Welcome to the Clinical Center Grand Rounds,
a weekly series of educational lectures for physicians and
health care professionals broadcast from the Clinical
Center at the National Institutes of Health in
Bethesda, MD.
The NIH Clinical Center is the world's largest hospital totally
dedicated to investigational research and leads the global
effort in training today's investigators and discovering
tomorrow's cures.
Learn more by visiting us online at http://clinicalcenter.nih.gov
OUR SPEAKER TODAY IS
DR. ELIZABETA NEMETH, WHO IS A
PROFESSOR OF MEDICINE IN THE
DAVID GEFFEN SCHOOL OF MEDICINE
AT UCLA, AND DIRECTOR OF THE
UCLA CENTER FOR IRON DISORDERS.
DR. NEMETH EARNED HER BACHELOR
OF SCIENCE IN MOLECULAR BIOLOGY
AT THE UNIVERSITY OF BELGRADE IN
YUGOSLAVIA AND THEN EARNED A
PH.D. IN CELL MOLECULAR AND
NEUROSCIENCES AT THE UNIVERSITY
OF HAWAII.
SHE COMPLETED POSTDOCTORAL
FELLOWSHIPS AT HAWAII AND THEN
AT CEDARS-SINAI MEDICAL CENTER
IN LOS ANGELES BEFORE JOINING
UCLA IN 2001.
AS MANY OF YOU WILL KNOW, IN HER
INVESTIGATIONS, SHE HAS
UNDERTAKEN THE STUDY OF IRON
HOMEOSTASIS AND ITS DISORDERS
WITH SPECIFIC FOCUS ON THE
FUNCTION OF THE HEPATIC PEPTIDE
HORMONE AND MORE RECENTLY ON ITS
RECEPTOR, THE IRON TRANSPORTER.
HER WORK HAS HELPED DEFINE THE
REGULATION OF HEPCIDIN, AND
ERYTHROPOIESIS.
IT HAS ALSO DESCRIBED THE ROLE
IN DIFFERENT IRON DISORDERS
INCLUDING HEREDITARY
HEMOCHROMATOSIS, THALASSEMIA AND
THE ANEMIA OF INFLAMMATION.
IT HAS ELUCIDATED A MECHANISM OF
ACTION AS THE LIGAND DESCRIBED
THE HORMONE ERYTHROPHERONE AND
ALSO DEVELOPED NOVEL POTENTIAL
HEPCIDIN TARGETED CANDIDATES FOR
THE TREATMENT OF IRON DISORDERS.
IN IN ADDITION TO BEING THE FOUNDER
AND DIRECTOR OF THE UCLA CENTER
FOR IRON DISORDERS, DR. NEMETH
IS ALSO DIRECTOR OF A PROGRAM AT
UCLA FOR JUNIOR FACULTY.
SHE'S A MEMBER OF THE NIH
MOLECULAR AND CELLULAR
HEMATOLOGY STUDY SECTION AND IS
CURRENTLY PRESIDENT OF THE
INTERNATIONAL BIOIRON SOCIETY.
IN 2021, SHE RECEIVED A PRIZE
FROM THE AMERICAN SOCIETY OF
HEMATOLOGY JUST A FEW MONTHS
AGO, WHICH IS AWARDED FOR
OUTSTANDING CAREER CONTRIBUTIONS
TO HEMATOLOGY, AND I THINK THAT
PRIZE TO MANY OF US WAS A VERY
WELL DESERVED HONOR CONSIDERING
THE BODY OF HER WORK OVER THE
LAST 20 YEARS.
HER TALK TODAY IS ENTITLED FROM
ANEMIA TO IRON OVERLOAD AND
INFECTION, THE PATHOBIOLOGY OF
IRON.
PLEASE WELCOME DR. NEMETH.
>> THANK YOU VERY MUCH,
DR. SCHECHTER AND COLLEAGUES.
IT'S TRULY AN HONOR TO GIVE THIS
LECTURE.
I WILL TRY TO SUMMARIZE THE
ADVANCES WE'VE MADE OVER THE
LAST 20 YEARS IN UNDERSTANDING
REALLY THE MOLECULAR
UNDERPINNINGS OF IRON PHYSIOLOGY
AND HOW THAT EXPLAINS
PATHOGENESIS OF DIFFERENT IRON
DISORDERS.
MY DISCLOSURES ARE I'M
ON THE ADVISORY BOARD FOR
ALL THESE LISTED, I'M ALSO A
STOCK SHAREHOLDER.
THESE ARE RELATED TO HEPCIDIN
DIAGNOSTICS OR THERAPEUTICS, AND
ALL MY GRABBED SUPPORT COMES
FROM NIH.
SO THANK YOU.
HERE ARE LEARNING OBJECTIVES FOR
TODAY.
TO UNDERSTAND THE PATHOGENESIS
OF IRON OVERLOAD DISORDERS,
UNDERSTAND THE PATHOGENESIS OF
INFLAMMATION AND UNDERSTAND THE
ROLE OF IRON IN HOST DEFENSE.
I WILL START VERY BROADLY.
JUST TO UNDERSTAND WHY DO WE
REALLY NEED IRON?
WHY IS IT SO ESSENTIAL?
THE COMMONLY KNOWN FUNCTIONS OF
IRON IS IN OXYGEN TRANSPORT AND
STORAGE AS WELL AS IN ATP
SYNTHESIS, SO IRON IS ACTUALLY
THE VERY AXE OM TO WHICH OXYGEN
ATTACHES FOR TRANSPORT AND
STORAGE OF OXYGEN.
AND IRON IS ALSO THE VERY ATOM
ALONG WHICH ELECTRON TRANSPORT
IS BEING CONDUCTED IN
MITOCHONDRIAL RESPIRATORY
COMPLEXES.
BUT IN ADDITION TO THESE, IRON
IS INVOLVED IN MANY, MANY OTHER
VITAL CELLULAR PROCESSES, FROM
OXYGEN SENSING DNA SYNTHESIS AND
REPAIR TO METABOLISM OF AMINO
ACIDS, ET CETERA.
SO ONE WONDERS WHY AARON IS
INVOLVED IN MANY PROCESSES.
FROM A CHEMICAL PER PERSPECTIVE, THE
EXPLANATION IS THAT IRON
ACTUALLY HAS A VERY VERSATILE
CHEMISTRY IN THAT IT CAN VERY
REGULARLY BOTH RELEASE AN
ELECTRON AND ACCEPT AN ELECTRON,
SO IT CAN MEDIATE EITHER
OXIDATION OR REDUCTION
REACTIONS.
BUT FROM THE EVOLUTIONARY
PERSPECTIVE, IT IS THOUGHT THAT
IRON WAS ACTUALLY ESSENTIAL FOR
THE VERY START OF LIFE.
INITIALLY, LIFE STARTED IN THE
EARLY SEAS, THEY WERE VERY
IRON-RICH AND OXYGEN-POOR AND
THEY'RE REFERRED TO AS FERR, OH
US OUS
PARADISE.
MORE AND MORE COMPLEX MOLECULES
FROM VERY SIMPLE MOLECULES AND
GASES, AND THAT AS THESE
MOLECULES BECAME MORE
COMPLEX, -- MORE AND MORE
REACTIONS AND THAT MAY BE ONE OF
THE EXPLANATIONS WHY IRON IS SO
EVER PRESENT IF IN LIFE.
THERE IS PRACTICALLY ALL OF THE
LIVING ORGANISMS REQUIRE IRON.
HOWEVER, IRON DISORDERS ARE VERY
COMMON GLOBALLY.
IF WE LOOK AT IRON INSUFFICIENCY
FORMS, IRON DEFICIENCY ANEMIA
WOULD BE THE PRIMARY ONE.
WORLD HEALTH ORGANIZATION LISTS
THAT AMONG THE FIVE GREATEST
CAUSE OF YEARS LIVED WITH
DISABILITY.
AND IT IS PARTICULARLY PREVALENT
AMONG WOMEN AND CHILDREN IN LOW
AND MIDDLE INCOME COUNTRIES.
HIGHLY COMMON ALSO IS ANEMIA OF
INFLAMMATION OR ANEMIA OF
CHRONIC DISEASE, IRON
MALDISTRIBUTION.
FREQUENTLY IRON DEFICIENCY AND
ANEMIA ARE CO-PRESENT.
ALSO MILLIONS OF PEOPLE
WORLDWIDE ARE AFFECTED BY IRON
EXCESS.
THE MOST PROMINENT DISORDERS ARE
HEMOCHROMATOSIS, WHICH IS THE
MOST COMMON -- MOST NOTABLE IN
NORTHERN EUROPEAN ORIGIN, AND
IRON LOADING ANEMIAS.
WE WILL GO THROUGH THE
PATHOGENESIS OF BOTH OF THESE.
SO THE WAY SYSTEMIC IRON
HOMEOSTASIS IS MAINTAINED IN
HUMANS IS ACTUALLY THROUGH THE
RECYCLING ECONOMY.
