>> GOOD AFTERNOON.

I THINK WE WILL START.

I'VE HAD SEVERAL E-MAILS FROM

PEOPLE WHO SAID THEY HAD TROUBLE

GETTING TO THE ELECTRONIC FINAL

EXAM.

YOU SHOULDN'T.

WE CHECKED IT OUT.

IT'S THERE, JUST LOG N IT'S

LISTED ON THE WEBSITE AND ENJOY

YOURSELF.

AFTER YOU'RE FINISHED, YOU MAY

HAVE TO TAKE IT A FEW TIMES BUT

IT'S EASY, PAINLESS.

AND YOU'LL GET A CERTIFICATE.

SO THIS IS THE LAST SESSION OF

THE COURSE IN WHICH WE DISCUSS A

PARTICULAR DISEASE.

NEXT WEEK IS THE FINALE WITH

MICHAEL GODDESSMAN AND KATHY

SOON AND MYSELF AND WE'LL HAVE A

ROUNDTABLE DISCUSSION AND

PRESENTATION OF DATA ON AS OF

NOW WHAT DOES THE FUTURE LOOK

LIKE FOR CAREERS IN BIOMEDICAL

SCIENCES.

SO IT'S CHANGED A LAST SINCE

LAST YEAR WHEN WE HAD THAT

SESSION WHICH WAS VERY HELPFUL

TO A LOT OF PEOPLE.

THIS ISN'T A BUNCH OF LECTURES

BUT REALLY MORE OF A DISCUSSION

AND DR. GODDESSMAN IN HIS

POSITION AS DEPUTY DIRECTOR OF

THE INTRAMURAL PROGRAM HAS

ACCESS TO ALL OF THE NIH DATA

AND KATHY HAS ACCESS TO GLOBAL

DATA REGARDING PARTICULARLY

INFECTIOUS DISEASE PROGRAMS.

AND I HAVE SOME UPDATING OF THE

AAMC ON CAREERS FOR PARTICULARLY

PH.D.s IN MEDICAL SCHOOLS AND

ALSO IN COLLEGES AND

UNIVERSITIES.

OKAY.

SO A CONSTANT THEME OF THIS

COURSE, WE TRIED TO GET EXCITED

ABOUTS THE NECESSITY OF

ESTABLISHING SOME BRIDGING

BETWEEN CLINICAL OBSERVATIONS

AND THEN TRYING TO UNDERSTAND

THAT A MORE FUNDAMENTAL LEVEL

WHAT'S GOING ON WITH THE IDEA

THAT WAS DEVELOPING BETTER TOOLS

FOR DIAGNOSIS AND THERAPY.

WELL,ATE DOESN', IT DOESN'T ALWAYS WORK OU
T

THAT WAY AS YOU RECALL FROM MANY

OF OUR SESSIONS BUT THE THINGS

THAT SPIN OUT FROM IT ARE VERY

IMPORTANT IN TERMS OF ADVANCING

BASIC BIOLOGICAL SCIENCE AND

ULTIMATELY THIS KIND OF

COMMUNICATION IS VERY ESSENTIAL

THING, A CHALLENGE THAT THE

BIOMEDICAL WORLD FACES WHICH

YOU'LL HEAR MORE OF NEXT WEEK.

SO TODAY WE'RE GOING TO DISCUSS

WE'RE VERY FORTUNATE IN HAVING

TWO GUESTS WHICH I'LL INTRODUCE

TO YOU IN A MOMENT WHICH ARE

EXPERTS IN THIS AREA.

I JUST WANT TO RELATE TO YOU A

PERSONAL EXPERIENCE BECAUSE

WE'VE BEEN INTERESTED IN THIS

DISEASE AT LEAST LEARNING ABOUT

IT FOR A LONG TIME.

THIS USED TO BE CALLED CELIAC

DISEASE AT ONE POINT WAS CALLED

A DUTCH DISEASE AND I THINK

THERE ARE TWO REASONS FOR IT.

ONE WAS HOLLAND DUTCH HEALTH

SYSTEM WAS NATIONALIZED IN THE

1920'S.

PEOPLE WHO HAD WHAT WAS CALLED

SCREW AT THE TIME, DIGESTIVE

DISEASE WHERE THEY LOSE WEIGHT

AND YOU'LL HEAR MUCH MORE ABOUT

THAT A LITTLE BIT LATER.

OFTEN THEY WERE IN FAMILIES,

THEY WERE CALLED SCREW HOUSES.

AT ANY RATE, THEY WERE FOLLOWED

BY ONE GROUP OF PEDIATRICIANS AT

THE UNIVERSITY, AND IN THOSE

DAYS THE TREATMENT WHICH IRWIN

ROSENBERG WILL GO IN MORE DETAIL

WAS BASICALLY A DIETARY

TREATMENT.

THERE WAS SOME SUCCESS AND

MORALS FAILURE.

THIS WAS -- AND MORE OR LESS

FAILURE.

THIS WAS A LETHAL DISEASE AND

CHILDREN DIED FROM IT AFTER

ANYWHERE FROM PERHAPS FIVE TO 20

YEARS OF JUST SORT OF WASTING

AWAY OF REALLY SERIOUS

MALNUTRITION.

DR. DICKY WHOM I HAD THE

PLEASURE OF MAKING A HOUSE CALL

WITH IN 1955 WAS A PROFESSOR AT

THE UNIVERSITY IN THE

WILHELMIA -- DURING THE LONG

PERIOD OF NAZI OCCUPATION WHEN

THE FAVORITE DIET AT THE TIME

WHICH WAS BANANAS WAS NO LONGER

AVAILABLE.

AND PHYSICIANS WERE FEARFUL THAT

ALL THESE CHILDREN WERE GOING TO

DIE.

DICKE METICULOUSLY FOLLOWED

THEIR COURSE DURING THE LONG

OCCUPATION WHEN THEY WERE BARELY

SURVIVING FROM THE LIMITED FOOD

THAT WAS AVAILABLE.

BUT THEN MOST OF THEM, IN FACT

ALL OF THEM RELOOPSE RELAPSED SHORTLY

AFTER EMANCIPATION WHEN THE

ALLIES STARTED DROPPING LOAVES

OF BREAD FROM THE SKY BECAUSE

BREAD DISAPPEARED FROM THE DUTCH

DIET.

DICK JEVMENT WAS E WAS A CLINICAL

PEDIATRICIAN WHO MADE THIS

OBSERVATION.

BREAD HAD SOMETHING TO DO WITH

CAUSING A RECURRENCE.

HE MADE VERY CAREFUL CLINICAL

STUDIES, OBSERVATIONAL.

HE DIDN'T MEASURE ANYTHING AT

THAT TIME.

AND HE WENT TO THE PROFESSORS OF

MEDICINE AND PEDIATRICS AND

SHOWED THEM WHAT HIS SUSPICION

WAS AND THEY KINDLY TOLD THEM TO

GO AWAY.

SO IT WAS NOT WITH ANY

SIMPLICITY THAT HE COULD SELL

THIS IDEA TO PEOPLE WHO WERE IN

A POSITION TO REALLY HELP HIM

STUDY WHAT WAS GOING ON.

AND THEN LOTS OF THINGS HAPPENED

THAT ARE SERENDIPITY AND I LIKE

THIS ONE BECAUSE HIS SON FELL IN

LOVE WITH THE DAUGHTER OF A VERY

FAMOUS LIPID CHEMIST WHO WAS AN

EXPERT IN LIPIDS.

FROM THE DAY DICK JEVMENE TOLD ME THE

STORY HE SAID THEY SHARED IDEAS,

WHAT DO YOU DO AND WHAT DO YOU

DO AND SO DICKY UNLOADED THE

STORY AND BEING A BIOCHEMIST AND

NOT A PHYSICIAN WHO MAYBE HAD

SOME PREJUDICE IN FAVOR OF ONE

OF THE EXISTING TBLEERS A THEORIES AS TO

WHAT THIS DISEASE IS ABOUT, HE

SAID FINE LET'S STUDY IT.

HE AND HIS COLLEAGUES WENT AHEAD

AND DID A SERIES OF CLASSIC

STUDIES OF IDENTIFYING PROTEIN

AS THE TOXIC ELEMENT.

THAT'S ON ONLY THE BEGINNING.

THE LAST THING I WOULD NOTE TO

YOU IS IN EUROPE THEY WERE

TREATING CHILDREN SUCCESSFULLY

WITH A GLUTEN FREE DIET FOR AT

LEAST TEN YEARS BEFORE IT WAS

ACCEPTED IN THE BIG CENTERS IN

THE UNITED STATES.

THERE WERE TWO REASONS FOR THAT.

ONE WAS THAT CORTISONE HAD BEEN

DISCOVERED AND WHEN YOU GIVE

CORTISONE TO THESE CHILDREN,

THEY FEEL FINE.

THEY ACT FINE, THEY DO FINE.

BUT TOO MUCH CORTISONE ISN'T

GOOD FOR A YOUNG CHILD SO THAT

IS NOT SOMETHING YOU KEEP PEOPLE

ON FOR A LONG TIME.

AND THEN ULTIMATELY A FEW

CAREFUL BALANCE STUDIES WERE

DONE IN THE UNITED STATES, ONE

OF WHICH THEY THORNDIKE

HOSPITAL, THE BOSTON CITY

HOSPITAL WHERE I WAS AT THE

TIME, AND SLOWLY IT BECAME PART

OF THE AMERICAN SCENE.

BUT IT WAS LIKE YOU KNOW FROM

MISSOURI SHOW ME KIND OF THING.

WELL, THAT'S ALL THAT I WANTED

TO SAY.

OKAY.

SO NOW WE'RE GOING TO HEAR VERY

EXCITING STORIES OF HOW THIS

KIND OF OBSERVATION HAS LED INTO

REALLY PROFOUND SCIENTIFIC

ADVANCE, HAVING A MUCH EVEN

BROADER CONTEXT THAN THE

DISEASE.

SO OUR FIRST SPEAKER TODAY IS

IRVIIRWIN VIDEOSBERG ROSENBERG WHO IS A

UNIVERSITY PROFESSOR AT TUFTS

MEDICAL SCHOOL UNIVERSITY.

IRV IS ONE OF THE WORLD'S MOST

RENOWN EXPERTS IN NEW TRIGGAL

SCIENCES AND -- NUTRITIONAL

SCIENCES AND HAS DONE

OUTSTANDING WORK CONCENTRATING

ON FOLATE AND RO FOLATE-RELATED

PRODUCTS NATIONALLY SO WE'RE

DELIGHTED HE COULD BE HERE

TODAY.

HE'S THE FORMER DEAN OF THE

SCHOOL OF NUTRITION, PROFESSOR

OF MEDICINE, PHYSIOLOGY AND

MAYBE ONE OR TWO OTHERS I'VE

FORGOTTEN BUT A MAN OF MANY

TALENTS, YOU'LL HEAR VERY KEEN

OBSERVATION.

OR SECOND SPEAKER IS BANA JABRI

WHO IS PROFESSOR OF MEDICINE AND

IMMUNOLOGY, HAVE I GOT IT RIGHT?

PATHOLOGY AND PEDIATRICS.

AT ANY RATE BANA RECEIVED HER MC

AND PH.D. DEGREE IN FRANCE,

TRAINED HERE AT THE UNITED

STATES IN GASTROENTEROLOGY FOR A

WHILE, WAS HERE AT THE NIH AS A

FOGARTY SCHOLAR.

WAS AT PRINCETON FOR A SHORT

WHILE AND THEN HAS BEEN AT THE

UNIVERSITY OF CHICAGO WHERE SHE

NOW HAS THE HEAD OF A LARGE

RESEARCH CLINICAL PROGRAM CENTER

IN CYSTIC FIBROSIS.

AND HER MAIN INTEREST IS IN T

CELL MEDIATED IMMUNE RESPONSES.

THE INNATE IMMUNE RESPONSES AND

WHAT DETERMINES WHAT TURNS THEM

ON AND HOW THEY REACT WITH OTHER

IMMUNE PROCESSES.

SO IT TURNS OUT AS YOU LEARN,

CELIAC DISEASE IS A KIND OF

AUTOIMMUNE DISEASE AND THAT'S

LED TO SOME VERY INTERESTING

OBSERVATIONS OF GREAT

IMPORTANCE.

SO THE NEXT THING THAT WE ARE

FORTUNATE IS THAT MS. ALICE

BASQUE IS WITH US AND ALICE IS

KIND ENOUGH TO TELL YOU THE

STORY OF HER DISEASE.

AND THEN WE'LL TELL YOU A LILT

BUILT ABOUT HER -- A LITTLE BIT

ABOUT HER.

SHE FOUNDED THE NATIONAL

FOUNDATION FOR CELIAC AWARENESS,

PUT SOME BROCHURES ON THE BACK

TABLE AND MATERIAL ON THE

WEBSITE.

IS A FIGURE NATIONALLY, GLOBALLY

AT THE NIH.

SOME OF YOU MAY HAVE READ ABOUT

HER IN NEWSPAPERS, TELEVISION,

NEWS INTERVIEWS.

SHE REALLY HAS BEEN A MAJOR

MOVER IN THE EDUCATIONAL ASPECT

TO PHYSICIANS AS WELL AS TO

PATIENTS.

AND IT TURNS OUT THAT ALICE HAS,

OR HAD CELIAC DISEASE.

SO WOULD YOU MIND, ALICE?

THANK YOU VERY MUCH FOR BEING

HERE.

>> THANK YOU.

I'LL STAND UP.

I WAS ASKED TO COME HERE TODAY

AND TALK A LITTLE BIT ABOUT MY

HAVING CELIAC DISEASE.

TYPICALLY I THINK MY STORY IS

VERY TYPICAL OF MOST PATIENTS.

SO IT TOOK ABOUT EIGHT YEARS FOR

ME TO GET MY DIAGNOSIS AND

ACTUALLY TAKE THE AVERAGE PERSON

TEN YEARS TO BE PROPERLY

DIAGNOSED.

SO I YOU BEE UNFORTUNATELY HAD SOME OF

THE SYMPTOMS I HAD FULL TERM

STILLBORN, THREE MISS CARRIAGES,

A TWO-POUND BABY, I LOST 25

POUNDS AND I SOUGHT THE ADVICE

OF 22 DOCTORS BEFORE I WAS

PROPERLY DIAGNOSED BY A

VETERINARIAN.

SO THAT'S REALLY, I KNOW, YOU'RE

SAYING WHAT, HOW COULD IT BE.

AND IT IS A DIAGNOSIS THAT YOU

GO ON A GLUTEN FREE DIET, THERE

IS A TREATMENT.

AND BELIEVE ME YOUR LIFE TURNS

AROUND.

LET ME TELL YOU WHAT LEAD UP TO

THAT TO GIVE YOU A LITTLE BIT OF

MY HIS TREATMENT AS A KID, I

DIDN'T HAVE ANY SIGNS OR

SYMPTOMS OF CELIAC DISEASE.

I WAS THE ONE OF THOSE LITTLE

KIDS WITH THE TYPICAL BIG POT

BELLY.

AS YOU COULD SEE I'M NOT OF

SMALL STATURE.

I'M NOT TEENY, FIVE FIVE FOOT

NINE.

EVERYTHING SEEMED FINE.

THE ONLY THING I HAD GROWING UP

THAT COULD BE A SIGN OF CELIAC

DISEASE WAS MIGRAINE HEADACHES.

AND I HAD, I GOT MARRIED.

I HAD MY OLDEST DAUGHTER AND SHE

WAS A FULL TERM BABY.

SHE WAS EIGHT POUNDS WHEN SHE

WAS BORN.

I TOOK A TRIP TO MEXICO AND

DURING THAT TRIP TO MEXICO I

ENDED UP WITH GERARDA AND WAS

TREATED TO GET RID OF THE

GUARDA.

AFTER I TOOK THAT TRIP TO MEXICO

IT TRIGGERED THAT OR THE

PREGNANCY OR SOMETHING IN MY

LIFE TRIGGERED THE FULL ONSET OF

CELIAC DISEASE AND THE SYMPTOMS.

BUT EVERY SIMPLE I HAD, THE

DOCTOR TREATED ME FOR THE

SYMPTOM.

THAT'S WHERE THE 22 DOCTORS CAME

IN.

SO MY HAIR WAS STARTING TO FALL

OUT, MY TEETH WERE ACTUALLY

GETTING, WERE BREAKING AND MY

TEETH WERE NOT IN GOOD SHAPE.

MY DENTIST ACTUALLY SAID THERE

WAS SOMETHING WRONG WITH ME

SYSTEMICALLY WRONG WITH ME.

MY MOM HAD DIED OF PANCREATIC

CANCER WHEN SHE WAS 52 YEARS

OLD.

SO I NATURALLY THOUGHT, AND I

WAS VERY VERY WORRIED THAT I HAD

SOME KIND OF CANCER.

SO THAT, YOU KNOW, I HAD SOME

ITCHY SKIN RASHES AND IF YOU

LOOK, THERE'S A SYMPTOM

CHECKLIST SO YOU CAN SEE IF YOUR

FAMILY HAS CELIAC DISEASE, IF

YOU LOOK AT THAT CHECKLIST I

ACTUALLY HAD PROBABLY ABOUT 90%

OF THE SYMPTOMS ON THAT

CHECKLIST.

I HAD TINGLING IN MY FINGERS AND

MY TOES SO I HAD THE PERIPHERAL

NEURO THERAPY AND I HAD TERRIBLE

TERRIBLE DIARRHEA.

I SHOULD NOT HAVE BEEN

OVERLOOKED.

