>> IT'S REALLY A PLEASURE TO
WELCOME YOU YOU ALL THIS
AFTERNOON TO THE LAST IN THE
SERIES OF WEDNESDAY AFTERNOON
LECTURES FOR THIS ACADEMIC YEAR
BEFORE THE BEGINNING OF THE
SUMMER HOLIDAY SEASON.
IT'S MY ENORMOUS PLEASURE TO
INTRODUCE THIS WEEK'S WEDNESDAY
AFTERNOON LECTURER, DR. JULES
HOFFMANN.
DR. HOFFMAN IS THE TRUE PIONEER
IN ELUCIDATING THE MECHANISMS OF
RESIST TONES MICROBIAL ORGANISMS
IN DROSOPHILA, WORK THAT HAS
PROFOUNDLY INFLUENCED OUR
UNDERSTANDING OF THE INNATE
IMMUNE SYSTEM IN HIGHER
ORGANISMS.
HE WAS BORN IN LUXEMBOURG AND
RECEIVED HIS Ph.D. FROM THE
UNIVERSITY OF STRASBOURG IN
FRANCE.
OVER HIS CAREER HE HELD VARIOUS
POSITIONS IN THE FRENCH NATIONAL
RESEARCH AGENCY, THE LATEST
BEING THAT OF DISTINGUISHED
CLASS RESEARCH DIRECTOR AND
MEMBER OF THE BOARD OF
ADMINISTRATION OF THE AGENCY.
FROM 1993 TO 2005, HE WAS THE
DIRECTOR OF
OF MOLECULAR AND CELLULAR
BIOLOGY IN STRASBOURG.
THE RESEARCH OF JULES HOFFMANN
IS CONTINUOUSLY CENTERED ON
STUDIES OF THE DEVELOPMENT AND
THE DEFENSE REACTIONS OF
INSECTS.
STARTING WITH THE GRASSHOPPER,
HE HAS GONE ON TO BIGGER AND
BETTER THINGS WITH THE
DRASOPHLA.
DR. HOFFMAN IN HIS LABORATORY
EXPLORED THE POTENT
ANTIMICROBIAL MECHANISMS OF
DRASOPHLA AS A PARADIGM OF THE
INNATE IMMUNE DEFENSES.
DISCOVERIES ELUCIDATING THE ROLL
OF TOL RECEPTORS HAD PROFOUND
IMPACT OF OUR UNDERSTANDING OF
THE INNATE IMMUNE SYSTEM IN
HUMAN HEALTH AND DISEASE.
HE AUTHORED OR CO-AUTHORD OVER
250 PUBLICATIONS AND EDITED
SEVERAL VOLUMES.
A MEMBER OF THE FRENCH NATIONAL
ACADEMY OF SCIENCES AT WHICH HE
SERVED AS VICE PRESIDENT IN 2005
AND 2006 AND PRESIDENT IN 2007
AND 2008.
IN ADDITION, HE IS A FOREIGN
ASSOCIATE OF THE US NATIONAL
ACADEMY OF SCIENCES AND THE
AMERICAN ACADEMY OF ARTS AND
SCIENCES.
HE WON NUMEROUS PRIZES,
INCLUDING THE WILLIAM B COLEY
AWARD.
WILLIAM COCK PRIZE, AND THE 2011
GARDENER INTERNATIONAL PRIZE IN
TORONTO.
PLEASE JOIN ME IN WELCOMING
DR. JULES HOFFMANN TO THE
PODIUM.
[APPLAUSE]
>> THANK YOU VERY MUCH FOR THIS
WARM WELCOME AND LADIES AND
GENTLEMEN, I'M VERY HONORED.
VERY HONORED WHEN I RECEIVED
THIS INVITATION TO GIVE THIS
AFTERNOONzV LECTURE.
AND WHAT I WOULD LIKE TO DO
IS -- THANK YOU.
WHATWHAT I WOULD LIKE TO DO IS
SHOW
YOU OR TELL YOU THE STORY WHICH
LED US TO UNDERSTAND SOME OF THE
BASIC ASPECTS OF DROSOPHILA
IMMUNE RESPONSE AND I' LIKE TO
PUT THIS INTO PERSPECTIVE INTO A
PHYLOGENETIC PERSPECTIVE,
EVOLUTIONARY PERSPECTIVE.
A QUESTION I'M OFTEN ASKED IS,
WHY DID YOU START WORKING ON THE
IMMUNE RESPONSE OF THE FLY IN
GENERAL?
INSECTS AS SHOWN HERE, ARE
FREQUENTLY ATTACKED BY VARIOUS
MICROORGANISMS, BACTERIA,
VIRUSES, PROTOZOA.
THIS CARTOON HERE WAS DRAWN BY
MY FATHER WHO WAS A PROFESSOR OF
ENTOMOLOGY AND LUXEMBOURG.
AND WE STARTED OUT ASKING, WHAT
COULD BE THE REACTIONS IN
INSECTS AGAINST THOSE VARIOUS
MICROORGANISMS?
IT WAS KNOWN FOR A LONG TIME,
CYTOSIS WAS IMPORTANT ASPECT OF
DEFENSE.
WE KNOW NOW THIS RESPONSE AND
EPITHELIAL RESPONSE AND SYSTEMIC
RESPONSE.
I WILL FOCUS ON THE SYSTEMIC
RESPONSE, WHICH HAS BEEN THE
CENTER OF OUR WORK OVER THE LAST
20 YEARS.
SOME OF OUR COLLEAGUES WORK ON
THE EPITHELIAL RESPONSE NOW.
TO START WITH, IN VERY SIMPLE
TERMS, LET ME SHOW YOU WHEN YOU
TAKE OFF THE GLOVE AFTER VARIOUS
TIME INTERVALS, YOU SEE THE
APPEARANCE IN THE CELL.
YOU SEE THE APPEARANCE OF
ANTIMICROBIOTIC ACTIVITY.
WE ASKED THREE QUESTIONS.
THIS IS THE LATE 80's OR
90's.
WHAT IS THE IDENTITY OF THE
MOLECULES WHICH ACCOUNT FOR THIS
INDUCED ANTIMICROBIAL ACTIVITY?
FROM THE EARLIER WORK OFANCE
BOWMAN, WE EXPECTED HAVING
WORKED ON ç BUTTERFLIES, WE
SUSPECTED THIS MOLECULE TO BE
PEPTIDES.
THE SECOND IMPRESSION WE WANTED
THEN IS IF THERE ARE PEPTIDES,
HOW IS THE EXPRESSION CONTROLLED
DURING THE PROCESS OF INFECTION?
AND FINALLY WE WANTED TO ADDRESS
THE QUESTION, HOW DOES AN INSECT
REALIZE THERE IS AN INFECTION
GROWING UP AND CAN IT
DISCRIMINATE DURING VARIOUS
TYPES.
SO TO MAKE A LONG STORY SHORT,
OVER SEVERAL YEARS WE ENDED UP
FINDINGS THAT IN THE FLY THERE
ARE SEVEN ANTIMICROBIAL PEPTIDES
WHICH ARE INDUCED AND GIVEN
VARIOUS NAMES
[READING]
SO THE TAKEHOME MESSAGE HERE IS
FOLLOWING IN FECKS, INJURY, USE
IN THE BODY, THE EQUIVALENT OF
THE MAMMALIAN LIVER, YOU INDUCE
THE EXPRESSION OF SEVERAL
FAMILIES OF ANTICIPATE MICROBIAL
PEPTIDE GENES AND THIS MOLECULE
SECRETES INTO THE BLOOD WHERE
THE OVERALL CONCENTRATION
REACHES HIGH CONCENTRATIONS IN
THE ORDER OF 500 MICROMOLAR.
I'M OFTEN ASKED IF THIS MOLECULE
CAN PLAY OR CAN HAVE POTENTIAL
ROLLS IN THERAPY AND WE COME
BACK TO THAT LATER IN
DISCUSSION.
SO FROM THIS POINT ON, WE WENT
TO ASK HOW ARE THE GENES
CONTROLLING THIS ANTIMICROBIAL
PEB TIDES, CONTROLLING IN
PENSION?
