WELCOME TO THE SIXTH INSTALLMENT
OF THE 21ST YEAR OF DEMYSTIFYING
MEDICINE, THE COURSE WHOSE GOAL
IS TO BRIDGE EXCITING
DEVELOPMENTS IN BIOLOGY AND
ENGINEERING WITH MEDICINE.
I'M DAN KASTNER, I AM THE
SCIENTIFIC DIRECTOR EMERITUS OF
THE NATIONAL HUMAN GENOME
RESEARCH INSTITUTE AND I WILL BE
YOUR HOST THIS AFTERNOON.
THE USUAL HOST AND FATHER OF THE
COURSE, DR. ARIAS, HAS ASKED ME
TO FILL IN FOR HIM.
THE PURPOSE OF THIS COURSE IS TO
ESTABLISH A DIALOGUE BETWEEN THE
WORLDS OF BIOLOGY AND
ENGINEERING AND MEDICINE, AND
THAT DIALOGUE CRACKLES EVERY
TUESDAY AFTERNOON FROM 4:00 TO
6:00 IN THE AFTERNOON FROM
JANUARY 4TH TO MAY THE THIRD.
I'D LIKE TO JUST SHOW
YOU A PICTURE TAKEN BY
DR. ARIAS' GRANDFATHER, WITH A
BOX CAMERA, OF THE CONSTRUCTION
OF THE BROOKLYN BRIDGE.
AND FOR THOSE OF YOU WHO DON'T
KNOW, THE BROOKLYN BRIDGE GOES
FROM MANHATTAN IN NEW YORK TO
BROOKLYN, AND IT WAS BUILT
BETWEEN 1869 AND 1883.
AND HERE YOU SEE IN THIS PICTURE
ACTUALLY TWO MEN WHO ARE ON A
CATWALK.
YOU CAN SEE TO THE LEFT.
ONE OF THEM WALKED OVER FROM
BROOKLYN AND THE OTHER FROM THE
MANHATTAN SIDE, AND THEY'RE
ACTUALLY HAVING A DISCUSSION
ABOUT THE CHOLERA PANDEMIC OF
1873.
AGAIN, IN THE TRADITION OF
BRINGING TOGETHER BASIC SCIENCES
WITH CLINICAL MEDICINE.
WELL, ON THE NEXT SLIDE, YOU
WILL SEE WHAT WE HAVE IN STORE
FOR US THIS AFTERNOON.
TWO STELLAR TALKS.
FIRST IS A TALK ENTITLED
EPIGENETIC CONTRIBUTION TO
SYSTEMIC LUPUS ERYTHEMATOSUS,
AND OUR SPEAKER WILL BE
DR. LINDSEY CRISWELL, WHO IS
CURRENTLY THE DIRECTOR OF THE
NATIONAL INSTITUTE OF ARTHRITIS
AND MUSCULOSKELETAL AND SKIN
DISEASES, AND SHE HAS A RESEARCH
LAB IN THE GENOME INSTITUTE, IN
THE GENOMICS OF AUTOIMMUNE
RHEUMATIC DISEASES SECTION OF
THE GENOME INSTITUTE.
BEFORE SHE CAME TO THE NIH, SHE
WAS THE VICE CHANCELLOR OF
RESEARCH AT UCSF MEDICAL SCHOOL.
SHE GOT HER MEDICAL DEGREE AT
UCSF, HER MPH AT BERKLEY, AND A
DOCTOR OF SCIENCES DEGREE IN
GENETIC EPIDEMIOLOGY AT THE
NETHERLANDS INSTITUTE FOR HEALTH
SCIENCES IN ROTTERDAM.
A FEW YEARS AGO, SHE WAS THE
HENRY KUNKEL YOUNG INVESTIGATOR
AWARD WINNER AND MORE RECENTLY
WAS INDUCTED INTO THE
ASSOCIATION OF AMERICAN
PHYSICIANS.
HER RESEARCH WORK CONCENTRATES
ON GENOME-WIDE ASSOCIATION
STUDIES OF LUPUS, RHEUMATOID
ARTHRITIS AND SJOGREN'S
SYNDROME, EPIGENETIC SIGNATURES
OF INFLAMMATION AND AUTOIMMUNE
DISEASE AND HEALTH DISPARITIES
IN THE AUTOIMMUNE DISEASES.
AND AS A SPECIAL TREAT TODAY,
DR. CRISWELL IS GOING TO BE
INTERVIEWING A PATIENT DURING
HER PRESENTATION.
MY COLLEAGUE GOT A LITTLE BIT
AHEAD OF THINGS THERE WHEN I
CLAPPED MY HAND.
