OF 1393 01:07:18,696 --> 01:07:19,030 THESE INSULTS? 1394 01:07:19,030 --> 01:07:23,034 >> IF YOU HAVE THE ANTIBODIES 1395 01:07:23,034 --> 01:07:23,601 THEY'LL GET IN. 1396 01:07:23,601 --> 01:07:24,702 >> SO EVEN IF THEY'RE IN 1397 01:07:24,702 --> 01:07:31,943 REMISSION, IF THAT COULD BE 1398 01:07:31,943 --> 01:07:32,210 OBSERVED? 1399 01:07:32,210 --> 01:07:32,877 >> OKAY, THAIRNGS. 1400 01:07:32,877 --> 01:07:33,811 >> REALLY BEAUTIFUL TALK, THANK 1401 01:07:33,811 --> 01:07:35,046 YOU. 1402 01:07:35,046 --> 01:07:38,282 I HAVE 2 QUESTIONS, 1 IS--SO 1403 01:07:38,282 --> 01:07:41,085 YOUR ANTIBODY IS AGONISTIC, IT 1404 01:07:41,085 --> 01:07:45,189 SIGNALS THROUGH THE NMDR 1405 01:07:45,189 --> 01:07:45,456 RECEPTOR. 1406 01:07:45,456 --> 01:07:47,692 >> IT'S CALLED A POSITIVE 1407 01:07:47,692 --> 01:07:50,128 ALOESTERRIC MODULATOR THIS, IS 1408 01:07:50,128 --> 01:07:51,329 WORK WE DID WITH COLLEAGUES AT 1409 01:07:51,329 --> 01:07:53,865 STONY BROOK SO IT WILL NOT 1410 01:07:53,865 --> 01:07:58,403 ACTIVATE THE NMDA RECEPTOR BY 1411 01:07:58,403 --> 01:07:58,636 ITSELF. 1412 01:07:58,636 --> 01:08:01,506 IT POTENTIATES THE ACTIVATION IF 1413 01:08:01,506 --> 01:08:02,940 GLUTAMATE OR NMDA IS THERE. 1414 01:08:02,940 --> 01:08:07,378 >> SO DO YOU THINK THAT THAT THE 1415 01:08:07,378 --> 01:08:08,413 HMGB1 RELEASE BECAUSE YOU 1416 01:08:08,413 --> 01:08:10,848 MENTIONED IT HAS TO COME FROM 1417 01:08:10,848 --> 01:08:12,150 NEURONS RATHER THAN FROM GLUE 1418 01:08:12,150 --> 01:08:15,186 MARIOUSA, SO DO YOU THINK THAT 1419 01:08:15,186 --> 01:08:20,458 IT'S PART OF SOME KIND OF 1420 01:08:20,458 --> 01:08:22,593 COMPENSATORY MECHANISM TO DOWN 1421 01:08:22,593 --> 01:08:23,928 REGULATE SYNAPSE SIS ON NEURONS 1422 01:08:23,928 --> 01:08:27,632 THAT ARE EXPRESSED OR EXCITED BY 1423 01:08:27,632 --> 01:08:27,965 TOXICITY? 1424 01:08:27,965 --> 01:08:31,469 >> YOU KNOW, I THINK THERE'S 1425 01:08:31,469 --> 01:08:37,975 PROBABLY A ROLE OF HMGB1 IN 1426 01:08:37,975 --> 01:08:40,478 MAINTAINING NORMAL SYNAPTIC 1427 01:08:40,478 --> 01:08:42,513 FUNCTION IN NEURONS BECAUSE IT 1428 01:08:42,513 --> 01:08:44,048 BINDS NEURONS. 1429 01:08:44,048 --> 01:08:47,051 IT CAN POTENTIATE, IT ALSO 1430 01:08:47,051 --> 01:08:50,688 POTENTIATES THE NMDA RECEPTOR. 1431 01:08:50,688 --> 01:08:54,559 WE ACTUALLY SEE MORE DENDRITIC 1432 01:08:54,559 --> 01:08:56,227 ARBORIZATION IN THE KNOCKOUT 1433 01:08:56,227 --> 01:08:58,529 MICE, SO I THINK IT MAY BE 1434 01:08:58,529 --> 01:09:00,064 INVOLVED IN NORMAL DEVELOPMENT 1435 01:09:00,064 --> 01:09:07,205 BUT I AM NOT A NEUROSCIENTIST 1436 01:09:07,205 --> 01:09:09,307 AND I AM ALREADY FAR AFIELD FROM 1437 01:09:09,307 --> 01:09:11,509 THINGS I KNOW. 1438 01:09:11,509 --> 01:09:14,178 SO I THINK YOU'RE RIGHT. 1439 01:09:14,178 --> 01:09:17,148 I THINK IT IS PLAYING A ROLE AND 1440 01:09:17,148 --> 01:09:20,418 IT PLAYS A ROLE NORMALLY, BUT 1441 01:09:20,418 --> 01:09:23,688 EXACTLY WHAT THAT ROLE IS, I 1442 01:09:23,688 --> 01:09:24,222 DON'T KNOW. 1443 01:09:24,222 --> 01:09:25,957 AND THE LAST QUESTION IS, I 1444 01:09:25,957 --> 01:09:28,092 DON'T THINK I HAD FULLY 1445 01:09:28,092 --> 01:09:34,265 UNDERSTOOD WHAT DO YOU MEAN BY 1446 01:09:34,265 --> 01:09:35,333 REMAINING INFLAMMATION, RIGHT? 