IT'S MY GREAT PLEASURE TO
INTRODUCE THE BEAUTIFUL LECTURE
TODAY.
FOR THOSE OF YOU MAYBE YOUNGER
GENERATION, NIH COMMUNITY, AT
NIH 45 YEARS, HIS CONTRIBUTION,
BILL WAS TRAINED AT NYU, MOVED
IN THE '70s HERE TO START HIS
OWN LAB, HEADING THE LABORATORY
FOR MANY YEARS.
OF COURSE HE'S REMEMBERED FOR
MANY, MANY, MANY SEMINAL
CONTRIBUTIONS IN NATION,
ESPECIALLY DISCOVERY OF IL-4,
ENTER PLAY BETWEEN T CELLS, B
CELLS, MAST CELLS, YOU NAME IT.
AND I WAS STRIKED TO SEE THE
FIRST PAPER, 1982,
IDENTIFICATION OF T CELL DERIVED
B CELL GROWTH FACTORS, DISTINCT
FROM IL-2.
AT THAT TIME WE DIDN'T CALL IT
IL-4 YET, BUT IT WAS CLEARLY
SOMETHING SEMINAL.
OF COURSE, BILL WAS SO CREATIVE,
FUNDAMENTAL IMMUNOLOGY, THE
GIGANTIC BOOK ON OUR DESKS,
FIRST EDITION 1984, AND ONE OF
THE EDITIONS HE REPORTS AT THAT
TIME WANTED TO ACKNOWLEDGE
EXPLOSION OF FIELD OF
IMMUNOLOGY, CONSOLIDATE THE
KNOWLEDGE IN THE FIELD.
1984, 800 PAGES, THOUGHT THAT
WOULD BE ENOUGH, RIGHT?
SO MOVE FORWARD, 2022, THE
EIGHTH EDITION OF FUNDAMENTAL
IMMUNOLOGY, NOW 1800.
WE'RE STILL IN EXPLOSIVE GROWTH
OF THE FIELD AND STILL NEED TO
CONSOLIDATE AND IT'S GREAT THAT
THE NAME OF BILL IS STILL IN THE
BIBLE OF THE FIELD.
BILL MOVED FROM THE FUNDAMENTAL
IMMUNOLOGY, BASIC IMMUNOLOGY TO
MORE CLINICAL.
OF COURSE, HE MANAGED THE OFFICE
OF AIDS RESEARCH IN THE '90s
WHEN A LOT OF THERAPIES WERE
BEING DEVELOPED.
ALSO FOUNDED THE VACCINE
RESEARCH CENTER, CONTRIBUTION
FOR PUBLIC HEALTH.
BILL WAS A MENTOR TO MANY, MANY,
MANY GREAT SCIENTISTS, TO NAME A
FEW TO INSPIRE PEOPLE, MAUREEN
HOWARD, FIRST AUTHOR.
MELISSA BROWN, BOB, MATT DAVIS,
AND MANY OTHERS.
MORE PERSONAL LIVE, I WAS NOT A
MENTEE PER SE BUT I JOINED RON
GERMAIN'S LAB IN 2000, MY DESK
WAY AS CROSS THE STORE FROM
BILL'S OFFICE.
I I WOULD BUMP INTO HIM AND
BENEFIT FROM HIS WISDOM AND
KINDNESS, AND HIS ABILITY TO
DISCUSS, I'M A THEORETICAL
PHYSICIST BY TRAINING, BILL
WOULD LISTEN TO MY CRAZY IDEAS,
WHAT WE'RE TRYING TO PUSH
FORWARD WITH RON, ASKING PROBING
QUESTIONS IN A KIND WAY, TELLING
ME LIKE, NO, CALM DOWN.
[LAUGHTER]
TRY TO LOOK AT THIS, SO ON AND
SO FORTH.
ESPECIALLY AT THIS TIME A LOT OF
DISCUSSION, AND BILL KEPT
HELPING ME EVEN WHEN I MOVED TO
SLOAN-KETTERING PUSHED ME TO DO
INFLAMMATORY WORK, IT WAS GREAT.
FOR THE YOUNG GENERATION, THE
LABORATORY OF IMMUNOLOGY AT THAT
TIME, SEMINAL SERIES, YOU HAD
RON AND BILL, A BIT
INTIMIDATING.
TO ME REMINDS ME OF LAW AND
ORDER, A GOOD COP AND BAD COP.
I'LL LET YOU GUESS WHO THE BAD
COP IS.
RON.
[LAUGHTER]
BILL'S MEMORY SHINES OVER ALL OF
US.
WE HOPE WE'RE FOLLOWING IN HIS
FOOTSTEPS, GREAT SCIENCE, THAT'S
WHAT WE'RE GOING TO DO TODAY SO
I'LL MOVE TO INTRODUCE RUSLAN
MEDZHITOV, SPEAKER FOR TODAY.
WE GREATLY APPRECIATE THAT YOU
ANSWERED THE INVITATION TO
DELIVER THIS LECTURE.
EVERY YEAR WHEN IMMUNOLOGY
INTEREST GROUP STARTS NOMINATING
PEOPLE FOR AWARDS OF BEAUTIFUL
LECTURE, WE CANNOT INVITE RUSLAN
EVERY MONTH, WE HAVE TO WAIT.
HE DELIVERED A LECTURE A FEW
YEARS AGO, SO WELCOME BACK.
TO INTRODUCE RUSLAN, TRAINED IN
BIOCHEMISTRY IN MOSCOW,
EVOLUTIONARY BIOLOGY.
THEN MOST IMPORTANTLY RUSLAN
MOVED IN 1994, IN THE LAB OF
CHARLES JANEWAY, NO PRESSURE ON
THE TRAINEES BUT I THINK RUSLAN
FIRST AUTHOR PAPER WAS A
BOMBSHELL FOR THE FIELD.
RUSLAN AND CHARLIE FIRST
REPORTED CLONING OF HUMAN
HOMOLOG OF TLR FLY RECEPTORS
IDENTIFIED AS KEY RECEPTORS TO
BUILT INNATE RESPONSE.
AGAIN, 1994.
THERE HAD BEEN SOME STATEMENT,
WE NEEDED SOMETHING TO REALLY
ACTIVATE THE IMMUNE SYSTEM, AND
THIS PAPER WAS ABSOLUTELY
REVOLUTIONIZED THE FIELD, THE
REST IS HISTORY.
NO PRESSURE ON TRAINEES, BUT TRY
TO FOLLOW UP ON THAT.
[LAUGHTER]
RUSLAN OF COURSE DIDN'T STOP
THERE, WENT ON TO MAKE
DISCOVERY, INFLAMMATION,
PROCESSING, INNATE SYSTEM SPEAK
WITH IMMUNE RESPONSE, AND SILVER
LINING OF ALL OF RUSLAN'S PAPER
FROM PERSONAL LEVEL IS THAT
SOMETIMES A BIT LIGHT ON DATA,
AGAIN GREAT, BUT CONCEPT IS VERY
CLEAR AND VERY CHALLENGING,
BETTER TO MAKE A POINT CLEARLY
WITH FEWER DATA, THE RATIO OF
IDEAS TO DATA IS IN THE RIGHT
PLACE.
ONE OF MY FAVORITE PAPERS FROM
2012, I THINK WE HAVE THE
ROADMAP FOR MANY YEARS TO TRY TO
UNDERSTAND IMMUNOLOGY, AGAIN
VERY BROAD VISTA, A LOT OF
PEOPLE IN THE FIELD.
AND I THINK IT'S A VERY GOOD
SETTING TO HAVE RUSLAN DELIVER
THE LECTURE TODAY BECAUSE IT'S A
GLOBAL VIEW OF IMMUNOLOGY WHICH
IS GREAT.
CME LECTURE, THE CODE ON THE
SCREEN, 57689, FOR PEOPLE ONLINE
IF YOU WANT TO ASK QUESTIONS
PLEASE DO TYPE YOUR QUESTIONS IN
LIVE FEEDBACK AND WE'LL TYPE IN
THE QUESTIONS AT THE END OF THE
SEMINAR.
AGAIN, GREAT TO HAVE RUSLAN
HERE.
THE FLOOR IS YOURS.
[APPLAUSE]
>> THANK YOU FOR THE
INTRODUCTION.
THANK YOU FOR INVITING ME.
IT'S A GREAT HONOR TO GIVE THE
LECTURE.
VERY SIMILAR KIND OF MEMORIES OF
BILL BEING THIS NICE GOOD COP,
KIND, WITH A LOT OF WISDOM.
HE WAS REALLY MONUMENTAL FIGURE
IN IMMUNOLOGY.
SO, I HAVE TO EXPLAIN THE TITLE,
WHICH IS SCHIZOPHRENIC.
THE REASON FOR THAT IS THAT WHEN
I WAS ASKED TO GIVE A TITLE, AS
IT HAPPENS YOU FORGET TO
RESPOND, FORGET TO RESPOND,
THERE'S E-MAIL NEEDED TODAY, I
PANICKED AND SENT THIS, JUST
POPPED IN MY HEAD.
I HAD SOME THOUGHT RELATED TO
THAT BUT WHEN ASKED TO SEND
ABSTRACT, WHAT I WAS LEARNING,
OBJECTIVES OR SOMETHING, I
FORGOT WHAT I SENT AND I THOUGHT
--
[LAUGHTER]
WELL, BILL PAUL LECTURE, I
THOUGHT TALK ABOUT ALLERGY, IT'S
HIS FIELD, I SENT THE ABSTRACT.
THIS MORNING WAS TRYING TO
FIGURE OUT HOW DO I GET OUT OF
IT.
[LAUGHTER]
AND I CAN'T.
SO IT WILL BE ABOUT ALLERGY BUT
IT'S NOT GOING TO BE THE TALK
ABOUT IMMUNOLOGY FROM FIRST
PRINCIPLES BUT I WILL TRY TO
CONNECT IT TO SOME COUPLE OF
POINTS THAT ARE MORE GENERAL.
SO, SORRY FOR THAT TYPE OF TITLE
THAT'S A LITTLE MISLEADING.
I PUT THEM BOTH HERE, MAKES NO
SENSE.
ANYWAY, I'LL TALK ABOUT ALLERGIC
DISEASES AND A COUPLE
PERSPECTIVES ON IT.
AND THE MAIN POINT WOULD BE
ABOUT, YOU KNOW, THE QUESTION ON
THE MIND OF MANY PEOPLE HAVE
ALLERGIES, WHY DO WE HAVE
ALLERGIES, WHY DO WE HAVE TO
SUFFER FROM IT?