NOW AT THAT TIME, WE WERE LUCKY
TO FIND IN THE FIRST GENE WE HAD
CLONED WAS THE TYROSINE GENE, WE
WERE LUCKY ç TO FIND RESPONSE TO
ELEMENTS, SIMILAR RESULTS WERE
OBTAINED ALSO FOR THE GENES BY
OUR SWEDISH COLLEAGUES.
NOW THEY BE HAD BEEN IDENTIFIED
A FEW YEARS EARLIER AND SO WHEN
WE MUTATED THE SIDES PRECISELY
AND LOOKED AT THE EXPRESSION, WE
COULD SEE MUTATING THE CAPPA B
RESPONSE ELEMENT WOULD ABOLISH
THE ABILITY.
SO THEY WERE WAITING FOR
MANDATORY INDUCTION OF
ANTIMICROBIAL PEPTIDES.
SO VERY SHORTLY, THE FLY HAS
FAMILY MEMBERS WHICH ARE DORSAL
AND GIF.
BOTH MOLECULES HAVE THIS HO
MOLOGIY DOMAIN WE ARE FAMILIAR
WITH IN A MAMMALIAN SYSTEM AND
THEY ARE RETAINED IN THE
CYTOPLASM IN CACTUS WHICH IS THE
EQUIVALENT OF ICAPPAB.
THE THIRD MOLECULE WAS
IDENTIFIED AND NAMED RELISH,
WHICH HAS THE ANCHORING IN
HIBITORY DOMAINS ON ITS C
TERMINISES AND WHICH REQUIRES
ASSOCIATION FROM THE INHIBITORY
DOMAIN IN CONTRAST TO DORSAL
WHICH WILL THEN FREE THE
HOMOLOGY DOMAIN AND ASSOCIATED
TRANSACTIVATED -- AND TO CONTROL
EXPRESSION OF ANTICIPATE
MICROBIAL PEPTIDE GENES IN THIS
CASE.
NOW THE PROBLEM OF NF-KAPPA B
HERE WAS THAT IN THE INITIAL
STAGE, ONLY DORSAL WAS KNOWN.
AND DORSAL WAS CONSIDERED AS A
MATTELY EXPRESSED GENE AND LET
ME SHOW YOU THE DORSAL HAD BEEN
IDENTIFIED IN GERMANY IN THE
EMBYRONIC SYSTEM.
SO THEY HAD SHOWN THROUGH
MUTATING GENES IN THE MOTHER
THAT ç MATERNAL EXPRESSED GENES
CONTROL AMONG OTHER THINGS THE
DOAL VENTRAL AXIS AND THE
EMBRYO OF DROSOPHILA AND THEY
SHOWED THIS WAS MEDIATED BY
DORSAL GENE WHICH WAS INHIBITED
BY THE ACTION OF THE CACTUS
GENE.
AT THAT TIME, NEITHER CACTUS HAD
BEEN CLONED.
I PRESENTED NF-KAPPA B FAMILY
MEMBER WHICH BECAME APPARENT A
FEW YEARS LATER AND CACTUS WE
KNOW IS WE HAVE KNOWN FOR QUITE
A LONG TIME IS AN ICAPPAB
EQUIVALENT.
NOW, THE SYSTEM ASSOCIATES UPON
RECEIVING A SIGNAL FROM
TRANSMEMBRANE RECEPTOR WHICH
REEFERS TO TOL BEFORE IT WAS
CLONED, JUST REFERRING TO THE
PHENOTYPE OF THE MUTATED EMBRYO.
AND TOLD BY INTERMEDIATES TO
ACTIVATE PHOSPHORYLATION OF
CACTUS.
TOL BECOMES ACTIVATED BY A
GROWTH FACTOR AND AGAIN ALL
THESE TERMS WERE CREATED BY
COLLEAGUES AND REFERRED TO THE
PHENOTYPES OF THE MUTATED
EMBRYOS.
AND IT BECOMES CLEAVED AS THE
END PRODUCT OF THE PROT LYTIC
CASCADE, SO A TRIGGER IN THE
FOLLICULAR CELLS WHICH ARE NOT
FULLY UNDERSTOOD YET, WILL
ACTIVATE THE CASCADE AND CLEAVE
A CYTOKINE IN OUR SYSTEM CLOSING
, AND ACTIVATE THE TOLL
RECEPTOR AND WE GO TO THE
TRANSCRIPTION OF EMBYRONIC GENES
BY NF-KAPPA B FAMILY ç MEMBER.
SO FAR FOR THIS INTRODUCTION,
WHEN WE GOT THE RESULTS WHICH I
HAVE MENTIONED EARLIER WHEN WE
CLONED THE GENES, WE THOUGHT
THAT IT MIGHT BE THAT EMBYRONIC
CASCADES HEARD ASTHMA TERNALY
EXPRESSED GENES, MIGHT ALSO PLAY
A ROLE IN THE IMMUNE RESPONSE IN
CONTROLLING THE EXPRESSION OF
ANTIMICROBIAL PEPTIDES.
WHAT WAS AGAINST THIS IDEA,
THESE GENES WERE MA MATERIALLY
EXPRESSED SO WE FIRST WENT ON TO
SHOW THEY WERE ALSO EXPRESSED
LATER IN DEVELOPMENT AND WE
COULD SEE THAT IMMUNE CHALLENGE
WAS UP REGULATING THE EXPRESSION
OF THE TYROSINE GENE.
NOW, IN THIS SLIDE, WE HAVE DONE
THIS AND LOOKED AT THE
EXPRESSION OF INDUCTION OF THE
TYROSINE THIS IS THE LOADED
CONTROL AND I MUST SAY TO OUR
UTTER DISAPPOINTMENT, ONE OF THE
GREATEST DISAPPOINTMENTS I
REMEMBER IN MY SCIENTIFIC
CAREER, THE TOL DEFICIENT
BACKGROUND THERE WAS NO FACT.
FORTUNATELY FOR US, WE DIDN'T
REALIZE THE IMPORTANCE AT THAT
TIME IMMEDIATELY, WE HAVE A LINE
IN OUR STOPS, A MUTATED LINE
WHICH LATER ON WE REFERRED TO AS
IMD, IN WHICH THERE>ñ WAS NO
INDUCTION OF THE TYROSINE GENE
BY THIS IMMUNE CHALLENGE.
NOW WHEN WE FOUND THE
DROSOMYCIN, ANTIFUNGAL PEPTIDES,
TWO WEEKS LATER, WE TESTED THEM
AND WE HAVE CONVERSE PHENOTYPE
THAT.
IS TO SAY THIS TIME WE SAW THAT
IT WAS NOT INDUCIBLE ANYMORE IN
THE BACKGROUND BUT TYROSINE
WAS -- EXCUSE ME IT WAS TRULY
INDUCIBLE IN THE IND BACKGROUND
WHICH THEN INDICATED TO US THAT
WE ç HAD PROBABLY TWO SIGNAL
PATHWAYS CONTROLLING EXPRESSION
OF THE ANTIMICROBIAL GENE
FAMILIES, ONE WHICH WOULD BE
PARTIAL REUSE OF THE FULL
PATHWAY OF EMBYRONIC DEVELOPMENT
AND OTHER WHICH WE PROPOSED TO
CALL IND PATHWAY.
WE HAD NOTHING IN OUR HANDS
EXCEPT FOR MUTANT FLY AND THESE
STAND FOR IMMUNE DEFICIENCY.
NOW, IMPORTANTLY FOR US AT THAT
TIME, WE COULD SHOW THAT IF WE
WERE TRYING TO INFECT FLIES, AND
IF WE INFECTED FLIES, WITH
E.COLI AS ILLUSTRATED HERE, WE
HAD -- YOU WILL SEE THE RED LINE
SHOWING SURVIVAL IN WILDTYPE
FLIES.
THEY ARE NOT AFFECTED, NOT
REALLY AFFECTED BY THIS E.COLI
AND THIS SWITCH WE ARE USING
HERE.
