>> ONE OF THE STUDENTS WHO IS WATCHING THIS ON VIDEO ASKED IF I WOULD BEGIN EACH LESSON WITH A SMALL RECAP OF WHERE THE IMPORTANT POINTS OF WHAT WE HAVE LEARNED SO FAR THAT ARE GOING TO BE APPLIED TO THIS SESSION. SO HERE THEY ARE. ONE, THAT YOU DON'T GET A PRIMARY IMMUNE RESPONSE UNLESS YOU ACTIVATE APC FOR STIMULATION, THAT YOU ACTIVATE APCs WHEN A CELL DIES BADLY AND SENDS A LARGE SIGNAL, I'M GETTING AN ECHO. IT DOESN'TSOME -- A TISSUE SENDING ALARM SIGNAL THAT INITIATES AN IMMUNE RESPONSE, IT'S A TISSUE PRESENTING ITS OWN ANTIGENS FOR ALLOWING ITS ANTIGENS TO GET TO UP ACTIVATED APC THAT INDUCE TOLERANCE. AND SIGNALS FROM TISSUES ALSO INFLUENCE THE CLASS OF IMMUNITY THAT YOU GET SO THAT IMMUNOLOGICAL CLASS SEEMS TO CHANGE FROM TISSUE TO TISSUE IN THE GUT -- STANDARD GUT IMMUNE RESPONSE IS IGA, THE STANDARD SKIN IMMUNORESPONSE IS PROBABLY A DTH, THE LUNG, EYE, PLACENTA, KIDNEY, AND THOSE AND PROBABLY MOST TISSUES DON'T LIKE DTHs, THEY DIE FROM INTERFERON GAMMA, TNF, ACTIVATED MACROPHAGES MAKING OXYGEN RADICALS, ET CETERA. SO IF WE TAKE THOSE THINGS, THOSE ASSUMPTIONS IN A WAY, I HAVE BEEN TOLD IF I WALK IN THE WRONG PLACE THE SPEAKERS ECHO. WELCOME APPLY -- WE CAN APPLY THEM TO THE TOPIC THAT BEFUDDLED IMMUNOLOGISTS FOR MORE THAN A CENTURY WHICH IS AUTO-IMMUNITY. I DON'T KNOW WHERE TO STAND. SO BEFORE WE GO INTO AUTOIMMUNE DISEASE, WHAT I WOULD LIKE TO DO IS GO THROUGH TOLERANCE. AND WE HAVE BEEN THROUGH BITS OF TOLERANCE OVER THE LAST FEW WEEKS, BUT LET'S CONCENTRATE ON IT FOR A FEW MINUTES BECAUSE I THINK THERE ARE THINGS THAT PEOPLE ARE TAUGHT THAT I THINK ARE PROBABLY INCORRECT OR AT LEAST THERE ARE ALTERNATIVE POINTS OF VIEW. SO I THINK WE HAVE ALL BEEN TAUGHT THAT THERE'S DELETION OF AUTOREACTIVE T-CELLS IN THE THYMUS. BY THE WAY, COULD YOU TURN THE MICROPHONE DOWN JUST A LITTLE BIT? MAYBE THAT WILL HELP ME MOVE AROUND A LITTLE, I'M NOT GOOD AT STANDING STILL. THANKS. SO A T-CELL GROWING UP IN THYMUS SEEMS TO DIE WHEN ITS T-CELL RECEPTOR IS STIMULATED, WHETHER IT GETS CO-STIMULATION OR NOT. SO WE HAD PAPER SHOWING THAT IF YOU ALLOW VERY ACTIVATED APCs TO DRAW INTO A THYMUS, THEY WILL INDUCE TOLERANCE DELETION TO THE ANTIGENS THEY PRESENT. AND WHAT THAT SAYS IS THAT IT'S NOT THE APC THAT MATTERS IN THAT PORTION OF TOLERANCE INDUCTIONS. THIS SEEMS TO BE A STAGE IN T-CELL DEVELOPMENT WHERE IF A T-CELL SEES ANTIGEN IT'S GOING TO DIE, NO MATTER WHAT THE CONTEXT OF THE PRESENTATION OF THAT ANTIGEN IS. SO T-CELLS THAT ARE GROWING UP IN THE THYMUS SPECIFIC FOR THYMIC EPITHELIUM, DIE, SPECIFIC FOR ANYTHING ON THE SURFACE OF A DENDRITIC CELL THEY DIE. IF THERE ARE SPECIFIC FOR ANYTHING ON THE SURFACE -- MOST THINGS ON SURFACE OF B CELLS THEY DIE BECAUSE THERE ARE B CELLS IN THE THYMUS. IN THE RAT IT'S UP TO 20%, IN THE MOUSE IT'S MORE LIKE TEN. THERE'S EVIDENCE THAT MACROPHAGES PICK UP BLOOD BORNE PROTEINS AND SUCH AND PRESENT THEM IN THE THYMUS AND THAT THE T-CELLS THAT CAN SEE THEM DIE, THAT WAS BREW KNOW'S WORK. AND SO IT REALLY LOOKS LIKE ANYTHING PRESENTED IN THE THYMUS WILL INDUCE TOLERANCE. WHAT IS THE FUNCTION OF THAT? I THINK THE MAIN FUNCTION OF THAT IS TO INDUCE TOLERANCE TO THE SURFACE MAP OF DENDRITIC CELLS. MOST TISSUES ISSUE TOLERANCE TO THEMSELVES BUT THEY DON'T CO-STIMULATE BUT DENDRITIC CELLS CO-STIMULATE SO YOU NEED TO GET RID OF T-CELLS THAT RESPOND TO SURFACE PRESENTED ANTIGENS ON A DENDRITIC CELL. ONCE YOU REMOVE THEM, YOU CAN TAKE CARE OF THE REST OF THEM IN OTHER PLACES. BUT YOU NEED TO REMOVE THEM BECAUSE DENDRITIC CELLS CAN CO-STIMULATE. SO WHEN I SAY THE SURFACE MAP WHAT DO I MEAN? WHAT IS A MAP? IT'S AN MHC ANTIGEN PROFILE. AND THE MAPS OF DIFFERENT CELLS ARE GOING TO VARY DEPENDING ON WHAT THAT CELL IS MAKING. AND THAT ACTUALLY SERVES AS A PROBLEM FOR AN IDEA WHICH IS CURRENT IN IMMUNOLOGICAL THEORY WHICH IS THAT THERE ARE CELLS IN THE THYMUS THAT CAN PRESENT ANTIGENS FOR PERIPHERAL TISSUES. SO THERE'S A MOLECULE CALLED AIR. PEOPLE THAT ARE MISSING IT HAVE A POLYGLANDULAR POLYAUTOIMMUNE DISEASE. THE IDEA IS THAT THE FUNCTION OF THIS GENE IS TO CAUSE CELLS IN THE THYMUS TO PRESENT ANTIGENS FROM PERIPHERAL TISSUES. SKIN, LIVER, ET CETERA. NOW, IT WOULD BE REALLY HARD FOR CELL IN THE THYMUS TO PRESENT ANTIGENS OF A LIVER CELL IN THE SAME WAY A LIVER CELL DOES WITHOUT BECOMING A LIVER CELL. WHY DO I SAY THAT? WHEN YOU THINK ABOUT THE SURFACE OF A CELL, AND THE MHC MOLECULES THAT THE DECOR RATE IT, CERTAIN PEPTIDES GET INTO THOSE MOLECULES AND OTHER PEPTIDES THAT CAN'T BECAUSE THEY DON'T HAVE THE RIGHT SEQUENCE. BUT AMONG ALL THE PEPTIDES THAT GET INTO ANY PARTICULAR MHC MOLECULE WHAT GOVERNS WHETHER THEY WILL GET THERE OR NOT? THE KINDS OF TINGS THAT ARE GOVERN THAT ASIDE FROM THAT PEPTIDES AFFINITY FOR THE GROOVE OF THE MHC MOLECULE WILL BE THINGS LIKE HOW MUCH OF THAT PEPTIDE IS MADE IN THAT CELL, HOW OFTEN IT'S DEGRADED, HOW OFTEN IT'S IMPROPERLY TRANSLATED, OR EVEN TRANSCRIBED. -- HAS AN EXPERIMENT SHOWING THAT CELLS ACTUALLY LIE ABOUT WHAT'S INSIDE THEM WHAT HIS LAW DID WAS TO MAKE A PIECE OF RNA FOR A PEPTIDE, THEY HAD T-CELLS THAT COULD SEE THAT PEPTIDE. THEN THEY SYNTHESIZED ONE EXTRA NUCLEOTIDE. SO THAT THE PEPTIDE WAS READ OUT OF FRAME. SO THAT PEPTIDE NOW WILL NOT BE THE RIGHT PEPTIDE, IT WILL BE THE WRONG PEPTIDE BECAUSE IT'S BEING READ OUT OF FRAME. THEY ASKED HOW OFTEN IS THE START CO-DON IMPERFECT SO THAT IT GETS READ IN-FRAME. DOES THAT MAKENESS SENSE? EVERYBODY WHAT I JUST SAID? SO BY CHEMICAL TECHNIQUES THEY COULDN'T SEE IT, THEY NEVER FOUND THE PEPTIDE BUT THEY HAD T-CELL CLONES THAT COULD SEE IT, WHEN THEY STUCK THE CONSTRUCT INTO APCs THE T-CELL CLONES RESPONDED. SO THE CELLS DON'T ALWAYS START EXACTLY AT THE START CODON PROPERLY. THEY SOMETIME MISTRANSLATE. SO ALL OF THESE THINGS ARE GOING TO CONTRIBUTE TO THE COMPETITION THAT VARIOUS PEPTIDES HAVE FOR GETTING INTO THE MHC GROOVE. IF YOU TAKE A SURFACE MAP OF A LIVER CELL, IN ORDER TO PROPERLY DUPLICATE THAT MAP YOU WOULD HAVE TO BE MAKING THE SAME THINGS THAT ARE BEING MADE INSIDE THE LIVER CELL, YOU WOULD HAVE TO BE DEGRADING THEM AT THE SAME RATE, UBIQUITINATING THEM AT THE SAME A RATE, PUTTING THEM THROUGH TAP AT THE SAME RATE, OTHERWISE COMPETITION IS NOT GOING TO BE THE SAME. AND THE DISPLAY OF PEPTIDES WON'T BE THE SAME AS IT IS ON A LIVER CELL. WHY DOES THAT MATTER? BECAUSE THE AFFINITY CUT-OFF FOR TOLERANCE DEPENDS -- AFFINITY IS AFFINITY BUT WHETHER YOU CAUSE THE T-CELL TO DELETE OR NOT DEPENDS ON AFFINITY AND ALSO THE CONCENTRATION WITH WHICH THAT PEPTIDE IS DISPLAYED. SO TO DISPLAY THE MAP OF THE LIVER CELL YOU BASICALLY HAVE TO BECOME A LIVER CELL. GO AHEAD. (OFF MIC) THE EXAMPLE YOU GAVE EARLIER ABOUT THE MISREAD PEPTIDE, I ASSUME THAT WOULD BE LIKE A REALLY LOW EFFICIENCY EVENT WHERE YOU -- A FEW ACTUALLY EXPRESS WITH REGARDS TO NORMALLY TRANSLATED VERSION? >> CORRECT. >> SO SEEMS TO BE A SIMILAR CASE WHAT YOU BROUGHT UP HERE THOUGH YOU HAVE HIGHER COMPETITION YOU MIGHT HAVE A LOW FREQUENCY EVENT THAT HAPPENS ENOUGH TO BE ABLE TO GET DELETION. >> OKAY. SO WHAT HE JUST SAID IS CORRECT, WHAT I JUST TALKED ABOUT ABOUT EXPERIMENTING IN -- LAB WHERE A PEPTIDE IS MISTRANSLATED WILL BE A LOW FREQUENCY EVENT COMPARED TO -- WELL, CERTAINLY A LOWER FREQUENCY EVENT THAN PROPER TRANSLATION OF. SO WHAT WILL HAPPEN IS P IF YOU HAVE A T-CELL THAT HAS HIGH AFFINITY FOR THAT PEPTIDE, EVEN THOUGH IT'S A LOW FREQUENCY EVENT, IT MIGHT GET DELETED. BUT A T-CELL WITH MEDIUM FREQUENCY FOR THAT PEPTIDE WON'T GET DELETED. IF YOU NOW HAVE A -- AND THAT WILL ALSO BE TRUE IN THE THYMUS. IF YOU HAVE A T-CELL LET'S SAY WHOSE JOB IS TO PRESENT PERIPHERAL ANTIGENS, PERIPHERAL PEPTIDES, THAT EVEN AT LOW FREQUENCY IT WILL CAUSE SOME DELETION. BUT IT WILL DELETE THE CELLS THAT CAN SEE IT AT THAT CONCENTRATION. NOW, THE ONES THAT GO OUT AND SEE IT SAY