AND THAT IS BECAUSE DURING THE
EVOLUTION, AS OXYGEN -- THE
OXYGEN CONTENT BECAME MUCH
HIGHER IN ATMOSPHERE, IRON
BECAME MUCH LESS AVAILABLE AND
SO LIVING ORGANISMS HAVE EVOLVED
TO RECYCLE IRON.
FLOOB IF WE LOOK AT THE TOTAL
IRON -- IN IN THE BODY, IT'S 3 TO
4 GRAMS, THE LARGEST IS IN RED
CELLS, HEMOGLOBIN, APPROXIMATELY
TWO THIRDS OF THE TOTAL IRON
AMOUNT.
AS I MENTIONED, IRON ECONOMIES
ARE RECYCLING ONE, SO YOU WILL
APPRECIATE THAT EVERY DAY, WE
ABSORB VERY LITTLE IRON, ONLY
1 TO 2 MILLIGRAMS, WHICH IS LESS
THAN .1% OF TOTAL BODY IRON.
SO WE ABSORB VERY LITTLE AND
THAT IS REALLY TO COMPENSATE FOR
THESE UNREGULATED IRON LOSSES
THAT OCCUR BY SLOUGHING OF
GASTROINTESTINAL CELLS OR SKIN
CELLS OR MINOR BLEEDS.
THE MAJOR REALLY FLOW OF IRON IN
THE BODY IS THROUGH THE BONE
MARROW, APPROXIMATELY
20 MILLIGRAMS A DAY IS TAKEN UP
TO SYNTHESIZE NEW RED BLOOD
CELLS.
AND THAT IRON IS THEN PRESENT AS
A COMPONENT OF HEMOGLOBIN IN RED
BLOOD CELLS, THEY LIVE
APPROXIMATELY FOR 120 DAYS,
THAT'S FOUR MONTHS, AND THEN
THEY GET RECYCLED BY MACROPHAGES
IN THE SPLEEN AND THE LIVER AND
APPROXIMATELY 20 MILLIGRAMS A
DAY IS RECYCLED BACK INTO
CIRCULATION.
AND YOU WILL APPRECIATE THE
PLASMA IRON LEVELS ARE ACTUALLY
PRETTY LOW, ONLY 3 TO
4 MILLIGRAMS, BUT A MUCH LARGER
FLOW OF IRON GOES THROUGH IT
EVERY DAY, SO REALLY PLASMA IRON
COMPARTMENT TURNS OVER SEVERAL
TIMES A DAY.
THAT IS WHY IT IS SUCH A
DRAMATIC COMPARTMENT THAT CAN
CHANGE OVER RELATIVELY EASILY.
DEPENDING ON WHETHER WE HAVE
IRON SURPLUS OR IRON DEFICIENCY,
WE CAN STORE IRON IN THE LIVER,
WHICH IS THE MAJOR STORAGE ORGAN
AND USUALLY CAN HAVE UP TO
1-GRAM OF IRON STORED.
WOMEN USUALLY HAVE LESS.
AND WHEN WE NEED IT, WE MOBILIZE
IT OUT OF THE LIVER FOR
PROCESSES.
SO HOW IS THIS SYSTEMIC IRON
HOMEOSTASIS REGULATE AND
MAINTAINED?
IT'S MAINTAINED BY REGULATING
FLOWS OF IRON INTO PLASMA.
AND THAT IS DONE THROUGH THE
PROTEIN CALLED THEIR OWE PORE
TIN, WHICH IS THE ONLY KNOWN
CELLULAR IRON EXPORTER, THE ONLY
CONDUIT FOR IRON TO ENTER
PLASMA.
SO PHARAOH PORE TIN IS EXPRESSED
ON -- THAT ABSORB IRON FROM THE
DIET.
IT'S EXPRESSED ON STLE NICK
MACROPHAGES THAT RECYCLE OLD RED
BLOOD CELLS AND IT'S ALSO
EXPRESSED ON HEPATOCYTES THAT
STORE IRON.
SO IS THE ONLY WAY FOR IRON TO
ENTER PLASMA.
THEREBY CONTROLS FLOWS OF IRON
INTO PLASMA.
SO HEPCIDIN IS THIS REALLY SMALL
PEPTIDE, 25 AMINO ASIDES LONG,
PRODUCED IN VERY LARGE
QUANTITIES IN THE LIVER, AND ITS
PRODUCTION IS REGULATED, WHICH
IN TURN HIGHLY REGULATED AND
THAT, IN TURN, REGULATES IRON
FLOWS.
IT'S ALSO VERY RAPIDLY CLEARED
IN THE KIDNEYS, BECAUSE IT IS SO
SMALL.
SO THIS IS HOW HEPCIDIN CONTROLS
IRON FLOWS.
HEPCIDIN IS A LIGAND FOR
FERROPORTIN, SO FERROPORTIN IS
THIS TRANS MEMBRANE 12 MULTIPASS
TRANS MEMBRANE PROTEIN THAT HAS
A CENTRAL CAVITY THROUGH WHICH
IRON IS EXPORTED FROM INSIDE A
CELL TO OUTSIDE OF THE CELL, AND
HEPCIDIN IS A SMALL PEPTIDE
WHICH INSERTS ITSELF INTO THE
CENTRAL CAVITY OF FERROPORTIN,
AND THUS OCCLUDES FERROPORTIN
AND PREVENTS FURTHER IRON
EXPORT.
IN ADDITION TO THAT, THIS
BINDING, THE DIRECT INTERACTION
CAUSES EU BIC WHICH NATION AND
THAT LEADS TO DESTRUCTION OF
BOTH LIGAND AND THE RECEPTOR.
SO IF WE LOOK IN THE CELLULAR
MODEL, HERE ARE CELLS EXPRESSING
FERROPORTIN TAGGED WITH
FLUORESCENT GREEN PROTEIN GFP.
IN THE ABSENCE OF HEPCIDIN,
FERROPORTIN IS ON THE CELL
SURFACE AND IT EXPORTS IRON.
BUT WHEN HEPCIDIN IS ADDED,
FERROPORTIN IS RAPIDLY
INTERNALIZED AND DEGRADED AND
THEN EXPORTED OUT OF THE CELL
STOCKS.
SO HOW THAT EXPLAINS HOW
HEPCIDIN CONTROLS INTESTINAL
IRON ABSORPTION.
WHEN HEPCIDIN IS LOW,
FERROPORTIN IS EXPRESSED ON THE
MEMBRANE OF THE DUE DUODENAL
ENTEROSITES.
ON IRON IS GOING TO BE DIRECTLY
EXPORTED INTO BLOOD.
BUT WHEN HEPCIDIN IS HIGH, EVEN
IF WE CONTINUE TAKING IRON ON
THE APICAL SIDE, THAT IRON IS
JUST GETTING STUCK WITHIN
DUODENAL ENTEROCYTES AND THESE
ARE SHORT LIVED CELLS, THEY GET
SLOUGHED OFF IN TWO TO THREE
DAYS, SO HEPCIDIN WILL -- HIGH
HEPCIDIN, LOWER IRON TRANSPORT
INTO BLOOD.
THE SIMILAR PRINCIPLE APPLIES,
SO WHEN HEPCIDIN IS LOW, AS
MACROPHAGES EXTRACT IRON FROM
HEMOGLOBIN, THAT IRON CAN BE
READILY EXPORTED THROUGH
FERROPORTIN WHICH IS EXPRESSED
ON THE SURFACE OF MACROPHAGES,
BUT WHEN HEPCIDIN IS HIGH, EVEN
THOUGH PHAGOCYTOSIS CONTINUES,
IRON IS GOING TO GET SEQUESTERED
WITHIN FERRATIN AND IRON WILL
NOT BE EXPORTED INTO PLASMA.
SO IF WE NOW PUT IT ALL TOGETHER
ON AN ORGANIZE LEVEL, WHEN
HEPCIDIN IS ELEVATED, THAT WILL
TARGET FERROPORTIN ON ALL OF THE
TARGET SITES THAT HANDLE MAJOR
IRON FLOWS, NARE FERROPORTIN WILL BE
DESTROYED AND THAT DECREASES
IRON FLOWS INTO PLASMA.
AS I MENTIONED, THIS PLASMA
COMPARTMENT IS VERY SMALL, AND
IT'S CONSTANTLY GETTING UTILIZED
BY THE BONE MARROW AND OTHER
CELLS IN THE BODY, SO IT'S GOING
TO GET VERY RAPIDLY DEPLETED,
AND THAT EXPLAINS HOW HYPOTHAT
WILL -- OCCURS.
THIS IS AN EXAMPLE IN MICE, HOW
WE CAN DO THIS IN A VERY -- YOU
CAN APPRECIATE WITHIN JUST ONE
HOUR, WE CAN ACHIEVE THIS
PROFOUND PIE HOE FAIR HYPOFERREMIA.
SO IN A WAY, HEPCIDIN IS TO IRON
WHAT INSULIN IS TO GLUCOSE.
