TO ALL OF YOU AROUND THE WORLD WHO ARE WATCHING THIS EIGHTH PROGRAM, 21st YEAR OF DEMYSTIFYING MEDICINE AT THE NIH, I SAY GOOD MORNING, GOOD AFTERNOON, OR GOOD EVENING, WHICH EVER IS APPROPRIATE. WE'RE DELIGHTED YOU'RE JOINING US. THE GOAL OF THIS PROGRAM IS TO BRIDGE THE EXCITING DEVELOPMENTS IN BIOLOGY AND ENGINEERING WITH MEDICINE. NOW, THE LOGO FOR THIS COURSE IS WHAT MANY OF US THINK IS THE MOST FAMOUS BRIDGE IN THE HISTORY OF THE WORLD. IT IS ALSO, BY THE WAY, THE FIRST QUESTION ON THE FINAL EXAM THAT WILL BE GIVEN TO YOU. IT'S THE BROOKLYN BRIDGE, CONNECTING BROOKLYN AND MANHATTAN, SYMBOLIC OF ADVANCES OF THE BRIDGING BETWEEN FUNDAMENTAL SCIENCE AND MEDICINE. LIKE THE PHYSICAL BRIDGE, THERE ARE DISAGREEMENTS ON BOTH SIDES OF A GAP AS TO WHETHER A BRIDGE SHOULD BE BUILT, AND IF SO HOW, AND MOST IMPORTANTLY ONCE A BRIDGE IS BUILT LIFE IS NEVER THE SAME ON EITHER SIDE. SO WE HOPE THESE PROGRAMS WHICH LINK ALL ASPECTS OF BIOLOGY, ENGINEERING, OCCASIONALLY SPACE, THE DEEP SEA VENTS OF THE OCEAN AND NEXT WEEK THE ORIGIN OF LIFE WILL BE STIMULATING AND PROVOKE THOSE WHO ATTEND AND LISTEN TO THINK MORE DEEPLY. THE INTENT OF THESE SESSIONS IS NOT TO OVERWHELM YOU WITH YESTERDAY'S RESEARCH DATA OR A MASSIVE AMOUNT OF INFORMATION TO BE REGURGITATED ON SOME TEST. WE'RE VERY FORTUNATE, NEXT SLIDE PLEASE, BECAUSE TODAY'S PROGRAM IS THE FIRST IN WHICH WE HAVE FIVE PARTICIPANTS. IT DEALS WITH THE TAXONOMY OF AUTO-INFLAMMATORY DISEASE. YOU ALL KNOW THE ANCIENTS RECOGNIZED INFLAMMATION BY VIRTUE OF A COMBINATION OF PAIN, REDNESS, LOSS OF FUNCTION AND HEAT, OR FEVER. IN MOST INSTANCES THAT FEVER WAS DUE TO SOME FORM OF INFECTIOUS AGENT. BUT WITH TIME IT TURNS OUT THAT INFLAMMATION HAS MANY CAUSES OTHER THAN INFECTION, PER SE. AND ONE OF THE MORE STRIKING GROUPS OF INFLAMMATION AND INFLAMMATORY DISEASES ARE THOSE THAT RELY UPON INHERITABLE DEFECTS IN THE BASIC PROCESS THAT LEADS TO INFLAMMATION, AUTO-INFLAMMATORY DISEASE. AND OUR SPEAKERS TODAY, AND THERE WILL BE THREE, PLUS TWO PATIENTS, THE FIRST TIME WE HAVE EVER HAD A QUINTET IN THE 20 YEARS OF THIS FORCE, THEY WILL BE DISCUSSING UNDER THE TITLE OF REIMAGINING THE TAXONOMY, THE CLASSIFICATION, OF AUTO-INFLAMMATORY DISEASES. NOW, THE RINGLEADER IN THIS PROGRAM IS DR. DAN KASTNER, WHO GRADUATED IN PHILOSOPHY FROM PRINCETON, MD/PHD FROM BAYLOR, MEDICAL RESIDENCY, CAME TO NIH IN 1985, HAS BEEN HERE EVER SINCE. HE DID A PROLONGED STINT AS SCIENTIFIC DIRECTOR OF THE NATIONAL HUMAN GENOME RESEARCH INSTITUTE, FROM WHICH HE IS NOW EMERITUS, IS CURRENTLY AN NIH DISTINGUISHED INVESTIGATOR AND CHIEF OF THE INFLAMMATORY DISEASE SECTION. HE IS ALSO NOTABLY THE CO-CHAIR OF THE COURSE IN DEMYSTIFYING MEDICINE. DAN'S RESEARCH HAS BEEN OF EXTRAORDINARY EXCITEMENT AND IMPORTANCE. HE BECAME INTERESTED IN INFLAMMATORY DISEASE, FEVER, FOR WHICH THERE WAS NO KNOWN INFECTION. ONE OF THE MORE COMMON CHIEF COMPLAINTS OF PATIENTS ADMITTED TO A HOSPITAL IS FEVER OF UNKNOWN ORIGIN. WITHIN THAT LARGE GROUP OF ETIOLOGIC FACTORS THERE ARE PATIENTS WHO HAVE GENETIC DISTURBANCES THAT LEAD TO FEVER, AND THEY LEAD TO INFLAMMATION TOO. AND IT WAS THROUGH THIS STUDY WHEN HE CAME TO NIH, A FAMILIAL MEDITERRANEAN FEVER FOR WHICH HE IDENTIFIED THE FUNDAMENTAL DEFECT AND DISCOVERED THE AGENT, PYRIN, LATER PARTICIPATED IN CLONING THE GENE THAT OPENED THE DOOR TO AUTO-INFLAMMATORY DISEASES AS DISORDERS OF THE INNATE IMMUNE SYSTEM AND PURSUED THROUGHOUT HIS BRILLIANT CAREER AT NIH THE ELUCIDATION OF AUTO-INFLAMMATORY DISEASES, THEIR MECHANISMS, THEIR GENETICS AND MEANS OF THERAPY. FOR THIS WORK DAN HAS RECEIVED MANY AWARDS AND HONORS, INCLUDING ELECTION TO THE NATIONAL ACADEMY OF SCIENCES, NATIONAL ACADEMY OF MEDICINE, IN 2018 FEDERAL EMPLOYEE OF THE YEAR, MORE RECENTLY RECEIVED THE ROSS PRIZE IN MOLECULAR MEDICINE, AND THE c-RAFFORD PRIZE IN POLY ARTHRITIS. HE WILL BE JOINED BY PROFESSIONAL COLLEAGUES DR. DANIELA SCHWARTZ, GRADUATED FROM RICE, M.D. WAKE FOREST, MEDICAL RESIDENCY VIRGINIA COMMONWEALTH UNIVERSITY, CLINICAL RHEUMATOLOGY AT NIH, FOLLOWED BY MEDSKER FELLOWSHIP WITH JOHN OH HEY AT NIH, AND IN 2018 GAME ASSISTANT CLINICAL INVESTIGATOR IN NIAID INTRAMURAL RESEARCH PROGRAM. NOTABLY WAS RECIPIENT OF THE PRESTIGIOUS AMERICAN SOCIETY OF CLINICAL INVESTIGATION YOUNG PHYSICIAN-SCIENTIST AWARD IN 2020. AND SHE WILL BE JOINED BY DR. KALPANA MANTHIRAM, ASSISTANT CLINICAL INVESTIGATOR IN NIAID, AS WELL. KALPANA RECEIVED HER MEDICAL DEGREE FROM UNIVERSITY OF TEXAS SOUTHWESTERN, RESIDENCY IN PEDIATRICS AT BOSTON CHILDREN'S AND BOSTON MEDICAL CENTER, PEDIATRIC INFECTIOUS DISEASE FELLOWSHIP AT VANDERBILT, AND IT WAS THERE THAT SHE BEGAN TO WORK ON THE MOST COMMON PERIODIC FEVER SYNDROME IN CHILDREN. SHE THEN WAS A POSTDOCTORAL RESEARCHER IN THE KASTNER LAB IN THE GENOME INSTITUTE WHERE SHE HAS STUDIED GENETIC RISK LOCI AND PATHOGENESIS OF PERIODIC FEVER, HAVE HAD IN IMMUNOLOGIC MECHANISM OF MUCOSAL INFLAMMATORY DISEASES, TO DEVELOP TREATMENT GUIDELINES AND SHE PROVIDES MEDICAL CARE FOR PATIENTS WITH AUTO-INFLAMMATORY DISEASES. SO, WITH THIS INTRODUCTION, WE ALL ARE ANXIOUSLY AWAITING THE EXCITING PRESENTATION TO FOLLOW, AND SO, DAN, PLEASE CARRY ON. >> WIN, THAT WAS A WONDERFUL, KIND INTRODUCTION. IT IS MY ENORMOUS HONOR AND PLEASURE TO BE HERE THIS AFTERNOON, OR THIS MORNING, OR THIS EVENING, WHENEVER IT IS FOR THOSE OF YOU WHO ARE PARTICIPATING IN THIS EVENT. IN ANY CASE, WE'RE GOING TO BE TALKING ABOUT THE AUTO-INFLAMMATORY DISEASES AND THINKING ABOUT HOW THEY ARE ORGANIZED, AND PROBABLY BEFORE WE GO EVEN A LITTLE BIT FURTHER THERE'S A LITTLE BIT OF HOUSEKEEPING THAT WE HAVE TO DO. I SHOULD DISCLOSE TO YOU THAT IN FACT I AND MY COLLEAGUES, DR. SCHWARTZ AND DR. MANHATTAN MANTHIRAM HAVE NO RELEVANT , AND EXPLAIN HOW THE TOOLS OF HUMAN GENOMICS HAVE ADVANCED OUR UNDERSTANDING OF THE AUTO-INFLAMMATORY DISEASES. AND IN THE SPIRIT OF THESE SESSIONS, AS DR. ARIAS POINTED OUT, WE ARE ALL ABOUT BUILDING BRIDGES. HERE YOU SEE A PHOTOGRAPH OF MY LAB TAKEN BEFORE THE PANDEMIC, SO SOCIAL DISTANCING WAS NOT IMAGINED AT THAT TIME. NO ONE WAS WEARING A MASK. MY LAB AND CLINICAL TEAM ALSO BEFORE THE PANDEMIC. OF COURSE, THE BRIDGE THAT BRINGS THEM TOGETHER IS OUR PATIENTS, WHAT INSPIRES US IN TERMS OF POSING NEW QUESTIONS, THAT DRIVES US TO TRY TO UNDERSTAND HUMAN DISEASE AND DEVELOP TARGETED THERAPIES. FOR THOSE NOT IMMUNOLOGISTS JUST A LITTLE BIT ABOUT THE TWO FLAVORS OF IMMUNITY. FIRST OF ALL ON THE LEFT WE HAVE ADAPTIVE IMMUNITY. THE FORM OF IMMUNITY THAT MANY OF YOU THINK OF, WHEN WE TALK ABOUT THE IMMUNE SYSTEM. IN WHICH T AND B LYMPHOCYTES ARE THE MAJOR PLAYERS, IN WHICH THE GENES FOR RECEPTORS, SOMATICALLY REARRANGE AND MUTATE, AND AUTOIMMUNE DISEASES ARE CHARACTERIZED BY HIGH TITER AUTOANTIBODIES OR ANTIGEN SPECIFIC T CELLS. ON THE OTHER HAND WE HAVE PHYLO GENETICALLY SYSTEM, MYELOCYTES OR MONOCYTES OR MACROPHAGES ARE THE MAJOR EFFECTORS, WHERE RECEPTORS OR GENES FOR RECEPTORS ARE HARD WIRED IN THE GERMLINE GENOME, AUTO-INFLAMMATORY DISEASES ARE CHARACTERIZEDDED BY SEEMINGLY UNPROVOKED INFLAMMATION. MY INTRODUCTION TO THE AUTO-INFLAMMATORY DISEASES OCCURRED BEFORE THE TERM AUTO-INFLAMMATORY EXISTED, IN 1985, I AS A NEW RHEUMATOLOGY FELLOW AT NIH SAW A PATIENT, A YOUNG MAN OF ARMENIA ANCESTRY, WHO PRESENTED TO US WITH A HISTORY OF LIFELONG ATTACKS OF FEVER USUALLY ON THE ORDER OF ONCE A MONTH, WITH ARTHRITIS, AFFECTING EITHER ONE JOINT OR SOMETIMES A COUPLE JOINTS AT A TIME. USUALLY IT WOULD BE THE KNEE OR ANKLE. THE KNEE COULD SWELL UP TO AN ENORMOUS SIZE, LIKE A GRAPEFRUIT, AS THEY SAY. AND AFTER HEARING HIS STORY, I DIDN'T KNOW WHAT REALLY HE HAD BUT FORTUNATELY THERE WERE COLLEAGUES OF MINE IN THE LAB FROM ISRAEL WHO DID RECOGNIZE THIS STORY VERY WELL AND POINTED OUT TO ME THAT THIS WAS PROBABLY FAMILIAL MEDITERRANEAN FEVER. SO FOR THOSE OF YOU WHO ARE NOT FAMILIAR WITH FMF LET ME DIGRESS FOR A MOMENT TO SAY FMF WAS FIRST DESCRIBED AT LEAST AS A SERIES OF PATIENTS BY DR. SHEPARD SEGAL, A PHYSICIAN AT MOUNT SINAI HOSPITAL IN NEW YORK IN 1945. AT THAT TIME, HE DESCRIBED 10 PATIENTS WHO WERE OF JEWISH ANCESTRY, AND HAD A HISTORY OF RECURRENT EPISODES OF SEVERE ABDOMINAL PAIN, SOMETIMES PROMPTING EXPLORATORY LAPAROTOMY. IT WAS NOT CANCER, NO DISEASE ASSOCIATED WITH IT, BENIGN PAROXYSMAL PERITONITIS, RECOGNIZED AS JEWISH POPULATIONS WITH EMIGRATING TO ISRAEL IN THE 1950s, DUBBED FAMILIAR FAMILIAL MEDITERRANEAN FEVER, DETERMINED IT WAS A RECESSIVELY INHERITED DISEASE AND OTHER GROUPS FOUND FAMILIAL MEDITERRANEAN FEVER COMMON IN JEWISH, ARAB, ARMENIA, TURKISH POPULATIONS AS WELL AS SOME OTHER MEDITERRANEAN POPULATIONS. CLINICAL FEATURES OF FMF INCLUDE AS THE NAME SAYS FEVER, ALSO STERILE PERITONITIS, ARTHRITIS AS WAS THE CASE FOR MY FIRST PATIENT, PLEURISY, SOME PATIENTS WILL HAVE DEPOSITION OF INFLAMMATORY PROTEIN, CLEAVAGE PRODUCT OF INFLAMMATORY PROTEIN IN THE KIDNEYS AND OTHER VITAL ORGANS, AND BEFORE THERE WERE TREATMENTS FOR FMF THOSE PATIENTS WOULD DEVELOP KIDNEY FAILURE, EVEN DIE FROM THE KIDNEY FAILURE. SO, BACK WHEN I FIRST SAW THAT PATIENT THIS WAS INCREDIBLY EXCITING, AS AN INTERESTING DISEASE, CAUSE OF IT WAS NOT KNOWN. IT WAS VERY STIMULATING TO THINK ABOUT WHAT COULD BE THE CAUSE OF IT. AND CERTAINLY AT THAT TIME THE HUMAN GENOME PROJECT WAS JUST COMING TO THE FORE, AS A WAY MAYBE OF FIGURING OUT WHAT THE CAUSE OF FMF MIGHT BE. I SORT OF TOOK TO THIS IN IN EARNEST WHEN I FINISHED MY CLINICAL WORK IN 1988. IN 1988 COULD WE FIND THE RECESSIVE GENE THAT IS MUTATED IN FAMILIAL MEDITERRANEAN FEVER? JUST AS BACKGROUND ON THAT, IN 1978, TEN YEARS BEFORE, DR. YW KAHN, WHO WAS AND STILL IS A PROFESSOR OF HEMATOLOGY AT UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, FOR THE FIRST TIME EVER FOUND THAT A POLYMORPHISM IN DNA, A VARIATION IN DNA, COULD BE IDENTIFIED AND POST SEGREGATED WITH DISEASE IN A FAMILY. A FAMILY WITH SICKLE CELL ANEMIA. THE FIRST TIME A DNA MARKER THAT SEGREGATED WITH DISEASE IN A FAMILY HAD BEEN IDENTIFIED. 1978. AND THEN A COUPLE YEARS LATER, IN 1980 DAVID BOTSTEIN SAID, WELL, IF YOU CAN DO THAT WITH ONE MARKER IN ONE FAMILY, THEN WE COULD MAKE A WHOLE BUNCH OF MARKERS AND A WHOLE BUNCH OF -- FROM A WHOLE BUNCH OF FAMILIES, AND IN FACT IDENTIFY A MAP, BUILD A MAP OF MARKERS THROUGHOUT THE HUMAN GENOME, AND COULD USE THAT TO MAP HUMAN DISEASE GENES AND EVEN TO IDENTIFY THOSE GENES EVENTUALLY. 