I WORKED AT THE TIME IN

MARKETING AND I HAD TO KNOW --

IT WAS TERRIBLE.

I HAD TO KNOW WHERE A BATHROOM

WAS, LOOKED IN EVERY CORNER.

I COULD NOT LIVE MY LIFE AND I

KEPT GOING TO THE DOCTOR.

THEY WOULD GIVE ME, IT WOULD BE

KOEPECTATE.

THE MIGRAINE HEADACHES.

IF YOU START TO LOOK FOR ALL THE

MEDICATIONS I WAS TAKING FOR

EVERY SYMPTOM I HAD I WAS TAKING

MEDICATION.

I HAD TERRIBLE BLOATING AND I

LOST 25 POUNDS.

THAT WAS A LOT OF WEIGHT.

I WAS 130 POUNDS.

I WAS ABOUT 105, 100 POUNDS.

AND THEN HAVING AL TERM STILL

BIRTH THREE MISCARRIAGES AND

THEN MY JUNK ES DAUGHTE YOUNGEST DAUGHTER 
WAS

TWO POUND WHEN SHE WAS BORN.

THAT'S WHEN I REALLY STARTED TO

SHED THE WEIGHTED AFTER SHE WAS

BORN.

I HAD INTRAUTERINE GROWTH

RETARDATION WHICH WE NOW KNOW I

WASN'T ABSORBING ALL THE

NUTRIENTS.

AND MY BODY WAS SHUTTING OFF I

THINK IN ORDER TO SAVE ME FOR

THE BABY.

LUCKILY SHE'S FINE.

SHE'S NOW 18 YEARS OLD.

SHE'S AT THE UNIVERSITY OF

MICHIGAN AND SHE IS DOING VERY

VERY WELL.

SO I FEEL VERY FORTUNATE THAT

SHE, THAT I WAS ABLE, THE

DOCTORS WERE ABLE TO SAVE HER.

BUT NOT UNTIL THE VETERINARIAN

SAID TO ME, YOU KNOW, ANIMALS

SOMETIMES HAVE TROUBLE WITH

GRAINS.

MAYBE IT'S THE GRAINS THAT

YOU'RE EATING THAT ARE CAUSING

YOUR PROBLEM.

BECAUSE THE GA GASTROENTEROLOGIST

HAD ME ON A DIET.

I WAS PUTTING OUT A LOT OF

STOOL.

I WAS A VERY VERY SICK WOMAN BY

THE TIME I WAS DIAGNOSED.

WHEN I SAW THE GASTROENTEROLOGY

GASTROENTEROLOGIST AND SAID THE

VETERINARIAN TOLD ME THERE'S

THIS DISEASE AND I DIDN'T EVEN

KNOW THE NAME OF IT THAT'S

CONNECTED TO WHEAT OR TO GLUTEN.

HE SAID YOU CAN'T HIDE THAT.

I SAID WHY.

HE SAID YOU'RE TOO TALL.

I SAID WELL WHAT'S THE TEST.

HE SAID IT'S A BLOOD TEST AND

I'M LIKE HERE'S MY ARM.

YOU'VE DONE EVERYTHING UNDER THE

SUN, IF YOU LOOK AT ALL OF THE

TESTS I HAD AND THE STUDIES AND

ALL THE GI STUDIES I HAD AND

NOTHING CAME UP.

THERE REALLY WAWNTZ, IT WAS

AGAIN ALL THIS MULTITUDE OF

SYMPTOMS.

AND SURE ENOUGH I ENDED UP WITH

HAVING THE TTG WAS ELEVATED.

I HAD POSITIVE SEROLOGY AND THEY

WENT IN AND DID THE ENDOSCOPY.

MY VILLI WAS FLATTENED.

WITHIN A COUPLE WEEKS OF GOING

ON A GLUTEN FREE DIET, I STARTED

TO FEEL BETTER.

NOW, THIS WAS 19 YEARS AGO.

SO THIS IS A LONG TIME AGO AND

THERE WAS NOT GLUTEN FREE FOOD

IN THE SUPERMARKETS.

I HAD TO ORDER MY FOOD FROM

CANADA.

THE FOOD WAS NOT READILY

AVAILABLE OR AFFORDABLE AND

THESE DAYS GLUTEN FREE PRODUCTS

ARE AFFORDABLE AND THEY ARE

AVAILABLE AND THERE IS THE

TREATMENT.

SO I FELT VERY FORTUNATE.

IT TOOK A COUPLE WEEKS TO START

TO FEEL BETTER.

WITHIN A YEAR I WAS BACK TO MY

NORMAL SELF.

I REALLY COULD START TO EXERCISE

AGAIN AND START TO REALLY

RESTORE MY HEALTH AND RECLAIM MY

LIFE.

THAT'S THE STORY.

ANYBODY HAVE ANY QUESTIONS?

MY MOTHER'S DEAD SO HE WE DON'T

KNOW THE GENETICS.

IN CELIAC DISEASE ALMOST

EVERYBODITH MY FAMILY HAS BEEN

JETALLGENETICALLY TESTED.

WE DON'T KNOW FROM IT COMES FROM

BUT MY MOTHER WAS DUTCH.

>> [INDISCERNIBLE]

>> THEY ARE DISCONNECTED.

AND SO I CAN'T REMEMBER THEM ALL

SO I CAN GO FROM MY HEAD TO TOE.

LET'S GO OVER THE SYMPTOMS.

WE DID THIS EARLIER TODAY.

I HAD BLOATING.

I HAD HARD TO FLUSH BOTH HARD OR

LOOSE STOOLS WHICH IS TYPICAL OF

CELIAC DISEASE.

DIARRHEA.

I HAD FATIGUE.

I HAD SOME ITCHY SKIN PROBLEMS

BUT I DID NOT HAVE DERMATITIS OR

KETAFORMIS WHICH IS A

MANIFESTATION.

I HAD NEUROPATHY.

I HAD JOINT PAIN, DEPRESSION.

I LOST A LOT OF WEIGHT.

IF YOU LOOK BACK WE TALKED BIT

WHEN I WAS 14 YEARS OLD I DID

GET MY MENSTRUAL PERIOD SO THERE

WAS DELAYED ONSET OF YOUR

MENSES.

WE KNOW THAT'S A SYMPTOMS OF

CELIAC DISEASE.

I DO HAVE THYROID DISEASE AS

WELL.

THOSE ARE REALLY MOST OF MY

SYMPTOMS.

I DID NOT HAVE OSTEOPOROSIS

WHICH IS VERY TYPICAL IN CELIAC

DISEASE.

I DID NOT HAVE ANEMIA.

AS WE'LL LEARN, EVERYBODY

PRESENTS VERY VERY TYPICALLY

DIFFERENTLY.

40% OF THE PEOPLE DON'T EVEN

HAVE ANY GASTROINTESTINAL ISSUES

AND THEY MAY NOT EVEN -- THEN

THEY HAVE VERY LITTLE SYMPTOMS

AT ALL OR WHAT THEY RECOGNIZE AS

SYMPTOMS UNTIL AFTER THEY'RE

DIAGNOSED.

>> OKAY.

>> THIS MAY BE RELEVANT.

YOU MAY ALREADY HAVE ANSWERED

THIS.

FOR SOMEBODY WHO HAS CELIAC,

OKAY, WHO HAS A CERTAIN LEVEL OF

SYMPTOMS WHATEVER WITH IT UPON

EATING GLUTEN, AFTER BEING OFF

OF GLUTEN FOR A PERIOD OF TIME,

IF THAT PERSON GOES BACK TO

GLUTEN ARE THE SYMPTOMS WORSE

THAN THEY WERE BEFORE THAT

ELIMINATED GLUTEN IN THE FIRST

PLACE?

>> I'M NOT A SCIENTIST.

I CAN SPEAK FROM MY OWN

PERSPECTIVE AND FROM YOU KNOW

THOUSANDS OF PEOPLE I'VE TALKED

TO.

IN MY CASE WHEN I DO EAT GLUTEN

AFTER I'VE BEEN OFF GLUTEN FOR A

LONG TIME, I DO HAVE SEVERE

SYMPTOMS.

I CAN TELL BECAUSE I'M HIGHLY

SYMPTOMATIC.

NOW THERE ARE PATIENTS THAT ARE

NOT SYMPTOMATIC.

I CAN TELL ALMOST IMMEDIATELY,

PRETTY SOON AFTER I'VE BEEN

EXPOSED TO GLUTEN THAT I'VE HAD

GLUTEN.

>> [INDISCERNIBLE]

OKAY.

YOU HAVE CELIAC, THAT MEANS YOU

HAVE DAMAGE.

THAT MEANS THAT YOU HAVE A

CERTAIN INTOLERANCE TO GLUTEN.

DO YOU BY BEING OFF GLUTEN MAKE

THAT INTOLERANCE TO GLUTEN

WORSE?

SO WHEN YOU GO BACK TO GLUTEN,

YOU'RE SENSITIVE TO THE GLUTEN

IS WORSE, NOT AS BAD, WORSE THAN

IT WAS BEFORE YOU WERE OFF

GLUTEN IN THE FIRST PLACE.

>> SO I THINK WE'LL LET

DR. ROSENBERG ADDRESS THAT WHEN

HE TALKS ABOUT SOME OF THE

CLINICAL ASPECTS OF IT, OKAY.

LISTEN, THANK YOU VERY VERY

MUCH.

[APPLAUSE]

>> OKAY, IRV.

WOULD YOU PLEASE PUT YOUR NAME

AND E-MAIL ADDRESS OF THE

INSTITUTE IN THE BOOK THAT GOES

AROUND.

>> I'M REALLY EXCITED TO BE PART

OF THIS PRESENTATION BECAUSE NOT

ONLY HAVE I KNOWN ABOUT THIS

COURSE THAT DR. ARIAS HAS BEEN

TEACHING FOR A NUMBER OF YEARS

AND HAS BEEN TAUGHT IN A COURSE

DURING THE EARLY YEARS.

CAN YOU HEAR ME NOW?

TAUGHT IN A COURSE IN THE EARLY

YEARS WHEN THAT WAS BEGUN AT

TUFTS UNIVERSITY.

BUT THIS CONDITION IS SUCH A

CENTRAL CONDITION IN THE AREA OF

THE CONNECTION BETWEEN TWO OF MY

OWN GREAT INTERESTS WHICH ARE

PHYSIOLOGY OF THE

GASTROINTESTINAL TRACT AND

NUTRITION.

IN FACT IT WAS CONDITIONS LIKE

THIS THAT DREW ME INTO THE FIELD

OF GASTRO OF INTRAWL GAS GASTROENTEROLOGY 
EARLY ON.

THERE IS A DIFFERENCE BETWEEN

CLINICAL OBSERVATION AND SOME

UNDERSTANDING OF UNDERLYING

BASIC PHYSIOLOGY, BIOCHEMISTRY

AND EVEN CELL BIOLOGY.

AND YOU'LL BE HEARING MORE ABOUT

THOSE BRIDGES AS THE AFTERNOON

GOES ON, ESPECIALLY WITH

DISCUSSION WITH DR. BANA JABRI.

SO IT'S BEEN ALREADY MENTIONED

THAT THIS IS A CONDITION WHICH

IS NOW BEING DIAGNOSED MUCH MORE

EFFECTIVELY AND FREELY, AND IT

HAS RESULTED IN A GREAT

PROLIFERATION OF PRODUCTS IN THE

MARKETPLACE THERE'S AN EXAMPLE

OF A GLUTEN FREE BREAKFAST BAR.

THERE ARE LITERALLY HUNDREDS OF

THESE PRODUCTS NOW IN THE

SUPERMARKETS.

WHICH I AT LEAST IN PART ARE A

RESPONSE TO THE KIND OF ADVOCACY

THAT HAS LED WHERE A PATIENT

WITH CELIAC, AND THIS IS NOT A

RARE DISEASE.

WE'LL TALK ABOUT ITS PREVALENCE

IN A FEW MINUTES.

WHERE THESE PEOPLE HAVE COME TO

INSIST THAT THE FOOD INDUSTRY IN

THE MARKET PROVIDE PRODUCTS

WHICH THEY CAN EAT HEALTHFULLY

AND NOT PRODUCE TERRIBLE

SYMPTOMS.

IT PROBABLY HAS PRODUCED AN

OVERREACTION IN THE FOOD

INDUSTRY WHERE SO MANY OF THESE

PRODUCTS WHICH ARE NOW NOT

MARKETED SIMPLY TO PROVIDE GOOD

HEALTHFUL FOODS FOR PATIENTS WHO

HAVE CELIAC DISEASE OR GLUTEN

ENTEROPATHY.

BUT ALSO AS A KIND OF A PANACEA

TO CURE MANY OF THE ILLS OF

MANKIND.

AND I THINK WE'RE ACTUALLY

FACING A SOMEWHAT DIFFICULT

CHALLENGE WHERE THE IDEA OF

GLUTEN-FREE FOODS CAN BE SO

HEAVILY MARKETED BY THE FOOD

INDUSTRY WHAT WILL LOSE TRACK OF

THE TRUE RELATIONSHIP BETWEEN

SOME OF THESE PRODUCTS AND THE

HEALTHFUL MANAGEMENT OF THE

DIETS OF PATIENTS LIKE ALICE

BASQUE.

I'LL MAKE JUST A COUPLE REMARKS

ABOUT ALICE'S OWN PERSONAL

HISTORY.

SHE TOLD US OF A NUMBER OF

THINGS THAT INDICATED SOME OF

THE NUTRITIONAL PROBLEMS FROM

WHICH SHE SUFFERED.

WHEN SHE TALKED ABOUT TINGLING

IN HER FINGERS, THIS WAS

PROBABLY NOT ONLY AN EXAMPLE OF

SOME OF THE NUTRITIONALLY

RELATED NEUROTHES NEUROPATHIES SHE HAD BUT

HAD TO DO WITH THE TEND SEE IN

SOME OF PATIENTS TO HAVE --

BECAUSE OF THEIR CALCIUM MAL

ABSORPTION AND CALCIUM

DEFICIENCY.

SHE TALKED ABOUT WEAKNESS AND

FATIGUE WHICH MAY HAVE BEEN

RELATED TO A NUMBER OF

NUTRITIONAL PROBLEMS INCLUDING

ANEMIA FROM WHICH SHE DIDN'T

SUFFER.

SHE TALKED ABOUT SHE DIDN'T HAVE

OSTEOPOROSIS.

THE BONE CONDITIONS ASSOCIATED

WITH CELIAC DISEASE IS NOT

OSTEOPOROSIS IT'S OSTEO

MALAYSIA.

IT'S REALLY A VITAMIN B

DEFICIENCY.

AND BECAUSE VITAMIN B IS AN

IMPORTANT VITAMIN ITS ABSORPTION

IN THIS CONDITION IS IMPAIRED

JUST AS THE ABSORPTION OF

OTHERS.

SOME PATIENTS WILL PRESENT,

CELIAC PATIENTS WILL PRESENT

WITH OSTEO MALAYSIA WITHOUT

OTHER SYMPTOMS OR PRESENT WITH

ANEMIA.

SO ONE OF THE WAYS THAT WE

SOMETIMES SEE THESE PATIENTS

PRESENT IS BECAUSE WHAT WE ARE

SEEING IS NOT SO MUCH THE GAS

GASTROINTESTINAL SYMPTOMS BUT

THE SECONDARY NUTRITIONAL

PROBLEMS WHICH ARE ASSOCIATED

WITH POOR ABSORPTION.

THESE AN ELEMENT IN ALICE

BASQUE'S PRESENTATION WHICH WE

NEED TO TAKE INTO ACCOUNT.

AND THAT IS THAT SHE WAS IN HER

30'S.

IF THIS IS A CONDITION THAT'S AT

LEAST IN SOME WAYS EVEN IN

INFANCY.

HOW DOES THIS, HOW   DOES IT

HAPPEN THAT WE CAN HAVE THIS

TALL ATTRACTIVE WOMAN WHO DRN

HAVE GROWTH STUNT -- WHO DID NOT

HAVE GROWTH STUNTING, DID NOT

HAVE GROWTH RETARDATION AND SO

FORTH.

AND I THINK THAT MYSTERY

CONTINUES TO CHALLENGE US,

PERHAPS DR. BANA JABRI WILL HAVE

SOME IDEAS ABOUT THE TEMPORAL

RELATIONSHIP OF THESE IMMUNE

FACTORS.

BUT LET ME JUST SAY ONE THING.

REMEMBER THAT IF THE PRIMARY

INTESTINAL LESION THAT WE'LL BE

TALKING ABOUT IS ONE LOSS OF

SURFACE AREA OF THE INTESTINAL

VILLI WE'LL TALK ABOUT IN HAS TO

BE THOUGHT OF IN TERMS OF THREE

DIMENSION.

NOT JUST THE FLATTENING OF VILLA

IN THE LOCATION WHERE THE BIOPSY

IS DONE BUT OVER WHAT LENGTH OF

THE INTESTINE IS THAT FATTENING

OCCURRING, AND THAT CAN HAVE A

LOT TO DO WITH THE SEVERITY OF

THE PRESENTATIONS.

AND SO EVEN IN ANSWER TO THE

QUESTION EARLIER ABOUT THE

REACTION TO GLUTEN CHALLENGE

LATER, SOME OF THAT HAS TO DO

WITH GA HOW MUCH OF THE INTESTINE

IS EXPOSED AND THEREFORE HOW

MUCH OF THE VARIOUS FLATTENING

EXTENDS OVER THE GA SEVERAL FEET OF

THE INTESTINE.