SO HEPCIDIN REGULATION IS REALLY
COMPLEX AND THAT IS RESPONSIBLE
FOR CONTROLLING THESE IRON FLOWS
AND MAINTAINING SYSTEMIC IRON
HOMEOSTASIS.
I'M GOING TO COVER THREE MAJOR
CIRCUITRY.
ONE OF THEM IS HEPCIDIN
REGULATION BY IRON.
SO THIS IS A CLASSICAL ENDOCRINE
ME
MECHANISM WHERE A HORMONE
CONTROLS A SUBSTRATE AND
SUBSTRATE IN TURN CONTROLS THE
HORMONE.
SO IT'S A FEEDBACK MECHANISM.
THE SAME AS EXISTS FOR, FOR
EXAMPLE, INSULIN AND GLUCOSE.
AND IN CASE FOR HEPCIDIN, BOTH
PLASMA IRON, SO CIRCULATING IRON
AS WELL AS LIVER STORES CAN
CONTROL HEPCIDIN PRODUCTION.
THIS JUST ENSURES WHEN WE HAVE
ENOUGH IRON, HEPCIDIN IS GOING
TO BE INCREASED AND PREVENT
FURTHER ABSORPTION OF IRON.
AS COULD BE EXPECTED,
ERYTHROPOIESIS ALSO RELEASES A
FACTOR THAT CONTROLS HEPCIDIN,
BECAUSE IT IS SUCH AN
IRON-INTENSIVE PRO CYST THAT IT
NEEDS TO HAVE MEANS TO
COMMUNICATE WHEN IT NEEDS MORE
IRON TO PRODUCE MORE RED BLOOD
CELLS.
AND THE THIRD CIRCUITRILY TALK
ABOUT IS HEPCIDIN REGULATION BY
INFLAMMATION, AND THIS IS PART
OF HOST DEFENSE MECHANISM.
SO IF WE LOOK AT HEPCIDIN
REGULATION BY IRON AT A BASIC
PHYSIOLOGY, HERE'S AN EXAMPLE OF
A VOLUNTEER THAT INGESTED A
SINGLE IRON PILL AND WE LOOKED
AT A TIME COURSE OF SERUM
HEPCIDIN, INGESTED, INCREASES
RAPIDLY AND THEN IT STARTS
COMING DOWN, AND THE REASON WE
HAVE THIS RETURN OF SERUM IRON
TO BASELINE IS BECAUSE HEPCIDIN
IS INCREASED.
SO AS IRON STARTS INCREASING IN
CIRCULATION, THAT IS A STIMULUS
FOR HEPCIDIN TO ALSO INCREASE.
AS HEPCIDIN GOES UP, IT CAUSES
IRON TO START COMING DOWN AND
THEN HEPCIDIN CAN START COMING
DOWN TOO.
SO THIS IS THAT CLASSICAL
ENDOCRINE FEEDBACK MECHANISM
WHERE SUBSTRATE AND HORMONE
REGULATE EACH OTHER TO ENSURE
THAT SERUM IRON IS IN THE
HOMEOSTATIC RANGE, 10 TO 30
MICROMOLAR.
NOW, WHAT IS THE MOLECULAR
MECHANISM UNDERPINNING THIS?
THAT ACTUALLY HAS BEEN ONE OF
THE MOST DIFFICULT TOPICS IN THE
IRON FIELD AND IT HAS TAKEN 20
YEARS TO MAKE THIS SCHEMA.
SO IT TURNS OUT THAT AT THE
CENTER OF HEPCIDIN REGULATION BY
IRON IS THE BONE MORPHOGENETIC
PATHWAY.
THE SPECIFIC LIGANDS THAT
REGULAR HEPCIDIN -- 2 AND 6, AND
THEY BIND TO CERTAIN PROTEIN
RECEPTORS AND THERE IS ALSO A
CO-RECEPTOR AND THIS CORY CORE
RECEPTOR ENSURES THAT CERTAIN
LIGANDS AND CERTAIN RECEPTORS
ARE GOING TO COME TOGETHER.
SO -- THROUGH STIMULATING -- S
DESCRIPTION FACTORS INCREASE
HEPCIDIN TRANSCRIPTION.
RELATIVELY RECENT TWIST TO THE
STORY IS THAT THESE BMP LIGANDS
ACTUALLY ARE PRODUCED BY LIVER
SIGN
SINUSOIDAL -- IT'S ACTUALLY THE
ENDOTHELIUM.
NOW HOW DOES IRON SENSING COME
INTO THIS?
THERE IS AN INCREASE IN IRON
STORES, IT TURNS OUT THAT
ENDOTHELIUM PRODUCES MORE
BMPs, BMP2 AND 6, AND THAT POE
10 SHAITS PHOSPHORYLATION AND --
INCITING TRANSCRIPTION.
HOWEVER, WE DON'T YET KNOW
EXACTLY HOW THESE IRON STORES
ARE SENSED, WHAT IS THE IRON
FORM THAT IS BEING SENSED, IS IT
BEING SENSED IN HEPATOCYTES OR
ENDOTHELIAL CELLS, SO THIS IS
ALL BEING WORKED OUT AND IT ONE
OF THE MAJOR QUESTIONS IN THE
FIELD.
I ALSO MENTIONED PLASMA IRON CAN
REGULATE HELP SIGH DIN, THROUGH
TRANSPARENT RECEPTOR 1 AND 2.
1 IS THE CLASSICAL RECEPTOR THAT
TAKES UP IRON INTO EVERY CELL IN
THE BODY, AND IN HEPATOSITES,
TRANSPARENT RECEPTOR ONE REACTS
WITH HFE, WHICH IS THE MOLECULE
THAT'S THE MOST COMMON CAUSE OF
HEMA CHROMATOCYST IN HUMANS.
RECEPTOR 2 IS THE HOMOLOGUE OF
TRANSPARENT RECEPTOR 1 AND IT
DOESN'T PARTICIPATE IN TAKING UP
IRON, BUT RATHER PARTICIPATES IN
IRON SENSING.
SO WHAT HAPPENS WHEN -- BINDING
TO RECEPTOR 1 DISPLACES HFE, AND
HFE THEN INTERACTS WITH THE BONE
MORPHOGENETIC PROTEIN RECEPTORS.
BINDING STABILIZES THE PROTEIN
AND WE THINK IT MAY ALSO
INTERACT WITH PROTEIN RECEPTORS.
SO WHAT HAPPENS IS THAT
PROPORTIONAL TO THE PLASMA IRON,
THERE IS THE FORMATION OF THIS
SUPER COMPLEX AROUND -- PROTEIN
RECEPTORS WHICH THEN
POTENTIATES -- SIGNALING
AND -- -- INCREASE IN STORED
IRON AND INCREASE IN PLASMA IRON
LEADS TO POTENTIATION OF PROTEIN
SIGNALING WHICH THEN INKREASES
HEPCIDIN TRANSCRIPTION.
SO WHY ARE THESE DETAILS
RELEVANT?
WELL, THAT EXPLAINS PATHOGENESIS
OF HEREDITARY HEMOCHROMATOSIS OR
AS WE NOW LIKE TO CALL IT, JUST
HEMOCHROMATOSIS.
SO WHAT IS THE MOLECULAR BASIS?
IT IS THE MUTATIONS IN HFE, THIS
IS THE MOST COMMON FORM, MU
HUMAN RELATIONS IN TRANSPARENT
RECEPTOR TWO, RECENTLY IN
BMP6 WHERE HE DESCRIBED --
AND -- SO MUTATIONS IN ANY OF
THESE REGULATORS OF HEPCIDIN OR
HEPCIDIN ITSELF ARE RESPONSIBLE
FOR A MAJORITY OF THE FORMS OF
HEREDITARY HEMOCHROMATOSIS.
WHAT HAPPENS MOLECULARLY OR
PATHOPHYSIOLOGY IS THERE'S
SENSING OF IRON SO HEPCIDIN WILL
NOT BE APPROPRIATELY RESPONSIVE,
WHICH THEN LEADS TO IRON
OVERLOAD.
NOW, WHY IS IRON BAD, WHY IS TOO
MUCH IRON BAD?
WHEN THERE'S EXCESSIVE IRON AB
SORMINGS, PLASMA TRANS FERRIN
GETS -- AS I MENTIONED THAT'S A
SMALL COMPARTMENT SO THIS IS
VERY -- IF THERE'S EXCESSIVE --
WHAT HAPPENS IS THE NEW FORM OF
IRON APPEARS IN CIRCULATION,
WHICH WE REFER TO AS
NON-TRANSPARENT-BOUND IRON BUT
IT'S REALLY IRON BOUND TO SMALL
ORGANIC MOLECULES OR MAYBE
LOOSELY BOUND TO ALBUMEN.
SO WHEN THIS FORM APPEARS, THERE
WILL BE UP TAKE OF THAT
NON-TRANSFERIN LN -BOUND IRON, AND
THESE TRANSPORTERS USUALLY UNDER
PHYSIOLOGICAL CONDITIONS
TRANSPORT OTHER METALS BUT WHEN
THEY AREN'T PRESENT IN EXCESSIVE
AMOUNTS, THOSE TRANSPORTERS WILL
ALSO TAKE UP -- AND WILL LOAD
THESE ORGANS.
