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>>TODAY'S PRESENTATION WHICH
IS WHEN HALF IS NOT ENOUGH, STAT
3 HAPLOINSUFFICIENCY AND FUNGAL
INFECTION OF THE BRAIN.
JOIN ME IN WELCOMING
TODAY'S PRECEPTORS WHO INCLUDE
DR. STEVEN HOLLAND, CHIEF OF THE
IMMUNO PATHOGENESIS SECTION AT
THE NATIONAL INTUITYS OF ALLERGY
AND INFECTIOUS DISEASES.
DR. MICHAIL LIONAKIS, AT THE
FUNGAL SECTION OF THE NIAID.
AND DR. AMY HSU, WHO IS A
BIOLOGIST IN THE IMMUNO
PATHOGENESIS SECTION OF NIAID
AND DR. DAVID KLEINER WHO IS
HEAD OF THE AUTOPSIES SECTION IN
THE LABORATORY PATHOLOGY CENTER
FOR CANCER RESEARCH HERE AT THE
NIH.
DR. HOLLAND?
>>WE'RE GOING TO TALK ABOUT
HAPLOINSUFFICIENCY AND WE WILL
GO THROUGH A LITTLE BIT WHAT
THAT MEANS THROUGHOUT THE COURSE
OF THE DAY.
BUT WE'RE TALKING ABOUT
COCCIDIOMYCOSIS, IT'S AN IRPT
ACTION AND IT'S TOXIC.
SO WE'RE TALKING ABOUT A 19
YEARLY FROM CALIFORNIA WHO
DEVELOPED COCCIDIOMYCOSIS DURING
PREGNANCY AND AT THAT POINT
SHE HAD RESPIRATORY FAILURE,
RECOVERED AND WAS TREATED WITH
FLUCONOSALL, AND DELIVERED A
HEALTHY BABY BOY, A YEAR LATER
SHE REQUIRED FURTHER TREATMENT
DUE TO OBSTRUCTION.
SEVERAL YEARS LATER SHE
DEVELOPED PROGRESSIVE AND
DEBILITATING BRAIN AND LUNG
DISEASE DESPITE TREATMENT WITH
POSACONAZOLE AND AMPH OTERICIH,
AND THEN LEDDER WAS LED TO A
LOBECTOMY.
SHE WAS HOSPITALIZED AGAIN FROM
THE SHUNT OBSTRUCTION AND WHEN
THE SHUNT WAS REMOVED AND
EXTERNALIZED SHE HAD A FATAL
INTERCEREBRAL BLEED.
HER SON WAS UNAVENGHTED IN TERMS
OF SUSCEPTIBILITY TO
COCCIDIOMYCOSIS, AT LEAST SO FAR
AS WE KNEWA THAT POINT.
AFTER HER DEATH HER MOTHER MADE
A BOLD AND IMPORTANT AND I THINK
BRAVE DECISION TO CHOOSE THAT
HER DAUGHTER'S DEATH NOT BE IN
VAIN: AND SHE REACHED OUT TO
CENTERS IN THE REGION.
SHE WAS IN CALIFORNIA WHO THEN
REACHED OUT TO US ASKING IF WE
COULD DO AN AUTOPSIES IN ORDER
TO FIGURE OUT WHAT WAS THE
PROBLEM.
SO I'M GOING TO STET THE STAGE
HERE BRIEFLY, I WILL COVER THE
TOPICS, WHAT IS COCCIDIOMYCOSIS,
HOW IS IT CONTRACTED, WHERE IS
IT ENCOUNTERED, HOW DOES IT
PRESENT CLINICALLY AND WHAT IS
THE EPIDEMIOLOGY, THE CLINICAL
EPIDEMIOLOGY OF THIS DISEASE?
AND THEN WE WILL MOVE TO THE
ACTION IN WHICH WE WILL PRESENT
THE AUTOPSIES, THE GENETICS OF
HER SUSCEPTIBILITY AND THEN WE
WILL TALK ABOUT FUNGAL
SUSCEPTIBILITY IN GENERAL.
SO COCCIDIOMYCOSIS IS CAUSED BY
THIS ORGANISM CALLED
COCCIDIDOSIS AND FOR OUR
PURPOSES WE WILL CONSIDER THEM 1
AND THE SAME.
THERE ARE SUBTLE DIFFERENCES
THAT ARE NOT CLINICALLY
IMPORTANT NOW.
IT EXISTED INITIALLY IN THE
ENVIRONMENT WHERE IT DESICCATES
AND WHEN IT DESICCATES IT
DISASSOCIATES INTO THESE SMALL
THINGS CALLED ARGT ROW
CANEDUCATIONALLIA AND IN THE
SETTINGS OF CONSTRUCTION OR WIND
OR HOUSE BUILDING OR AND SO ON.
THESE GET INHALED BY HUMANS AND
MANY OTHER MAMMALS WHERE THEY
DEVELOP THEN INTO THESE SMALL
GROWING ORGANISMS CALLED
SPHEREIOLES THAT RUPTURE INSIDE
THE BODY AND RELEASE THESE
THINGS CALLED ENDOSPORES HERE
THAT CONTINUE TO CYCLE ALONG.
THIS IS WHAT THEY LOOK LIKE IN
THE TISSUE.
THIS IS A SPHEREIOLE THAT YOU
SEE HERE CHOK FULL OF ENDOSPORES
AND THIS IS THE SPHEREIOLE
RUPTURING.
NOW THIS WAS IDENTIFIED EARLY
ON, IN THE 1880S BY THIS MAN,
ALEJANDRO POSADES, AND HE
IDENTIFIED THIS ORGANISM IN
CHICKENS, AND THEN IDENTIFIED
THEM IN HUMANS.
AND CAME UP AND EVENTUALLY IT
WAS NAMED COCCIDOIDES, POSADA
SII, IN HIS HONOR AND YOU'LL
NOTICE HE ALSO INVENTED THE
MUSTACHE.
[LAUGHTER]
THIS IS MUCH MORE COMMON HERE IN
THE SOUTHWESTERN UNITED STATES
THROUGHOUT THE SAN JUAQUIN AND
RIO GRAND VALLEYS AND IS
EXTENDING INTO THE UPPER
NORTHWEST FOR A VARIETY OF
DEFINITE REASONS I SUSPECT.
NOW THE EPIDEMIOLOGY OF THIS
ORGANISM IS IMPORTANT TO
UNDERSTAND.
THERE ARE THOUGHT TO BE 150,000
PEOPLE INFECTED EACH YEAR WITH
THIS ORGANISM IN THE
SOUTHWESTERN PART OF THE UNITED
STATES.
SO ARIZONA, NEW MEXICO, WEST
TEXAS, LAS VEGAS, CALIFORNIA,
ONLY A THIRD OF THOSE PEOPLE
EVER COME TO MEDICAL ATTENTION,
AND ONLY A THIRD OF THOSE GET
DIAGNOSED SO LARGE BURDEN, SMALL
RECOGNITION, OUT OF THOSE 15,000
WHO GET DIAGNOSED, SOMEWHERE
AROUND HALF HAVE WHAT IS CALLED
A PULMONARY SYNDROME
CHARACTERIZED AS VALLEY FEVER,
THAT IS COUGH MALAISE, FEVER,
AND THEN A SMALL NUMBER GO ON TO
DEVELOP WHAT WE CALL
DISSEMINATED COCCIDIOMYCOSIS OR
DCM.
AND ALTHOUGH THE RISK GROUP IS
LARGE, THE MORTALITY ON A TOTAL
BASIS IS RELATIVELY SMALL.
BUT IT IS OF COURSE MORE THAN WE
WOULD LIKE TO SEE.
OUR EXPERIENCE WITH THIS
ORGANIZATIONS INFORM AND IT'S
PROBLEMS STARTED WITH THIS YOUNG
MAN HERE SEEN AT THE NIH IN A
REFERRAL FROM JOHN GALGIANI AT
THE UNIVERSITY OF ARIZONA AND
THIS WAS A BOY WHO AT 16 HAD
BEEN A FOOTBALL PLAYER UNTIL HE
DEVELOPED DISEASE IN HIS SPINE
FOR WHICH HE REQUIRED
INSTRUMENTATION, AND THEN YOU
CAN SEE HERE, EXTENSIVE DISEASE
IN HIS PELVIS, THESE ARE NOT
NATURAL BREAKS.
SO HE CAME TO US WITH
DISSEMINATED DISSEMINATED
COCCIDIOMYCOSIS AS WELL AS A
DISSEMINATED MICROBACTERIAL
INFECTION AND THAL CASE,
MICROBACTERIAL M. KANSASII, AND
HE HAD A DISRUPTION IN THE INTER
FERON GAMMA RECEPTOR ANDEE HAD
ABOUT WORKING ON THAT FOR
SOMETIME. AND BECAUSE OF WHAT
WE KNEW ABOUT THAT AND THIS
PROCESS WE TREATED HIM WITH
INTERFERON-GAMMA YOU CAN SEE
THIS WAS BEFORE AND AFTER
INTERFERON IN ADDITION TO
ANTIFUNGAL DRUGS.
THE APPROXIMATE BEFORE PICTURE
IS WHEN HE WAS ON ANTIFUNGAL
DRUGS ALONE AND THE AFTER WHEN
HE WAS ON THE PLUS INTERFERON.