AND WHY IS IT BECOMING SO
COMMON.
AND SO IT HAS TO DO WITH THIS
TRADEOFFS WE DEAL WITH ANY TYPE
OF DEFENSE SYSTEMS, SO JUST TO
PUT IT A LITTLE BIT OF
INTRODUCTORY PERSPECTIVE, SO
THIS IS HOW WE CAN THINK OF
DIFFERENT TYPES OF INFLAMMATION,
AND THEIR INTENDED CAUSES AND
UNINTENDED SORT OF CONSEQUENCES,
BIOLOGICAL CONSEQUENCES.
WE NOW APPRECIATE THAT THERE ARE
SEVERAL DIFFERENT TYPES OF
INFLAMMATION SO FOR NOW I THINK
WE CAN DISTINGUISH FOUR,
INFECTION, A CLEAR INTENDED
PURPOSE TO PROTECT FROM
PATHOGENS.
AND EXAGGERATED RESPONSES LEAD
TO COLLATERAL DAMAGE AND SEPSIS
WITH TISSUE DAMAGE INTENDED
RESPONSE IS TISSUE REPAIR, WHEN
EXAGGERATED CAN LEAD TO
FIBROSIS, PROMOTE TUMOR GROWTH,
THEN INFECTION AND DAMAGE IS NOT
THE ONLY PROBLEMS IN THE WORLD
OF ANIMALS.
SO NOXIOUS SUBSTANCES, TOXINS,
NOXIOUS CHEMICALS, COMING WITH
FOOD, METABOLITES, VENOMS.
WE DON'T APPRECIATE THEM AS MUCH
NOW BECAUSE WE'RE NOT GENERALLY
EXPOSED TO THEM IN THE
INDUSTRIALIZED WORLD BUT IT
PLAYED AN IMPORTANT ROLE IN
EVOLUTION.
I THINK THE DEFENSE FROM THEM IF
IT'S METABOLIC DEFENSE,
DETOXIFICATION, OTHERWISE
EXPULSION, NEUTRALIZATION, SO
ON.
THAT'S THE PART THAT I THINK
LEADS TO WHEN EXAGGERATED LEADS
TO WHAT WE CALL ALLERGIES.
THE NORMAL COUNTERPART OF
ALLERGIES IS DIFFERENCE FROM
NOXIOUS ENVIRONMENTAL
SUBSTANCES.
FINALLY THE FOURTH DOESN'T
HAPPEN, INTENDED PURPOSE,
BECAUSE IT'S A CONSEQUENCE OF
MISMATCH BETWEEN EVOLUTIONARY
HISTORY AND MODERN ENVIRONMENT,
MODERN LIFESTYLE AS WE KNOW CAN
BE GREAT BUT HAVE COSTS, VARIOUS
MODERN DISEASES, METABOLIC,
CARDIOVASCULAR, AGING-ASSOCIATED
DISEASES.
BUT THE POINT HERE IS THAT FOR
ALLERGIES IN PARTICULAR, WE CAN
DRAW THE SAME PARALLELS IN THE
MORE SIMPLER BETTER UNDERSTOOD
CASE OF INFECTIONS THAT YOU
HAVE.
IMMUNE PROTECTION BUT IT COMES
WITH THE COST.
AND IF IT'S EXAGGERATED THEN WE
CALL IT DISEASE.
AND MORE GENERALLY IF YOU THINK
ABOUT THE COST OF DEFENSES,
WHICH ARE HISTORICALLY ALWAYS
FIRST WERE THOUGHT OF AS
DISEASES, BUT WE NEED TO
DISTINGUISH TWO VERY DIFFERENT
TYPES OF COSTS OF DEFENSES, AND
TRUE FOR ANY DEFENSES, AND IT'S
VERY MUCH TRUE FOR INFLAMMATORY
DEFENSES, TWO TYPES OF COSTS OF
INFLAMMATION.
ONE IS ON THE RIGHT SIDE THAT'S
THE MORE FAMILIAR ONE, IT'S
UNINTENTIONAL BUT UNAVOIDABLE
LOSS OF FUNCTION AT THE EXTREME
WILL BE COLLATERAL DAMAGE.
THAT'S JUST SOMETHING WE CAN'T
AVOID.
BUT IT'S PART OF THE COST WE
PAY.
THE OTHER IS MORE INTERESTING,
THAT IS INTENTIONAL SUPPRESSION
OF LOW PRIORITY FUNCTIONS.
THAT NEEDS TO HAPPEN IN ORDER
FOR THE IMMUNOINFLAMMATORY
RESPONSE TO DO ITS JOB, THANKED
IS MORE BY DESIGN, BUT OF COURSE
IF IT'S -- IT COMES WITH A COST
BECAUSE YOU SUPPRESS SOME OTHER
FUNCTIONS.
WHEN IT'S EXAGGERATED ALSO CAN
BECOME PROBLEMATIC AND CAN LEAD
TO DISEASE.
AND BOTH OF THESE CONTRIBUTE TO
ULTIMATE SORT OF CAUSE OF
INFLAMMATORY RESPONSE AND CAN
CONTRIBUTE TO INFLAMMATORY
DISEASES, BUT THESE ARE VERY
DIFFERENT TYPES.
ONE IS INTENDED AND WELL
ORCHESTRATED, JUST CAN BECOME
ACKNOWLEDGE RATED --
EXAGGERATED, THE OTHER IS
COLLATERAL DAMAGE.
BOTH AT A COST TO FITNESS,
IMPORTANT FOR SURVIVAL, COMING
WITH A COST.
LIKE ANY TRAITS IN ORDER TO BE
EVOLUTIONARY STABLE BENEFITS
SHOULD BE HIGHER THAN THE COST
AND AS WE CAN SEE HERE ANYTHING
IN THE GREEN PART OF THE SQUARE
BENEFIT HIGHER THAN COST WOULD
BE EVOLUTIONARILY SELECTED FOR.
ANYTHING IN THE RED SIDE WOULD
BE SELECTED AGAINST, COSTS MORE
THAN BENEFIT.
IN THIS AREA WHERE BENEFIT
HIGHER THAN COST YOU CAN
APPRECIATE THAT IF BENEFIT IS
VERY HIGH, ACCEPTABLE COST CAN
BE HIGH AS WELL.
AND THIS IS EVOLUTIONARY SORT OF
POINT OF VIEW, AND PATIENT OR
DOCTOR POINT OF VIEW OF THE SAME
EXACT PLOT WOULD BE LIKE THIS.
SO ANYTHING ON THE RIGHT SIDE OF
THE SQUARE WOULD BE CONSIDERED
TO BE DISEASE.
EVEN THOUGH IT'S EVOLUTIONARILY
STABLE, AND THESE ARE THE
CONDITIONS WE EXPERIENCE, FOR
EXAMPLE, IN ACUTE ILLNESS, WITH
VERY SEVERE SEQUENCES OF HIGH
MAGNITUDE DEFENSE RESPONSES,
INFLAMMATORY RESPONSE, OR
ANAPHYLACTIC RESPONSE, AND THE
REASON THEY EXIST IS BECAUSE --
NOT BECAUSE THEY ARE GOOD FOR
THAT PARTICULAR PERSON AND THAT
PARTICULAR SITUATION BUT BECAUSE
OF AVERAGE IN THE COURSE OF
EVOLUTION IN VERY DIFFERENT
ENVIRONMENTS ON AVERAGE THAT
PROVIDED BETTER BENEFIT THAN NOT
HAVING THAT TYPE OF RESPONSE.
AND INCIDENTALLY WHAT'S
INTERESTING IS MOST OF THE
STUDIES OF VARIOUS TYPES OF
EXPERIMENTAL MODELS OF DISEASES,
THEY -- BASICALLY WE DRAW THE
LINE SOMEWHERE, WHERE WE JUST
SAY, WELL, ANIMALS DIE, BUT IN
THIS WAY THERE'S A LOT OF
INTERESTING BIOLOGY THAT'S
HIDDEN THAT LIVES OVER HERE.
AND THIS IS BECAUSE WE DON'T
KNOW THAT BIOLOGY WELL, THAT'S
WHY CRITICAL CARE MEDICINE IS
ALSO NOT WHERE OTHER BRANCHES OF
MEDICINE ARE IN TERMS OF
UNDERSTANDING HOW TO HELP
PATIENTS.
BECAUSE UNDERLYING BIOLOGY IS
NOT WELL STUDIED.
AND THAT'S ONE AREA WE'RE
INTERESTED IN.
BOUGH -- BUT IN THE CONTEXT OF
THIS TALK I'M BRINGING IT UP
BECAUSE IN SEVERE ALLERGIC
REACTIONS CAN BE A NUISANCE,
THEY CAN BE LIFE-THREATENING,
ANAPHYLACTIC REACTIONS CAN BE
LIFE-THREATENING, AND THE
QUESTION IS WHAT TYPES OF
MECHANISMS ENABLE IT AND WHAT
CAN WE DO ABOUT IT.
SO, TO QUICKLY REMIND YOU WHAT I
WILL TALK ABOUT IS ALLERGIC
IMMUNITY, TYPE 2 IMMUNITY FOR
SIMPLICITY TO REMIND YOU WE HAVE
TWO TYPES OF IMMUNE RESPONSES TO
MICROBIAL PATHOGENS, TYPE 1
RESPONSE AND MACRO PARASITES AS
WELL AS ALLERGENS, WHETHER WE
HAVE TYPE 2 RESPONSEN BOTH CASE
EXAGGERATION, EXAGGERATED
RESPONSE CAN LEAD TO SEPSIS AND
ANAPHYLAXICS, AND FOR TYPE 1
IMMUNITY WE KNOW BASIC
PRINCIPLES THAT THERE'S
COMBINATION OF ANTIGEN WITH SOME
IMMUNOGENIC STIMULUS, TYPICALLY
SOMETHING DERIVED FROM CONSERVED
MICROBIAL STRUCTURES DETECTED BY
INNATE RECOGNITION RECEPTORS,
THAT'S WHAT DRIVES TYPE 1
RESPONSE .
IN THE CASE OF TYPE 2 RESPONSE
WE DON'T HAVE GOOD UNDERSTANDING
WHAT THE ADJUVANT RESPONSE WILL
BE, SOME FUNCTIONAL RECOGNITION
IN SOME CASE, ENZYMATIC ACTIVITY
LIKE VENOMS AND OTHER TYPES OF
ENZYMES, PROTEASES, LIPASES, SO
FORTH, AND SOMETIMES OTHER
FEATURES STILL ILL DEFINED.