LET'S RETURN FOR, WE ALREADY

HEARD A NUMBER OF DIFFERENT

NAMES HERE AND I WANTED TO JUST

SPEND A COUPLE MINUTES ON THESE

NAMES BECAUSE THEY'RE ILL

ILLUSTRATIVE OF HOW DIFFICULT IT

WAS TO COME INTO THE

UNDERSTANDING OF THIS CONDITION.

THEY EACH HAVE THEIR OWN

CONTRIBUTION TO THE HISTORY AND

EVEN THE DIAGNOSIS.

CELIAC DISEASE WAS THE TERM THAT

WAS USED IN THE 19TH CENTURY,

I'LL MENTION IN A FEW MINUTES.

REDISCOVERY OF A DESCRIPTION OF

THIS IN THE FIRST CENTURY.

AND WHICH THE TERM CELIAC WAS A

DERIVATION OF THE GREEK -- WHICH

REFERRED TO A KIND OF INTESTINAL

DIARRHEAL CONDITION.

AND CELIAC IS KIND OF THE

LATINIZATION OF THAT GREEK -- I

MISAPOLOGIZE FOR THE MISPEELING

HERE.

IT SIMPLY MEANT THIS WAS

STEATORR HEALTH A, LOSS OF FAT

IN THE STOOLS WITHOUT A KNOWN

CAUSE.

IT WAS KIND OF PATHETIC BUT IT

WAS REALLY IDENTIF IDIO IDIO PATHIC AND TH
IS

IN A SENSE BRINGS US BACK TO THE

ANECDOTE THAT DR. ARIAS

MENTIONED EARLIER WHERE THERE

WAS A CONNECTION BETWEEN

DR. DICKE AND DR. VANDCOMEER.

ONE OF THE CAUSES OF THE KIND OF

SYMPTOMS THAT WE SEE WITH THIS

DISEASE IS REALLY RELATED TO THE

AMOUNT OF FAT THAT'S IN THE

STOOL THAT CAUSES THE STOOL TO

FLOAT AND BE GREASY AND

DIFFICULT TO FLUSH AND SO FORTH.

IT'S TURNS OUT VANDCOMER WAS ONE

OF THE WORLD'S EXPERT IN HOW TO

MEASURE FAT IN GASTROENTEROLOGY

AND THEREFORE IT TURNS OUT HE

BECOMES A VERY IMPORTANT PERSON

IN THIS HISTORY OF HOW STOOL IS

E LOOSEEELUCIDATED.

THERE'S A TRUMP CAL TROPICAL SPRUE --

TROPICAL SPRUE WAS A CONDITION

OF MAL ABSORPTION WEAKNESS

ANEMIA IRON AND FOLATE

DEFICIENCY AND SO FORTH COULD

ALSO B BEA SEVERELY CONTRIBUTORY

TO GROSS RETARDATION, WEIGHT

LOSS MALNUTRITION.

AND THEN AS NOW ITS CAUSE WAS

UNCERTAIN.

BUT THE QUESTION SOMETIMES

THERE'S THE QUESTION THAT WAS

RAISED IN ALICE BAST'S STORY

MAYBE YOU HAVE TROPICAL SPRUE.

WHETHER SHE DID HAVE TROPICAL

SPRUE.

I THINK THE DOCTORS WHO ASKED

THAT QUESTION DEPOSIT KNOW WHAT

TROPICAL SPRUE WAS BECAUSE WE

DON'T REALLY KNOW WHAT TROPICAL

SPRUE IS NOW.

A MILDER FORM IS TROP PULL

ENTEROPATHY -- TROPICAL

ENTEROPATHY, AGAIN THE GREEK

TERMS FOR ENTERO, THE INTE INTESTINE

AND TROPA FOR PATHOLOGY.

IT WAS LATER THAT THE TERM

GLUTEN WAS USED AFTER THE

CAUSATIVE AGENT IN THE DIET WAS

BETTER ELUCIDATED.

JUST A REVIEW OF THAT, THIS

REFERENCE TO THIS CONDITION

BY -- WHICH WAS REFERRED TO

AS -- AND LATER DIAGNOSED OR

TRANSLATED AS CELIAC.

IN THE 18TH CENTURY, THE DID YOU

EVER TERM -- DUTCH TERM SPRUE

STARTED TO BE USED.

IT'S A LITTLE MYSTIFYING.

IT'S NOT CLEAR WHETHER SPRUE WAS

ALSO RELATED TO THE KIND OF

SYMPTOMS THAT OCCURRED AFTER A

DRINKING OR EATING SPREE.

AND OF COURSE SPRUE WAS

ASSOCIATED WITH A LOSS OF A LOT

OF FLUID AND DIARRHEA AND SO

FORTH.

SAMUEL  GEE IN ENGLAND WROTE

REALLY THE FIRST IMPORTANT PAPER

OF THE CELIAC AFFLICTION, CELIAC

REFERRING AGAIN TO THE GREEK --

AND I THINK MADE AN OBSERVATION

I'LL MENTION IN A MOMENT WHICH

IS CRITICAL TO THE HISTORY OF

OUR UNDERSTANDING OF THIS.

IN THE 20TH CENTURY, WE HAVE THE

OBSERVATIONS BY DICKE THAT

DR. ARIAS MENTIONED, AND HE

WROTE ABOUT THE HARMFUL EFFECT

OF CERTAIN TYPES OF CEREAL.

AND AGAIN, THIS OBSERVATION WAS

INTENSIFIED GREATLY BY THE

OBSERVATION OF WHRACHED OF THE

GREAT HUNGER -- WHAT HAPPENED OF

THE GREAT HUNGER OF FAMINES IN

HOLLAND DURING WORLD WAR II WITH

THE REINTRODUCTION OF GRAIN

PRODUCTS WHICH HAD BEEN

UNAVAILABLE DURING THE FAMOUS

HUNGER WINTERS AND SO FORTH.

THERE WAS A GREAT WORSENING OF

THE MANAGEMENT OF PATIENTS WITH

THE CELIAC DISEASE EVEN THOUGH

IT WASN'T AT ALL CLEAR WHAT THE

RELATIONSHIP WAS EXCEPT THAT IT

SEEMED TO BE HARMFUL EXCEPT WITH

A CERTAIN TYPE OF CEREAL.

AND THEN IT'S -- I DIDN'T KNOW

THIS STORY ABOUT HIS

RELATIONSHIP TO DICK JEVMENT'S

RELATION -- DICKE'S RELATIONSHIP

WITH VANDCALLER AND HIS

RELATIONSHIP WITH THE SPRUE WHO

MADE THE ADDITION YOU

OBSERVATION THAT THIS WAS

RELATED TO THE CEREAL GRAINS.

HE STARTED DOING SOME OF THE

FIRST TRACTIONATION.

AND ONE OF THE PEOPLE THAT

REPORTED THAT THERE WAS A LOT OF

INSIDABLE TRACTION OF PROTEIN

IN, FROM WHEAT, THAT TURNED OUT

TO AT LEAST BE THE FOCUS OF THE

CULPRIT.

I THINK FOR THE PURPOSES OF THIS

VERY CREATIVE WAY OF TEACHING

ABOUT MEDICINE THAT DR. ARIAS

MENTIONED THAT ONE CAN HOPE TO

USE SOME BRIDGING BETWEEN THE

OBSERVATIONS IN THE CLINICAL

SETTING AND THE OBSERVATIONS

THAT COME FROM THE LABORATORY,

THIS IS I THINK A REMARKABLE

EXAMPLE OF THE WAY IN WHICH THIS

BRIDGING MIGHT OCCUR.

IN THE 19TH CENTURY THAT HE

WROTE HIS TREATISE ABOUT CELIAC

DISEASE.

HE MERELY ENDED THE TREATISE

WHERE THE STATEMENT IF THE

PATIENT CAN BE CURED AT ALL, IT

MUST BE BY MEANS OF DIET.

BUT IN TERMS OF WHAT WE COULD

REALLY LEARN ABOUT THE OFFENDING

AGENT.

AND TWO GA GASTROENTEROLOGISTS IN

THE 1950'S, JUST BEFORE THE

ADVENT OF THE INTESTINAL BIOPSY

WROTE A TREATISE, A WHOLE

MONOGRAPH ON CELIAC DISEASE, AND

SAID MANY INVITING AVENUES ARE

OPEN FOR EXPLORATION IN THE

ELUSIVE CAUSE OF CELIAC DISEASE.

IT IS LIKELY HOWEVER THAT THE

ETIOLOGY OF THE CONDITION WILL

BE DISCOVERED IN THE COURSE OF

WORK RELATED TO THE TREATMENT OF

THE CONDITION.

I THINK THIS IS REALLY AN

INTERESTING FORWARD LOOKING

OBSERVATION AND I THINK IF YOU

THINK OF THE NUMBER OF DISEASES,

NOT JUST ALLERGIES, BUT THERE

ARE A NUMBER OF DISEASES IN

WHICH THE TREATMENT ACTUALLY

PERCEIVES THE UNDERSTANDING OF

THE PATHOGENESIS AND LEADS US IN

THE DIRECTION OF REALLY HELPING

TO UNDERSTAND WHAT IS THE REAL

ETIOLOGY OF THE DISEASE.

I MENTIONED THE DIAGNOSIS WHICH

IS RELATED AS I INDICATED TO THE

TREATMENT AND THE RESPONSE TO

TREATMENT IN THIS CONDITION.

REALLY I THINK TOOK A GREAT

ADVANCE IN THE 1950'S WITH THE

ADVENT OF THE NEW TECHNIQUE

WHICH WE HAD AVAILABLE TO US IN

THE FIELD OF MEDICINE AND

GASTROENTEROLOGY AND THAT WAS

THE -- INTESTINAL BIOPSY.

THIS IS THE CASE WHERE THE TUBE

COULD BE A VERY SMALL TUBE

SOMETIMES EVEN ALMOST CAPILLARY

SIZE COULD BE INTRODUCED INTO

THE INTESTINE WITH A CAP SEUL

INTO THE TUBE BY -- CA CAPSULE BY

SUCTIONING IT WE COULD LOOK AT

THE MORPHOLOGY OF THE INTESTINE.

IT WAS VERY HARD TO IMAGE THE

INTESTINAL MORPHOLOGY AT THAT

POINT WITHOUT IT EXCEPT THAT

SURGERY -- SO THIS WAS A VERY

IMPORTANT DEVELOPMENT.

AND THEN IT WAS PROCEEDED BY

SOME TIME THE DEVELOPMENT OF

SOME OF THE KINDS OF BLOOD TESTS

THAT ALICE BAST TOLD US ABOUT

AND WHOSE BASES THEREBY

DISCUSSED IN A GOOD DEAL MORE

DETAIL BY DR. BANA JABRI.

AND THESE WERE TESTS WHICH

RANGED FROM HLA ANTIGENS TO MORE

SPECIFIC -- ANTIBODIES AND ALSO

INCLUDED SOME INFLAMMATORY

CYTOKINES.

WHY PRO INFLAMMATORY CYTOKINES

WHICH YOU'LL SEE IN A MOMENT.

THIS IS AN INFLAMMATORY

CONDITION OF THE INTESTINE.

THIS IS THE INFLAMMATION OF A

GOOD DEAL OF THE PROBLEMS

ASSOCIATED WITH CELIAC DISEASE.

THIS IS WHAT THE NORMAL

INTESTINAL BIOPSY LOOKS LIKE.

AND I THINK YOU CAN SEE THAT THE

VILLI, WHICH ARE AT THE SURFACE

OF THE SMALL INTESTINE AND WE

CAN ACTUALLY GET A BEAUTIFUL

SAMPLE OF THIS WITH EVEN A THIRD

OF THE TIME OF ENDOSCOPY, THE

VILLI ARE GREATLY INCREASE THE

SURFACE AREA OF THE INTESTINE

AND EVEN AT THE SURFACE OF THE

VILLI ARE MICROVILLI WHICH

FURTHER INCREASE THE SURFACE

AREA, AND ALSO PROVIDE SOME OF

THE ENZYMES THAT ARE INVOLVED IN

THE INTESTINAL DIGESTION WHICH

IS NECESSARY FOR THE ABSORPTION

OF NUTRIENTS.

YOU'LL NOTICE THAT WHILE THERE

IS, THERE IS SOME CELLULARITY IN

THE EPITHELIAL TISSUE HERE, IT'S

NOT ANYTHING THAT ONE WOULD CALL

INFLAMMATION.

NOW IF YOU COMPARE IT WITH THE

CELIAC BIOPSY, YOU CAN SEE NOT

ONLY RIGHT IN THE BEGINNING, YOU

CAN SEE THAT THERE'S A GRADED

DEAL OF CELLULARITY THAT'S

ASSOCIATED WITH FLAMMIT INFLAMMATORY

CELLS WHICH ARE LARGELY

LYMPHOCYTES AND THEIR

SPECIFICITY TO BE DISCUSSED I

THINK BY DR. JABRI.

THE OTHER THING THAT'S HAPPENING

HERE IS NOT ONLY HAVE THESE

VILLI BEEN LOST, WHERE WE HAVE

NOW A REALLY FLAT INTESTINE, BUT

THEREFORE THERE'S A GREAT LOSS

OF SURFACE AREA.

AND WHAT WE SEE IS THAT THESE

CROOKS HERE WHICH ARE

DEGENERATIVE CELLS OF THE

INTESTINE THAT ARE TRYING TO

MOVE CELLS UP THESE VILLI TO

POPULATE THE VILLI BECAUSE THIS

INTESTINE, THESE CELLS TURN OVER

AT THE RATE OF EVERY TWO OR

THREE DAYS.

SO THERE'S DEGENERATIVE AREAS OF

THE INTESTINE NOW EXTENDS TO THE

WHOLE THICKNESS OF THE

INTESTINE.

THERE'S THIS REACTION IN THE

INTESTINE TO TRY TO GENERATE

CELLS BECAUSE OF THE LOSS OF THE

VILLI.

NOW I MENTIONED TO YOU, SO THIS

IS A SNAPSHOT AT ONE LOCATION,

THIS HAPPENS TO BE IN THE DUO DO --

DUODENUM, A VERY IMPORTANT ISSUE

OF HOW SEVERE THE SYMPTOMS ARE

GOING TO BE AND HOW BAD THE MAL

ABSORPTION IS GOING TO BE OVER

WHAT LENGTH THE INTESTINE THIS

LESION.

AND WE DON'T GENERALLY DO

BIOPSIS OVER THE WHOLE LENGTH OF

THE SMALL INTESTINE.

SO THAT'S AN IMPORTANT AREA OF

CONSIDERATION.

NOW JUST A COMPARISON.

THIS HAPPENS TO BE TROPICAL

ENTEROPATHY.

THAT TROPICAL CONDITION WHICH IS

NOW CALLED ENVIRONMENTAL

ENTEROPATHY BECAUSE IT DIDN'T

JUST EXIST IN THE TROPICS.

BUT IT EXISTS WHEREVER IT

APPEARS THAT THERE IS UNSANITARY

CONDITIONS THAT MAY BE MULTIPLE

INFECTIOUS EPISODES AFFECTING

THE INTESTINE.

NOTICE THAT THESE ARE VERY

DIFFERENT STAGES OF SEVERITY.

HERE IS ONE WHERE THE INTESTINE

IS NEARLY NORMAL.

HERE YOU'RE SEEING SOME BLUNTING

OF THE VILLI WITH INFLAMMATION.

HERE IT'S MORE SEVERE BLUNTING

AND HERE IS THE SAME KIND OF

FLAT INTESTINE.

THE INTESTINE APPEARS NOT TO

HAVE A GREAT, A GREAT SPECTRUM

OF ABILITIES TO RESPOND TO

DAMAGE WHICH IN THE CASE OF

CELIAC DISEASE IS DAMAGE IN THE

PRESENCE OF GLUTEN OR POSSIBLY

EVEN THE SMALLER FRACT SURE OF

GLUTEN.

IN CASE OF TROPICAL CONDITIONS,

WHATEVER THEIR OFFENDING AGENT

IS, WE END UP WITH AN INTESTINAL

BIOPSY THAT'S NOT TOO DIFFERENT

FROM WHAT WE SAW EARLIER WITH

CELIAC.

SO IT'S NOT SURPRISING THAT

THERE WAS SOME CONFUSION EARLY

ON AS TO WHETHER OR NOT THIS WAS

A FORM OF THE KIND OF TROPICAL

MAL ABSORPTION THAT HAS BEEN

DESCRIBED PARTICULARLY STRONGLY

IN SOUTH INDIA AND OTHER PLACES.

BUT CLEARLY IT'S BEEN SEPARATED.

WE NOW KNOW A GREAT DEAL MORE

ABOUT THE PATHOGENESIS OF CELIAC

DISEASE THAN WE DO INTEREST

ENVIRONMENTAL ENTEROPATHY WHICH

IS NOW REAPPEARED AND THERE'S A

LARGE GATES FOUNDATION STUDY

THAT FOUND OUT HOW IMPORTANT

THIS MIGHT BE WITH ITS WIDE

PREVALENCE IN CONTRIBUTING TO

MALNUTRITION IN CHILDREN AROUND

THE WORLD.

NOW JUST TO EMPHASIZE FURTHER

THE IMPORTANCE OF THIS

MORPHOLOGY.

HERE AGAIN IS THE NORMAL

INTESTINE WITH ITS VILLI.

AND THESE, THIS EPITHELIUM IS

LOADED WITH VARIOUS KINDS OF

ENZYMES AND SUCH AS THOSE THAT

WILL SPLIT LACTOSE AND ENSUMS

THAT WILL HELP -- ENZYMES THAT

WILL HELP IN THE FINAL DIGESTION

OF PEPTIDES AND PROTEINS.