YOU CAN APPRECIATE IN LIVER AND
HEART IRON UPLOADING, HIGHLY
ABNORMAL.
ONCE THIS EXCESS FREE IRON IS
ACCUMULATED, IT WILL CATALYZE
GENERATION OF HARMFUL OXYGEN
RADICALS.
YOU CAN SEE THIS EXAMPLE OF
FENTON REACTION AND THEY WILL
NOW DAMAGE ALL OF THE VITAL CELL
STRUCTURES: DNA, RNA, PROTEINS,
CELL MEMBRANES.
SO THEN ON THE ORGANISMAL LEVEL,
YOU CAN -- MAY SUFFER SOME
DAMAGE, SO LIVER IS USUALLY THE
PRIMARY ORGAN THAT WILL GET
DAMAGED BECAUSE THAT IS THE ONE
THAT EXPRESSES MOST OF THESE
TRANSPORTERS AND WILL TAKE UP
MOST OF THE IRON.
AND SO THERE MAY BE HEPATIC FAY
BRO CYST AND IN SOME PATIENTS
DEVELOPMENT OF CIRRHOSIS AND
EVEN CANCER.
CARDIOMYOPATHY MAY OCCUR.
THERE COULD BE ANTERIOR
PITUITARY FAILURE, DIABETES,
HYPOGONADISM, ET CETERA.
SO ANY ORGAN THAT ENDS UP HAVING
EXCESSIVE IRON ACCUMULATION WILL
BE DAMAGED.
NOW WHICH ORGANS WILL ACCUMULATE
IT WILL DEPEND ON THE SEVERITY
OF IRON OVERLOADS.
AND HERE IS AN EXAMPLE OF THE
MOST SEVERE FORM OF
HEMOCHROMATOSIS, WHICH USED TO
BE CALLED JUVENILE
HEMOCHROMATOSIS.
IN THIS CASE, IT WAS A
25-YEAR-OLD MAN, HE PRESENTED
WITH ABDOMINAL PAIN,
HEPATOMEGALY, SYMPTOMS OF HEART
FAILURE, AND HEART BIOPSY WAS
PERFORMED AND THEN SOME -- CLOSE TO
100%, VERY HIGH FERRATIN, WHERE
NORMAL RANGE IS HERE.
HE HAD EVIDENCE OF DIABETES AND
LIVER DAMAGE.
AND UNFORTUNATELY, TWO DAYS
AFTER DIAGNOSIS, THE PATIENT
DIED FROM HEART FAILURE.
SO THIS SEVERE FORM OF
HEMOCHROMATOSIS CAN BE
ACTUALL LETHAL.
ON AUTOPSY, LARGE AMOUNTS OF
IRON IN THE HEART WERE FOUND,
THE LIVER, THE PANCREAS, LYMPH
NODES, TESTES, ADRENAL GLANDS,
AND NO MATURE SPERMS WERE
OBSERVED.
SO CLASSICAL HEMOCHROMATOSIS.
SO SPECIFIC, IN THIS SPECIFIC
PATIENT, HEMOJU VE LIN ENSURES
RECEPTORS WILL COME TOGETHER AND
IT'S ESSENTIAL FOR HEPCIDIN
PRODUCTION.
SO THEN TO SUMMARIZE THE
PATHOGENESIS OF HEMOCHROMATOSIS,
IT IS CAUSED BY MUTATIONS IN
HEPCIDIN REGULATORS OR HEPCIDIN
ITSELF LEADING TO HEPCIDIN
DEFICIENCY.
THERE IS A VARIETY OF DEGREES OF
HEPCIDIN DEFICIENCY.
THERE IS ABSOLUTE OR RELATIVE
HEPCIDIN DEFICIENCY, AND THE
SEVERITY OF DISEASE WILL DEPEND
ON THE SEVERITY OF HEPCIDIN
DEFICIENCY.
AND THAT UNLEASHES IRON FLOWS
INTO PLASMA.
I DIDN'T MENTION BUT AS YOU CAN
EXPECT, THERE CAN ALSO BE A FORM
OF HEMOCHROMATOSIS RESULTING
FROM MUTATIONS IN HEPCIDIN
RECEPTOR, SO THIS IS A RARE FORM
OF HEMOCHROMATOSIS, AND THE GAIN
OF FUNCTION MUTATIONS IN
FERROPORTIN THAT RESULT IN
RESISTANCE TO HEPCIDIN.
SO AGAIN, YOU CAN THINK OF THIS
AS AN EQUIVALENCE TO INSULIN AND
GLUCOSE SYSTEM, WHERE YOU CAN
HAVE INSULIN RESISTANCE OR
INSULIN DEFICIENCY RESULTING IN
DIABETES.
IT IS THE SAME THING IN HEMOCROW
SEW CYST, HEPCIDIN DEFICIENCY OR
RESISTANCE TO HEPCIDIN THAT
RESULTS IN HEMOCHROMATOSIS.
SO THE MAJORITY OF FORMS ARE
HELP SIGH
HEPCIDIN-DEFICIENT FORM,
CONSTANTLY INCREASED -- WHICH
WILL LEAD TO TOTAL BODY ON
OVERLOAD.
THERE IS SATURATION OF IRON PLAS
FER F. --
WILL LOAD THE LIVER, THE HEART
AND -- ET CETERA.
AND SO AS YOU CAN APPRECIATE
THEN, HEPCIDIN ITSELF COULD BE
USEFUL AS THERAPY IN
HEMOCHROMATOSIS SIMILAR TO HOW
INSULIN IS USED FOR DIABETES.
SO THAT WAS THE DISCUSSION ABOUT
HEPCIDIN REGULATION BY IRON.
AND
WHAT GOES WRONG IN THAT
CIRCUITRY.
NOW I'M GOING TO TALK ABOUT HELP
SIGH DIN REGULATION BY
ERYTHROPOIESIS AND DISEASES
ASSOCIATED WITH THAT CIRCUITRY.
ERYTHROPOIESIS ITSELF IS AN
INCREDIBLY INTENSE PROCESS.
IF YOU LOOK AT THE SHEER NUMBER
OF EE RIRT ROW SITINGS -- WE MAKE APPROXI MATELY
2.5 MILLION ERYTHROCYTES PER
SECOND, AND EACH OF THOSE NEEDS
OVER A BILLION ATOMS OF IRON TO
SYNTHESIZE HEMOGLOBIN.
SO INCREDIBLY INTENSE PROCESS,
AND YOU CAN APPRECIATE THAT IRON
SUPPLY HAS TO BE COORDINATED
WITH -- ACTIVITIMENT SO FOR THE
LAST 50 YEARS, IT HAS BEEN
ASSUMED AND ALSO DEMONSTRATED
INDIRECTLY THAT THERE IS -- BUT
WE HAVE RECENTLY DISCOVERED THE
REGULATOR OR A REGULATOR THAT
ENABLES COMMUNICATION BETWEEN
ERYTHROPOETIC ACTIVITY IN IRON.
PART OF THAT OF COURSE IS
REGULATION OF HEPCIDIN, SO
HEPCIDIN HAS TO BE SUPPRESSED TO
ALLOW MORE IRON TO BE AVAILABLE.
SO YOU CAN SEE HERE AFTER
PHLEBOTOMY OR EPO
ADMINISTRATION, HEPCIDIN IS
PROFOUNDLY SUPPRESSED RAPIDLY,
SO MORE THAN TENFOLD.
WHAT WE WANTED TO DO WAS TO
IDENTIFY A FACTOR THAT WOULD
HAVE THE -- WE ANALYZED BONE
MARROW IN THE MICE WHERE THIS
ADVANCED ACTIVITY IS OCCURRING
AND LOOK FOR SECRETED PROTEINS
THAT WILL HAVE PROFILES --
EXPRESSION PROFILES OPPOSITE OF
WHAT HAPPENS TO HEPCIDIN.
AND SURPRISINGLY, WE IDENTIFIED
ONLY ONE SECRETED PROTEIN THAT
FITS THIS DESCRIPTION, THIS
IDEA, AND WE EVENTUALLY NAMED IT
EE RIR ROW FAIR ON, BECAUSE IT'S
PRODUCED BY ERYTHROBLASTS, FERR
IS BECAUSE IT REGULATES IRON,
AND ONE BECAUSE IT'S A HORMONE.
SO WE CALL IT FOR SHORT -- IT'S
A MEMBER OF THIS LARGER GROUP OF
TNF-LIKE PROTEINS THAT'S ALSO A
MEMBER.
WE STILL DON'T UNDERSTAND THE
COMPONENTS OF THE STRUCTURE THAT
ARE IMPORTANT FOR ITS ACTIVITY
BUT WE DO KNOW THAT IT IS A
STRESS HORMONE.