THAT MAKES THIS AREA STILL NOT
WELL DEVELOPED, NOT NEARLY AS
WELL AS UNDERSTANDING OF
INITIATION TYPE 1 IMMUNITY,
ONGOING QUESTIONS IN THE FIELD,
BUT GENERALLY THE IDEA WOULD BE
SOME KIND OF NOXIOUS ACTIVITY
WHEN COMBINED WITH ANTIGEN IS
WHAT DRIVES TYPE 2 RESPONSE.
AND THE POINT OF IT IS THAT THE
SUBSEQUENT EXECUTION OF THIS
RESPONSE WILL BE PROTECTIVE.
AND THAT'S WHAT BRINGS ME TO
THIS POINT THAT WHEN WE THINK OF
ALLERGIES WE TYPICALLY THINK OF
IT AS A DISEASE STATE.
BUT I THINK WE NEED TO
DISTINGUISH BETWEEN ALLERGIC
DISEASES AND ALLERGIC DEFENSES.
WHAT'S THE NORMAL COUNTERPART OF
ALLERGIC RESPONSES?
FOR A WHILE, THE DOMINATING
THOUGHT WAS THAT, WELL, ALLERGY
IS JUST A MISTAKE THE IMMUNE
SYSTEM MAKES AND NORMAL
COUNTERPART DEFENSE FROM
PARASITES.
I THINK THAT'S NOT ENTIRELY
CORRECT.
I THINK THE NORMAL COUNTERPART
IS DEFENSE FROM NOXIOUS
SUBSTANCES, AND MANY REASONS TO
THINK THAT, THAT THE RESPONSE,
ALLERGIC RESPONSE IS NOT JUST A
MISTAKE.
THERE'S ONE NUANCE I'LL CAMPAIGN
AT THE -- EXPLAIN AT THE END.
IT'S NOT JUST A MISTAKE, IN THE
CASE OF FOOD ALLERGIES IN
PARTICULAR, PEOPLE WHO ARE
ALLERGIC TO CERTAIN FOODS, THEY
ARE RESPONDING TO THE SAME
ALLERGEN FROM THE SAME FOOD
SOURCES.
IF IT'S A MISTAKE OF THE IMMUNE
SYSTEM IT'S MAKING THE SAME
MISTAKE AGAIN AND AGAIN, CAN'T
BE JUST RANDOM MISSIC THAT.
ALL ALLERGIES SYMPTOMS ALL HAVE
TO DO WITH EXPELLING SOMETHING
KNOCK SHOULD GOES FROM THE BODY,
AND MOREOVER EXACT SAME
REACTIONS OCCUR IN PEOPLE
WITHOUT ALLERGIES, IF YOU
SNEEZE, COUGH, TOUCH IRRITANTS
IT WILL CAUSE ITCHING, FOOD
POISONING DIARRHEA, PROMOTING
ELIMINATION FROM THE BODY.
ALLERGIC IMMUNITY, THOSE
DEFENSES ARE MOSTLY OPERATED BY
NEURONAL REFLEXES, AND ALLERGIC
RESPONSES SUPERIMPOSED, MORE
PROBLEMATIC POTENTIALLY.
FROM THAT PERSPECTIVE WE CAN
THINK OF ALLERGIC DEFENSES AS
OPTIMAL EXECUTION OF TYPE 2
RESPONSE, WHEN EXAGGERATED
RESULTS IN ALLERGIC DISEASES,
AND THEN WE CAN PREDICT THERE'S
ANOTHER AREA OF PATHOLOGY WHERE
DIFFERENCES ARE INEFFICIENT.
SO THIS IS VERY MUCH
PARALLELLING WHAT WE KNOW ABOUT
IMMUNITY TO MICROBES, CAN HAVE
IMMUNE PATHOLOGY, CAN HAVE
IMMUNODEFICIENCY.
IN THE CASE OF ALLERGIC DEFENSES
WE DON'T KNOW WHAT THAT IN THE
LEFT CORNER IS, QUESTION MARK,
BUT THIS WOULD BE JUST
PREDICTION THAT THERE MAY BE A
CLASS OF CONDITIONS WHICH MAY
NOT KNOWN TO BE CAUSED BY THAT
BUT PREDICTED TO BE CAUSE BY
INSUFFICIENT ALLERGIC DEFENSES,
AGAINST NOXIOUS SUBSTANCES.
SO, THE QUESTION THEN WE ARE
INTERESTED IN, RESPONSE
INITIATED, WHAT I WILL FOCUS ON
NOW IS A BIG ENIGMA IN THE FIELD
WHAT MAKES SOMEBODY ALLERGIC OR
HYPERSENSITIVE?
EVERYBODY HAS IGE RESPONSES,
TRIGGERED BY APPROPRIATE
STIMULI, BUT ONLY A SUBSET
BECOME HYPERSENSITIVE OR WHAT WE
CALL ALLERGIC.
THIS IS NOT ALL OR NONE TYPE OF
DISTINCTION, PEOPLE CAN BE
ALLERGIC TO DIFFERENT DEGREES,
BUT WHAT MAKES SOMEBODY ALLERGIC
OR HYPER DEFENSE IS THE
QUESTION.
ANTIBODIES OF HIGH AFFINITY ARE
REQUIRED BUT BEYOND THAT IT'S
NOT CLEAR WHAT EXACTLY DEFINES
HYPERSENSITIVE STATE.
AND SO THAT'S ONE OF THE BIGGEST
QUESTIONS IN THE FIELD BECAUSE
WE WOULD WANT TO BE IDEALLY ABLE
TO REVERSE THAT STATE.
BUT THE QUESTION THAT I WILL
FOCUS ON IN THE FIRST PART, MY
TALK WOULD HAVE TWO PARTS.
THEY DEAL WITH TWO ASPECTS OF
THE ENVIRONMENT THAT FROM
DIFFERENT PERSPECTIVES THAT MAKE
ALLERGY PROBLEMATIC IN MODERN
WORLD.
THE FIRST ONE, SO WHY INCIDENCE
OF ALLERGIC DISEASE IS
INCREASING, OVER THE PAST FEW
DECADES DRAMATICALLY, THE WAY TO
EXPLAIN IS ENVIRONMENTAL
INFLUENCES, CANNOT BE GENETIC IN
THAT TIME SCALE.
WE'RE INTERESTED IN WHAT IS IT
IN THE ENVIRONMENT.
IT'S A VERY HARD QUESTION
BECAUSE SO MANY THING IN THE
ENVIRONMENT IN THE LAST 30
YEARS, RIGHT?
IT'S EASY TO FIND SOMETHING THAT
HAS PERFECT CORRELATION, AND
THERE ARE SOME USUAL SUSPECTS,
LIKE CLEANER WORLD, MORE SORT OF
CHANGED DIETS, CHANGED
MICROBIOTA, WHATEVER THE
ENVIRONMENTAL FACTOR IS.
THEY PROBABLY ALL CONTRIBUTE TO
VARIOUS DEGREES.
THIS IS JUST A PICTURE SHOWING
HOW ENVIRONMENT CONTRIBUTES TO
INCIDENCE OF ALLERGIES AND HOW
IT VERY MUCH RELATES TO
INDUSTRIALIZATION, EATING FOODS
THAT ARE HIGHLY PROCESSED,
LIVING IN A CLEAN ENVIRONMENT,
USE OF ANTIBIOTICS, HYGIENE
PRODUCTS, SO FORTH.
AND SO CLEARLY SOMETHING ABOUT
THE ENVIRONMENT HAS BEEN
LONGSTANDING SORT OF HYPOTHESIS
THAT CLEAN ENVIRONMENTS ARE THE
ONES THAT PROMOTE DEVELOPMENT OF
ALLERGIES.
WHY THAT IS IS WHAT -- THAT'S
THE QUESTION THAT IS -- THAT
WE'VE BEEN INTERESTED IN.
SO, BASIC PREMISE WOULD BE THAT
IMMUNE SYSTEM EVOLVED UNDER
CONDITIONS THAT -- ENVIRONMENTAL
CONDITIONS DIFFERENT THAN WHAT
WE ENJOY CURRENTLY, NORMAL
EVOLUTIONARILY, NORMAL
CONDITIONS WOULD BE HIGH
MICROBIAL EXPOSURE AND 100%
PARASITIC INFECTION, EVERY
ANIMAL IN THE WILD HAS
PARASITES.
AND THAT WOULD BE THE NORMAL
STATE.
BUT THE REASON IT'S IMPORTANT IS
BECAUSE THAT'S WHAT IMMUNE
SYSTEM NORMALLY DEALS WITH.
THAT'S WHAT IT EVOLVED TO DEAL
WITH, TO OPERATE UNDER THOSE
CONDITIONS.
AND IN THE MODERN ENVIRONMENT
THOSE CONDITIONS CHANGE
DRAMATICALLY, CHARACTERIZED BY
REDUCED EXPOSURE TO MICROBES,
PARASITES, FOREIGN ANTIGENS IN
GENERAL.
SO, WE WANTED TO ASK TO WHAT
DEGREE THAT CONTRIBUTES TO
PREDISPOSITION TO ALLERGIES.
HOW ENVIRONMENTAL FACTORS
INFLUENCE SENSEIZATION.
IN THE FIRST PART OF THE TALK WE
USED SO-CALLED PET SHOP MICE,
THAT YOU BUY IN A PET SHOP, BRED
NOT AS PETS BY THE WAY BUT FOOD
FOR SNAKES, PET SHOP MICE IS A
BETTER NAME.
THESE ARE BASICALLY WILD MICE
THAT ARE CAUGHT SOMEWHERE IN THE
BARN, AND GENETICALLY DIVERSE,
VERY DIRTY WITH ALL KINDS OF
MICROBES.
AND WE -- THE GOAL WAS TO
INVESTIGATE THEIR IMMUNE SYSTEM
AS COMPARED TO SPF MICE,
PATHOGEN FREE THAT LIVES IN
ENVIRONMENTS, DESCRIBED THE
MODEL AS PET SHOP MICE A FEW
YEARS AGO, CHARACTERIZED BASIC
IMMUNOLOGICAL CHARACTERISTICS OF
THESE MICE AND WHY THEY COULD BE
GOOD MODEL FOR VARIOUS
QUESTIONS.
SO THIS IS WHAT THESE GUYS LOOK
LIKE.