BUT NOW I'LL CLAP MY HANDS AND
NOW WE SHOULD GO AHEAD TO THE
SECOND TALK, WHICH IS ENTITLED
ANCYTOKINE AUTO ANTIBODIES:
IMPORTANT UNDERAPPRECIATED
COFACTORS IN RARE AND COMMON
CONDITIONS.
THE SPEAKER WILL BE THE
INCOMPARABLE DR. STEVEN HOLLAND,
NIH DISTINGUISHED INVESTIGATOR,
HE HAS A LAB THERE IN THE NIAID
AS WELL.
HE'S THE EMERITUS DEPUTY DIRECT
DIRECTOR FOR INTRAMURAL CLINICAL
RESEARCH, GOT HIS MEDICAL DEGREE
IN INFECTIOUS DISEASES
FELLOWSHIP AT JOHNS HOPKINS AND
HE'S A MEMBER OF THE NATIONAL
ACADEMY OF MEDICINE.
HIS RESEARCH INTEREST IS IN THE
GENETIC SUSCEPTIBILITY TO
PRIMARY IMMUNODEFICIENCY
DISEASE, MECHANISMS OF BACTERIAL
PATHOGENESIS, AND CYTOKINES AND
THEIR RECEPTORS IN THE
PATHOGENESIS AND THERAPY OF
INFECTIONS.
WELL, WITHOUT FURTHER ADO, WE
NEED TO GET ON TO IT BECAUSE WE
HAVE A SPK SPECTACULAR SESSION IN
STORE FOR US, AND I WOULD JUST
LIKE TO HAVE DR. CRISWELL TAKE
IT AWAY!
SO THANK YOU SO MUCH, DAN, FOR
THAT INTRODUCTION, AND MY THANKS
TO WIN TO PRESENT PART OF THIS
SERIES.
IT'S A GREAT HONOR AND
PRIVILEGE.
AND I HAVE NO DISCLOSURES TO
REPORT.
SO I'M GOING TO BEGIN WITH A
VERY BRIEF OVERVIEW OF LUPUS.
AS WE HEARD, WE HAVE A WONDERFUL
OPPORTUNITY TO INTERVIEW A
WOMAN, JENNIFER, WHO HAS
EXPERIENCED LIFE WITH LUPUS FOR
MANY, MANY YEARS.
I FIRST MET JENNIFER WHEN SHE
VOLUNTEERED FOR ONE OF MY
RESEARCH PROJECTS AND I KNOW
YOU'LL REALLY ENJOY HEARING HER
STORY.
AFTER THE INTERVIEW WITH
JENNIFER, I'LL SHARE WITH YOU
SOME OF THE PROGRESS RELATED TO
DEFINING THE GENETIC
CONTRIBUTION TO THE DISEASE,
INCLUDING HOW IT'S HELPED US
UNDERSTAND ETIOLOGIC PATHWAYS
THAT OPERATE IN LUPUS, AND THEN
I'LL SHARE WITH YOU WHAT WE'RE
LEARNING ABOUT THE EPIGENETIC
CONTRIBUTION TO THE DISEASE.
I'LL FOCUS ON STUDIES INVOLVING
THE EPIGENETIC MODIFICATION OF
DNA METHYLATION, IN PART BECAUSE
OF THE IMPORTANT LINK TO THE
ENVIRONMENT.
SO LUPUS IS THE PROAT TYPIC
SYSTEMIC AUTOIMMUNE DISEASE.
LIKE MANY AUTOIMMUNE DISEASES,
WOMEN ARE AT DRAMATICALLY
INCREASED RISK COMPARED TO MEN
WITH A TENFOLD INCREASE.
ETHNIC MINORITIES ARE ALSO AT
INCREASE FOR DISEASE, A REALLY
STRIKING FEATURE.
THE DISEASE IS ASSOCIATED WITH
VERY SUBSTANTIAL MORBIDITY AND
MORTALITY.
THE ETIOLOGY IS COMPLEX, BUT
THERE IS A CLEAR-CUT GENETIC
CONTRIBUTION.
AND THERE IS NO PATH PNEUMONIC
TEST FOR DIAGNOSIS, WHICH HAS
BEEN A MAJOR CHALLENGE, NOT ONLY
FOR DIAGNOSIS BUT ALSO FOR
TRYING TO UNDERSTAND THE
ETIOLOGIC CONTRIBUTION TO THE
DISEASE.
IT'S A CHRONIC ILLNESS WITH NO
CURE.
ALTHOUGH THERE HAS BEEN RECENT
PROGRESS IN THIS DISEASE.