THESE ARE NOT THE AGGRESSIVE
STRAINS IN GERMANY.
BUT WHEN WE COMPARE THE SURVIVAL
TO THESE BACKGROUND, YOU SEE THE
MAPPING IS DRAMATICALLY
AFFECTED.
IN OTHER WORDS REALLY THE
PATHWAY PLAYS IN BACTERIA.
REMEMBER IT INDUCES EXPRESSION
IN TYROSINE.
IMPORTANTLY AGAIN, SUCH FLIES
WOULD SURVIVE NORMALLY INFECTION
AS WILDTYPE INFECTION BY FUN
GIAND THE SECOND SLIDE HERE IN
THE SERIES LOOKING AT HERE
DRAMATICALLY AFFECTED AS
COMPARED TO WILDTYPE.
AND THIS PICTURE WHICH WAS IN
OUR CELL PAPER --
[SPEAKING FRENCH]
-- WE HAD AyM FLYOVER GROWN
HERE,
A DEFICIENT FLY HERE.
NOW LET ME JUST PAUSE A SECOND
AND SAY, WE CAME FROM THE
DROSOPHILA BACKGROUND AND WE HAD
A COLLABORATION AT THAT TIME
WITH SEVERAL OTHERS.
LET ME POINT OUT WHY THIS WAS
IMPORTANT AT THAT PRECISE TIME.
SO IT HAD BEEN DESCRIBED OR WAS
KNOWN THAT ANDROGEN PRESENTING
CELLS WERE ACTIVATING
T-CELLS 
THIS IS AN ANTIGEN
PRESENTING CELL WHICH IS AN I
IFT CELL
SO IT WAS KNOWN THAT WHEN
MICROBIAL LIGANDS INTERACT WITH
THIS ANTIGEN PRESENTING CELL,
THEY ACTIVATE NF-KAPPA B BY AN
UNKNOWN RECEPTOR AND THEN THE
NF-KAPPA B UP REGULATION OF
EXPRESSION OF MOLECULES CYTOKINE
PRODUCTION AND SO ON.
THIS WAS AND THIS ENDS UP THIS
ASPECT OF INNATE IMMUNITY
STIMULATES ADAPTIVE IMMUNITY.
THIS WAS A PARADIGM OF
ADAPTATION OF ACTIVATION OF
ADAPTIVE IMMUNITY WHICH WAS
AVAILABLE AT THAT TIME AND HAD
BEEN PROPOSED PARTICULARLY
BY -- AS YOU MAY KNOW
NOW LET ME SHOW YOU THE RESULTS
PUT INTO PERSPECTIVE OF THAT
PERIOD.
SO, ON ONE SIDE OF THE SLIDES WE
SEE HERE CD14, WHICH WAS KNOWN
AT THAT TIME TO BE ABLE TO BIND
LPS, ONE OF THE PROTOTYPICAL
INDUCERS OF INACTIVE ADAPTIVE
IMMUNITY.
IT WAS GPI ANCHORED AND WE ARE
LOOKING FOR SOMETHING.
LOOKING FOR SOMETHING WHICH
ACTIVATES NF-KAPPA B.
IT WAS AN INTERESTING
INDICATION.
ACTIVITIES KNOWN THAT
INTERLEUKIN 1 RECEPTOR SEEMS,
VIA THE DOMAIN HERE, IT HAS
EXTRA CYTOPLASMIC IG-LIKE
DOMAINS.
SO IN HERE WE SHALL TOLL SEEMS
TO FIT INTO THE PATTERN OF
THE -- WHICH IN CD14 BINDS LPS
AND INTERESTINGLY IT PASSES THE
DOMAIN CLOSE TO THE ONE WHICH IN
THE INTERLEUKIN ONE RECEPTOR
ACTIVATORS NF-KAPPA B.
THIS THEN SUGGESTED THAT THERE
WAS AT LEAST IN ONE MET ZERO AN
SYSTEM, THIS WAS A CHI MERA OF
THE EXOCYTOPLASM DOMAIN.s
AND THIS CHIMERA WAS CAPABLE OF
HELPING THE FLY DEFEND ITSELF
AGAINST MICROBIAL AGGRESSION.
NOW FROM THERE, AS YOU MAY KNOW,
SEVEL STUDIES IN A VERY SHORT
PERIOD, SO OUR STUDY WAS IN 96,
ONE YEAR LATER THAN JANUARY IN
COLLABORATION AT THAT TIME, AND
ONE FOUND MA
MAILMAILIAN -- HUMAN HOMOLOGUE I
SHOULD SAY, AND THEY COULD SHOW
BY TRANSFECTING THE
TRANSMEMBRANE DOMAIN IN HUMAN
CELLS HOOKED TO AN CD4 DOMAIN
THAT THEY COULD ACTIVATE NF
CAPPA B ADAPTIVE IMMUNE
RESPONSE.
AND A YEAR LATER BY CLONING THE
LPS GENE IN MICE WHICH WERE
NONRESPONSIVE TOANDO TOXIN.
HE COULD SHOW IT WAS IN FACT
EXOCYTOPLASMIC DOMAIN OF THIS
RECEPTOR, THE DOMAIN REACTED TO
LPS AND THEN CONVEYED A MESSAGE
TO NF-KAPPA B.
AND IN PARALLEL, OR A LITTLE BIT
LATER THEN, IN JAPAN HE DID A
SERIES OF VERY IMPORTANT STUDIES
IN WHICH HE CLARIFIED THE
LIGANDS OF THE MAMMALIAN
EQUIVALENCE OF THE FLY, TOLL,
WHICH I REFERRED TO AS TLR, AND
SHOWN HERE.
AT A ALL BIND TO MICROBIAL
LIGANDS.
THE LPS PEPTIDES AND THERE ARE
OTHER RECEPTORS WHICH ARE NOT ON
THIS CYTOMASM MEMBRANE ç WHICH
IS
IN RESPONSE SO VARIOUS SIGNALS.
I HAVE NO TIME TO GO INTO DETAIL
BUT IT IS WELL ESTABLISHED.
AS A RESULT, WE HAVE ADAPTIVE
PROTEINS AND THEN PRODUCTION OF
ANTIMICROBIAL PEPTIDES AND
ACTIVATION OF ADAPTIVE IMMUNE
RESPONSES.
THEN WE COME BACK TO THE FLY
NOW.
SO, WE USUALLY THOUGHT OF COURSE
THAT TOL MIGHT REACT TO ITEMS
AND IT TOOK SOME TIME TO SHOW IT
WAS NOT THE CASE BUT IT WAS
SLOWLY PLAYING THE ROLE IN THE
EMBYRONIC DEVELOPMENT WHICH WAS
BINDING TO TOL AND ACTIVATING
TOLL AND ITSELF WAS CLEAVED VIA
PROTEOLYTIC CASCADE WHICH WAS
INDUCED INFECTION.
IT WAS CLEAR ALSO THE FLY HAD
NINE TOOLS, NOT ONLY ONE.
AND SO THE IDEA WAS CLOSEST TO
THE SITUATION WHICH WOULD
PARALLEL THAT FOUND IN MAMMALS.
THAT IS TO SAY VARIOUS TOLL
RECEPTORS HELP DISTINGUISH
BETWEEN VARIOUS INFECTIONS.
IN IS NOT TO BE THE CASE AND UP
TO NOW THERE IS NO DEMONSTRATION
THAT ANY OF THESE OTHER TOLLS
PLAYS A ROLE, AT LEAST CAREFULLY
IN THE SYSTEMIC IMMUNE RESPONSE
AS I DESCRIBED IN THESE SLIDES.
SO HOW ARE THESE MOLECULES, HOW
ARE THESE LIGANDS RECOGNIZED?
SO IT WAS IN THE LABORATORY WHO
IN 2000, WE WERE LOHNG UNBIASED
MUTAGENESIS IN VARIOUS MICROBES
GENERATED AN ISOLATED MUTANT FLY
REFERRING, IN WHICH POSITIVE
BACTERIA WERE NOT INDUCED IN
ANYMORE RESPONSE AND THE FLIES
WERE DYING FROM THE SIMPLE
STREPTOCOCCUS INFECTION.