ON THE RIGHT, CLEAN, SPF MICE.
ON THE LEFT PET SHOP MICE, YOU
SEE THEY CLEARLY GENETICALLY ARE
VERY DIVERSE, LOOK DIFFERENT,
BEHAVE DIFFERENTLY, FULL OF
STUFF ON THE RIGHT.
THIS IS NOT EVEN COMPLETE LIST
BUT THEY GOT IT ALL.
THEY GOT PROTOZOA, PARASITES,
BACTERIA, FUNGI, VIRUSES OF ALL
KINDS.
THEY ARE FULL OF THAT.
YOU GIVE ANY ONE OF THIS TO SPF
MICE YOU INFECT THEM AND SEE
WHETHER THEY GUY.
THESE DIES HAVE IT ALL.
THAT'S THEIR NORMAL STATE.
THAT'S ONE KIND OF -- ACTUALLY
PRETTY AMAZING FACT, RIGHT?
THEY HAVE ALL THIS.
COLONIZATION.
YOU CAN'T EVEN CALL IT INFECTION
BECAUSE THEY ARE NOT SICK.
IT'S JUST THEIR NORMAL STATE.
AND THAT SHOULD TELL US
SOMETHING ABOUT WHAT THE NORMAL
STATE OF THE IMMUNE SYSTEM OF
THE ORGANISM HAS TO DEAL WITH.
WE USE THESE MICE.
WHAT THIS ALLOWS, WE ARE LOOKING
AT GENETICALLY VERY
HETEROGENEOUS GROUP OF MICE FULL
OF NORMAL SORT OF EXPOSURE TO
MICROBES OF ALL KINDS AND
COMPARING TO WHAT WE NORMALLY
USE IN THE LABS, SPF CONDITION
IN BRED MICE OF A PARTICULAR
STRAIN.
WHEN WE SUBJECT THEM TO EXACT
SAME PROTOCOL FOR SENSITIZATION,
THIS IS A MODEL WHERE WE USE
SUBCUTANEOUS ALBUMIN, IF YOU
CHALLENGE THEM THIS IS
TEMPERATURE DROP, THIS IS RESULT
OF ANAPHYLACTIC REACTION.
IF IT'S SEVERE, IT WILL KILL
MILES. -- MICE.
PET SHOP MICE ARE REALLY
PROTECTED FROM IT.
THIS TYPE OF GRAPH I'LL SHOW
SEVERAL TIMES, DELTA IN
TEMPERATURE.
HIGHER THE GRAPH, STRONGER
ANAPHYLACTIC REACTION, AS YOU
CAN SEE THESE MICE ARE
PROTECTED.
EVEN THOUGH THEY MAKE
ANTIGEN-SPECIFIC IGE.
THAT'S THE PART THAT I THINK IS
REALLY IMPORTANT THAT THEY DO
MAKE IGE JUST FINE.
ANTIGEN-SPECIFIC IGE.
BUT IT DOESN'T RESULT IN
ANAPHYLAXIS.
AND SO THEN WE ASKED WHETHER IF
WE TAKE OUR CLEAN MICE TO RULE
OUT THIS IS JUST SOMETHING LIKE
REALLY WEIRD RANDOM GENETIC
EFFECT.
AND WE CROSS-FOSTER THEM WITH
PET SHOP MICE, SO THIS IS
ANAPHYLACTIC REACTION IN CONTROL
SPF MICE, IF CO-HOUSED WITH
DIRTY MICE ACQUIRE SOME
MICROBES, BECOME MORE PROTECTED.
IF FOSTERED BY PET SHOP MICE
THEY ARE COMPLETELY PROTECTED.
JUST ACQUIRING MICROBES FROM THE
DIRTY MICE MAKES THEM PROTECTED.
THAT'S CONSISTENT WITH
EPIDEMIOLOGICAL STUDIES IN
HUMANS LIVING IN A MORE NATURAL
SORT OF DIRTY ENVIRONMENT,
PROTECTIVE GROWING UP ON THE
FARM IS PROTECTIVE, SO FORTH.
AND THEY ARE PROTECTED NOT
BECAUSE THERE'S ANY KIND OF
DEFECT IN THE ALLERGIC
INFLAMMATION BECAUSE IF WE
BYPASS THE SENSITIZATION STATE
AND GIVE PASSIVE SYSTEMIC
ANAPHYLAXICS ON THE LEFT THEY
WOULD AN A TAMPA LACKS AS WELL.
IF WE GIVE COMPOUND, INDUCE HIS
THAT MEAN THEY WOULD ANAPHYLAX
AS WELL.
THERE'S A COMMON TREND, SO T
DEPENDENT ANTIBODIES ELEVATED
COMPARED TO SPF MICE SHOWN HERE
WITH IgGs AND NIGA,
DEPENDENT ANTIBODIES SEEM TO BE
OPPOSITE TREND, PROBABLY THE
CONSEQUENCE OF THEM MOSTLY
SWITCHING.
SO THEY HAVE HIGH ANTIBODY
LEVELS, AND WE TOOK ABOUT 20+
VERY DIFFERENT GENETICALLY
DISTANT MOUSE STRAINS FROM
JACKSON LAB, WE CHOSE THEM BASED
ON BEING MAXIMALLY DIFFERENT
GENETICALLY, SHOWN HERE.
WE COMPARED SENSITIZATION IN ALL
OF THEM TO PET SHOP MICE, WHICH
ARE IN THE RED.
AND AS YOU CAN SEE, THE RESPONSE
IS VARIED, THIS IS FOR GENETIC
REASONS, ALL SPF, BUT DIFFERENT
GENETIC BACKGROUNDS.
COMPARING TO GENETICALLY
HETEROGENEOUS PET SHOP MICE,
WHICH ARE RED.
THEY HAVE MUCH -- THIS IS,
AGAIN, THE SAME TYPE OF
IMMUNIZATION AND ALUM, THEY
DEVELOP VERY ROBUST IgG
RESPONSE, WHICH IN SPF MICE IT'S
ALMOST NOT THERE, BUT PET SHOP
MICE DEVELOP STRONG IgG TO
RESPONSE.
THIS BY THE WAY, ALUM IS AN
ADJUVANT USED IN HUMANS, CAN
INDUCE APPROPRIATE RESPONSE FOR
VACCINATION AGAINST MICROBIAL
ANTIGENS, IT WILL INDUCE IgG,
FOR EXAMPLE.
THAT'S NOT THE CASE IN SPF MICE
BUT IT IS THE CASE IN MORE
NATURALLY EXPOSED PET SHOP MICE.
SO THEY HAVE ELEVATED
ANTIBODIES, AND PROTECT FROM
ALLERGY, THEY GENERATE BOTH IGE
AND IgG IN RESPONSE TO
ALLERGIC SENSITIZATION, MEANING
USE OF ALUM, SIMILAR TO ADULT
HUMANS.
ADULT HUMANS WILL INDUCE BOTH
TYPE I AND TYPE II RESPONSE.
YOU MAY REMEMBER WHEN Th1 AND
Th2 SUBSETS WERE DISCOVERED
FOR A LONG TIME IN THE HUMAN
FIELD IT WAS ARGUED THEY DON'T
HAVE THE CLEAR DISTINCTION
BETWEEN Th1 AND Th2.
THAT'S GENERALLY TRUE FOR ADULT
HUMANS.
AND SO ALLERGY-SPECIFIC
ANTIBODIES PROTECTIVE FROM
ALLERGIES, WHY IS THE ANTIBODY
RESPONSE TO THE SAME
IMMUNIZATION DIFFERENT IN PET OF
PET SHOP MICE AND SPF.
WHEN WE LOOKED AT RESPONSE IN
SPF AND PET SHOP MICE WITHOUT
IMMUNIZATION, NEITHER OF THOSE
MICE WERE NOT EXPOSED TO IT, IN
SPF THERE'S NO RESPONSE BUT IN
PET SHOP MICE THERE'S A
RESPONSE.
IT'S NOT A VERY HIGH TITER BUT
IT'S THERE.
AND IF WE TAKE -- SORRY, THE SPF
MICE, I'M SORRY, IF WE TAKE PET
SHOP MICE, PUT THEM IN SPF
CONDITIONS, THEY LOSE IT.
GROW UP IN CLEAN ENVIRONMENT,
THEN THEY DON'T HAVE THE
ANTIBODY RESPONSE REAVE SO THEY
HAVE TO BE DUTY TO HAVE IT EVEN
THOUGH THEY DIDN'T SEE IT.
WHEN WE LOOKED AT -- NORTH TO
CHARACTERIZE THAT FURTHER WE
DEVELOPED THIS ANTIBODY
SCREENING PLATFORM, THAT ALLOWS
YOU US TO LOOK AT EPITOPE
RESPONSE, LINEAR BUT
NEVERTHELESS THAT WAS
INFORMATIVE SO WE USED THIS
SYSTEM WHERE IT'S A BACTERIAL
DISPLAY ESSENTIALLY OF EPITOPES,
AND THEN THIS IS SHOWING THAT IT
WORKS, WHEN WE INDUCE EXPRESSION
OF THE ANTIGEN AND THEN
ANTIBODIES WILL RECOGNIZE THE
APPROPRIATE EPITOPE AND THEN IF
WE USE MONOCLONAL ANTIBODIES AS
CONTROL IT SHOWS EXACTLY IN
WHICH POSITION THEY EPITOPES
ARE, AND ON THIS GRAPH THIS IS
THE POSITION ON X-AXIS, TWO
EPITOPES RECOGNIZED BY THE
MONOCLONAL ANTIBODIES, TO SHOW
THE SYSTEM WORKS.
WE USE THAT SYSTEM AND COMPARED
ANTIBODY REACTIVITIES TOWARDS
DIFFERENT EPITOPES, FROM PET
SHOP MICE VERSUS SPF MICE,
WITHOUT AND WITH IMMUNIZATION,
AND THIS IS WHAT HAPPENS.
THE TOP IS SPF MICE.
AS EXPECTED WITHOUT IMMUNIZATION
THERE'S NO ANTIBODIES REACTIVE
TO OVA.
AFTER IMNATION YOU SEE REACTION
TO EPITOPES, IN PET SHOP MICE
PLENTY OF ACTIVITIES TOWARDS
EPITOPES OF ALBUMIN.
WITH IMMUNIZATION IT CHANGES,
EVEN WITHOUT IMMUNIZATION
THERE'S PLENTY OF RESPONSES.
SAME TRUE WITH T CELLS.