ITS EXPRESS IS VERY LOW AT LACE
LINE BUT AFTER EE POE INJECTION,
THERE'S A HUGE INCREASE IN PRO
TUCKS OF ERYTHROFERRONE.
WHAT IT DOES IS ENABLE HEPCIDIN
SUPPRESSION.
SO HERE'S WILD TYPE MICE AFTER
PHLEBOTOMY, YOU CAN SEE THERE'S
A HUGE SUPPRESSION OF HEPCIDIN,
MORE THAN TENFOLD, BUT SO THE
CONSEQUENCE OF THIS AS FAR AS WE
KNOW SO FAR IS THAT IF -- THERE
IS NO HEPCIDIN REPRESSION AND
DELAYED RECOVERY OF ANEMIA.
THERE ARE OTHER WAYS FOR AN
ORGANISM TO RECOVER FROM ANEMIA,
SO EVENTUALLY THIS IMPAIRMENT IS
OVERCOME BUT THERE'S CERTAINLY A
DELAYED RECOVERY.
SO THIS WAS PROBABLY TO ENABLE
RAPID RECOVERY IN NOW, HOW DOES
ERFE ACT?
AGAIN IT TARGETS THIS PATHWAY,
SO ERFE IS ACTUALLY A TRAP FOR
BMPs, PARTICULARLY FOR 2 AND 6 BUT IT CAN ALSO BIND SOME
OTHER BMPs.
SO ONCE ERFE TRACKS THESE
BMPs, SMAD PHOSPHORYLATION IS
DECREASED AND TRANSCRIPTION IS
SUPPRESSED.
THAT IS THE WAY IT POTENTLY --
SO PHYSIOLOGICAL ROLE OF -- IS
TO ENABLE MORE IRON TO REACH THE
BONE MARROW AND IT'S PART OF
THIS NOW AS WE UNDERSTAND
THREE-HORMONE CIRCUITRY TO
RESPOND TO ANEMIA, OR AFTER
HEMORRHAGE.
SO IF THERE IS ANEMIA OR HIGH
POX YAM.
EPO IS THE THE MAIN STIMULUS
FOR -- IN THE LIVER TO DECREASE
HEPCIDIN PRODUCTION, AND THEN IN
TURN, ENABLES MORE IRON TO BE
AVAILABLE FOR ERYTHROPOIESIS.
TO ENSURE THAT BONE MARROW IS
GOING TO GET A SUFFICIENT AMOUNT
OF IRON.
BUT THERE IS THE DARK SIDE TO
THIS CIRCUITRY AS WELL, AND THAT
HAPPENS IN HEMOTBLOA HEMOGLOBINOPATHIES.
HERE'S, FOR EXAMPLE, A
PRESENTATION OF A PATIENT THAT
WAS IRON OVERLOADED BUT EVEN
WITHOUT TRANSFUSIONS, SO IT WAS
A 61-YEAR-OLD MAN.
HE HAD A DIAGNOSIS OF BETA
THALASSEMIA, BUT HE HAD THIS
MILD ELEVATION OF SERUM
TRANSAMINASES, BUT
INTERESTINGLY, WAS NOT
TRANSFUSED MUCH AT ALL, ONLY
3 UNITS OF PACKED RED BLOOD
CELLS, AND HE WAS MAINTAINING
HEMOGLOBIN IN A RANGE OF CLOSE
TO 10, BUT HE ACTUALLY WAS
IRON-OVERLOADED, HE HAD AN
ENLARGED LIVER, MRI SHOWED A
HIGH AMOUNT IN HIS LIVER AND HE
HAD NO OTHER CONFOUNDING FACTORS
THAT COULD EXPLAIN THIS IRON
OVERLOAD.
SO THESE PATIENTS, PATIENTS WITH
ANEMIA, SUCH AS BETA
THALASSEMIA, THEY DO DEVELOP
IRON OVERLOAD EVEN WHEN NOT
TRANSFUSED, BUT IF THEY'RE
TRANSFUSED, IRON OVERLOAD
WORSENS EVEN MORE.
SO DISEASES IN THIS CATEGORY
ANEMIA FROM INEFFECTIVE
ERYTHROPOIESIS ARE THALASSEMIA,
THE ONE THAT THE PATIENT HAD,
BUT THERE'S ALSO BETA
THALASSEMIA MAJOR OR TRANSFUSION
DEPENDENT BAY THAT THALASSEMIA.
OTHERS OTHER REALLY, THEY ALL
HYPERABSORB IRON IF THEY'RE NOT
TRANSFUSED, AND THEIR
PATHOGENESIS OF IRON OVERLOAD
PHENOCOPIES THAT HE HEREDITARY --
AND WE CALL THEM IRON LOADING
ANEMIAS.
THERE IS SUPPRESSION OF
HEPCIDIN, SO HEPCIDIN IS
RELATIVELY LOW CONSIDER THE
SEVERITY OF IRON OVERLOAD, AND
HEPCIDIN IS LOW BECAUSE OF
OVERPRODUCTION OF EE RIRT ROE
FERRONE, BY EXUBERANTLY
PROLIFERATING ERYTHROBLASTS AND
THAT IN TERMS -- YOUR HEALTHY
SUBJECTS HAVE VERY LOW LEVELS
OF -- THALASSEMIA HAS MUCH
HIGHER LEVELS OF EE ERYTHROFERRONE.
RIGHT BEFORE THE TRANSFUSION
CYCLE, THERE IS A MUCH HIGHER
CYCLE OF ERYTHROFERRON,, BUT
THEN TRANS FUSIONS WRM --
ERYTHROPOIESIS CAN SUPPRESS IT.
YOU CAN ALSO SEE -- WHEN
ERYTHROFAIRN IS HIGH, HEPCIDIN
WILL BE PROFOUNDLY SUPPRESSED.
SO THE WAY WE NOW UNDERSTAND
PATHOGENESIS OF IRON LOADING IN
THESE ANEMIAS IS THAT THERE IS
HIGH LEVEL OF EPO IN THESE
CONDITIONS WHICH STIMULATES THE
BONE MARROW, EXPANDS THE NUMBER
OF ERYTHROID PRECURSORS, AND
THEY PRODUCE VERY LARGE AMOUNT
OF ERYTHROFAIR OWN, HORMONE,
WHICH CAUSES HEPCIDIN
SUPPRESSION AND RELATIVE
HEPCIDIN DEFICIENCY, AND NOW IT
LOOKS THE SAME AS FOR
HEMOCHROMATOSIS.
THERE IS EXCESSIVE IRON FLOWS,
TRANS FERRIN GETS SATURATED,
NON- -- APPEARS AND THAT LOADS
LIVER, HEART AND THEN THE
PREGLANDS.
IT HAS BEEN SPECULATED NOW BEING
TRIED WHETHER WE CAN USE
HEPCIDIN AGONISTS TO CORRECT
THIS EFFICIENCY AND PREVENT IRON
OVERLOAD OR POTENTIALLY USE ER
IF E ANTAGONISTS, WHETHER THAT
COULD SER SERVE AS USEFUL THERAPY TO
PREVENT AN OVERLOAD.
THE LAST CIRCUITRY I WILL TALK
ABOUT IS HELP SEIDEN REGULATION
BY INFLAMMATION.
THIS IS VERY IMPORTANT FOR HOST
DEFENSE.
EARLY ON WE NOTICED IT IS
DRAMATICALLY -- HE WAS A SUBJECT
THAT HAD -- AND SEPSIS, MORE
THAN 100 FOLD ELEVATED, AND AS
THE PATIENT WAS TREATED WITH
ANTIBIOTICS, HEPCIDIN WENT DOWN
TO THE NORMAL RANGE.
WE CAN MODEL THIS IN MICE AS
WELL, AND WE HAVE SHOWN USING
MOUSE MODELS THAT INTERLEUKIN
6 IS THE CRITICAL MEDIATOR OF
THIS HEPCIDIN REGULATION BY
INFLAMMATION, SO IT'S REALLY A
TYPE 2 PHASE REACTANT.
HERE'S AN EXAMPLE OF A BACTERIAL
INFECTION.
WHEN WE LOOK AT WILD TYPE MICE,
THERE IS SEVERAL THOUSAND FOLD
INCREASE OF HEPCIDIN PRODUCTION
BUT NOT -- FOR THIS RESPONSE.
AND IT HAS BEEN SPECULATED ALSO
ALL ALONG THAT IN WOULD BE
IMPORTANT FOR INNATE IMMUNITY,
AND THEY HAD -- INFECTION PREND,
THAT WOULD INCREASE HEPCIDIN,
HELP SIGH BIN AGAINST
EXTRACELLULAR INFECTIONS BY
LIMITING EXTRACELLULAR IRON
AVAILABILITY AND THAT COULD BE
PACK TIER YOE STATIC POTENTIALLY
AND ALLOW THE REST OF THE IMMUNE
SYSTEM TO GET RID OF THE
PATHOGENS.