BUT ALSO WITH SOMETHING THAT

TRANSCONTAMINATES WHICH END UP

BEING PART OF THE APPROACH TO

THE DIAGNOSIS FOR THIS

CONDITION.

AND JUST A NICE WAY OF SHOWING

THAT IF YOU USE DECENTING

MICROSCOPE, YOU -- DESEE THE

AREA OF THE INTESTINE.

DEHERE'S THE INTESTINE WITH VERY

FEW INFLAMMATORY CELLS BEFORE

AND AFTER THE INTRODUCTION OF

THE GLUTEN AND YOU CAN SEE THE

SHARP INCREASE IN INFLAMMATION

WHICH WILL ALSO LEAD TO CHANGES

IN THE MORPHOLOGY OF THE

INTESTINE.

SO AS I SAID, THERE'S BEEN A

REMARKABLE ADVANCE IN OUR

UNDERSTANDING OF THE DIFFERENT

KINDS OF TESTS WHICH YOU WILL BE

HEARING ABOUT IN A FEW MINUTES

THAT ARE USED IN THE DIAGNOSIS

OF THIS CONDITION SO THAT NOW

THE WORK HORSE IN DIAGNOSIS OF

CELIAC DISEASE IS NOT SO MUCH

THE INTESTINAL BIOPSY AND THE

MORPHOLOGY BECAUSE IN FACT THE

TESTS.

THESE TESTS AS SHOWN HERE HAVE A

RANGE OF SENSITIVITIES AND SPES

FIST TEASE BUT IN QUITE SPES

SPECIFICITIES IN FACT NOTED IN

THE DIAGNOSIS OF CELIAC.

THEY CAN BE USED AS A MARKER NOT

WHAT WE USED TO DO WITH THE

BIOPSIS WHERE WE COULD LOOK AT

THE BIOPSIS BEFORE AND AFTER

GLUTEN EXPOSURE

 OF THE

ANTI-GLIAL AND BODIES.

WE MENTIONED THAT IT'S ONE OF

THE SUBFRACTIONS, PROBABLY THE

ALCOHOL SOLUBLE FRACTION OF

GLUTEN.

YOU CAN FOLLOW THE CHANGES IN

THESE ANTIBODY LEVELS IN BLOOD

 AFTER

PUTTING PATIENTS ON A GLUTEN

FREE DIET AS ANOTHER WAY OF

DOING THE THERAPEUTIC CHALLENGE

TO MAKE THIS DIAGNOSIS.

I THINK YOU'RE GOING TO BE

HEARING MORE ABOUT THIS.

I WON'T TAKE TIME EXCEPT TO

POINT OUT THAT IF WE TALK ABOUT

THE PREVALENCE OF THIS

CONDITION, WE'RE REALLY TALKING

ABOUT THE QUESTION ABOUT WHAT

CONSTITUTES ACTUALLY THE

DIAGNOSIS OF CELIAC DISEASE.

YOU COULD TALK ABOUT THE ICEBERG

HERE IN WHICH CELIAC IS ONLY AT

THE TIP OF THE ICEBERG WHILE

OVER A MUCH LARGER AMOUNT OF THE

POPULATION YOU HAVE THE HLH

ANTIBODY DC2 OR DC8.

WHERE THE OTHER TESTS ALSO RANGE

OVER A RANGE WHERE YOU HAVE BOTH

THE CLINICAL PRESENTATION OR A

RATHER SILENT CONDITION WHERE

THIS IS STILL CELIAC DISEASE.

AND THEN IT RAISES AN

INTERESTING QUESTION ABOUT WHAT

WE SHOULD BE TALKING ABOUT WHEN

WE TALK ABOUT THE PREVALENCE OF

THIS CONDITION.

WHICH OF THESE CUT OFFS SHOULD

WE BE USING WHEN WE TALK ABOUT

PREVALENCE.

AND WE MIGHT SAY WELL, THE

HIGHEST INCIDENCE OF DIAGNOSED

CELIAC DISEASE IS IN THE

POPULATION THAT IS IN CELTICS

ESPECIALLY IN THE NORTHWEST OF

IRELAND.

THEIR PREVALENCE IS MAYBE AS

MUCH AS A HUNDRED WHICH REALLY

MAKES THIS A HIGHLY PREVIOUS

LUNT --PREVALENT AND COMMON CONDITION

THAN LET'S SAY IN INDIA BUT NOT

ABSENT.

THE FEMALE TO MALE RATIO TENDS

TO BE ABOUT 2-1.

AND I THINK PERHAPS WE CAN HEAR

MORE ABOUT THAT IN A MINUTE.

I WON'T GO INTO THIS BUT EXCEPT

TO SAY THAT THERE ARE A NUMBER

OF TOXIC PRODUCTS IN GRAINS, NOT

JUST GLEE DIN WHICH CAN CAUSE

PROBLEMS SUCH AS A RAIN OF

RESPONSES TO WHEAT, RIGHT,

BARLEY AND RHODES.

THERE WERE HIDDEN SOURCES OF

GLUTEN OR OFFENDING AGENTS IN

THE DIET RANGING, BEERS HAVE

ENOUGH TO, IN THE MALTS AND SO

FOARLT TO BSOFORTH TO BE OFFENDING.

SO FAMOUSLY THEN THE COMMUNION

WAFERS THAT HAVE CAUSED TROUBLE

WITH PEOPLE IN THE CATHOLIC

CHURCH.

YOU CAN EVEN HAVE ENOUGH IN SOME

OF THE LI LIPSTICKS AND THINGS

LIKE -- TO BE OFFENDING.

ING LIOFFENDING.

FINALLY I WANTED TO POINT OUT

AND I THINK THIS IS ALSO

PRESENTED IN THE STAFF

PRESENTATION.

NOT ONLY IS THERE A REMARKABLE

VISUALITREMARKABLEVARIABILITY IN THE WAY I
N THIS

CELIAC DISEASE PRESENTS BUT

THERE'S A REMARKABLE LIST OF

DIFFERENT CONDITIONS THAT ARE

ASSOCIATED WITH CELIAC DISEASE

MAY SHARE SOME OF THE ELEMENTS

OF THE PATHOGENESIS AND I THINK

WE'LL BE HEARING A LITTLE BIT

MORE ABOUT THAT.

OF THESE CONDITIONS CAN BE

ROUGHLY PUT IN THE CATEGORY OF

AUTOIMMUNE DISEASE.

BUT NOT ALL.

SOME OF THEM I THINK ARE

REPRESENTATIVE OF SECONDARY

MALNUTRITION OR BECAUSE OF

DIETARY AND VITAMIN

DEFICIENCIES.

AND THEN THERE'S A BUNCH OF

OTHER ASSOCIATIONS -- SYNDROME

WHICH IS CLEAR LEANNA TOE IMMUNE

CON-- AN AUTOIMMUNE CONDITION

THAT AFFECTS THE SALARY GLANDS

AND OTHER PARTS KINDS OF

VASCULAR LOW ABNORMALITIES THAT

INCLUDING DR. ARIAS'S INTERESTS

WHICH IS AUTOIMMUNE LIFER

DISEASE.

THERE'S A GREAT DEAL -- LIFER --

LIVER DISEASE.

THERE'S A GREAT DEAL MORE TO

LEARN ABOUT WHY THESE

ASSOCIATIONS ARE PRESENT.

MY GUESS IS AS WE LEARN AND

DR. JABRI WILL TELL US ABOUT

WILL MAKE AN EVEN BETTER

CONNECTION.

LET ME END BY REMINDING YOU

THAT THE CHALLENGES SAT

SAMUEL GEE PRESENTED IN THE 19TH

CENTURY AND -- MENTIONED THAT

SOMEHOW THE ETIOLOGY OF THIS

CONDITION WILL BE DISCOVERED IN

THE COURSE OF WHAT'S RELATED TO

THE TREATMENT.

I THINK YOU'LL FIND HOW MUCH

PROGRESS WE'VE MADE IN THE NEXT

PRESENTATION.

>> ALL RIGHT, THANK YOU.

ARE THERE ANY QUESTIONS?

>> [INDISCERNIBLE]

 HIGH PERPORTION THAT ARE NOT

ADEQUATELY DIAGNOSED.

DO YOU THINK IF A PATIENT IS TO

BE SEEN BY A PHYSICIANS THROUGH

YEARS THAT ANTI-TISSUE

TRANSCONTAMINATES AND IJ

ANTIBODIES SHOULD BE PART OF

EVERYBODY'S INITIAL WORK UP LIKE

A CHEST X-RAY OR AN EKG.

IF YOU'RE GOING TO MISS HALF A

MILLION CASES IN THE U.S. OR GO

THROUGH TEN YEARS OF SUFFERING,

ARE THESE OF SUFFICIENT VALUE

FOR EVERYONE TO HAVE THIS

SCREENED?

>> I THINK I'M GOING TO HAVE TO

REFER THAT QUESTION TO THE

DISCUSSION.

BANA, DO YOU WANT TO COMMENT ON

THAT?

>> ACTUALLY THE PROBLEM THAT

YOU'RE GOING TO SEE IS THAT NOT

ALL PATIENTS WITH ANTIBODIES

HAVE ACTUALLY INTESTINAL

ADHESIONS.

WE STILL KNOW VERY LITTLE ABOUT

HOW IMPORTANT IT IS TO TREAT

PATIENTS WHO DON'T HAVE

INTESTINAL LESIONS BUT HAVE A

ANTIBODIES.

>> I THINK ANOTHER REACTION TO

THAT IS YES, THERE IS QUITE A

SPECTRUM OF ACTUALLY CLINICAL

CONDITIONS THAT ARE ASSOCIATED  

WITH THE PRESENCE OF POSITIVE

ANTIBODIES.

AND I THINK IT'S CLEAR THAT WE

PROBABLY ARE STILL UNDER

DIAGNOSING THIS CONDITION AND

PERHAPS THAT KIND OF SCREENING

WOULD BE USEFUL BUT I THINK ON

THE OTHER SIDE, WE REALLY DON'T

WANT TO USE THE ANTIBODY TO MAKE

THE FINAL DIAGNOSIS AND THEN PUT

PEOPLE ON A VERY RETRICKIVE

GLUTEN -- RESTRICTIVE GLUTEN

FREE DIET.

>> IF THE PATIENT IS PUT ON A

GLUTEN FREE DIET DO THEY RETURN

TO NORMAL, DOES THE BIOPSY LOOK

NORMAL AT THAT POINT?

>> THE ANSWER IS TWO THINGS WILL

HAPPEN ON A GLUTEN-FREE DIET.

FIRST OF ALL THERE WILL BE

REGRESSION OF THE LENGTH OF THE

INTEINTESTINE OVER WHICH THIS

ABNORMALITY OCCURS AND THERE

WILL BE RETURN TO NEAR NORMALCY

IF THE GLUTEN FREE DIET IS

REALLY WELL ADMINISTERED.

IF THAT DOESN'T HAPPEN THEN

THERE'S THE QUESTION ABOUT

WHETHER IT IS RELATING TO THE

PROTECTIVENESS OF WHICH GLUTEN

IS REMOVED FROM THE DIET.

BUT BOTH IN TERMS OF ANTIBODIES

AND EVEN INTESTINAL BIOPSIS THAT

CAN BE RECOVERY OF --

>> WE'LL HAVE TIME TO DISCUSS

THIS FURTHER AFTER DR. JABRI'S

TALK.

>> IS THERE ANY RELATIONSHIP

BETWEEN CROHN'S AND CELIACS?

>> NOT TO MY KNOWLEDGE.

SOMETIMES YOU COULD HAVE A

YOUNGSTER PREADOLESCENT COME IN

WITH GROSS RETARDATION, WHICH IS

PROBABLY RELATED TO THE

MALNUTRITION.

BUT THEY ARRIVED AT THAT

CONDITION IN DIFFERENT WAYS IN

THE CASE OF CROHN'S AND CELIAC.

I DON'T KNOW WHETHER THERE'S ANY

CONNECTION ACTUALL ACTUALLY WITH

PATHOGENESIS.

>> [INDISCERNIBLE]

>> THE QUESTION IS, DO, CAN OATS

BE EATEN.

THE DICTUM IS THAT ALTHOUGH OATS

REPRESENT A MUCH LESS SEVERE

CHALLENGE THAN GLUTEN, THAT OATS

SHOULD BE REMOVED FROM A

GLUTEN-FRFREE DIET.

THERE ARE SOME CROSSOVERS IN THE

PROTEINS IN THESE DIFFERENT

GRAINS AND IT'S ENTIRELY

POSSIBLE THAT THERE IS, THAT

THIS IS HARDLY A DOSE EFFECT

WITH OATHS AS OPPOSED TO LET'S

SAY WHEAT GLUTEN.

BUT I THINK THROUGH STILL IS NOT

A FULL UNDERSTANDING OF THE SORT

OF SUBTLETIES O SUBTLETIES BETWEEN OATS AN
D

WHEAT IN THIS CASE.

>> LET'S PROCEED.

ALL RIGHT.

HERE YOU GO.

>> FOR THE AUTO ANTIBODY -- DO

YOU HAVE A BETTER CHANCE TO --

CELIAC DISEASE LATER IN YOUR

LIFE?

I MEAN THERE ARE SOME

INDIVIDUALS WHO HAVE THE

ANTIBODY BUT THEY DON'T HAVE

SYMPTOMS.

DO THEY DEVELOP CELIAC DISEASE

LATER IN THEIR LIFE OR DO THEY

HAVE BETTER CHANCE TO DEVELOP?

>> CLEARLY NOT EVERYONE THAT HAS

THE HLA WILL EVER DEVELOP CELIAC

DISEASE.

EVEN SOME WITH THE ANTIBODIES

PERHAPS, ALTHOUGH THEY EXPRESS

SUSCEPTIBILITY.

WHETHER THE PRESENCE OF THE

ANTIBODY INDICATES WHEN OVER THE

LIFE CYCLE YOU'RE MORE LIKELY TO

DEVELOP SYMPTOMATIC DISEASE, I

DON'T KNOW AND PERHAPS BANA

JABRI CAN COMMENT ON THAT.

>> I'LL GET BACK TO THAT

QUESTION.

>> OKAY.

BANA IS GOING TO ANSWER THAT FOR

YOU SHORTLY.

OKAY.

IRV, WE NEED THE MICROPHONE.

>> OH YES.

>> IF YOU HAVE A QUESTION YOU

CAN INTERACT.

I'M GOING TO TRY TO DISCUSS WHAT

YOU HAVE LEARNED THROUGH THE

WORK OF MANY PEOPLE ACTUALLY IN

EUROPE AND THE UNITED STATES

ABOUT THE PATHOGENESIS OF CELIAC

DISEASE AND TRY TO RELATE IT

BACK TO CLINICAL PRESENTATIONS.

SO AS DR. ROSENBERG HAS ALREADY

TOLD YOU, IT IS A DISEASE THAT

HAS AN AUTOIMMUNE COMPONENT

BECAUSE THE ANTIBODIES THAT ARE

DIRECTED AGAINST AN ENZYME THAT

IS CALLED TISSUE -- AND YET IT

IS A DISEASE THAT'S INDUCED BY

A -- GENESIS ANTIGEN WHICH IS

GLUTEN IT IS SOMETHING TO THINK

ABOUT BECAUSE IT IS A DISEASE

INDUCED BY -- SOME KIND OF

AUTOIMMUNE.

THE OTHER THING THAT RELATES

CELIAC DISEASE TO AN AUTOIMMUNE

DISORDER IS THAT INSTEAD OF

HAVING GLOBAL INFLAMMATION AND

GENERAL DESTRUCTION, IT'S

SELECTIVE DESTRUCTION OF THE

SURFACE -- SO IN THAT REGARD

IT'S ALSO MUCH CLOSER TO AN

ORGAN SPECIFIC AUTOIMMUNE

DISORDER SUCH AS -- AND IT HAS

ALSO A VERY STRICT ASSOCIATION

TO HLA.

MORE THAN 99.9% OF THE PATIENTS

HAVE HLA -- WHICH IS ACTUALLY

THE SAME PREDISPOSING HLA THAN

TYPE ONE DIABETES.

THIS IS VERY TRIC STRICT APPLICATION

IS VERY CLOSE TO WHAT IS KNOWN

AS AUTOIMMUNE DISORDERS.

SO CELIAC DISEASE IS THAT THE --

DESTROYED AND YOU HAVE -- SHOULD

OPEN FILTRATION BY -- BUT ALSO

BY PLASMA CELLS.

AND AT THE SAME TIME -- YOU HAVE

THIS HUGE INFILTRATION BY --

LYMPHOCYTES.

THIS IS ALSO VERY DIFFERENT FROM

WHAT YOU SEE IN -- HOST DISEASE

DURING INTESTINAL -- WHERE

ACTUALLY THE FIRST TESTS THAT

ARE BEING TARGETEDDOR THE --

WHAT YOU SEE IS AN INFILTRATION

THAT IS -- AND ONLY APPEARS VERY

LATE IN THE DISEASE.

WHEREAS IN CELIAC DISEASE THE

INFILTRATION IS REALLY FIRST IN

THE -- AND YOU HAVE APPLICATION

WHICH PROBABLY ALREADY REFLECTS

SOME KIND OF -- DESTRUCTION AND

ATTEMPTS TO RESTORE THE

EPITHELIUM.