ON LIVER, AT HIGHER CONCENTRATION ON A LIVER SO IT DON'T WON'T DO DELETED. -- WON'T BE DELETED. SO DELETION IN THE THYMUS BECAUSE OF THIS MAP PROBLEM, EVEN IF AIR WERE FUNCTIONING PERFECTLY, UNLESS YOU ACTUALLY MAKE LIVER CELLS AND KIDNEY CELLS AND SKIN CELLS AND WHATEVER IN THE THYMUS, YOU'RE NOT GOING TO DELETE ALL THE T-CELLS THAT CAN SEE THE ANTIGENS IN THE PERIPHERY. >> YOU WON'T DELETE -- >> YOU WANT TO DELETE LOWER AFFINITY, YOU WANT TO DELETE MEDIUM AFFINITY AND YOU WANT TO DELETE THE HIGH AFFINITY THAT AREN'T SO HIGH THEY CAN'T GET DELETED WITH SAY THREE COPIES. YOU NEED TO DELETE WHATEVER CAN SEE, WHATEVER THE CONCENTRATION IS IN THE PERIPHERY. I SAW ANOTHER HAND. (OFF MIC) >> IF IT'S GOING TO BE MORE THAN A SHORT SENTENCE GO TO MICROPHONE. IN POLITENESS FOR PEOPLE WATCHING. >> SO I'M STILL WRY TRIKING TO WRAP MY HEAD AROUND THIS BECAUSE ANTIGENS THAT ARE PRESENTED IN THE PERIPHERY WON'T GET CO-STIMULATION SO THEY WON'T -- IT'S ALMOST LIKE THIS SYSTEM IS IN SOME WAYS UNNECESSARY OR REDUNDANT. >> THE THYMUS? -- >> THE AIR SYSTEM. >> THAT'S CORRECT. >> OKAY. >> THAT'S WHAT I THINK TOO BUT THAT'S CERTAINLY NOT WHAT THE FIELD THINKS. SO FOR A WHILE IT WAS THOUGHT AIR WAS EXPRESSED ONLY IN THE THYMUS. AND THEN SHANNON FURRILY SHOWED IT EXPRESSED IN PERIPHERAL LYMPHNODES. ONE OF THE ANTIGENS THAT HAS BEEN STUDIED QUITE A BIT IN ITS RELATIONSHIP TO PRESENTATION BY AIR IN THYMUS IS INSULIN. AND SO IF THERE IS AIR, T-CELLS TO INSULIN, T-CELLS SPECIFIC TO INSULIN AT CERTAIN AFFINITY GET DELETED. IF THERE'S NOT AIR THEY DON'T. IT'S KIND OF INTERESTING TO ME T-CELLS HAVE INSULIN RECEPTORS. THEY NEED INSULIN, I DON'T KNOW IF THEY NEED IT IN THE PERIPHERY BUT IT SEEMS THAT IT'S AN ASSUMPTION OF COURSE WHEN A CELL PUTS UP A RECEPTOR FOR SOMETHING THAT IT NEEDS THAT -- NAMES HA SOMETHING BUT LET'S ASSUME THAT FOR THE MOMENT. T-CELLS PUT UP INSULIN RECEPTORS SO IT MIGHT BE THAT THEY NEED INSULIN FOR THEIR DEVELOPMENT. AND THAT THE FUNCTION OF AIR OR AT LEAST A SUBSET DOES. AND THAT THE FUNCTION OF AIR A, IS TO MAKE ENOUGH INSULIN. ARE REMEMBER NO ISLETS NO BETA CELLS MAKING INSULIN AS FAR AS I KNOW. PERHAPS THE FUNCTION OF AIR IS TO MAKE ENOUGH INSULIN IN THIS ECTOPIC PLACE. FOR THERE TO BE ENOUGH INSULIN THERE FOR T-CELLS TO GET IT. OF COURSE INSULIN IN BLOOD BUT LEVELS GO UP AND DOWN AS YOU EAT AND FOR T-CELL DEVELOPMENT THAT MAY NOT BE A GOOD IDEA SO YOU MAY NEED A STEADY SOURCE OF INSULIN THAT. THAT'S TOTAL HAND WAVING THE BUT AT LEAST WITH THE MAP IDEA IT WOULD SEEM THE AIR EVEN IF IT'S FUNCTIONING TO CAUSE DELETION ANYTIME THYMUS CAN'T DO THAT GOOD A JOB. SO IF THERE ARE ANY EVIDENCE THAT IT DOESN'T DO THAT GOOD A JOB, ONE OF THE PAPERS THAT WAS ON THIS LIST OF NINE THAT I SENT YOU, SO SORRY. WAS THE FIRST PAPER THAT CAME OUT OF MY LAB AFTER I MOVEED TO THE NIH. -- MOVED TO THE NIH. AND IT WAS BY (INDISCERNIBLE). MY FIRST POST-DOC HERE. IT WAS BEFORE AIR BUTTED DOES COVERED. I WISH WE COULD CONSOLIDATE AGAIN, MY Ph.D. SUPERVISOR ONCE TOLD ME IF YOU WANT TO PUBLISH IN THE GX MED, YOU SHOULD READ THE GX MED 20 YEARS AGO AND REPEAT SOME OF THOSE EXPERIMENTS WITH MORE MODERN TECHNOLOGY AND THAT WILL GET YOU BACK IN THE GX MED. I WISH WE COULD DO THE THIS EXPERIMENT NOW, POST ARE. IT WAS DONE PRE- THE DISCOVERY OF ARE AND THE PEOPLE WHO PUBLISHED ON IT NEVER MENTION IT SO IT'S REALLY OBSCURE JOURNAL CALLED THE JOURNAL OF EXPERIMENTAL MEDICINE. WE TOOK D-6 MALE OR FEMALE THYMUSES EITHER FETAL OR KNEE NIGH TALL AND TRANSPLANTED THEM INTO BOLE C NUDE MICE. I MENTION THIS EXPERIMENT ONCE BEFORE. THEY HAVE NO THYMUS, NO T-CELLS. BUT IF YOU GIVE THYMUS UNDER KER KIDNEY CAPSULE WHICH IS A NICE PLACE TO PUT THINGS BECAUSE THEY GET GOOD BLOODS LIE IF YOU GIVE THYMUS THE CELLS WILL GROW UP IN THE B-6 THYMUS AND GO INTO THE PERIPHERY. THEY BECOME TOLERANT OF BOB C BECAUSE THEY ARE THEMSELVES BALD C AND PRESENTENING THYMUS AND ABCs ARE BALD C AND PRESENTENING THE THYMUS BUT THE EPITHELIUM IS B-6 SO THE QUESTION NOW IS ARE THEY TOLERANT OF B-6 PERIPHERAL TISSUES? WOULD ANYBODY LIKE TO MAKE A PREDICTIONS? HOW MANY SAY THEY WILL BE TOLERANT. 2. HOW MANY SAY NO, THEY WON'T BE TOLERANT. 1, 2, 3, 4, 5, 6, 7. THE REST REST OF YOU ARE WIMPS. CHOOSE, FROM WHAT YOU KNOW. FOR WHAT YOU THINK YOU KNOW, ARE THEY TOLERANT? 1, 2, 3, 4, 5. OR NOT TOLERANT. 1, 2, 3, 4, 5, 6, 7, 8, 9. GOOD. THEY'RE NOT. SO WE TRANSPLANTED B-6 SKIN AND THAT WAS REJECTED WE TRANSPLANTED SPLEEN, THAT'S HARD TO DO BECAUSE IF YOU CUT A SPLEEN IT BLEEDS AND KEEPS BLEEDING BECAUSE I WON'T CLOT SO WE USE FORCEPS AND SQUISH THE CAPSULE TOGETHER AND MADE PILLOWS OF SPLEEN AND THEY WERE REJECTED. IF WE TRANSPLANTED B-6 THYMUS. THE EPITHELIUM WAS ACCEPTED AND BONE MARROW WAS REJECTED. THEY WERE RED AND NASTY LOOKING, THERE WAS A HUGE REJECTION RESPONSE GOING IN, O GOING ON IN THERE. ALL THE BONE MARROW COMPONENTS AS FAR AS WE CAN ANALYZE WERE REJECTED. AND THE THYMIC EPITHELIUM WAS NOT. TO SHOW IT WAS REALLY NOT DAMAGED WE ANALYZE THOSE THYMUSES SOMETIME LATER AND SAW THAT IN THESE NEW THYMUSES THAT HAD NOT BEEN REJECTED THE BALD C STEM CELLS WERE GROWING UP THERE AND BECOMING T-CELLS DOUBLE POSITIVE SINGLE POSITIVE ASKER EXACTLY AS THEY DID IN THE FIRST THYMUS WE TRANSPLANTED. THEY LOOK EXACTLY LIKE THEY WOULD LOOK IF THEY HAD BEEN GROWING UP IN BALD C THYMUS. >> QUESTION HOW DO YOU KNOW THERE WEREN'T BLACK SIX (INAUDIBLE)? >> IT'S REALLY GOOD QUESTION. SO THE QUESTION IS, HOW DO WE KNOW THERE WEREN'T NIBLICK BLACK 6 STEM CELLS, BONE MARROW DERIVED CELLS? HERE? TWO WAYS. WE TREATED WITH DIOXYGUANOSINE, AND THE OTHER ONE WE IRRADIATED THEM 3,000 RAD, THAT WASN'T IN THE PAPER BUT IT GIVES YOU THE SAME RESULT SO FOR THOSE WHO WANT TO CULTURE THYMUS IN DEI DON'T KNOW CITY GUANOSINE TO GET RID OF BONE MARROW COMPONENTS YOU CAN IRRADIATE WITH 1500 RADS FOR THE SAME RESULT. YOU GET RID OF BONE MARROW AND KEEP THE THYMIC EPITHELIUM, MUCH QUICKER AND EASIER, AND A LOT EASIER ON THE THYMUS ACTUALLY TO GET -- THEY GET BIGGER AND MAKE MORE CELLS. SO WE WERE NOT THE ONLY LAB TO TO THIS, THEY FOUND IF THEY PUT IN THYMUSES, THAT THEY WOULD TOLL RISE FOR THYMUS BUT NOT FOR T-CELLS OR B CELLS. WHAT THIS SAYS IS THYMUS TOLL RISES FOR THYMUS. >> EPITHELIAL CELLS ARE SURVIVING. >> THERE WAS CORTEX MEDULLA? >> CORTEX AND MEDULLA. >> AND THE IF YOU LACK AT T-CELL DEVELOPMENT, IT LOOKS NORMAL. SO CELLS THAT POSITIVELY SELECT ARE STILL THERE AND CELLS THAT NEGATIVELY SELECT ARE STILL THERE. YOU GET THE NORMAL NUMBER, RATIOS OF CD4 TO CD8, SO ON. THE EPITHELIUM REALLY HAD NOT BEEN DAMAGED. >> INTERESTING. BECAUSE THERE IS A NEW PAPER IN NATURE IMMUNOLOGY SAYING THE CORTEX IN THE THYMUS HAVE PROTEOSOME. THAT MADE ALL THE ANTIGENS EXPRESSING T CELLS DIFFERENT TO ANY TYPE OF CELL BUT P IT IS ONLY WORKING CORTEX NOT MEDULLA. >> THAT'S FINE. WHAT'S HAPPENING HERE IS THE CORTEX IS TOLERIZING FOR ITSELF, WITH ITS DIFFERENT PROTEOSOME AND THE MEDULLA ARE IS TOLERIZING FOR ITSELF, BUT NOT FOR SKIN, SPLEEN, T-CELLS, B CELLS, ET CETERA. THAT DOESN'T SAY THAT ARE DOESN'T WORK, IT JUST SAYS THAT IT IS NOT THE ANSWER TO PERIPHERAL TOLERANCE. WHAT IS PRESENTED IN THE THYMUS IS NOT ENOUGH TO GIVE YOU PERIPHERAL TOLERANCE. IT HAS TO TOLERIZE FOR ITSELF. TWO WAYS PEOPLE THINK IT DOES THAT, TISSUES PRESENT CLASS ONE. MOST OF THEM, NOT ALL BUT MOST. AND SOME OF THEM ALSO CLASS # AND RATS FOR EXAMPLE KIDNEY CELLS EXPRESS CLASS 2. IN HUMANS T-CELLS EXPRESS CLASS 2. AND SO A T-CELL THAT IS CIRCULATING THAT SEE AS PERIPHERAL ANTIGEN UNDER HEALTHY CONDITIONS WILL GET SIGNAL ONE WITHOUT SIGNAL 2 AND DIE. NOW, THAT'S A SIMPLIFICATION BECAUSE IT COULD BE SIGNAL ONE PLUS SIGNAL 2 PLUS CO-INHIBITORY SIGNALS WITH WHICH MAY DIFFER FROM TISSUE TO TISSUE. I THINK THE CO-INHIBITOR SIGNALS ARE PROBABLY IMPORTANT FOR THE TOLERANCE INDUCTIONS. THE