1980. AND THEN IN 1988, HERE'S FRANCIS COLLINS, HOT IN THE PURSUIT OF THE GENE FOR CYSTIC FIBROSIS, ALTHOUGH HE HAD NOT YET FOUND IT IN 1988. AT THAT POINT IT SEEMED LIKE MAYBE WE COULD FIND THE GENE FOR FAMILIAL MEDITERRANEAN FEVER, IT HADN'T YET BEEN DONE IN EXACTLY THAT WAY, THAT FAR. BUT MAYBE WORTH A TRY. AND SO I ESTABLISHED A COLLABORATION WITH THE SHEBA MEDICAL CENTER IN ISRAEL, AND HAD A FIELD TRIP IN THE SUMMER OF 1989 WITH MY COLLEAGUE AND COLLABORATOR, WE VISITED A NUMBER OF FAMILIES WITH FAMILIAL MEDITERRANEAN FEVER, IN ISRAEL, SOME CAME TO HIS CLINIC, SOME WE WENT TO THEIR HOUSES. HERE IS A PHOTOGRAPH OF ONE OF THOSE FAMILIES, THIS PHOTOGRAPH HAS BEEN ADJUSTED TO COMPLY WITH HIPAA REQUIREMENTS SO THAT NO CONFIDENTIALITY WOULD BE BREACHED. IN ANY CASE, HERE THEY ARE, ONE OF THOSE FAMILIES. HERE'S A WHOLE SET OF PEDIGREEES WE DREW BLOOD FROM DURING THAT TIME. AND HERE'S MY LAB A YEAR OR SO LATER. MY FIRST POSTDOC WHO HAS GONE ON TO HAVE A DISTINGUISHED YEAR IN HUMAN GENETICS, LUIS GRU BRERG, WHO BECAME A CASHEDDOLOGYIST, TRYING TO USE NEW TECHNIQUES OF HUMAN GENOMICS TO FIND THAT GENE BUT AT THAT TIME THERE WERE ONLY ABOUT 300 MARKERS THROUGHOUT THE WHOLE HUMAN GENOME. SO THERE WAS AT LEAST A CHANCE THAT WE'D NEVER FIND IT, IF THE GENE WAS IN THE WRONG PLACE RELATIVE TO THE MARKERS. WELL, FORTUNATELY, WE PERSISTED AND EVENTUALLY DID FIGURE OUT THAT THE GENE FOR FMF, THIS WAS IN 1992, IS ON THE SHORT ARM OF CHROMOSOME 16. SO THAT WAS GREAT. BUT THEN WE HAD OUR NEXT JOB CUT OUT FOR US, WHICH WAS ACTUALLY TO DEVELOP MAPS OF THAT REGION OF CHROMOSOME 16 BECAUSE IT HAD NOT BEEN MAPPED. AND SO IT WAS UP TO US AS THE EXPLORERS OF THAT REGION OF CHROMOSOME 16 AND WE HAD A COUPLE OF GENETIC MARKERS THAT ULTIMATELY WE HAD NARROWED THINGS DOWN TO AND THEN WE USED A SET OF COSMIDS THAT HAD BEEN DEVELOPED AT A LABORATORY AT DEPARTMENT OF ENERGY AT LOS ALAMOS, HOME OF THE ATOMIC BOMB. I SET UP A COLLABORATION WITH THEM. WE ESTABLISHED THIS MAP GOING FROM TELOMERES TO THE CENTROMERE, ULTIMATELY WE WERE ABLE TO CREATE THESE OVERLAPPING COSMIDS IS, A MAP OF OVERLAPPING COMS, A MILLION BASE PAIRS IN SIZE COVERED BY 170 OR SO COMSES, USING THAT WERE ABLE TO NARROW THINGS DOWN TO 100,000 BASE CARES, 100 KB. THEN WE USED A TYPE OF PLASMID THAT ALLOWED US TO PULL OUT EXONS. YOU SEE THE COSMIDS HAD NOT BEEN SEQUENCED, THE TOE HOLD TO FIND THE GENE, THAT TOOK US UNTIL 1997. SO NINE YEARS ALTOGETHER FROM THE TIME OF STARTING THIS PROJECT TO ACTUALLY FINDING THE GENE MUTATED, AND DENOTED THAT AS PYRIN. IT WAS ABSOLUTELY WORTH IT BECAUSE THIS TURNED OUT TO BE A GENE THAT ENCODED A PROTEIN THAT WAS NOT KNOWN BEFORE, THAT WAS THE BEAUTY ESPECIALLY AT THE TIME, YOU COULD FIND THESE THINGS THAT WERE TOTALLY NEW AND HADN'T BEEN SEEN BEFORE, RECOGNIZED BEFORE, IMAGINED BEFORE EVEN. AND OF COURSE I HAD A NUMBER OF COLLABORATORS, WE HAD A NUMBER OF COLLABORATORS AT THAT TIME. RIGHT OFF WE FOUND INTERESTING THINGS ABOUT POPULATION BIOLOGY OF FMF. WE FOUND THAT MODERN DAY CARRIERS OF FMF MUTATIONS IN FACT ARE DESCENDED FROM ANCIENT FOUNDERS FROM BIBLICAL TIMES PROBABLY. SO THAT, FOR EXAMPLE, THERE'S THIS ONE MUTATION CALLED V726A, PROJECTED PATH IS SHOWN ON THIS MAP. SO V726A IS FOUND IN THE ASHKENAZI JEWISH POPULATION OF EASTERN EUROPE, IT'S FOUND IN TURKISH POPULATION, ARMENIANS, IRAQI JEWS, EVEN AN ISOLATED POPULATION IN THE MIDDLE EAST. HOW DO WE KNOW THEY ARE CONNECTED WITH ONE ANOTHER? BECAUSE THEY HAVE THE SAME MUTATION ON THE SAME DNA FINGERPRINT OF CHROMOSOMES, AND SO BASICALLY WE CAN TELL BY THE OTHER DNA MARKERS THAT IN FACT THERE WAS A COMMON ANCESTOR. SIMILARLY FOR THE M694V MUTATION YOU SEE THE DOTTED LINE HERE, DASHED LINE. THAT MUTATION IS SEEN IN THE SAFARDI JEWISH POPULATION OF NORTH AFRICA, TURKISH, ARMENIA, IRAQI JEWISH POPULATION AS WELL. AGAIN, SAME MUTATION ON THE SAME ANCESTRAL CHROMOSOME, A DIFFERENT ANCESTRAL CHROMOSOME FROM V 726A. WE'LL COME BACK TO THAT FASCINATING OBSERVATION. IN ADDITION, WE DID LEARN SOMETHING ABOUT THE BIOLOGY OF INFLAMMATION. WE LEARNED EVENTUALLY, NOT RIGHT AWAY, IT TOOK A LITTLE BIT OF TIME, BUT WE LEARNED THAT IN FACT THE N-TERMINUS OF THIS PROTEIN, PYRIN PROTEIN ENCODED BY THE GENE MUTATED IN FMF, ENCODES A DOMAIN CALLED THE PYRIN DOMAIN. THIS ALLOWS FOR THE FORMATION OF A CHARGE DIPOLE, YOU CAN SEE THE POSITIVE CHARGES IN BLUE, NEGATIVE CHARGES ARE IN RED, AND SO YOU CAN HAVE A SITUATION WHERE THE PYRIN DOMAIN OF ONE PROTEIN INTERACTS WITH PYRIN DOMAIN BY VIRTUE OF POSITIVE-NEGATIVE CHARGES, A FUNDAMENTAL WAY PROTEINS OF THE INNATE IMMUNE SYSTEM CAN INTERACT WITH EACH OTHER IS BY COGNATE PYRIN DOMAIN INTERACTIONS, THERE ARE SOME 20 PROTEINS IN THE HUMAN GENOME THAT HAVE A PYRIN DOMAIN. WHO ILLUSTRATE WHAT HAPPENS, WE HAVE A SILENT MOVIE. SO HERE WE GO. THIS MOVIE IS ENTITLED THE INFLAMMASOME, IT'S A MACROMOLECULAR COMPLEX THAT ACTIVATES CERTAIN CYTOKINES, CERTAIN MEDIATORS OF INFLAMMATION. WE SEE THE STAR OF THE SHOW, THE INACTIVE NLRP 3, NOT PYRIN, IT'S LIKE PYRIN, HAS A PYRIN DOMAIN AT THE END, N-TERMINUS, THE RED CLOWN NOSE APPEARANCE ON THE END OF THE NLLRP 3. 3. THE NLRP 3 PEOPLE MADE THE MOVIE. HERE YOU SEE THE DISC FORMING, BY THE INTERACTION OF PYRIN DOMAINS, LIFE-LIKE INTERACTIONS FROM DIFFERENT PROTEINS. HERE IT IS COMING ON A SIDE VIEW, LOOKS LIKES A FLYING SAUCER COMING IN. NOW YOU'LL SEE SOMETHING INCREDIBLE HAPPEN. THAT IS THAT YOU HAVE OTHER MOLECULES COMING IN THAT ARE CALLED ASC. I WON'T TELL YOU WHAT IT STANDS FOR, THEY HAVE A RED PYRIN DOMAIN AT ONE END. YOU SEE IT'S FORMING A FILAMENT OF LIKE-LIKE INTERACTIONS, AND STICKING OUT ON THE OUTSIDE ARE THESE BROWN DOMAINS, WHICH ARE CALLED CARD DOMAINS, SIMILAR TO PYRIN DOMAINS BUT HAVE THEIR OWN SET OF INTERACTIONS. NOW YOU'RE GOING TO SEE TEST BASE 1, ENZYME THAT CAN CLEAVE CYTOKINES, IT'S COMING IN AND BINDING TO THESE FILAMENTS BY VIRTUE OF CAR DOMAIN INTERACTION. YOU SEE CASPASE 1 HAS A CARD DOMAIN, AND ASC HAS A CARD DOMAIN. NOW THEY ARE ASSEMBLED, SELF-ACTIVATING, CLEAVING MOLECULES OF IL-1 AND IL-18, WHICH ARE PRO-INFLAMMATORY CYTOKINES, AND NOW HERE YOU SEE COMING IN THE BLUE AND GRAY MOLECULE, GASORIMIN D, THE N-TERMINAL FRAGMENTS ARE FLOATING OFF TO THE RIGHT NOW, THE INFLAMMASOME IS DISASSEMBLING AND FLOATING OFF. AND IN A MOMENT WE'RE GOING TO SEE THE N-TERMINAL FRAGMENTS COMING IN FOR THE FINAL ACTION SO HERE WE SEE THE GASORIMIN MOLECULES, YOU SEE THE GRAY N-TERMINAL FRAGMENTS, THEY ARE GOING TO FORM A CIRCLE, AND THAT CIRCLE IS GOING TO FORM A POREE THAT CAN INSERT ITSELF INTO THE CELL MEMBRANE, DISRUPT OSMOTIC GRADIENT, CAUSE THE CELL TO BURST. THEN THE CYTOSINES THAT WERE ACTIVATED IL-1 AND IL-18 GET RELEASED AND OTHER THINGS THAT TRIGGER INFLAMMATION ALSO GET RELEASED. SO THAT IS THE STORY OF HOW THIS ALL WORKS. OOPS. AND WITH REGARD TO PYRIN, PYRIN CAN FORM AN INFLAMMASOME, REGULATED BY THE MOLECULE RHO A, ACTIVATES A PROCESS BY WHICH PYRIN IS PHOSPHORYLATED AND THERE'S AN INHIBITOR MOLECULE THAT PREVENTS FORMATION OF PYRIN IN INFLAMMASOME. WHEN RHO A IS DISRUPTED, THE PROCESS IS STOPPED. WHAT CAUSES RHO A TO BE DISRUPTED? ACTUALLY BACTERIAL TOXINS, BACTERIAL TOXINS DISRUPT RHO A. PYRIN INFLAMMASOME IS CAUSED WHEN A CELL GETS INFECTED BY CERTAIN BACTERIA, IT'S A DEFENSE AGAINST THOSE BACTERIA. NOW, ONE CAN ALSO ASK, AT LEAST SOMEONE MIGHT ASK, I WAS ASKING, WE WERE ASKING, OUR GROUP WAS ASKING, AND I THINK YOU WOULD WANT TO KNOW TOO, WHY IS IT THAT THERE ARE SUCH HIGH CARRIER FREQUENCES FOR FAMILIAL MEDITERRANEAN FEVER IN MULTIPLE MIDDLE EASTERN POPULATIONS? YOU PROBABLY DIDN'T KNOW THERE WERE SUCH HIGH CARRIER FREQUENCIES BUT THERE ARE. TOTAL FOR FMF MUTATIONS IN TURKISH, ARMENIA, NON-ASHKENAZI, BETWEEN 10 AND 12% CARRIERANCY. IS FREQUENCY. FOR CYSTIC FIBROSIS, MOST COMMON IN NORTH AMERICA, 4%. CARRIER FREQUENCY FOR THE SICKLE CELL TRAIT IN THE AFRICAN AMERICAN POPULATION IS 6 TO 8%. SO, 10 TO 12%, THAT IS HIGH. AND THAT DOES MAKE ONE THINK THAT MAYBE THERE WAS SOMETHING THAT WAS SELECTING FOR THOSE HIGH CARRIER FREQUENCIES BUT TO PROVE THAT YOU'VE GOT TO DO MORE THAN JUST THINK IT. YOU HAVE TO ACTUALLY CHECK TO SEE WHAT IS THE SIZE OF THE DNA FINGERPRINT, THE HAPLOTYPE, THAT IS ASSOCIATED WITH THE MUTATION IN CERTAIN HIGH RISK POPULATIONS. WE HAPPEN TO HAVE DATA FOR THAT FROM THE TURKISH POPULATION AND CAN SAY THE HAPLOTYPE ASSOCIATED WITH THE M 694V MUTATION CAN GO OUT AS MUCH AS A MEGABASE, A MILLION BASE PAIRS ON EITHER SIDE OF THE GENE. WHEREAS THE ANCESTRAL ALLELE, WILDTYPE ALLELE, IT'S LIKE A SPIKE THERE. IT DOES NOT HAVE A WIDE HAPLOTYPE. THAT'S THE KIND OF THING YOU WANT TO SEE IF YOU'RE LOOKING FOR EVIDENCE OF SELECTION, YOU CAN ALSO SAY THAT THAT HAPLOTYPE IS ON THE TAIL OF THE CURVE OF DISTRIBUTION OF SIMILAR HAPLOTYPES, HAPLOTYPES OF SIMILAR FREQUENCY IN THE TURKISH POPULATION. IT SHOULD BE AT THE TAIL OF THE CURVE IF THERE'S SELECTION GOING ON. CAN YOU BY MATHEMATICAL APPROACHES, YOU CAN CALCULATE A COEFFICIENT OF SELECTION, FOR FMF MUTATIONS IN THE TURKISH POPULATION, AND THAT TURNS OUT TO BE 0.077. PUT THAT IN PERSPECTIVE, THE SELECTION CO-EFFICIENT FOR LACK CASE PERSISTENCE, ABILITY ABILITY TO DIGEST COWS MILK IN THE YOUR POPULATION, 0.056, SO QUITE HIGH COLLECTION COEFFICIENT, THAT ALLOWS US TO ESTIMATE THE AGE OF THESE FMF MUTATIONS, IT RANGES SOME WHETHER BETWEEN TWO AND FIVE THOUSAND YEARS, PROBABLY IT DID ARISE IN BIBLICAL TIMES. SO THEN OF COURSE YOU CAN ASK THE QUESTION, WELL, WHAT WOULD HAVE BEEN SELECTING FOR THESE HIGH FMF CARRIER FREQUENCIES? ILLUSTRATED ON THIS SLIDE, WE OF COURSE WERE THINKING ABOUT THE USUAL SUSPECTS AND CERTAINLY YERSINIA PESTIS IS A SUSPECT. THE PLAGUE BACTERIUM DOES MAKE TOXINS WHICH CAN ACTIVATE THE PYRIN INFLAMMASOME, YOP-E AND YOP-T AND SHOULD BE A DEFENSE BUT IN APLAGUES PLAGUE MAKES A TOXIN WHICH INACTIVES, POISONS. BUT WITH FMF IT IS IMMUNE TO THAT ACTIVATING PROCESS. ON THIS SLIDE IT SHOWS IN NORMAL PEOPLE WHO HAVE A NORMAL VERSION OF THE FMF GENE, THAT FMF PROTEIN PYRIN GETS HEAVILY PHOSPHORYLATED BY THE PLAGUE YOP-M TOXIN. PEOPLE WITH FMF, PYRIN IS RESISTANCE, THEY DO NOT HAVE THE SAME EFFECT OF PLAGUE TOXIN. THAT RESULTS IN INCREASED IL-1 PRODUCTION, BOTH BY CARRIERS OF THE FMF MUTATION AND PEOPLE THAT HAVE FMF, WE'VE MADE KNOCK-IN MICE THAT HAVE THESE MUTATIONS AND THEY ARE TO SOME EXTENT PROTECTED FROM INFECTION