SO NOW WHEN YOU HAVE THE

ANTIGEN, YOU HAVE RESTORATION --

BUT I THINK IT'S IMPORTANT ALSO

TO KEEP IN MIND THAT --

RESTRAIRGRESTORATION IS VARIABLE.

IN THE UNITED STATES IT'S UP TO

30% OF PATIENTS ONLY PARTIALLY

RESPOND TO A GLUTEN FREE DIET.

SOME PATIENTS NEED MANY MONTHS

TO ACTUALLY GET BETTER.

AND UNDERSTANDING WHY IT TAKES

SUCH A LONG TIME AND IF IT'S

EXTREMELY JUST RELATED TO THE

WAY GLUTEN -- OR LINKED TO SAM

PATHOGENESIS IS IMPORTANT AND

I'M GOING TO DISCUSS WITH YOU

SOME UNDERSTANDING OF SOME BASIC

MECHANISM WE CAN MAYBE EVEN

UNDERSTAND WHY SOME PATIENT WITH

A GROOTEN FREE DIET ONLY GETS

PARTIALLY BETTER.

THE FORM OF THAT IS CALLED --

WHERE ACTUALLY PATIENTS BECOME

COMPLETELY NON-RESPONSIVE TO A

GLUTEN FREE DIET AND CAN THEN

DEVELOP LYMPHOMA.

THIS IS VERY VERY RARE

COMPILATION BUT IT EXISTS.

ACTUALLY YOU CAN SEE IT HERE

THAT THE VILLI ARE RESTORED BUT

THEY DON'T HAVE THE SAME LENGTH

THAN IN THE NORMAL PATIENT.

INTESTINAL GLUTEN IS CRITICAL.

IT'S IMPORTANT TO -- THE

PREVALENCE OF CELIAC DISEASE

WITH THE FREQUENCY OF HLA --

THERE IS A CORRELATION BUT

THERE'S CERTAINLY SOME OUT LIAR.

I THINK THESE OUTLIERS TELL US A

LOT.

FOR INSTANCE ONE OUTLIER THAT IS

REALLY INTERESTING IS -- BECAUSE

THAT IS -- LACK OF GENETICS AND

THERE'S A VERY HIGH PREVALENCE.

IN THIS PART OF RUSSIA THERE'S

EXTREMELY LOW PREVALENCE.

IT IS THOUGHT THAT IT'S REALLY

THE ENVIRONMENTAL CONDITIONS IN

WHICH PEOPLE LIVE THAT ACTUALLY

MAY DETERMINE THIS DIFFERENCE IN

PREVALENCE.

THIS POINT TO THE FACT THAT

ENVIRONMENTAL OTHER THAN

GENETICS ALSO PLAY AN IMPORTANT

ROLE.

AND THEN YOU HAVE SITUATIONS

WHERE IT SEEMS THAT THE AMOUNT

OF DEEP CONSUMPTION IS

IDENTICAL, AND THE PREVALENCE OF

HLA IS THE SAME AND YET THERE'S

A BIG DIFFERENCE.

AND THIS POINTS TO OTHER GENETIC

RISK FACTORS HLA -- ACCOUNTS FOR

40% OF THE GENETIC RISK.

IF YOU REMOVE THOSE OUTLIERS YOU

SEE THERE'S A CORRELATION -- AND

THE PREVALENCE OF -- ANOTHER

INTERESTING THING WE HAVE

LEARNED THROUGH GENETIC STUDIES

IS THE FACT THAT SOME OF THE

GENES THAT HAVE BEEN GENES THAT

HAVE BEEN CONSIDERED GENES FOR

CELIAC DISEASE HAVEN'T ACTUALLY

POSITIVELY SELECTED.

DC2 -- DOESN'T SEEM TO HAVE BEEN

POSITIVELY SELECTED EVEN THOUGH

IT IS HIGHLY PRESENT IN THE --

THE USAGE OF WHEAT HAS STARTED

BUT THE ACTIVITY GENES ARE

HIGHLY POSITIVELY SELECTED WHICH

WOULD PROJECT THAT -- CONFERRED

A SELECTIVE ADVANTAGE.

AND MAYBE THE SAME THING THAT

PROMOTES DISEASE ARE THE SAME

KIND OF GENES THAT HAVE HELPED

US TO BE PROTECTED AGAINST

INFECTIONS.

AND THIS ALSO I THINK SHOULD BE

LOOK AT MORE CAREFULLY AND

THERE'S SOMETHING AN INTERESTING

HYPOTHESES THAT THE LEVEL OF

INFLAMMATION IS ALSO THE WAY WE

RESPOND TO INFECTION OR

INTESTINAL INFECTION AND MAY

EVEN CONFER SOME LEVEL OF

PROTECTION BUT THOSE EXPERIMENTS

NEED TO BE DONE.

THE OTHER THINGS WE HAVE LEARNED

THROUGH GENETIC STUDIES IS

SOMETHING I HAVE POINTED OUT

EARLIER WHICH IS IF YOU CONSIDER

ALL THE GEAP GAINS THAT HAVE BEEN FOR

GENO-WIDE STUDIES AND YOU

NORMALIZE THE NUMBER OF GENES

THAT OVERLAP GENETIC RISK FACTOR

COMMON TO CELIAC DISEASE AND

AUTOIMMUNE DISORDERS IS MUCH

HIGHER THAN WITH INFLAMMATORY

BOWEL DISEASE.

SO THIS AGAIN POINTS TO THE FACT

THAT CELIAC DISEASE HAS MUCH

MORE POINTS IN COMMON WITHIN

AUTOIMMUNE DISORDER THAN WITH

INFLAMMATORY BOWEL MOVEMENTS.

WHEN YOU DO -- ANALYSIS, YOU

FIND THAT YOU HAVE GENES THAT

ARE IMPLICATED WITH ANTIGEN

PRESENTATION, CHEM CHEMOKININS BUT

THERE ARE ALSO GANGS THAT ARE

REALLY RELATED -- GENES THAT ARE

RELATED TO THE GH ONE

RESPONSE -- GAMMA AND GENES THAT

ARE RELATED TO NATURAL KILLER

RECEPTOR ACTIVATION.

I'LL GET BACK TO THOSE BECAUSE

THOSE GENETIC STUDIES ARE IN

AGREEMENT WITH A NUMBER OF

FUNCTIONAL STUDIES THAT HAVE

HAPPENED.

SO DR. ROSENBERG HAS ALREADY

ALLUDED TO THE CELIAC -- AND I

THINK THIS IS A VERY INTERESTING

EXAMPLE OF THE HUMAN DISEASE

THAT YOU CAN STUDY AND THAT CAN

BRING INSIGHTS TO HUMAN DISEASES

IN WAYS THAT NO OTHER DISEASE

CAN BECAUSE WE KNOW THE ANTIGEN,

WE KNOW THE HLA APPLICATION AND

YOU CAN HAVE ACCESS TO THE

TISSUE.

WHICH IS NOT THE CASE FOR

EXAMPLE FOR QURAN YOU CAN

DIABETES.

BUT -- CHRONIC DIABETES.

THERE ARE MANY THING WE CAN

LEARN STUDYING CELIAC DISEASE

THAT CAN APPLY TO OTHER

AUTOIMMUNE DISORDERS.

BECAUSE THERE IS NO ANIMAL

MODELS FOR CELIAC DISEASE UNLIKE

FOR -- BOWEL DISEASE AND BECAUSE

THE HUMAN TISSUES COULD BE MORE

READILY ACCESSIBLE, IF YOU HAVE

ALMOST A MIRROR IMAGE BETWEEN

CELIAC DISEASE AND BOWEL DISEASE

IS THAT YOU HAVE MUCH MORE HUMAN

STUDIES AND ANIMAL MODELS ARE

ALMOST EVER ONLY COMING IN NOW

FOR -- BOWEL DISEASES HAVE BEEN

THE OPPOSITE.

BUT WHAT YOU SEE IN CELIAC

DISEASE IS THAT YOU HAVE AS I

ALREADY INDICATED A SPECTRUM OF

DISEASE.

SO I HAVE A FORM OF DISEASE THAT

HAS BEEN -- CELIAC DISEASE AND

OTHER POTENTIAL CELIAC DISEASE

WHILE YOU HAVE ALL THE STIGMAS

OF AN ABNORMAL ADOPTIVE IMMUNE

RESPONSE WITH THE PREPARE PRESENCE OF --

AND ALSO HAD BEEN STUDIED DONE

TO ACTUALLY IDENTIFY T CELLS

THAT CAN RECOGNIZE PEPTIDE IN

THE CONTEXT OF HLA -- AND THAT

PRODUCE GAMMA.

AND YET THOSE PATIENTS HAVE A

NORMAL HISTOLOGY.

IF YOU WANTED TO MAKE A

PARALLEL, YOU COULD SAY IT ISN'T

SIMILAR TO WHAT YOU CAN SEE IN

MEASURES THAT HAVE ANTI-INCIDENT

ANTIBODIES AND HAVE NO DIABETES

OR IN THE -- YOU DON'T HAVE --

AND I THINK THIS REALLY POSES

THE QUESTION OF WHAT ADDITIONAL

SIGNALS ARE REQUIRED IN ADDITION

TO A DEVELOPMENT OF AN ANTIGEN

SPECIFIC IMMUNE RESPONSE THAT

GOES TO THE NEXT STEP WHICH IS

TISSUE RETRACTION.

SO THEN YOU HAVE CELIAC DISEASE

WITH ATROPHY AND THE SAME KIND

OF IMMUNLOGICAL CHARACTERISTIC.

AND THEN THERE ARE THINGS I'M

NOT GOING TO DISCUSS BUT I CAN

ANSWER QUESTIONS IF YOU'RE

INTERESTED IN IS THE ULTIMATE --

WHICH IS GOING TO BECOME

INDEPENDENT FROM GLUTEN

EXPORTER.

WHAT I WANT TO DO IS DISCUSS

WITH YOU THE DIFFERENT STEPS

THAT ARE NECESSARY TO GO TO --

IMMUNE RESPONSE AND THEN TO

DEVELOPING TISSUE RETRACTION.

THE QUESTION IS HOW DO WE

ACTUALLY DEVELOP AN ABNORMAL

RESPONSE TO GLUTEN.

NOW, AS WAS ELUDED TO THE

FREQUENCY OF HLA-22A IS UP TO 40

OR 50%.

AND YET EBB IN FINLAND, ONLY 2%

OF THE GLOBAL POPULATION

DISRUPTS CELIAC DISEASE.

WHAT THIS TELLS YOU IS THE

HLA22H ARE REQUIRED BUT THEY'RE

CERTAINLY NOT SUFFICIENT TO

ACTUALLY DEVELOP THE DISEASE.

AND WE'RE GOING TO DISCUSS --

BECAUSE 99% OF THE PATIENTS HAVE

THAT HLA AND WHEN THEY DON'T

VISIT THEY HAVE EITHER THE ALPHA

OR THE BETA CHAIN OF THE --

MOLECULE.

I'M GOING TO DISCUSS WHAT OTHER

ELEMENTS ARE CONNECTED.

NOW, IF YOU THINK ABOUT --

MOLECULES OF PEOPLE WHO ARE

NOT -- THE MOLECULES ARE GOING

TO BE THE MOLECULES THAT PREVENT

ANTIGEN TO IMMUNE CELLS TO

INDUCE ACTIVATION.

NOW DEPENDING ON THE NATURE OF

THE -- THAT ARE PRESENT IN

THIS -- THESE MALL QUEUES ARE

GOING TO PRESENT A DIFFERENT SET

OF PEPTIDES.

FOR EXAMPLE IF YOU ARE HAVE A

VIRAL INFECTION AND YOU HAVE THE

WRONG NH2 MOLECULES THAT -- YOU

WILL NOT BE ABLE TO MOUNT AN

IMMUNE RESPONSE.

AND DEPENDING ON THE NATURE OF

THESE PACKETS WHERE ACTUALLY ALL

THE POLYMORPHISMS ARE YOU'RE

GOING TO BIND A DIFFERENT KIND

OF PEPTIDES.

THERE ARE DIFFERENT TYPES OF

HLA -- MOLECULES -- ETCETERA AND

AS I INDICATED IT'S REALLY THE

Q2 AND Q8 THAT IS PREDISPOSED TO

CELIAC DISEASE AND NOT OTHER

TYPES OF -- SEARCHES HLADR OR

DP.

THERE HAVE BEEN STUDIES THAT

HAVE BEEN DONE AND I THINK HAVE

REALLY HELPED US ALREADY

UNDERSTAND HOW SUCH AN IMMUNE

RESPONSE CAN OCCUR.

SO THE IF YOU ARE THINGS YOU

NEED TO HAVE IS THE GENERATION

OF PEPTIDES THAT CAN BIND TO

THESE MOLECULES.

WHAT IS SPECIAL TO GLUTEN IS

THAT GLUTEN IS EXTREMELY RICH

AND IMPORTANT.

IT TURNS OUT THAT THE PRESENCE

OF -- RENDER GLUTEN RESISTANCE

TO THE ENZYMATIC DIGESTION OF

ENZYMES THAT ARE PRESENT ON

THE -- SO WHAT IS HAPPENING IS

THAT YOU REALLY GENERATE A

DIGESTIVE PROTEIN AND YOU

GENERATE PEPTIDES OF SUFFICIENT

LENGTH THAT THEY CAN ACTUALLY

BIND TO THE NHA MOLECULES AND

INDUCE AN IMMUNE RESPONSE.

THE OTHER CHARACTERISTIC OF THIS

PROTEIN IS THAT IT IS EXTREMELY

RICIA IRICH IN GLOOT -- THAT IT'S RECOGNIZ
ED

BY TISSUE -- AND WHAT THIS

ENZYME CAN DO IS IT CAN CONDUCT

GLUTAMINE INTO CHARGES -- HAVE

POSITIVELY CHARGED PACKETS.

SO YOU'RE ACTUALLY GENERATING

PIP TIDES WITH NEGATIVE CHARGES

THAT CAN BIND WITH HIGHER

AFFINITY TO ANY MALL EXEULZ THAT

HAVE MASSACHUSETTS -- MOLECULES

THAT HAVE POSITIVELY CHARGED --

THIS STUDY DONE BY THE GROUP --

HAVE TREMENDOUSLY HAD UNDERSTAND

HOW YOU CAN MOUNT IMMUNE

RESPONSE.

HOWEVER THERE ARE STILL SOME

ELEMENTS THAT SUGGEST THAT THERE

ARE MANY THINGS WE STILL DON'T

UNDERSTAND.

AND ONE OF THEM IS THAT YOU CAN

IDENTIFY T CELLS IN THE BLOOD OF

CELIAC PATIENTS THAT CAN

RECOGNIZE GLUTEN PEPTIDES THAT

ARE IN THE CONTEXT OF THE D R&D

P.

WHAT THIS MEANS IS THAT YOU CAN

HAVE T CELLS THAT CAN RECOGNIZE

GLUTEN PEPTIDES OUTSIDE OF THE

PRESENTATION -- AND THIS

OBSERVATION -- WHERE YOU CAN

TAKE ALMOST ANY KIND OF MOUSE

WITH ANY KIND OF GENETIC

BACKGROUND AND SEE THEN RESPOND

TO GLUTEN PEPTIDES SO IF YOU

TAKE A -- MUNICIPAL O MEUTION MOUSE AND YO
U -- YOU

CAN SEE A RESPONSE BEING

PRODUCED.

SO THIS REALLY PUTS THE QUESTION

OF WHY IS THIS ASSOCIATION

WITH -- MOLECULES AND THERE MAY

BE THINGS THAT WE DON'T

UNDERSTAND COMPLETELY.

AND I THINK ONE KEY CONSEN CONCEPT OF

THE STORY IN -- AND I'M GOING TO

GO INTO THAT A LITTLE FURTHER IS

THAT IN ORDER TO ACTUALLY

DISRUPT THE DISEASE, YOU NEED TO

REACH A FREQUENCY OF

PATHOLOGICAL T CELLS.

SO IF YOU ARE AT A FREQUENCY

BELOW CERTAIN LEVELS, ARE EVEN

THOUGH YOU HAVE A RESPONSE, THE

RESPONSE IS NOT OF SUFFICIENT

MAGNITUDE SO THAT YOU CAN SEE

THE DISEASE.

AND WHAT IS ABSOLUTELY CRITICAL

IS TO REACH THAT THRESHOLD.

AND SO HOW DOES, HOW DO DC2 AND

8 HELP TO ACTUALLY REACH THAT

THRESHOLD THAT CAN LEAD TO

GLUTEN.

SO I JUST WANT TO SHOW YOU HOW,

BECAUSE I WILL GET A LITTLE BIT

MORE INTO DETAIL ABOUT THE T

CELL RECEPTOR AND THE PEPTIDE I

WANTED TO SHOW YOU THE

STRUCTURE.

SO THIS IS THE IMAGE C

MOLECULE -- ON TOP OF THAT YOU

HAVE THE IMMUNE CELL WITH THE T

CELL RECEPTOR -- AND YOU SEE

THAT THERE ARE PARTICULAR

LESIONS OF THIS T CELL RECEPTOR

THAT DIRECTLY CONTACT THE

PEPTIDE.

AND THE RESPONSES HAVE TO DO

WITH HOW PEPTIDES ARE BOUND TO

MOLECULES AND WHAT KIND OF T

CELL RECEPTORS THAT CAN RECRUIT

SO THAT THEY CAN RECOGNIZE THIS

IMAGE OF THE PEPTIDE COMPLEX AND

THEN INDUCE ACTIVATION OF T

CELLS.