BUT AT THE SAME TIME, ONE COULD
SPECULATE THAT -- COULD
POTENTIALLY PROMOTE
INTERCELLULAR INFECTIONS WHICH
ARE COUNTERPRODUCTIVE, SO BY
TARGETING FERROPORTIN --
THEORETICALLY HIGH HEPCIDIN
COULD POTENTIATE GROWTH OF --
ORGANISMS.
THE ROLE IN INNATE HI MEUD IT.
WE DECIDED TO -- LOOKED AT THE
SPECTRUM OF PATHOGENS SO WE
LOOKED AT SOME CLASSICALLY
SIDEROPHILIC WHICH ARE KNOWN PO
EXPERIENCE IN OUR OVERLOADED
PATIENTS.
OVERLOADED, YOU CAN LOOK AT --
I'M JUST GOING TO BRIEFLY
SUMMARIZE, THERE WAS NO EFFECT
ON GRAM POSITIVE STEF LOW COCCUS
AUREUS OR MICRO BACK HERE YA
AND -- THAT IS NOT TO SAY THAT
THESE PATHOGENS DON'T NEED IRON.
ALL OF THE BACK FEAR YA USES
IRON, ET CETERA.
IT IS JUST THAT THE HOST
MANIPULATION -- LEVELS DO NOT
AFFECT THE VIRULENCE OF THESE
BACTERIA.
BUT, HEPCIDIN AND IRON VARIATION
VERY MUCH AFFECTED THE VIRULENCE
GROWTH OF GRAM-NEGATIVE
ORGANISMS AS WELL AS THE
SIDEROPHIRIC ONES WHICH ARE ALSO
GRAM-NEGATIVE.
SO WE ACTUALLY -- NATURALLY
UNLOADED AND WE LOOKED AT SIR
VIAL, AND REALLY THE DIFFERENCE
WAS DRAMATIC.
AS BIG A DIFFERENCE IN SURVIVAL
AS WE HAVE SEEN.
ALL OF THE WILD TYPE MICE IN
THESE MODELS, E. COLI, THEY ALL
FAIR BETTER, HAD MUCH -- THE
DEATH WAS EXTREMELY RAPID,
WITHIN HALF A DAY.
THIS BACK TIER YON REPLICATED
EVERY 10 MINUTES IN THE PRESENCE
OF EXCESS IRON.
SO FROM THIS PERSPECTIVE, EVEN
E. COLI AND KLEBSIELLA COULD BE
CONSIDERED SIDERO -- AND IN ALL
OF THESE INFECTIONS,
TREATMENT -- AGONISTS COMPLETELY
RESCUED MICE FROM MORTALITY.
SO IT IS ALL ABOUT EXTRACELLULAR
IRON AVAILABILITY THAT PROMOTES
RAPID GROWTH IN THESE PACKAGES.
AND THIS IS CONSISTENT WITH
CLINICAL OBSERVATIONS, SO HERE
IS AN EXAMPLE, A CASE REPORT OF
PREVIOUSLY HEALTHY 59-YEAR-OLD
WOMAN.
SHE ATE RAW SEAFOOD AT A
RESTAURANT.
AND THEN SHE DEVELOPED
INFECTION.
SHE WAS HOSPITALIZED, LEG WAS
AMPUTATED, SHE REQUIRED
OPERATIONS TO SAVE HER ARM.
YOU ACTUALLY HEAR THESE
ANECDOTAL STORIES ABOUT PEOPLE
WHO ATE RAW SEAFOOD AND DIED
RAPIDLY OR WERE FISHING OR
CRABBING AND THEN GOT SCRATCHED,
DEVELOPED A SEVERE INFECTION OR
HAD TATTOOS AND WENT SWIMMING
AND DEVELOPED SEVERE INFECTION.
IN THOSE DRAMATIC CASES AS WELL
AS IN THIS CASE, PATIENTS ARE
INFECTED WITH VIBRIO VULNIFICUS,
PRESENT IN WARM COASTAL WATERS
AND IS PRESENT IN RAW SEAFOOD.
THIS PATIENT UNBEKNOWNSTED TO
HER HAD HEMOCHROMATOSIS, AND
THIS BE UNFORTUNATELY HAS VERY
HIGH MORTALITY.
NOW WHAT IS THE MECHANISM BY
WHICH HEPCIDIN PROTECTS AGAINST
INFECTION?
WE HAVE LOOKED AT MULTIPLE
POINTS, WE WANTED TO SEE IF IT
AFFECTS INITIALLY INNATE IMMUNE
RESPONSE, HEPCIDIN DID NOT
AFFECT THAT.
IT DID NOT EXERT DIRECT
ANTIMICROBIAL ACTIVITY EITHER
AND IT PURELY FUNCTIONS BY
CONTROLLING IERNL CONCENTRATIONS
IN CIRCULATION.
SO EVEN WHEN WE TAKE HELP SIGH
DIB KNOCKOUT MICE, IF WE IRON
DEPLETE THEM, TO PREVENT PREBS
PRESENCE OF THIS -- IT'S ALL
ABOUT CIRCULATING IRON IN TBRAM
GRAM-NEGATIVE INFECTIONS.
BUT WHAT WAS SURPRISING US IS
WHY WOULD IT MAKE SUCH A
DIFFERENCE WHETHER IRON TRANS
FERRIN LEVELS ARE DIFFERENT?
IN HEALTHY SUBJECTS, IRON IS
BOUND TO TRANS FERRIN, IT HAS
EXTREMELY -- TO MOST MICROBES
EXCEPT FOR THE ONES THAT
ACTUALLY HAVE RECEPTORS FOR
TRANS FAIRN.
WE KNOW THERE'S
NON-TRANSFERRIN-BOUND IRON AND
THAT IRON IS PRESENT WHEN
TRANSFERRIN IS THE RANGE OF
MOTION EXCEEDS MAYBE 70 TO 80%.
HERE ARE A NUMBER OF CONDITIONS,
WHAT HAPPENS, AFTER TRANSFUSION,
HEMOLYSIS OR BONE MARROW LESION.
THIS ONE COULD BE EASILY
ACCESSIBLE TO MICROBES, SO WE
WANTED TO SEE WHICH OF THESE
FORMS ENHANCES GROWTH OF THE
PATHOGENS.
AND TURNS OUT IT IS THIS
NON-TRANSPARENT -- IRON.
WHEN WE DID EX VIVO EXPERIMENTS
WHERE WE SUPPLEMENTED HUMAN
PLASMA WITH INCREASING
CONCENTRATIONS OF IRON, WE
MANAGED TO GRADUALLY SATURATE
TRANSFERRIN, AND THEN WE WOULD
EITHER NOT HAVE NTBI PRESENT.
FOR EXAMPLE, WHEN WE LOOKED
AT -- IN THE ABSENCE OF
NON-TRANSFERRIN-BOUND IRON,
THERE'S NO -- REALLY RAPID
GROWTH BUT NOT -- ON PRESENCE.
IF WE ADD THE SAME AMOUNT OF
IRON IN THE FORM OF
HOLOTRANSFERRIN, IT DOES NOT
GROW AT ALL.
SIMILARLY, HERE IS INCREASING
PLASMA IRON LEVELS BEFORE
NON-TRANSFERRIN, IT GROWS
RAPIDLY ONLY IN THE PRESENCE OF
NON-TRANS FAIRNT -- THE WAY WE
NOW UNDERSTAND THE FUNCTION OF
HEPCIDIN IN INNATE IMMUNITY IS
THAT DURING INFECTION, THERE IS
INCREASED RISK OF GENERATING
THIS NON- -- FOR TWO REASONS.
ONE, MACROPHAGES ARE
PHAGOCYTOSING ERYTHROCYTES -- SO
THERE'S POTENTIAL FOR INCREASED
OUR DELIVERY TO PLASMA FROM
THESE MACROPHAGES.
BUTST RESULTING IN BACKING UP OF
IRON IN PLASMA.
SO WHEN HEPCIDIN IS INDUCED
EARLY IN INFECTION, YOU WILL
KEEP ON TSH IT LANDLORD NOT
APPEAR FOR INCREASED TRANSPARENT
SITUATION.
AND WE ACTUALLY DID SEE THIS IN
MOUSE MODELS, THAT THAT IS
EXACTLY WHAT HEPCIDIN DOES.
IF WE LOOK AT WILD TYPE MICE WHO
HAVE SEVERE INFLAMMATION, YOU
CAN SEE THIS IS MY SERUM IRON
BEFORE INFLAMMATION, THIS IS
AFTER INFLAMMATION.
YOU CAN APPRECIATE IF THERE IS
HYPOTHEIR EMIA, BUT IF WE LOOK
AT HEPCIDIN KNOCKOUT MICE BEFORE
AND AFTER INFLAMMATION, THERE IS
AN INCREASE IN IRON RELEASE INTO
CIRCULATION.
SO INDEED, HEPCIDIN IS THE
FACTOR THAT PREVENTS THIS
EXCESSIVE IRON RELEASE INTO
CIRCULATION.