BALANCE JUST LIKE NK CELLS, IT'S A BALANCE OF CO-STIMULATORY SIGNALS AN CO-STIMULATORY SIGNALS SO SIGNAL ONE MINUS 2, THAT'S WHAT I MEAN. SO IF WE THINK ABOUT HOW GOOD TISSUES COULD BE AT DOING THAT, TISSUES ARE GOING TO VARY. SO THE LIVER IS HUGE. IT'S NOT VARY KATEED. SO SAY YOU HAVE -- SAY YOU HAVE TWO T-CELLS THAT LEAVE THYMUS ON THE SAME DAY. ONE IS SPECIFIC FOR A LIVER ANTIGEN THAT ISN'T IN THE THYMUS AND THE OTHER ONE IS SPECIFIC FOR A BRAIN ANTIGEN THAT ISN'T IN THE THYMUS. SO BECAUSE THE LIVER IS HUGE AND NOT -- AND BECAUSE TISSUES -- T-CELLS SEEM TO TRAFFIC OUT OF THE BLOOD INTO A TISSUE, BACK THROUGH THE LYMPHATICS AND BACK INTO THE BLOOD ABOUT ONCE EVERY 24 HOURS, THAT T-CELL SPECIFIC FOR LIVER ANTIGEN IS FAIRLY SOON GOING TO SEE THE LIVER ANTIGEN AND GET TOLERIZED. THE T-CELL SPECIFIC FOR A BRAIN ANTIGEN IS IN SLIGHTLY DIFFERENT CONDITION BECAUSE THE BRAIN IS BARRICADED. NOT COMPLETELY THERE ARE TISSUES THAT TRAVEL THROUGH IT BUT NOT AS P AS TRAVEL THROUGH THE LIVER SO THE T-CELL SPECIFIC FOR A BRAIN ANTIGEN WILL CIRCULATE FOR LONGER BEFORE I GOES THROUGH THE BRAIN OR BRAIN DRAINING NODES AND GET TOLERIZED. SO I WOULD PREDICT JUST APRIORI THAT IF WE WERE ABLE TO LOOK AT ALL SPECIFICITIES OF NAIVE T-CELLS IN OUR PERIPHERY, AT ANY PARTICULAR TIME WE WOULD FIND MORE AUTOREACTIVE T-CELLS TO TINY ENDOCRINE ORGANS LIKE ISLETS, OR BARRICADED ORGANS LIKE BRAIN. BECAUSE T-CELL THAT CAME OUT OF THE THYMUS LAST WEEK MAY NOT HAVE GONE THROUGH THERE YET. DOES THAT MAKE SENSE? SOME TISSUES ARE BETTER AT TOLERIZING THAN OTHERS. THE LIVER IS GO GOOD TOLERIZING FOR ITSELF IN CERTAIN COMBINATIONS OF RATS AN MICE AND CERTAIN HUMANS YOU CAN TRANSPLANT A LIVER IT WILL UNDERGO A HUGE REJECTION REACTION BUT THAT REJECTION REACTION STOP AND THE LIVER INDUCES TOLERANCE. REALLY GOOD AT TOLERIZING. IF YOU GIVE LIVER PLUS HEART YOU HAVE LESS REJECTION OF THE HEART THAN IF YOU JUST GAVE THE HEART. EVEN THOUGH YOU HAVE A MUCH HIGHER DOSE OF ANTIGEN, FOREIGN ANTIGEN BECAUSE LIVER IS SO GOOD AT TOLERIZING FOR ITSELF. OKAY SO WHAT'S IMPORTANT OUT OF THAT? THYMUS CAN'T DO IT ALL. B, DIFFERENT TISSUES ARE GOING TO BE DIFFERENTIALLY GOOD INDUCING TOLERANCE IN THEMSELVES. SO HOLD THOSE TWO ASSUMPTIONS FOR A BIT AND WE'LL GET INTO AUTO-IMMUNITY. BEFORE WE GET INTO AUTOIMMUNE DISEASE, I WANT TO REMIND YOU OF TWO CONDITIONS THAT ARE NOT CALLED DISEASE OR NOT CALLED AUTOIMMUNE DISEASE BECAUSE WE KNOW WHAT THE ANTIGEN IS, AND THE REACTION STOPS A WHEN ANTIGEN GOES AWAY, THE FIRST IS RHEUMATIC FEVER. MOST PEOPLE WHEN FIGHTING STREPTOCOCCUS CLEAR THE BUG WITHOUT A HUGE AUTOIMMUNE PROBLEM. BUT EVERY SO OFTEN YOU GET A CHILD WHO MAKES A RESPONSE TO STREP THAT ALSO CROSS REACTS ON THE HEART. USUALLY THE HEART VALVE, AND WHILE THEY'RE FIGHTING THE STREP THEY'RE DESTROYING THEIR HEART. PHYSICIANS WHO TAKE CARE OF THEM TELL ME THE BEST THING THEY CAN DO FOR THEM IS TO BUT THEM ON A TON OF PENICILLIN, CLEAR THE STREP, BECAUSE WHEN THEY CLEAR THE STREP, THE AUTOIMMUNE RESPONSE WANES, IT DOESN'T DISAPPEAR IN A DAY, THE ANTIBODIES LAST A WHILE BUT AUTO-IMMUNITY STOPS AND THEY KEEP KIDS ON PENICILLIN UNTIL THEIR 20s. THEN MIRACULOUSLY THEY CAN TAME THE THEM OFF PEN AND NEXT TIME THEY GET STREP THEY DON'T DESTROY THEIR HEARTS. AND I THINK THAT'S BECAUSE IF YOU CAN KEEP THEM FROM GETTING STREP FOR 20 YEARS THE HEART HAS TIME TO INDUCE ENOUGH TOLERANCE TO ITSELF THAT THE NEXT STREP INFECTION ISN'T A PROBLEM. SO WE DON'T CALL THAT AUTOIMMUNE DEES BECAUSE WE KNOW WHAT INNS STATES IT AND THE REACTION STOPS. WHEN THE INSTIGATING ENTITY GOES AWAY. THE SECOND ONE THAT WE DON'T CALL AUTOIMMUNE DISEASE IS SILL YAK DISEASE. THERE'S NO AUTOIMMUNE COMPONENT AT LEAST IN THE BEGINNING OF THE DISEASE HERE. THERE BECOME AUTOIMMUNE COMPONENTS LATER AS YOU GET MORE DESTRUCTION BUT THAT DOESN'T SEEM TO BE THE BEGINNING. WHAT'S HAPPENING IN PEOPLE WITH CILIAC THEY RESPOND TO A PEPTIDE DUBBED A TOXIC PEPTIDE IN GLIDEN WHICH IS A COMPONENT OF GLUE TIN WHICH IS A COME PENT OF GRAINS SUCH Z -- COMPONENT OF GRAIN SUCH AS WHEAT. PEOPLE WITH CILIAC ARE MAKING A DISREGULATED GUT RESPONSE TO THIS TOXIC PEPTIDE. NOW, I DON'T KNOW WHY IT'S TOXIC TO SOME PEOPLE AND NOT OTHER PEOPLE AND I DON'T THINK THAT'S KNOWN. BUT WHAT SEEMS TO BE GOING ON HERE IS THEY'RE MAKING THE WRONG KIND OF RESPONSE. THEY'RE MAKING MORE OF A TH 1 TH-17 DESTRUCTIVE RESPONSE IN THE GUT. THAN NORMAL PEOPLE. NORMAL WHATEVER NORMAL IS. PEOPLE WHO DON'T HAVE CILIAC. SAME IS TRUE HERE IF YOU TAKE AWAY BREAD, IF THEY STOP EATING WHEAT, GLUE TIN, THE RESPONSE STOPS THEVILLERY REGENERATE AND THEY'RE FAIRLY NORMAL, AS SOON AS THEY EAT WHEAT AGAIN THEY GET ANOTHER INFLAMMATORY REACTION. THIS IS LESS AN AUTOIMMUNE RESPONSE THAN AUTOINFLAMMATORY RESPONSE. WE DON'T CALL IT AUTOIMMUNE DISEASE BECAUSE WE KNOW WHAT THE ENGINE IS, AND THE REACTION STOPS WHEN YOU FAKE THE ANTIGEN AWAY. KEEPING THOSE TWO THING MS. MIND LET'S GO THROUGH SOME OF THE THINGS THAT PEOPLE DO CALL AUTOIMMUNE DISEASE. SO AUTOIMMUNE DISEASE, THERE ARE PEOPLE CLONING AUTO-IMMUNITY GENES. THERE ARE PEOPLE WHO THINK THAT AUTO-IMMUNITY IS LIKE ONE BIG UMBRELLA TOPIC. AND CLONING AUTO-IMMUNITY GENES. AND THEY'RE GOING TO FIND EVERY GENE INVOLVED IN AN IMMUNE RESPONSE AND THEN SOME. I DON'T THINK THERE IS ONE BIG UMBRELLA CALLED AUTO-IMMUNITY, I THINK THERE ARE AT LEAST FIVE CATEGORIES OF AUTOIMMUNE DISEASE AND FOUR OF THEM THERE'S NOTHING WRONG WITH THE IMMUNE SYSTEM. SO LET'S GO THROUGH THEM. MANY OF THESE CATEGORIES WERE MADE UP BY OTHER PEOPLE, THEY HAVE BEEN AROUND FOR A LONG TIME, I MODIFIED A COUPLE OF THEM A BIT, I MADE ONE UP. LET'S START WITH THE FIRST ONE, THE FIRST ONE IS KIND OF BORING. REALLY BORING. YOU HAVE AN INFECTION. AND YOU DON'T KNOW IT. IF I GAVE YOU A MOUSE THAT WAS DYING OF LYMPHOCYTEIC CHORIO MENINGITIS, THE VIRUS AND YOU DIDN'T KNOW THERE WAS A VIRUS THERE YOU WOULD THINK IT WAS AN AUTOIMMUNE ANTI-BRAIN DISEASE. BECAUSE THE VIRUS INFECT IT IS CHORIO MENINGES, THE BLOOD BRAIN BARRIER, THE KILLER CELLS GO KILL THE VIRUS INFECTED CELLS. THAT OPENS UP THE BLOOD BRAIN BARRIER AND THAT IS NOT GOOD FOR THE BRAIN. THAT'S NOT AUTOIMMUNE, IT'S IMMUNE SYSTEM DOING ITS JOB. IT'S JUST FIGHTING AN INFECTION. MY FAVORITE DISEASE HERE IN HUMANS IS LUNG. SO LYME DISEASE WAS FIRST DIAGNOSED AS JUVENILE RHEUMATOID ARTHRITIS. THIS WAS KIND OF AN EPIKEPTE IN THIS LITTLE VILLAGE CALLED LYME IN CONNECTICUT I THINK. EPIDEMIC. ALL THESE KIDS WERE COMING DOWN WITH A RATHER RARE DISEASE, JUVENILE RHEUMATOID ARTHRITIS. THE CDC SENT THIS YOUNG DOC OUT TO SEE WHAT WAS GOING ON. AND HE KIND OF STOLE A NURSE'S OBSERVATION, THAT MANY OF THE KIDS GETTING THE DISEASE HAD ADDRESSES THAT SHOWED THEY LIVED NEAR THE WOODS. AND SUGGESTED THAT IT WAS A PARASITE. TELL ME HOW MANY PHYSICIANS KNOW THE ADDRESSES OF THEIR PATIENT? TURNS OUTS IT'S A PARASITE, BARALIA, NOT JUVENILE RHEUMATOID ARTHRITIS. WHEN YOU CLEAR THE PARASITE IN ALMOST ALL CASES, YOU CLEAR THE PROBLEM, THE DISEASE STOPS. HOW MANY OTHER CASES OF RHEUMATOID ARTHRITIS DO YOU THINK MIGHT BE SOMETHING LIKE LYME? I'LL GIVE AN EXAMPLE, I MENTIONED I KNOW PEREZ DIAZ BEFORE WHEN I TALKED HOW SHE SHOWED THAT CD4 T-CELLS CLEAR TUMORS THAT CD8 T-CELL CAN'T CLEAR. SHE HAS A SISTER LIVING IN MEXICO CITY AND HER SISTER WAS DIAGNOSED WITH LUPUS. AND THIS IS MEXICO, I SUGGEST THAT SHE GET TEST FORD LYME. SHE WENT BACK TO HER DOCTOR AND ASKED TO BE TESTED. THE DOCTOR SAID YOU'RE NUTS. YOU LIVE IN THE CITY, YOU COULDN'T POSSIBLY HAVE LYME SO SHE WAS ON PREDNISONE AND GOD KNOWS WHAT FOR FOUR YEARS AND JUST GETTING WORSEFUL THEN A NEW RESEARCHER CAME TO UNIVERSITY THERE WHO SPECIALIZED IN LYME. HE WENT TO THE CITY AND CONTACTED THE DOCS AND ASKED FOR PATIENTS THAT HAD VARIOUS DISEASES SO HER DOCTOR CAME BACK AND SAID WOULD YOU LIKE TO BE TESTED