AND SO AGAIN, IF THE THRESHOLD

IS IMPORTANT, HOW CAN THAT

TRANSLATE PRACTICALLY IN WHAT WE

KNOW ABOUT CELIAC DISEASE.

SO THE FIRST THING THAT I'M NOT

SHOWING HERE IS THAT IT HAS BEEN

NOTICED BY A NUMBER OF

INVESTIGATORS THAT IF YOU HAVE

TWO HLADC MOLECULES OR IF YOU

HAVE TWO HLAD8 MOLECULES YOU ARE

AT MUCH HIGHER RISK OF

DEVELOPING THE DISEASE.

SO THERE IS A KIND OF GENE

EFFECT.

SO THE MORE MOLECULES YOU

HAVE -- THE MORE YOU ARE AT RISK

OF THE DISEASE.

THE OTHER THING THAT IS KNOWN IS

THAT IN CELIAC DISEASE YOU HAVE

A STRONGER, MUCH STRONGER

APPLICATION WITH DQ8 THAN -- DQ2

SIRE THAN WITH DQ8 WHICH IS THE

OPPOSITE OF WHAT YOU SEE IN TYPE

ONE DIABETES.

IT TURNS OUT THAT DQ2 HAS A

POCKET THAT IS, CAN THAT VERY

EASILY BIND TO PROTEINS.

AND THERE ARE NOT MANY POCKETS

IN THE MOLECULES THAT CAN

READILY BIND TO -- AS YOU KNOW

ARE HIGHLY PRESENT IN GLUTEN

PEPTIDES.

AND THIS IS NOT THE CASE FOR

DQ8.

FOR INSTANCE THROUGH THE WORK

ALSO OF UNDER CURRENT, THE

NUMBER OF POTENTIAL PEPTIDES

THAT COMBINE TO DQ8 IS LOWER

THAN THE AMOUNT OF PEPTIDES THAT

COMBINE TO DQ2.

AND MAYBE THIS IS ONE ELEMENT

THAT MAKES MAIN WHY YOU HAVE A

STRONGER APPLICATION WITH DQ2

THAN YOU HAVE WITH DQ8.

ANOTHER OBSERVATION IS THAT

PATIENTS WHO HAVE DQ2.5 ARE MUCH

MORE SUSCEPTIBLE TO CELIAC

DISEASE THAN PATIENTS WHO HAVE

2.2.

AND THE ONLY DIFFERENCE BETWEEN

TWO PATIENTS IS A CHANGE OF

TYROSINE IN THE [INDISCERNIBLE]

MOLECULE.

AND WHAT THE GROUP HAS SHOWN IS

THAT THE -- OF THE PEPTIDE IS

MUCH MORE -- 2.5.

SO WHAT HAPPENS IS THAT YOU HAVE

MUCH MORE STABLE PEPTIDE

COMPLEXES AND YOU HAVE DQ2.5

THAN DQ2.2.

THE FACT YOU HAVE MUCH MORE

STAIN IMAGE TO DO IN PEPTIDE

COMPLEXES ALSO EXPLAIN WHY YOU

CAN ACTUALLY INDUCE A MUCH

STRONGER IMMUNE RESPONSE AND

RECRUIT MORE T CELLS.

THE OTHER WAYS TO THINK ABOUT

THAT IS REALLY GETTING AT THE

HEART OF THE QUESTION OF THE

ASSOCIATION WITH DQ8.

AND THIS IS SOMETHING THAT WE

HAVE TOUCHED UPON BY ACTUALLY

MOVING FROM HUMAN INTO MOUSE.

BECAUSE IT'S VERY DIFFICULT WHEN

YOU DO HUMAN STUDIES TO REALLY

UNDERSTAND THE INITIATION OF THE

IMMUNE RESPONSE.

AND THERE HAS BEEN A CONTROVERSY

IN THE FIELD AS TO WHETHER

PATIENTS INITIALLY MOUNT A

IMMUNE RESPONSE AGAINST -- THE

PEPTIDE THAT HAS NOT BEEN

CHANGED BY -- AND THEN MOUNT A

RESPONSE AGAINST THE DAMAGED

PEPTIDE WITH THE SECONDARY

ACTIVATION OF -- OR WHETHER THE

INITIAL IMMUNE RESPONSE IS

ACTUALLY DIRECTED AGAINST THE --

PEPTIDES.

AND IT'S INTERESTING TO ALSO

UNDERSTAND THE IMPORTANCE OF

SOME VERY SPECIFIC CHANGES IN

AMINO ACIDS BECAUSE DQ8 AND DQ29

DIFFERENCES WITH THE OTHER MULE

CALLS IS INSTEAD OF HAVING A --

AT POSITION 57 IN THE BACK UP

CHAIN, YOU HAVE -- THIS IS MOUSE

OR HUMAN DEPENDING ON THE

MOLECULE.

WHAT PEOPLE HAVE SHOWN USING

MOUSE MODELS IS THAT IF YOU JUST

MUTATE THE SINGLE AMINO ACID IN

MICE AND MAKE IT GO BACK TO --

THEN MICE DON'T DISRUPT A TYPE

ONE DIABETES.

SO IT SHOWS YOU HOW STRONG THIS

POLYMORPHISM IS IN INDUCING THE

DISEASE.

AND YET WE STILL KNOW ABOUT HOW

THIS POLYMORPHISM IMPACTS.

AND I WANT TO GIVE YOU HERE IS

ONE EXPLANATION THAT WE HAVE

IDENTIFIED FOR STUDIES THAT WE

HAVE DONE IN MICE.

SO WHAT'S IMPORTANT TO KNOW WHEN

YOU THINK ABOUT THE T CELL

RECEPTORS THAT ARE BEING

RECRUITED IS THAT WHAT IS CALLED

A CDR FREE AGENT THAT CONTACT

THE PEPTIDE IS A LESION THAT HAS

BEEN GENERATED THROUGH --

COMBINATIONS.

SO THE REASON WE CAN HAVE AN

ADAPTIVE IMMUNE RESPONSE IS

BECAUSE WE CAN GENERATE --

DIFFERENT TYPES OF CELIAC THAT

CAN CONTACT DIFFERENT FORMS OF

PEPTIDE COMPLEXES.

AND ONCE YOU HAVE THE RIGHT T

CELL RECEPTOR THEN YOU WILL

EXPAND THE T CELL RECEPTOR IN

RESPONSE TO A GIVEN ANTIGEN.

AND LIKE ALEX SAI AL -- IN THE STUDIES

THAT ARE SHOWN, IF YOU HAVE A

PEPTIDE THAT DOES NOT HAVE A

NEGATIVE CHARGE YOU ARE ACTUALLY

RECRUITING T CELLS THAT HAVE A

NEGATIVE CHARGE IN THE -- AND SO

YOU COMPENSATE FOR THE LACK OF

THE NEGATIVE CHARGE IN THE

PEPTIDE BY RECRUITING T CELLS

THAT HAVE -- AND THIS SEEMS TO

HAVE STABILIZED IN THE PEPTIDE

COMPLEX.

WHEN YOU HAVE NOW -- PEPTIDES

THEN YOU DON'T NEED TO RECRUIT T

CELLS THAT HAVE THIS NEGATIVE

CHARGE.

AND THE OTHER CHARACTERISTIC IS

THAT THIS NEGATIVE CHARGE

DOESN'T COME TO RECOGNIZE

DIRECTLY IN THE T CELL

RECEPTOR -- DIRECTLY THIS CHARGE

IN THE PEPTIDE.

AND SO WHAT WE SEE IS THAT IF

YOU IMMUNIZE WITH THE PEPTIDE

YOU ARE GENERATING.

T CELLS THAT CAN RESPOND TO THE

DAMAGED PEPTIDE SO THAT'S

REACTIVE.

EVEN IF YOU IMMUNIZE ONE PEPTIDE

YOUR T CELLS 50% OF THE T CELLS

YOU GENERATE CAN RECOGNIZE

THE -- PEPTIDE.

IF YOU IMMUNIZE THE -- PEPTIDES

YOU HAVE THE SAME THING.

BUT WHAT HAPPENS IS THAT IF YOU

IMMUNIZE THE -- PEPTIDE YOU

DON'T RECRUIT THOSE T CELLS

WHICH CAN ONLY BE RECRUITED WHEN

YOU HAVE THE -- PEPTIDE.

AND SO WHEN YOU LOOK AT THE

FREQUENCY OF T CELLS TO GENERAL

RATE AFTER THIS DIFFERENT

IMMUNIZATION, YOU SEE THAT THE

HIGHEST FREQUENCY OF T CELLS YOU

CAN GENERATE IS IF YOU IS A

IMMUNIZED THE -- PEPTIDES AND

THE REASON IS THAT THIS ALLOWS

TO RECRUITMENT ONLY THOSE T

CELLS BUT THOSE T CELLS WITH THE

NEGATIVE CHARGE.

SO YOU HAVE A HIGHER FREQUENCY

OF A POTENTIAL -- AND SO THE WAY

WE SEE POTENTIALLY THE ROLE OF

HLADQ8 AND WE SHOW THIS IS

REALLY DEPENDENT ON THE --

POLYMORPHISM IS THAT YOU HAVE AN

MOLECULE THAT CAN OPERATE

WHEN -- IS NOT ACTIVE AND THE

WORK OF -- HAS SHOWN THAT IT IS

NOT ACTIVE IN THE NORMAL GAP.

AND UNDER THOSE CONDITIONS THAT

PEPTIDES, THE GLUTEN PEPTIDES

CAN GENERATE A T CELL RESPONSE

BY RECRUITING T CELLS WITH A

NEGATIVE CHARGE.

AND THIS INFLAMMATORY RESPONSE

CAN ACTUALLY INDUCE ACTIVATION

OF -- YOU KNOW THAT TO BE THE

CASE BECAUSE IN THE MOUSE MODEL

YOU HAVE TO SEE -- ACTIVATION

JUST UPON GENERATION OF

INFLAMMATORY T CELLS.

ONCE YOU HAVE ACTIVATED

TRANSSCRIPT ASE YOU HAVE

GENERATE THE NEGATIVE CHARGE

THAT ALLOWS TO RECRUIT NEW T

CELLS.

AND BECAUSE YOU AMPH AMPLIFY THE

MAGNITUDE OF THE T CELL RESPONSE

YOU CAN REACH THAT THRESHOLD.

THIS HAS REALLY TO DO WITH THIS

PARTICULAR POLYMORPHISM THAT

ALLOWS TO RECRUIT T CELLS THAT

ARE CROSS REACTIVE AND THAT HAVE

DIFFERENT CHARACTERISTICS.

SO YOU CAN SAY YOU HAVE A

PEPTIDES THAT ARE NOT DIGESTIVE.

YOU HAVE PEPTIDES THAT HAVE THE

RIGHT SCWNS T SEQUENCE -- CHARGES SO THAT 
NOW YOU

CREATE PEPTIDES OF HIGH ACTIVITY

AND YOU HAVE A MOLECULE THAT CAN

OPERATE BEFORE AND AFTER THE

TRANSCRIPT -- AND THE ENZYME

BECOMES ACTIVE.

AND SO YOU CAN EXPLAIN HOW YOU

CAN ULTIMATELY ACTIVATE T CELLS.

BUT WHAT REALLY WAS NOT

EXPLAINED IS WHY WOULD YOU

INDUCE AN INFLAMMATORY RESPONSE

AGAINST A FOOD ANTIGEN IN

ABSENCE OF AN INFECTION.

YOU CAN UNDERSTAND WHY YOU MOUNT

AN IMMUNE RESPONSE BUT WHY WOULD

THAT IMMUNE RESPONSE BE OF

INFLAMMATORY NATURE.

I SHOULD HAVE SHOWN THAT SLIDE

BEFORE.

I JUST WANTED TO POINT OUT THAT

THE -- MODIFICATIONS ARE ALSO

SEEN IN -- WHERE YOU HAVE WHEN

DOES THE PEPTIDE OF -- WHICH IS

THE HLA WHICH IS -- AND IT IS

ALSO FOR THE TRANSLATIONAL

MODIFICATION OCCUR IN THE

CONTEXT OF TYPE ONE DIABETES.

AND WE THINK THAT BY USING HLA

ASSOCIATION -- MODIFICATION, IT

COULD BE A WAY TO IDENTIFY

ANTIGEN.

SO JUST GOING BACK, I'M SORRY TO

SWITCH THE SLIDES.

THE QUESTION NOW BECOMES WHY DO

WE INDUCE AN INFLAMMATORY IMMUNE

RESPONSES THAT IS OF THE -- AND

WHAT I'M GOING TO SHOW YOU IS

THAT TISSUE SIGNALS -- ARE GOING

TO BE KEY TO ACTUALLY INDUCE

INFLAMMATORY RESPONSE TO AN ORAL

ANTIGEN.

SO IN THE PAST YEARS WE HAVE --

AND HAVE LEARNED A LOT ABOUT HOW

THE IMMUNE SYSTEM INTERACTS WITH

THE MICRO -- THIS IS ABSOLUTELY

CLEAR WE HAVE THE -- PROVIDES

NUTRIENTS WHICH REDUCES THE

U.S.-RUSSIA CALORIE INPUT AND

MANY OTHER THINGS.

SO OBVIOUSLY OUR IMMUNE SYSTEM

HAS EVOLVED NOT TO REJECT THE

MICRO -- BUT TO ACCEPT IT AND TO

CONTINUE IT.

AND SO ONE TYPE OF IMMUNE

RESPONSE THAT WE SEE BEING

DEVELOPED AGAINST THE MICRO --

WE DON'T WANT TO REACT TO FOOD

ANTIGEN THAT EASILY.

SO ONE TYPE OF IMMUNE RESPONSE

THAT WE SEE HAPPENING IN

RESPONSE TO LUMINAL ANTIGEN IN

THE PRESENCE OVER TGF -- WHICH

ARE BOTH HIGHLY PRESENT IN

THE -- PRODUCED BY DENDRITIC

CELLS BUT ALSO BY INTESTINAL

CELIAC CELLS AND IN PRESENCE

OF -- ACID YOU SEE THE

DIFFERENTIATION OF T CELLS THAT

HAVE THE CAPACITY TO -- MA'AM

TREE T CELLS.

AND INDUCE -- SYSTEMIC.

PROMOTE THE FACTS WHICH AND IGA

IT CANNOT BE DIGESTED.

IT HAS CONTAINED -- WITHOUT

ACTUALLY INDUCING IMMUNE

INFLAMMATION.

SO THE RESPONSE IN THE GUT IS A

RESPONSE THAT CREATES ANTIBODIES

THAT HAVE -- PROPERTIES BUT CAN

STILL CONTAIN BACTERIA AND IS IN

RESPONSE THAT -- PRE VENTS

TISSUE DESTRUCTION.

AND SO WHAT HAPPENED IN THE

CONTEXT OF CELIAC DISEASE WHERE

YOU INGEST PROTEINS THAT ARE

NORMALLY IS PRESENTED WITH THE

DISEASE ALREADY TO THE

DIFFERENTIATION OF REGULATORY --

SO WHEN WE STUDIED THE

INTESTINAL -- OF CELIAC PATIENTS

WE NOTICED THAT WAS ONE CYTOKINE

THAT WAS HIGHLY UP REGULATED IN

THE CELIAC MUCOSA AND THE

CYTOKINE IS -- A LOT ABOUT THIS

BECAUSE -- IDENTIFIED THIS

CYTOKINE.

AND THIS CYTOKINE IS UP

REGULATED IN ACTIVE CELIAC

PATIENTS -- CONTROL PATIENTS.

AND THIS CYTOKINE CAN BE INDUCED

IN THE CONTEST OF INFLAMMATION

IN THE CONTEXT OF INFECTION.

IT SEEMS TO BE INDUCED BY GLUTEN

WHEN YOU PUT IT ON -- GLUTEN

FREE DIET PATIENTS BUT WE DON'T

KNOW EXACTLY WHAT IN CELIAC

DISEASE INDUCES UP REGULATION

OF -- IN THE CELIAC MUCOSA BUT

THIS CYTOKINE IS CERTAINLY UP

REGULATED.

AND SO IT TURNS OUT THAT THERE

IS A MOUSE MODEL WHERE YOU

CAN -- PROMOTER AND IN THAT

CONTEXT YOU DON'T OVER EXPRESS

IO15 IN THE -- BUT YOU HAVE OVER

EXPRESSION IN THE LAMINA

APPROPRIAT -- TOCOLLECT MICE THAT HAS LEVE
LS

OF -- OVER EXPRESSION COMPARED

TO CONTROLS A THAT WERE VERY,

THAT WERE IN THE RANGE OF WHAT

WE SEE IN ACTIVE CELIAC DISEASE.

AND THE REASON WHY THIS MICE

DON'T EXPECT IO15 IN THE

EPITHELIUM IS BECAUSE WE DON'T

KNOW -- DO NOT EXPRESS HLA IN

EPITHELIUM THEY EXPRESS IT ON T

CELLS ON APT BUT NOT ON -- AND

WHAT WE FOUND IS THAT IF YOU

OVEREXPRESS I15 UNDER THAT

PROMOTER IN MICE THAT EXPRESS

DQ8 YOU HAVE INDUCTION OF A

GAMMA ANTI-GLUTEN IMMUNE

RESPONSE THAT YOU DON'T SEE IN

MICE THAT ONLY HAVE DQ8.

AND YOU SEE HERE THE FREQUENCY

OF INTERGUAM AW INTERGAMMA T CELLS THAT YO
U

FIND IN THE -- OF THE MICE

INGESTING GLUTEN WHEN I15 IS

EXPRESSED BUT NOT WHEN I15 IS

ABSENT.