THAT GOT US INTERESTED IN WHAT
WERE THE OTHER FACTORS THAT
MIGHT BE ASSOCIATED WITH
DISSEMINATED COCCIDIOMYCOSIS AND
IN A REVIEW OF DISCHARGE RECORDS
FROM ARIZONA AND SOUTHERN
CALIFORNIA IN ENDEMIC REGIONS,
WE IDENTIFIED THAT 1 OF THE
CRITICAL RISK FACTORS WAS RACE
AND ETHNICITY AND WHAT YOU SEE
HERE IS THAT THE RATES OF
DEVELOPING DISSEMINATED
COCCIDIOMYCOSIS BASED ON
HOSPITAL DISCHARGE WERE ALMOST
10 FOLD HIGHER IN THOSE
SELF-IDENTIFIED AS BEING OF
AFRICAN--OF HAVING AN ETHNICITY
OF AFRICAN ORIGIN AS OPPOSE TO
ANY OTHER ETHNICITY.
IN ADDITION, IT'S BEEN WELL
KNOWN IN THE SOUTHWEST THAT
PEOPLE WHO ARE RECEIVING TUMOR
NECROSIS BLOCKERS, ARE AT MUCH
HIGHER RISK OF DEVELOPING
DISSEMINATED AND PULMONARY
COCCIDIOMYCOSIS OVER THE GENERAL
POPULATION.
AND THIS TELLS US THAT THAT LIMB
OF IMMUNITY, SO WE'VE SEEN THAT
ISHT FERON GAMMA IS IMPORTANT
NOW TNF IS EXPRNT WE KNOW THERE
ARE OTHER LIMBS INNATE AND
ADAPTIVE IMMUNITY THAT ARE
IMPORTANT.
SO AS WE LOOK FURTHER INTO THESE
ISSUES WE SAW THAT THERE WERE
OTHER RISK GROUPS WE NEEDED TO
CAPTURE.
ONE OF THE MOST IMPORTANT AS
SEEN IN OUR PATIENT TODAY WAS
PREGNANCY.
AND YOU CAN SEE HERE THAT A
LARGE NUMBER OF PEOPLE ARE
RELATIVELY LARGE NUMBER OF
PEOPLE DEVELOP DISSEMINATED
DISEASE IN THE SETTING OF
PREGNANCY AND SURVIVAL WAS ONLY
42%.
THIS REMINDS US THAT PREGNANCY
IS AN INTRINSICALLY SOMEWHAT
IMMUNOSUPPRESSIVE CONDITION THAT
CONFERS CERTAIN RISK TO CERTAIN
INFECTIONS, SO WITH WE PUT ALL
THAT TOGETHER, NOW SEVERAL YEARS
AGO, WE COULD ONLY FIND 8 CASES
OF GENETIC ABNORMALITIES
ASSOCIATED WITH THE DISSEMINATED
COCCIDIOMYCOSIS SHOWN HERE, THE
AUTOSOMAL DOMINANT MUTATIONS IN
INTERFERON-GAMMA, RECESSIVE
MUTATIONS IN THE IL12 RECEPTOR
AND SOME GAIN OF FUNCTION
MUTATIONS IN STAT 1.
DESPITE THE FACT THAT THERE WERE
150,000 CASES EACH YEAR.
SO STOP AND THINK, WE HAVE
150,000 INFECTIONS PER YEAR,
ONLY 15,000 GET DIAGNOSED BUT
THERE ARE A THOUSAND
DISSEMINATED CASES PER YEAR,
THERE'S CLEARLY SOMETHING
SPECIAL ABOUT THOSE INDIVIDUALS
AND YET WE'VE ONLY IDENTIFIED 8.
DOES THAT SEEM REASONABLE?
HELL NO.
AND THAT IS WHAT STARTED US TO
WORK ON THIS.
SO WE'RE GOING TO GO AND TALK
ABOUT THE SPECIFICS OF THIS
PATIENT AND OF OTHER THINGS BUT
BEFORE WE MOVE ON, I WANT TO
TAKE 1 MOMENT TO TALK ABOUT WHY
THIS EVENT IS SO IMPORTANT, WHY
THIS KIND OF SECTION OF CPC IS
SO IMPORTANT.
AND I WANT TO POINT OUT THAT THE
ALTRUISM AND THE BRAVERY OF THIS
FAMILY WAS REALLY SPECIAL, THIS
MOTHER REACHED OUT TO FIND A
HOSPITAL THAT WAS WILLING TO DO
AN AUTOPSIES.
THINK ABOUT HOW MANY FAMILY,
DOCTORS DON'T EVEN APPROACH, OH
IT WOULD BE TOO TRAUMATIC, IT'S
TOO HARD TO TALK ABOUT
AUTOPSIES, HELL NO.
IF YOU THINK THE PATIENT WHO
DIED HAD THE MOST SUCCESSFUL
THERAPY POSSIBLE, DON'T ASK.
BUT IF YOU THINK THAT YOU CAN DO
BETTER IF YOU KNOW MORE, THIS IS
WHERE YOU NEED TO BE.
SO IF IT HADN'T BEEN FOR HER
COMMITMENT WE WOULDN'T KNOW
ABOUT THIS.
WE OFTEN, I HEAR PEOPLE SAY ALL
THE TIME, I DON'T NEED TO DO AN
AUTOPSIES I KNOW EVERYTHING
BECAUSE WE HAVE CAT SCANS, WE
HAVE BLOOD WORK.
WRONG, WRONG, WRONG.
I CANNOT EMPHASIZE ENOUGH WHAT A
FELLACIOUS ASSUMPTION THAT IS.
I'VE NEVER BEEN INVOLVED IN
AUTOPSIES WHERE WE DIDN'T LEARN
SOMETHING, NOT ALWAYS THE CAUSE
OF DEATH BUT OFTEN THINGS ABOUT
THE DISEASE, IF YOU DON'T WANT
TO KNOW, DON'T LOOK BUT IF YOU
WANT ANSWERS YOU HAVE TO SEEK
AND IN ORDER TO SEEK, YOU HAVE
TO ASK THESE QUESTIONS AND
THAT'S HOW WE GET THERE THROUGH
THIS KIND OF PROCESS.
SO I'LL TURN IT OVER HERE TO
DR. DAVE KLEINER WHO WILL SHOW
US WHAT WE LEARNED AT AUTOPSY.
>>THANK YOU STEVE FOR THE
VERY KIND--I'M NOTE EVEN SURE
WHAT TO SAY.
YOUR KIND WORDS ABOUT PERFORMING
AUTOPSIES AND WHAT HE SAID IS
QUITE CRITICAL AND THERE IS
ACTUAL DATA TO SUPPORT ALL OF
THOSE POINTS THAT HE MADE.
SO I'M GOING TO GO THROUGH THE
AUTOPSIES FINDINGS, THIS IS
GOING TO BE STRAIGHT PATHOLOGY
AND THEN WE'RE GOING TO--BUT THE
AUTOPSIES WHAT THAT DID WAS
PROVIDE ACCESS TO THE TISSUE AND
AN OPPORTUNITY TO INVESTIGATE
MORE WHAT WAS GOING ON.
SO WITHOUT FURTHER ADO, WE WILL
START IT IN THE LUNGS, 1 OF THE
FIRST OBSERVATIONS THAT WE MADE
AFTER WE SECTIONED THE LUNGS WAS
THAT THERE WAS BRONCHIECTASIS,
IT'S A CONDITION WHERE THE
BRONCH I BECOME DILATED ALL THE
WAIUTE TO THE PLURAL SURFACE AND
YOU CAN SEE HERE IS THE LUMEN OF
THE BRONCHIAS, WHICH IS VERY
FIBROTIC, VERY ATTENUATE UD
EPITHELIUM, ULCERATE INDEED
PLACES AND YOU CAN TELL THIS IS
DILATED BECAUSE IT'S FLAT AND
NORMAL BRONCH I ARE NOT FLAT,
THEY'RE ROUND AND ADJACENT TO
THE BRONCHUS WAS PNEUMONIA THAT
WAS PROBABLY FINAL IN THIS
PATIENT'S LIFE AND FUNGAL.
WE WHEN YOU LOOK IN THE
SURROUNDING TISSUE WE WERE ABLE
TO SEE IN THIS PARTICULAR
SECTION A SMALL FIBROTIC NODULE
AND AROUND THE EDGES OF THE
FIBROTIC NODULE, YOU CAN SEE
GIANT SELLS, THAT HAVE ENGULFED
ORGANISMS, THAT ARE ACTUALLY
FAIRLY RAZE TO SEE ON THE H& E
WITH THESE LITTLE EMPTY HOLES
BUT WE USE SPECIAL STAINS, IN
THIS CASE A SILVER STAIN TO
HIGHLIGHT THE ORGANISMS AND YOU
CAN SEE THAT THEY'RE VERY NOT
WELL PRESERVED, NOT NEARLY AS
PRETTY AS THE PICTURE STEVE
SHOWED THEY'RE DEFINITELY THE
COCCIDIOMYCOSIS ORGANISMS.
WE LOOKED OF COURSE, A FULL
AUTOPSIES, WE LOOKED EVERYWHERE
WHEN WE SAMPLED THE ADRENAL
GLANDS WE FOUND SMALL WHITE
LESIONS IN THE ADRENAL GLANDINGS
ON BOTH SIDEs AND UNDER
MICROSCOPIC SECTIONS AGAIN A
SMALL FIBROTIC NODULE AND AGAIN
YOU CAN SEE THESE LITTLE HOLES
HERE WHICH ARE THE ORGANISMS AND
OVER HERE I HAVE A P A S STAIN
WHICH HIGHLIGHTS FUNGAL
ORGANISMS BECAUSE OF THE
GLYCOPROTEINS IN THE FUNGAL WALL
AND THEN A SILVER STAIN.
THESE ORGANISMS WERE A LITTLE
BIT BETTER PRESERVED SO YOU CAN
SEE A SPHEREIOLE WITH SOME OF
THESE SMALLER SIS FORMS INSIDE
AND IT LOOKS LIKE IT'S IN THE
PROCESS OF BREAKING OPEN.