FOR LYME? SHE DIDN'T SAY I ASKED YOU THIS FOUR YEARS AGO. ANYWAY SHE WAS TESTED FOR LYME AND SHE WAS SKY HIGH. FOUR YEARS WITH LYME, UNDIAGNOSED. NOT FUN. I'M SURE IT'S STILL HAPPENING. GO AHEAD. >> QUICK QUESTION. I ADMIT I'M PROBABLY NOT UP ON LYME DISEASE CURRENTLY BUT I ALWAYS THOUGHT THERE WAS SOME LIKE MIMICRY, THAT AFTER YOU CLEAR THE BUG YOU HAVE AUTO-IMMUNITY. >> SO THE QUESTION IS, LET ME SEE IF I CAN GET IT VERBATIM, I'M NOT UP TO THE LATEST IN LYME BUT I THOUGHT THERE WAS SOME EPITOPE MIMICRY YOU CAN CLEAR THE LYME AND CONTINUE TO HAVE THE DISEASE. THAT MAY BE TRUE. BUT I ALSO THINK IN MANY CASE WHERE IS PEOPLE SUPPOSEDLY CLEAR THE LYME AND CONTINUE TO HAVE SYMPTOMS THERE ARE ACTUALLY NOT CLEARED. SO THE YOUNG GUY FROM THE CDC, WHO IS NOW OLDER GUY CAME TO THE NIH SEVERAL YEARS AGO TO GIVE A TALK AT MAIDER. THE ONLY TIME I WALKED INTO MASUR AND POLICE WERE LINING THE WALL. INTERESTING, WHY? ANYWAY, ONE THING HE TALKED ABOUT WAS THAT, THE IDEA THAT PEOPLE WHO CLEAR THE LYME WHO GET ON ANTIBIOTICS FOR MONTHS AND CLEAR THE LYME AND CONTINUE TO HAVE SYMPTOMS NOW HAVE AN AUTOIMMUNE DISEASE TRIGGERED BY THE LYME AND IS NOW SELF-CONTINUING. I (INAUDIBLE) BEFORE ANYBODY ELSE AND SAID HOW DO YOU KNOW THE LYME IS CLEARED JUST BECAUSE YOU CAN'T FIND BY PCR IN THE BLOOD. EXCUSE ME? BEKNOW THAT SYPHILIS HIDES, HERPES HIDES, WE KNOW THAT OTHER PATH PATHOGENS CAN HIDE. HOW DO YOU KNOW IT'S GONE BECAUSE YOU CAN'T FIND IT BY PCR IN A COUPLE OF HUNDRED MICROLITERS OF BLOOD? HE'S FIGHTING WITH THE INSURANCE COMPANIES WHO DON'T WANT TO PAY FOR PEOPLE TO CONTINUE TO BE ON ANTIBIOTICS YET THERE ARE BUNCH OF PEOPLE OUT THERE WHO DO WELL IF THEY CONTINUE ON THE ANTIBIOTICS BUT PHYSICIANS WON'T CONTINUE TO GIVE IT TO THEM, BECAUSE INSURANCE COMPANIES AND THIS GUY FIGHTING WITH THEM TAKE THEM TO COURT. THERE'S SOMETHING DANGEROUS ABOUT CERTAINTY AND THE CERTAINTY THAT WE HAVE THE TECHNOLOGY TO FIND PARASITES THAT MIGHT BE HIDING I THINK IS KIND OF EGOTISCAL AND DANGEROUS. IT'S TRUE THERE MAYBE AN EPITOPE THAT CROSS REACTS BUT WHICH BRING ME TO MY SECOND CATEGORY. >> IF THAT'S TRUE IT WOULD BE THE SAME ALMOST AS RHEUMATIC FEVER. >> WOULD BE THE SAME AS RHEUMATIC FEVER. LET'S DO THAT. HANG ON. LET'S DO THIS TO RHEUMATIC FEVER. CATEGORY 2. SO CATEGORY ONE IS YOU HAVE AN INFECTION IN THE TARGET ORGAN AND YOU DON'T KNOW IT'S THERE. REMEMBER THERE ARE VIRUSES THAT ARE CALLED HEPATITIS VIRUSES THAT AREN'T ITIS VIRUSES BECAUSE THEY DON'T CAUSE INFROMMATION IN THE LIVER, ONLY DISCOVERED WHEN PEOPLE STARTED LOOKING IN LIVERS FOR VIRAL RNA AND VIRAL DNA SO A BUNCH OF THEM. NOT REALLY CAUSED DISEASE BUT THEY'RE THERE. FOR ALL WE KNOW THEY COULD CAUSE DISEASE IN SOME PEOPLE. THE SECOND CATEGORY IS SIMILAR, BUT SUBTLY BUT IMPORTANTLY DIFFERENT. THAT IS THE CATEGORY PEOPLE HAVE CALLED MOLECULAR MIMICRY. MOLECULAR MIMICRY. THIS IS YOU HAVE AN INFECTION THERE IS MOLECULE ON INFECTIOUS AGENT WHICH CROSS REACTS WITH THE MOLECULE ON SELL. THE FAVORITE HERE IS RHEUMATIC FEVER. THE IMPORTANT THING THIS IS THE WHOLE THING STOPS WHEN YOU GET RID OF THE BUG. SO MANY, MANY PEOPLE HAVE SUGGESTED THAT MOLECULAR MIMICRY CAN INITIATE AN AUTOIMMUNE DISEASE. AND IF YOU THINK BACK TO YOU'RE STUCK THE IN THE OLD MODEL OF THE SELF-ON SELF-THAT ONCE YOU GET AN IMMUNE RESPONSE GOING, THE MERE PRESENCE OF THE ANTIGEN WILL MAINTAIN IT. THEN THAT WORKS BECAUSE YOU GET YOUR MEMORY CELLS, BECAUSE OF THE PATHOGEN, AND NOW YOU HAVE YOUR OWN ANTIGEN TO MAINTAIN THE RESPONSE. BUT THE MODEL SAYS YOU DON'T KNOW, YOU NEED ACTIVATED APC TO DO THAT. ONCE THE PATHOGEN IS GONE, THERE ARE NOT ACTIVATED APCs PRESENTING THOSE ANTIGENS SO THE IMMUNE RESPONSE STOPS AND THE EVIDENCE FOR RHEUMATIC FEVER TELLS US THE IMMUNE RESPONSE STOPS. SO I WOULD SAY AGAIN FOR LYME IT WOULD BE THE SAME. IF YOU MAD A PERSON, AND I'M SURE THEY'RE OUT THERE WHO HAVE SOME PEPTIDE OR SUGAR OR EPITOPE, THAT IS ALSO ON THE LYME, IF YOU REALLY GOT RID OF THE LYME THE AUTOIMMUNE RESPONSE SHOULD STOP. NOW WHAT'S SUBTLY AND IMPORTANTLY DIFFERENT BETWEEN THE TWO? THEY'RE BOTH INFECTIONS. HERE THERE ISN'T NECESSARILY ANY AUTOIMMUNE COMPONENT. THE T-CELLS ARE AGAINST THE VIRUS OR THE PATHOGEN. WHICH MEANS THE REACTION HAS TO BE IN THE TARGET TISSUE. THE INFECTION HAS TO BE IN THE TARGET TISSUEFUL LCMV BRAIN. INFECTS A BUNCH OF OTHER ORGANS AS WELL. HERE THERE IS A CROSS REACTION. SO THE INFECTION NEED NOT BE IN THE TARGET TISSUE. YOU CAN HAVE INFECTION IN THE GUT, THAT CROSS REACTS ON THE BRAIN. AS LONG AS YOU'RE FIGHTING THAT INFECTION IN THE GUT YOU MIGHT BE FIGHTING SOMETHING IN THE BRAIN. WE'LL COME BACK TO THAT. THAT'S THE SUBTLE DIFFERENCE BUT AN IMPORTANT DIFFERENCE. HERE THERE'S NO AUTO-IMMUNITY. HERE THERE IS AUTO-IMMUNITY DRIVEN BY THE PATHOGEN. AND THE PATHOGEN NEED NOT BE IN THE TARGET TISSUE. IN BOTH THESE CATEGORY THERE'S NOTHING WRONG WITH THE IMMUNE SYSTEM. IT'S DOING ITS JOB. IT'S FIGHTING A PATHOGEN. IN THIS CASE THERE'S NO RESPONSE AGAINST SELF, IN THIS CASE THERE IS RESPONSE AGAINST SELF AND PEOPLE ASKED THE QUESTION FOR 80 YEARS, HOW DO WE BREAK TOLERANCE? WHY DO WE BREAK TOLERANCE? WHY DO THESE KIDS WITH STREP BREAK TOLERANCE TO THE HEART? AND I SAY THAT'S THE WRONG QUESTION. YOU CAN'T BREAK WHAT YOU DON'T HAVE. I THINK WE'RE NEVER TOLL RAPT. NEVER IS A BIG WORDFUL AS THRONG AS THE THYMUS IS PUTTING OUT T-CELLS AND BONE MARROW PUTS OUT B CELLS WE'RE NOT TOLERANT. WITH WE'RE IN THE PROCESS CONSTANTLY OF BECOMING TOLERANT. THE TIRE TISSUES ARE INDUCING TOLERANCE TO THEMSELVES BUS THE TISSUE THAT LEFT THE THYMUS LAST WEEK AGAINST THE BRAIN MAY NOT HAVE BEEN TOLERIZED YET. THE T-CELLS THAT LEFT THE THYMUS YESTERDAY AGAINST THE SPECIFIC FOR HEART MAY NOT YET BE TOLERANT WHEN YOU GET STREP. THE B CELLS MICE ARE MAKING 30 MILLION NEW B CELLS EVERY DAY. NO IDEA WHAT THAT NUMBER IS IN HUMANS BUT PROBABLY LOTS MORE. THAT'S A LOT OF NEW B CELLS EVERY DAY. MANY ARE NOT TOLERANT WHEN THEY COME OUT OF THE BONE MARROW. WE ARE NEVER TOLERANT. AND YOU KNOW, THIS IS KNOWN FOR A LONG TIME. PEOPLE HAVE FOUND AUTOREACTIVE B CELLS IN BLOOD, THEY HAVE FOUND AUTOREACTIVE C CELLS IN BLOOD. AND THEY WONDER WHY THEY DON'T CAUSE DISEASE. I THINK THE REASON THEY DON'T CAUSE DISEASE BECAUSE ON THE WHOLE THEY'RE THERE. THEY'RE NOT GETTING ACTIVATED, NOT SEEING ALARM SIGNALS AN CO-STIMULATION SO SLOWLY THEY'RE GETTING TOLERIZED. >> BASED ON THAT YOU SAID RHEUMATIC FEVER IT'S MORE A STOCHASTIC TYPE SITUATION WHERE YOU MAY OR MAY NOT GET THAT BASED PURELY ON WHETHER YOUR CELL IS TOLERIZED AT THAT MOMENT OR NOT? >> THE QUESTION IS FOR EXAMPLE RHEUMATIC FEVER IS IT ENTIRELY STOCHASTIC? IS IT JUST CHANCE WHEN YOU GET RHEUMATIC FEVER YOU MIGHT HAVE A B CELL THAT CAN SEE THAT BUG IN THE HEART? IT'S TWO THINGS I THINK. A CHANCE. THREE THINGSFUL AGE, AND THREE, WHETHER YOU HAVE THE PEPTIDE, ALLELE ON THE PEPTIDE ON THE HEART THAT CROSS REACTS WITH THE BUG. WE'RE A DIVERSE POPULATION, HUMANS, WE MAY NOT ALL HAVE THAT CROSS REACTIVE ANTIGEN. AND WHY AGE? BECAUSE AS WE AGE THE THYMUS PUTS OUT FEWER AND FEWER T CELLS EACH DAY. AND I DON'T KNOW ABOUT THE BONE MARROW BUT PREDICT THE BONE MARROW IS ALSO PUTTING OUT FEWER AND FEWER B CELLS EACH DAY. WE DID NOT EVOLVE TO LIVE IN A WORLD WITH 747s. WE EVOLVED TO LIVE IN A WORLD THAT HAD CAVES AND SMALL VALLEYS AND WE GREW UP IN THOSE CAVES AND SMALL VALLEYS AND THERE WEREN'T A LOT OF TRAVELERS. SO WE REALLY NEEDED ALL THAT PRODUCTION EARLY IN LIFE. SO WE CAN GET MEMORY THE TO ALL THOSE DISEASES IN OUR ENVIRONMENT. AND AFTER A WHILE WE HAVE A GOOD SUPPLY OF MEMORY CELLS. SO WE DON'T NEED SUCH RAPID PRODUCTION OF T-CELLS AN B CELLS, KIND OF LIKE LANGUAGE. WE LEARN MOST LANGUAGE IN THE FIRST TEN YEARS OF LIFE. UNLESS YOU'RE A SYRIAN REFUGEE AND HAVE TO LEARN SWEDISH. ONE OF THE FEW COUNTRIES THAT'S TAKING