SO THIS SLIDE JUST ILLUSTRATES
SOME OF THE MANY MANIFESTATIONS
OF THE DISEASE.
ESPECIALLY PROMINENT ARE A
VARIETY OF SKIN MANIFESTATIONS
IN LUPUS.
SHOWN HERE IS THE CLASSIC
BUTTERFLY RASH, DISCOID RASH
WHICH CAN BE QUITE DISFIGURING,
PHOTOSENSITIVITY CAN BE
OBSERVED, CAN BE VERY PROMINENT.
KIDNEY INVOLVEMENT IS ONE OF THE
MOST SERIOUS COMPLICATIONS OF
THE DISEASE.
AND CAN LEAD TO END STAGE RENAL
FAILURE, EVEN DEATH.
INVOLVEMENT OF THE CENTRAL
NERVOUS SYSTEM IS RELATIVELY
COMMON.
ARTHRITIS IS ALSO COME, BUT
THERE ARE MANY MORE
MANIFESTATIONS NOT PICTURED ON
THE SLIDE.
LUPUS IS ALSO STRIKING FOR THE
NUMEROUS AUTO ANTIBODIES THAT
ARE PRESENT AMONG INDIVIDUALS
WITH THE DISEASE.
MANY OF WHICH HAVE VERY SPECIFIC
CLINICAL ASSOCIATIONS.
THESE INCLUDE THROMBOSIS,
ANTISSA AND SSB SKIN
MANIFESTATIONS WITH NEONATAL
HEART BLOCK, ANTIDOUBLE STRANDED
DNA ANTIBODIES ARE ASSOCIATED
WITH RENAL DISEASE.
THERE'S ALSO INCREASING EVIDENCE
THAT THE ANTIBODIES MAY HAVE THE
STRONGEST ASSOCIATIONS WITH
SPECIFIC GENETIC FACTORS.
SO NOW LET ME TURN TO JENNIFER'S
STORY.
I'M GOING TO TOUCH UPON HER
EXPERIENCE GETTING DIAGNOSED
WITH LUPUS, WHAT IT MEANT IF SHE
CONTEMPLATED HAVING CHILDREN.
THE MANY CHALLENGES SHE
EXPERIENCED LIVING WITH LUPUS,
WHAT IT WAS LIKE TO BE A LUPUS
PATIENT IN THE ERA OF COVID, AND
LASTLY, THE ROLE OF RESEARCH,
WHAT THAT'S MEANT TO HER, OVER
THE PAST COUPLE OF DECADES.
THANK YOU SO MUCH FOR JOINING
US.
I KNOW THE AUDIENCE IS GOING TO
REALLY APPRECIATE HEARING YOUR
STORY.
SO WHY DON'T YOU BEGIN BY
TELLING US YOUR EXPERIENCE
GETTING DIAGNOSED, WHAT YOUR
FIRST FEW SYMPTOMS WERE, WHAT
LED TO THE DIAGNOSIS AND WHAT
YOU WERE EXPERIENCING AT THAT
TIME.
>> FIRST THANK YOU FOR HAVING
ME.
I'M HONORED TO BE ABLE TO SHARE
MY STORY TODAY.
IN TERMS OF DIAGNOSIS, I WAS
DIAGNOSED JUST OVER 30 YEARS
AGO, SO I'VE LIVED MORE THAN
HALF OF MY LIFE WITH LUPUS.
I JUST FINISHED MY SECOND YEAR
OF UNDERGRADUATE STUDIES AT THE
TIME, AND REALLY IT WAS AROUND
MAY OF THAT YEAR, TWO THINGS
HAPPENED SIMULTANEOUSLY.
THE FIRST THING WAS I DEVELOPED
A VERY ROBUST COUGH, AND PAIN IN
THE CHEST WITH DEEP BREATHS.
AND THAT WAS DIAGNOSED FAIRLY
QUICKLY BY MY PRIMARY CARE
PROVIDER AS WHOOPING COUGH.
SO I WAS GIVEN TYLENOL WITH
CODEINE TO HELP ME SLEEP.
AND THAT WAS THAT.
SIMULTANEOUSLY, I HAVE A ROUTINE
PHYSICAL AND THE LAB RESULTS
FROM THAT PHYSICAL KEPT COMING
BACK AB NOR MA'AM, SO I'D GO
BACK AND GIVE MORE BLOOD AND
THEY'D RUN MORE TESTS.
OVER THE COURSE OF SEVERAL
MONTHS I HEARD INITIALLY FALSE
POSITIVE FOR SYPHILIS, WHICH I
KNEW WAS NOT THE CASE.