THERE WAS A NODULE IN THE LEFT
BREAST AND SO IT WAS ABOUT HALF
A CENTIMETER IN SIZE, FULL OF
NECROTIC MATERIAL, AND A
FIBROTIC CAPSULE AROUND THE EDGE
AND HERE IS ANOTHER 1 OF THESE
SMALL FIBROTIC NODULES.
AGAIN, YOU CAN SEE ORGANISMS
HERE AND THERE WERE ALSO
ORGANISMS OUT IN THE NECROTIC
MATERIAL.
THE UNIQUE THING ABOUT THIS
PARTICULAR SITE WAS NOT ONLY DID
WE FIND THE SPHEREIOLES, BUT WE
ALSO FOUND HEIGHT FULL FORMS OUT
IN THE NECROTIC MATERIAL AROUND,
IN THE CENTER OF THIS ABSCESS.
AND THEN 1 OTHER THING THAT WE
FOUND IN THE BODY CAVITY ITSELF
WAS ALONG THE LEFT VENTRICULAR
ENDOCARDIUM, THERE WAS A SMALL
PATCH OF HEMORRHAGE WE SAMPLED
AND YOU CAN SEE DOWN HERE BELOW
OUR NORMAL MY O CARDIO
SIGHTS,--MY O CARDIO SITES,
THEY'RE NOT NECROTIC BUT ABOVE
THAT WE HAVE AN AREA OF NECROSIS
AND HEMORRHAGE, WE DIDN'T FIND
ORGANISMS HERE BUT I DID SUSPECT
THIS WAS A SITE INFECTED BY
FUNGAL INFECTION.
BUT IN THE BRAIN WHICH WAS OF
COURSE THE PATIENT'S FINAL EVENT
WAS A BRAIN HEMORRHAGE.
WE FOUND INVOLVEMENT OF
SEEREBERALART RYES BY FUNGAL
ORGANISMS CAUSING THIS
VASCULITIS SO YOU CAN SEE THE
WALL OF THE ARTERY HERE AND 1
SIDE INVOLVED BY INFLAMMATION,
WHICH HAS PENETRATED THROUGH THE
MUSCULAR WALL.
YOU CAN SEE THAT THERE ARE
NUTRIFILLS HERE AS WELL AS LOTS
OF LYMPHOCYTES AND AGAIN IF YOU
LOOK CAREFULLY CAN YOU FIND
THESE GIANT SELLS WITH
ORGANIZATIONS INFORMS INSIDE
THEM.
SO HERE'S A LOW POWER SILVER
STAIN OF THAT ARTERY SO YOU
CANEE THERE ARE FUNGAL FORMS IN
THE WALL OF THE ARTERY AS WELL
AS LITTLE GROUPS OF FUNGAL FORMS
OUTSIDE.
AND HERE THEY ARE IN CLOSE UP SO
AGAIN WE HAD THE HIGH FORMS IN
THE WALL AND CAN YOU SEE THEM AT
LOW MAGNIFICATION AND THEN MORE
OF THE TYPICAL SPHOARIOLES AND
YEAST FORMS ELSEWHERE, SO IN
SUMMARY FROM THE AUTOPSIES, WE
CONFIRMED THAT SHE STILL HAD AT
THE TIME OF DEATH
COCCIDIOMYCOSIS INVOLVING THE
BRAIN, LUNGS, ADRENALS AND
BREAST.
WE TOOK CULTURES AT THE TIME
WHICH WERE POSITIVE FOR THE
ORGANISM AND THEN THERE WAS THIS
FOCAL LEFT VENTRICULAR
HEMORRHAGIC ENDOCARDITEIS WHICH
WAS ALSO FUNGAL BUT WE DIDN'T
DEFINE ORGANISMS AND CAUSE OF
DEATH WAS NO SURPRISE,
INTERSEEREBERAL HEMORRHAGE,
UNDERLYING CAUSE OF DEATH
DISSEMINATED COCCIDIOMYCOSIS.
SO I WILL TURN THIS OVER NOW TO
THE NEXT SPEAKER.
>>IT'S NO SURPRISE
I'M GOING TO GIVE IT AWAY THAT
WE ARE DEALING WITH A PATIENT
WITH A STAT 3 MUTATION.
COURTESY OF DR. KLEINER HE ROUGH
ATOM VIEDED ME WITH TISSUE, WE
HAD HEART AND SPLEEN TISSUE,
IOALATED DNA, PERFORMED WHOLE
EXOHM SEQUENCES WHICH IDENTIFIED
A HAPPEN LO STAT VARIANT IN THE
STAT 3.
IT'S IN THE MIDDLE OF THE GENE
EXON 14 OF 24 AND CHANGES TO
STOP CODON.
SO IT'S A PREMATURE TERMINATION,
IT'S NOT NOW IN NATIONAL LIBRARY
OF MEDICINEAD WHICH IS A DAT
BASE OF 40,000 INDIVIDUALS WHICH
HAVE BEEN SEQUENCED AND IT HAS A
CAD SCORE OF 41.
THAT PUTS IT IN THE TOP .01% OF
DAMAGING VARIANTS POSSIBLE IN
THE GENOME.
STAT 3 IS A GENE AS IS
CONSTRAINED AGAINST MUTATIONS.
WE KNOW WHAT THE MUTATION RATE
IS ACROSS THE HUMAN GENOME AND
SO GIVEN THE SIZE OF A GENE, WE
CAN CALCULATE WHAT WOULD BE THE
EXPECTED NUMBER OF MUTATIONS
THAT OCCUR, NUMBER OF VARIANTS
THAT OCCUR JUST BY CHANCE AND
YOU CAN BEND THOSE BY FUNCTION
WHETHER THEY'RE SYNONYMOUS SO
THEY DON'T CHANGE THE IMMUNO
ACID, IN THIS SENSE IT DOES
CHANGE THE AMINO ACID WHICH
WOULD BE A SPLICE MUTATION.
AND YOU CAN SEE THAT THE
SYNONYMOUS CHANGES, THE NUMBER
OBSERVED OVER THIS 140,000 ARE
INDIVIDUALS IS EXACTLY WHAT YOU
WOULD EXPECT.
BY CORN TRAOF THE THE MISSENSE
CHANGES ARE ONLY A THIRD WHAT
YOU WOULD EXPECT INDICATE
NOTHING NORMAL HEALTHY PEOPLE,
MISSENSE CHANGES IN STAT 3
AREN'T USUALLY COMPATIBLE WITH
THAT NORMAL HEALTHY PHENOTYPE
AND EVEN MORE STRIKING IS LOSS
OF FUNCTION MUTATIONS, THERE'S
ONLY 1 PRESENT IN NOMAD.
SO 2%.
IN FACT, STAT 3 IS 1 OF THE MOST
CONSTRAINED GENES IN THE GENOME
AGAINST MUTATIONS.
SO WHAT IS STAT 3 ON DO, IT'S A
MEMBER OF THE STAT FAMILY OF
TRANSCRIPTION FACTORS WHICH
STANDS FOR SIGNAL TRANSDUCTION,
AND ACTIVATOR OF TRANSCRIPTION.
UPON EXTRA CELLULAR CYTOKINES
SUCH AS THOSE LISTED ABOVE, IN
THE BIND TO THE COGNATE
RECEPTORS, THOSE KINASES WHICH
ARE BOUND TO THE RECEPTORS KROS
PHOSPHORYLATE AND PHOSPHORYLATE
THE RECEPTOR WHICH PROVIDES A
DOCK BEING SITE FOR THE STAT
MOLECULE TO BIND.
AT THAT POINT THE JAGS WILL
PHOSPHORYLATE THE STATS, THEY
WILL DECOUPLE FROM THE RECEPTOR,
FORM HETEROGENEOUS OR O OR
HOMODIMERS WITH OTHER STAT
MOLECULES AND THAT DISCIPLINARY
MERRIC STAT 3 MOLECULE IN THIS
CASE, STAT 3 WILL TRANSLOCATE TO
THE NUCLEUS, BIND RECOGNITION
SITES ON THE DNA AND DRIVE
TRANSCRIPTION OF TARGET GENES.
SO EACH HEALTHY INDIVIDUAL
SHOULD HAVE 2 COPIES, IT'S AN
AUTOSOMAL GENE, SO HAVE YOU 2
COPIES OF WILD-TYPE STAT 3, BOTH
OF WHICH CAN PROVIDE TRANSCRIPT,
BOTH OF WHICH CAN PROVIDE
PROTEIN AND EACH OF WHICH LEADS
TO NORMAL PHYSIOLOGY.
IN THE CASE OF DOMINANT NEGATIVE
MUTATIONS WHICH WERE THE FIRST
MUTATIONS IDENTIFIED IN STAT 3,
THESE LEAD TO WILD-TYPE IN BLUE,
1 MUTANT ALLELE SHOWN IN ORANGE
OR PINK DEPENDING ON YOUR EYES,
AND THAT MEANS THAT 50% OF THE
TRANSCRIPT MADE AND THE 50% OF
THE PROTEIN MATED ARE GOING TO
CONTAIN A MUTATION.
SO AS I MENTIONED DOMINANT
NEGATIVE STAT 3 MUTATIONS CAUSE
AUTOSOMAL DOMINANT HYPER IGE
SYNDROME, USING IL6 AS AN
EXAMPLE, CAN YOU SEE THE STAT
MOLECULES BINDING TO THE
RECEPTOR AFTER CYTOKINE BINDING
AND IT CAN BE A WILD-TYPE STAT 3
MOLECULE OR A MUSEUM STANT STAT
3 MOLECULE BUT WHEN THE DIMERS
FORM, 3 OUT OF 4 OF THOSE DIMERS
WILL CONTAIN A MUTATION AND
WHILE THEY CAN TRANSLOCATE TO
THE NUCLEUS, THAT MEANS 3 OUT OF
THE 4 TIMES IT BYPASSEDS TO THE
TRANSCRIPTION PROMOTER, TO THE
PROMOTER SITE, YOU WILL HAVE
ABNORMAL OR DECREASED
TRANSCRIPTION.