THEM. WITH WE OUGHT TO BE ASHAMED. HOW FEW WE'RE TAKING. SORRY, OFF TOPIC HERE. I'M AN IMMIGRANT. I FEEL FOR IMMIGRANTS. SO IT IS GOING TO BE CHAOTIC MT. SENSE THAT YOU MAY HAVE THAT B CELL MADE. IT'S GOING TO BE RELATED TO AGE BECAUSE WE'RE GOING TO HAVE FEWER OF THEM MADE. MY SKIN HAS ALMOST HAD 70 YEARS TO TOLERIZE FOR ITSELF. AND MY THYMUS ISN'T PUTTING OUT TOO MANY T-CELLS. A FEW. PEOPLE THOUGHT THEY QUIT COMPLETELY, THEY DON'T BUT THEY SLOW DOWN A LOT SO I'M PRE-- PROBABLY PRETTY TOLERANT TO SKIN T. IT'S DOING ITS JOB HERE. FIGHTING INFECTION. AND WE HAVE TO STOP ASKING THE QUESTION HOW DO YOU BREAK TOLERANCE BECAUSE WE'RE NEVER TOLERANT. THIRD CATEGORY. (INDISCERNIBLE) CELL DEATH. THIS IS A CATEGORY OF AUTO-IMMUNITY THAT CAN ONLY EXIST I THINK, UNDER THE AUSPICES OF THE DANGER MODEL WHICH SAYS THAT GOOD DEATH DOESN'T GIVE YOU AN IMMUNE RESPONSE AND BAD DEATH DOES. SO HOW DOES BAD DEATH REED TO AUTO-IMMUNITY? MY FAVORITE DISEASE HERE IS RUE PUS. -- LUPUS. I THINK LUPUS IS 300 DISEASES. CAUSED BY ALL KINDS OF THINGS. ONE MAJOR CATEGORY OF THINGS IS GENES THAT GOVERN DEATH. THERE ARE A LOT OF GENES THAT GOVERN DEATH. PROGRAM CELL DEATH. IN C ELEGANS, I THINK THERE ARE 19 SAID GENES. AND 11 OF THOSE ARE ABOUT CLEANING UP THE MESS, SCAVENGING AND SO ON. SO FOR EVERY GENE THEY FIND IN THE WORM THEY FIND FIVE TO TEN IN VERTEBRATES. THAT'S A LOT OF GENES GOVERNING DEATH. THAT'S A LOT OF POTENTIAL MUTATIONS. THAT COULD CAUSE ONE FORM OR ANOTHER OF BAD DEATH. AND THE DANGER MODEL SAYS THAT BAD DEATH IS GOING TO GIVE YOU ALARM SIGNALS THAT GIVES YOU IMMUNE RESPONSE. SO I THINK MORE THAN 18 YEARS AGO NOW I GAVE AN EXAMPLE OF THIS TO A MEDICAL SCHOOL CLASS IN GERMANY. HERE IS WHAT I SUGGESTED. IT WAS COMPLETELY OUT OF THE AIR. ONE OF THOSE HAND WAVING. SO YOU ALL KNOW THAT WHEN YOU GET A REALLY GOOD IMMUNE RESPONSE TO SOMETHING LIKE FLU, THE B CELLS GO TO GERMINAL CENTERS IN THOSE GERMINAL CENTERS THEY DIVIDE. AND START MAKING 2000 ANTIBODY MOLECULES PER SECOND AND THEY MUTATE. IN FACT, THEY HYPER MUTATE. THE THOUGHT IS THAT THEY DO THAT IN ORDER THE GENERATE B CELLS THAT HAVE HIGHER AFFINITY TO SAY FLU. AND THE IDEA IS THAT ANY B CELL WHICH MUTATES TO HIGHER AFFINITY WIN IN THE RACE FOR T-CELL HELP BECAUSE IT PICKS UP MORE ANTIGEN GETS MORE HELP. THAT WAY YOU CAN RAISE AFFINITY TO IMMUNE RESPONSE AS YOU GO. HYPERMUTATION DOES NOT ONLY GIVE YOU B CELLS WITH HIGHER AFFINITY BUT B CELLS WITH LOWER AFFINITY. IN FACT, YOU GET B CELLS THAT DON'T MAKE ANY ANTIBODY AT ALL ANY MORE, YOU GET B CELLS THAT MAKE LITTLE BITS AND PIECES OF ANTIBODY. YOU HAVE A BUNCH OF B CELLS THAT LOSE THE RACE. WHAT HAPPENS TO THEM IF THEY DIE? WITH THEY DIE BY NORMAL PROGRAM CELL DEATH. THAT'S SO MUCH DEATH IN GERMINAL CENTERS THERE'S SPECIAL SCAVENGERS TO PICK UP THE CAIING B CELLS. THEY'RE CALLED PINGABLE BODY MACROPHAGES. PINGABLE BECAUSE THEY'RE STAINABLE AND STAINABLE BECAUSE THEY'RE SO FULL OF THE BODY'S APOPTOTIC B CELLS. B CELLS ARE DIE BIG NORMAL PROGRAM CELL DEATH. AND HERE IS WHAT I SUGGESTED. SUPPOSE YOU HAD A PERSON WHO HAD A MUTATION IN THE SCAVENGER RECEPTOR THAT THE BODY PA CROW PHAGOS USE TO PICK UP THE DYING B CELLS. THE B CELLS WOULD CITY DIE BY NORMAL PROGRAM CELL DEATH BUT THEY WOULDN'T GET SCAVENGED SO THEY DO WHAT UNSCAVENGING DYING CELLS DO, THEY FALL APART. IT'S CALLED SECONDARY NECROSIS. THEY FALL APART. THEY RELEASE ALARM SIGNALS AND DNA RNA TUBULIN, ALL THOSE INTRACELLULAR MOLECULES THAT YOU MAKE IMMUNE RESPONSES TO IN LIEU PUS. LUPUS IS NOT A GENERALIZED AUTOIMMUNE DISEASE. YOU DON'T GET ANTIBODIES TO MHC CLASS ONE OR TWO. YOU DON'T GET THEM TO INSULIN RECEPTORS. S. YOU GET ANTIBODIES TO INTRACELLULAR COMPONENTS. SO THIS IS A PERSON WITH A LUPUS FLAIR EVERY TIME THEY MADE IMMUNE RESPONSE THAT CAUSED GERMINAL CENTERS TO HAPPEN. SO IT'S ONE OF THE EXAMPLES THAT SHOWED ME IT'S REALLY HARDLY WORTH TALKING TO PEOPLE OVER 50 BUT REALLY GOOD GOOD TALKING TO PEOPLE UNDER 50, MEDICAL SCHOOL CLASS. ONE OF THE STUDENTS GREW UP TO BECOME A RHEUMATOLOGIST. MARTIN HERMAN. I GAVE YOU TO READ ONE OF HIS PAPERS. WHERE HE WENT AND LOOKED AT HIS LUPUS PATIENTS, HE FOUND INDEED THERE WAS A SUBSET THAT HAD MUTATIONS IN THE TINGIBLE BODY MACROPHAGES ABILITY TO PICK UP DYING B CELLS. SO THAT'S ONE MUTATION. HOW MANY MUTATIONS OF HOW MANY GENES DO WE POTENTIALLY HAVE THAT DRIVE LUPUS? SO PEOPLE SAY TO ME HOW DO YOU EXPLAIN THAT LUPUS IS PRIMARILY A FEMALE DISEASE? THIS IS SOMETHING NO PREVIOUS MODEL HAS BEEN ABLE TO EXPLAIN. SO HERE IS THE POTENTIAL EXPLANATION. SO THERE'S AN INTERESTING DETAIL, GOD IS IN THE DETAILS. PRE-PUBERTY ONSET LUPUS. HARDLY HAS A FEMALE BIASFUL IT HAS SLIGHT FEMALE BIAS. POST PUBERTY ONSET LUPUS HAS THE STRONG FEMALE BIAS. SO I THINK THERE ARE TWO REASONS WHY FEMALES GET LUPUS MORE THAN MALES. ONE, THERE'S DEATH THAT GOES ON IN FEMALE BODIES THAT DOESN'T GO ON IN MALE BODIES. WE POP AN OVARY EVERY MONTH. WE KILL OFF CLEAN UP AND REGENERATE AN ENTIRE UTERINE LINING EVERY MONTH. THAT'S A LOT OF DEATH, THAT'S A LOT OF CLEANING UP. THAT'S A LOT OF GENES INVOLVED. SO I SUGGESTED TO RHEUMATOLOGISTS THAT WHEN THEY GET A YOUNG WOMAN POST PUBERTY, 14 TO 20, THAT IS COMING -- PRESENTING WITH LUPUS, PUT IT ON THE PILL, AND DON'T LET HER CYCLE AND SEE WHAT HAPPENS. YOU KNOW SOME PEOPLE WITH LUPUS GET BETTER DURING PREGNANCY. WHEN THEY GET WHOPPING RESPONSE AT THE END OF PREGNANCY, PUT THEM ON THE PILL AND DON'T LET THEM CYCLE. AND THEY WON'T DO IT. THIS IS NOT NORMAL AND TWO THINGS TO SAY TO THAT. ONE, IT'S NOT NORMAL, I THINK I SAID THIS BEFORE, IT'S NOT NORMAL TO CYCLE EVERY MONTH. WE DIDN'T EVOLVE TO DO THAT. FOR MOST OF OUR EVOLUTION UNTIL DISCOVERY OF THE PILL, WE CYCLED RARELY, WE WERE EITHER PREGNANT OR LACTATING. PEOPLE CALCULATEED THAT, HOW OFTEN DID WOMEN USED TO CYCLE? RARELY. WE ARE NOW FORCED TO CYCLE EVERY MONTH. SECOND THING FOSI TO THAT, WHEN I WAS A TEENAGER I WAS SO FED UP WITH THAT PARTICULAR PHYSIOLOGY THAT I WENT TO TWO FAMILY DOCTORS, THIS IS BEFORE YOU NEEDED PARENTAL CONSENT AND GOT THE PILL FROM BOTH AND KEPT MYSELF NON-CYCLING FOR FOUR YEARS, IT WAS GREAT. I DON'T HAVE LUPUS. PUT THEM ON THE PILL AND DON'T LET THEM CYCLE. IT'S CALLED DIAGNOSIS BY TREATMENT. SO I THINK THAT'S ONE REASON WOMEN HAVE MORE LUPUS THAN MEN. HERE IS THE OTHER. THIS AGAIN IS SOMETHING THAT CAN ONLY BE HELD IF YOU HOLD THE ASSUMPTIONS OF THE DANGER MODEL. GO AHEAD. HE KNOWS HE WILL BE TALKING A LITTLE BIT. >> SO THEN IN PLACES WHERE WOMEN DO HAVE LACTATING OR PREGNANT. >> YOU PREDICT THERE WOULD BE -- >> I DON'T KNOW -- YOU'RE REALLY GOOD AT DOING THIS. YOU TAKE WHAT I SAY AND YOU IMMEDIATELY GO TO MAKING A PREDICTIONS ABOUT SOMETHING. IT'S REALLY RARE AND IT'S REALLY GOOD. THAT WOULD BE A PREDICTION. IN PLACES WHERE WOMEN ARE NOT CYCLING AS MUCH. YOU WOULD PREDICT THE FREQUENCY OF LUPUS WOULD BE LOWER. HERE IS THE SECOND REASON THAT I THINK WOMEN GET MORE LUPUS THAN MEN, THAT WOULD ALSO BE TRUE IN THOSE PLACES. AND THAT IS THAT WE TOX FEW OURSELVES MORE THAN MEN DO. AT LEAST IN WESTERN COUNTRIES. EXCEPT FOR A FEW JOBS LIKE WORKING IN A DYE COMPANY OR BEING A HAIR DRESSER OR PLASTICS, I DON'T KNOW. WOMEN TOX FEW THEMSELVES MORE THAN MEN DO, WE POLISH THE FLOORS WE WASH THE DISHES AND THE CLOTHES AND THE WALLS. WE DYE OUR HAIR, WE WEAR MAKEUP, WE LATHER OURSELVES WITH CREAMS THAT WE HAVE NO IDEA WHAT'S IN THEM. WE TOXIFY OURSELVES. IF YOU THINK IMMUNITY IS STRICTLY BASED ON THE RECOGNITION OF FOREIGNNESS, TOXICITY SHOULDN'T MATTER. BUT IF THE HEALTH OF OUR TISSUES CAN ALSO GOVERN WHETHER WE MAKE AN IMMUNE RESPONSE AND IF WE MAKE AN IMMUNE RESPONSE WHAT KIND OF IMMUNE RESPONSE WE MAKE, THEN TOXICITY MATTERS. (OFF MIC) >> WHAT ABOUT SOMETHING LIKE SMOKING. (OFF MIC) >> YOU WOULD BE TOX FEWING YOURSELF DAILY ALL THE TIME. I DON'T KNOW IF THE