IF YOU TAKE T CELLS FROM SPF
UNIMMUNIZED, THERE'S NO RESPONSE
TO EITHER.
WHEN THEY ARE IMMUNIZED YOU
START SEEING RESPONSE TO TL 8
BUT NOT ALBUMIN, PET SHOP MICE
THERE'S PLENTY OF RESPONSE TO
BOTH EVEN THOUGH THEY HAVEN'T
SEEN EITHER ONE.
THIS IS REMINISCENT OF WHAT
HAPPENS, WHAT'S REPORTED IN
HUMANS, IT WAS DEMONSTRATED WHEN
THEY LOOK FOR SPECIFIC
ANTI-VIRAL EPITOPES, RESPONSES
IN T CELLS, THEY SEE THAT THEY
HAVE T CELLS REACTIVE TO
PARTICULAR EPITOPES EVEN THOUGH
FOR EXAMPLE HIV AT THE TOP THEY
WERE NOT INFECTED OR VACCINATED,
THAT SEEMS TO BE THE GENERAL
RULE, ONLY NOT THE CASE WITH SPF
MICE THAT DON'T HAVE THAT.
SPF MICE LAST LIKE HUMANS, DIRTY
MICE ARE MORE -- SO THIS IS JUST
TO SHOW THAT THERE IS THIS
REACTIVITY OF T CELLS IN BOTTOM
CD4 T CELLS, WITH Th2
RESPONSES THE SITUATION IS
DIFFERENT, THERE'S NOT MUCH OF
TYPE 2 MEMORY RECALL RESPONSE,
BUT IT'S VERY STRONG WITH TYPE 1
RESPONSE.
SO, CONCLUSION FROM THAT PART IS
THAT PET SHOP MICE FROM
PREEXISTING RESPONSES, BOTH
IgG AND T CELLS, AND THIS MUST
BE SPECIFIC TO SOMETHING BECAUSE
WE HAVEN'T SEEN THIS, MUST BE
CROSS-REACTIVE TO SOMETHING THEY
HAVE BEEN EXPOSED TO.
THIS CROSS REACTIVITY IS WHAT WE
DETECT WHEN WE DO THESE
EXPERIMENTS.
AND THEY GENERATE THIS MIXED
Th1/Th2 RESPONSE, UNLIKE SPF
MICE BUT SIMILAR TO ADULT
HUMANS, IMMUNE SYSTEM IS IN A
DIFFERENT STATE.
WE CAN LOOK AT IT THIS WAY IN
TRUE NAIVE STATE, MIMICKED BY
SPF MICE, IN GRAY NAIVE T CELLS,
THEN YOU PERFORM ALLERGIC
SENSITIZATION, GENERATE Th2
AND IgG RESPONSE, THEY WILL
BECOME ALLERGIC.
IF YOU DO ORAL TOLERANCE, EXPAND
T REGSES, PROTECTED, THERE'S
ALREADY PREEXISTING NATURAL TYPE
1 RESPONSE IN THE NATURAL CASE,
THAT PROTECTS THEM FROM
DEVELOPING ALLERGY, EVEN THOUGH
WOULD HAVE TYPE 2 RESPONSE, JUST
THEY WILL NOT BE HYPERSENSITIVE,
THAT'S WHAT NATURAL STATE S
EVERYONE HAS IGE RESPONSE, NOT
EVERYONE IS HYPERSENSITIVE.
PREDICTION IS PET SHOP MICE
SHOULD BE SUSCEPTIBLE TO
DEVELOPING ALLERGY IF THEY ARE
SENSITIZED BEFORE THEY DEVELOP
THAT STATE OF THE IMMUNE SYSTEM.
BEFORE THEY DEVELOP THAT
ANTIGENIC EXPERIENCE, WHERE THEY
NOW CROSS-REACT TO ALL SORTS OF
ANTIGENS.
AND SPF MICE CONVERSELY SHOULD
BE PROTECTED BY PRIOR
CROSS-REACTIVE EXPOSURES.
THIS IS THE EXPERIMENT ABOUT THE
FIRST PART, WHERE WE TOOK PET
SHOP MICE, SO IF YOU SENSITIZE
AS ADULTS THEY ARE PROTECTED,
SHOWN IN GREEN.
THEN WE SENSITIZE THEM AT
POSTNATAL DAY 7, BEFORE THEY
DEVELOPED ALL THIS STATE OF THE
IMMUNE SYSTEM, EXPOSED TO ALL
THE ALLERGENS, DAY 58, 65, WE
CHALLENGE THEM AND NOW THEY ARE
ALLERGIC AND THEY ANAPHYLAX.
IF THEY ARE EXPOSED PRIOR TO
DEVELOPING ALL THE ANTIGENIC
EXPERIENCE THEN THEY ARE
SENSITIVE.
THAT'S THE WINDOW OF
VULNERABILITY, ALSO FITS WITH
WHAT WE KNOW IN HUMANS WHERE IN
BABIES ARE MUCH MORE SENSITIVE
TO DEVELOPING ALLERGIC
REACTIVITY.
OKAY.
TO LOOK AT IT IN A DIFFERENT WAY
WE TOOK THIS, TO SEE WHETHER
THERE WOULD BE CROSS-REACTIVITY,
WE COULD MIMIC THAT IN SPF MICE.
WE SENSITIZED THEM WITH AL UM
OVA BUT CHALLENGED WITH CHICKEN
ALBUMIN OR DUCK OR EVEN TURTLE.
AND THESE ALL HAVE DIFFERENT
DISTANCES IN TERMS OF SEQUENCES.
EVEN AS YOU GO DOWN IN DISTANCE
FROM LEFT TO RIGHT, REACTIVITY
GOES DOWN BUT REACTIVITY IS
THERE EVEN TO THIS
CROSS-REACTIVE NON-IDENTICAL
ANTIGENS.
MORE CLEARLY SEEN WITH OUR
ANTIGEN SCREENING SYSTEM WHERE
CHICKEN OVA IS THE ONE THAT IS
HUNDRED PERCENT MATCH AND GOES
DOWN BUT YOU STILL SEE THIS
REACTIVITY.
THIS IS JUST TO SAY THAT THERE
IS THIS CROSS-REACTIVE IMMUNITY
THAT CAN BE EVEN ARTIFICIALLY
DEVELOPED HERE WITH JUST USING
ONE ANTIGEN.
THIS LEADS US TO THE MODEL WHERE
WE THINK OF ONE AFFECT OF
VULNERABILITY TO ALLERGIES,
ASSOCIATED WITH MORE THAN CLEAN
ENVIRONMENT IS THE FOLLOWING.
THAT NEONATAL STATE THE ONLY
ANTIGENS THE ANIMAL WOULD SEE IS
SELF-ANTIGENS, IF THEY DEVELOPED
IN CLEAN ENVIRONMENTSPF
COMMENSALS WOULD BE EXPOSED TO
DIETARY, THERE ARE MANY OTHER
ANTIGENS THAT ARE NOT EXPOSED
TO.
IN THE PET SHOP MICE AND ALSO IN
NATURAL CONDITIONS FOR HUMANS,
WHEN YOU GO FROM THIS NEONATAL
STATE AND GET EXPOSED TO THIS
HUGELY DIVERSE ANTIGENIC
ENVIRONMENT, YOU DEVELOP
RESPONSES THAT THROUGH
CROSS-REACTIVITY WILL COVER THE
ENTIRE ANTIGENIC SPACE.
AND THAT'S WHAT MAKES THEM
PROTECTED FROM DEVELOPING
ALLERGIC REACTIVITY AFTER THAT
STATE IS ESTABLISHED.
OVER THERE ON THE RIGHT THERE
WOULD BE GAPS IN WHAT'S COVERED
BY ANTIGENIC SPACE AND IF
ALLERGY
ALLERGIN FITS IN, YOU WOULD BE
PROTECTED.
IN TERMS OF LIFE HISTORY COURSE
HERE THE PET SHOP MICE AT THE
TOP WOULD SHOW SITUATIONS
SIMILAR TO HUMANS IN NATURAL
ENVIRONMENTS WHERE THIS WINDOW
OF SUSCEPTIBILITY IS SHORT IN
THE EARLY STAGES OF LIFE,
THERE'S A SHORT WINDOW BEFORE
YOU ARE EXPOSED TO THE
ALLERGENS, THAT'S WHEN YOU'RE
VULNERABLE.
IT QUICKLY CLOSES DOWN BY
DEVELOPING ALL THE OTHER
REACTIVITIES, FILLING ANTIGENIC
SPACE BY VARIOUS ANTIBODY AND T
CELL REACTIVITIES.
SPF MICE IT'S NOT CLEARED AS
MUCH, AND THEY CAN MAINTAIN
SUSCEPTIBILITY.
HUMANS IN INDUSTRIALIZED
ENVIRONMENT SOMEWHAT SIMILAR TO
SPF MICE THE WINDOW IS EXTENDED,
THEY ARE MORE PRONE.
IT HAS TO DO WITH THE ABILITY OF
THE SYSTEM TO COVER AS MUCH AS
ANTIGENIC SPACE DUE TO NATURAL
EXPOSURE TO ANTIGENIC
ENVIRONMENT, AND THAT'S WHAT
PROVIDES PROTECTION.
THAT'S ONE ASPECT OF PROVIDING
PROTECTION.
THE SECOND PART THAT I WILL
QUICKLY GO THROUGH HAS TO DO
WITH ANOTHER ASPECT OF THE
ENVIRONMENTAL FACTOR THAT MAKES
ALLERGIES PROBLEMATIC, NOT ABOUT
DEVELOPING THEM OR NOT BUT WHAT
MAKES THEM PROBLEMATIC.
AND THAT HAS TO DO WITH
BASICALLY EVOLUTIONARY TRAP,
WHEN ANIMALS OR HUMANS EVOLVE
UNDER CERTAIN CONDITIONS, AND
THEN IN ENVIRONMENT CHANGE THEY
STILL REACT THE SAME WAY, AND
THAT LEADS TO THEIR DEMISE OR
DISEASE.
SO, FOR EXAMPLE, TURTLES TRYING
TO CROSS THE ROAD, YOU TURN THEM
AROUND THEY STILL CROSS THE ROAD
BECAUSE THEY DIDN'T EVOLVE WITH
CARS RUNNING AROUND, THIS SORT
OF THING.