BY YERSINIA PESTIS AND ONE CAN SIMULATE FREQUENCY OF FMF MUTATIONS FOR EXAMPLE IN THE TURKISH POPULATIONS USING INFORMATION IN TERMS OF SELECTION OF COEFFICIENT, AGE OF MUTATION, SOME HISTORICAL DATA AND CARRIER FREQUENCIES ARE PRETTY MUCH WHAT ONE WOULD EXPECT BASED ON WHAT WE HAVE SEEN IN THAT POPULATION. SO, IN ANY EVENT, THAT'S JUST A LITTLE BIT, MAYBE MORE THAN WHAT YOU WANTED TO KNOW, BUT IT'S INTERESTING, I THINK ANYWAY, INFORMATION ON FMF. WELL, ALL THAT WAS GOING ON, WE WERE SEEING OTHER PATIENTS THAT HAVE UNEXPLAINED RECURRENT FEVERS. AND IT TURNED OUT THAT A GROUP OF THOSE PATIENTS ACTUALLY HAD A DIFFERENT KIND OF PERIODIC FEVER WHERE THE ATTACKS LASTED MUCH LONGER THAN IN FMF, DOMINANTLY INHERENTED RATHER THAN RECESSANT, PATIENTS DIDN'T RESPOND TO USUAL TREATMENT FOR FMF. IN 1999, A COUPLE YEARS AFTER WE HAD FOUND GENE, SOME HAVE MUTATIONS IN TNF RECEPTOR GENE, WE CALLED THAT DISEASE TRAPS, AND CAME UP WITH THE TERM AUTO-INFLAMMATORY SYNDROMES THE THAT TIME. IN BOTH CASES THESE ARE DISEASES IN WHICH PATIENTS HAVE RECURRENT FEVERS SEEMINGLY UNPROVOKED WITHOUT HIGH TITER AUTOANTIBODIES OR ANTIGENS, T CELLS OF AUTOIMMUNE DISEASE. SO WE DIDN'T KNOW WHETHER THERE WERE GOING TO BE MORE AUTO-INFLAMMATORY DISEASES OR NOT BUT WE LET THE IMAGINATION RUN WILD AND WE WROTE THIS PAPER IN 2000 SUGGESTING WHAT OTHER DISEASES MIGHT BE AUTO-INFLAMMATORY DISEASES AND EVEN PROPOSING A CLASSIFICATION SCHEME FOR THEM. AND ONE GROUP OF THEM WE SUGGESTED WAS THE FAMILIAL URTICARIAL SYNDROMES, FEVERS AND PEOPLE BREAK OUT WITH HIVES WITH FEVERS, THERE ARE SUCH DISEASES AS THAT. THEN A YEAR LATER, MUCH TO OUR SURPRISE AND DELIGHT, DR. HAL HOFFMAN AT THE UNIVERSITY OF CALIFORNIA SAN DIEGO PUBLISHED A PAPER IN WHICH HE SHOWED THAT THOSE TWO DISEASES, FAMILIAL URTICARIAL, GENE MUTATED IN THOSE DISEASES ENCODES A PYRIN DOMAIN, NLRP 3, AT THAT POINT IT AND IL-1 ACTIVATION WAS BEGINNING TO BE UNDERSTOOD, LED US TO THINK PERHAPS WE COULD TREAT PATIENTS WITH THE MOST SEVERE FORM OF DISEASE OF THAT SORT, WE COULD TREAT THEM WITH IL-1 INHIBITORS. THIS IS WORK OF MY COLLEAGUE, RAFAEL GOLDBACH-MANSKI, ON NEONATAL ONSET MULTI-SYSTEM INFLAMMATORY DISEASE, THIS IS THE BEFORE AND AFTER. BEFORE TREATMENT THESE PATIENTS HAD HIVES, CONJUNCTIVITIS, INFLAMMATION OF THE LINING AROUND THE BRAIN WHICH COULD LEAD TO BLINDNESS AND DEAFNESS AND INTELLECTUAL DISABILITY. THEY HAD INFLAMMATION OF THE COCHLEA THAT COULD LEAD TO DEAFNESS. AFTER A COURSE OF A POTENT INHIBITOR, IT WENT AWAY, THE FOUNDATION FOR FDA APPROVAL OF THIS DRUG, THIS BIOLOGIC, AND IN FACT THE KIDS THAT HAD BEEN TREATED WITH THIS ARE STILL ON ANAKENRA 20 YEARS LATER. INSTEAD OF HAVING A VERY POOR PROGNOSIS WE KNOW OF A NUMBER OF THEM ATTENDING COLLEGE. SO IT'S REALLY A WONDERFUL THING TO SEE. SO, NOW WE'RE ON TO THE NEXT CHAPTERS AND TO MY COLLEAGUES. SO THE NEXT CHAPTERS, WELL, THEY ARE WRITTEN BECAUSE THE COST OF DNA SEQUENCING WENT DOWN DRAMATICALLY AFTER 2007, SO THIS IS THIS HAS LED TO EXPLOSION IN TERMS OF THE NUMBER OF AUTO-INFLAMMATORY DISEASES WE CAN IDENTIFY IN WHICH PATHWAYS OTHER THAN IL-1 ARE INVOLVED. IN WHICH THERE ARE MANY MONOGENIC DISEASES, AND IN WHICH IN FACT THERE ARE GENETICALLY COMPLEX DISORDERS AS WELL. THIS IS JUST A FIGURE FROM A PAPER THAT WAS PUBLISHED IN "SCIENCE," A FEW MONTHS AGO, ON THE AUTO-INFLAMMATORY DISEASES JUST HIGHLIGHTING TEN OF THE DISEASES. THERE ARE NOW AROUND 50 MONOGENIC AUTO-INFLAMMATORY DISEASES, LOTS OF ROOM FOR CHANGING THE TAXONOMY, IMPROVING THE TAXONOMY OF THESE DISEASES. AND WE'RE GOING TO FOCUS FOR THE REST OF THIS SESSION ON DISORDERS IN WHICH PATIENTS PRESENT WITH FEVER BUT ALSO WITH PAINFUL ORAL ULCERS, PAINFUL SORES IN THEIR MOUTH. ONE SUCH DISEASE IS A DISEASE CALLED BEHCET'S DISEASE, SEEN IN THE MIDDLE EAST, AS WELL AS ALONG MARCO POLO'S SILK ROUTE GOING TO THE FAR EAST, TO CHINA, JAPAN, KOREA. AND PATIENTS WITH BEHCET DISEASE ARE PAINFUL ORAL DISEASE, PUS IN THE CHAMBER OF THE EYE, , ULCERATION OF THE GENITAL REGION, THEY MAY DEVELOP A PUSTULE, A FASCINATING GROUP OF DISEASES, I'M SURE YOU'LL BE DELIGHTED AS DOCTORS SWATHS AND DR. MANTHIRAM REGALE YOU. I WILL TURN THINGS OVER TO DR. DANI SCHWARTZ. >> HELLO, ALL. CAN YOU SEE MY SCREEN? >> YES. >> OKAY. I'M GOING TO PUT MYSELF ON LASER POINTER AND I WANT TO START BY THANKING YOU FOR THE OPPORTUNITY TO SHARE THIS RESEARCH WITH YOU. I WILL BE TALKING TO YOU ABOUT A DISEASE THAT IS VERY NEAR AND DEAR TO MY HEART, AND AFTER DR. KASTNER TOLD YOU ABOUT AUTO-INFLAMMATORY DISEASES, I'M GOING TO TELL BUT SITUATIONS WHERE AUTOINFLAMMATION ISN'T JUST AUTO INFLAMMATION, USING HA20 AS A CARDINAL EXAMPLE. AS A DISCLOSURE I WANT TO LET YOU KNOW I WILL DISCUSS THE GENERAL CONCEPT OF TARGETED OFF-LABEL THERAPIES FOR THIS DISEASE USING VARIOUS NUMBER OF TARGETED TREATMENTS THAT WE'VE USED FOR THESE PATIENTS THAT ARE OFF LABEL. I WOULD LIKE TO START BY TELLING YOU ABOUT ONE OF THE INDEX PATIENTS FOR THIS DISEASE, A PATIENT WHO YOU'LL BE HEARING FROM DIRECTLY AT THE END OF THIS TALK. AND THIS YOUNG LADY WAS DIAGNOSED AT THE AGE OF 10 WITH JUVENILE IDIOPATHIC ARTHRITIS, THIS IS BECAUSE SHE DEVELOPED VERY SEVERE ARTHRITIS WITH SYSTEMIC INFLAMMATION, HAD SOME RESPONSE TO STANDARD BIOLOGICS THAT YOU USE TO TREAT THIS DISEASE BUT NOT COMPLETE RESPONSE. YOU CAN SEE HERE THESE AREN'T HER JOINTS, THIS IS ANOTHER HA20, THIS IS A VERY TYPICAL EXAMPLE OF WHAT SHE HAD. AS TIME WENT BY, AT THE AGE OF 14, HER DISEASE WORSENED DESPITE TREATMENT WITH STANDARD BIOLOGICS FOR JUVENILE IDIOPATHIC ARTHRITIS AND BEGAN TO DEVELOP ORAL ULCERS, SEVERE NEUROLOGIC DISEASE, UNCONTROLLABLE MOVEMENTS, SEVERE RETINAL INFLAMMATIONS THAT LED TO BLINDNESS WITH RAPID ONSET, DIAGNOSED WITH SYSTEMIC LUPUS, TREATED WITH LUPUS THERAPY, INCOMPLETE RESPONSE AND CONTINUED TO SUFFER FROM BOTH NEUROLOGIC DISEASE AND CONTINUED JOINT DISEASE AND ORAL ULCERS. AT THIS POINT AT THE AGE OF 15 WAS REFERRED TO THE NATIONAL INSTITUTES OF HEALTH LUPUS PROTOCOL FOR EXPERIMENTAL AUTOLOGOUS BONE MARROW TRANSLANT, RECEIVED HER OWN BONE MARROW, INTENSIVE CONDITIONING AND IMMUNOSUPPRESSIVE REG MESSAGE. HER SYMPTOMS TRANSIENTLY GOT BETTER FOR ABOUT A FEW YEARS, BUT THEN BETWEEN THE AGES OF ABOUT 22 TO 23 THEY CAME BACK AND CAME BACK WITH A VENGEANCE. SHE HAD WORSENING NEUROLOGIC SYMPTOMS, WOULD HAVE EPISODES OF AGAIN UNCONTROLLED MOVEMENTS, PLATELETS BEGAN TO BE DESTROYED, ITP, ORAL ULCERS CAME BACK, JOINT INFLAMMATION CAME BACK, SHE BEGAN TO ALSO EXPERIENCE GENITAL ULCERS. AND THIS REALLY BEGAN TO LEAVE THE DOMAIN OF WHAT YOU WOULD TYPICALLY SEE IN A PATIENT WITH LUPUS, AND AROUND THIS TIME DUE TO HER EXTENSIVE FAMILY HISTORY, GENETIC TESTING WAS PERFORMED BY OUR GROUP AND WE INDEED IDENTIFIED A MUTATION IN THIS GENE TNFAIP 3 WHICH INCODES FOR PROTEIN A20. YOU CAN SEE P6 IS OUR PATIENT. THIS IS HER FAMILY. WE FOUND THAT SHE HAD A BIOLOGICAL SISTER, MOTHER, AUNT WHO HAD SIMILAR SYMPTOMS, TO HER. AND THIS MUTATION SEGREGATED DISEASE AROUND THE SAME TIME FOLLOWING ANOTHER FAMILY AND FOUND MUTATIONS IN THE SAME GENE IN THAT FAMILY. AND THROUGH WORKING WITH COLLABORATORS WHO FOLLOWED OTHER FAMILIES WITH INHERITED FORMS OF BECHETS'S FOUND MUTATIONS IN THREE ADDITIONAL FAMILIES AS WELL AS ONE OTHER FAMILY FROM A LARGER COHORT OF TURKISH AND JAPANESE PATIENT. WE WENT ON AND HERE YOU SEE THIS IS OUR PATIENT. WE'RE ABLE TO SEE COMPARED WITH A HEALTHY VOLUNTEER, THE EXPRESSION OF A20 PROTEIN WAS REDUCED IN THIS PATIENT'S CELLS, SO THIS WAS A HAPLOINEFFICIENCY, NOT ENOUGH OF THE PROTEIN, SHE DID NOT EXPRESS THE MUTANT FORM SO REALLY IT WAS JUST SHE DIDN'T HAVE ENOUGH OF THIS PROTEINS WHICH BRINGS US TO HOW DID THIS LACK OF A 20 COME TO CAUSE DISEASE? A20 PRIOR, SO IN ITS FIRST DAYS BEST STUDIES AS INHIBITOR OF NF-kappaB SIGNALING, SO DR. KASTNER TOLD YOU ABOUT MUTATIONS IN TNF RECEPTOR. WHEN IT ACTIVATES IN INDUCTION OF INFLAMMATION, THIS ACTIVATION LEADS TO UBIQUITINATION, TAGGING ON OF MOLECULES INTO VARIOUS POSITIONS OF DOWNSTREAM SIGNALING MOLECULES, AND SOME OF THESE MODIFICATIONS ACTIVATE AND SOME OF THEM INACTIVATE. TWO OF THE ACTIVATING MODIFICATIONS ARE THE STICKING ON OF UBIQUITIN TO LYSINE 63, AND LINEAR, A20 REMOVES K63 AND LINEAR UBIQUITIN, LIKE RIP 1, THESE ACTIVATE REMOVAL INACTIVATES SIGNALING MOLECULES. ADDITIONALLY, UBIQUITINS CAN BE LAGGED ON LYSINE 48, TARGETS MOLECULES FOR DEGRADATION. A20 ALSO WILL ADD UBIQUITINS AND TARGET THE SAME MOLECULES TO DEGRADATIONS SO THREE MECHANISMS, TARGETS INFLAMMATORY -- THIS INFLAMMATORY PATHWAY FOR INFLAMMATION. NOT ENOUGH A20, TOO MUCH NF-kappaB SIGNALING, INCREASED INFLAMMATION. AND INDEED WHEN YOU LOOK AT CELLS FROM OUR PATIENT WITH HA20 THAT'S WHAT YOU SEE. YOU SEE INCREASED PHOSPHORYLATION IN OUR PATIENT, INCREASED ALPHA DEGRADATION AND SO THAT INCREASED NF-kappaB SIGNALING VERY CONSISTENT WITH ENHANCED INFLAMMATION AND REDUCED A20 IN OUR PATIENTS. BUT WHAT INFLAMMATORY PATHWAY ISN'T ENOUGH, A20 INHIBITS THE NLRP 3 INFLAMMASOME. WORK HAS DEMONSTRATED THIS, INDEED WHEN YOU LOOK BACK AT OUR PATIENT YOU SEE SHE ALSO HAS INCREASED IL-1 BETA RELATIVE TO HEALTHY VOLUNTEER, AND THIS DOES GO THROUGH THE INFLAMMASOME, TREAT AND THEY NO LONGER OVERPRODUCE IL-1 BETA. BUT APPARENTLY, TWO INFLAMMATORY PATHWAYS STILL, A20 IS IMPORTANT FOR INHIBITING THIS INFLAMMATORY FORM OF CELL DEATH KNOWN AS NECROPTOSIS, AND DEFECTS IN NECROPTOSIS CAN LEAD TO AUTOINFLAMMATION IN A SYNDROME CALLED CREA. WORK HAS SHOWN IN AN A20 DEFICIENT CELL YOU'LL SEE ENHANCED NECROPTOSIS, OR INFLAMMATORY CELL DEATH, AND THERE IS YET A FOURTH INFLAMMATORY PATHWAY THAT A0 SEEMS TO REPRESS, THAT IS TYPE I INTERFERON SIGNALING, WHICH HAS BEEN DESCRIBED IN THE PATHOGENESIS OF OTHER AUTO-INFLAMMATORY DISEASES BY DR. MANSKIS GROUP, AND WE HAVE SEEN THAT PATIENTS WITH HAPLOINAS FAR IN-- SUFFICIENCY HAVE INCREASED PHOSPHORYLATION OF STAT1, ACTIVATED DOWNSTREAM OF TYPE I INTERFERONS. NOW WE HAVE A SITUATION WHERE RATHER THAN HAVING ONE DYSREGULATED PATHWAY WE HAVE AT LEAST FOUR POTENTIAL INFLAMMATORY PATHWAYS THAT ARE DYSREGULATED. AND TO MAKE MATTERS EVEN MORE COMPLICATED, I TOLD YOU THAT A20 HAS MULTIPLE FUNCTIONS THAT ARE INVOLVED IN UBIQUITIN EDITING, AND EACH DOMAIN OF THE PROTEIN IS IMPORTANT FOR DIFFERENT UBIQUITIN EDITING FUNCTION. FOR EXAMPLE, THIS ZINC FINGER 7 DOMAIN IS VERY IMPORTANT FOR LINEAR UBIQUITINNATION AND DEUBIQUITINNATION, THIS