INCIDENCE OF LUPUS IS HIGHER IN SMOKERS THAN NON-SMOKERS. THAT WOULD BE ANOTHER ONE. THIS -- THE MODEL MAKES A LOT OF PREDICTIONS THAT A WOULD NOT BE MADE BY OTHER MODELS. AND THEY'RE CERTAINLY WORTH LOOKING AT. I DON'T KNOW IF ANYBODY HERE IS AN EPIDEMIOLOGIST BUT THAT WOULD BE SOMETHING TO LOOK AT. THAT WOULD BE SOMETHING TO LOOK AT. DO WOMEN IN AFRICA HAVE A LOWER FREQUENCY OF LUPUS THAN WOMEN HERE. I BET THEY DO, THEN THEY MOVE HERE. I THINK THERE IS SOME EVIDENCE ACTUALLY THAT WOMEN OF AFRICAN DESCENT HAVE HIGHER FREQUENCY OF LUPUS, I DON'T KNOW WHAT THAT WOULD BE DUE TO, GENES AGAIN. SO OUR GENES ARE AGAINST US IN THAT SENSE, AND THE WAY WE BEHAVE IS ALSO AGAINST US IN THAT SENSE. I THINK LUPUS IS 300 DISEASES. AND THE TREATMENT OF ONE MAY NOT BE THE TREATMENT OF ANOTHER. DEPENDS WHICH GENE IS WORKING DEPENDS WHICH TOXICITY IS WORKING. THERE IS AN EXAMPLE OF PREGNANCY ASSOCIATED LUPUS. WHICH I JUST LEARNED ABOUT RECENTLY. WHERE A WOMAN WILL HAVE LUPUS WHILE SHE'S PREGNANT. AND IT GOES AWAY WHEN SHE STOPS BEING PREGNANT. SHE USUALLY STOPS BEING PREGNANT BECAUSE SHE MISCARRIES. PUT ALL THAT TOGETHER, IT KIND OF HINTS TO ME AT LEAST THAT THAT LUPUS IS BEING DRIVEN BY SOMETHING WRONG WITH PROGRAM CELL DEATH IN THE FETUS. THERE'S A LOT OF PROGRAM CELL DEATH THAT GOES ON DURING FETAL DEVELOPMENT. IF THAT FETUS HAS A GENETIC MUTATION THAT'S A REDUNDANCY, HAS A MUTATION THAT CAUSES SOMETHING IN THAT NORMAL PROGRAM CELL DEATH PROCESS TO GO WRONG, IT COULD BE DRIVING AN IMMUNE RESPONSE. TO THE INTRACELLULAR COMPONENTS OF THOSE TISSUES. PROBABLY BECAUSE OF THAT MUTATION, IT'S NOT GOING TO MAKE IT THROUGH DEVELOPMENT. SO IT MISCARRIES. AND BECAUSE OF THAT MUTATION IS DRIVING LUPUS IN ITS MOTHER. UNTIL IT'S GONE. ONCE AGAIN YOU GET RID OF THE PROBLEM THE AUTOIMMUNE PROBLEM STOPS. NONE OF THOSE DETAILS ARE EXPLAINABLE BY OTHER MODELS. IT'S DOING ITS JOB, RIGHT? IT'S RESPONDING TO ALARM SIGNALS FROM CELLS DYING BADLY OR FROM CELLS DYING WELL BUT NOT SCAVENGED PROPERLY. THE FOURTH CATEGORY I DIDN'T MAKE UP, IT'S A SUBSET OF THREE, IT WAS MADE UP BY OLIVEIA ROSEN AT HOPKINS AND THE DISEASE THEY WORK WITH IS SCLERODERMA. THEY CALL THIS IMMUNE IMPRESSIONISM SO SCLERODERMA. SCLERODERMA IS A DISEASE WHICH OFTEN HAPPENS TO PEOPLE WHO HAVE RHENOS SYNDROME, I HAVE RHENOS, IT'S A BAD RESPONSE TO COLD OR A NON-PHYSIOLOGICAL RESPONSE TO COLD, USUALLY WHEN WE GO OUT IN THE COLD OUR CAPITAL LAYERS OPEN UP. SOME OF US WHEN WE GO OUT IN THE COLD IT GETS WORSE AS YOU GET OLDER, YOUR CAPILLARIES SHUT DOWN. THEY SHUT DOWN EARLY. AND THEY SHUT DOWN IN AREAS INNERVATED BY SINGLE MAIN NERVE SO YOU GET PART OF YOUR FINGER GOES WHITE. AND ANOTHER PART OF YOUR FINGER GOES WHITE. PART OF YOUR TOE GOES WHITE THEN ALL GO WHITE AND THEY HURT A LOT. I DISCOVERED BY THE WAY IF YOU HAVE SCLERODERMA, I'M SORRY, RHENOS SYNDROME, ONE WAY TO STOP IS WEARING EAR MUST HAVES IN WINTER. P IF YOU CAN KEEP YOU'RES WARM THAT NEUROLOGICAL REACTION DOESN'T HAPPEN AS MUCH. WHAT HAPPENS IS THESE PEOPLE START MAKING ANTIBODIES TO SKIN. SCLERODERMA IS COOL MIDDLE AGE BECAUSE YOUR SKIN TIGHTENS AND YOU LOSE YOUR WRINKLES BUT THEN YOU TIGHTEN EVEN MORE AND MORE AND YOUR HEART STOP WORKING AND YOUR LUNGS STOP WORKING AND YOU DIE. AND ANTONIO AND OLIVEIA ROSEN WORK ON THIS DISEASE, TO MAKE A LONG STORY SHORT, A LOT OF WORK IN A COUPLE OF SENTENCES, WHAT THEY DIVERSE FIRST IS ANTIBODIES IN SCLEROCAN DERMA ARE PROTEINS IN INSIDE THE NUCLEOWILLS OF CELLS. THESE ARE PROTEINS BEHIND TWO MEMBRANES. YOU ASK HOW DOES ANTIBODY HAVE AFFECT WHEN ITS TARGET IS PROTECTED BY THE PLASMA MEMBRANE AND NUCLEOLAR MEMBRANE? MORE DETAIL, THE ANTIBODIES -- THE PROTEINS THOSE ANTIBODIES ARE AGAINST ARE SUBSET OF THE PROTEIN MS. THE NUCLEOTHROUGHS, SUSCEPTIBLE TO METAL LOW PROTEASES. THEY CAN TAKE A KER LOW DERMA PATIENT AND PUT SO MUCH IMMUNOSUPPRESSION THEY DON'T MAKE IMMUNE RESPONSE AT ALL, THEY HAVE TO PUT THEM IN THE HOSPITAL AND WATCH THEM AND THE DISEASE KEEPS GETTING WORSE. WHAT THEY HAVE CONCLUDED FROM THAT IS THAT THE AUTOIMMUNE RESPONSE IN SCLERODERMA IS NOT THE CAUSE OF THE DISEASE. THE DISEASE IS A DISEASE. AND I DON'T KNOW THEY KNOW WHAT CAUSES IT YET. BUT WHAT THEY THINK IS THAT THE DESTRUCTION THE DAMAGE, BAD CELL DEATH THAT HAPPENS BECAUSE OF WHATEVER IS CAUSING SCLERODERMA INDUCES THIS AUTOIMMUNE RESPONSE. THAT THE RESPONSE ISN'T CAUSING THE DISEASE, IT'S JUST A RESPONSE TO THE DESTRUCTION CAUSED BY DISEASE. THE REASON THEY CALL IT IMMUNE IMPRESSIONISM IS THEY SAY IF YOU STUDY ANTIBODIES, THE ANTIBODIES WILL PAINT A PICTURE OF WHERE YOU OUT TO BE LOOKING SO THEY'RE LOOKENING THE NUCLEOLUS TO FIND OUT WHAT'S GOING ON THERE DRIVING THE SCLERODERMA. THESE FOUR CATEGORIES, IMA MINE SYSTEM IS DOING ITS JOB. IT'S FIGHTING INFECTION IN THE TARGET TISSUE, FIGHTING INFECTION THAT CROSS REACTS. IT'S FIGHTING I THINKS SOMETHING THAT IS CAUSING BAD DEATH. OR HERE AGAIN FIGHTING SOMETHING THAT'S CAUSING BAD DEATH. IT'S DOING ITS JOB. THE FIFTH CATEGORY IS ONE WHERE I THINK THERE IS SOMETHING WRONG WITH THE IMMUNE RESPONSE, THAT IS THAT YOU MAKE THE WRONG CLASS. THE TWO DISEASES THAT I THINK FIT IN HERE ARE DIABETES TYPE ONE AND MULTIPLE SCLEROSIS. SO IF YOU HAVE AN IMMUNE RESPONSE THAT WAS INITIATED BY ANY ONE OF THE TOP FOUR CATEGORIES, YOU HAD AN INFECTION, YOU HAD INFECTION THAT CROSS REACTS, YOU HAVE BAD DEATH SOMEWHERE, BAD SCAVENGING, BAD DEATH SOMEWHERE, YOU MAY STILL NOT GET DESTRUCTION OF THE TISSUE. IF THE TISSUE INSTRUCTIONS ARE STILL FUNCTIONING PROPERLY. IF YOU MAKE A NON-DESTRUCTIVE CLASS OF IMMUNITY, YOU MAY HAVE THE AUTOIMMUNE RESPONSE BUT YOU WON'T HAVE AUTOIMMUNE DESTRUCTION. HERE I THINK YOU GET AUTOIMMUNE DESTRUCTION BECAUSE YOU MAKE THE WRONG KIND OF RESPONSE. SO ONE OF THE PAPERS THAT WAS ON THE LIST OF PAPERS TO READ, WAS FROM KEVIN LAUGHTY'S GROUP SHOWING THAT IN DIABETIC MICE EARLY ON IN THE AUTOIMMUNE RESPONSE, YOU HAVE AN AUTOIMMUNE RESPONSE, YOU HAVE T-CELLS THAT CAN SEE ISLETS, THEY INFILTRATE THE ISLETS. THEY MAKE A RING AROUND THE OUTSIDE INSIDE BUT NOT COMPLETELY IN THE ISLET. AND THEY DON'T DESTROY IT. THAT CAN GO TWO YEARS IN REAL MICE. AND THEN SUDDENLY AND CHAOTICALLY, RANDOMLY, AN ANIMAL WILL SWITCH TO A DESTRUCTIVE RESPONSE. YOU CAN PREVENT THAT SWITCH BY GIVING COMPLETE ADJUVANT EARLY IN LIFE. SO THEY HAVE THE AUTOIMMUNE RESPONSE. THEY STILL HAVE AUTOIMMUNE INFILTRATION BUT THE ISLETS DON'T DIE. SO THAT SAYS THAT YOU CAN GET AN IMMUNE RESPONSE THAT DESTROYS YOU BY ANY ONE OF THESE CATEGORIES IF YOU HAVE THE WRONG CLASS. LET'S TAKE MS AS A FAIRY TALE EXAMPLE. AGAIN, NOT SURE THIS IS HOW MS WORK BUS THIS IS HOW IT COULD WORK. WE KNOW ALSO IN MS THAT IF YOU CAN SWITCH THE RESPONSE FROM THE TH-1 TH-17 DESTRUCTIVE AGENT ORANGE TYPE RESPONSE, TO A TH-2/TH-3 FOR EXAMPLE FEEDING BRAIN PROTEIN, REMEMBER HOWARD WINER FED BRAIN PROTEINS TO MICE AND IMMUNIZED THEM. AND SHOW THEY DID NOT GET THE PARALYZING MS LIKE DISEASE. THEY STILL HAD A RESPONSE BUT DIFFERENT KIND OF RESPONSE. DOESN'T DESTROY THE BRAIN. HERE IS A FAIRY TALE. SUPPOSE THERE'S AN INFECTION IN THE GUT. AND MOST OF US GET THIS INFECTION AND CLEAR IT WITHOUT A PROBLEM. IT HAPPENS TO US SEVERAL TIMES IN LIFE JUST BECAUSE JUST BECAUSE YOU CLEAR INFECTION DOESN'T MEAN THAT THAT PATHOGEN ISN'T OUT THERE IN THE ENVIRONMENT. IT COMES BACK TO YOU WHEN YOU KIDS GO TO SCHOOL, IT COMES BACK TO YOU WHEN YOU CHANGE ENVIRONMENTS. IT COMES BACK TO YOU BECAUSE YOU EAT THE WRONG SALAD, IT COMES BACK TO YOU FOR ALL KINDS OF REASONS, STILL OUT THERE. BUT THE SECOND TIME YOU MAKE A RESPONSE YOU CLEAR IT SO FAST YOU HARDLY NOTICE BECAUSE YOU HAVE A MEMORY RESPONSE. SO FOR EXAMPLE, THOSE OF US WHO ARE ALIVE IN 1976, AND OLD ENOUGH TO GET FLU WHEN H 1N 1 FLU CAME THROUGH A COUPLE OF YEARS AGO WE DIDN'T GET SICK. WE HAD A MEMORY RESPONSE TO