IN THE CASE OF THE PATIENT WE'RE
DISCUSSING TODAY, WE HAVE AN
EARLY STOP CODON AND THAT MEANS
WE HAVE TRANSCRIPT AND PROTEIN
PRENT FROM THE ALLELE, AND MANY
GENES THAT WOULD BE FINE BUT I
WILL SHOW YOU TODAY THAT IT'S
NOT.
IN THE CASES OF
HAPLOINSUFFICIENCY, COMPARING IT
TO THE AUTOSOMAL DOMINANT LOSS
OF FUNCTION MUTATIONS, WE HAVE
AN ISSUE OF QUANTITY, NOT
QUALITY.
EVERYTHING MADE IS WILD-TYPE,
THERE'S JUST NOT ENOUGH OF IT.
SO THAT'S WHAT YOU WOULD PREDICT
FROM WHAT WE KNOW HERE'S HOW WE
CAN PROVE IT.
WE DIDN'T HAVE A LOT OF SAMPLE
AVAILABLE FROM THIS PATIENT, SHE
WAS DECEASED.
WE GOT SAMPLE FOR DNA BUT NOT
FOR PROTEIN.
OR TRANSCRIPT.
FORTUNATELY, THERE WAS ANOTHER
PATIENT FROM DR. LIONAKIS'S LAB
WHO HAD THE SAME MUTATION AND A
50 YEAR HISTORY OF
[INDISCERNIBLE].
SO HERE YOU'RE LOOKING AT CDNA
FROM PBMCs FROM A PATIENT WITH
A MISSENSE CHANGE.
THIS DOESN'T EFFECT THE RNA AND
YOU CAN SEE HERE THE CDNA
SHOWING 2 PEEKS, THE WILD-TYPE
IN BLACK, MUTANT IN GREEN AND
THEY'RE BOTH EXPRESSED ROUGHLY
EQUALLY.
BY CONTRAST THE PATIENT WITH THE
R24/23 STOP SHOWS WILD-TYPE
SEQUENCE HERE.
NOW WE CAN STABILIZE THAT
TRANSCRIPT USING PROTEIN
SYNTHESIS INHIBITOR, THIS HAS
TRANSLATION AND INHIBITS
NONSENSE MEDIATED TO K WHICH IS
A PROOF READING MECHANISM AND
WHEN YOU DO THAT THERE'S NO
DIFFERENCE IN THE MISSENSE OF
THE PATIENT HOWEVER IN THIS CASE
OF THE R423 STOP, NOW WE RESCUED
THE MUTANT ALLELE SHOWN IN RED
PROVING THIS UNDERGOES NONSENSE
MEDIATED K AND NO TRANSCRIPT
FROM THE MUTANT ALLELE FROM THE
PATIENT.
BUT DOES THAT EFFECT PROTEIN?
WE RAN WESTERN BLOTS, YOU
CLEARLY SEE BY EYE COMPARED TO A
HEALTHY CONTROL OR AGAIN THE
MISSENSED PATIENT, CAN YOU
CLEARLY SEE REDUCED LEVELS OF
STAT 3 COMPARED TO BETA ACTIN
AND USING [INDISCERNIBLE] WE CAN
QUANTIFY THIS SHOWING THERE'S
LESS AND IF WE USE THE HEALTHY
CONTROL SAMPLES AS 1 AND
NORMALIZE TO THAT, CAN YOU
QUANTIFY THIS AT ABOUT 35-40%
THE TOTAL LEVEL OF STAT 3, IN
THESE PATIENTS.
BUT AGAIN, IT'S A TRANSCRIPTION
FACTOR, SO THE JOB OF A
TRANSCRIPTION FACTOR IS TO
ACTIVATE TRANSCRIPTION.
SO DOES THIS IMPACT THE TARGET
SEQUENCING OR THE TARGET SIGNALS
IT NEEDS TO DO.
USING IL-21, WHICH SIGNALS
THROUGH STAT 3 AND LOOKING AT
SOCS3 TRANSCRIPT, THESE ARE
T-CELLS FROM A PAPER THAT WAS
RECENTLY PUBLISHED, THIS IS 4
HEALTHY CONTROLS WITH 4 PATIENTS
WITH AUTOSOME AT IGE AND YOU SEE
THE DECREASED LEVEL OF
TRANSCRIPT.
SO THESE PEOPLE WERE THINKING
THAT SINCE BONE MARROW
TRANSPLANTATION CARRIES LOTS OF
RISKS FOR IT, FOR IMMUNE
DEFICIENCIES, MAYBE THEY COULD
SIMPLY SILENCE THE MUTANT ALLELE
AND WITH THAT RESTORE SIGNALING
BECAUSE NOW YOU WILL HAVE
SIGNALING THROUGH THE WILD-TYPE
AND WHEN THEY DID THAT USING
THIS PATIENT, SO THOU THEY
SILENCED THE MUTANT ALLELE, THEY
HAVE EXPRESSION FROM THE
WILD-TYPE ALLELE AND YET THAT IS
INSUFFICIENT TO RESTORE SOCS 3
TRANSCRIPT LEVELS SHOWING THAT
HALF IS NOT ENOUGH.
SO IN ADDITION TO THE PATIENT
WE'RE DISCUSSING HERE TODAY
SHOWN BY THE RED ARROW, THE
INITIALLY PUBLISHED PAPER IS
SHOWN ON TOP THIS, IS A PATIENT
WITH INVASIVE ASPER GEELOSEIS,
REPORTED BY LIANOKIS'S LAB, AND
ALSO HAPLOINSUFFICIENCY 3 WITH
THAT PATIENT, THERE WAS ANOTHER
PATIENT WITH COCCI MENINGITIS,
AS WELL AS NEW PATIENT WITH CNS
ASPERGILLOSIS, A PATIENT WITH
CRYPTO MENINGITIS AND CMC FROM
DR. ROSENZWEIG'S LAB.
SO THIS IS MISSENSE AND
NONSENSE, THIS COMES FROM THE
NATIONAL LIBRARY OF MEDICINEAD
DATA SET.
WE DEMONSTRATED THESE BY THE
DATA THAT LEADS TO DECREASED
STAT 3 PROTEIN LEVELS AS SEEN IN
WESTERNS AND DIMINISH DOWN
STREAM TARGET TRANSCRIPTS AND
REALLY IMPORTANTLY THAT WHILE
STAT 3 HAPLOINSUFFICIENCY TEND
TO APPEAR TO HAVE NORMAL
IMMUNITY, THIS WOMAN HAD NO
SIGNS OF BEING SICK UNTIL SHE
WAS CONFRONTED WITH THIS FUNGAL
INFECTION.
AND YET INVASIVE FUNGAL
INFECTIONS ARE A COMMON THEME.
AND THIS IS A SCHEMATIC SHOWING
THE DEGREE OF STAT 3 SIGNALING,
SO IF HAVE YOU A HOMOZYGOUS
KNOCK OUT LIKE IN MICE THAT'S
EMBRYONIC LETHAL, STAT 3 HYPER
IGE SYNDROME CALLED BY AUTOSOMAL
DOMINANT STAT 3 MUTATION SYSTEM
MULTISYSTEMIC SYNDROMIC DISEASE
AND HERE ARE 3 HAPLOs, THAT
HAVE THE FUNGAL INFECTION.
AND WITH THAT I WILL PASS IT TO
DR. LIANOKIS TO PUT THIS FUNGAL
INFECTION IN GENERAL.
>>THANKS, AMY, SO WHAT I WILL
TRY TO DO IN THE LAST 15 MINUTES
OF THIS GRAND ROUND SYSTEM TRY
TO DISCUSS WHY DO THESE
INDIVIDUALS THAT LACK PROPER
STAT 3 SIGNALING DEVELOP FUNGAL
DISEASE.
SO THE INFECTIONS THAT AMY
SUMMARIZED IN THE SLIDE EARLIER
THAT WE'VE SEEN IN THE CONTEXT
OF THE NOW 2 GENETIC SIN DROMS
FOR LOSS OF FUNCTION OF STAT 3.
THE AUTOSOMAL DOMINANT HYPER IG
SYNDROME, HYMARY INSUFFICIENCY
THAT STEVE HOLLAND AND ALEX
[INDISCERNIBLE] HAVE ENROLLED
AND SEEN THROUGH THE DECADES
MULTIPLE PATIENTS HERE AT THE
NIH.
AS WELL AS THE MORE RECENT
DISCOVERY OF STAT 3
HAPLOINSUFFICIENCY ARE LISTED
HERE.
THERE ARE MULTIPLE FUNGAL
PATHOGENS THAT RELY ON DIFFERENT
IMMUNE HOST DEFENSE REQUIREMENTS
FOR PROTECTION.
MOLD INFECS PRIMARILY
ASPERGILLOSIS, SO 2 PATIENTS
BOTH OF WHICH HAD CNS DISEASE
AND 1 HAD VERY MILD PULMONARY
DISEASE SO VERY UNUSUAL FOR WHAT
WE THINK OF FOR ASPERGILLOSIS,
WHICH IS A TYPICALLY INHALED
PATHOGEN, SO BOTH
COCCIDIOMYCOSIS AND
HISTOPLACENTAS MOZIS FALL UNDER
THIS CATEGORY AS WELL AS
MUCOCUTANIOUS FUNGAL INFECTIONS
AS WELL AS DERMA TIARAS FIELD
FUNCTIONSITOSEIS, SO IN THE
INTEREST OF TIME AND WHY WE DO
UNDERSTAND WHY IT HAPPENS SO
STAT 3 IS A IMPORTANT REGULATOR
OF UPREGULATING T-CELL THROUGH
GAMMA T UPREGULATION, SO IN BOTH
OF THOSE SETTINGS, WE THINK WE
HAVE AN UNDERSTANDING WHY THESE
INFECTIONS HAPPEN.