SO THIS SHOWS YOU THAT JUST BY

OVER EXPRESSING I15 ABSENT OF

ANY INFECTION, YOU CAN ACTUALLY

INDUCE INFLAMMATORY RESPONSE TO

AN ORAL ANTIGEN.

AND YOU HAVE ALSO INDUCTION OF

TB8 GAMMA TEST.

AND THIS FAIRLY MIMICS WHAT'S

BEEN DESCRIBED IN THE CONTEXT OF

CELIAC PATIENTS WHILE YOU HAVE

TB4 AND TB8 ANTI-GLUTEN -- GAMMA

PRODUCING T CELLS.

NOW GENOME-WIDE APPLICATION

STUDIES HAVE POINTED OUT TO AN

APPLICATION WITH -- DEPENDENCY

WHICH PROMOTES INTERGAMMA

PRODUCING CELLS AND I23 FOR

CROHN'S DISEASE AND -- IS NOT

GOING TO BE IN AGREEMENT WITH ME

BUT IN CELIAC PATIENTS YOU

HAVE -- GAMMA RESPONSE BUT VERY

LITTLE OF AN I17 RESPONSE.

HERE YOU HAVE VERY LOW LEVELS --

EXACTLY THE HUMAN SITUATION

WHERE YOU HAVE A PREDOMINANCE --

GAMMA RESPONSE AND -- SO WHAT IS

QUITE REMARKABLE HERE IN THESE

MICE IS THAT THEY REALLY

REPRODUCE THE SAME KIND OF T

CELL RESPONSE YOU FIND IN

HUMANS.

AND IN ADDITION TO MOUNTING THE

T CELL RESPONSE, THESE MICE HAVE

ANTI--- APPEAR BODIES AND THEY

DO DEVELOP ANTIBODIES AGAINST

TRANSCRIPT TERM ASE AND WE HAVE

INDID YOU CANNION OF ANT

BEADS -- AT THE SAME TIME YOU

HAVE -- LYMPHOCYTOSIS.

BUT YOU DON'T HAVE ATROPHY.

SO AGAIN, THIS IS EVERYTHING YOU

WOULD FIND IN WHAT PEOPLE CALL

IN CELIAC DISEASE WHICH IS A

FORM OF CELIAC DISEASE YOU FINE

IN POTENTIAL CELIAC PATIENTS

WHERE YOU HAVE NORMAL VILLI BUT

WHERE YOU HAVE ANTI-TRUST

DETERMINANTS ANTIBODIES.

T CELLS THAT CAN RECOGNIZE

GLUTEN AND PRODUCING GAMMA --

LYMPHOCYTOSIS.

SO MAYBE IN THE INTEREST OF TIME

I'M GOING TO SKIP THIS PART.

SO NOW WHY CAN'T YOU MOUNT A,

WHY UNDER THOSE CONDITIONS DON'T

YOU SEE TISSUE DESTRUCTION.

SO POTENTIAL CELIAC PATIENTS

EXIST.

AND ALL THE EFFORTS THAT HAVE, I

MEAN THAT SOME INVESTIGATORS IN

THE FIELD HAVE ATTEMPTED TO

DEVELOP A FULL MOUSE MODEL OF

CELIAC DISEASE HAVE FAILED.

SO WHAT -- IS A MOUSE THAT --

IMMUNIZING SYSTEMICALLY WITH

ANGIOGRAMS BUT THERE WAS NO

ACTUAL -- THE GROUP OF --

TRANSGENIC MICE THAT I EXPECT

HLADQ2 EXPEK PRES AND EXPRESS T CELLS THAT

WOULD RECOGNIZE GLUTEN PEPTIDES

BUT THOSE MICE DID NOT HAVE

ATROPHY.

SO THIS IS AGAIN TO THE FACT

THAT YOU CAN HAVE EVERYTHING --

ANTI-GLUTEN T CELL RESPONSE BUT

THIS IS NOT SUFFICIENT TO SEE

THE ATROPHY.

SO WHAT ARE THE ADDITIONAL

SIGNALS THAT ARE REQUIRED TO

ACTUALLY SEE TISSUE DESTRUCTION.

AND IN THIS PART, I'M GOING TO

TELL YOU ABOUT THE IMPORTANCE

OF -- LYMPHOCYTES.

SO ONE CHARACTERISTIC OF CELIAC

DISEASE IS THIS HUGE

INFILTRATION OF THE INTE INTESTINAL

EVEEPITHELIUM BECAUSE THEY ARE IN

BETWEEN -- AND AT THE ACTUALLY

EXPRESS -- THAT RECOGNIZE

EXPRESSED ON THE -- SO IT'S A

VERY CLOSE PHYSICAL CONNECTION

BETWEEN THE -- LYMPHOCYTES AND

EPITHELIUM -- AND THIS HUGE

INFILTRATION OF THE EPITHELIUM

BY T CELLS IS REALLY A HALLMARK

OF CELIAC DISEASE.

NOW THE REASON PEOPLE HAVE

REALLY NEGLECTED DIDN'T CONSIDER

THAT THOSE, THIS IN

FILTRATION -- BECAUSE NOBODY

COULD IDENTIFY -- LYMPHOCYTES

THAT RECOGNIZE PEPTIDES.

THOSE T CELLS WERE IDENTIFIED IN

THE LAMINA -- SO THE HYPOTHESES

THAT WAS PROPOSED SOME YEARS AGO

WAS THAT MAYBE THIS LI LYMPHOCYTES

THAT ARE EFFECTOR CELLS BECAUSE

THEY CAME, THEY ARE PROBABLY IN

RESPONSE TO THE MICRO -- THEY

ARE ALREADY IN AN EFFECTOR STAGE

BUT THOSE T CELLS -- EPITHELIAL

CELLS NOT BASED ON THE

RECOGNITION OF GLIDING PEPTIDES

BUT BASED ON THE, ANYTHING OF

SIGNALS THAT COULD EVEN TO THE

REDUCTION OF THE T CELL RECEPTOR

ACTIVATION THRESHOLD AND LEADING

T CELLS NOW TO RECOGNIZE

ANTIGENS -- ARE EVEN MICROBIAL

ANTIGENS DIRECTLY RECOGNITION OF

STRESSED LIGANDS BY NATURAL

KILLER RECEPTORS.

I'M JUST GOING TO SUMMARIZE THE

WORK THAT WE HAVE DONE -- IS

THAT WE HAVE SHOWN INITIALLY

THAT IN A NORMAL MUCOSA

LYMPHOCYTES HAVE VERY LOW LIPID

CAPACITY.

AND ON TOP OF THAT, THEY EXPRESS

MAINLY INHIBITORY NATURAL KILLER

RECEPTORS, AND VERY LOOSE LEVELS

OF ACTIVATING -- BUT WHAT

HAPPENED THE EPITHELIUM HAVE NO

STRESSED LIGANDS UNDER NORMAL

CONDITIONS.

WHAT HAPPENS IN CELIAC DISEASE

IS THAT YOU HAVE A CHANGE IN THE

EPITHELIUM THAT LEADS TO THE UP

REGULATION TO THE NUMBER OF

STRESS MOLECULES -- AND YOU HAVE

INDUCTION OF THE -- THAT I WAS

TELLING YOU ABOUT.

BUT THIS TIME INSTEAD OF BEING

IN THE LAMINA PROXYA AND THE

LYMPHOCYTES OF CELIAC PATIENTS

ARE VERY DIFFERENT FROM -- LIMB

SITES OF NORMAL -- LYMPHOCYTES

OF NORMAL INDIVIDUALS THAT THEY

HAVE LOST THE EXPRESSION OF

INHIBITORY RECEPTORS.

THE INSTEAD OF THAT THEY HAVE

HIGHLY REGULATED -- AND OTHER

ACTIVATING RECEPTORS -- AND SO

YOU HAVE NOW A SITUATION WHERE

YOU HAVE EPITHELIUM THAT

EXPRESSES TRUST SIGNALS THAT CAN

BE RECOGNIZED BY RECEPTORS THAT

ARE PRESENT -- LIMB S LYMPHOCYTES.

BEEF SHOWN THAT THOSE

LYMPHOCYTES -- T CELL RECEPTOR

IN AN INDEPENDENT MANNER

EPITHELIUM CELLS EXPRESSING

THOSE STRESS LIGANDS.

YOU HAVE NO NEED FOR GLUTEN

PEPTIDES   AND YOU CAN REALLY

HAVE A DESTRUCTION OF THE

EPITHELIUM THAT IS JUST BASED ON

THE EXPRESSION OF THOSE STRESS

SIGNALS.

AND I THINK THAT THIS NOTION

DOESN'T APPLY ONLY TO CELIAC

DISEASE BUT APPLIES MORE

GENERALLY TO ORGANS SPECIFICALLY

TO IMMUNE DISORDERS.

IF YOU HAVE AN EFFECTOR CELL

THAT'S BEEN GENERATED IN YOUR

LYMPH NODES RETURNS TO A TISSUE

WHERE THE ANTIGEN IS PRESENT IS

THIS TISSUE IS PERFECTLY HEALTHY

AND DOESN'T EXPRESS ANY STRESS

SIGNALS OR INFLAMMATORY SYNAPSE.

THOSE EFFECTOR CELLS WILL NOT BE

EFFECTIVE KILLER CELLS.

THEY NEED TO BE -- BY THE TISSUE

AND ADDITIONAL SIGNALS TO BECOME

KILLER CELLS AND YOU GET TISSUE

DAMAGE.

AND WE HAVE SEEN THAT IN THE

CONTEXT OF RHEUMATOID ARTHRITIS.

WE HAVE SENT AT THAT TIME ALSO

LATELY BY STUDYING -- ARTHRITIS

AND ONLY AT CD8 CELLS BUT AK

CELLS AND GASTITIS BY THE

GROUP -- HAS SUGGESTED THAT IN

THE CONTEXT OF TYPE ONE

DIABETES.

SO OKAY.

SO THE EPITHELIUM WITH ALL ITS

STRESS LIGANDS CAN ACTIVATE THE

LYMPHOCYTES AND THEY TEND TO --

ATROPHY.

BUT WE ALSO KNOW THAT YOU

REQUIRE THAT YOU -- AND THAT IN

ABSENCE OF DQ -- YOU DON'T HAVE

CELIAC DISEASE.

SO THIS POSES THE QUESTION OF

WHAT IS THE INTERPLAY BETWEEN

THE EPITHELIUM STRESS RESPONSE

AND THE PRESENCE OF THE ADAPTIVE

ANTI-IMMUNE RESPONSE DQ2 AND

DQ8.

I'M GOING TO DISCUSS WITH YOU IS

THAT WE THINK AND WE STILL DON'T

HAVE -- TO REALLY NEED A

CORPORATION BETWEEN THESE TWO IN

ORDER TO HAVE TISSUE DAMAGE.

AND THERE'S A VERY INTERESTING

CYTOKINE BECAUSE IT'S A CYTOKINE

THAT IS NOT SECRETED BUT NEEDS

TO BE TRANSPRESENTED AND IS

EXPRESSED LOCALLY.

SO CELIAC PATIENTS AS I

INDICATED ALREADY -- IN THE

INTESTINAL EPITHELIUM AND OVER

EXPRESS I16 IN THE LAMINA

PROPRIA -- WHEN WE USE MICE --

THEY HAVE NORMAL -- MEANING THE

EXPRESSION OF I15 THE EPITHELIUM

CANNOT SUBSTITUTE FOR THE I15

OVEREXPRESSION OF THE LAMINA

PROPRIA AND THAT THE TWO

LOCATIONS SEEM TO BE REQUIRED.

AND THIS IS AGAIN BECAUSE I15 IS

PRESENTED BY THE PRIVATE I15

ALPHA CHAIN TO T CELLS THAT CAN

RESPOND TO THE -- GAMMA

RECEPTOR.

SO THE MODEL THAT I WOULD LIKE

TO DISCUSS WITH YOU BASED ON

HUMAN DATA AND ALSO ON THE MOUSE

MODELS WE HAVE DEVELOPED IS THAT

IN ORDER TO HAVE THE ATROPHY,

YES YOU NEED THE LICENSING OF

LYMPHOCYTES AND THE LICENSING --

INHIBITORY -- ACTIVATING THE

RECEPTOR AND CHANGE OF THE

ACTIVATION STATUS BY ACTIVATION

OF A NUMBER OF KINASES.

BUT IN ORDER TO ALLOW THIS

LICENSING OF -- LYMPHOCYTES, YOU

REQUIRE AT THE SAME TIME THE

ADAPTIVE IMMUNE RESPONSE AND

THE -- SO IF THIS MODEL IS TRUE,

THEN YOU WOULD ANTICIPATE THAT

POTENTIAL CELIAC PATIENTS WHO

HAVE ANTI--- THAT HAVE NO

ATROPHY SHOULD LAST IN THE --

STRESS RESPONSE BECAUSE IF THEY

HAD IT THEN THEY WOULD ACTIVATE

THE LYMPHOCYTES AND THEY WOULD

HAVE THE ATROPHY.

CONVERSELY, YOU WOULD ALSO

ANTICIPATE THAT MEMBERS OF THE

CELIAC PATIENTS MAY HAVE --

STRESS RESPONSE INDEPENDENTLY

FROM MOUNTING AN ADAPTIVE

ANTI-IMMUNE RESPONSE.

AND SO HERE WHAT WE DID IS WE

DID -- STUDY, WE LOOKED AT

IMMUNOCHEMISTRY EXPRESSION OF

STRESS MARKETS AND I16 ON THE

EPITHELIUM OF INDIVIDUALS THAT

HAVE NORMAL VILLI BUT HAS EITHER

ANTI--- ANTIBODIES THAT ARE THE

POTENTIAL CELIAC PATIENTS OR

FAMILY MEMBERS OF CELIAC

PATIENTS WITHOUT ANTI-TERMAL ASE

EXAMINE WHAT YOU SEE AS THE

PATIENTS THAT ARE POTENTIAL

CELIAC PATIENTS HAVE VERY LOW

LEVEL OF I15 EXPRESSION WHEREAS

THE MEMBERS OF CELIAC PATIENTS

THAT HAVE HIGH LEVEL OF I15

EXPRESSION.

AND WHEN WE LOOK AT THE

LYMPHOCYTES WE FOUND THAT

WHETHER YOU ARE A POTENTIAL

SELECT PATIENT OR FAMILY MEMBER

WITH I15, YOU DON'T LOSE THE

EXPRESSION OF INHIBITORY NK

RECEPTORS.

AND LIKE ACTIVE CELIAC PATIENTS.

AND YOU ONLY -- AND YOU DON'T --

NG2 MOLECULES.

WHAT YOU HAVE ARE -- LYMPHOCYTES

THAT DON'T HAVE THE FULL --

PHENOTYPE WHEN YOU HAVE EITHER

ONE OR THE OTHER.

SO IN ORDER TO REALLY ADDRESS

THE QUESTION WHETHER THE

COMBINATION OF THE TWO CAN LEAD

TO -- LYMPHOCYTE ACTIVATION, WE

WENT AND TO THE MOUSE MODEL.

SO YOU MAY REMEMBER, THE MICE

THAT OVER EXPRESS IO15 AND

THE -- PROMOTER HAS LOTS OF --

I'M GOING TO SHOW YOU THAT THE

MICE THAT OVER EXPRESS I15 --

HAS INCREASED -- LYMPHOCYTES

WITH ACTIVATING RECEPTORS.

AND NOW WHAT HAPPENS WHEN YOU

CROSS THE TWO MICE AND YOU HAVE

I16 OVER EXPRESSION IN BOTH

LOCATIONS.

SO FIRST OF ALL IN ABSENCE OF

GLUTEN YOU DON'T SEE THE

ATROPHY.

WHAT YOU SEE IN MICE THAT OVER

EXPRESS I15 IN THE LAMINA

PROPRIA IS THE HIGHER FREQUENCY

OF -- BUT YOU SEE IN MICE THAT

OVER EXPRESS -- SEQUENCING OF

DC8 CELLS IN THE EPITHELIUM --

TRANSGENIC MICE.

NOW -- DIGESTIVE GLUTEN AND YOU

LOOK AT THE FREQUENCY OF

LYMPHOCYTES WITH ACTIVATING

RECEPTORS IN ABSENCE OF ANY OF

THE RECEPTORS THE FREQUENCY'S

VERY LOW.

IF YOU NOW TAKE THE MICE THAT

HAVE LOTS OF -- YOU SEE THAT YOU

HAVE A PRESENCE OF GLUTEN --

INCREASE IN THE ABSOLUTE NUMBER

OF THE -- LYMPHOCYTES.

IF YOU NOW LOOK AT MICE THAT

OVER HE CAN PRESS IO15 IN THE

EPITHELIUM AT THE BASE LEVEL IN

THE ABSENCE OF GLUTEN, THEY HAVE

THE HIGHER FREQUENCY OF THIS --

LIMB FIGHTS -- NK RECEPTORS BUT

THIS FREQUENCY DOES NOT CHANGE

WHEN THE MICE IS GLUTEN AND YOU

HAVE THE SAME PHENOTYPE IN MICE

THAT OVER EXPRESS IO15 IN MOTE

COMPARTMENTS.

-- BOTH CARPENTERS.

IF YOU -- BOTH COMPARTMENTS.

-- LYMPHOCYTES WITH THE --

RECEPTORS THAT YOU REALLY NEED

BOTH ELEMENTS IN ORDER TO HAVE

THIS EXPANSION OF -- LYMPHOCYTES

WITH A KILLER PHENOTYPE.