IN THE CONTEXT OF ALLERGIES,
WHAT THAT MEANS IS IF IT IS
INDEED THE WAY WE THINK BIT THAT
IT'S A PROTECTIVE RESPONSE
AGAINST NOXIOUS SUBSTANCES, ONCE
YOU ARE EXPOSED TO SOMETHING
THAT CAUSES ALLERGY, LET'S SAY
HOUSE DUST MITE, IN -- WELL, IN
THE WILD IT WON'T BE HOUSE DUST
MITE BUT SOMETHING SIMILAR,
LET'S SAY POLLEN UNDER A TREE,
FROM SOME TREE, SO BASICALLY ALL
YOU DO IS DON'T SLEEP UNDER THAT
TREE.
GO TO THE OTHER SIDE OF THE
RIVER AND YOU'RE FINE.
IF THERE'S A PLANT THAT MAKES
YOUR STOMACH UPSET, REMEMBER
WHAT IT IS AND DON'T EAT THE
PLANT, JUST AVOID THEM.
IN MODERN ENVIRONMENT IF YOU'RE
ALLERGIC TO HOUSE DUST MITE THE
ONLY WAY TO MIMIC WHAT NATURE
INTENDED IS NOT TO LIVE INDOORS
WHICH IS NOT AN OPTION.
THAT SORT OF -- THAT'S THE
PRINCIPLE OF EVOLUTIONARY TRAP.
WITH ALLERGIES, WE THINK AND
THERE'S PLENTY OF EVIDENCE WITH
HUMANS THAT ONE IMPORTANT ASPECT
OF ALLERGIC DEFENSE IS
BEHAVIORAL DEFENSE, AVOIDING
EXPOSURE.
ONCE THE SYSTEM DETECTED
SOMETHING IS PROBLEMATIC, TRIES
TO REMEMBER IT AND AVOID IT.
THAT'S BEHAVIORAL DEFENSE.
THAT'S WHAT WE STUDIED.
I'LL GO QUICKLY THROUGH THIS
PART.
BUT I WANT TO GET TO THE FINAL
POINT.
BUT THE HISTORY OF THAT IS
ACTUALLY THERE'S BEEN STUDIES
ABOUT 30 YEARS AGO IN BRAZIL
FROM A GROUP WHERE THEY LOOKED
IT THE QUESTION WHETHER
ALLERGIES WOULD PROMOTE AVERSE
BEHAVIORS, MADE MICE ALLERGIC TO
CORN OR PEA PEANUTS, GAVE THEM
CHOICE TO EAT BOTH, THEY CHOOSE
ONE OTHER THE OTHER, OVER 30
YEARS AGO.
WE WANTED TO STUDY WITH MODERN
APPROACHES TO LOOK IN MORE
DETAIL.
WE USE THIS PREFERENCE TEST,
EITHER MAKE MICE ALLERGIC OR
NOT, AND THEN WE GIVE THEM A
CHOICE TO DRINK CLEAN WATER,
REGULAR WATER, OR WATER OF THE
ALLERGEN THEY ARE SENSITIVE TO.
AND IT'S SO HAPPENS WHICH WAS
GOOD FOR EXPERIMENTAL PURPOSES
THEY ACTUALLY -- IF THEY ARE NOT
ALLERGIC THEY PREFER THE WATER
WITH ALBUMIN FOR SOME REASON BUT
GOOD FOR US, MADE RESULTS MORE
CLEAR.
IN CONTROL MILES THEY PREFER
ALBUMIN WATER, IF ALLERGIC THREE
LOSE PREFERENCE, OVER TIME START
AVOIDING.
48 WEEKS PAST THEY NOW PREFER
DRINKING CLEAN WATER AND AVOID
OVALBUMIN WATER.
IF YOU USE BSA THEY ARE FINE.
THEY WILL CONTINUE DRINKING IT.
ANTIGEN SPECIFIC RESPONSE,
BEHAVIORAL RESPONSE, AND THE
NEUROBIOLOGICAL ASPECTS OF
AVOIDANCE BEHAVIOR, IN THE
CONTEXT OF SICKNESS, CIRCUITS
THAT ARE INVOLVED IN INDUCING,
FOR EXAMPLE, ANOREXIA AND
AVOIDING FOOD CONSUMPTION,
INCLUDES INFORMATION COLLECTED
THAT COMES FROM VISCERAL SENSORY
NEURONS AND COMMUNICATES WITH A
MAJOR BREAK ON BEHAVIORS LIKE
FOOD CONSUMPTION.
THAT INFORMATION ALSO THEN
PASSED ON TO AMYGDALA TO
GENERATE MEMORIES ABOUT THE
NEGATIVE EXPERIENCES TO AVOID IT
IN THE FUTURE.
WE FOUND THAT IF WE MAKE MICE
ALLERGIC AND THEN EXPOSE THEM TO
ALLERGEN, ALL THESE BECOME
ACTIVATED WHEN MICE EXPERIENCE
NEGATIVE STIMULI THAT INDUCE
AVOIDANCE BEHAVIOR, THEY WILL
BECOME ACTIVATED, AND THAT
RESPONSE IN THE BRAIN IS
DEPENDENT ON IG ANTIBODIES,
WITHOUT THEM AVOIDANCE GOES AWAY
AND ACTIVATION OF THE BRAIN
AREAS GOES AWAY.
SO IT'S ANTIGEN-SPECIFIC
BEHAVIORAL RESPONSE.
AND BECAUSE IGE ALSO DEPENDS ON
CELLS SHOWN HERE.
THE QUESTION IS HOW DO MUST
CELLS COMMUNICATE WITH THE
NERVOUS SYSTEM, CENTRAL NERVOUS
SYSTEM TO PROMOTE AVERSIVE
BEHAVIORS.
THERE ARE TWO MECHANISMS, FAST
AND SLOW, VERY MUCH SIMILAR TO
SOME OTHER TIMES OF AVERSIVE
BEHAVIORS, FOR EXAMPLE PAIN.
THERE'S A FAST PAIN, WHICH IS
MEDIATED BY A-BETA FIBERS, FAST
RESPONSE WHEN YOU WITHDRAW FROM
TOUCHING SOMETHING PAINFUL, AND
THERE'S SLOW PAIN MEDIATED BY C
FIBERS, MUCH MORE PROLONGED.
WE THINK THERE'S SOMETHING
SIMILAR.
MECHANISTICALLY IT'S NOT THROUGH
DIFFERENT TYPES OF FIBERS BUT
IT'S DIFFERENT TYPES OF SIGNALS.
THE FIRST THING WE FOUND THERE
IS THIS HORMONE EXTREMELY
INTERESTING INDUCED WHEN THERE'S
SOMETHING OFF.
IT PATHOGENS, TOXINS, DNA
DAMAGE, SO FORTH, INDUCES
PROTECTIVE RESPONSE LIKE NAUSEA,
ANOREXIA, CAN BE PROBLEMATIC IN
CACHEXIA.
RECEPTOR IS EXPRESSED IN THE
BRAIN AREA RESPONSIBLE FOR
VOMITING, NAUSEA, THESE TYPES OF
PROTECTIVE RESPONSES FROM
TOXINS.
AND SO WHAT WE FOUND IS THAT GDF
15 IS ROBUSTLY INFUSED WHEN
SENSITIZED MICE ARE EXPOSED TO
ALLERGEN.
AND, YEAH, THIS IS JUST I THINK
TIME COURSE THERE.
AND THIS PRODUCTION IS DEPENDS
ON IgG AND MAST CELLS.
IT IS KNOWN TO ACT AND INDUCE
NAUSEA AND AVERSION, THAT'S ONE
MECHANISM.
WHEN WE BLOCK GDF 15 AVOIDANCE
BEHAVIOR GOES AWAY AND THEY KEEP
CONSUMING OVALBUMIN THAT THEY
ARE ALLERGIC TOO.
HOW DO MUST CELLS TURN ON THE
PRODUCTION?
IT WAS NOT COMING FROM MUST
CELLS, TURNS OUT IT WAS COMING
FROM -- IT REQUIRED A DIFFERENT
PATHWAY THAT OPERATES IN MAST
CELLS, THESE LEUKOTRIENES, THE
TARGET DRUGS CAN INHIBIT THEM OR
GENETIC KNOCKOUTS, THAT'S WHAT
WE USED.
AND FOUND THAT IF WE BLOCKED
LEUKOTRIENE, BY DIFFERENT STEPS
OF SYNTHESIS, ON THE LEFT YOU
SEE AVOIDANCE IS ABLATED.
AND IF WE USE THE KNOCKOUT IT
GOES AWAY COMPLETELY SO THE MICE
NOW DON'T DISTINGUISH AND THEY
CONTINUE CONSUMING EVEN THOUGH
THE REST OF THE ALLERGIC
RESPONSE IS THERE, INTESTINAL
INFLAMMATION, DIARRHEA, BUT THEY
KEEP EATING SOMETHING THAT'S BAD
FOR THEM.
AND SO, BASICALLY WHAT WE FOUND
IS THAT TWO PATHWAYS, BOTH
INITIATED BY ANTIGEN RECOGNITION
OF ALLERGEN, ACTS ON TWO
PATHWAYS, EPITHELIAL CELLS IN
THE LARGE INTESTINE INCLUESES
PRODUCTION, REPORTED IN THE
CONTEXT OF KIEM THERAPEUTIC
DRUGS, HOW LTC INDUCES WE STILL
ARE WORKING OUT SOME DETAILS BUT
SEEMS LIKE IT'S DOWNSTREAM OF
LTC4.
FOR FAST RESPONSE THROUGH VAGUS
POPULATION OF VAGAL NEURONS
STIMULATED AND GO INDUCE THE
SAME CIRCUMSTANCES THAT I SHOWED
BEFORE.
THERE'S TWO PATHWAYS LEADING TO
AVERSION.
AND THAT BIOLOGY WE THINK IS A
VERY IMPORTANT PART OF ALLERGIES
WE ABUSE IN THE MODERN WORLD
BECAUSE AVOIDANCE ALTHOUGH IT'S
THE MOST EFFECTIVE WAY AND
SOMETIMES POSSIBLE IN MANY
SITUATIONS NOT POSSIBLE TO
COMPLETELY AVOID SOMETHING.
LIKE I DESCRIBED WITH HOUSE DUST
MITE.
EVEN WITH FOOD ALLERGIES WHERE
YOU THINK, WELL, AVOIDING
PEANUTS ALLERGIES ARE
PROBLEMATIC IN THE NATURAL
WORLD, YOU HAVE 150 SOURCES OF
FOOD, WE REDUCED EVERYTHING TO
JUST FEW, PEANUTS-BASED FOODS
BECOME VERY DOMINANT AND HARD TO
AVOID.