I WILL SPEND MOST OF OUR TIME
DISCUSSING THE FIRST 2 WHERE
IT'S A BIT MORE UNCLEAR.
SO WHAT I WILL DO IS VERY
BRIEFLY DISCUSS HOW WE ALL
DESPITE EXPOSURE, DEFEND
OURSELVES AGAINST THESE
INFECTIONS, THESE ARE
OPPORTUNISTIC INFECTIONS AND TRY
TO PUT THAT IN CONTEXT IN
REGARDS TO WHAT WE KNOW OR WANT
TO KNOW ABOUT STAT 3.
SO ASKER GILLIS IS A UBIQUITOUS
MOLD.
WE RIGHT NOW INHALE SOME SPORES
IN THIS WONDERFUL ROOM.
AND DESPITE THAT WE DON'T GET
ASPERGILLOSIS AND THAT IS
BECAUSE WE HAVE VERY, VERY
IMPORTANT INNATE IMMUNE
RESPONSES IN OUR LUNGS.
PRIMARILY NUTRIFILLS AND
MONOCYTES MACROPHAGES THAT DON'T
ALLOW US TO GET IN TROUBLE
BECAUSE THOSE INHALE
CONEDUCATIONALLIA AND THE EARLY
TERMS OF THAT FOR HYPH ACE GET
DESTROYED SO MANY OF YOU HAVE
SEEN ASKER GILLOSEIS IS THE
SETTING OF PROLONGED CHEMO
THERAPY OR BUT NOT NORMAL
PATIENTS OF FUNCTIONS OR NUMBERS
OF NUTRIFILL.
NOW, HOW DO THOSE NUTRIFILLS DO
THEIR TRICK?
ANOTHER PRIMARY INSUFFICIENCY
ALSO FOLLOWED THROUGH BY
DRS. CALIN, AND MOLLIC AND
STEVE'S GROUP, DISEASE HAVE
GIVEN US AN IMPORTANT INSIGHT
INTO THAT.
SO WHAT YOU SEE HERE IS THE FAIG
O STUDIES FAG
O STUDIES -
-PHAGE O STUDIES OF MULTIPLE
ENDOCRINE PRODUCE THE SUPEROXIDE
AND THROUGH NOT VERY CLEAR
MECHANISMS INTRACELLULARLY ASPER
GILLIS CAN GET CONTROL.
SO MUTATIONS IN MANY OF THESE
SUBUNITS CAUSE THESE PROTOTYPIC
4 ASPER GILL ISOTOPE, DEDEFENSE,
AND 40% OF THOSE PATIENTS OVER
THE COURSE OF THEIR LIFETIME
WILL DEVELOP ASPERGILLOSIS
INDICATE THANKSGIVING AXIS IS
ABSOLUTELY CRITICAL FOR OUR
NUTRIFILLS TO DEFEND AGAINST
ASPER GILLIS.
IT ALSO TELLS US THAT 60% OF
PATIENTS DESPITE CONSTANT
EXPOSURE DON'T GET ASPER GILL
ONOSEIS, MEANING THEY'RE ALSO
DEPENDENT MECHANISMS THAT ARE
CRITICAL HERE.
THOSE ARE LESS CLEAR.
NOW, WHEN WE TALK ABOUT THE
SYNDROME OF AUTOSOMAL DOMINANT
HYPER IG SYNDROME, WORK FROM
STEVE'S LAB HERE PUBLISHED ABOUT
A DECADE AGO, LOOKEDDA THE
SUSCEPTIBILITY OF THESE PATIENTS
TO INVASIVE PULMONARY
ASPERGILLOSIS AND AS CAN YOU
APPRECIATE HERE UP TO 25-30% OF
THE THESE PATIENTS CAN DEVELOP
ASKER GILLOSEIS, HOWEVER AS YOU
NOTEOT ASTERISK, ALL OF THOSE
CASES DEVELOPED IN PATIENTS WHO
ALREADY HAVE STRUCTURAL LUNG
DISEASE, THIS SYNDROME CAUSES
TISSUE REMODELING DEFECTS, WHICH
THAT LEAD TO NATIONAL LIBRARY OF
MEDICINEAT O SILLS AND LEADS TO
BRONCH YECTOSEIS, AND THE WHY IT
LEADS TO THE AUTODOMINANT HYPER
IG SYNDROME IS HAPPENING IS NOT
BECAUSE THE PATIENTS HAVE AN
IMMUNE DEFECT BUT THEY STRUCTURE
OF LUNG THAT MIGHT LEAD TO THAT.
THESE PATIENTS HAVE BEEN TESTED
FOROXIDATIVE BURSTS AND THEY ARE
QUITE NORMAL.
NOW THIS IS THE INDEX PATIENT
THAT AMY MENTIONED EARLIER.
IN IS AN UNFORTUNATE GENTLEMEN
WHO WAS FINE UNTIL HIS 30S,
UNTIL HE WASN'T FINE SO HE
DEVELOPED SIGNUEICITIS, IT WAS
THOUGHT BACTERIAL BUT IT WAS
ASPER GILLIS, DESPITE THE
MULTIANTIFUNGAL DRUGS HE WAS
PLACED ON, HE DEVELOPED SINUS
ORBITAL BRAIN DISEASE WHICH WAS
FIGHTAL REQUIRED HIS ORBIT TO BE
REMOVED SURGICALLY AND DESPITE
THAT SECONDARY TO THE INFECTION.
THIS PATIENT DID NOT HAVE
PULMONARY DISEASE AND CERTAINLY
DID NOT HAVE PULMONARY
STRUCTURAL LUNG DISEASE,
THEREFORE MADE US THINK AS THE
SECOND PATIENT WE'VE SEEN HERE
WHICH I'M NOT SHOWING DUE TO THE
INTEREST OF TIME YOU DON'T NEED
STAT 3 INSUFFICIENT TO GET ASKER
GILLOSEIS.
THIS IS THE PATHOLOGY OF THAT
INDIVIDUAL PATIENT.
IT'S SIMILAR TO THE OTHER
PATIENT AS WELL WITH STAT 3
HAPLOINSUFFICIENCY AND
ASPERGILLOSIS AND WHAT YOU SEE
IS NECROSIS AND GRANULA TIS
RESPONSE WITHOUT THE PRESENCE OF
THOSE NUTRIFILLS THAT ARE
CRITICALLY IMPORTANT.
INDICATING THAT PERHAPS WHETHER
ACCUMULATION OR RECRUITMENT OF
CELLS OR THEIR PRESENCE AND
TISSUE MIGHT NOT BE SUFFICIENT
TO CONTROL THE DISEASE.
SO WE DON'T QUITE UNDERSTAND HOW
NUTRIFILLS IN THIS CONTEXT ARE
IMPAIR BUD IT DOES RAISE
IMPORTANT QUESTIONS ABOUT WHAT
WE NEED TO LOOK TO RETHINK OF
HOW MOLD DISEASE MIGHT HAPPEN IN
STATES OF STAT 3 DEFENSE.
NOW THE PATIENT WE DISCUSSED
TODAY HAD DISSEMINATED
COCCIDIOMYCOSIS, OTHER PATIENTS
WITH ON THE STUDIES OF MULTIPLE
ENDOCRINAL DOMINANT HYPER IG
SYNDROME AND STAT 3
HAPLOINSUFFICIENCY CAN DEVELOP
HISTOPLASMOSIS, THE FREQUENCY OF
THOSE AS WHAT WE DISCUSS ABOUT
ASPER GILLIS IS A BIT LESS
CLEAR, A LOT OF PATIENTS IN
ORDER TO GET THESE PATIENTS NEED
TO GO TO ENDEMIC AREA, SO IT'S
NOT LIKE ASPER GILLIS WHERE IT'S
EVERYWHERE, AND A LOT OF
PATIENTS ARE PUT ON EABT FUNGAL
DRUGS BECAUSE THEY HAVE MUCOSAL
[INDISCERNIBLE] THEY MIGHT HAVE
MOLD SUSCEPTIBILITY SO THAT
PROBABLY PROTECTS A LOT OF THEM
FROM DEVELOPING INFECTIONS SO
IT'S UNCLEAR HOW FREQUENT THAT
MIGHT BE IN AUTOSOMAL DOMINANT
HYPER ID SYNDROME BUT THERE ARE
SEVERAL CASES THAT HAVE NOW BEEN
REPORTED.
NOW IN THIS SET OF INFECTIONS
NUTRIFILLS ARE NOT CRITICAL FOR
DEFENSE, AND NEWT ROUGH ATOM
PENIC PATIENTS DON'T DEVELOP
HISTOPLASMOSIS OR COXOSEIS, THE
CLASSIC GROUP OF IMMUNO
COMPROMISED PATIENTS THAT WE ALL
LEARN THROUGH THE DECADES THAT
CAUSE THE--PROMOTE
SUSCEPTIBILITY AND HIV/AIDS SO
DECREASE IN CD4 T-CELLS IS NOT
GOOD.
LETUZMAB WHICH CAN DEPOLICE THE
CD4 T-CELLS CAN DESTROY THESE,
IT'S ACTUALLY THE T-CELLS THAT
PRODUCE INTERFERON-GAMMA
NATURALLY THAT ACT ON THE
RECEPTOR MACROPHAGES ACTIVATE
JACK STAT SIGNALING THAT DRIVE
MACROACTIVATION IN THE CROSS
TALK TO HANDLE YEAST CELLS
WHETHER IT'S HISTOPLASMA AND
COCCIDIOMYCOSIS
INTERRACELLULARLY OR
ENDOSPHEREIOLES THAT BROKE OUT
EARLY OR EXTRA CELLULARILY.