HE WENT ON TO CLONE THE GENE AND
WE FOUND THAT IT CORRESPONDED
WITH A MEMBER OF A FAMILY OF
GENES WHICH HAD BEEN EARLIER
IDENTIFIED AGAIN IN BUTTERFLIES
IN JAPAN AND WHICH WERE NAMED
AFTER THEIR CAPABILITY OF
RECOGNIZING THOSE LIGANDS.
I'LL TRY TO BE SHORT ON THIS.
THE IMPORTANTHING IS THAT THEY
ALL HAVE HERE A GROOVE WHICH IS
AN ANCIENT GROOVE AND THIS IS
CONSERVED IN MANY OF THE
MOLECULES.
THOSE MOLECULES ARE REFERRED
TO --
[INDISCERNIBLE]
THOSE MOLECULES ARE ANCIENT
ALREADY PRESENT.
AND SOME OF THESE -- SO THERE
ARE CIRCULATING MOLECULES AND
TRANSMEMBRANE MOLECULES AND SOME
OF THESE HAVE LOST THEIR
ACTIVITY AND TRANSFORMED FROM A
CATALYTIC FUNCTION INTO A
RECOGNITION FUNCTION.
AND I'LL ILLUSTRATE THIS IN THE
NEXT SLIDE.
SO THIS WOULD BE A CHIMERA
ARTIFICIAL MOLECULE AND IN THIS
POSITION, WE HAVE A LIGAND HERE
AND WE HAVE
[INDISCERNIBLE]
NOW WHAT IS CLEAVED BETWEEN THIS
HERE AND THE PEPTIDES?
AND THIS RENDERS PEPTIDOGLYCAN
AWAY, A WAY FOR THE ç FLY TO
DECREASE THE PEPTIDOGLYCAN.
AND THIS IS ZINC ION.
NOW DURING EVOLUTION N-SOME OF
THE MEMBERS OF THIS FAMILY, THIS
COORDINATION HAS BEEN LOST
THROUGH MUTATION AND
SURROUNDING.
WE HAVE AN EXAMPLE OF THIS
FAMILY AND IT COULD BE SHOWN
THAT A SPECIFICALLY RECOGNIZE
THE FORM OF LIGANDS WHICH CAN
DOMINATE IN GRAND POSITIVE
BACTERIA.
WILL RECOGNIZE AMINO ACID, THE
ONE THAT IS STILL DOMINANT IN
NEGATIVE BACTERIA.
SO IN ALL THIS HAS SHOWN, LET ME
JUST POINT OUT TO THE NAMES OF
THE PEOPLE SEVERAL LABORATORIES
WHICH WERE INVOLVED IN THIS.
WE HAVE NOT DIRECTLY BEEN
INVOLVED IN THE BIOCHEMICAL PATH
WHICH HAS SOLVED THIS PROBLEM.
SO, NOW I'LL GO TO SLIDES WHICH
WILL SUMMARIZE WHAT WE HAVE
LEARNED ABOUT THE RECOGNITION OF
MICROBES IN THE SYSTEM.
SO POSITIVE BACTERIA INDIRECT
WITH ONE OF THE FORMS OF THIS
GLYGAND PROTEIN.
THERE IS AN ASSOCIATION WITH
ANOTHER MOLECULE WHICH I WILL
NOT GO INTO AND THEN A SERIES OF
SERUM PROTEASES WHICH WILL GO
AND WHICH WILL ACTIVATE THE
SO-CALLED PROCESSING ENZYME
WHICH IS SHOWN HERE.
AND THAT WILL THEN ACTIVATE
TOLL.
SO THIS IS THE CASE OF A GRAND
POSITIVE INFECTION.
FUNGAL INFECTION INTERACTS WITH
ANOTHER PROTEIN WHICH IS CALLED
GLYGAND BINDINGñM PROTEIN.
IT'S NOT IDENTICAL TO THE OTHERS
BUT IT IS WELL CHARACTERIZED NOW
OF THE SAME SIZE AND HAS BINDING
DOMAINS.
THIS WILL THEN ACTIVATE THIS
AGAIN THIS SAME CASCADE AND LEAD
TO THE ACTIVATION OF RECEPTORS
AND THIS IS INTERESTING POINT
WHICH HAS BEEN WORKED OUT.
THIS IS ESSENTIALLY WORKED OUT
BY OTHERS.
HERE THIS HAS SHOWN THAT
MICROBIAL PROTEINS CAN ACTIVATE
THIS SYSTEM VIA DEDICATED
CIRCULATING ZIONO GENE WHICH
THEY NAMED -- AND IF I CAN JUST
SAY A LITTLE ON THIS.
THIS IS REALLY IMPORTANT IN AS
FAR AS WE KNOW THAT MOST OF THE
MICROORGANISMS SECRETE
PROTEASES.
THIS IS THE CASE FOR PROTOZOAN
INFECTIOUS AGENTS AND IN THIS
CASE, THIS IS SHOWN HERE FOR IN
THE CASE OF -- AND THIS PRECISE
CASE WHERE THEREb
 WERE MUTANT
S
AVAILABLE ON THE FUNG SIDE
MUTANTS, OUR COLLEAGUES WERE
ABLE TO SHOW REALLY THAT FUNGAL
PROTEASE INTERACTS WITH THE
CERTAIN DROSOPHILA AND CLEVES IT
AND FEEDS INTO THIS CASCADE AND
TO ACTIVATION OF THE TOLL
PATHWAY.
SO THIS WOULD BE, IN TERMS OF
DISCUSSIONS WHICH HAVE BEEN
AROUND IN THE FIELD FOR 20
YEARS.
THIS WOULD BE THE CASE OF
RECOGNITION EVER MICROBIAL
LIGANDS AND HERE WE WOULD HAVE A
CASE OF RECOGNITION OF
ENDOGENOUS ABNORMAL MOLECULES.
AND TO FINISH WITH THIS
ASPECT, ç
NEGATIVE BACTERIA INTERACT WITH
ANOTHER MEMBER OF THE PROTEIN,
LC, WHICH IS A TRANSMEMBRANE
RECEPTOR AND ACTIVATES DIRECTLY
THIS SYSTEM OF THE CASCADE TO
WHICH OUTCOMES IN SECONDS.
SO, HOW DO YOU ESTABLISH NOW
SOME OF THE ESSENTIAL SECTORS OF
THE IMMUNE RESPONSE OF THE FLY?
HAVING COME PREVIOUSLY TO A
POINT WHERE WE UNDERSTAND HOW
THOSE MICROBES CAN ACTIVATE THE
CASCADES WHICH LEADS TO THE
EXPRESSION OF THE ANTIMICROBIAL
PEPTIDE AND TURNS TO CASCADES
NOW.
THAT IS TO SAY LET US LOOK AT
HOW NF-KAPPA B IS ACTIVATED IN
DROSOPHILA.
WE HAVE SEEN THE MICROBIAL
SENSORS FOR FUNGI AND BACTERIA.
AGAIN THE INTERACTS WITH TOLL
AND THEN TOLL IN DIRECTS
WITH -- WHICH HAS BEEN CONSERVED
IN MAMMALS.
SO THIS IS TWO DOMAINS HERE AND
THEN ASSOCIATION WITH THE
KINASE, PELLE AND IT SEEMS TO BE
THIS KINASE DOMAIN IS
PHOSPHORYLATING CACTUS.
CACTUS BECOMES PHOSPHORYLATED
AND WE SHOULD SAY WE HAVE TO
KNOW YET WHICH KINASE REALLY
DOES THIS EFFECT AND FROM AFTER
PHOSPHORYLATION, CACTUS BECOMES
DEGRADED AND EITHER IN THE
LARVAE DORSAL OR -- TRANSLOCATED
IN ç THE NUCLEUS, TO CONTROL THE
EXPRESSION OF THE
GENE -- HUNDREDS OF GENES IN
THIS PROCESS AND THIS THIS HAS
BEEN STUDIED BY VARIOUS
MICROARRAY ANALYSIS IN VARIOUS
LABORATORIES AND MOST OF -- 50%
OF THE GENES WHICH ARE IN USE
ARE A FUNCTION OF WHICH WE
CANNOT CLEARLY RELATE YET TO THE
IMMUNE PHENOTYPES.