THEN I HEARD A CONNECTIVE TISSUE
DISORDER POTENTIALLY.
I RECALL HEARING POTENTIALLY A
BLOOD CANCER.
SO THIS SERIES OF DISTURBING
RESULTS SORT OF PARALLELLED THE
TRACK OF THE REALLY PERSISTENT
AND UNCOMFORTABLE COUGH.
AFTER ABOUT THREE MONTHS OF
THIS, I RECEIVED A CALL FROM A
NURSE IN THE PRIMARY CARE OFFICE
WHO SAID THE DOCTOR HAD READ AN
ARTICLE, AND THE DOCTOR
SUSPECTED THAT THE WHOOPING
COUGH WAS ACTUALLY PLUR SEE, AND
THAT THE ABNORMAL LABS WERE DUE
TO ANTIPHOSPHOLIPID ANTIBODIES.
AND SHE TOLD ME THREE THINGS
THAT DAY.
IT WAS THE DAY BEFORE MY 20TH
BIRTHDAY, THAT I LIKELY HAD
SYSTEMIC LUPUS, THAT I WAS AT
VERY HIGH RISK FOR A STROKE, AND
THAT IT WAS UNLIKELY I WOULD
EVER BE ABLE TO CARRY A
PREGNANCY BECAUSE OF THE
CLOTTING RISK.
MY PARENTS PAID OUT OF POCKET
FOR ME TO SEE A RHEUMATOLOGIST
SO I WOULDN'T HAVE --
IMMEDIATELY THAT I HAD LUPUS.
AND WHEN I ASKED WHAT WAS GOING
TO HAPPEN TO ME, I WAS TOLD,
"WE'LL KNOW IN A YEAR."
>> SO WHAT A DEVASTATING BLOW AT
THE AGE OF 20, YOU'RE IN
COLLEGE.
I CAN ONLY IMAGINE WHAT WAS
GOING THROUGH YOUR HEAD.
SO I KNOW THAT YOU WENT ON TO
HAVE SOME OTHER MANIFESTATIONS
THAT YOU STRUGGLED TO KIND OF
FIND THE RIGHT TREATMENT AND
BALANCING THAT WITH SIDE EFFECTS
AND I THINK THE AUDIENCE WOULD
ALSO BE INTERESTED IN HEARING
MORE ABOUT HOW YOU PURSUED YOUR
DESIRE TO HAVE CHILDREN.
AND HOW YOU GOT TO THE POINT
WHERE THAT BECAME A POSSIBILITY
AND THEN YOUR EXPERIENCE WITH
YOUR PREGNANCY.
>> YES.
WELL, DURING THAT YEAR, IT
BECAME CLEAR THAT I WAS GOING TO
HAVE PRIMARILY ARTHRITIS IN
MULTIPLE JOINTS, INFLAMMATORY
ARTHRITIS BECAME MY MAIN
CHALLENGE.
ALSO PHOTOSENSITIVITY, RASHES IN
THE SUN.
I DEVELOPED A FULL MYLAR RASH
WHILE PREGNANT, SO I'VE HAD SOME
SKIN COMPONENTS.
I WILL SAY THAT BEING TOLD I
COULDN'T HAVE CHILDREN WAS NOT
SOMETHING I WAS WILLING TO
ACCEPT.
AND I HAVE TO SAY THAT BECAUSE I
WAS INVOLVED AS A RESEARCH
SUBJECT IN YOUR RESEARCH
PROJECTS, I THINK I HAD SO MUCH
FAITH IN RESEARCH AND POTENTIAL
ADVANCEMENT IN OUR UNDERSTANDING
OF THIS DISEASE THAT I REALLY
PUSHED AND WAS FINALLY CONNECTED
WITH A HIGH RISK O.B. WHO WAS
WILLING TO TAKE ON MY CASE, AND
I FOUND A TEACHING HOSPITAL, I
WANTED DELIBERATELY TO GIVE
BIRTH IF I COULD GET PREGNANT AT
A TEACHING HOSPITAL BECAUSE I
BELIEVED I COULD GET THE LATEST,
MOST ATTENTIVE CARE THERE.
SO IN 2000, IN MY VERY LATE
20s, WHEN I FINALLY WAS READY
TO HAVE CHILDREN, THE PLAN WAS I
WOULD GIVE MYSELF TWICE DAILY
INJECTIONS OF LOVENOX TO SORT OF
PROPHYLACTICALLY PREVENT ANY
KIND OF CLOTTING, AND OTHER RISK
FACTORS I KNEW OF, I HAD
ANTIBODIES THAT PUT THE -- WOULD
PUT THE BABY AT RISK FOR FETAL
HEART BLOCK, SO THEY WERE
MONITORING FOR THAT, OBVIOUSLY
HOPEFULLY TRYING TO KEEP MY
LUPUS UNDER CONTROL.