SO YOU HEARD STEVE SAY THAT
THROUGH THE YEAR THERE HAVE BEEN
CLOSE TO 8 PATIENTS THAT HAVE
BEEN IDENTIFY AS A PROOF OF
CONCEPT THEY JUST TOLD THAT YOU
THIS ACCESS IS CRITICAL FOR HOST
DEFENSE AGAINST THE FUNGI BUT
ONLY 8 PATIENTS.
AND OUR PATIENT DID NOT HAVE
MUTATIONS IN THE
INTERFERON-GAMMA IL12AXIS.
SO IN SEARCH OF MORE THAN 6 OR 8
PATIENTS OUT OF THE THOUSANDS
PER YEAR, THAT DEVELOP
DISSEMINATED DISEASE, STEVE'S
GROUP PUBLISHED THIS ELEGANT
PAPER JUST A FEW MONTHS AGO,
THEY DID WHOLE EXOHM SEQUENCES
IN PATIENT WHO IS HAD
DISSEMINATED MYCOSIS AND
VERIFIED THOSE FINDINGS IN AN
INDEPENDENT COHORT OF PATIENT
WHO IS HAD DISSEMINATED
COCCIDIOMYCOSIS MYCOSIS AND IN
THIS CASE, THEY DIDN'T ONLY
FOCUS ON RARE DELETERIOUS
MUTATIONS LIKE THE 1S WE JUDGE
UOF THE DISCUSSED IN THE
PREVIOUS SLIDE BUT ALSO MORE
COMMON POPULATION VARIANCE, THAT
IS VARIANTS THAT MIGHT BE THERE
AND IN THE SETTING OF THE PROPER
EXPOSURE AND A VIRULENT FUNGUS,
COCCIDIOMYCOSIS, IT CAN ACTUALLY
CAUSE MORE SEVERE DISEASE.
AND INDEED, NOT THROUGH THE
INTERFERON-GAMMA 12 ACCESS BUT
THROUGH A FUNGAL PATHWAY OF
RECOGNITION THAT IS A PROLIFICT
DETECTEDIN 1 THAT RECOGNIZES
[INDISCERNIBLE], THAT THE
PLC GAMMA 2 AND 2 IMPORTANT
MOLECULES CALLED DUOX1 AND
DUOXAC1, ALL COMERS ENROLLED
PROSPECTIVELY WITHOUT BIAS, THAT
HAD MUTATIONS IN THE GENES.
SO GOING FROM 8 PATIENTS TO NOW
BEING ABLE TO UNDERSTAND 50% OF
THE WIDE DISSEMINATED
DISSEMINATED COCCIDIOMYCOSIS
HAPPENS.
NOW AGAIN OUR PATIENT DID DIDN'T
HAVE MUTATIONS IN THOSE GENES.
HOWEVER 1 POSSIBILITY WE'RE
CONSIDERING IS BECAUSE IN DATA
I'M NOT SHOWING HERE FOR THE
INTEREST OF TIME AMY AND STEVE
HAVE SHOWN THAT THOSE 2
MOLECULES HERE DEPEND ON STAT 3
FOR TRANSCRIPTION, IT IS
POSSIBLE THAT PERHAPS STAT 3
DEFICIENCY STATES IMPAIR THIS
ACCESS THAT LEADS TO EPITHELIAL
PARASITE PRODUCTION THAT MIGHT
HELP CONTROL COCCIDIOMYCOSIS.
AND IN FACT, DUOX1 MICE ARE
HIGHLY SUSCEPTIBLE, SO 1
POSSIBILITY THAT COULD PERHAPS
STAT 3 IS THROUGH THESE RECENT
DISCOVERY.
ANOTHER POSSIBILITY IS THAT, AS
I MENTIONED, LYMPHOCYTE
MACROPHAGE CROSS TALK AND
ULTIMATELY MACROPHAGE IS
IMPORTANT FOR CONTROLLING THESE
FUNGI, SO, 1 OTHER POSSIBILITY
IS THAT INDEPENDENT OF DUOX1 OR
IN CONCERT WITH DUOX1 IMPACTS,
PERHAPS ACTIVATION OF
MACROPHAGES THROUGH IL6 OR OTHER
CYTOKINES THAT DO RELY ON STAT 3
SIGNALING MIGHT BE SUBOPTIMAL
AND THAT'S NOTHING THAT HAS NOT
BEEN EXAMINED BEFORE.
IERVETION L6 INHIBITORS HAVE
BEEN REPORTED AS TNF INHIBITORS
AS YOU HEARD EARLIER TO START
THIS, THIS IS PLAUSIBLE,
TESTABLE AND SOMETHING THAT IS
IMPORTANT TO DO.
SO, WHERE ARE WE GOING FROM
HERE?
AMY IS HERE TO DO RNA SEQUENCING
OF BOTH STAT 3
HAPLOINSUFFICIENCY AND AUTOSOMAL
DOMINANT HYPER IG SYNDROME HUMAN
LEUKOCYTES.
FOLLOWING STIMULATION WITH
FUNGAL PATHOGENS AND/OR CERTAIN
STAT 3 ASSOCIATED CYTOKINES.
SO WHICH OF THOSE ARE IMPAIRED?
WHICH PATHWAYS ARE
DIFFERENTIALLY IMPAIRED WHEN YOU
ARE MISSING 50% VERSUS 75-80% OF
THE STAT 3 SIGNALING?
AS I ALLUDED EARLIER, I THINK WE
NEED TO REVISIT WHETHER THERE
MIGHT BE SUBTLE ASPER GILLIS
DEFECTS IN NUTRIFILLS FROM STAT
3 PATIENTS THAT PERHAPS IN THE
SETTING OF AUTOSOMAL DOMINANT
HYPER IG SYNDROME WHERE THE
RESTRUCTURAL LUNG DISEASE, THEN
THEY ADDED EFFECT CAN MAGNIFY
THE PROBLEM AND YOU END UP WITH
30% OF PATIENTS GETTING ASKER
GILLIS OR IN THE CONTEXT OF STAT
3 HAPLOINSUFFICIENCY, WITHOUT
THE STRUCTURAL LUNG DISEASE,
DEPENDING ON THE EXPOSURE OF THE
PATIENT MIGHT SUFFICE AS WELL TO
DO THAT.
DURING SOME OF THESE THINGS WILL
REQUIRE MOUSE WORK WHERE STAT 3
HAPPEN LO INSUFFICIENT MICE CAN
BE COMPARED WITH HYPER IG MICE,
AND ULTIMATELY TRY TO UNDERSTAND
BETTER THIS DISEASE, BOTH FROM
THE CONTEXT OF COCCIDIOMYCOSIS
BUT ALSO ASPERGILLOSIS, THERE IS
A VERY, VERY INTERESTING
PREDELEKS FOR THE CNS THAT IT'S
IMPORTANT TO UNDERSTAND THE
ANATOMICAL SIDE BY WHICH THESE
SPECIFIC ABERRANTS SEEM TO DRIVE
THESE SO NOT ONLY PULMONARY
THESE BEING PATHOGENS THAT ARE
INHALED BUT ESCAPE OF THAT AND
LANDING INTO THE BRAIN.
SO I WILL LEAVE YOU WITH THIS
SLIDE THAT HIGHLIGHTS IN IN
PARTICULAR REVIEW, THAT WAS
PUBLISHED RECENTLY, NOT JUST
STAT 3, BUT ALSO STAT 1 AND 6
THAT WILL FALL INTO THE PARADIGM
SO AS AMY SHOWEDDED EARLIER WE
HAVE A NORMAL ACTIVITY OF STAT 3
WHEN WE HAVE 2 COPIES THAT ARE
NOT MUTATED.
THERE IS A DISEASE ENTITY WE
DISCUSS TODAY WHICH IS GAIN OF
FUNCTION STAT 3.
THOSE ARE UNFORTUNATE PATIENT
WHO IS HAVE TOO MUCH OF STAT 3
AND IN THE KOVEN TEXT OF THAT,
THEY GET VERY SEVERE
INFLAMMATION AND AUTOIMMUNITY
AND ACTUALLY JACK INHIBITORS ARE
USED NOW TO BRING THAT SIGNALING
DOWN FROM HERE TO NORMAL IN
ORDER TO AMELIORATE SOME OF
THOSE DISEASE MANIFESTATIONS.
BUT IN THE LOSS OF FUNCTION OF
STAT 3, WE GET, IMMUNO
DEFICIENCY, SO THE WELL
DESCRIBED SYNDROME OF AUTOSOMAL
DOMINANT HYPER IG SYNDROME WHERE
AS AMY SHOWED YOU ABOUT 75 OR
80% OF THE STAT 3'S LOST IS A
SIM DROAM THAT CAUSES FUNGAL
DISEASE AS WE DISCUSSED IT NOW.
MANY PATIENTS DEVELOP SEVERE
STAPHYLOCOCCAL INFORMATIONS,
THEY GET SCOLIOSIS, IS OTHERS,
TISSUE REMODELING DEFECTS, VERY
SEVERE ASTROPHY.
AND TODAY WE SHOW YOU THAT THE
PATIENT THAT HER FAMILY
CONDUCTED, STEVE HERE A FEW
YEARS BACK, ARE OTHER
OBSERVATIONS THROUGH THE YEARS
OF A LOT OF PATIENTS THAT WERE
LISTED EARLIER BY AMY, THAT
THERE IS ANOTHER ENTITY OF STAT
3 DEFICIENCY THAT IS ABOUT AND
IN THAT PARTICULAR ENTITY ONLY
FUNGAL DEC HAPPENS.