SO THIS WOULD BE FOR THE
ACTIVATION OF DORSAL BY THE TOLL
PATHWAY.
IT IS ALSO KNOWN, I HAVE NO TIME
TO GO INTO THIS.
ALSO THERE ARE SIGNIFICANT
INFORMATION THAT ARE AVAILABLE
HOW THE SYSTEM IS TURNED DOWN AT
ANY GIVEN MOMENT.
ONE WAY IS TO INCREASE THE
GENES, THE CACTUS GENE WHICH
PRESENTS OR OF COURSE
CONTRIBUTES UP STREAM AND THEN
ALSO IN USE IN RESPONSE AND THEY
WILL USE THIS ABILITY OF
CLEAVAGE ASPECTS.
NOW LET ME TURN TO THE SECOND
PATHWAY.
I MENTIONED THAT MAYBE TOO
RAPIDLY IN THE BEGINNING THERE
ARE SOME LARGE NF-KAPPA B FAMILY
MEMBERS -- WHICH IS EQUIVALENT
TO MAMMALIAN 105.
NOW AS I MENTIONED, AGAIN
BACTERIA VIA THEIR ACID FORM OF
PEPTIDE GLIKE AN AND THE
TRANSMEMBRANE RECEPTOR AND A
SERIES OF EVENTS WHICH
INCLUDES -- I TRIED TO BE AS
SIMPLE AS POSSIBLE.
THIS FIRST VARIOUS HOMOLOGUE OF
MAMMALS WHICH IS PRESENT HERE
AND HOMOLOGOUS TO MAMMALIAN
CASPASE 8.
NOW THERE OCCURS A PROCESS HERE
IN W
HERE AND THEN THROUGH IP2 WHICH
IS A LIGAND, WE WILL HAVE
ACTIVATION OF INB AS ILLUSTRATED
HERE.
THIS WAS NICELY WORKED UP IN THE
UNITED STATES IN ASSOCIATION
WITH OUR LABORATORY.
AND THEN WE HAVE BINDING TO
THIS -- PROBABLY THE IDEA WHICH
IS NOW WILL BIND TO THE CHAIN AS
WILL THE FLY EQUIVALENT OF NEMEO
IKK GAMMA WHICH IS SHOWN HERE.
SO THERE IS A COMPLEX IN THE FLY
HERE, THE EQUIVALENT IKK BETA
AND GAMMA.
NO EQUIVALENT TO IKK ALPHA.
SO THE IDEA IS THAT WE HAVE AS A
RESULT OF THE ASSOCIATION WITH
THE GLYGAND AND ITS RECEPTOR.
A SERIES OF EVENTS OCCUR WHICH
PROBABLY ALL OCCUR ALL YEAR.
AND THIS CHAIN MAY BE
APPROXIMATELY THE CYTOPLASM
MEMBRANE UP HERE.
AND IT WILL ASSOCIATE VARIOUS
PARTNERS HERE WHICH PLAY A ROLE
LIKE IKK GAMMA, TAK1 KINASE AND
OF COURSE IND WHICH IS SHOWN
HERE.
IND HAS A DOMAIN AND
INTERESTINGLY THIS DOMAIN IS
CLOSEST TO THE ONE WE FIND IN
MAMMALIAN TNF RECEPTOR PROTEINS.
NOW WHAT THEN HAPPENS IS THAT
ONCE IKK BETA HAS BEEN
PHOSPHORYLATED, THIS COMPLEX
WILL PHOSPHORYLATE RELISH
ILLUSTRATED HERE WITH THE
INHIBITING DOMAINS AND THIS IS
TRANSLOCATION PART, WHICH WILL
CONTRIBUTE TO THE EXPRESSION OF
THE RESPONSIVE GENES.
THIS PART REMAINS IN THE
CYTOPLASM.
SO AS A RESULT, WE HAVE
EXPRESSION VERY RAPIDLY TYROSINE
AND HUNDREDS OF GENES REMAIN
RELATIVELY UNCERTAIN IN THE
CONTEXT OF IMMUNE RESPONSE OF
THE FLY.
I SHOULD ALSO ADD DOWNSTREAM OF
THIS KINASE PART 1 SHOWS
ACTIVATION OF THE KINASE PATHWAY
WHICH DOES NOT TAKE PART IN THE
IN DUNK OF TYROSINE.
SO I THOUGHT IT COULD BE HELPFUL
IF I SUMMARIZED WHAT I SAID
ABOUT THESE TWO PATHWAYS WHICH
IS SOMETHING WHICH IS ESSENTIAL
IN THE FOLLOWING CARTOON.
LET ME PUT THE TWO PATHWAYS, ONE
NEXT TO THE OTHER.
SO THIS IS THE TOLL PATHWAY IN
THE FLY IN THE CONTEXT OF THE
IMMUNE RESPONSE.
THIS IS IMPORTANT TO NOTE THAT
WE HAVE PROT LYTIC CASCADES.
THIS IS IN CONTRAST WITH MAMMALS
WHERE YOU HAVE DIRECT
INTERACTION OF THE MICROBIAL
LIGANDS RECEPTORS.
SO MICROBIAL LIGANDS CAN INDUCE
THIS.
OF COURSE ALSO DEVELOPMENTAL
CUES AS ILLUSTRATED HERE BECAUSE
THAT'S THE WAY WE HAVE COVERED
THE WORLD OF TOLL RECEPTOR AND
THEN AS I POINTED OUT, PROTEASE
ILLUSTRATED IN THE CASE HERE CAN
ALSO ACTIVATE.
SO IT'S A PLATFORM WHICH
INTEGRATES VARIOUS SYSTEMS,
VARIOUS CUES ACCORDING TO THE
SITUATION.
THEN VIA THIS CACTUS, SO WE
COULD SAY HERE, P65 AND ICAPPAB,
WE, THIS SYSTEM BECOMES
ASSOCIATED AND WE HAVE ç
ACTIVATION OF GENE EXPRESSION.
ON THE OTHER HAND, THE MD
PATHWAY IN THIS CASE WE HAVE A
TRANSMEMBRANE RECEPTOR.
WE DO NOT HAVE AN UPSTREAM
CASCADE.
WE MICROBIALIZE DIRECTLY WITH A
PATHWAY RECEPTOR WHICH WE KNOW
IN THE CASE OF DAP FLY CANNED
AND THEN RELISH, VERY COMPLEX
SITUATION CASCADE, RELISH
BECOMES CLEAVED AND THIS PART
WILL GO AND IN DEUCE IMMUNE
RESPONSE.
POINTS WHICH I WOULD LIKE TO
MAKE HERE IS THAT GOOD EVIDENCE
THAT THIS PATHWAY IS PROBABLY
NOT DEVELOPMENTAL PATHWAY SO AS
WE CAN TELL.
IT PROBABLY IS INITIALLY
DEVELOPMENTAL REGULATOR.
THIS PATHWAY IS REALLY MUCH MORE
RESPONSE PATHWAY TO INFECTION
BUT ALSO TO A STRESS SIGNAL AND
TO VERY SERIES OF UNFOLDED
PROTEINS AND PROBLEMS TO OTHER,
TO THE DEGENERATIVE SIGNALS.
WE KNOW FOR INSTANCE THE FLY
LEVELS OF PARKINSON'S DISEASE,
THIS PATHWAY IS INITUDES.
WE KNOW ALSO THAT IN AGING FLIES
IT IS INITUDES.
WE KNOW THAT IN DNA TWO
DEFICIENT FLIES, AND THIS
IS -- I -
[INDISCERNIBLE]
SO THAT IS THE REASON WHY I PUT
HERE IN DODGINESS LIGANDS.
AND POLYIS IN THE AUDIENCE
SAYING THESE ARE DAMAGED SIGNALS
AND IN DEUCE -- WHICH IS A
POSSIBILITY.