SO TO THE BEST OF OUR KNOWLEDGE,
THE ROLE OF HELP SIGH BIN IN
INNATE IMMUNITY IS TO BLOCK
PRODUCTION OF THIS TRANS -- IRON
AND DEPENDS ON GROWTH OF THAT
FORM OF IRON.
BUT DISEASES THAT ARE ASSOCIATED
WITH INCREASED PRODUCTION OR
PRESENCE OF NON- -- FUN DPAL FUNGAL
INFORECASTS AND THOSE PRESENT AS
IMPAIRED HEPCIDIN PRO DUCK, SO
HEMOCHROMATOSIS, DIFFERENT IRON
LOADING ANEMIAS, CHRONIC LIVER
DISEASE WHERE HEPCIDIN
PRODUCTION IS ALSO IMPAIRED.
OR THESE CONDITIONS ARE
ASSOCIATED WITH DECREASED IRON
CONSUMPTION BECAUSE OF IMPAIRED
ERYTHROPOIESIS, SO THAT WILL BE
AFTER CHEMOTHERAPY, WHEN
ERYTHROPOIESIS IS SUPPRESSED,
IRON WILL BACK UP IN
CIRCULATION, AND THERE'S INDEED
HIGH RISK OF GRAM-NEGATIVE
SEPSIS WHEN IT'S PRESENT.
ALSO AFTER BONE MARROW ABLATION,
THERE'S HIGHER RISK OF INVASIVE
FUNGAL INFECTION, ASPERGILLUS
CAN USE -- AND RABDLY INCREASE
ITS GROWTH.
AND ALSO THERE IS RISK WITH
EXOGENOUS -- WITH TRANSFUSION.
SO I MENTIONED THAT HEPCIDIN IS
AN ESSENTIAL COMPONENT OF HOST
DEFENSE, BUT TO CONTROL THIS
IRON AVAILABILITY PATHOGENS, BUT
THERE IS A DOWNSIDE TO IT.
WHEN WE HAVE A PRESENCE OF
INFLAMMATORY DISORDERS, THIS
MECHANISM BECOMES MALADAPTIVE.
THIS IRON RESTRICTION THEN CAN
CONTRIBUTE TO ANEMIA -- A
DEVELOP.
ANEMIA OF INFLAMMATION.
IRON RESTRICTION IS ONLY ONE
COMPONENT.
DIRECT EFFECT ON REDUCING RED
BLOOD CELL LIFESPAN IS ANOTHER,
DECREASED EPO PRODUCTION IN THE
KIDNEYS AND SUPPRESSING
ERYTHROID DIFFERENTIATION, BUT
IRON RESTRICTION IS A MAJOR
CONTRIBUTOR.
THIS IS OF COURSE MEDIATED BY
HELP
HEPCIDIN EXCESS.
THIS WAS SHOWN IN CHRONIC KIDNEY
DISEASE, IN MANY IB FLAM INFLAMMATORY
DISORDERS FROM AUTOIMMUNE
DISEASES, INFECTIONS, CRITICAL
CARE PATIENTS, BURN PATIENTS HAD
EXTREMELY HIGH LEVELS.
EVEN MODERATE ELEVATION WAS
OBSERVED IN OBESITY.
AND THEN MULTIPLE FORMS OF
CANCER HAVE ELEVATED HEPCIDIN,
AND ALL OF THESE PATIENTS ARE AT
HIGH RISK OF DEVELOPING ANEMIA
OF INFLAMMATION.
AND YOU CAN APPRECIATE HERE THAT
IN COMPARISON TO -- THIS
SELECTION OF PATIENTS HAD MUCH
ELEVATED HEPCIDIN LEVELS.
SO THE WAY HIGH HEPCIDIN
CONTRIBUTES, THERE IS INCREASED
HEPCIDIN PRODUCTION BY IL-6
PRIMARILY WHICH TARGETS
FERROPORTIN.
NOW IRON FLOWS ARE RESTRICTED,
THIS PLASMA COMPARTMENT GETS
RAPIDLY DEPLETED SO HYPOFAIR
EMIA RESULTS AND AS THERE'S
CHRONIC HYPOFERREMIA, THAT
EVENTUALLY LEADS TO -- AND OR
HYPOTHERAPY -- IS BLOCKING -- AN
TAG NIGMS COULD BE USED FOR
TREATMENT OF ANEMIA AND
INFRAMATION.
SO
INFLAMMATION.
SO TO SUMMARIZE WHAT I TOLD YOU
ABOUT ADVANCES MADE IN THE LAST
TWO AT THE CADE ABOUT SYSTEMIC
IRON REGULATION IS THAT IT IS
MEDIATED BY THE INTERACTION
BETWEEN HEPCIDIN, ITS RECEPTOR
FERROPORTIN TO CONTROL IRON
DELIVERY TO BLOOD PLASMA.
NOW WE CAN EXPLAIN IRON OVERLOAD
SITUATIONS WHICH RESULTS FROM JE
DME TICK HEPCIDIN REFRISCH SEE,
WHERE EXCESSIVE INTERFERON HAS
GENERATED.
FOR IRON RESTRICTED CONDITIONS,
WE NOW KNOW THAT IRON
RESTRICTION IS ANEMIA PARTIALLY
CALLED BY INFLAMMATORY --
HEPCIDIN IS IMPORTANT FOR
RESISTANCE TO CERTAIN PART JENS
AND SO CERTAIN
PATHOGENS -- GRAM NEGATIVES.
THE CLINICAL -- IT CAN BE
TARGETED FOR DRUG LEADS AND A
NUMBER OF POTENTIAL THERAPEUTICS
ARE UNDER DEVELOPMENT AND ARE IN
PHASE 2 TRIALS.
SO THANK YOU VERY MUCH.
THIS IS THE UCLA CENTER FOR IRON
DISORDERS AND ALL MY COLLEAGUES
WHO ARE INVOLVED IN THIS WORK.
SO THANK YOU.
>> THANK YOU.
THERE ARE SEVERAL QUESTIONS THAT
HAVE BEEN SUBMITTED, AS WELL AS
I HAVE A FEW QUESTIONS.
LET ME BEGIN BY ASKING, YOU
ALLUDED TO HEPCIDIN AGONISTS AND
ANTAGONISTS.
CAN HEPCIDIN ITSELF OR A
SYNTHETIC PEPTIDE SIMILAR TO BE
USED THERAPEUTICALLY AS SUCH?
>> YES.
>> DOES IT -- ARE THE
PHARMACOKINETICS ADEQUATE FOR
UTILIZATION?
>> SO A DRUG -- SO THERE ARE
MULTIPLE FORMS OF HEPCIDIN
AGONISM, AND THEY SPAN FROM FULL
LINK HEPCIDIN TO SLIGHTLY
SMALLER HEPCIDIN TO MINI
HEPCIDIN, WHICH IS A SMALL
PEPTIDE, TO SORT OF A MICRO
HEPCIDIN WHICH IS JUST A SMALL
MOLECULE.
SO EVERYTHING EXISTS IN THE
PIPELINE FROM SMALL TO FULL
LENGTH HEPCIDIN, AND THE
CONSIDERATION IS, WILL THAT BE
RAPID CLEAR THAT IT HAS TO BE
INJECTED CONTINUOUSLY.
SO THE MINI AND MIDI HEPCIDINS
HAVE BEEN ENGINEERED IN SUCH A
WAY THAT THEY CAN PERSIST LONGER
IN CIRCULATION.
EVEN FULL LENGTH HEPCIDIN SEEMS
TO HAVE BEEN FORMULATED IN SUCH
A WAY THAT IT CAN LAST A LITTLE
BIT LONGER.
SO IN THIS CASE, FORMULATION
ACTUALLY HELPS TO PROLONG ITS
PRESENCE IN CIRCULATION.
AND THEN THE SMALL MOLECULES GET
TAKEN RAPIDLY.
SO MULTIPLE APPROACHES HAVE BEEN
TAKEN.
SO FAR ONLY SMALL MOLECULES ARE
CURRENTLY AVAILABLE BUT --
OTHERWISE THEY'RE BEING INJECTED
SUBCUTANEOUSLY AND ARE IN
CLINICAL TRIALS.
>> THANK YOU.
LET ME ASK ONE FURTHER QUESTION.
YOU MENTIONED THAT INEFFECTIVE
ERYTHROPOIESIS CAUSES EXCESS
ERYTHROFERRONE.
HOW IS ERYTHROFERRONE PRODUCTION
LINKED TO ERYTHROPOIESIS, PER
SE, OR INEFFECTIVE
ERYTHROPOIESIS IN PARTICULAR?
>> SO THE CELLS THAT PRODUCE EE
RIR ROW FERRONE ARE PRECURSORS
AND THEY'RE VERY EXPANDED.
IT'S THE BODY'S ATTEMPT TO MAKE
MORE RED BLOOD CELLS BUT IT'S A
FUTILE ATTEMPT.
SO THE PRECURSORS ARE EXPANDED
WITH THE VERY CELLS THAT PRODUCE
ERYTHROFERRONE.