BASICALLY THE IDEA THAT NORMALLY
INDUCTION OF THIS RESPONSE IS
AVERSION, UNPLEASANT FEELINGS IN
ADDITION TO EXPELLING SOMETHING
INDUCES AVOIDANCE A NATURAL AND
EFFECTIVE WAY IN THE WILD.
IN THE MODERN ENVIRONMENT IT'S
HARD TO DO THAT.
SO THIS PART, WHAT IT SUGGESTS,
IT EXTENDS THIS IDEA THAT
NEURONS, IN THE SENSORY
PHYSIOLOGY NEURONS CAN SENSE
SOMETHING DIRECTLY LIKE
OLFACTORY NEURONS OR INDIRECTLY
THROUGH SPECIALIZED SENSORY
CELLS, USUALLY EPITHELIAL CELLS
THAT DETECT SOMETHING FOR
EXAMPLE TASTE BUD CELLS DETECT
TASTE IN THE TONGUE AND
COMMUNICATE TO SENSORY NEURONS,
HERE CELLS DETECT VIBRATIONS,
COMMUNICATE TO NEURONS, ENTERING
THE CELLS IN THE GUT DETECT
NUTRIENTS, COMMUNICATE TO
NEURONS.
WHAT WE'RE ADDING MAST CELLS
WHEN DETECT ALLERGENS DETECT
NEURONS.
WHAT CAN BE DETECTED IS NOW
BECAUSE IT'S IGE, EXPANDING THIS
SCOPE OF SENSORY MODALITY,
ALMOST TO INFINITY, OF COURSE
ANYTHING COULD BE AN ALLERGEN
POTENTIALLY, YOU CAN MAKE
ANTIBODIES TO ALMOST ANYTHING.
IT'S A WAY FOR THE IMMUNE SYSTEM
TO EXPAND SENSORY CAPABILITIES
OF THE NERVOUS SYSTEM OF THE
SENSORY PATHWAYS, AND MOREOVER
THAT EXPANSION CAN BE FOR ANY
PARTICULAR CONTEXT WOULD BE
ANTIGEN SPECIFIC.
IN PRINCIPLE ONE CAN MANIPULATE
THESE TYPES OF BEHAVIORS AT
LEAST THROUGH SPECIFIC ANTIGENS.
AND TO FINISH I WANT TO PUT IT
IN THE OTHER CONTEXT WHY THESE
FINDINGS WITH AVOIDANCE AND
COMMUNICATION BETWEEN NERVOUS
SYSTEM, IT'S INTERESTING TO US,
ILLUSTRATES THIS IS AN EXAMPLE
OF ASSOCIATIVE LEARNING.
CLASSICAL EXAMPLE IS PAVLOV'S
DOGS, TO TYPES OF STIMULI,
ANIMAL IS HARD WIRED TO RESPOND
IN A STEREOTYPIC WAY.
MEAT HERE INDUCES PRE-PROGRAMMED
RESPONSE LIKE SALVATION, SO ON.
CONDITIONED STIMULUS LIKE RING
OF A BELL DOESN'T INDUCE THAT
RESPONSE, IF THEY ARE COMBINED,
BY ASSOCIATION, CONDITIONED
STIMULUS INDUCE CONDITIONED
RESPONSE.
THAT'S CLASSICAL CONDITIONING.
IN THE IMMUNE SYSTEM EXACT SAME
SITUATION WHERE WE HAVE SIMPLER
EXAMPLE WITH TYPE 1 IMMUNITY,
UNCONDITIONED STIMULUS WHICH
WOULD BE MICROBIAL STRUCTURES
THAT ARE DETECTED BY PATTERN
RECOGNITION RECEPTORS LIKE LPS,
TLR, PRE-PROGRAMMED RESPONSE
NOTHING TO LEARNED, LEARNED
THROUGH EVOLUTION.
IF WE HAVE CONDITIONED STIMULUS
WHICH WOULD BE ANTIGEN, DETECTED
BY ANTIGEN RECEPTORS THAT
GENERATE, DON'T KNOW WHAT THAT
MEANS, NO RESPONSE, IF YOU
COMBINE THEM HAVE YOU
ASSOCIATION AND YOU HAVE
ADAPTIVE IMMUNE RESPONSE.
NOW CONDITIONED STIMULUS,
ANTIGEN ALONE WILL INDUCE
CONDITIONED RESPONSE, THE SAME
PRINCIPLE IN BOTH CASES.
THEN A PHENOMENON MAKES A
CONNECTION TO THE ASSOCIATED
LEARNING IN ALLERGIES,
PHENOMENON IS KNOWN AS
CONDITIONED FLAVOR AVERSION,
WHEN YOU EAT SOMETHING THAT
DOESN'T AGREE WITH YOU, AND THEN
THAT FLAVOR OF THAT FOOD THAT
MADE YOU SICK YOU REMEMBER IT
AND CAN NEVER EAT IT AGAIN,
RIGHT?
SO OFTEN IT COMES FROM SEAFOOD,
PROBABLY NOROVIRUS INFECTION OR
SOMETHING LIKE THAT MAKES YOU
VERY BAD FOOD POISONING, AND
THEN YOU CAN'T STAND SMELL FOR
DECADES, RIGHT?
ALMOST ALL THE PEOPLE HAVE SOME
EXPERIENCE OF THAT SORT.
WHAT HAPPENS HERE IS THAT
THERE'S SOME TOXIN THERE.
WE DON'T HAVE SPECIAL SENSES
LIKE THROUGH SMELL OR TASTE TO
DETECT THE TOXIN.
THE ONLY WAY WE CAN DETECT IS
BECAUSE IT MADE US SICK.
BUT WE WANT TO AVOID IT IN THE
FUTURE.
SO WHAT WE DO, WE MEANING
ANIMALS, ASSOCIATE WITH
SOMETHING THEY CAN DETECT, IN
THIS CASE FLAVOR, TASTE, AND
SMELL.
NEXT TIME THEY TASTE OR SMELL,
THEY SAY I WON'T EAT IT, LAST
TIME I ATE IT I WAS SICK.
THAT'S WHAT CONDITIONED FLAVOR
AVERSIONS ONE OF THE MOST POTENT
PARADIGMS IN ASSOCIATIVE
LEARNING, IT WORKS WITH ONE TRY.
AND SO IN THIS CASE WHAT WE HAVE
SOMETHING WE CANNOT DETECT,
TOXIN.
WE DON'T HAVE ANY SENSORS FOR
IT.
IT MAKES US SICK.
AND THERE'S SOMETHING WE CAN
DETECT, WHICH IS FLAVOR.
WE ASSOCIATE THEM.
WHAT IF THERE IS NO FLAVOR?
AND THAT'S THE CASE OF ALLERGIC
CONDITIONED RESPONSES.
SO AGAIN IF YOU HAVE LET'S SAY
SOME FOOD ANTIGENS, AND THERE'S
NOTHING NOXIOUS, NOTHING CAUSING
MALAISE, JUST NORMAL RESPONSE TO
FOOD, IF THERE'S SOMETHING
NOXIOUS THERE THAT CANNOT BE
DETECTED BY ANY OF THE SYSTEMS,
BUT WOULD MAKE YOU SICK, YOU
WANT TO ASSOCIATE WITH SOMETHING
YOU CAN DETECT.
IF IT'S FLAVOR, FINE.
YOU DEFECT FLAVOR.
IF IT'S NOT THEN WHAT DO YOU DO?
THAT'S WHERE WHERE THIS COMES ,
PROTEIN ANTIGENS, IT WILL DETECT
THEM, WHATEVER MADE YOU SICK,
NEXT TIME YOU SEE THIS ANTIGEN
DON'T EAT IT, THAT'S WHAT I
THINK IS THERE.
THE PURPOSE OF THIS RESPONSE.
BOTH CONDITIONED FLAVOR AVERSION
AND ANTIGEN SPECIFIC AVERSION,
YOU CAN THINK, WELL, THIS IS
KIND OF SILLY SYSTEM BECAUSE
MOST OF THE TIME THINGS WILL NOT
HAVE TOXINS.
AND WE KNOW THAT ALLERGIC
IMMUNITY IS ERROR PRONE.
IT'S NOT THAT IT MAKES --
DOESN'T MAKE MISTAKES, IT DOES
BUT IT'S SPECIFIC TIMES OF
MISTAKES.
BASICALLY MAKES FALSE POSITIVE
ERRORS.
THE REASON FOR THAT IS, THAT'S
MY LAST SLIDE, EVERY SENSORY
SYSTEM HAS TO OPTIMIZE
SPECIFICITIES, THERE'S A
TRADEOFF, YOU CANNOT OPTIMIZE
BOTH.
WHICH ONE DO YOU OPTIMIZE?
THAT DEPENDS ON THE VALENCE OF
THE STIMULUS.
IF IT'S POSITIVE, SOMETHING
GOOD, LIKE FOOD OR WHATEVER,
THEN MAXIMIZE SPECIFICITY AND
THAT'S PRONE TO FALSE NEGATIVE
ERRORS.
THAT BASICALLY MEANS THAT WE
ALWAYS WANT SOMETHING BETTER,
RIGHT?
IF IT'S NEGATIVE VALENCE, FALSE
NEGATIVE ERROR WOULD BE COSTLY
BECAUSE THAT CAN KILL YOU,
CAUSES ILLNESS.
WHAT YOU DO INSTEAD MAXIMIZE
SENSITIVITY, AND THAT IS MAKING
IT PRONE TO FALSE POSITIVE
ERROR.
SO IT'S BETTER SAFE THAN SORRY.
YOU REACT TO SOMETHING, YOU
DIDN'T HAVE TO, BUT IT'S BETTER
THAN NOT REACTING.
THAT'S THE IDEA.
SO ALLERGIC IMMUNITY IS
ILLUSTRATING THAT PRINCIPLE IT'S
VERY PRONE TO FALSE POSITIVE
ERRORS BECAUSE IT MAXIMIZED
SENSITIVITY OVER SPECIFICITY.
I'LL RECOGNIZE THESE PEOPLE THAT
DID THE WORK.
THANK YOU VERY MUCH, AGAIN, FOR
YOUR ATTENTION.
[APPLAUSE]
>> WE'RE PAST THE HOUR BUT THIS
GROUP IS CONDITIONED TO HAVE
LECTURES UNTIL 5:00, SO PROBABLY
CAN'T HANG OUT TOO LONG.