1447 01:09:35,333 --> 01:09:38,836 SO YOU SHOWED THAT THERE IS NO 1448 01:09:38,836 --> 01:09:42,773 ANTIBODY THERE, SO, I'M ASSUMING 1449 01:09:42,773 --> 01:09:46,611 THERE IS NO HNG B1, THE HNG B1 1450 01:09:46,611 --> 01:09:50,882 CONTINUES TO BE SECRETED TO A 1451 01:09:50,882 --> 01:09:51,315 YEAR'S TIME. 1452 01:09:51,315 --> 01:09:52,950 >> BUT IS IT SECRETED MORE IN 1453 01:09:52,950 --> 01:09:54,952 THIS MICE THAN IN THE CONTROL 1454 01:09:54,952 --> 01:09:56,087 MICE IN. 1455 01:09:56,087 --> 01:09:57,989 >> OH, ABSOLUTELY, I SHOWED YOU 1456 01:09:57,989 --> 01:10:01,592 THE PICTURE OF, SOPHISTICATED WE 1457 01:10:01,592 --> 01:10:05,897 CAN'T SEE SECRETED HMGB1, WE SEE 1458 01:10:05,897 --> 01:10:07,064 CYTOPLASMIC HMGB1 AND WHEN IT 1459 01:10:07,064 --> 01:10:09,534 LEAVES TO THE NUCLEUS TO GO TO 1460 01:10:09,534 --> 01:10:11,135 THE CYTOPLASM IT'S ACETALATED 1461 01:10:11,135 --> 01:10:13,137 AND RIGHT AND THEN SECRETED NYOU 1462 01:10:13,137 --> 01:10:15,907 SHOULD BE ABLE TO MEASURE HMGB1 1463 01:10:15,907 --> 01:10:17,775 IS SEE A SAMPLE OF THIS. 1464 01:10:17,775 --> 01:10:19,877 >> YEAH, YEAH, WE PROBABLY COULD 1465 01:10:19,877 --> 01:10:23,147 GETTING CSF OUT OF MICE WE'VE 1466 01:10:23,147 --> 01:10:26,684 DONE, IT'S NOT EASY AND 1467 01:10:26,684 --> 01:10:29,554 MEASURING HMGB1 IS ALSO NOT A 1468 01:10:29,554 --> 01:10:30,421 HIGHLY SENSITIVE ASSAY. 1469 01:10:30,421 --> 01:10:30,988 BUT YOU'RE RIGHT. 1470 01:10:30,988 --> 01:10:32,723 WE SHOULD DO IT. 1471 01:10:32,723 --> 01:10:37,428 >> AND YOU SEE THE CYTOPLASMIC 1472 01:10:37,428 --> 01:10:41,232 HMGB1 IN NEURONS, NOT NOT IN 1473 01:10:41,232 --> 01:10:42,533 MICROGLIA. 1474 01:10:42,533 --> 01:10:43,000 >> IN NEURONS. 1475 01:10:43,000 --> 01:10:43,701 IN NEURONS. 1476 01:10:43,701 --> 01:10:46,304 >> THANK YOU. 1477 01:10:46,304 --> 01:10:48,739 >> SO I WAS JUST WONDERING ABOUT 1478 01:10:48,739 --> 01:10:50,274 1 THING, AND ARE ALL THESE 1479 01:10:50,274 --> 01:10:52,877 ANTIBODIES COMING IN FROM THE 1480 01:10:52,877 --> 01:10:55,713 OUTSIDE OR AFTER THE BLOOD BRAIN 1481 01:10:55,713 --> 01:10:57,815 BARRIER IS OPENED CAN THEY COME 1482 01:10:57,815 --> 01:10:59,417 IN AND SETTLE INSIDE THEMSELVES 1483 01:10:59,417 --> 01:11:02,620 AND PRODUCE ANTIBODY IN C2 AND 1484 01:11:02,620 --> 01:11:06,490 IF YES, ANYBODY USING RETUX MAB? 1485 01:11:06,490 --> 01:11:09,260 NETWORK SO YOU KNOW RETUX MAB 1486 01:11:09,260 --> 01:11:10,928 HAS NOT WORKED IN THE CLINICAL 1487 01:11:10,928 --> 01:11:15,733 TRIALS IN LUPUS, NOBODY, I 1488 01:11:15,733 --> 01:11:17,101 ACTUALLY ASKED GENENTECH TO DO 1489 01:11:17,101 --> 01:11:18,636 BRAIN STUDIES IN THOSE TRIAL 1490 01:11:18,636 --> 01:11:20,538 ANDS THEY DIDN'T. 1491 01:11:20,538 --> 01:11:21,639 SO I DON'T KNOW ANYTHING ABOUT 1492 01:11:21,639 --> 01:11:24,508 THE BRAINS OF PEOPLE WITH THAT. 1493 01:11:24,508 --> 01:11:27,044 WE ACTUALLY ARE PARTNERING WITH 1494 01:11:27,044 --> 01:11:29,981 A CAR T-CELL GROUP TO LOOK AT 1495 01:11:29,981 --> 01:11:31,048 BRAINS NOW. 1496 01:11:31,048 --> 01:11:33,384 BUT WE DON'T SEE ANY B-CELLS IN 1497 01:11:33,384 --> 01:11:34,685 THE BRAIN AND IF YOU LOOK AT 1498 01:11:34,685 --> 01:11:45,196 PEOPLE LIKE THIS, IF YOU LOOK