I WANTED TO SHOW THE SLIDES TO
MAKE THE DISTINCTION ç CLEAR.
NOW THE QUESTION, DO THOSE
PATHWAYS DO THEY CROSS TALK?
THERE IS NO CLEAR ANSWER TO
THAT.
THERE ARE OF COURSE SOME REASONS
TO BELIEVE THAT IF YOU PUSH, YOU
WILL IT IS NOT ESTABLISHED YET
WHETHER THIS IS CROSS TALK AND
I'M NOT CONVINCED THAT THE
FAMILY MEMBERS HERE CAN DIMERIZE
AS PROPOSED.
SO, I WOULD NOW LIKE TO TAKE
THIS INFORMATION TO HAVE A LOOK
AT THE EVOLUTION IN THE LAST
PART OF MY PRESENTATION.
THE EVOLUTION OF THIS SYSTEM.
SO, OF COURSE WHEN WE STARTED
DOING THIS WORK, WE WANTED TO
SEE AT THAT TIME, VERY FRANKLY,
WHEN I TRIED TO CONVINCE THE
DIRECTOR LAST TIME OF THE
DEPARTMENT IN OUR RESEARCH
AGENCY, HE WAS VERY RELUCTANT TO
FUND THIS WORK IN SAYING THAT WE
DON'T KNOW IF ONE HAS ANY IMMUNE
RESPONSE SINCE WE DON'T KNOW IF
THIS IS RELEVANT AND WHAT ARE WE
GOING TO DO?
IF SOMEONE SHOULD TAKE THIS UP
IT SHOULD BE A MEDICAL DOCTOR
AND NOT YOU AS A VIDEOOLOGIST.
SO I WOULD LIKE TO PUT NOW
THE -- SOOLGIST -- PUT INTO
PERSPECTIVE OF WHAT WE HAVE
LEARNED IN OTHER GROUPS.
SO THIS IS THE TOLL RECEPTOR AND
INTERACTION -- CAN YOU SEE THIS?
I HOPE YOU CAN.
INTERACTING WITH RESPECT TO THE
CYTOKINE AND I JUST HAVE A FEW
CASCADES TO BLUR THE
INFORMATION.
SO WE HAVE KINASE HERE AND IN IN
CASE, AS I MENTIONED, WE ARE NOT
SURE WHICH IS PHOSPHORYLATED
CACTUS.
AND HERE --
[INDISCERNIBLE]
AND THEN AFTER THE ASSOCIATION,
WILL ACTIVATE GENE ç
TRANSCRIPTS.
SO THERE IS WONG FIRST
DIFFERENCE.
IT IS LPS.
AND THEN WE HAVE TO SOME EXTENT,
WE DO NOT HAVE THIS SERIES HERE
WITH ACTIVATION FROM KINASE AND
IKK COMPLEX AND THEN ICAPPAB AS
POINTED OUT.
TO YOU LET US TURN TO IND.
IN THE CASE EVER IND, WE HAVE,
IN THE CASE OF TLR4, WE HAVE
INDUCTION BY MICROBIAL LIGANDS.
HERE IS LTS.
WE HAVE SELECTED IN OTHER TLR
AND WE COULD ALSO HAVE LIGANDS.
SO WE HAVE IND AND WE HAVE THE
IKK COMPLEX AND THEN HERE WE
EXPLAINED TO YOU ACTIVATION OF
CLEAVAGE.
AND THEN FINALLY LET US PUT
HERE, TNF.
NOW YOU WILL SEE THAT TNF WHICH
WILL REACT TO A CYTOKINE IN THE
CASE OF TOLL, WHICH IS
EQUIVALENT TO MAMMALIAN, EXCUSE
ME TO THE IND.
WE HAVE THE IKK COMPLEX AND THE
GAMMA EQUIVALENT WITH SOME
SLIGHT MODIFICATIONS.
THIS IS THE FULL PATHWAY.
THIS IS THE MENTION OF THE TWO
PATHWAYS IN THE FLY AND THE
MAJOR PATHWAYS, MAJOR PATHWAYS
IN THE MOUSE.
AND YOU SEE HOW CONCEPTUALLY
THIS SYSTEM IS EQUIVALENT.
WHICH OF COURSE NO ONE
ANTICIPATED IN THE 90's.
NOW THIS THEN BEGS THE QUESTION,
WHEN DOES IT APPEAR?
SO, WE DON'T SUPPOSE THE FLY WAS
THE ANSWER TO MAMMALS.
WHEN DID THIS SYSTEM APPEAR IN
NATURE?
IN THE NEXT SLIDE I'LL SHOW
SOMETHING WHICH I COULDN'T HAVE
SHOWN A FEW YEARS AGO.
THIS IS ç WORK WHICH WAS DONE IN
BOSTON.
AND THEY WERE LOOKING AT THE
GENOME, MANY GENOMES WHICH HAVE
BEEN SEQUENCED IN THE LAST FEW
YEARS AND MANY MORE ARE COMING
OUT AND THEY WERE LOOKING AT THE
SEA ANON ME AND THEY FOUND IN
THIS SLIDE, IT WAS A PART WHICH
DATES 2-3 YEARS BACK.
THEY FOUND AN EQUIVALENT IN THE
GENOME SEQUENCE OF TLR WITH A
TIER DOMAIN AND IKK AND TAK1 AND
NF-KAPPA B.
THIS CAME AS NO SURPRISE.
IT WAS NOT TOTALLY CONVINCING
UNTIL RECENTLY THE SAME GROUP,
ANOTHER GROUP, WEREgh7 
EXPERIMENTALLY SHOWING IN CELL
SYSTEMS THAT THE TOLL COULD
REALLY DIRECT THE SYSTEM AS I
HAVE SHOWN IN THE FLY BY TAK
IKK WAS DEPENDENT ON THE SYSTEM
AND NF-KAPPA B.
THEY WERE INSTEAD THAT THE
SEQUENCE  WE HAVE SEEN IN THE
FLY, ALSO IS RELATIVE IN THE
STELLA.
NOW WE COME TO THE QUESTION,
WHETHER DID ALL THIS APPEAR?
IN THIS SLIDE I TRIED TO
SUMMARIZE THE EVOLUTION AS ONE
MIGHT SEE.
IT HAS APPEARED PROBABLY 1.2.
AND WE HAVE THE ILLUSTRATIONS
HERE SO SPONGES ARE AMONG THE
MOST EARLIEST LIFE FORMS WHICH
APPEARED IN PRECAM BRIE ON AND
THEN WE HAVE THE SEPARATION OF
THE SEA ANON MES AND IN ç SECTS.
THEN WE HAVE ECHINODERMS AND
THEN HEMICHORDATES AND THEN THE
CHORDATES.
LET'S ASK THE FOLLOWING
QUESTION.
WHAT ARE RELEVANT WITNESSES OF
THESE CASCADES?
WHEN DID THEY APPEAR?
WHEN DID TOLL APPEAR?
WHEN DID NF-KAPPA B APPEAR AND
TAK1 AND THE ANTIMICROBIAL
PEPTIDES APPEAR?
AND IN JUST ONE CLICK, I'LL SHOW
YOU THE ANSWER.
THEY APPEARED VERY EARLY ON AND
THE SPONGES WE HAVE
ANTIMICROBIAL PEPTIDES AND
NF-KAPPA B AND TOLL AND ALL
ALONG THE EVOLUTIONARY RANGE.
SO, IN OTHER WORDS, IN CONTRAST
TO WHAT THE COMMUNITY BELIEVES,
IMMUNITY IS VARIATION PROCESS
NOT ONLY IN TERMS OF FIGHTING
AND MYSTICAL WAYS INVADING
MICROORGANISMS BUT ALSO AT THE
MOLECULAR AND CELLULAR LEVEL.
NOW WHAT THEN HAS CHANGED?
WHY AREN'T WE ALL RELYING ON
INNATE IMMUNITY?
SO LET ME CENTER ONE SECOND ON
THE STEMS.