I THINK RAISING VERY IMPORTANT
QUESTIONS WITH REGARDS TO HOW
50% MIGHT BE SUFFICIENT TO
PROTECT AGAINST ALL OF THESE
OTHER PROBLEMS HERE, HOW THOSE
RELATE TO THE SPECIFIC TISSUES,
THE SPECIFIC CELLS, SO SOME OF
THOSE WE COULD EVENTUALLY ANSWER
WITH EXPERIMENTAL APPROACHES WE
HAVE.
I THINK IT'S ALSO IMPORTANT IN
THE SETTING OF A LOT OF PATIENTS
BEING GIVEN JACK INHIBITORS, AND
WHETHER IT'S 50% OR GREATER THAN
50% JACK 1, JACK 2 INHIBITION
AND HOW THIS MIGHT AFFECT
BACTERIAL FUNCTION AND PERHAPS
OTHER PROBLEMS AS WELL AS SEEN
HERE.
WITH THAT I WOULD LIKE TO THANK
YOU FOR YOUR ATTENTION AND WE
ARE ALL HAPPY TO TAKE ANY
QUESTIONS.
[ APPLAUSE ]
>>PAM STRATEGIC PLANON, THE
OBGYN IN THE ROOM.
I WOULD LIKE TO FOCUS ON THE
FACT THAT THIS WOMAN WAS
PREGNANT OR THIS OCCURRED AROUND
PREGNANCY BECAUSE I THINK THAT
THE VASCULAR CHANGES THAT HAPPEN
RELATED TO THE CENTRAL NERVOUS
SYSTEM THAT AREN'T WELL
UNDERSTOOD MAY CONTRIBUTE TO THE
FORMATION OF THE CNS FUNGAL
INFECTION AND SINCE WE CURRENTLY
HAVE A MATERNAL HEALTH CRISIS IN
THE UNITED STATES, I ENCOURAGE
YOU TO THINK ABOUT THE
RELATIONSHIP THAT OCCURS WITH
THE INFLECTION POINT OF
PREGNANCY AND IN DISEASES LIKE
THIS.
>>THANK, PAM AND AS STEVE
ALLUDED TO THERE'S A SELECT
GROUP OF PATHOGENS THAT ACTUALLY
CAUSE DISEASE, LISTERIA WHICH
ALWAYS GOES TO THE BRAIN ALSO,
SO.
>>THANK YOU PAM FOR SETTING UP
MY QUESTION WHICH IS WITH CASE
1, TO ME IT SEEMS QUITE
MIRACULOUS BUT DESPITE THE
POSSIBLY ITIS DURING PREGNANCY
THE SON IS NORMAL, SO I WAS
WONDERING OF COCCIDIOMYCOSIS WAS
FETAL DEMISE, SO ANY THOUGHTS ON
WHY THE FETUS WAS SPARED AND THE
CHILD IS QUITE HEALTHY?
>>STEVE HAVE YOU ENCOUNTER
OTHER COCCIDIOMYCOSIS CASES
THROUGHOUT THE YEARS WITH
PREGNANCY?
MAYBE CAN YOU COMMENT ON THIS?
>>SO THANKS, I THINK IT'S A
CRITICALLY IMPORTANT QUESTION.
SHE ACTUALLY GOT SICK RIGHT
BEFORE PREGNANCY WITH A FLU-LIKE
SYNDROME.
AND SHE HAD WHAT THEY CALLED
MONO, AS IS TYPICALLY THE CASE,
AND HAD A LITTLE BIT OF EMILY
NODE ADEN OPEN MEETINGATHY AND
THAT POINT SHE STARTED HER
TREATMENT AS I UNDERSTAND IT AND
THEN SHE GOT SICK DURING
PREGNANCY STILL WAS ABLE TO
DELIVER BUT I BELIEVE SHE WAS ON
TREATMENT WHEN THAT HAPPENED SO
I DON'T KNOW WHAT THE FREQUENCY
OF TRANSMISSION TRANSPLACENTA
SENTALLY IS, IT'S NOT A HUNDRED%
FOR SURE, AND IN THIS PARTICULAR
CASE THE CHILD WAS NOT ONLY
HEALTHY AT DELIVERY BUT WHEN WE
WENT BACK EVENTUALLY AND CHECKED
HIM GENETICALLY HE WAS
UNAFFECTED.
>>AND RELATED TO THAT, WHY WE
THINK THE RECURRENCE--I THINK IT
WAS A YEAR LATER?
>>I CAN'T ANSWER THAT.
I THINK, SO YOU KNOW I NEVER MET
THIS PATIENT IN LIFE AND GETTING
RECORDS HAS BEEN COMPLEX.
TO BE BRIEF.
SO I CAN'T SPEAK TO ALL OF THOSE
NUANCES, I THINK SHE WAS ON
TREATMENT FOR AT LEAST PART OF
THE TIME FOLLOWING PREGNANCY.
WHAT I DON'T KNOW IS WHETHER SHE
WENT THROUGH A PERIOD WHEN SHE
WAS OFF THERAPY AND THAT WAS
DURING THAT THAT SHE RELAPSED IN
THE CNS.
I SUSPECT THAT IT'S TRUE AS PAM
SUGGESTS THAT HER FUNDAMENTAL
DISSEMINATION AND SEVERE DISEASE
WAS DURING PREGNANCY AND IT WAS
DURING THAT TIME THAT I WAS TOLD
SHE DEVELOPED A DRAINING SINUS
OUT OF HER LEFT SHOULDER.
SO I SUSPECT THAT SHE HAD
DISSEMINATED DISEASE BECAUSE OF
HER STAT 3 MUTATION, BUT THAT
GOT WORSE BECAUSE OF PREGNANCY
AND IT MAY BE THAT DURING
PREGNANCY SHE CAME BACK INTO
CARE AND HAD SOME FLUCONASAL FOR
A WHILE BUT SOMEWHERE ALONG THE
LINE GOT PRESCRIBING OPERATELY
ILL AND I CAN'T EXPLAIN WHY
THINGS GOT WORSE A YEAR LATER.
I DON'T KNOW THE ANSWER TO THAT.
>>THANK YOU.
>>STEVE, [INDISCERNIBLE]
ALLUDED TO THIS A BIT AS HE
ENDED THE TALK.
YOU KNOW JACK STAT INHIBITORS
ARE USED FOR MORE AND MORE
INDICATIONS SHOW WORRIED SHOULD
WE BE ABOUT LOOKING FOR THESE
KINDS OF INFECTIONS IN PATIENTS
WHO ARE ON JACK STAT INHIBITORS?
AND SHOULD WE BE PROVE LACTIC
ACIDOSEISING PATIENT WHO IS ARE
ON JACK STAT INHIBITORS?
>>SO SO, YOU KNOW JACK
INHIBITORS ARE PUT IN THE WATER
THESE DAYS AND OF COURSE EVERY
JACK INHIBITOR IS DIFFERENT WHAT
THE UNDERLYING DISEASE IS
DIFFERENT AND THE DOSE OF THE
JACK INHIBITOR BECAUSE THESE
EXHIBIT DOSE EFFICACY AND
TOXICITY AND WHETHER YOU HAVE
JACK INHIBITOR WHETHER ON
STEROIDS OR SOMEONE GETS A JACK
INHIBITOR BUT THERE ARE CLEAR
REPORTS OF INDEMMIC FUNGAL
INFECTIONS AND MACROPHAGE FUNGAL
DISEASE, I THINK THAT TOGETHER
WITH MICROBACTERIAL INFECTIONS
AND VIRAL INFECTIONS WITH THE
INTERRACELLULARLY HANDLED
PATHOGENS, I THINK THAT'S QUITE
CLEAR.
THERE ARE SOME REPORTS OF
ASPERGILLOSIS, NOT MANY, BUT AS
YOU ARE AWARE, MOST OF THE
TRIALS WHEN THE DRUG IS GETTING
APPROVED, TELLS US HALF IF NOT
THAT THE TRUE TO SUSCEPTIBILITY
TO A BIOLOGIC MIGHT BE DOWN THE
LINE.
THE QUESTION OF PROPHYLAXIS
COMES DOWN TO WHAT IS THE NUMBER
OF INFECTIONS AND HOW MANY OF
THEM ARE IN THE DENOMINATOR OF
THE TOTAL NUMBER OF PATIENTS AND
THEN HOW MANY YOU NEED TO TREAT
WITH WHAT DRUG AND HOW TOXIC IT
WILL BE AND A THING I'M
CONVINCED FOR HISTOAND COX AND
ENDEMIC LAYERS EVERYBODY NEEDS
TO BE ON FLUCONASALL.
THE ADD COMPLICATION THERE IS
THAT THERE'S INHIBITORS BETWEEN
JACK INHIBITORS AND ASOLs, SO
UNLESS THERE'S A COMPELLING
EPIDEM YOJICAL SIGNAL SO FOR
PATIENTS WE PUT PATIENTS ON
VALCYCLOVIRAND IT IS A SAFE
DRUG, SO I THINK WE WILL SEE
MORE OF THEM BUT IT'S GOING TO
BE DEPENDING ON THE DOSE THAT
PATIENT POPULATION AND I THINK
UNTIL WE HAVE MORE OF THAT
INFORMATION, IT WILL BE MORE
DIFFICULT TO ESTABLISH
PROPHYLAXIS REGIMENS.
>>THANK YOU.
>>THANKS FOR THE INTERESTING
PRESENTATION, I WAS WONDERING
ABOUT THE AUTOPSIES IF SOMEONE
COULD LIKE ELABORATE A BIT MORE
ON INTERESTING FINDINGS IN TERMS
OF NEUROSTUFF THAT WAS GOING ON?
>>DAVID?
>>WELL, I THINK IN THIS
PARTICULAR CASE, THE MAIN THING
THAT WE FOUND WAS THE
DISSEMINATED INFECTION AND THE
CONSEQUENCES OF THAT.