DOMAIN, IS IMPORTANT FOR TAKING OFF CASES, THAT'S PART OF THE ACTIVATION THAT I TOLD YOU ABOUT OF NF-kappaB, WHEREAS THIS HERE ZINC FINGER 4 IS IMPORTANT FOR K48 EQUILIBRIUMATION. RECENT WORK HAS SHOWN THIS DOMAIN HERE IS VERY IMPORTANT FOR PREVENTING ARTHRITIS AND TNF DEPENDENT RESPONSES, WHEREAS YOU NEED BOTH ZINC FINGER 4 AND ZINC FINGER 7 TOGETHER IN ORDER TO SUPPRESS THE INFLAMMASOME AND IL-1 BETA PRODUCTION. AND SO NOW COMING BACK TO OUR SYNDROME, HAPLOINSUFFICIENCY OF A 20, WE HAVE MULTIPLE DOMAINS THAT INHIBIT DIFFERENT INFLAMMATORY INFLAMMATORY PATHWAYS, FOUR PATHWAYS, COULD THIS CAUSE A DIFFERENT PHENOTYPE IN PATIENTS WITH HAPLOINSUFFICIENCY OF A20, DESCRIBED AS BEHCET-LIKE DISEASE. I'M GOING TO TAKE YOU BACK TO SOMETHING DR. KASTNER TOLD US THEY BEGINNING OF THE TALK, THAT AUTOINFLAMMATION IS CAUSED BY DYSREGULATED OR OVERACTIVATED INNATE IMMUNE RESPONSE WITHOUT HIGH TITER AUTOANTIBODIES, DYSREGULATED RESPONSE, A CLASSIC FEW OF THE DISORDERS OF IMMUNE DYSREGULATION WHERE EACH HAS ITS OWN BIN. BUT THIS IS THE VIEW IN 2022. SO AS SEQUENCING HAS BECOME CHEAPER AND CHEAPER, WE'VE DISCOVERED MORE OF THESE DISEASES, WE CAN SEE THAT THERE ARE GENES THAT ARE EXPRESSED IN INNATE CELLS AND IN ADAPTIVE CELLS, AND THAT ARE IMPORTANT FOR INNATE IMMUNITY AND ADAPTIVE IMMUNITY, AND I THINK THAT NO DISEASE IS MORE EMBLEMATIC THAN HA20 BECAUSE TNF A-3 IS EXPRESSED EVERYWHERE, IMPORTANT FOR MANY TYPES OF BIOLOGIC PROCESSES. AND SO, FOR EXAMPLE, A20 MUTATIONS DO CAUSE AUTOIMMUNITY, IF YOU LOOK AT PATIENTS WITH HAPLOINSUFFICIENCY OF A 20, MANY DO HAVE BONA FIDE HIGH TITER AUTOANTIBODIES, THAT YOU DON'T SEE IN DISEASES LIKE FMF OR TRAPS, AUTOIMMUNE THYROID DISEASE, KIDNEY DISEASE THAT LOOKS INDISTINGUISHABLE FROM LUPUS. AUTOIMMUNITY IS NOT THE ONLY TYPE OF IMMUNE DYSREGULATION. WE ALSO SOMETIMES WILL SEE PATIENTS WITH IMMUNE DEFICIENCY, IN SOME PATIENTS THAT MANIFESTS WITH CURRENT RESPIRATORY INFECTION BUT WE'VE SEEN PATIENTS WHO PRESENT WITH CURRENT GASTROINTESTINAL INFECTION, DISEASES THAT MIMIC SEVERE COMBINED IMMUNODEFICIENCY. AND THEN SOMETIMES WE'LL SEE PATIENTS WITH YET ANOTHER TYPE OF IMMUNE DYSREGULATION, A20 IS ALSO IMPORTANT FOR CELLULAR PROLIFERATION, AND SOMATIC MUTATIONS IN A20 OR LINKED TO LYMPHOMA. AND SO HAPLOINSUFFICIENCY OF A20 HAS BEEN DESCRIBED TO CAUSE LYMPHOPROLIFERATIVE INHERITED DISEASES, YET ANOTHER TYPE OF IMMUNE DYSREGULATION, AND FINALLY JUST LAST YEAR DID A POPULATION SURVEY OF MULTIPLE AUTO-INFLAMMATORY DISEASES, FOUND SIGNATURE FOR CLINICAL AND IMMUNOPHENOTYPIC FINDINGS CONSISTENT WITH ALLERGY IN PATIENTS WITH HAPLOINSUFFICIENCY, LINKED TO DEVELOPMENT OF COMMON ASTHMA. NOW WE HAVE A DISEASE THAT CROSSES MULTIPLE DIFFERENT TYPES OF IMMUNE DYSREGULATION AND REALLY DOES EXPAND OUR CONCEPTION OF WHAT IT MEANS TO HAVE AN AUTO-INFLAMMATORY DISEASE. AND THEN THE QUESTION BECOMES THIS ISN'T SOMETHING LIKE A PYRIN MUTATION WHERE YOU HAVE ONE PATHWAY AND CAN TARGET THAT PATHWAY OR IN THE CASE, YOU TARGET IL-1, HOW CAN WE TREAT THESE PATIENTS? WE'RE LEFT WITH TRYING TO TARGET SOME THE CYTOKINES AND PATHWAYS A20 IS IMPORTANT FOR REPRESSING. WE CAN USE INHIBITORS OF TNF REPRESSING DOWNSTREAM OR TARGET IL-1 BETA BECAUSE WE KNOW THAT A20 IS IMPORTANT FOR REPRESSING INFLAMMASOME. OR WE CAN USE CLINICAL JAK/STAT INHIBITORS TO TARGET RESPONSES DOWNSTREAM OF TYPE I INTERFERON. WE'VE DONE ALL THESE THINGS IN VARIOUS PATIENTS WITH SOME SUCCESS AND SO COMING BACK TO OUR PATIENT, HOW DID WE TARGET HER DISEASE? WELL, I TOLD THAT YOU AT THE AGE OF 23, WE DIAGNOSED OUR PATIENT WITH HAPLOINSUFFICIENCY OF A20. AND WE SAW THAT SHE HAD INCREASED PRODUCTION OF IL-1 BETA. AND SO WE KNEW INFLAMMASOME-TARGETED TREATMENT WAS A SUCCESSFUL WAY TO ADDRESS MANY OF THESE OTHER AUTO-INFLAMMATORY DISEASES, THE INFLAMMASOME WAS ACTIVATED THIS WAS SUCCESSFUL FOR SIX YEARS, NEARLY IN REMISSION, VERY LOW DISEASE ACTIVITY WITH SOME FLARES THAT COULD BE ADDRESSED WITH INCREASED DOSE. AND SHE WAS VERY SUCCESSFULLY TREATED, UNTIL ABOUT AGE 29. AND AT THAT AGE SHE BEGINS TO DEVELOP INCREASED BACK PAIN WHICH THEN PROGRESSED TO INCREASED ARTHRITIS, INCREASED SYSTEMIC INFLAMMATION, THEN FINALLY NEUROLOGIC SYMPTOMS. AND THIS LED TO AN ESCALATION OF HER THERAPY UNTIL WE WERE SUPPRESSING MULTIPLE A20-ASSOCIATED PATHWAYS INCLUDING INFRAM SO MANY AND JAK/STAT SIGNALING, SYSTEMIC STEROIDS, CONTINUED TO HAVE FLARES WITH NEURAL INFLAMMATION DESPITE VERY INTENSIVE IMMUNE SUPPRESSION WITH MANY DIFFERENT PATHWAYS BEING TARGETED. THE QUESTION BECAME DID WE HAVE ANYTHING ELSE TO OFFER THIS PATIENT OR PATIENT LIKE HER WHO IS ON MULTIPLE TARGETED THERAPIES OR EVEN BROAD THERAPIES AND STILL UNCONTROLLED WITH POTENTIALLY ORGAN THREATENING DISEASE. AND THE ANSWER IS THAT, YES, THERE IS. THIS IS VERY, VERY NEW DATA. BUT IN TWO PATIENTS NOW THERE HAVE BEEN REPORTS THAT AN ALLOGENEIC STEM CELL TRANSPLANT, DIFFERENT FROM THE TRANSPLANT OUR PATIENT HAD HAD WHICH HAD BEEN AUTOLOGOUS, GIVING A PATIENT SOMEBODY ELSE'S IMMUNE SYSTEM, TWO PEDIATRIC TREATMENTS THAT WERE NOT SUCCESSFUL TREATED WITH ALLOGENEIC STEM CELL TRANSPLANTS AND WERE ABLE TO GET OFF OF THEIR MEDICATIONS AND HAVE VERY SUCCESSFUL OUTCOMES. THEY DID HAVE SOME DAMAGE FROM PRIOR DISEASE BUT THEY WERE SUCCESSFUL BOTH IN TERMS OF THEIR ENGRAFTMENT AND RESPONSE TO TRANSPLANT. AND THAT IS INDEED THE COURSE THAT WE CHOSE TO FOLLOW WITH OUR PATIENT. SHE DID ELECT TO PURSUE TRANSPLANT WHICH WE HOPE WILL BE -- WILL START WITHIN THE NEXT COUPLE WEEKS. SHE WAS ADMITTED JUST THIS WEEK WHICH IS WHY SHE COULDN'T BE HERE IN PERSON TODAY. AND WHY HER INTERVIEW WAS RECORDED. BEFORE I PROCEED ONWARD TO HER INTERVIEW I WANT TO FIRST ACKNOWLEDGE AND THANK ALL THE PEOPLE WHO CONTRIBUTED TO THIS WHIRLWIND OF RESEARCH OF HA20 THAT I'VE PUT YOU THROUGH. AND THAT INCLUDES STUDENTS AND MEMBERS OF MY GROUP AND MOST PARTICULARLY SARAH BLACKSTONE WITH INTERFERON 20 PRODUCTION AS WELL AS MY MENTORS AT NIAID, JOSH AND PAM, OF COURSE THE BIG GROUP AT NHGRI INSTRUMENTAL IN MY FELLOWSHIP AND HA 20 PATIENTS AND FAMILIES THAT GENEROUSLY AGREED TO PARTICIPATE IN THE RESEARCH. I'M GOING TO ALLOW US TO PROCEED TO THE RECORDED INTERVIEW WITH THE PATIENT WHO GENEROUSLY AGREED TO SHARE HER THOUGHTS DESPITE PREPARING FOR HER TRANSPLANT. >> THANK YOU FOR SHARING YOUR EXPERIENCES LIVING WITH HA20. I'M GOING TO ASK YOU SOME QUESTIONS BOTH ABOUT LIVING WITH HA 20 AS WELL AS BEING A PATIENT WITH COMPLEX INFLAMMATORY DISEASE MORE GENERALLY. I'M GOING TO ASK YOU IF YOU COULD PLEASE DESCRIBE TO US THE SYMPTOMS THAT YOU AND YOUR FAMILY MEMBERS HAVE HAD OVER THE LAST SEVERAL YEARS AND SPECIFICALLY HOW THEY MIGHT BE SIMILAR OR DIFFERENT BETWEEN YOU AND YOUR FAMILY MEMBERS. >> THANKS FOR HAVING ME IN TODAY. THE INTERESTING THING ABOUT MY FAMILY AND I IS THAT THE WAY IN WHICH OUR DISEASE MANIFESTS WAS SYMPTOMS REALLY VARYING IN SCOPE AND SEVERITY. WE'VE ALL EXPERIENCED AT ONE POINT OR ANOTHER SKIN INFLAMMATION, JOINT INFLAMMATION, ORAL AND GENITAL SORES. IN ADDITION TO SYMPTOMS, ONE OF MY FAMILY MEMBERS ALSO EXPERIENCES G I AND KIDNEY INFLAMMATION, I'VE EXPERIENCED EYE INFLAMMATION, KIDNEY AND G.I. INFLAMMATION, ITP. >> A LOT OF VARIABILITY BETWEEN YOU AND YOUR FAMILY MEMBERS AS WELL AS SOME COMMON THINGS. AND LOOKING BACK WE'VE REVIEWED YOUR MEDICAL HISTORY, WHICH WAS VERY LONG AND COMPLEX, DURING THIS TALK, AND I WAS WONDERING IF YOU COULD TELL US WHAT SYMPTOMS YOU MIGHT HAVE HAD THAT COULD HAVE PROMPTED CONCERN FOR PERIODIC FEVER OR AUTO-INFLAMMATORY GENETIC SYNDROME, THINGS LIKE FEVERS, DISCRETE FLARES DURING THE COURSE OF YOUR DISEASE. SURE, SO ONE COMMON THING THAT MOST PATIENTS THAT LIVE WITH CHRONIC ILLNESS, THEY DON'T SOUND THE ALARM WITH MINOR SYMPTOMS. I FALL UNDER THAT CATEGORY. BUT THINKING BACK, ESPECIALLY, YOU KNOW, DURING THIS FLARE OVER THE PAST TWO YEARS, THINKING ABOUT WHAT THE MINOR SYMPTOMS WERE IN THE BEGINNING, WHICH INCLUDES SEVERE HEAD AND BACK PAIN, G.I. INFLAMMATION, HAIR LOSS, SKIN INFLAMMATION, THEN ALSO EXCESSIVE SLEEPING, EXCESSIVE FATIGUE. >> DO YOU FEEL LIKE YOUR SYMPTOMS OCCURRED MORE IN DISCRETE FLARES OR MORE OF A CONTINUOUS ESCALATION OF YOUR SYMPTOMS THAT STAYED THERE ALL THE TIME? >> SO, PRIOR TO RECEIVING MY FIRST TRANSPLANT, MY FLARES DEFINITELY, YOU KNOW, LASTED A CONSIDERABLE AMOUNT OF TIME, AND THEY -- NEVER GOT BETTER. THEY WOULD ADD A MEDICATION OR CHANGE A MEDICATION, I WOULD FEEL SLIGHTLY BETTER, I WOULD REGRESS AGAIN. IT WASN'T REALLY UNTIL JUNE 2013 I RECEIVED THE RIGHT DIAGNOSIS AND RIGHT TREATMENT OPTION THAT MY DISEASE REALLY, YOU KNOW, WAS UNDER CONTROL AT THAT POINT. AND I STILL EXPERIENCED, YOU KNOW, MORE MINOR FLARES AND DISEASE ACTIVITY, BUT THEY WERE VERY MANAGEABLE WITH JUST INCREASING A LITTLE BIT WITH THE PREDNISONE OR WITH THE ANAKINRO, I WAS ABLE TO GET BACK TO BASELINE DOSES. >> THINKING BACK THROUGHOUT, YOU STARTED TO HAVE SYMPTOMS WHEN YOU WERE QUITE YOUNG AND HAVE NOW BEEN DEALING WITH THIS FOR MANY YEARS. HOW DO YOU FEEL THAT HAVING A GENETIC INFLAMMATORY DISORDER HAS AFFECTED YOUR LIFE? >> SURE. SO, OBVIOUS ANSWER TO THIS IS, YOU KNOW, BECAUSE I HAD THE RETINA INFLAMMATION IN 2005, THAT LED TO DISABILITY, LIKE THIS HAD THE MOST PROFOUND IMPACT ON MY DAILY LIFE AND WILL CONTINUE FOR THE REST OF MY LIFE. BUT THINKING REALLY BACK TO, YOU KNOW, THESE PAST TWO YEARS AND THIS CURRENT FLARE, IT HAS BEEN -- WHAT HAS BEEN HARDER TO DEAL WITH IS MENTAL ANGUISH AND UNCERTAINTY OF HAVING A CHRONIC ILLNESS ESPECIALLY IN THE MIDST OF A PANDEMIC. THE FEAR AND PANIC OF, YOU KNOW, HAVING A VERY COMPLEX CONDITION WHILE ALSO MANAGING -- ALSO LIVING DURING A PANDEMIC HAS BEEN VERY CHALLENGING. AND IT'S REALLY ONE OF THE REASONS WHY, YOU KNOW, THIS UNCERTAINTY AS TO WHY I'VE DECIDED TO MOVE TOWARDS HAVING THE TRANSPLANT BECAUSE, YOU KNOW, I KNOW THAT THE PANDEMIC WILL END, BUT MY LIFE WILL NOT GET BETTER. AND THIS FEAR AND UNCERTAINTY AND UNKNOWN IS GOING TO CONTINUE. SO THIS IS MY OPPORTUNITY TO GET BACK TO HAVING MY LIFE BACK. >> AND I WANT TO ACKNOWLEDGE THAT THIS REALLY HAS BEEN A VERY DIFFICULT TWO YEARS FOR YOU. ESPECIALLY THE LAST SIX MONTHS OR SO AS WE'VE SORT OF APPROACHED THIS TRANSPLANT. AND ONCE AGAIN THANK YOU FOR SHARING THAT WITH US. BECAUSE I KNOW IT'S BEEN HARD HAVING GONE THROUGH IT TOGETHER WITH YOU. HOW DO YOU FEEL THAT COMING TO THE NIH HAS HELPED YOU? >> YES, I'VE BEEN COMING TO