SO WHAT HAS APPEARED TO THE
SURPRISE OF EVERYONE IS THAT YOU
Ja,
 222 TOLL-LI
KE RECEPTORS.
YOU HAVE 203 -- I HAVE NOT
MENTIONED THE OTHER RECEPTORS
BECAUSE THEY ARE NOT PRESENT IN
THE FLY BUT THEY ARE
INTRACELLULAR RECEPTOR MOLECULES
INVOLVED IN A VARIETY OF
DEFENSE -- PARTICULARLY PLAYING
A ROLE IN CROHN'S DISEASE.
AND ALSO 218 SCAVENGER RECEPTORS
SUSTAINED.
THERE ARE ONLY SIX IN THE FLY.
SO IT'S JUST A FANTASTIC
EXPLOSION OF THESE RECEPTORS.
BUT LOOK AT THE FLUX, WE SEE
STILL A VERY LARGE NUMBER,
48THRs, 92NLRs OF THE
SCAVENGER RECEPTORS.
WHEN THEE APPEARED, MAYBE THOSE
CANDIDATES -- IN THE SEA MEDIUM
AND THEN THERE WERE SO MANY
UNEXPECTED PATHOGENS COMING UP
AND THAT'S WHY WE NEED SO MANY.
EXPERIMENTAL, NONE OF THESE
MOLECULES HAS BEEN DOCUMENTED TO
PLAY A ROLE.
SO THIS IS GENOME SEQUENCING.
THIS PROPOSAL THAT THE LARGE
NUMBER OF PATHOGENS WOULD
EXPLAIN THE SITUATION IN A LARGE
NUMBER CERTAINLY NOT VAL ID
ID -- ZERO NLR LIKE THE FLY AND
22 SCAVENGER RECEPTORS IT'S
PROBABLY TOO EARLY TO SPECULATE
ON WHAT HAS OCCURRED HERE AND
INSTEAD, I WANT TO GO WITH YOU
RAPIDLY TO THE LAST POINT I WANT
TO MAKE HERE.
SO WHAT IS REALLY ç CHANGED?
BETWEEN THESE GROUPS AND US IN
TERMS OF TWO VERTEBRAES?
SO, WHAT HAS CHANGED?
WHAT IS ABSENT FROM ALL THE
OTHER GROUPS AS THE SOMETIME
HERE AFTER THE FIRST WHOLE
GENOME APPLICATION.
THERE WAS A BIFURCATION OF
LYMPHOCYTE LINEAGE FROM
THE -- LINEAGE.
THIS IS DISCUSSED IN MUCH DETAIL
IN THIS COMMUNITY.
AND THE DEVELOPMENT OF LONG
LIVED LYMPHOCYTES WITH THE
POTENTIAL FOR SELF RENEWAL AND
SELECTIVE CLONAL EXPANSION.
AND THIS IS REALLY BEEN THE
MAJOR CHANGES OF CELL BIOLOGY,
FIRST THE TOLL AT THE BASIS OF
THE CORRELATES AND THEN THE
SEPARATION OF THE ACTIVATION AND
THE OTHER GROUPS WHICH HAVE THE
FULL SKELETON.
BOGUE GROUPS HAVE DEVELOPED
MASSIVE ANTIGEN RECEPTORS.
AND FISH GREW FISH AND -- VVJ
RECOMBINATION IS FAMOUS WHICH IT
IS A COMPLEX SYSTEM AND VERY
VARIABLE.
IT'S NOT A REALLY
HOMOGONOUS -- FROM ALL THE
GROUPS, MANY VARIATIONS THAT
WHICH ALLOW TO DO THIS.
AND THE OTHER SIDE WE HAVE MANY
PEOPLE INVOLVED IN THESE STUDIES
AND THERE ISzV ANOTHER
MANIPULATION IN THE VLR,
VERIABLE RECEPTOR, TWO TYPES OF
LYMPHOCYTE CELLS
[INDISCERNIBLE]
A CELLS AND B-CELLS.
SO THIS IS WHAT MAKES THE
DISTINCTION BETWEEN US,
INCLUDING FISH WITH US HERE.
AND IT'S A VERY IMPORTANT TOOL
OF DEFENSE AND OF COURSE IT DOES
NOT SHOW MAMMARY.
MY LAST SLIDE WILL GIVE YOU
PHILOSOPHY.
IT IS WRONG TO SAY THAT THE FLY
CAN LOOK AT THE FLY TO
UNDERSTAND HOW ADAPTIVE IMMUNE
SYSTEM HOLDS.
THE FLY DOESN'T HAVE AN ADAPTIVE
IMMUNE SYSTEM.
THE POINT I WANT TO MAKE IS
GIVEN ALL THESE GROUPS, TH
WERE ALL SEPARATEED AFTER ONE
EXPLOSION.
ALL THESE EVOLVED ACCORDING TO
DIFFERENT CONSTRAINTS BUT
STARTING FROM THE SAME POOL.
AND MOLECULAR MODDUALS --
[INDISCERNIBLE]
SO STELLA IS CLOSE AS YOU CAN
GET TO HUMAN IN TERMS OF
MOLECULES INVOLVED IN IMMUNITY.
THERE IS NO NF-KAPPA B AND STILL
THEY SURVIVE.
BUT NOT AS WELL AS GOOD AS WE
DO.
IT DEPARTMENT USUALLY STAY THE
SAME WAYS AS DROSOPHILA. ç
DROSOPHILA HAS LOST THE NOTCH
RECEPTOR WHEREAS THERE ARE MANY
OF THIS ABOUT 70 -- ABOUT 200
HERE IN THE ANTIOXIDANTS.
SO EACH GROUP HAS FROM A COMMON
BACKGROUND OF MOLECULAR MODELS
HAS ITS OWN WAY FOR CONSTRAINTS
AND THE OPTIONS IT HAD IN
EVOLUTION AND THE TAKE HOW MANY
MESSAGE I LIKE TO STOP HERE AND
SAY THAT IT HAS BEEN FANTASTIC
PERIOD BECAUSE OF COURSE OF
THIS -- NO ONE WOULD EXPECT I
WOULD COME TO THIS UNDERSTANDING
AND MUCH OF THIS IS STILL
HYPOTHETICAL BUT I THINK WE HAVE
20 YEARS AGO AND ALL THIS WORK
WAS DONE BY MANY OF MY EXCELLENT
COLLEAGUES IN THE LABORATORY AND
THOSE AND OTHER GROUPS, I JUST
LIKE TO ACKNOWLEDGE QUICKLY.
SO I STARTED THIS WORK WITH MY
WIFE.
AND SHE WAS ALSO WORKING ON
DROSOPHILA.
WAS A CHEMIST
[READING]
AND OTHER PEOPLE WHOSE NAME I
MENTIONED ALREADY AS WELL AS:
SO THANK YOU VERY MUCH FOR YOUR
ATTENTION.
[APPLAUSE]
>> THANK YOU FOR THAT FANTASTIC
SEMINAR.
WE HAVE A RECEPTION THAT WILL BE
IN THE LIBRARY AFTERWARDS.
BUT PERHAPS IF THERE ARE SOME
QUESTIONS FROM THE GROUP BEFORE
WE ADJOURN TO THE RECEPTION?
I SEE ONE ALREADY.
GO AHEAD.
>> SO MY QUESTION WAS, WHEN YOU
SHOWED THE IND PATHWAY YOU WERE
SHOWING THE UBIQUITINATION, I
WAS WONDERING IF WE LOOKED AT
UBIQUITINNIZATION AND MAYBE WITH
AGENCY IF IT IS NOT ENOUGH OR
TOO MANY OF UBIQUITIN MOLECULES
THAT MIGHT ACTUALLY INTERFERE?
>> I'M SORRY.
I'M NOT CERTAIN I UNDERSTAND
YOUR QUESTION.
YOU'RE ASKING --
>> WITH THE IND, YOU SHOWED
UBIQUITIN MOLECULES.
SO IF YOU HAVE TWO FEW OR TOO
MANY, DO YOU ACTUALLY ç GET AB
RANT ACTIVATION OF NF-KAPPA B,
WITH AGE, COULD MAKE SENSE?