THAT FLU. IF WE GOT SICK IT WAS A COUPLE OF SNIVELS IN A COUPLE OF DAYS. SO YOU CLEAR IT BUT IT'S STILL OUT THERE. AND WHEN IT COMES BACK YOU MAKE A STRONGER MEMORY RESPONSE. SO YOU HAVE AN INFECTION IN THE GUT. AND FOR MOST OF US THAT'S FINE. BUT EVERY SO OFTEN YOU HAVE A PERSON WHO HAS LIKE RHEUMATIC FEVER WHO HAS A PEPTIDE IN THE BRAIN THAT HAS A MIMICKING EPITOPE ON THAT INFECTIOUS AGENT. AND THEY'RE FINE TOO. THEY DON'T HAVE ARE THE RIGHT MHC TO PRESENT THAT PEPTIDE. REMEMBER MHC MOLECULES AMONG OTHERS ARE INVOLVED IN AUTOIMMUNE DISEASE. MANY OUT IMMUNE DISEASES. SO CROSS REACTIVE PEPTIDE IN THE BRAIN, INFECTION, GUT, HE'S FINE, BECAUSE HE DOESN'T HAVE RIGHT MHC TO PRESENT THAT PEPTIDE. THEN YOU HAVE OTHER PEOPLE THAT HAVE THE RIGHT MHC TO PRESENT THAT PEPTIDE. BUT DON'T HAVE CROSS REACTIVE PEPTIDE SO THEY'RE FINE. EVERY SO OFTEN YOU HAVE SOMEBODY WHO HAS THE CROSS REACTIVE PEPTIDE IN THE BRAIN AND THE RIGHT MHC TO PRESENT IT. AND THEY'RE STILL FINE. WHEN THEY MAKE A RESPONSE IN THE GUT THEY TEND TO MAKE IGA. AND THE T-CELLS THAT ARE STIMULATED BY ARCPC FROM THE GUT GET INSTRUCTIONS TO GO BACK TO THE GUT. SO THEY'RE FINE. NOW RARELY YOU HAVE SOMEBODY WHO HAS CROSS REACTIVE PEPTIDE IN THE BRAIN, THE RIGHT MHC TO PRESENT IT, GETS THE INFECTION, AND IS A LITTLE SILIAC, SO EITHER BECAUSE OF WHAT THEY'RE EATING OR DRINKING, WHAT ENVIRONMENT THEY'RE IN, WHAT DRUGS THEY'RE ON, THE GUT AND IMMUNE SYSTEM ARE NOT COMMUNICATING WELL ABOUT WHAT KIND OF IMMUNE RESPONSE TO MAKE IN THE GUT. SO THEY MAKE TH-1 OR 17 RESPONSE AND THOSE CELLS DO GO TO THE BRAIN. SO EVERY TIME THEY HAVE THIS INFECTION THEY FLAIR. THIS IS A PERSON GOING TO HAVE MS FLAIR EVERY TIME THEY GET THAT INFECTION. DOES THAT SCENARIO MAKE ANY SENSE TO ANYBODY HERE? (OFF MIC) >> IS IT A LONG QUESTION? >> MAYBE. >> GO TO THE MICROPHONE. >> WITH DIABETES YOU HAVE -- THE FIRST THING YOU NEED TO HAVE IS CELLS GETTING TO THE ISLETS AND THEY HAVE TO BE SPECIFIC FOR THOSE. SO THEY DIDN'T OBVIOUSLY GET TREATEDDED IN THE THYMUS. DELETED IN THYMUS. SO YOU HAVE A FAILURE ON THAT SCENE BECAUSE THEY WOULDN'T BE THERE OTHERWISE. ONCE THERE THEY HANG OUT A WHILE AND NOTHING HAPPENS AND THEN SOMETHING HAPPENS AND THEN THEY MAKE THEIR OWN RESPONSE. SO YOU HAVE TO HAVE TWO FAILURES. >> TWO HITS. YEAH. PRESENTED TWO HITS. GOOD IDEA. >> SO IN A WAY IT'S LIKE IT COULD BE -- FIVE COULD BE A COMBINATION OF SEVERAL ACTUALLY. IT COULD EVEN BE BAD DEBT MAYBE THAT'S THE TRIGGER, SOMETHING LIKE THAT. >> THAT'S RIGHT. IN FACT THERE WAS THE SHANNON TURLEY PAPER ON THAT LIST. DID YOU READ IT? >> I READ ALL OF THEM BUT I DON'T REMEMBER. >> AMAZING. HOW MANY READ ALL NINE PAPERS? TWO. CONGRATULATIONS. THAT'S TOUGH GOING. IN SHANNON'S PAPER SHE SHOWED THERE WAS A WAVE OF APOPTOSIS THAT HAPPENS IN THE PANCREAS IN OUR MOUSE STRAINS THAT SHE TESTED. THIS IS NORMAL, IT ALSO HAPPENS IN NAD MICE BUT ALSO NORMAL MICE. YOU CAN GET IMMUNE ACTIVITY. AND SO ONE POSSIBILITY IS THAT NOD MICE, SOMETHING THAT GOES WRONG WITH THAT WAVE OF APOPTOSIS. IT MAKES SENSE IN A WAY THAT HAPPENS BECAUSE THE MOUSE GOES FROM DRINKING MOTHER'S MILK TO EATING FOOD. AND SO THE STUFF PANCREAS HAS TO DO HAS TO CHANGE. SO WE CAN IMAGINE THAT YOU HAVE ONE WHOLE POPULATION OF CELLS THAT NEED TO DISAPPEAR, ANOTHER POPULATION THAT NEEDS TO APPEAR. >> THAT WAS ANOTHER QUESTION I HAD. IT SEEMS LIKE YOU HAVE THIS POTENT THIAL BAD DEBT THAT MAYBE BAD DEATH IN EVERYBODY BUT IF YOU DON'T HAVE THE CELLS THERE, THEY'RE INFILTRATE, THEN IT'S NO PROBLEM. BUT -- >> I DOUBT IT'S BAD DEATH IN EVERYBODY, THE REASON FOR THAT IS EVOLUTION TENDS TO WORK NOT 100% WELL BUT READY WELL. HAVING BAD DEATH AT THAT POINT -- IN FACT IF WE -- WAIT WAIT WAIT WAIT WAIT. IF WE LOOK AT ORGANS WHERE WE KNOW A LOT OF DEATH HAPPENS, LIKE THE THYMUS, GERMINAL CENTERS, RIGHT, WE KNOW THAT THERE ARE INCREDIBLY GOOD SCAVENGERS IN THOSE PLACES TO PICK UP THE DYING CELLS, HARDLY BEFORE YOU CAN SEE THEM. AND MY GUESS IS THAT THAT ALSO -- IN FACT TURLEY SHOWS THAT, THAT IN GENERAL IN NORMAL MICE, THE DEATH -- MAYBE IT WAS LAUGHTY, THE DEATH GOING ON DOESN'T GET YOU BODIES, NOT A LOT OF ANTIGEN PRESENTATION AND SO ON BUT IN NODs IT DOES. SO I DON'T THINK I HAPPENS TO EVERYBODY. >> I MEAN IN THE THYMUS THAT'S AN ONGOING THING, WHEREAS THIS IS A TEMPORARY THING SO MAY NOT BE THAT BAD IF IT'S NOT CLEANED UP THAT WELL BUT IF YOU HAVE CELLS, I GUESS WHAT I GET AT, DO YOU HAVE PEOPLE OR MOUSE MODELS WHERE YOU HAVE INFILTRATING CELLS THAT STAY THERE FOREVER AND NEVER PROGRESS? DO YOU HAVE LONG TERM NON-PROGRESSERS, IS THAT COMMON? >> I DON'T KNOW. I KNOW ONE EXAMPLE, I DON'T KNOW IF I MENTIONED IT BEFORE FROM THE HIDEERBERG GROUP WHERE HIDEELBERG GROUP, WHERE IN A WAY THIS IS YOUR TWO HITS, ANOTHER EXAMPLE. THEY HAVE A TRANSGENIC T-CELL SPECIFIC FOR H 2B, THIS IS CLASS ONE MAJOR HISTOCOMPATIBILITY MOLECULE. THEY HAVE VARIOUS TRANSGENICS. THAT EXPRESS H 2B IN VARIOUS TISSUES. SO ONE IS THE TIP OF THE TONGUE, WE WON'T GO THROUGH THAT ONE ONE IS LIVER. SO THEY HAVE THIS MOUSE THAT HAS H 2B ON THE LIVER. THEY HAVE THIS CD L 8 T-CELL TRANSGENIC THAT IS AGAINST H 2B. AND THEY CAN MAKE KILLERS CTL, FROM THIS MOUSE. THEY CAN IMMUNIZE THAT MOUSE UNTIL FULL OF HOT KILLERS. THEY TAKE THE KILLERS OUT AND TRANSFUSION THEM INTO THE ONE THAT IS EXPRESSING H 2B ON THE LIVER AND YOU PREDICT THE LIVER IS RAPIDLY DESTROYED. BUT IT ISN'T. JUST SITS. AND EVEN THOUGH THEY CAN MEASURE KILLING FROM KILLERS AT THE TIME THEY PUT THEM IN, THEY JUST SIT. UNTIL THEY GIVE THE RECIPIENT MOUSE A LOW DOSE OF LIVER TROPIC VIRUS OR THEY GIVE IT A VIRUS THAT ATTACKS LIVER OR CARBON TETRA CHLORIDE. CCL-4 WHICH IS LIVER TOXIC. SO THEY GIVE A LOW DOSE OF CARBON TETRA CHLORIDE THAT TOX FEWS THE LIVER, THEY PUT IN THE KILLERS AND LIVER IS WIPED OUT. BUT AAS LONG AS LIVER IS HEALTHY THEY'RE OKAY SO ANOTHER EXAMPLE, YOU NEED HIT 1 TO TURN ON THE KILLERS AND HIT 2 -- I MENTIONED THIS DURING LESSON ON TUMORS. THAT YOU NEED TO DO SOMETHING TO THE TUMOR TO GET CELLS TO GO IN THERE. BACK TO AUTO-IMMUNITY. SO WE HAVE A FAIRY TALE ABOUT MS. YOU HAVE GOT THE PERSON WITH THE PEPTIDE THAT CROSS REACTS ON THE PATHOGEN, THEY HAVE THE RIGHT MHC, THEY'RE A LITTLE SILIAC, SO MAKING THE WRONG IMMUNE RESPONSE TO PATHOGEN. WHAT DRIVE IT IS CELLS TO THE BRAIN? IN FACT WHAT DRIVES THE CELLS TO WEAR IN THE BRAIN? THIS IS A QUESTION AROUND MS FOR A LONG TIME AND I ONLY LEARNED IT A FEW YEARS AGO DURING SERIES OF LECTURES CALLED TRANSLATING MEDICINE. WHERE ONE MONTH SOME MD COMES TO TALK TO US AND THE NEXT MONTH ONE OF US WILL TALK TO AN M.D.. ABOUT WHAT WE'RE DOING. THERE IS A GUY TALKING ABOUT MS AND HE SHOW AD SERIES OF MRI SLIDES OF A SINGLE PATIENT WHO WAS A RELAPSING REMITTING MS PATIENT. WHAT REALLY SURPRISED ME IS HOW RANDOMLY THE LESIONS IN THIS PATIENT WERE PLACED. SO THERE WAS NO PREDICTING WHERE A LESION -- THE NEXT LESION WOULD BE FROM WHERE THE LESIONS HAD BEEN PREVIOUSLY. IT LOOKED RANDOM. THAT'S A QUESTION AROUND FOR A WHILE IN MS. WHY? WHAT CAUSES THE LESIONS TO HAPPEN WHERE THEY HAPPEN? WHAT CAUSE IT IS THE T-CELLS TO GO TO THAT PART OF THE BRAIN? HERE IS A DANGER MODEL IDEA. WE KNOW THAT IF YOU CUT THIS FACIAL NERVE THE MICROGLIA AT THE BRAIN END OF THAT NERVE BECOME ACTIVATED. AND UPREGULATE THOSE MOLECULES WE EXPECT IN APC TO UPREGULATE IF IT WANTED TO STIMULATE T-CELLS. CD40, CD8 0, CD8 6, MHC CLASS 2. MICROGLIA LOOK LIKE THEY'RE TRYING TO BE REALLY GOOD PRESENTING CELLS. FOR T-CELL JUST BY CUTTING THE NERVE. YOU DO DAMAGE TO THE NERVE AND THE BRAIN END WAKES UP AND SAYS I NEED IMMUNITY. LOOKS LIKE. SO IMAGINE THIS PERSON WHO IS FIGHTING THIS GUT INFECTION THAT CROSS REACTS ON THE BRAIN WEARS CONTACTS AND DRIVING LATE AT NIGHT AND BIG SEMI COMES AT IT WITH LIGHTS ON, LIGHT DAMAGE IT IS RETINA. SO THEY GOT DAMAGE ON THE RETINA AND