NIH SINCE 2005 AND HAD MY FIRST TRANSPLANT IN 2006. AND I'VE BEEN RECEIVING CARE IN MANY CASE SINCE THEN. AND HAVING ACCESS TO THIS MEDICAL CARE IS TRULY INVALUABLE. BUT I THINK, YOU KNOW, ALSO REALLY IMPORTANT TO MENTION IS AS A PATIENT WITH A CHRONIC RARE CONDITION, THAT IS VERY COMPLEX, YOU KNOW, FINDING MOMENTS WHERE YOU'RE MORE AT PEACE ARE HARD TO COME BY. AND NIH GIVES THOSE MOMENTS TO PATIENTS. WHAT I MEAN BY THAT IS BECAUSE -- BECAUSE NIH IS UNMATCHED IN MY OPINION TO ANY OTHER CARE YOU CAN RECEIVE ANYWHERE ELSE, YOU KNOW, FROM MEDICAL STAFF, DOCTORS, NURSES, STAFF ACROSS ALL DEPARTMENTS, YOU KNOW, THERE'S NEVER A MOMENT WHERE I THINK MY CARE OR TREATMENT IS GOING TO BE COMPROMISED OR I WON'T BE GIVEN THE BEST OPTIONS. SO BECAUSE I DON'T HAVE TO WORRY AS MUCH ABOUT THAT, YOU KNOW, I GET THESE MOMENTS OF PEACE. AND THAT'S -- FOR PATIENTS GOING THROUGH INCREDIBLE HEALTH CHALLENGES, THAT'S TRULY A GIFT. >> YEAH, THANK YOU. I'M REALLY GLAD TO HEAR THAT WE'VE BEEN ABLE TO HELP YOU LIKE THAT. AND THEN THE LAST THING I WANT TO ASK YOU IS WHAT YOU WOULD LIKE THE MEDICAL COMMUNITY AND SORT OF THE BIOMEDICAL RESEARCH COMMUNITY TO KNOW BOTH ABOUT HA20 AND MORE GENERALLY ABOUT LIVING WITH A COMPLEX GENETIC INFLAMMATORY DISEASE. SURE. SO, WHEN I THINK ABOUT THE ENTIRETY OF MY MEDICAL JOURNEY, ONE THING THAT HAS REMAINED TRUE AND CONSTANT IS HAVING TRUST IN YOUR MEDICAL TEAM AND YOUR DOCTORS. AND THAT'S SOMETHING THAT I HAVE CERTAINLY FOUND AT NIH. AND TRUST CAN BE REALLY FOUND IN MANY WAYS. AND FOR ME, WHAT THAT REALLY MEANS IS THAT HAVING THIS RARE GENETIC CONDITION MEANS MY MEDICAL TEAM WILL THINK OUTSIDE THE BOX AND OUTSIDE THE SCOPE OF WHAT IS THE GENERAL THINKING. AND THEN KIND OF TRANSLATING THAT TO ME, YOU KNOW, MAKING DECISIONS THAT NOT ONLY WILL IMPACT MY LIFE TODAY BUT ALSO THINKING ABOUT HOW IT'S GOING TO IMPACT MY FUTURE. AND SO TRUST IS REALLY CRUCIAL TO ME AS A PATIENT WITH A CHRONIC CONDITION. >> THANK YOU VERY MUCH FOR SHARING WITH US ALL OF THAT. I KNOW THIS WAS DIFFICULT AND PARTICULARLY IN THIS TIME AS YOU'VE BEEN SORT OF APPROACHING THE TRANSPLANT SO WE REALLY APPRECIATE IT. AND THANK YOU ONCE AGAIN. NOW I'M GOING TO GO BACK TO THE TALK. >> THANK YOU. >> AND I THINK THAT I CAN'T SAY ANYTHING MORE ELOQUENT THAN MY PATIENT HAS SAID ABOUT LIVING WITH A CHRONIC INFLAMMATORY DISEASE. WITH THAT I'M GOING TO TURN THIS TALK OVER TO MY COLLEAGUE DR. MANTHIRAM WHO IS GOING TO TELL US ABOUT GENETIC ARCHITECTURE OF DISEASES ON THE SPECTRUM. >> THANK YOU, DR. SCHWARTZ. THANK YOU VERY MUCH FOR THE OPPORTUNITY TO SPEAK WITH YOU IN THIS DEMYSTIFYING MEDICINE SERIES. NOW, I WANTED TO SHARE WITH YOU THE STORY OF A PECULIAR BUT FAIRLY COMMON PERIODIC FEVER SYNDROME, PFAPA SYNDROME, HOW IT MAY BE A FACET OF BEHCETEST DISEASE. I'LL DISCUSS OFF LABEL USE OF THE MEDICATIONS LISTED ON THE SLIDE. WHAT IS FPAPA SYNDROME? IT'S AN ACRONYM, PERIODIC FEVER, APTHOUS STOMATITIS, PHARYNGITIS, ADENITIS, DESCRIBED AT VANDERBILT AFTER RESEARCHERS LED BY DR. EDWARDS SERIES A SERIES OF PATIENTS WITH RECURRENT FEVER EPISODES THAT STARTED IN TODDLER TO PRESCHOOL AGE RANGE, HIGHLY STEREOTYPICAL, INTERESTINGLY THESE EPISODES HAD REGULAR TIMING, AND IN SOME PATIENTS REGULARITY OF THE EPISODES WAS SO REGULAR THAT PARENTS COULD PREDICT APPROXIMATELY WHEN THE NEXT EPISODE WOULD OCCUR AND WOULD START PLANNING THEIR VACATIONS AND MAJOR FAMILY EVENTS AROUND THAT TIME. TYPICALLY EPISODES LASTED FROM 3 TO 5 DAYS, HAPPENED APPROXIMATELY EVERY MONTH, SO SOME PATIENTS HAVE DESCRIBED IT AS A FEVER MENSTRUAL CYCLE. DURING FLARES PATIENTS HAVE IN ADDITION TO FEVER, CANKER SORES, INFLAMMATION OF TONSILS, CERVICAL ADENITIS, LYMPH NODES IN THE NECK, ASIDE FROM THIS ASYMPTOMATIC BETWEEN. PREDNISONE ABORTED THE FLARES WITHIN HOURS, THE FEVER WOULD RESOLVE. BUT UNFORTUNATELY IN MANY PATIENTS THE EPISODES WOULD OCCUR MORE FREQUENTLY WITH STEROID TREATMENT. LATER IT WAS FOUND THAT TONSILLECTOMY LEADS TO COMPLETE CESSATION OF FLARES IN MOST PATIENTS WITH FPAPA. WE BELIEVE IT'S LIKELY UNDERDIAGNOSED, AS MANY PATIENTS ARE MISDIAGNOSED AS HAVING RECURRENT VIRAL INFECTIONS, RECURRENT TONSILLITIS, IT REALLY REQUIRES OBSERVANT PART, ASTUTE CLINICIAN TO SEE THE EPISODES ARE HIGHLY STEREOTYPICAL, THERE'S REGULAR TIMING TO THE FLARES, OR THERE'S APTHOUS ULCERS, SO MANY GO UNDIAGNOSED, SOME OF YOU MAY REALIZE YOU HAVE SYMPTOMS, SOMETHING SIMILAR, WHEN YOU WERE A CHILD. THESE ARE PICTURES OF CANKER SORES ON THE INSIDE OF THE LIP OR INSIDE OF THE CHEEK AND IN MOST PATIENTS, UNDER A CENTIMETER IN SIZE, RESOLVE IN A FEW DAYS, THERE ARE SOME PATIENTS WHO HAVE MORE SEVERE ULCERS. AND THIS IS AN IMAGE OF EXUDATES THAT MIGHT BE SEEN ON TONSILS OF A PATIENT DURING A FLARE. SO LONG TERM PATIENTS, FPAPA MOST HAVE FLARES, LONG-TERM FOLLOW-UP STUDY OF PATIENTS OVER THE COURSE OF 20 YEARS FROM VANDERBILT, YOU CAN SEE WITH TIME EPISODES BECOME SHORTER, FROM FIVE DAYS TO LATER CLOSE TO THREE DAYS, EPISODES BECOME LESS FREQUENT UNTIL THEY SORT OF PETER OUT. AND IN THIS STUDY ABOUT MOST PATIENTS WHO HAD RESOLUTION OF FLARES HAD FLARES FOR ABOUT SIX YEARS. HOWEVER, THERE WERE A GROUP OF PATIENTS, NINE OUT OF 60, PERSISTENT FEVER EPISODES AT THE TIME OF FOLLOW-UP, ONE WAS EVENTUALLY DIAGNOSED AS HAVING BECCET'S DISEASE. MOST PATIENTS CONTINUE TO HAVE APTHOUS ULCERS AFTER FEVERS RESOLVE AND GENITAL RASHES, ATYPICAL, CONSISTENT WITH BEHCET'S DISEASE, CONCLUDING FPAPA MAY BE RELATED TO ULCERATIVE DISORDERS. WE NOTICED ABOUT A QUARTER OF PATIENTS WITH FPAPA HAD A FAMILY MEMBER WITH THE SYNDROME, AND MANY OF THESE FAMILY MEMBERS DIDN'T EVEN REALIZE THAT THEY HAD FPAPA. IT WAS ONLY AFTER WE TOOK A CLOSE HISTORY THAT WE REALIZED THEIR FEVER EPISODES MET THE CRITERIA FOR THE SYNDROME. BUT IN ADDITION TO FPAPA ITSELF, FAMILY MEMBERS OF PATIENTS WITH THIS SYNDROME ALSO ARE MORE LIKELY TO HAVE RECURRENT TONSILLITIS, UNDERGONE TONSILLECTOMY, RECURRENT APTHOUS ULCERS, THIS SHOWS PERCENTAGE OF SIBLINGS OF PATIENTS WITH FPAPA TWO HAVE RECURRENT APTHOUS ULCERS, HIGHER THAN THAT OF CONTROLS WITHOUT THE SYNDROME. FAMILIAL CLUSTERING OF FPAPA PROMPTED US TO SEARCH FOR GENETIC RISK VARIANTS, SO INITIALLY WE DID WHOLE EXOME SEQUENCING ON FAMILIAL CASES BUT UNFORTUNATELY WE WEREN'T ABLE TO IDENTIFY RARE VARIANTS THAT EXPLAINED THE DISEASE IN MOST OF OUR PATIENTS. AND SO WE HYPOTHESIZED INSTEAD THAT FPAPA IS A COMPLEX GENETIC DISORDERS, MANY COMMON GENETIC VARIANTS CONTRIBUTE TO THE RISK. AND IN FACT MANY OF THESE VARIANTS MAY BE NON-CODING REGIONS WHERE THEY AFFECT EXPRESSION OF NEARBY GENES. SO AS WE BEGIN TO SHIFT OUR STUDY OF FPAPA, TO COMPLEX DISORDER, THERE WERE GENOMIC STUDIES OF TWO ULCERATIVE DISEASES THAT CAUGHT OUR ATTENTION. FIRST IS BEHCET'S DISEASE. DR. SCHWARTZ GAVE US A WONDERFUL PRESENTATION ABOUT A MONOGENIC FORM CAUSED BY RARE VARIANTS IN THE TNFAIP3 GENE, THESE MUTATIONS HAVE HIGH EFFECT SIZE IN THE RISK OF AN INDIVIDUAL TO DEVELOP BEHCET'S DISEASE. TO IDENTIFY COMMON VARIANTS WHICH EACH HAVE LOW EFFECT SIZE, GENOME-WIDE ASSOCIATION STUDIES ARE USED, GWAS, IN A GWAS STUDY THOUSANDS TO MILLIONS OF SINGLE NUCLEOTIDE POLYMORPHISMS FROM ACROSS THE GENOME ARE GENOTYPED IN A LARGE NUMBER OF INDIVIDUALS, WITH THE DISEASE AND THOSE WITHOUT THE DISEASE. AND THEN THE SNPs ENRICHED OR REDUCED AMONG INDIVIDUALS WITH THE DISORDER ARE IDENTIFIED AND THESE ARE RISK VARIANTS FOR THE DISEASE. WHEN YOU LOOK AT THE RISK VARIANTS YOU CAN BEGIN TO UNDERSTAND MECHANISM OF VARIOUS COMPLEX DISEASES. SO FOR BEHCET'S DISEASE, DR. KASTNER AND THEIR GROUP HAVE DONE MULTIPLE GWASs, THIS IS INSTRUMENTAL IN HELPING US UNDERSTAND THE PATHOGENESIS OF THIS ULCERATIVE DISORDER. AND THEY FOUND THAT THE MOST SIGNIFICANT RISK FACTOR WAS AT THE MHC LOCUS, IN FACT THE MOST IMPORTANT RISK -- MHC TYPE WAS A CLASS 1 MHC AND POLYMORPHISMS IN ERAP 1, THAT TRIMS PEPTIDES TO BE LOADED WERE ALSO RISK FACTORS IN INDIVIDUALS WITH HLAB 51. IN ADDITION THEY FOUND MANY VARIANTS NEAR THESE GENES, MANY OF WHICH ARE INFLAMMATORY GENES THAT WERE RISK FACTORS FOR BEHCET'S DISEASE, INVOLVED IN Th1 AND Th17 ACTIVATION, CD8 POSITIVE T DEVELOP ACTIVATION MYELOID INFLAMMATION IN ADDITION TO MAINTAINING INTEGRITY OF THE MUCOSAL BARRIER. SO IN AGGREGATE THESE GENES RISK LOCI HAVE BEGUN TO HELP US UNDERSTAND PATHOPHYSIOLOGY OF BEHCET'S DISEASE. ANOTHER GWAS WAS PUBLISHED FOR RECURRENT APTHOUS ULCERS, COLLABORATION WITH 23ANDME AND U.K. BIOBANK INCLUDED A LARGE NUMBER OF INDIVIDUALS HAVING PEOPLE HAVE YOU EVER HAD CANKER SORES, AND THEY CHECKED YES, THEY WERE CASES, IF NOT THEY WERE CONTROLS. THEY IDENTIFIED MANY RISK LOCI FOR RECURRENT APTHOUS ULCERS, RUN OF THE MILL PER SE CANKER SORES. INTERESTINGLY, MANY OF THE EXACT SAME GENETIC RISK VARIANTS OR LOCI DR. KASTNER AND DR. REMMERS CHARACTERIZED WERE VARIANTS FOR APTHOUS ULCERS. RECURRENT APTHOUS ULCERS AND BEHCET'S DISEASE ARE OVERLAP, QUESTIONING -- BEGGING THE QUESTION, PHENOTYPIC OVERLAP WITH THE DISEASES DOES IT ALSO HAVE GENOTYPICAL OVERLAP. SO IN ORDER TO ADDRESS THIS WE SCREENED THREE COHORTS OF CAUCASIAN INDIVIDUALS WITH FPAPA FOR RISK VARIANTS AND WE COMPARED THOSE VARIANT FREQUENCES TO THOSE AMONG EUROPEANS IN THE GENERAL POPULATION FROM LARGE DATABASES. AND WE FOUND THAT MANY OF THESE VARIANTS WERE ALSO SIGNIFICANTLY ASSOCIATED WITH FPAPA, IN FACT THIS ONE NEAR THE IL-12A GENE HAD ODDS RATIO OVER 2, QUITE HIGH FOR A COMPLEX GENETIC DISORDER. THE COMMONALITY OF GENETIC SUSCEPTIBILITY LOCI AMONG THE THREE DISORDERS WE BELIEVE PUTS THEN IN A COMMON FAMILY, IN FACT WE PROPOSED THAT THESE DISORDERS BE GROUPED ON A SPECTRUM OF DISEASE CALLED BEHCET'S SPECTRUM DISORDERS, AND THIS IS ON THE SEVERE END, CURRENT APTHOUS ULCERS ON MILD END, FPAPA IN BETWEEN. THIS MADE A LOT OF SENSE BECAUSE WE SEE PATIENTS WHO FALL IN BETWEEN, PATIENTS WHO HAVE GENITAL ULCERS, RASHES DURING THEIR REGULAR FEVER FLARES, ALSO SEE PATIENTS WHO HAVE RECURRENT APTHOUS ULCERS WITH SYSTEMIC SYMPTOMS BUT DON'T HAVE FEVER. AND SO THIS CONCEPT OF THE SPECTRUM HAS BEEN REALLY IMPORTANT FOR US TO UNDERSTAND PATIENTS THAT DON'T QUITE FIT INTO THESE EXISTING DIAGNOSTIC ENTITIES AND WHO SORT OF FALL SOMEWHERE IN BETWEEN, IT'S BEEN HELPFUL FOR US TO UNDERSTAND THE MECHANISM OF THEIR DISEASE AND THINK ABOUT WHAT TREATMENT MODALITIES WE MAY USE. SO, IN TERMS OF GENETIC RISK LOCI, STRONGEST WAS UPSTREAM OF IL-12A, AND IN ORDER TO