NOW WHAT ABOUT THE INTES INTUNL

INTUNL -- INTESTINAL

MORPHOLOGY -- PUBLISHED

PREVIOUSLY.

THE NICE THAT WE ARE USING

EXPRESS IO15 IN THE EPITHELIUM

AT SIMILAR LEVELS AS THOSE WE

FIND IN CELIAC PATIENTS AND

THOSE MICE DO NOT DISRUPTED --

ATROPHY.

NOW TAKE THE MICE THAT OVER

EXPRESS IO15 IN THE EPITHELIUM

AND THE LAMINA PROPRIA, IN

ABSENCE OF GLUTEN THEY HAVE THE

NORMAL MUCOSA AND NOW WHEN YOU

FEED THEM THEY -- ATROPHY.

AND THIS IS THE -- SHOWING A

HIGH INDUCTION OF EPITHELIUM

PROLIFERATION IN DHOA THOSE MICE.

THIS IS THE QUANTIFICATION OF

THE RICIA.

NOW WE WANTED --  QUANTITY FACE

OF THE RATIO.

IF YOU REALLY NEED THE RIGHT HLA

IN ORDER TO DISRUPT THE AT FEE,

WHAT WOULD HAPPEN IN THE MICE

THAT HAS I15 IN BOTH

COMPARTMENTS BUT ACTUALLY -- ONE

HYPOTHESES COULD BE THAT THIS

LEADS TO -- OVEREXPRESSION IN

WAYS WE SEEM TO UNDERSTAND OR IF

IT MEANS THIS IS INDEPENDENT AND

YOU REQUIRE -- ATROPHY.

WHAT WE FOUND -- BECAUSE NOW WE

CAN GO AND EVEN ACQUIRE MORE

INDEPARTMENT THE ROLE OF HLAQ8

WE FOUND THAT WHEN I16 WAS

EXPRESSED IN BOTH COMPARTMENTS,

WE DID NOT SEE AN INCREASE IN

THIS ACTIVATING T CELLS AND WE

DID NOT SEE -- LYMPHOCYTES AND

WE DID NOT SEE THE ATROPHY.

EVEN THOUGH THOSE MICE HAVE LOTS

OF -- SO THIS IS GOING TO POSE A

QUESTION OF WHAT INDUCES I15 IN

THESE TWO COMPARTMENTS AND IF

THERE'S A DIFFERENTIATION

RESERVATION OF THE EPITHELIUM

AND THE LAS LAMINA PROPRIA AND

WHAT'S THE SEQUENCES OF EVENTS

IN INDIVIDUALS THAT ARE GOING TO

DISRUPT CELIAC DISEASE BUT ALSO

WHAT IS THE ROLE OF DQ8 AND WHAT

IS THE ROLE OF TRANSNER TRANSTHE --

IMMUNE RESPONSE THAT IS REQUIRED

TO MOVE TO -- LYMPHOCYTE

ACTIVATION.

AND WE HAVE ALREADY IN

COLLABORATION WITH -- SOME

PRELIMINARY GOT WHERE WE KNOW

NOW THAT TERM NAIFS IS ACTIVATED

IN THE MICE THAT'S JANS TRENDIC

AND OUR HYPOTHESES IS GOING TO

BE WHEN YOU BLOCK TRANS--

ACTIVATION IT LEADS TO

DIMINISHED AMPLITUDE OF THE T

CELL RESPONDENTS.

AND IN ABSENCE OF A CERTAIN

AMPLITUDE OF THE T CELL

RESPONDENTS THERE WILL NOT BE

THE ATROPHY.

SO IF YOU PUT THIS IN THE COME

TEXT OF WHAT YOU KNOW IN

PATIENTS, YOU DO HAVE PATIENTS

THAT ARE POTENTIAL SELECT

PATIENTS OR PATIENTS WITH --

THAT HAVE ANTIBODIES BUT DON'T

HAVE THE ATROPHY -- THE QUESTION

AS TO WHETHER THE IMMUNOCOMPLEX

IS -- IN THE DISRUPTION OF THE

SKIN DISEASE.

YOU HAVE ALSO INDIVIDUALS AND

AMONG FAMILY MEMBERS AMONG

FAMILY MEMBERS THAT WILL TELL

YOU THAT THEY ARE GLUTEN

SENSITIVE.

THEY WILL TELL YOU THAT THEY

HAVE INTESTINAL SYMPTOMS AND

WHEN THEY GO ON A GLUTEN FREE

DIET THEY SEE BETTER.

AND THE QUESTION IS COULD IT BE

THAT IN THE PATIENTS THAT

HAVE -- IN ABSENCE OF THAT

IMMUNE RESPONSE, THESE

INDIVIDUALS HIGHLY SENSITIVE TO

GLUTEN INJECTION AND COULD IT BE

THAT UNDER THOSE CONDITIONS YOU

HAVE -- WE LOOKED UNDER

MICROSCOPY IN SOME OF THOSE

INDIVIDUALS AND WE HAVE FOUND

THAT THEIR EVEN TEA EPITHELIUM IS NOT

NORMAL.

MORPHOLOGICALLY IT LOOKS NORMAL

AND YOU GO AND LOOK AT THE KESM

TREE MARKETS LF CHEMISTRY

MARKETS WITH MICROSCOPY THERE

ARE ACTUAL DEFECTS.

AND YOU REALLY NEED THE

COMBINATIONS OF THE TWO TO HAVE

THE ATROPHY.

AND MORE GENERALLY, THERE'S IS

NOTION THAT CELIAC DISEASE IF

YOU CALL THE CELIAC DISEASE A

GLUTEN INDUCED PATHOLOGY WHICH

IS NOT -- AWE LEARNI ALLERGIC IGE RESPONSE

AND YOU TAKE THE NORMAL

RESPONSES TO GLUTEN AND ADAPTIVE

NEURORESPONSES TO GLUTEN OR

ABNORMAL -- COULD IT BE THIS

DIRECT, THAT IF YOU LOOK AT THE

WIDE SPECTRUM OF THE DISEASE AND

YOU ASK THE QUESTION DEPENDING

ON THE -- TYPE RESPONSE YOU

INDUCE TO GLUTEN, CAN THAT LEAD

TO VERY DIFFERENT

MANIFESTATIONS.

SO IF YOU HAVE A T CELL RESPONSE

ANTI-GLUTEN -- STRESS RESPONSE

YOU'LL HAVE CLASSICAL CELIAC

DISEASE.

IF YOU HAD GENERATION OF IMMUNE

COMPLEXES, YOU COULD HAVE

CERTAIN GENETIC CONDITIONS.

YOU COULD HAVE ONLY SKIN

LESIONS.

WE KNOW THAT A NUMBER OF

PATIENTS ONLY HAVE -- SYMPTOMS

AND HAVE ANTI--- ANTIBODIES.

COULD THERE BE A LINK BETWEEN

THE SYSTEMIC RESPONSES AND --

NEURO -- AND WHAT WOULD BE THE

PATHOGENESIS OF THESE

NEUROLOGICAL DISEASES.

AND THEN FINALLY WHAT ACTUALLY

IS RESPONSIBLE FOR THIS --

STRESS RESPONSE AND IF THEY'RE A

SUBSET OF PATIENTS WITH

IRRITABLE BOWEL SYNDROME AND

HYPER SENSITIVE TO GLUTEN.

AND I THINK BY REPUTTING THE

QUESTION IN THE -- CONTEXT AND

BY ASKING THE QUESTION WHAT ARE

THE IMMUNE EPITHELIUM MECHANISMS

THAT COULD LEAD TO DIFFERENT

TYPE OF EFFECTOR RESPONSES THAT

EACH CAN LEAD TO DIFFERENT TYPE

OF MANIFESTATIONS, WE CAN GO --

THOSE MEASURES AND DO DIFFERENT

TYPES OF STUDIES.

SO IRRITABLE BOWEL SYNDROME, WE

ARE GOING TO LOOK AT EPITHELIUM

STRESS RESPONSES AND WE WILL GO

AND LOOK AT CHANGES -- AND ASK

THE QUESTION ARE THERE SUCH

CONSTITUTIVE DEFECTS AND WHAT IS

THE LINK TO GLUTEN.

AND SO HERE I WOULD LIKE TO

THANK THE PEOPLE IN THE LAB WHO

HAVE DONE THE WORK OVER THE

YEARS, WILLIAM -- AND VALLEY --

HAVE PLAYED A KEY ROLE IN

LOOKING AT THE -- DEVELOPED THE

TRIPLE MOUSE MODEL WITH

ATROPHY -- HAS BEEN DOING THE

STUDIES ON THE ROLE OF HLADQ8

AND -- HAD HAS WORKED ON THE NK

PHENOTYPE OF INTERPRETIVE

LYMPHOCYTES.

THEN WE HAVE IMPORTANT CLINICAL

COLLABORATORS AND -- HAVE HAD

OUR STUDIES -- FOR THE STUDIES

ON -- STUDIES -- THANK YOU.

[APPLAUSE]

>>

>> [INDISCERNIBLE] IF YOU LOOK

AT THE -- AT THAT TIME HAS

REALLY THE MOST, THE HIGHEST

INCREASE IN CELIAC DISEASE, IT'S

LYMPHOMA.

IT'S MUCH MORE THAN CANCERS OF

THE INTESTINE.

IT'S REALLY THE LYMPHOMA AND BC

LYMPHOMA.

ONE THING THAT WE SEE IS THAT

YOU HAVE DISRUPT SHUMENT -- I HAVE

SHOWN BECOMES EVEN MORE

PRONOUNCED AND -- LYMPHOCYTES

BECOME COMPLETELY INSENSITIVE TO

THE REQUIREMENTS OF T CELL

RECEPTOR ACTIVATION AND BECOME

HIGHLY DEPENDENT ON I15 -- SO IT

SEEMS THAT IT'S ALMOST THEND

SPECTRUM OF THIS HIGH ACTIVATION

OF -- LYMPHOCYTES.

SO WHAT WE DON'T KNOW YET IS

WHETHER -- STEP PROGRESSION FROM

T CELLS TO THOSE ABNORMAL --

LIMB SITES OR WHETHER THEY

ARRIVE EVEN OF A -- POPULATION

OF CELLS THAT EXIST IN NORMAL

INDIVIDUAL AT VERY LOW FREQUENCY

AND -- SEE THAT PATIENT.

>> WHAT CAUSES -- ATROPHY?

>> I THINK IT'S REALLY THE

RECOGNITION OF STRESS SIGNALS BY

THOSE ACTIVATING KILLER

RECEPTORS THAT DESTROY THE

EPITHELIUM -- PUT THEM IN FRONT

OF THE EPITHELIAL TARGET

CELLS -- KILL THEM.

IF YOU TAKE THE -- LYMPHOCYTES

AND -- AS WE WERE ABLE TO DO IT,

YOU CAN REALLY SHOW THAT THEY

CANKILL EPITHELIUM CELLS AGAIN

BASED ON STRESS SIGNALS.

I THINK THAT YOU DO HAVE A

SELECTIVE DESTRUCTION OF THE

CELLS THAT EXPRESS THE STRESS

LIGANDS AND THAT'S WHY IT'S A

TARGETED KILLING.

IT'S NOT A NON-SPECIFIC KILLING

EVEN THOUGH IT GOES TO IMMUNE

RECEPTORS IT'S STILL A TARGETED

KILLING OF STRESS CELLS.

AND THE REST IS NOT ATTACKED.

>> I THINK WE RECALL, I MAY BE

WRONG ABOUT THIS, STUDIES OF THE

TURNOVER OF CELLS AND THIS

DISEASE.

AND SURPRISINGLY, IF I RECALL

CORRECTLY, THEY WERE EXTREMELY

RAPID.

IT WASN'T THAT THE CELL CYCLE

WAS BEING INTERRUPTED OR THAT

THERE WAS SOME AGING LIKE

THING -- THEY WERE ACTUALLY

BEING TURNED OVER.

IS THAT WRONG?

>> WHEN YOU DO MOUSE STUDIES AND

YOU DESTROY THE SURFACE

EPITHELIUM, THE MOST -- INCREASE

IN THE -- SO THERE IS A

FEEDBACK -- EVEN THOMA EPITHELIUM THAT

INDUCES A CHANGE IN THE PLIK

ASIAN.

-- APPLICATION.

SO IF THIS ECOMES SENSITIVE

WITH THE ABNORMAL CHANGING OF

THE EPITHELIUM THEN WHY WHEN YOU

REMOVE GLUTEN WOULD YOU SEE A

NORMALIZATION OF THE NUMBER

OF -- CORRELATES WITH THE

NORMALIZATION OF THE VILLI.

I KNOW THAT SOME PEOPLE -- BUT I

JUST -- BASED ON NOW THAT WE

KNOW MORE BASED ON WHAT KIND OF

MECHANISMS.

>> I SAW YOU -- ALPHA FOR

EXAMPLE TO INDUCE IO15 AND IO15

OR ALPHA.

CAN YOU GET AWAY WITH IO

INTERFERON ALPHA --

>> SO THE STUDIES -- HAS SHOWN

THAT YOU HAVE RECEPTORS OF

PATIENTS INCREASE -- INTERFERON.

AND WE DID LOOK AT THE MUCOSA --

AND WE SEE THAT -- OF THEM HAVE

UP REGULATION OF -- INTERFERON

AND WE DID THAT EITHER BY

LOOKING -- OR BY USING -- ALPHA

BUT NOT ALL PATIENTS WITH IO15

HAVE -- AND SO WHAT WE'RE DOING

NOW IS TO HAVE A COLLABORATION

WITH -- BECAUSE OVER 13 YEARS TO

HAVE ACTUALLY PERFECTED THE

PATIENTS BEFORE THEY -- HAVE

TAKEN FAMILY MEMBERS AT RISK,

DON'T ASK ME HOW BUT THEY HAVE

SEQUENTIALLY BIOPSIS AND WE ARE

STUDYING RIGHT NOW THESE

BIOPSIS.

WHAT I CAN TELL YOU ALREADY

BASED ON WHAT WE'RE SEEING

THEY'RE NOT TO BE EXPRESSED.

AT SOME TIME YOU INDUCE ONE OR

THE OTHER OR BOTH.

BUT I DON'T THINK IT'S

NECESSARILY CORRELATED.

AND SO -- WHAT HAPPENS, I CANNOT

TELL YOU THAT QUESTION.

>> SHOULD WE BE LOOKING AT IO15

IN PERHAPS SOME OF THESE OTHER

MARKERS IN TRYING TO UNDERSTAND

THIS HIGHLY PREVALENT

ENVIRONMENTAL ENTEROPATHY WHERE

THERE'S CONSISTENT EXPOSURE TO

PERHAPS INFLAMMATORY STIMULI AS

A BASIS FOR UNDERSTANDING SOME

VILLI ATROPHY WHICH IS SEEN

UNDER THOSE CONDITIONS.

>>> ABSOLUTELY.

IT WILL BE I THINK WE HAVE TO GO

BACK AND REINVESTIGATE YOU KNOW,

WHAT DO YOU SEE.

THE MOUSE MODELS SHOW --

COLLABORATION WITH THE JAPANESE

GROUP, IF YOU OVER EXPRESS IO15

IN THE EVE EPITHELIUM YOU CAN HAVE

THE ATROPHY ALONE.

SO IT MAY BE -- IT WILL BE

INTERESTING TO GO BACK TO THOSE

PATIENTS&DO THEY OVER EXPENSE

IO15 IN WHICH COMPARTMENT IT'S

WHAT DEGREE.

>>> IF YOU HAVE -- TO GO BACK --

BIOPSY -- IF YOU HAPPEN TO HAVE

SERUM, ONE COULD MEASURE SERUM

IO15, IO15 OR ALPHA, ONE COULD

OR -- BACK THERE COULD MEASURE

IO, IO15 OR ALPHA PERHAPS WHICH

IS FIVE TIMES NORMAL IN ACTIVE

CELIAC.

SO IF IO15IO15 OR AL GOT IN THE

GUT WERE INVOLVED IT -- IN THE

GUT INVOLVED MIGHT BE

REREFLECTED AND/OR STORED.

>> YOU COULD ASK THE QUESTION

WHY IS THE GENOME WIDE

APPLICATION ONLY MAINLY

IMMUNLOGICAL VIEWS IN CELIAC

DISEASE.

I DON'T THINK THAT THERE'S YET A

CLEAR EPITHELIUM GENE THAT'S

BEEN IDENTIFIED.

I THINK THE WAY THE STUDIES WERE

DONE ARE NOT CORRECT BECAUSE IF

THERE IS A FREQUENCY OF PATIENTS

THAT HAVE ALREADY -- ON THAT

LEVEL AND YOU PUT THEM TOGETHER,

FOR EXAMPLE THE FAMILY MEMBER --

30% OF THEM WOULD NORMALLY --

YOU WOULDN'T HAVE ENOUGH, YOU

WOULDN'T SEE IT.

AND THEN MAINLY AFTER STUDIES --

FOR THE COMBINED -- IDENTIFYING

THE GENES.

BUT FOR EACH ORGAN SPECIFIC

IMMUNE DISORDER YOU WOULD HAVE A

SPECIFIC TISSUE GENE.

SO YOU WOULDN'T BE ABLE TO DO

THAT -- I THINK WE HAVE TO

RETHINK ABOUT THAT.

>> I WANT TO THANK YOU VERY

MUCH.

AND IRV, THANK YOU VERY MUCH.

>>

[APPLAUSE]

>> YOU'RE VER IT'S BEEN A VERY INSTRUCTIVE

AFTERNOON.