I PREDICT IF THEY'RE GOING TO HAVE A FLAIR, THAT FLAIR WOULD HAPPEN AT THE END OF OPTIC NERVE SOMEWHERE WHEREVER THOSE RETINAL NERVES GO. OR THE PERSON WAS MOVING FURNITURE AND DROPPED ONE ON HIS FOOT. AND PREDICT THE LESION WOULD BE AT THE END OF WHATEVER NERVE -- WHATEVER PART OF THE BRAIN FOOT NERVES END UP IN. I HAVE NO IDEA HOW YOU WOULD TEST THAT. YOU CAN'T TEST IT IN MICE BECAUSE DISEASE IN MICE IS NOT A CEREBRAL DISEASE, IT'S A SPINAL COLUMN, SPINAL CORD DISEASE, THAT'S WHY IT'S NOT THE BEST MODEL FOR MS, THE BEST WE HAVE, I DON'T KNOW HOW TO TEST EXCEPT I SUGGESTED TO SOME AUTOIMMUNE DOCS NEUROLOGISTS WHATEVER THAT THEY ASK THEIR PATIENTS TO KEEP REALLY GOOD RECORDS OF WHAT HAPPENS TO THEM. ANY INTERVIEWS THEY GET. AND THE ANSWER I GET IS NOBODY WOULD BE ABLE TO DO THAT. I MEAN FAIR ENOUGH, IT'S AN IDEA ABOUT WHY THE LESIONS HAPPEN WHERE THEY HAPPEN, IT'S BASED TOP DANGER MODEL. BUT NOT SURE I WILL HELP ANYBODY'S TREATMENT IMMEDIATELY. SO PHYSICIANS MIGHT NOT CARE ABOUT KNOWN KNOWING IF THEY CAN'T DO ANYTHING ABOUT WHAT THEY KNOW. (OFF MIC) ONE OF THE FUNDAMENTAL DIFFERENCES BETWEEN (INAUDIBLE) IN THAT SPECULATIVE MODEL IS THERE SOMETHING ADULTS DO THAT CHILDREN >> INTERESTING SO TO REPEAT FOR PEOPLE WATCHING. ONE DIFFERENCE BETWEEN MS AND DIABETES IS AGE OF ONSET. IS THERE SOMETHING ADULTS DO THAT CHILDREN DON'T DO? THAT WOULD GIVE THEM MS? THERE'S A THEORY OUT THERE, WHICH IS VERY CUTE BUT I DON'T KNOW IF IT'S RIGHT BUT HERE IT IS. THERE IS EVIDENCE FROM EPIDEMIOLOGY THAT MS IS A NORTHERN HEMISPHERE DISEASE. SO PEOPLE IN NORTHERN HEMISPHERE GET IT, PEEP MILLION SOUTHERN DON'T BUT IT'S NOT WHERE YOU ARE WHEN YOU GET IT THAT MATTERS, IT'S WHERE YOU GREW UP. TURNS OUT IT'S NOT JUST WHERE YOU WERE BOX IT'S WHERE YOU HAPPEN TO BE. BETWEEN THE AGES OF SOMETHING LIKE 14 TO 22. SO WHAT ARE WE DOING BETWEEN 14 AND 22? ONE THING THAT HAPPENS TO PEOPLE BETWEEN 14 AND # 2, WE GET EPISTEIN BARR VIRUS. SO 70% OF INCOMING COLLEGE FRESHMEN DO NOT HAVE EBD AND 95% OF OUTGOING COLLEGE SENIORS HAVE EBV. THIS IS KISSING DISEASE. WE GET IT BY KISSING EACH OTHER. EVERY SO OFTEN SOMEBODY GETS MONONUCLEOSIS FROM IT BUT MOST GET THE VIRUS AN NEVER NOTICE, IT'S VERY WELL ADAPTED TO LIVING IN HUMANS. SO THAT'S PART ONE OF THIS THEORY. PART TWO OF THE THEORY IS THAT IN FACT FOR THIS, THE AMOUNT OF VITAMIN D WE HAVE INFLUENCE IT IS KIND OF IMMUNE RESPONSE WE MAKE. IF WE'RE LOW IN VITAMIN D, WE TEND TO MAKE MORE DESTRUCTIVE IMMUNE RESPONSE, IF WE'RE HIGHER IN VITAMIN D WE MAKE LESS DESTRUCTIVE RESPONSE. SO PEOPLE IN SOUTHERN HEMISPHERE TEND TO BE HIGHER IN VITAMIN D THAN PEOPLE IN THE NORTHERN HEMISPHERE. SO PUT THOSE TWO TOGETHER, WHAT IT IS THAT ADULTS YOUNG ADULTS DO THAT LITTLE CHILDREN DON'T, THEY'RE INFECTED BY EBV, MORE AS WE SPEND TIME IN FRONT OF COMPUTER SCREENS, WE BECOME MORE AND MORE VITAMIN D DEFICIENT. SO REALLY NICE QUESTION. I HAVE NO IDEA IF THAT'S THE ANSWER BUT I HEARD A GUY TALK -- I WISH I COULD REMEMBER HIS NAME, I HEARD A LECTURE IN A MEETING AND I JUST WAS REALLY STRUCK BY HOW RIGHT IT SOUNDED. >> I HEARD (INAUDIBLE) >> I'M SORRY. RIGHT. LATITUDE. >> YES. YES. YOU'RE ABSOLUTELY RIGHT. I'M WRONG THERE. OKAY. SO WHAT'S GOING ON HERE? MANY THINGS COULD BE GOING WRONG HERE, ONE TISSUE COULD HAVE A MUTATION IN WHATEVER SIGNALS IT GETS THE IMMUNE RESPONSE TO TELL WHAT KIND OF CLASS TO MAKE. THE IMMUNE CELLS COULD HAVE A MUTATION IN THE RECEPTOR THAT PICKS UP THAT SIGNAL. SO YOU CAN HAVE SOMETHING WRONG WITH B CELLS, T CELLS, MACROPHAGES, SOMETHING WRONG WITH THE TISSUE. AND IT COULD BE THE ENVIRONMENT. I DON'T KNOW IF THE BPA THAT LEECHES OUTS OF OUR WATER BOTTLES CHANGES IMMUNITY BUT IT'S SOMETHING TO THINK ABOUT. WE TOXIFY OURSELVES MORE AN MORE AND MORE ON THIS PLANET. THE INCIDENCE OF AUTO-IMMUNITY IS GOING UP. SO IT'S GOING UP AT A RATE PROBABLY NOT DUE TO CHANGES IN GENETIC FREQUENCY. BUT WE CERTAINLY HAVE CHANGES IN THING WE WAS NOT EVOLVED TO DEAL WITH AND THAT WE ARE NOW DEALING WITH. IN WHAT WE EAT, WHAT WE BREATHE, SO ON. SO HERE IS ONE OF MY FAVORITE TOXINS. CHLORINE. I GREW UP AFTER WE IMMIGRATED HERE I GREW UP IN LOS ANGELES. AND ONE OF THE THINGS YOU LEARN IF I HAD AN AQUARIUM I WOULD FISH AND IT WOULD STINK AND MY MOTHER WOULD MAKE ME CLEAN IT. ONE THING YOU LEARN IN LA, YOU HAVE TO LET THE TAP WATER STAND FOR THREE DAYS BEFORE YOU PUT YOUR FISH IN IT. BECAUSE THERE'S ENOUGH CHLORINE MANY THE TAP WATER TO KILL FISH. IT IS NOT NICE STUFF. IT IS A POISON. WE PUT ANYTIME OUR WATER BECAUSE IT'S A POISON SO I GOT TOGETHER WITH A UNINITIALLY WITH AN EPIDEMIOLOGIST TO ASK THE QUESTION HAS THE RISE IN AUTO-IMMUNITY AND THE RISE IN ALLERGY AND ASTHMA THAT WE HAVE SEEN SINCE THE '50s ANY CORRELATION WITH RISE IN THE NUMBER OF PLACES THAT PUT CHLORINE IN THEIR WATER? BY THE WAY, OLYMPIC SWIMMERS HAVE A HIGH INCIDENCE OF ASTHMA. THEY BREATHE A LOT OF CHLORINE. THE ANSWER WAS NO. SO ALLERGY AND ASTHMA COME UP MOSTLY IN THE '50s, STARTED REALLY COMING UP MANY THE '50s IN FINLAND AND PLACES LIKE THAT. WHEN EACH VILLAGE PUTS CHLORINE IN WATER IN LOCAL RECORDS SO EASY DATA TO GET, THE ANSWER WAS NO. BUT THERE WAS A HINT JUST A HINT, THESE DATA ARE MORE DIFFICULT TO GET. THAT IT CORRELATED WITH THE ADVENT OF SHOWERSES JUST A HINT. SO IT USED TO BE CHRISTIAN PEOPLE AT LEAST WOULD TAKE A BATH ON SATURDAY NIGHT, ALL THE FARMERS TAKING A BATH ON SATURDAY NIGHT SO WE CAN BE CLEAN FOR CHURCH ON SUNDAY. FILL THE BATHTUB, DADDY GETS FIRST, KIDS GET IT NEXT, MOM GETS LAST WHEN IT'S COLD AND STINKY. WE DON'T DO THAT ANY MORE. WE HAVE A SHOWER EVERY DAY. WE BREATHE HOT CHLORINE EVERY DAY. WHAT IS THAT DOING TO OUR LUNG? WHAT IS THAT DOING TO OUR SKIN? TO OUR TISSUE'S ABILITY TO SEND THE PROPER SIGNALS TO THE IMMUNE SYSTEM? ANY CORRELATION BETWEEN CHLORINE AND OTHER NASTIES THAT WE PUT IN OUR WATER IN OUR ENVIRONMENT AND THE RISE IN ALLERGY AND ASTHMA? I DON'T KNOW THE ANSWER TO THAT BUT IT'S SOMETHING THAT SHOULD BE TESTABLE, I WOULD THINK. SO SORRY I TALKED TOO LONG WE HAVE THREE MINUTES. THAT'S AUTO-IMMUNITY, FROM A DANGER MODEL POINT OF VIEW. ANY QUESTIONS? THINGS THAT DON'T FIT? >> I HAVE A QUESTION. IT SEEMS IN THE LAST LITTLE DISCUSSION THE LAST ONE, OF YOUR AUTOIMMUNE HYPOTHESIS WOULD BE THEY SEEM TO CORRELATE CLOSELY WITH INFECTION. SEEMS LIKE INFECTION -- >> EXCEPT BAD DEATH HERE. >> RIGHT. SO WOULDN'T THE HYPOTHESIS BE THAT IN AREAS WITH HIGHER INFECTION RATES, YOU WOULD HAVE MORE AUTO-IMMUNITY SO CONTRA EVIDENT TO THE JUST OPPOSITE WITH LATITUDE THAT IN THE TROPICS YOU WOULD HAVE MANY MORE INFECTIONS YOU WOULD HAVE QUITE A BIT MORE UT IMMUNITY. >> AT FIRST BLUSH MAYBE BUT A SECOND BLUSH MAYBE NOT. BECAUSE ONE OF THE THINGS WE'RE LEARNING IS THAT OUR COMMENCE SALS AT LEAST ARE ALSO ABLE TO INFLUENCE THE KIND OF IMMUNE RESPONSE WE MAKE. CATEGORY 5 HERE. SO FIRST THESE TWO -- BAD DEATH. NOT NECESSARILY CORRELATED WITH INFECTION. WHAT ONE MIGHT FORGET AGAIN UMBRELLA OF AUTO-IMMUNITY IS CERTAIN AUTOIMMUNE DISEASES MIGHT BE CORRELATED WITH CERTAIN INFECTIONS. BUT OVERALL INFECTION MAY NOT. IN MOUSE MODELS THAT TURNS OUT TO BE TRUE. SO MLD MICE GET WORSE IF THEY'RE IN A CLEAN ENVIRONMENT THAN IF THEY'RE IN A DIRTY ONE. MICE AGAIN TCR TRANSGENIC MICE WITH EAE GET WORSE IF IN A DIRTY ENVIRONMENT. SO DIRT LOTS OF BACTERIA, WHATEVER, MAKES DIABETES BETTER AND EAE WORSE SO I DON'T KNOW HOW I WOULD MAKE THAT PREDICTION. ANY OTHERS? OKAY. NEXT WEEK WE'RE MEETING ON MONDAY. THE TUESDAYS WHEN I FIRST GOOD PLACE LAST MARCH, I CAN ONLY GET SO MANY HOURS AT LIPSETT. LIPSETT IS USED A LOT. FROM IS AN INFORMATION GROUP BOOKED EVERY OTHER TUESDAY THIGH USED IT LAST TUESDAY AND WE DIDN'T HAVE CLASS, THEY'LL USE IT NEXT TUESDAY AND WHAT I MANAGED TO DO IS BOOK FOR MONDAY BUTLY SEND OUT A NOTICE FOR WHEN THE NEXT CLASS IS. THANK YOU SO MUCH FOR COMING.