UNDERSTAND THE FUNCTIONAL SIGNIFICANCE OF THIS VARIANT WE OBTAINED BLOOD FROM INDIVIDUALS WHO CAME TO THE NIH BLOOD BANK AND GENOTYPED THEM FOR THIS RISK ALLELE, THOSE WHO ARE HETEROZYGOUS IN RED, HOMOZYGOUS FOR RISK ALLELE? GREEN. WE EXTRACTED MONOCYTES AND STIMULATED THEM WITH INTERFERON AND LPS AND MEASURED IL-12 PRODUCTION. WE FOUND THAT INDIVIDUALS WHO CARRIED THE VARIANT PRODUCED MON -- MONOCYTES PRODUCED MORE IL-12 AND MORE IL-23 WHICH IS ANOTHER PRO-INFLAMMATORY CYTOKINE. PREVIOUSLY THIS VARIANT NEAR STAT 4 HAS BEEN ASSOCIATED WITH INCREASED STAT4 EXPRESSION AND STAT4 IS IMPORTANT IN DOWNSTREAM SIGNALING FROM IL-12 AND IL-23. THIS VARIANT NEAR IL-10 ASSOCIATED WITH EXPRESSION, AND THIS VARIANT IS ASSOCIATED WITH DECREASED CCR 1 EXPRESSION, A CHEMOKINE RECEPTOR THAT HELPS MONOCYTES TRAFFIC TO SITES OF INFLAMMATION SO IT'S HYPOTHESIZED DECREASED CCR1 MAY CONTRIBUTE TO DIMINISHED MUCOSAL BARRIER, MAY HAVE OTHER FUNCTIONS AS WELL. SO, IN AGGREGATE THESE VARIANTS ARE -- APPEAR TO BE LINKED TO HEIGHTENED ANTIGEN PRESENTING CELL, ELEVATED IL-12 DOWNSTREAM SIGNALING WITH STAT4 POLARIZES AND ACTIVATES Th1 CELLS TO PRODUCE INTERFERON GAMMA, ELEVATED IL-23 AND STAT4 POLARIZE TOWARD Th17 PHENOTYPE AND DECREASED IL-10 LEADS TO FURTHER ACTIVATION OF T CELLS. AND THIS FIT WELL WITH WHAT WAS KNOWN ABOUT THE IMMUNOLOGY OF FPAPA FLARES, SO PATIENTS WERE FOUND TO HAVE HIGH EXPRESSION OF INTERFERON GAMMA IN THESE GENES, HIGH EXPRESSION OF Th1 CHEMOKINES IN THEIR BLOOD, ALSO IN THE TONSIL. WE'VE FOUND THAT THEY HAVE HIGH EXPRESSION OF THE SUBUNITS OF IL-12 DURING THEIR MONOCYTES DURING FLARES. AND I MENTIONED EARLIER THAT TONSILLECTOMY LEADS TO RESOLUTION OF FLARES IN MANY PATIENTS, SO WE'VE BEGUN TO LOOK AT THE IMMUNOLOGY OF THE TONSILS AS WELL, AND WE FOUND THAT THE CD4 POSITIVE T CELLS IN THE TONSILS OF PATIENTS WITH FPAPA HAVE ELEVATED Th1 AND Th17 RELATED CYTOKINES COMPARED TO TONSILS FROM CONTROLS WHO HAVE ANATOMIC ISSUES. WE FOUND CD4 POSITIVE T CELLS IN PATIENTS WITH FPAPA ALSO PRODUCE SIGNIFICANTLY MORE INTERFERON GAM AND IL-17 UPON STIMULATION WITH PMA IONAMYCIN. WE FOUND ASSOCIATIONS, MOST OF THESE WERE UNIQUE TO FPAPA, THEY WEREN'T RELATED TO THE OTHER DISORDERS ON THE BECHECT SPECTRUM EXCEPT ONE. ALONG THE SPECTRUM HLA IS STRONG RESPECTER FOR BECHET'S DISEASE, FPAPA APPEARS TO BE IN THE MIDDLE. HLR RISK ALLELES MAY BE DIFFERENT AND MAY AFFECT THE PHENOTYPE ALONG THE SPECTRUM. IT'S WITH GREAT PLEASURE THAT I'D LIKE TO INTRODUCE TO YOU ONE OF MY PATIENTS, HOLLI IS A PHYSICIAN, I'VE HAD THE PRIVILEGE OF FOLLOWING HER AND HER CHILDREN AT THE NIH FOR THE PAST SIX YEARS. HOLLI PRESENTED TO US WITH INFLAMMATORY DISEASE THAT HAD SOME FEATURES OF BEHCET'S DISEASE BUT SHE AND CHILDREN ARE FPAPA WHEN YOUNGER, BEFORE WE REALIZED THE CONNECTION BETWEEN THE SYNDROMES THAT WE BEGAN SEEING HER. SO, I HOPE HOLLI CAN HEAR ME. THERE'S HOLLI. THANK YOU. THANK YOU VERY MUCH, HOLLI, FOR BEING HERE WITH US TODAY AND FOR SHARING YOUR STORY. I WANTED TO START BY ASKING YOU TO SHARE YOU AND YOUR CHILDREN'S SYMPTOMS OF FPAPA AND HOW YOU WERE DIAGNOSED. >> YES. THANKS FOR HAVING ME. IT'S AN HONOR TO BE HERE AND SHARING OUR STORY. I THINK WHEN EVERYTHING STARTED OUR DAUGHTER WAS 11 MONTHS OLD. SHE'S THE YOUNGER OF OUR TWO CHILDREN. SHE STARTED HAVING FEVERS. THEY WOULD BE 104, 105, AND SHE WOULD PLAY THROUGH IT BUT WOULDN'T DRINK A WHOLE LOT. AND MY KIDS WEREN'T IN DAY CARE. WE HAD A NANNY IN THE HOUSE. SHE WOULD HAVE THESE FEVERS. IT WOULD BE EVERY THREE, THREE AND A HALF WEEKS, WE COULD ALMOST SET AN ALARM TO IT. I KIND OF LAUGHED IN YOUR PRESENTATION, YOU MENTIONED THE VACATIONS. AND WE WOULD SCHEDULE THINGS BECAUSE OF BECKY'S FEVERS. WE WOULD GO TO THE PEDIATRICS, THEY WOULD TELL US, OH, SHE HAS ULCERS AND SWOLLEN LYMPH NODES, IT'S JUST A VIRUS. AND FINALLY I SAID, LOOK, SHE HAS NO ILL CONTACTS. THERE'S SOMETHING GOING ON HERE. WE CAN SET AN ALARM TO IT, NOBODY ELSE IS SICK. AND SO A WORKUP WAS DONE. THEY DID GENETIC TESTING FOR THE FAMILIAL MEDITERRANEAN FEVER, IT WAS NEGATIVE. THEN I DID READ A LITTLE BIT ABOUT THE FPAPA SYNDROME, I'M GOING TO TRY PREDNISONE. I DID TELL THE PEDIATRICIAN AFTER THE FACT, THE FEVER WENT AWAY, MIRACULOUS. WE CONTINUED THAT BUT OVER TIME THE FEVERS BECAME FOR FREQUENT INSTEAD INSTEAD OF 3 WEEKS WAS 2 1/2. BECKY HAD TONSILS OUT AT 23 MONTHS OLD, FEVER WENT AWAY, IT WAS GREAT. OUR SON WAS 8, THIRD OR FOURTH GREAT STARTED GETTING FEVERS AND SORE THROATS. I SAID TO THE PEDIATRICS DO YOU THINK IT'S THE SAME THING AS OUR DAUGHTER HAD? SHE SAID YES, I DO. THE ENT TOOK HIS TONSILS OUT. MY MOTHER SAID, YOU KNOW, YOU ALWAYS HAD FEVERS. AND I DID. I REMEMBER MISSING 21 DAYS OF SCHOOL IN THIRD GRADE OVER FEVERS AND SORE THROATS AND WOULD FEEL PRETTY WELL. MY MOTHER WOULD LOOK AT ME AND SHE KNEW I HAD THE FEVER. AND WHEN WE WENT TO ENT THEY SAID, WELL, WE'RE NOT TAKING TONSILS OUT, IT'S GETTING WARM, SHE'S NOT GOING TO GET SICK. MY MOTHER ARGUED AND SHE SAID HE'LL GET A FEVER, IT WILL COME IN TWO WEEKS, SURE ENOUGH IT DID. I HAD MY TONSILS OUT. BETWEEN THIRD AND FOURTH GRADE. DIDN'T MISS MUCH SCHOOL AFTER THAT. THE EFFECT WAS DIFFICULT. I REMEMBER MISSING SO MUCH SCHOOL I DIDN'T KNOW HOW TO ADDRESS AN ENVELOPE ONE TIME. I REMEMBER THIS. MY KIDS -- SAL MISSED QUITE A BIT IN THE PROCESS TOO. AND I HAVE CONTINUED TO HAVE -- MY FEVERS WENT AWAY BUT I'VE CONTINUED TO HAVE ULCERS THROUGH THE YEARS AND SOME JOINT PAINS. AS THIS WAS GOING WITH MY KIDS, I WAS SEEING A RHEUMATOLOGIST BECAUSE I'D HAVE JOINT THINGS WHERE I CURRENT TURN DOORKNOBS, HAVING DIFFICULTY BUT NOBODY COULD EVER PUT A FINGER ON ANYTHING. AND OUR SON WAS BETTER, AND THEN THREE YEARS AFTER HE HAD HIS TONSILS OUT STARTED GETTING -- WOULD HAVE SHORTNESS OF BREATH EPISODES AND I WORKED IN THE E.R. FOR 18 YEARS, HE WOULD COME IN THE E.R. AND, OH, HE HAS PNEUMONIA. I NEVER LOOKED AT X-RAYS. HE HAD PLURAL EFFUSION TWICE, MYOCARDITIS AND PERICARDITIS. THE RHEUMATOLOGIST SAID DOES HE HAVE JOINT PAIN? NO. WE THOUGHT ABOUT IT. MULTIPLE TIMES BOTH OF OUR KIDS ARE JOINT STUFF, SAL DIDN'T ACOLYTE ONE TIME BECAUSE HE COULDN'T WALK. WE WERE REFERRED TO THE NIH, A WONDERFUL EXPERIENCE. >> THANK YOU FOR SHARING THAT. YOUR STORY REALLY SHOWS HOW IT CAN TAKE SOME TIME TO REACH THE DIAGNOSIS, AND I THINK IT REALLY REQUIRES OBSERVANT PARENT AS YOU WERE FOR YOUR KIDS. SO YOU STARTED TO MENTION THAT EVEN AFTER TONSILLECTOMY YOU BEGAN TO HAVE SOME -- NEW SYMPTOMS, AFTERWARDS, THAT WERE MORE INDICATIVE OF BEHCET'S DISEASE, I WONDERED IF YOU COULD MENTION SOME OF THOSE AND WHEN YOU STARTED TO REALIZE THAT THERE WAS SOMETHING ELSE GOING ON. >> WELL, I'VE HAD -- I'VE ALWAYS REMEMBERED HAVING ULCERS. I WOULD COMPLAIN ABOUT IT. SOMETIMES IT'S HARD TO EAT AND SPEAK WITH AN ULCER. MY MOM WOULD SAY YOU ATE TOO MANY TOMATO SANDWICH OR ORANGES. WE DIDN'T KNOW DIFFERENT. THERE WOULD BE TIMES I WAS WORSE THAN OTHERS. LOOKING BACK I THINK STRESS MAY HAVE AGGRAVATED SOME OF THAT. I ALWAYS HAD SOME SORT OF JOINT PAIN WHERE I WOULDN'T BE ABLE TO RAISE MY SHOULDER AND WE WENT TO ORTHOPEDICS AND THEY WOULD TELL ME, OH, YOU KNOW, IT'S FROM SWIMMING OR CHEERLEADING. IN COLLEGE I COULDN'T WALK ONE WEEKEND, BECAUSE MY KNEE HURT. IT SWELLED UP. I WAS CRAWLING IN MY DORM ROOM, STUDENT HEALTH TOLD ME, OH, YOU HAVE OSGOOD SLAUGHTER'S DISEASE, THAT DOESN'T HAPPEN TO A 22-YEAR-OLD, THERE WAS SOMETHING MORE GOING ON. I DID HAVE PERIODS WHERE I WOULD BE OKAY, AND WHEN I WAS A RESIDENT, I WAS 26, 27, I HAD EYE ISSUES, TROUBLE WITH VISION, GOT SENT TO OPHTHALMOLOGY, UVIITIS, NOBODY COULD PUT THE PIECES TOGETHER. THEY SAID TO ME, WELL, MAYBE IT'S A THYROID PROBLEM. DOWN THE ROAD I WAS DIAGNOSED, THAT'S BEEN UNDER CONTROL AS WELL BUT I THINK IN THE LAST FEW YEARS MY BIGGEST PROBLEMS HAVE BEEN THE JOINT ISSUES AND ULCERS HAVE GOTTEN WORSE BUT RIGHT NOW I'M ON AN INHIBITOR, [AUDIO DISTORTION] >> THANKS, HOLLI. YEAH, AS TIME WENT ON LIKE A LOT MORE OF THESE BEHCET'S FEATURES CAME UP, SIGNIFICANT ORAL ULCERS MORE SEVERE THAN THE MILDER ONES WE SEE IN FPAPA SYNDROME. REMEMBER YOU HAD ALSO TOLD ME YOU HAD RASHES AND THERE WERE TIMES YOU MENTIONED THAT YOU WOULD DEVELOP LESIONS AT THE SITE OF TRAUMA TO YOUR SKIN. COULD YOU DESCRIBE THAT A LITTLE BIT FOR US? >> YEAH, PROBABLY LIKE A YEAR AND A HALF AGO, I DON'T KNOW, I FELL AND HAD A SCRAPE ON MY KNEE. NO BIG DEAL. A WEEK OR SO LATER I GET LIKE A BOLUS KIND OF LESION AT THAT SITE. EVERY NOW AND THEN IF I BUMP THAT, IT DOES COME BACK. I NEVER HAD THAT WITH BLOOD WORK. I'VE HAD A LOT OF BLOOD WORK, MORE WHEN IT'S SOME SORT OF TRAUMA I SEE THAT WITH OR IF I SCRATCH REALLY HARD SOMETIMES AND BREAK SOMETHING OPEN I'LL SEE THAT. I ALSO REMEMBER HAVING A RASH WHERE THEY WERE RED WHEELS AND HAD CENTRALIZED CLEARING. I WENT TO STUDENT HEALTH AT THAT POINT. PROBABLY WAS SECOND YEAR MEDICAL SCHOOL. AND IT WAS VERY STRESSFUL TIME. NOBODY COULD FIGURE IT OUT. EVENTUALLY IT WENT AWAY. I'VE HAD STRANGE RASHES THROUGH THE YEARS. A FEW YEARS AGO HAD ANOTHER ONE, THAT WAS BIOPSIED, SHOWED INFLAMMATORY REACTION. >> I THINK YOUR DISEASE EXEMPLIFIES HOW IT'S HARD TO PINPOINT EXACTLY WHAT IT IS THAT YOU HAVE, LIKE A CLEAR DISEASE ENTITY THAT DEFIES EXISTING DISEASE CLASSIFICATIONS IN SOME CASE. I WAS WONDERING IF YOU COULD TALK TO US ABOUT HOW HAVING AN INFLAMMATORY DISEASE LIKE THIS HAS AFFECTED YOUR LIFE. >> OH, I TRY NOT -- I THINK I COULD RELATE -- [AUDIO DISTORTION] IGNORE IT, I DON'T KNOW THAT'S ALWAYS BEEN THE BEST THING. BUT COMING TO THE NIH HAS BEEN EXTREMELY HELPFUL. AND I REMEMBER AT ONE POINT I WAS FRUSTRATED NOBODY COULD FIGURE OUT WHAT WE HAVE. DR. COLBERT GAVE ME THE BEST ADVICE AS A PATIENT, AND I THINK BEING A PHYSICIAN SOMETIMES MAKES IT DIFFICULT BECAUSE I WANT TO KNOW WHAT I HAVE. PART OF MY TYPE A PERSONALITY DOESN'T HELP BUT THAT BUT DR. COLBERT SAID GIVE IT TIME. DON'T NET ANYBODY -- LET ANYBODY LABEL YOU. WE'LL FIGURE IT OUT. IF WE LABEL YOU, WE MIGHT GIVE YOU THE WRONG TREATMENT. IT'S OKAY NOT TO LABEL YOU. THAT WAS THE BEST ADVICE ANYONE HAD GIVEN TO ME. BECAUSE I'VE BEEN MORE PATIENT WITH IT. AND I KNOW HAVENING -- HAVING THE GROUP AT THE NIH IS WONDERFUL, YOU'VE BEEN SUPPORTIVE, LIKE DR. SCHWARTZ'S PATIENT HAVING TRUST IN EVERYBODY. AS A PHYSICIAN, ESPECIALLY IN THE E.R., WHEN YOU SEE PEDIATRICIANS, EVERYBODY IS SO WORRIED ABOUT GETTING PEOPLE OUT THE DOOR