IN ADDITION TO THAT, THOSE CELLS
ARE STIMULATED BY EWO, AND EWO
IS HIGH, BECAUSE THE PATIENTS
ARE -- PLUS LARGER NUMBER OF
CELLS THAT PRODUCE ERFE BOTH
CONTRIBUTE TO HIGH LEVELS IN
INEFFECTIVE --
>> THANK YOU.
DR. EPSTEIN ASKED, IS THERE ANY
EVIDENCE THAT -- LESIONS IN
TUBERCULOSIS OR SARCOIDOSIS ARE
RELATED TO IERP LEVELS IN IRON LEVELS IN THE
MACROPHAGES OR OTHER
INFLAMMATORY CELLS?
HAS THAT BEEN STUDIED?
>> THERE HAS BEEN A SPECULATION
THAT INTRACELLULAR IRON WILL
PLAY A ROLE.
HOWEVER, WHEN WE MANIPULATED
IRON, EITHER MADE HIGHER IERNL
IN MACROPHAGES OR MADE LOWER
IRON IN MACROPHAGES,
MANIPULATING IRON LEVELS IN
MACROPHAGES DID NOT AFFECT IN
ANY WAY THE GROWTH OF MTB, AND
IT WAS NOT DONE JUST BY US,
ANOTHER LAB AT OXFORD DID THE
SAME THING.
SO MANIPULATING MACROPHAGE IRON
LEVELS DID NOT CHANGE THE GROWTH
RATE OF MTB, BUT MTB DOES NEED
IRON.
IT'S JUST THAT BECAUSE IT'S SO
SLOW GROWING, IT CAN OBTAIN
WHATEVER RNA NEEDS INITY SLOW
MANNER, SO CHANGING -- LEVELNOT
HAVE AN EFFECT.
BUT A LITTLE BIT OF IRON IS
NECESSARY AND IT SEEMS THAT THE
PATHOGEN IS ABLE TO OBTAIN IT
AND BECAUSE IT'S GROWING SO
SLOWLY, IT JUST DOESN'T NEED AS
MUCH AS ONCE.
>> THANK YOU.
BEFORE I CONTINUE WITH THE
QUESTIONS, LET ME -- ONE
LISTENER ASKED FOR THE CME
NUMBER.
LET ME JUST GIVE THAT AGAIN.
36712, FOR THOSE WHO NEED THAT
NUMBER.
DR. THIEN ASKS IF YOU COULD
DESCRIBE HOW THE MUTATIONS IN
PIEZ01 AFFECTS IRON LEVELS IN
MACROPHAGES.
I'M NOT QUITE SURE WHY FOCUSING
ON THAT, BUT SHE ASKED ABOUT
THAT RELATIONSHIP.
>> SO PIEZ01 WAS ACTUALLY THE
MOLECULE MOST RECENTLY THE
FEATURE OF -- IT'S DN IT HAPPEN
TO BE -- GAIN OF FUNCTION
MUTATION END UP WITH HIGHER IRON
LEVELS.
WE'RE NOT QUITE SURE WHAT THE
ACTUAL ROLE OF PIEZ01 IS, BUT IT
VERY POSSIBLE THAT FOR CELLS
SUCH AT MACROPHAGES THAT HAVE A
LOT OF MECHANICAL DISTORTION,
FOR EXAMPLE, RELATED TODAY
ERYTHROPHAGOCYTOSIS, THERE IS A
LOT OF CHANGING IN MECHANICAL
TENSION, THAT SOMEHOW IT SENSES
THAT.
AND THERE'S AN ALTERATION OF
IRON HOMEOSTASIS, THERE IS MORE
IRON BEING RETAINED WITHIN
MACROPHAGES.
WHAT IS INTERESTING ABOUT THAT,
ONE IS THERE IS A DISEASE THAT
RESULTS FROM GAIN OF FUNCTION
MUTATIONS IN PIEZ01, ALSO
ASSOCIATED WITH IRON OVERLOAD,
BUT ALSO THERE IS A HIGH
PREVALENCE OF POLYMORPHISM IN
AFRICAN POPULATION IN PIEZ01,
THAT SEEMS LIKELY SOMEWHAT
PROTECTIVE AGAINST MALARIA BUT
UNFORTUNATELY RESULTS IN HIGHER
IRON LOAD IN THESE PATIENTS.
>> THANK YOU.
DR. CARRINGTON ASKS, COULD
DYSREGULATION OF HEPCIDIN IMPACT
THE RESPONSE TO IMMUNE
CHECKPOINT THERAPY OF CANCER?
>> I DON'T KNOW EXACTLY YET, BUT
WHAT WE DO KNOW IS THAT IRON
RESTRICTION DOES AFFECT B AND
T-CELL CLONAL EXPANSION AND
ADAPTIVE IMMUNE RESPONSE.
SO WHEN CELLS HAVE TO BE RAPIDLY
EXPAND, SUCH AND B AND T-CELLS,
THEY ABSOLUTELY NEED A LOT OF
IRON IN ORDER TO EXPAND.
IT HAS BEEN SHOWN THAT WHEN
HEPCIDIN IS ELEVATED AND CAUSES
IRON RESTRICTION, THAT WILL
IMPAIR THE T AND B CELL CLONAL
INFECTION.
SO ADAPTIVE IMMUNITY, BUT
NOTHING HAS BEEN STUDIED
YESTERDAY .
>> DR. THIEN, THE REASON FOR HER
QUESTION, THE PIEZ01 MUTATION IS
APPARENTLY FOUND IN ABOUT 30% OF
SICKLE CELL PATIENTS.
WHICH I DID NOT KNOW.
>> THAT COULD BE BECAUSE OF THE
CONNECTION TO AFRICA.
SO PROBABLY EVOLUTIONARILY, IT
WAS FOR PROTECTION OF MALARIA.
INTERESTINGLY, PIEZO1 -- HOLE
THE WHOLE PATHOLOGY NEEDS TO
COME TOGETHER STILL WILL BE
EXPLORED IN MORE DETAIL.
>> I THINK WE HAVE TIME FOR
PERHAPS ONE MORE QUESTION.
DR. PORCHENKO ASKS WHAT IS THE
ROLE OF HEPCIDIN PRODUCED BY
NON-HEPATIC CELLS LIKE
MACROPHAGES?
>> THERE ARE LOCAL CELLS THAT.
IT'S NOW BECOMING APPARENT THAT
THEY DO CONTRIBUTE TO SOME
IMPORTANT FUNCTIONS LOCALLY.
SO FOR EXAMPLE, THE BEST
DESCRIBED ONE IS PRODUCTION OF
HEPCIDIN BY CARDIOMYOCYTES IN
THE HEART, WHERE IT CAN CONTROL
LOCAL CARDIOMYOSIDE IRON LEVELS,
AND IF YOU KNOCK OUT EITHER THAT
OR HEPCIDIN RECEPTOR IN THE
HEART, IT COMPLETELY IMPAIRED
MAINTENANCE OF CARDIAC
HOMEOSTASIS AND ACTUALLY CAN
CAUSE LETHALITY IN MICE.
HEPCIDIN IS ALSO EXPRESSED IN
MACROPHAGES.
JUST TO WHICH EXTENT THAT
CONTRIBUTES TO LET'S SAY CONTROL
THE INFECTION HAS NOT BEEN QUITE
CLARIFIED.
SYSTEMATIC DECEPTION OF HIGH --
NEEDS TO BE DONE TO COMPLETELY
UNDERSTAND THE CONTRIBUTION, BUT
I'M PRETTY SURE THAT SOME LOCAL
CONTROL WILL BE NECESSARY.
THERE IS ALSO PRODUCTION OF
LOCAL HEPCIDIN BY DENDRITIC
CELLS IN THE GUT, AND THAT WAS
JUST -- THE SUSCEPTIBILITY TO
INFLAMMATORY BOWEL DESEIZE,
WHETHER OR NOT IT'S PRESENT IN
CELLS.
>> THANK YOU INVESTMENT THE 1:00 HOUR HAS JUST STRUCK AND I,
AT LEAST IN THE EAST, A LITTLE
EARLIER FOR YOU.
BUT ON BEHALF OF THE COMMITTEE
AND OF NIH AS A WHOLE, I'D LIKE
TO THANK YOU VERY MUCH FOR THIS
SUPERB TALK AND CLARIFYING AT
LEAST FOR SEVERAL HOURS IN MY
MIND THE COMPLEX INTERACTIONS
BETWEEN THESE FACTORS, I HOPE
THERE ARE NO MORE FACTORS
DISCOVERED, BUT IT DELIGHTFUL AS
MY WIFE INDICATED TO UNDERSTAND
SO MUCH NOW COMPARED TO THE
UNCERTAINTY THAT PERMEATED ALL
OF SO-CALLED BENIGN HEMATOLOGY
FOR THE PREVIOUS 50 YEARS.
THANK YOU VERY MUCH.
>> THANK YOU VERY MUCH.
IT WAS A PLEASURE TO
PARTICIPATE, AND THANK YOU FOR
INVITING ME.
>> GOOD DAY.
>> BYE.