>> YES, THAT MAY BE SO.
THAT MAY BE SO.
YOU'RE RIGHT WITH AGE THE INSECT
SPONTANEOUSLY ACTIVATE THE IND
PATHWAY.
AND I THINK I REALIZE IT HAS
ALREADY BEEN TOO LONG.
SO THE SYSTEMS MUCH MORE
COMPLEX.
IF YOU GIVE ME 20 SECONDS, WE
HAVE DONE A PROTEOMICS ANALYSIS
OF MOLECULES BINDING THROUGH THE
CONONKEL PATHWAY MBERS AND WE
HAVE ISOLATED 320 PROTEINS OF
WHICH ABOUT 150 GIVE PHENOTYPE
UPON RNAI.
50% OF THOSE ARE CONSERVED IN
THE MAMMALIAN TNF PATHWAY.
YOU SEE THIS IS JUST THE
BEGINNING OF THIS AND I DIDN'T
WANT TO OVER LOAD YOU.
BUT YOU'RE PERFECTLY FINE.
>> SO, AS I HAVE SEEN FOR THE
DROSOPHILA, THE NUMBER OF TOLLS
AND THERE IS NO FUNCTION FOR THE
OTHERS.
>> I'M SORRY?
I SHOULD SAY THEY ARE ALL
INVOLVED IN EMBYRONIC
DEVELOPMENT.
ALL OF THEM.
BUT NOTHING SYSTEMIC.
>> SO PERHAPS THERE IS A LITTLE
MISLEADING OR CONFUSING TO LOOK
AT THE RECEPTOR, THE NUMBER OF
RECEPTORS IN DIFFERENT SPECIES
AND MAYBE SHOULD LOOK AT THE
EFFECT OF THE MECHANISMS OR IN
TERMS OF MICROBIAL PEPTIDES IN
THE GENOME BECAUSE THOSE ARE
DIRECT FACTORS IN THE IMMUNE
RESPONSE VERSUS THE RECEPTORS,
THE NUMBER OF RECEPTORS AND
KNOWN FUNCTION.
>> YOU'RE PERFECTLY RIGHT.
LET ME JUST ANSWER OR SAY THE
FOLLOWING THING. ç
NUMBER 1, ANTIMICROBIAL PEPTIDES
ARE PRESENT IN ALL THE GROUPS
AND NOW RECENTLY THIS IS FUNNY,
RECENTLY IN A GROUP IN GERMANY,
HAS ISOLATED IN HUMANS.
SO WE PRODUCED THOSE PEPTIDES.
SO THAT IS TRUE.
THAT HAS BEEN DONE.
SO ANTIMICROBIAL PEPTIDES IS
RIDE.
SO REGARDING THE TOLL LIKE
RECEPTOR GIVEN THE NUMBERSES,
YOU'RE RIGHT.
AND AS I MENTIONED, IT HAS NOT
BEEN INVESTIGATED WHETHER THEY
REALLY DO PLAY A ROLE.
>> BUT MANY OF THEM DO.
>> OKAY.
BUT IT HAS BEEN INVESTIGATED.U
WHAT HAS BEEN DONE IT A
DEVELOPMENTAL REGULATOR OR
IMMUNE REGULATOR?
SO, YOU FIND THIS COMMONALTY
GOING BACK TO THE MULTICELLULAR
ANIMALS, THAT'S AS FAR BACK AS
YOU MENTION, SO WHAT HAPPENS IF
YOU GO BACK EVEN FURTHER TO
SINGLE CELLULAR ANIMALS OR
PLANTS AND EVEN BACK FURTHER TO
PRO CAREIOTS?
>> IT IS AN IMPORTANT QUESTION.
AND LET ME POINT OUT THERE ARE
ANTIMICROBIAL PEPTIDES PRODUCED
BY BACTERIA AND THIS IS
WELL-KNOWN AM BACTERIA DO FIGHT
IN OUR GUT:
THEY FIGHT EACH OTHER WITH
ANTIMICROBIAL PEPTIDES.
IT'S NOT CLEAR AS FAR AS I CAN
TELL FROM THE LITERATURE IF
SOMETHING PRETTY SO AN -- IT HAS
BEEN LOOKED AT -- WOULD YOU KNOW
ALAN -- NO.
TO MY KNOWLEDGE IT HAS NOT BEEN
FOUND BUT NOT IN ç THE WAY WE
LOOKED.
>> SO IF IT WERE ME, AS OPPOSED
TO YOU, I WOULDN'T BE LOOKING
JUST TO THE EDGE OF MICROBIAL
PEPTIDES.
I WOULD BE LOOKING FOR THE
SYSTEM THAT IS RESPOND TO THEM
BECAUSE I THINK THOSE SYSTEMS
ALSO RESPOND TO OTHER FORMS OF
DAMAGE.
SO RATHER THAN LOOKING AT WAR,
HOW ABOUT LOOKING AT HUMANS.
>> YOU'RE RIGHT.
YOU'RE RIGHT.
IT'S SOMETHING WE STILL HAVE TO
BE DONE AND WE WILL KEEP IT IN
MIND.
IT HAS NOT BEEN DONE.
>> [OFF MIC]
>> IT HAS NOT BEEN DONE SO FAR.
>> WHAT IS SO STRIKING IS IN THE
VERTEBRATES THE TLRs, WE OFTEN
REFER TO AS MICROBIAL SENSORS,
THE STRIKING THING IT'S A
MICROBIAL SENSOR.
>> DO YOU HAVE A FEELING WHETHER
THAT IS THE TOTAL OR THE
RECOGNITION ELEMENT THAT LEADS
TO THE CLEAVAGE OF -- IS LARGER?
>> SO SETSLER IS A MEMBER OF THE
NEUTRAL FAMILY.
SIX MEMBERS LIKE THAT.
WE ARE ALL ACTIVATED DURING
DEVELOPMENT, INCLUDING THE
IMMUNE.
SO I WOULD SAY THAT THE ç
PATHWAYS
WHICH ILLUSTRATED TO YOU ARE
PROBABLY THE END STORY IN TERMS
OF SYSTEMIC IMMUNE RESPONSE
BECAUSE YOU CAN COMBINE.
YOU CAN COMBINE THE VARIOUS
PATHWAYS.
SO THAT'S WHY I BELIEVE THIS IS
THE END OF DESPERATE.
NOW I SHOULD POINT OUT IN A
MAMMALIAN SYSTEM, THERE IS MORE
TO IT.
THIS PLAYED A ROLE IN OUR IMMUNE
DEFENSES.
YOU MAY NOT BE AWARE OF THAT.
PARTICULARLY STATENS.
DID THAT ANSWER YOUR QUESTION?
>> MY POINT WOULD BE THE THREE
ELEMENTS, THREE SENSES THAT YOU
WOULD EXPLAIN, ARE THEY SO
CENTRAL?
-- I THINK --
>> THAT THE MICROBIAL AGENT
CANNOT MUTATE TO ESCAPE THEM?
>> MUCH MORE OPEN-MINDED.
>> WHAT WILL ACTIVATE THE
PROCESSING ENZYME MAY BE MANY
OTHER MOLECULES.
IT'S NOT TO POINT OUT IN TERMS
OF GENETIC EXPERIMENTS.
BUT IT CAN BE DONE.
YOU HAVE TO USE THE SCREENS.
>> YOU SAID IN DROSOPHILA THAT
MICROBIAL -- IN HUMANS, IT IS
KNOWN AS MATRIX TO
ACTIVATE -- ABSOLUTELY.
YOU ARE RIGHT.
WE WERE LOOKING INTO THAT
DIRECTION.
WE CANNOT DO EVERYTHING IT WOULD
BE VERY INTERESTING IF SOMEONE
TOOK THIS UP IN THE MAMMALIAN
SYSTEM.
ABSOLUTELY.
CALL IT TO A CLOSE.
THANK YOU VERY MUCH. AND WE'LL
01:01:05.833,00:00:00.000
HAVE A RECEPTION IN THE LIBRARY