THAT WE DON'T ALWAYS TAKE THE TIME TO LISTEN TO OUR PATIENTS. AND I THINK THAT'S WHAT MADE THE DIFFERENCE AT THE NIH. YOU GUYS HAVE SAT DOWN AND YOU'VE LISTENED. AND IT'S BEEN GOOD. >> WELL, THANK YOU VERY MUCH FOR SHARING YOUR STORY. I'M SURE MORE QUESTIONS MIGHT COME UP IN THE SESSION, SO I'M JUST GOING TO -- I HAVE A COUPLE MORE SLIDES AND I WILL OPEN FOR QUESTIONS. THANK YOU VERY MUCH, HOLLI. SO, OUR NEXT STEPS ARE TO DO A GWAS FOR FPAPA, WE'RE IN THE PROCESS OF RECRUITING ENOUGH PATIENTS, GIVING US THE OPPORTUNITY TO COMPARE THE GENETIC ARCHITECTURE OF THREE DISORDERS ON THE BEHCET'S SPECTRUM AND FURTHER UNDERSTAND WHERE FACTORS MAY DETERMINE WHERE A PATIENT FALLS ON THE SPECTRUM. DIAGNOSING FPAPA IS DIFFICULT, BASED ON CLINICAL HISTORY SO UNDERSTANDING THE MECHANISM MAY HELP US BETTER DEVELOP OBJECTIVE DIAGNOSTIC MARKERS. LASTLY UNDERSTANDING THE MECHANISM OF THESE DISEASES INCLUDING DISEASES ON THE SPECTRUM BETWEEN EXISTING CLASSIFICATIONS LIKE HOLLI'S MAY OPEN UP NEW OPTIONS FOR TREATMENTS, LIKE' PREMO LAST, JAK/STAT INHIBITORS, IL6 INHIBITION HAS BEEN HELPFUL, APREMILAST. AS WE BETTER UNDERSTAND WE CAN HONE IN ON THE RIGHT THERAPIES FOR THESE PATIENTS. SO WITH THAT I AM GRATEFUL TO ALL OF THE CLINICIANS AND RESEARCHERS WHO HELP US IN RECRUITING PATIENTS FOR OUR GENETIC STUDIES AND ARE PART OF THE FPAPA GENETICS CONSORTIUM AND VERY GRATEFUL TO MY MENTORS, DR. KASTNER, DR. REMMERS, WHO ARE INSTRUMENTAL IN THIS PROJECT AS WELL AS ALL THE OTHER MEMBERS OF OUR TEAM. I DON'T HAVE TIME TO GO THROUGH EVERYONE'S NAME. ALSO COLLABORATORS AND PATIENTS WHO DONATED TIME, OBSERVATIONS, SAMPLES, AND I'D LIKE TO THANK HOLLI FOR BEING HERE AND SHARING INSIGHTFUL OBSERVATIONS. AT THIS POINT WE'RE HAPPY TO TAKE QUESTIONS. >> OKAY. FIRST OF ALL, I WANT TO ON BEHALF OF ALL OF US WHO HAVE BEEN LISTENING TO THANK THE THREE SPEAKERS, PARTICULARLY THE TWO PATIENTS WHO SO ELOQUENTLY DESCRIBED THE DIFFICULTIES OF THEIR DISEASE. SEVERAL YEARS AGO, THERE WAS A POSTDOCTORAL FELLOW, Ph.D. FELLOW, WHO WROTE TO ME AND PRAISED THE IDEA OF HAVING THE ABILITY TO SEE PATIENTS, NORMALLY Ph.D. SCIENTISTS DON'T DO. AND HE SAID THAT THE VIRTUE WAS THAT IT PUTS A HUMAN FACE ON A DISEASE. AND I'VE ALWAYS REMEMBERED THAT. AND I THINK IT'S A VERY POWERFUL ASPECT OF THIS COURSE AND OF THE BASIC PRINCIPLES. NOW, WE'VE HAD A SERIES OF QUESTIONS, AND SO I WILL POSE THEM AND THEN PERHAPS WHOEVER -- WHICHEVER OF YOU FEEL IS APPROPRIATE TO ANSWER. ONE QUESTION TO ASK, WHETHER THERE WAS A ROLE FOR PROTEASOME INHIBITORS, PARTICULARLY TARGETING NF-kappaB. AND IN THE TREATMENT OF AUTO-INFLAMMATORY DISEASES, PERHAPS IN GENERAL BUT SPECIFICALLY EARLIER ONES THAT WERE DISCUSSED. WOULD ONE OF YOU LIKE TO RESPOND? >> MAYBE DR. SCHWARTZ, SHE'S BEEN TALKING ABOUT NF-kappaB WOULD WANT TO START OFF ANYWAY. >> YEAH, I CAN TALK ABOUT IN THE SETTING OF HOW 20 AND MAYBE SOME OF THE PROTEASOME-RELATED DISEASES, AND IN THE SETTING OF HA20 AND DISEASES WITH INTERFERON SIGNATURE ONE OF THE THINGS WE SEE, IT'S A DEFECT IN PROTEASOME FUNCTION. AND BECAUSE OF THAT YOU CAN GET ACTIVATION OF THE UNFOLDED PROTEIN RESPONSE LEADS TO ENHANCED INFLAMMATION, INCREASED INTERFERON SIGNALING, AND IT'S DEFECTIVE PROTEASOME FUNCTION AND BUILDUP OF THESE DEGRADATION PRODUCTS THAT CAUSES THAT INFLAMMATORY PATHWAY. IN THAT SCENARIO WHERE YOU HAVE INCREASED TYPE I INTERFERON SIGNALING, I THINK ONE WOULD HAVE TO BE CAUTIOUS IN USING PROTEASOME INHIBITORS AS OPPOSED TO OTHER TARGETED THERAPIES THAT I HAD MENTIONED. I'M GOING TO PASS TO DR. KASTNER TO MENTION WHETHER IN SOME OF THE OTHER NEWER SYNDROMES THAT THAT'S BEEN DISCUSSED BECAUSE THERE'S THAT OVERLAP WITH THE MYELODYSPLASTIC SYNDROMES. >> YES, THANK YOU VERY MUCH, DANI. AND I TOTALLY AGREE THAT THERE ARE THE PROTEASOME-RELATED AUTO-INFLAMMATORY DISEASES WHERE IN FACT PROTEASOME DYSFUNCTION CAN LEAD TO INFLAMMATION. IN VEXUS, A DISEASE CAUSED BY SOMATIC MUTATIONS, ACQUIRED MUTATIONS IN A PATHWAY THAT LEADS TO UBIQUITYLATION, THAT CAN LEAD TO PROTEINS THAT OUGHT TO BE GOTTEN RID OF, THERE'S BEEN DISCUSSION OF PROTEASOME INHIBITORS BUT SO FAR TO MY KNOWLEDGE THERE HAVE BEEN NO TRIALS, THERE'S THE CAUTION THAT WE'RE NOT SURE THE IT'S GOING TO BE BENEFICIAL OR HARMFUL BUT MAY GET RID OF THE CELLS THAT ARE THE MUTATION, THAT'S A THOUGHT MAYBE THAT WOULD WORK. I DON'T THINK THERE HAVE BEEN ANY STUDIES OF PROTEASOME INHIBITORS THAT HAVE BEEN CONDUCTED. >> A VERY IMPORTANT QUESTION, ARE YOU STILL ENROLLING PATIENTS IN THESE STUDIES? IF YES, COULD YOU PLEASE POINT OUT SOME KEY ELIGIBILITY FACTORS. IN OTHER WORDS, WHAT DO YOU LOOK FOR, FOR A PERSON TO BE RECRUITED INTO THESE STUDIES BECAUSE MANY PEOPLE HAVE FEVERS, MANY PEOPLE HAVE SOME ULCERS. WHERE DO YOU DRAW THE LINE? IF NOT THE PERSON WANTS TO KNOW WHETHER YOU PROVIDE CONSULTATION AND WHAT'S THE BEST WAY OF CONTACTING YOU FOLKS? >> WELL, I'LL START OUT MAYBE BUT I THINK MY COLLEAGUES HAVE ALSO THINGS THAT THEY WOULD WANT TO SAY. SO FIRST OF ALL WE DO ACCEPT PATIENTS INTO OUR PROTOCOL, OUR NATURAL HISTORY PROTOCOL, ON AUTO-INFLAMMATORY DISEASES. AND WE DO ALSO PROVIDE CONSULTATION TO PHYSICIANS WHO HAVE QUESTIONS FOR US. SO, WITH REGARD TO THE RESEARCH PROTOCOL, NATURAL HISTORY PROTOCOL, CLEARLY THERE ARE LOTS AND LOTS OF PEOPLE WHO HAVE UNDIAGNOSED FEVERS. THAT'S FOR SURE. AND UNFORTUNATELY, MORE OF THEM THAN WHAT WE COULD REASONABLY ACCOMMODATE. SO WE ARE INTERESTED IN INDIVIDUALS THAT MAY HAVE UNUSUAL MANIFESTATIONS OF THEIR CONDITION OR MAY HAVE TOTALLY UNDIAGNOSED CONDITIONS WHERE THERE'S THE POSSIBILITY THAT WE MIGHT DISCOVER A NEW DISEASE IN THE COURSE OF EVALUATING THOSE INDIVIDUALS. AND SO WE DO FOCUS ON PERHAPS THOSE VERY DIFFICULT CASES OR UNDIAGNOSED CASES, WE WILL SOMETIMES DEPENDING ON CIRCUMSTANCES AT LEAST FOR MAYBE A SINGLE VISIT EVALUATE SOMEONE WHO HAS A KNOWN DISEASE WITH JUST MAYBE SOME PROBLEM WE COULD HELP WITH. WITH REGARD TO CONSULTATION FOR SURE, IT'S BEST IF WE RECEIVE THAT FROM THE PATIENT'S PHYSICIAN SO WE CAN GET MEDICAL RECORDS ASSOCIATED WITH THAT. CERTAINLY I'M MORE THAN HAPPY TO RESPOND TO E-MAILS. DAN.KASTNER AT NIH.GOV. I'M HAPPY TO TRY TO ANSWER THEM. AND KALPANA AND DANI, DO YOU WANT TO SAY ANYTHING? >> I'M ALWAYS HAPPY TO ANSWER E-MAILS. DANIELA.SCHWARTZ@NIH.GOV. I'M NOT RECRUITING PATIENTS BECAUSE I'M NOT SURE IF DR. ARIAS MENTIONED I WILL BE STARTING A TENURE TRACK POSITION AT THE UNIVERSITY OF PITTSBURGH OVER THE SUMMER AND HOPEFULLY RECRUITING PATIENTS THERE BUT NO LONGER TO THE NIH CLINICAL CENTER ANYMORE. HOWEVER, I'M ALWAYS HAPPY TO CONSULT OR SPEAK WITH ANY INTERESTED PHYSICIANS OR PATIENTS WHO HAVE QUESTIONS ALTHOUGH AGAIN FORMAL CONSULTATIONS SHOULD IDEALLY COME FROM PHYSICIANS IF POSSIBLE. >> I'M CURRENTLY RECRUITING PATIENTS WITH FPAPA SYNDROME FOR THE GWAS SO I NEED TO GET A THOUSAND PATIENTS, QUITE A FEW. AND IN ADDITION I'M ALSO SEEING PATIENTS WITH SYMPTOMS ON THE BEHCET'S SPECTRUM LIKE HOLLI, SHE AND HER FAMILY, SHE MENTIONED HER SON HAVING OTHER INFLAMMATORY FEATURES. I THINK FAMILIES LIKE HER HAVE REALLY HELPED OPEN OUR EYES TO THE CONNECTIONS BETWEEN THESE DISORDERS AND MADE US THINK OUTSIDE THE BOX AND NOT JUST TO SAY THIS IS WHAT YOU HAVE BUT TO TRY TO HAVE AN OPEN MIND AND THINKING ABOUT THEM. SO I THINK IT'S REALLY CRITICAL THAT WE HEAR THEIR STORIES AND THINK ABOUT WHAT THE PATHOGENESIS. I'M KALPANA.MANTHIRAM@NIH.GOV AND I'M HAPPY TO LOOK AT CLINICAL FEATURES TO SEE IF THEY MAY BE ELIGIBLE FOR MY STUDIES. >> THERE'S ALSO A clinicaltrials.gov WHICH COVERS MANY CLINICAL TRIALS WHICH MAY BE ANOTHER ENTRY. ONE QUESTION THAT COMES UP, MANY OF THESE DISORDERS HAVE THE DESCRIPTION OF PERIODIC. WHAT MAKES THEM PERIODIC? >> WELL, THAT'S DR. MANTHIRAM'S QUESTION FOR STARTERS. >> I'M STUDYING THE MOST PERIODIC OF THE PERIODIC FEVERS. SO I THINK SHORT ANSWER, WE DON'T KNOW QUITE YET BUT WE'RE BEGINNING TO LOOK AT THE IMMUNE STATE DURING FLARES AND NON-FLARE PERIODS. WE SEE THE SORT OF OSCILLATION DURING FLARE HIGH IMMUNE ACTIVATION, DURING FLARING IMMUNE SUPPRESSION MONOCYTES FAIL TO ACTIVATE NORMALLY. SO I THINK THAT MAY PLAY A ROLE. IT MAY BE THE NATURAL WAY THE IMMUNE SYSTEM STOPS OVERACTIVATED STATE BUT THERE MAY BE FEEDBACK MECHANISMS THAT LEAD TO CYCLING THAT LEAD TO EXTREME PERIOD, SEEN IN FPAPA BUT THERE DOES APPEAR TO BE OSCILLATING ACTIVATION AND SORT OF SUPPRESSED STATES DURING THE FLARE AND NON-FLARE PERIODS THAT WE'RE LOOKING MORE CLOSELY TO DEFINE AND UNDERSTAND. >> SO I GUESS AS PART OF THAT IS YOU MEASURE INFLAMMATORY CYTOKINES FOR EXAMPLE AT ONE TIME, AT MANY TIMES IN AN INDIVIDUAL? IS THERE A CIRCADIAN RHYTHM? IS IT RELATED TO OTHER ENDOCRINE CHANGES? MENSTRUATION? IS IT RELATED TO -- WHAT ABOUT THE SECOND AND THIRD DIMENSION OF THE CHANGES OBSERVED IN BLOOD LEVELS OR EVEN GENE EXPRESSION, OTHER THAN AT SINGLE TIMES IN GIVEN GROUPS OF INDIVIDUALS. >> GREAT QUESTION. I THINK WITH THESE PERIODIC SYNDROMES IT'S REALLY IMPORTANT TO LOOK LONGITUDINALLY AS PATIENTS, NOT AT ONE TIME PERIOD. SO WE'VE BEEN LOOKING FLARE AND NON-FLARE BUT I THINK YOU'RE RIGHT, THAT EVEN LOOKING MORE CLOSELY AT MORE FREQUENTLY I THINK AT WHAT HAPPENS AS THE FLARE BEGINS, MAY BE CRITICAL. MAYBE THE HORSE IS OUT OF THE BARN WHEN YOU GET THE SIGNAL, BUT UNDERSTANDING AS EPISODE STARTS MAY BE SOMETHING, SOMETHING WE'RE LOOKING INTO DOING IN THE FUTURE. AS FAR AS TRIGGERS I HAVE SOME PATIENTS WHO FIND THAT THEIR EPISODES ARE WORSE, THESE ARE PATIENTS WHO CONTINUE TO HAVE FLARES WHEN THEY ARE OLDER. THAT THEIR EPISODES ARE WORSE WITH STRESS, FEMALES WITH MENSTRUAL CYCLES, WONDERING MAYBE HOLLI COULD CHIME IN ABOUT TRIGGERS FOR HER FLARES AND WHAT THINGS MADE IT WORSE FOR HER. >> I THINK MY -- STRESS DEFINITELY IS A TRIGGER. I WORK NIGHT SHIFT IN THE E.R. FOR SIX YEARS CONTINUOUS WHEN MY KIDS WERE SMALLER, THAT'S WHEN I REALLY STARTED GETTING WORSE, LACK OF SLEEP, INTERRUPTED SLEEP. I'M NOW ON AN EIGHT TO FIVE SCHEDULE, THAT'S HELPED. OUR SON IS IN ALABAMA GOING TO COLLEGE, IT'S WARMER. WE'RE IN THE NORTHEAST. HE'S GETTING LESS FLARES. MAYBE THE COLD SOMETIMES AGGRAVATED HIS, HE WAS ALWAYS WORSE IN THE LATE FALL, WINTER PERIODS. >> YOU BROUGHT UP A TIMELY QUESTION WHICH COMES UP IN EVERY ONE OF THESE SESSIONS WE HAVE. THAT IS, WHAT'S THE EFFECT OF THE COVID INFECTION AND PANDEMIC ON THE PARTICULAR -- ANY OF THESE DISEASES? DO WE HAVE A HANDLE? IS THERE