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.