SO THERE WAS A STRUCTURAL DAMAGE
IN THE LUNG.
BRONCHIECTASIS IS OFTEN SEEN IN
THESE PATIENTS FOR MECHANISMS
THAT I DON'T FULLY UNDERSTAND
MYSELF BUT IT CREATES AN
OPPORTUNITY FOR MORE INFECTION
IN THIS ALTERED ARCHITECTURE.
THERE WEREN'T ANY BRAIN FINDINGS
SPECIFICALLY OUTSIDE THE DAMAGE
THAT WAS CAUSED BY THE
HEMORRHAGE AND YOU KNOW THAT
PRIMARILY WAS--IS A PRESSURE
MEDIATED DEATH AND WHEN YOU GET
HEMORRHAGE INTO THE BRAIN, BUT
IN GENERAL, IN AUTOPSIES THAT WE
PERFORM HERE WE DO TAKE KIND OF
A WHOLISTIC APPROACH TO WHAT WE
DO AND IN CONTRAST TO SOME OTHER
PROGRAMS THAT I'M AWARE OF WHERE
THE PATHOLOGIST WILL ASK, YOU
KNOW WHAT ARE THE SPECIFIC
QUESTIONS THAT THE CLINICIAN HAS
AND JUST GO AFTER THOSE
PARTICULAR TARGETS, WE WILL LOOK
AT EVERYTHING WE SUBMIT
MICROSCOPIC, YOU KNOW TISSUES ON
EVERYTHING.
SO, OUR CHANCES OF PICKING UP
EXTRA FINDINGS, I THINK ARE GOOD
AND OFTEN TIMES YOU KNOW LATER
ON QUESTIONS ARISE, WELL, YOU
KNOW THIS WAS HAPPENING IN LIFE,
IS THERE AN EXPLANATION FOR
THAT?
AND SOMETIMES WE'RE ABLE TO
PROVIDE AN ANSWER.
>>THANK YOU FOR THE
PRESENTATION.
I WAS JUST CURIOUS ABOUT THE
CONCEPT OF PROPHYLACTICS AND THE
OTHER 1S, SO I'M LOOKING AT IT
FROM THE POINT OF THE COMMON--I
THINK SOMEBODY TALKED ABOUT THE
COMMON VARIANT IN ASPER GILLIS
THAT HAS BEEN IDENTIFY ALSO, SO
LOOKING FOR THE FURTHER EVIDENCE
OF THIS CONDITION SEEMS TO BE
HIGHER IN CERTAIN POPULATION DOE
WE KNOW IF SOME OF THESE
VARIANTS [INDISCERNIBLE]
POPULATIONS AS WE COULD THINK
ABOUT PROPHYLACTICS FOR THE
INDUCED POPULATION?
>>SO THAT'S A GREAT QUESTION.
WHAT WE SAW WAS THE COMMON
VARIANT, 1 TENDS TO BE NORTHERN
EUROPEAN TRICKLING THROUGH AND
THE OTHER TENDS TO BE SPECIFIC
TO AFRICAN AND AFRICAN DESCENT.
SO THAT'S 1 AND WE DEMONSTRATED
IN KEEPING WITH THE IDEA THAT
TNF INHIBITORS ARE MAJOR RISK
FACTORS PATIENTS WITH DETECTEDIN
1 OR PLC12, DON'T STIMULATE SO
THAT APPEARS TO BE THE
MECHANISM, THE PLC VARIANT IS A
NORTHERN EUROPEAN VARIANT SO WE
DIDN'T SEE IT AMONG THE AFRICAN
DESCENT PEOPLE IN THE COHORT,
THE DUOX1 AND DUOXONCEA TEND TO
BE THE INDIVIDUALS FROM AFRICAN
HISPANIC DESCENT.
THE DIFFERENCE THERE IS THAT THE
PLC GAMMA 2 INDETECTEDIN 1OR
INDIVIDUAL SPECIFIC MUTATIONS OR
VALID
VARIANTS SO WE CAN LOOK FOR 4 TO
ENCOMAS ALL OF THAT.
THE DUOX1 VARIANTS AND HEECH
PERSON HAD THEIR OWN UNIQUE
VARIANT SO IT'S HARDER, WE COULD
MAKE A PREDICTION BUT THEN
YOU'RE TALKING ABOUT DOING EXOHM
OR GENOME SEQUENCING ON EACH
PERSON.
IT MAY MAKE MORE SENSE IF YOU
THOUGHT ABOUT DOING IT
PROPHYLACTICALLY TO DEVELOP A
FUNCTIONAL ASSAY WHERE IT
DOESN'T MATTER THEN WHAT THE
UNDERLYING GENETICS ARE BUT YOUR
RISK BACK IN THE ENVELOPE
CALCULATION SAYS YOUR RISK OF
GETTING INFECTED IN THE ENDEMIC
AREA IS 3% OF THE YEAR, SO CAN
YOU LIVE THERE 30 YEARS AND
NEVER GET INFECTED SO YOU'RE
PLAYING THAT GAME, TOO.
IF YOU THINK ABOUT THE
POPULATION AND THERE ARE ONLY
150,000 INFECTIONS PER YEAR.
>>YEAH, MAYBE SOMETHING LIKE
[INDISCERNIBLE] WHERE YOU
[INDISCERNIBLE] JUST HAVING LIKE
AN AREA OF THOSE SPECIFIC GENES
[INDISCERNIBLE] FOR THEM AND
THOSE POPULATION FOR
SO--[INDISCERNIBLE] MAYBE THAT'S
SOMETHING YOU CAN--
>>YEAH, YEAH, I THINK THE OTHER
THING THEY ARE DOING IS A
VACCINE IS IN DEVELOPMENT AND
IT'S--THEY'VE DONE DOG TRIALS,
THEY'RE STARTING A FIRST IN
HUMAN TRIAL AND IT MAY MAKE MORE
SENSE TO SIMPLY VACCINATE PEOPLE
WHO MIGHT BE AT HIGHER RISK
VAGHTER THAN DOING GENETICS.
>>THANK YOU.
>>YEAH.
>>HI, I'M A GENETICIST AND A
STAFF CLINICIAN AT NHGRI AND I
WAS JUST CURIOUS ABOUT THE
PATIENT AND HOW THE PATIENT WAS
PARENTALLY HEALTHY BEFORE SO I
THINK IT WAS JUST SO
INTERESTING.
HAVE YOU CONSIDERED LOOKING AT
DATABASES LIKE THE ALL OF US
WHERE IT'S WHOLE EXOHM
SEQUENCING OF LARGE NUMBER OF
APPARENTLY HEALTHY INDIVIDUALS
AND IF YOU CAN PICK UP ANY OF
THOSE INDIVIDUALS WHO HAVE
HETEROZYGOUS LOSS OF FUNCTION
MUTATIONS EEVALUATE THEM WHEN
THEY'RE HEALTHY, I DON'T KNOW.
>>RIGHT.
WE HAVEN'T PURSUED THE ALL OF US
DATABASE YET, I MEAN IT WASN'T
AVAILABLE FOR PUBLIC COMSUMPTION
UNTIL RECENTLY, SO WHEN WE DID
THIS, THIS WAS A YEAR AGO WHAT
WE WELL TO WORK WITH WAS
NATIONAL LIBRARY OF MEDICINEAD
AND THERE WAS 1 PATIENT IN NOMAD
WITH A STAT 3 VARIANT.
BY CONTRAST THE DETECTEDIN 1 AND
PLC 2 VARIANTS ARE 7%
POPULATION.
>>MUCH MORE REAL.
>>AND THOSE WE CAN GET HERE
FROM THE NIH BLOOD BANK.
WE CAN FIND PEOPLE WHO ARE
HETEROGENEOUS ORY ZYGOUS,
DUOX DUOX1, BECAUSE EACH PERSON
HAS A SPECIFIC VARIANT THEN YOU
HAVE TO DO FUNCTIONAL STUDIES
FIRST TO DEMONSTRATE WHETHER OR
NOT A VARIANT IS DELETERIOUS
BEFORE YOU GO ON AND LOOK AT
ADDITIONAL THINGS.
>>THANK YOU.
>>I MIGHT VERY, VERY QUICKLY AN
IMPORTANT POINT FROM THAT SO
EXPOSURE IS CRITICAL AS AMY
ALLUDED TO SO ACTUALLY IN THE
FAMILY THAT [INDISCERNIBLE] BEEN
ALERTED FOR, EVEN WITHIN THE
SAME FAMILY THE PEN STRANTS OF
THE DISEASE IS INCOMPLETE
MEANING NOT ALL THE PATIENTS IN
THE SAME FAMILY BEING AFFECTED
HAVE FUNGAL DISEASE, SO THAT
GOES TO PERHAPS 50% INSUFFICIENT
FOR SOME TO HANDLE CERTAIN
EXPOSEDDURES, SO I THINK
IT'S--IT HAS THE INFECTIOUS
EXPOSURE IN THE AMOUNT OF IT, I
THINK IN THE EQUATION HERE.
>>THANK YOU.
FROM THE COHORT BEFORE I ASK MY
QUESTION, I WANT TO PUT IN AN
AD ARE THE RESEARCH FESTIVAL FOR
HOW TO USE IT AND SIGN UP, MY
QUESTION IS HOW CAN YOU TELL THE
STAT 3 MUTATION FOR THE GERM
LINE OR SOMATIC ALSO HAS CASES.
>>GERM LINE.
GERM LINE.
>>YEAH.
>>ALL RIGHT.
THANK YOU EVERYONE FOR
ATTENDING.
IF YOU HAVE ANY FURTHER
QUESTIONS YOU CAN STILL SUBMIT
THEM AND WE WILL TRY TO GET BACK
TO YOU BY E-MAIL.
THANKS.
[ APPLAUSE ]