SOME -- IS THE VIRUS IT SEVER PARTICIPATING IN SOME OF THESE INFLAMMATORY PROCESSES? WHAT DO WE THOUGH ABOUT THE RELATIONSHIP BETWEEN COVID AND THE AUTO-INFLAMMATORY DISEASES, BOTH AS CLINICAL MANIFESTATIONS, ALSO IN TERMS OF THE UNDERLYING SCIENCE? >> ACTUALLY I WANT TO POINT OUT ONE OF OUR COLLEAGUES, DR. RAFAELA GOLDBACK, PUBLISHED THIS WEEK ADDRESSING THAT QUESTION. I READ IT THIS MORNING IN ANTICIPATION OF THIS EXACT TALK. AND SHE FOLLOWED SEVERAL PATIENTS WITH MUTATIONS IN NLRP 3 AND PROTEASOME GENES, THOSE PATIENTS SOME OF THEM DID DEVELOP COVID-19 INFECTION, ONE OF THEM WAS SEVERELY AFFECTED, THAT PATIENT HAD UNDERLYING LUNG DISEASE. AND RESPONDED WELL TO IMMUNOMODULATORS USED FOR SEVERE COVID, THAT PATIENT RECEIVED IL6 INHIBITOR, THE OTHER PATIENTS HAD MILD DISEASE AND MANY OF THEM HAD COVID VACCINATIONS THAT WERE TOLERATED REALLY WELL, A COUPLE HAD TO TAKE A FEW EXTRA DOSES OF ANAKINRA. BASED ON THE BEST DATA WE HAVE WHICH ARE THOSE DATA, AND OBSERVATIONAL SORT OF I GUESS FOLLOW-UPS OF PATIENTS IN THE COHORT THAT VACCINATION IS WELL TOLERATED IN OUR PATIENTS, SOME DO NEED A COUPLE EXTRA DOSES OF IMMUNE MODULATORS, AND THAT SIMILAR TO MANY PATIENTS WITH RHEUMATIC DISEASES THERE IS PROBABLY INCREASED RISK OF SEVERE COVID INFECTION, THEY ARE PATIENTS WITH CHRONIC INFLAMMATORY DISEASES, BUT THE MAJORITY OF THEM CAN DO WELL WITH APPROPRIATE MONITORING AND CARE, ALTHOUGH IT'S GOOD TO INVOLVE THEIR PROVIDERS SOONER RATHER THAN LATER. DR. KASTNER OR DR. MAN MANTHIRAM, DO YOU HAVE ANYTHING TO ADD? >> I TOTALLY AGREE WITH WHAT DR. SCHWARTZ SAID. ON BALANCE, WE DEFINITELY RECOMMEND IN FAVOR OF VACCINATION, IN FAVOR OF IMMUNIZATION AGAINST SARS-COV-2 IN PATIENTS WITH AUTO-INFLAMMATORY DISEASE. THE RISK/BENEFIT RATIO IS DEFINITELY IN FAVOR OF HAVING VACCINATION. I CAN TELL YOU THAT OCCASIONALLY THERE ARE SOME ANECDOTAL CASES WE'VE SEEN. I SAW ONE PATIENT A FEW MONTHS AGO, A WOMAN WITH FAMILIAL MEDITERRANEAN FEVER, WHO HAD BEEN IN REMISSION. SHE WAS IN HER 60s, IN REMISSION FOR A NUMBER OF YEARS. AND HAD HER VACCINATION AND THEN SHE HAD SOME ATTACKS OF FMF THAT WERE SORT OF STIRRED UP BY THE VACCINATION. BUT STILL WE WERE ABLE TO GET THAT UNDER GOOD CONTROL EASILY, CERTAIN THE RISK ASSOCIATED WITH COVID IS SUBSTANTIAL. AND SO WE DO RECOMMEND IN FAVOR OF VACCINATION FOR OUR PATIENTS. >> ALSO IN MY HA20 PATIENTS THE FEW THAT HAD INCREASED SYMPTOMS OF THEIR DISEASE WITH VACCINATION IT'S BEEN VERY MANAGEABLE, VERY EASY TO CONTROL. AND WE'VE BEEN HAPPY TO SEE THEY TOLERATED WELL, VERY MUCH RECOMMENDED FOR THAT GROUP. >> WITH PATIENTS WITH FPAPA, THE CONCERN WAS THAT WITH THE HEIGHTENED MYELOID CELL AND T CELL FUNCTION WHETHER THESE PATIENTS MIGHT HAVE HYPERIMMUNE RESPONSE TO THE VIRUS BUT WE HAVEN'T SEEN THAT TO BE THE CASE. WE HAVE MOST PATIENTS RESPOND, DON'TS SEEM TO HAVE SEVERE SIDE EFFECTS WITH THE VACCINATION. I THINK HOLLI IS HERE, HER SON DID HAVE A FLARE I BELIEVE AFTER HIS SECOND DOSE OF THE VACCINE AND WE HAVE SEEN THAT AS DR. SCHWARTZ AND DR. KASTNER MENTIONED, ABLE TO BE UNDER CONTROL. >> AN INTERESTING QUESTION, DAN, THAT MAYBE YOU WOULD REFER TO. GIVEN THE GEOGRAPHIC HISTORY OF FMF, DOES IT HAVE ANY BEARING ON THE ORIGIN OF THE ASHKENAZI? AH, WELL, YOU KNOW, IT'S A VERY INTERESTING QUESTION WITH REGARD TO THE RELATIONSHIP BETWEEN FMF MUTATIONS AND ASHKENAZI POPULATION. AND CERTAINLY WE DO SEE AS I WAS SHOWING ON THAT MAP PARTICULAR MUTATION, V7236A MUTATION, THAT'S SEEN IN THE ASHKENAZI POPULATION, AND IS SEEN ON A PARTICULAR HAPLOTYPE. YOU KNOW, THAT GIVES US REASON TO BELIEVE THAT IN FACT AT LEAST THE ORIGIN OF THAT POPULATION FOR SURE IS IN THE MIDDLE EAST, AND, YOU KNOW, IT'S INCREDIBLE WHEN WE WENT TO ISRAEL BACK IN 1989, WHEN I WAS IN ISRAEL DRAWING BLOOD ON THE PATIENTS, I WENT TO A COUPLE DRUSE VILLAGES, THE POPULATION OF PEOPLE THAT LIVE IN ISOLATED MOUNTAIN VILLAGES, THEY HAVE THEIR OWN RELIGION. AND HAVE STAYED ISOLATED FROM THE REST OF THE POPULATION OF THE MIDDLE EAST FOR THE LAST THOUSAND YEARS. AND THEY HAVE THE SAME MUTATION ON THE SAME HAPLOTYPE AS THE ASHKENAZI POPULATION DOES. SO, IT'S REALLY FASCINATING, YOU KNOW, THINKING ABOUT WHAT THIS TELLS US IN TERMS OF THE HISTORY OF THESE PEOPLE. YOU KNOW, OF COURSE IT CAN'T TELL US EXACTLY WHAT'S HAPPENED STEPPED BY STEP AS THEY HAVE SPREAD ACROSS THE WORLD, BUT IT CERTAINLY DOES TELL US SOMETHING ABOUT THEIR ORIGINS. >> IT'S WHAT IAM SHEBA, FOR WHOM THE SHEBA MEDICAL CENTER WAS NAMED, REFERS TO THIS AS GENETICS OF MIGRANT POPULATIONS, A AND STUDIED THEM. IS THERE INFORMATION ABOUT THOSE INDIVIDUALS, SAY, FROM NORTH AFRICA, SOUTH AFRICA, THE -- I'VE FORGOTTEN SOME NAMES WHERE THERE WERE CLAIMS OF ACTUALLY BEING DESCENDED FROM ANCIENT TIMES, FROM THE HEBREW GROUP AND SOME OF THEM. >> ARE YOU TALKING ABOUT ETHIOPIAN -- >> YES, I'M SORRY. >> ARE YOU TALKING ABOUT THE ETHIOPIAN POPULATIONS THAT EMIGRATED IN '80s AND 90s? >> THAT'S PART OF IT, AND THE DESCRIBE WITH THE MIDDLE EASTERN GENE MARKER ON THE Y CHROMOSOME. >> YES, YES, YES. YES, SO WE HAVEN'T LOOKED AT THE FMF MUTATIONS IN THOSE INDIVIDUALS BUT YOU'RE RIGHT, IT'S A FASCINATING THING, AND THE ANTHROPOLOGY OF IT ALL. THAT'S PART OF THE REASON I LOVE DOING THIS. HAVING A CHANCE TO LOOK AT THOSE KINDS OF THINGS AND IT'S PEOPLE, YOU KNOW, THAT'S THE MOST WONDERFUL THING OF IT ALL, YOU KNOW, JUST THE FACT THAT WE'RE DEALING WITH OTHER PEOPLE. >> SO ONE LAST QUESTION OF A PRACTICAL ONE THAT HAS COME UP BEFORE. YOU SAY THAT THE PATIENTS WHOM YOU STUDY ARE REFERRED BY THEIR PHYSICIANS TO YOU. BUT WHAT ABOUT THE INDIVIDUAL PATIENTS IN A FAMILY WHERE, YOU KNOW, A CHILD, LOTS OF CHILDREN HAVE RECURRENT FEVERS AND THERE AREN'T MANY ANSWERS, AT WHAT POINT DO YOU DRAW THE LINE AS TO WHEN YOU BEGIN A PHYSICIAN -- A PHYSICIAN SHOULD BEGIN TO THINK OF THESE DISEASES, THE CLINICAL SCOPE OF WHICH SEEMS TO BE EXPANDING, NOT CONTRACTING, SO WHAT WOULD YOU ADVISE PATIENT AND PHYSICIANS WHEN TO BEGIN TO THINK ABOUT -- >> WELL, IT'S A GREAT QUESTION. AND FOR SURE, YOU KNOW, AT LEAST IN TERMS OF THINKING ABOUT GENETIC DISORDERS, SOMEONE WHO HAS A VERY EARLY ONSET AND WHO HAS SEVERE DISEASE, WE FOR SURE THINK ABOUT THE POSSIBILITY OF GENETIC DISEASE IN THOSE INDIVIDUALS. NOWADAYS WITH THE AVAILABILITY OF GENETIC TESTING, IT HAS BECOME EASIER AND EASIER AND PHYSICIANS ARE DOING IT MORE AND MORE JUST TO SCREEN FOR VARIANTS IN THE PERIODIC FEVER GENES IN PANELS THAT ARE AVAILABLE FROM SOME OF THE COMMERCIAL GENETIC TESTING COMPANIES, AND SO IN SOME CASES THAT'S THE WAY IT HAPPENS. BUT I THINK THAT, YOU KNOW, YOUR POINT THAT THE SCOPE IS INCREASING AND THE NUMBERS ARE INCREASING AND SO IT'S IMPORTANT FOR PHYSICIANS TO THINK OF THESE DISEASES SOONER RATHER THAN LATER. AND CERTAINLY I WOULD RATHER BE ASKED A FEW TOO MANY TIMES AND THEN FIND SOMEONE WHO DOES HAVE ONE OF THESE CONDITIONS THAT ARE TREATABLE, AND, YOU KNOW, IN SOME CASES LIKE FOR FAMILIAL MEDITERRANEAN FEVER AT LEAST SOME PEOPLE THAT HAVE THAT DISEASE CAN DEVELOP AMYLOIDOSIS, WHICH AS I MENTIONED CAN LEAD TO THINGS LIKE KIDNEY FAILURE. SO I'D MUCH RATHER ERR ON THE SIDE OF ASKING TOO MANY QUESTIONS THAN NOT ASKING ENOUGH. >> YEAH, I WANT TO POINT OUT THAT SEQUENCING IS, AS DR. KASTNER MENTIONED, BECOMING CHEAPER AND CHEAPER TO THE POINT WHERE MANY PATIENTS CAN EVEN GO AND GET AN EXOME SEQUENCE DONE PRIVATELY AND SO IT HAS BECOME EASIER TO SAY THIS PATIENT DOESN'T FIT INTO A BIN OF A CERTAIN DISEASE AND MAYBE LOOKING BACK IN RETROSPECT THEY HAVE HAD ORAL ULCERS OR GENITAL ULCERS. WE'VE HAD A PATIENT WHO CAME TO US AT THE AGE OF 45 AND, OH BY THE WAY, HE'S HAD ORAL ULCERS SINCE HE WAS 8, NO ONE THOUGHT ANYTHING OF IT BECAUSE EVERY EVERYONE GETS THEM, DON'T THEY? NOT EVERYONE DOES, THEY HAD A HAPLOSUFFICIENCY OF HA20. >> DANIELA, MAYBE YOU CAN RESPOND TO THIS. WHY DOES THE DISEASE SEEM TO GO AWAY IN SOME PATIENTS WITH TIME OR AT LEAST GREATLY BECOME MODIFIED, DO YOU HAVE ANY THOUGHTS ABOUT THAT? >> ARE YOU TALKING ABOUT HAPLOINEFFICIENCY OF A20 GOING AWAY OVER TIME? >> YEAH, MY UNDERSTANDING FROM SOME OF THE PRESENTATION IS THAT IT DOESN'T ALWAYS GET WORSE AND SOME OF THESE. >> OH, THAT'S ACTUALLY FOR DR. MANTHIRAM. THAT'S HER DISEASE, I WISH MY DISEASE WENT AWAY BUT UNFORTUNATELY NO, MINE DOES NOT. THAT'S NOR DR. MANTHIRAM. >> FOR MOST PATIENTS THE EPISODES WITH FAPPA, FEVER SEEMS TO RESOLVE, MOST HAVE APTHOUS ULCERS BEFORE THEY REACH ADOLESCENCE. ONE MAY BE INVOLUTION OF TONSILS. TONSILLECTOMY LEADS TO RESOLUTION OF THE FEVER EPISODES IN MOST PATIENTS WITH THE DISEASE, HOLLI IS AN EXCEPTION, BUT I THINK THE TONSILS MAY NATURALLY GET SMALLER WITH TIME SO THAT MIGHT BE ONE FACTOR THAT MAYS A ROLE BUT WE HAVEN'T FULLY UNDERSTOOD BECAUSE GENETIC RISK VARIANTS WE IDENTIFY ARE STILL PRESENT EVEN AFTER -- EVEN BEYOND CHILDHOOD. MORE WORK IS NEEDED. TO YOUR PRIOR QUESTION ABOUT WHEN TO SUSPECT A PERIODIC FEVER, I WANTED TO ADD THAT NORMAL CHILDREN CAN HAVE VERY FREQUENT VIRAL INFECTIONS, OVER TEN PER YEAR THAT CAN BE NORMAL BUT ONE QUESTION THAT REALLY IS IMPORTANT TO ME ARE THE EPISODES ALL THE SAME? DO THEY ALL -- THESE PARENTS WERE SAY, I JUST KNOW THAT'S WHAT IT IS. I TRUST THEM BECAUSE THEY SORT OF GET A SENSE OF THE PATTERN OF THE DISEASE. SO I THINK THAT STEREOTYPICAL NATURE IS REALLY IMPORTANT AND IF ANYONE SUSPECTS THEIR CHILD OR THEMSELVES HAS A PERIODIC FEVER, REALLY HELPFUL THING TO START MAINTAINING A SYMPTOM DIARY OR FEVER DIARY. SO WE CAN START SEEING IF THERE'S A PATTERN TO HOW THESE EPISODES PRESENT. >> ALL RIGHT. ALL GOOD THINGS COME TO AN END. I THINK WE THANK YOU ALL FOR THIS REALLY EXCITING PANDORA'S BOX THAT YOU OPENED FOR THOSE OF US WHO DON'T THINK ABOUT THIS ALL THE TIME TO THINK ABOUT. AND I TRUST THAT THAT'S TRUE FOR THE LARGE AUDIENCE THAT WILL BE WATCHING. PARTICULAR THANKS TO THE TWO PATIENTS WHO KINDLY SHARED THEIR PERSONAL EXPERIENCES, WHICH IS SUCH AN IMPORTANT ITEM. I JUST WOULD MENTION IN CLOSING TO REMIND YOU THAT NEXT WEEK WE HAVE AN EXTRAORDINARY BRIDGE, THE BRIDGE BACK TO THE CREATION OF LIFE. AND SO WE WILL HAVE A LEADING BIOCHEMICAL EVOLUTIONARY BIOCHEMIST, NICK LANE FROM UNIVERSITY COLLEGE, LONDON, AND A LEADING CELL BIOLOGIST, JENNIFER LIPPINCOTT-SCHWARTZ, WE'RE GOING TO DISCUSS THE ORIGIN OF LIFE AS VIEWED THROUGH THEIR PERSPECTIVES OF THEIR INDIVIDUAL RESEARCH. SO THANK YOU ALL AGAIN. AND PLEASE ENJOY. THANK YOU.