A HANDFUL OF QUESTIONS, MAYBE
YOU OVER THERE FIRST, MAYBE FOUR
QUESTIONS WE CAN DO.
>> FIRST, THIS WAS I THOUGHT A
PERFECT BILL PAUL LECTURE, THE
CONTRIBUTIONS TO TYPE 2 IMMUNITY
THAT WERE DISCUSSED HERE.
WITH REGARD TO THE PET SHOP
MICE, AND THE HYPOTHESIS OF
REPEATED -- HIGH MICROBIAL
ANTIGEN EXPOSURE, I WOULD THINK
ONE OF THE CONSEQUENCES OF THAT
WOULD BE DEVELOPMENT OF A MUCH
MORE ROBUST PERIPHERAL POWERING
SYSTEM LIKE ABILITY TO PRODUCE
IL-10 AND B CELLS OR TREGS AND
SO ON.
SO I WAS WONDERING IF YOU
BLOCKED IL-10 IN THE SETTING,
DID - YOU -- COULD YOU REVERSE?
>> CAN YOU REMOVE THE BREAKS IN
ALLERGIC -- YEAH, WE DON'T KNOW.
WE HAVEN'T DONE THAT EXPERIMENT.
WE'VE DONE EXPERIMENTS WITH
INDUCING TOLERANCE IN THE MICE
BUT I MEAN I SEE WHAT YOU MEAN
AND I AGREE WITH YOU COMPLETELY
THAT THEY ALSO HAVE OF COURSE
NOT JUST INCREASED REACTIVITY TO
EVERYTHING BUT MUCH INCREASED
COMPORTMENT THAT PROBABLY
CONTRIBUTES BUT WE CAN SEE THE
CROSS-REACTIVITY IS SUFFICIENT
WE'VE DONE EXPERIENCE WITH
TRANSFERS AND SO ON BUT I AGREE
TREGS WOULD BE -- THERE'S
SOMETHING WE COULD TRY IF IT'S
BLOCKING.
>> JUST BECAUSE IN THE CONTEXT
OF HELMINTH INFECTION IN PEOPLE,
IL-10 IS ALWAYS LIKE THE KEY,
ONE OF THE KEY CYTOKINES.
>> WE HAVEN'T DONE SPECIFIC
EXPERIMENT BUT IT WOULD BE GOOD
TO TRY IT, YEAH.
>> HI.
SO, YOU MADE A POINT THAT IT'S
THE EARLY EXPOSURE TO ANTIGENS
THAT SOMEHOW FILL OUT A
REPERTOIRE AND THAT'S MISSING IN
THE SPF.
BUT SINCE THE ANTIBODY
REPERTOIRE T-CELL RECEPTOR IS
ALMOST INFINITE, HOW DO YOU --
WHAT'S THE HOLE, AND HOW DO YOU
FILL IT?
THAT IS, ARE THERE PARTICULAR
SPECIFICITIES, OR IS IT THAT
YOU'RE GENERATING BROADLY
CROSS-REACTING ANTIBODIES EARLY
THAT ARE FILLING OUT LARGE
THINGS?
OR ARE THERE -- COULD ONE
IDENTIFY SPECIFIC ANTIGENS WITH
SOME CAREFUL WORK THAT COULD
PLUG THESE HOLES MOST OPTIMALLY
AND THEN PREVENT ALLERGY?
>> YEAH, THE SECOND PART IS
EXACTLY WHAT WE'RE THINKING
ABOUT TRYING TO EXPORT LIKE FOR
THERAPEUTIC PURPOSE ALSO.
THE FIRST PART IS THE HARDER
QUESTION.
WE DON'T KNOW BECAUSE WHAT WE'VE
TRIED SO FAR IS LIMITED.
JUST EXTRAPOLATING WITH THAT
MODEL.
BUT I THINK THE NOTION THAT WE
KIND OF ARE GETTING CONVERTED TO
IS THAT THE IDEA OF ANTIGEN
SPECIFICITY, IT MAY BE BETTER OR
AT LEAST ALTERNATIVE WAY TO
THINK BIT, NOT SPECIFICITY BUT
REACTIVITY.
SPECIFICITY IS VERY RELATIVE
TERM, RIGHT?
AND REACTIVITY IS MORE NEUTRAL
AND I THINK MORE CORRECT WAY TO
TALK ABOUT IT, THAT YOU CAN
REACT TO SOMETHING, THAT MAY NOT
HAVE BEEN ANTIGEN SPECIFIC BUT
THE QUESTION QUANTITATIVELY IS
HOW MUCH YOU COVER, HOW MUCH
SPACE YOU COVER.
AND WE HYPOTHESIZE THAT YOU
COVER ON AVERAGE MAYBE ENOUGH,
AND THAT WOULD ON AVERAGE
PROVIDE THE STATE WHEN IMMUNE
SYSTEM IN ADULT IS NEVER LIKE
TRULY NAIVE, BUT THERE'S ALWAYS
SOME REACTIVITY.
BUT IT MAY BE BIASED TO THINK
MAYBE MORE COMMON IN THE
ENVIRONMENT.
THAT WOULD MAKE SENSE,
BIOLOGICALLY, BUT WE DON'T KNOW
THAT.
THAT'S THE QUESTION THAT'S
DEFINITELY WE NEED TO EXPLORE
FURTHER TO SEE WHETHER WE CAN
SEE IF THERE ARE STILL GAPS IN
--
>> RIGHT, BEING ABLE TO BE
TOLERANT TO PROTEIN-LIKE
STRUCTURES VERSUS SOME WEIRD
CHEMICAL STRUCTURE THAT WOULD
NOT BE THERE.
>> RIGHT, EXACTLY.
SO THAT'S THE QUESTION.
ONE CAN THINK OF DIFFERENT TYPES
OF REACTIVITY PROFILES, SO CAN
IMAGINE SOMETHING SHALLOW LIKE
THIS WHERE IN THE MIDDLE HIGHEST
AFFINITY, DEVIATIONS ARE HIGH,
SURFACES MAY BE SMOOTHER SORT OF
SURFACE, YOU MAKE TEN VERSUS
EIGHT HYDROGEN BONDS, THE PEAK
WOULD BE SHARP.
PARTICULAR IN STRUCTURE TO
DETECT IT.
WONDERFUL SYSTEM BUT MAYBE
BIASED, THINKING ABOUT
SPECIFICITY.
>> THANK YOU.
>> FASCINATING.
I HAVE A QUESTION ABOUT THIS
EARLY EXPOSURE SENSITIZATION.
SO WHAT YOU DESCRIBED LARGELY
FITS WITH SO-CALLED HYGIENE
HYPOTHESIS.
BUT ONE VARIATION I'M NOT SURE
IF YOU WERE SAYING THIS IS THAT
IT DEPENDS ON THE SKEWING OF THE
IMMUNE SYSTEM AT THE TIME OF
FIRST EXPOSURE.
SO, IF YOU'RE EXPOSED TO A LOT
OF ENVIRONMENTAL MICROBES, AT AN
EARLY AGE, THAT SKEWS YOU MORE
TOWARD A Th1 TYPE RESPONSE AND
THEN WHEN YOU'RE EXPOSED YOU
MAKE AN IgG RESPONSE RATHER
THAN AN IGE RESPONSE, WHEREAS IF
AN INFANT IS MORE Th2 SKEWED
THAN EXPOSURE MIGHT LEAD TO AN
ALLERGIC SENSITIVITY.
AND THINKING IN THAT WAY I
WANTED TO ASK A PRACTICAL
QUESTION, WHICH IS, FOR A LONG
TIME PEDIATRICIANS RECOMMENDED
NOT EXPOSING INFANTS AND YOUNG
CHILDREN TO PEANUTS TO AVOID
DEVELOPING ALLERGIES BUT THAT
FLIPPED IN THE LAST FIVE OR TEN
YEARS, THE RECOMMENDATION IS
EXPOSURE KIDS VERY EARLY TO
PEANUTS AND OTHER POTENTIAL
ALLERGENS.
HOW DOES THAT FIT AND WHERE IS
THE CUTOFF BETWEEN SENSITIZATION
AND --
>> THANKS.
THIS IS AN IMPORTANT
DISTINCTION.
HOW MUCH THE COVERAGE, ANTIGEN
COVERAGE CONTRIBUTES VERSUS
EFFECTOR TYPE VERSUS
TOLERIZATION.
IN THE CASE OF THE PEANUT
FEEDING TO BABIES IT'S ALL ABOUT
INDUCING THIS TOLERANCE,
EXTENDING TREGS SPECIFIC FOR
PEANUT ANTIGENS.
THERE'S THAT CONTRIBUTION.
AND IN THAT CASE I THINK
PROTECTION PROBABLY WORKS
THROUGH THAT MECHANISM, AS YOU
IMPLY, INDUCING TOLERANCE
TOWARDS THE PARTICULAR ANTIGEN.
IN THE CASE OF DEVIATING
RESPONSE TO OPPOSITE TYPE OF
RESPONSE, VERSUS ANTIGEN
COVERAGE, IT'S HARDER TO
DISASSOCIATE FOR US, DEVIATED
IgG TYPES OF ANTIBODIES
PROVIDE PROTECTION, IT'S BOTH,
HAVING ANTIBODIES AND OF THAT
PARTICULAR TYPE.
IT'S HARDER TO DISTINGUISH, AND
I THINK THEY PROBABLY SHOULD BE
DISTINGUISHED OUT OF INTEREST
BUT I THINK GENERALLY WOULD
OPERATE TOGETHER.
BUT DISTINGUISHING FROM THE
PATHWAY THAT LEADS TO THE
TOLERANCE TO TREG EXPANSION
VERSUS ANTIGENIC COVERAGE I
THINK THESE OPERATE ON DIFFERENT
TIME SCALES, DISCRETE EVENT IN
EARLY LIFE DEVELOPING TREGS
VERSUS CONTINUOUS ACCUMULATION
OF SPECIFICITIES OR REACTIVITIES
TOWARDS DIFFERENT ANTIGENS THAT
TAKES MAYBE YEARS IN HUMANS TO
DEVELOP.
>> OKAY.
THANK YOU.
>> LET ME REPEAT THE CME CODE,
57689.
WE'LL HAVE A RECEPTION I BELIEVE
WITH PEANUTS AND FRIED CALAMARI
OUT THERE.
[LAUGHTER]
HURRY UP.
LET'S THANK OUR SPEAKER ONE LAST
TIME.
[APPLAUSE]