THE WILDCARD WAS WHEN I DID GET
PREGNANT, IT WAS A SPONTANEOUS
TWIN PREGNANCY, SO THEN
MULTIPLES CAME INTO PLAY.
I WAS FINE, REALLY, UNTIL THE
END OF MY 33RD WEEK, AND I
DEVELOPED SUDDENLY VERY HIGH
BLOOD PRESSURE, AND NOTICEABLE
SWELLING.
I WAS ADMITTED TO THE HOSPITAL
AND THE HIGH RISK O.B., I
REMEMBER HIM, MY DOCTOR WAS OUT
OF TOWN, HIS PARTNER WAS THERE,
AND HE SAID, WHERE ARE YOUR
LIVER LABS?
HE KEPT ASKING ME OVER AND OVER
AGAIN.
THERE WEREN'T ANY LIVER LABS.
BUT HE SUSPECTED AND CONFIRMED I
HAD HELP SYNDROME.
SO THEY DELIVERED THE BABIES BY
EMERGENCY C-SECTION AT EXACTLY
34 WEEKS.
ONE WAS 3 POUNDS 12 OUNCES, THE
OTHER WAS 5 POUNDS ROUGHLY.
I REMAINED HOSPITALIZED FOR A
WEEK, DEVELOPED CLOTS IN THE
C-SECTION THAT WAS LEFT OPEN AND
PACKED DAILY FOR ABOUT SIX WEEKS
TO HEAL.
VERY PAINFUL.
THE BABIES WERE IN THE NICU FOR
ABOUT TWO WEEKS, BUT WE ALL
SURVIVED.
>> REMARKABLE.
AND THAT WAS THE HELP SYNDROME
WHICH IS A FORM OF SEVERE
PREECLAMPSIA FOR THE AUDIENCE,
VERY SCARY PERIOD.
SO SO MAYBE YOU CAN SHARE A
LITTLE ABOUT LUPUS AS A CHRONIC
ILLNESS.
YOU ENDED UP HAVING TO CHANGE
HEALTH INSURANCE PLANS OVER TIME
AND HOW YOU STRUGGLED WITH
CONTINUITY OF CARE AND THEN
MAYBE YOU COULD TALK ABOUT THE
NEW MEDICATION THAT WAS ADDED,
VANLISTA, AND WHAT THAT MEANT
WHEN WE ENTERED THE ERA OF THE
PANDEMIC.
>> YES.
WELL, LOOKING BACK OVER 30
YEARS, TWO THEMES HAVE BEEN
FAIRLY CONSISTENT CONSISTENT
WITH THE WORKLOAD OF MANAGING
LUPUS.
IT'S A SIGNIFICANT AMOUNT OF
WORK TO MANAGE A CHRONIC
ILLNESS, AND IN PARTICULAR, ONE
WHICH NOT ALL DOCTORS ARE VERY
WELL VERSED, THAT PUTS A LOT OF
RESPONSIBILITY BACK ON THE
PATIENT.
CERTAINLY CHALLENGES, CARE
CONTINUITY, ANY LIFE CHANGE IN
THE UNITED STATES, BECAUSE WE
HAVE A FRAGMENTED HEALTH SYSTEM,
OFTEN NECESSITATES A CHANGE IN
INSURANCE AND A CHANGE IN
PROVIDERS.
AND EVEN IF ALL YOUR PROVIDERS
USE THE SAME ELECTRONIC HEALTH
RECORD, IT DOESN'T ENSURE
CONTINUITY OF TREND LINES.
EVEN THOUGH THEY'RE AVAILABLE,
APPOINTMENTS ARE SHORT AND IT'S
NOT READILY AVAILABLE TO
PROVIDERS.
SO I FIND A LOT OF
RESPONSIBILITY FOR CARE
CONTINUITY FALLS ON THE PATIENT.
SOMETIMES I MISS THE DAYS OF
HAND-CARRYING RECORDS BETWEEN
PROVIDERS, BECAUSE THAT WAS A
LITTLE MORE -- SEEMED MORE
RELIABLE OFTENTIMES.
THE OTHER THING THAT HAS BEEN A
REAL -- MEDICATIONS FOR LUPUS,
IN TERMS OF, A, WE HAVEN'T HAD A
LOT OF NEW MEDICATIONS UNTIL
FAIRLY RECENTLY.
AND IT'S NOT UNUSUAL TO HAVE
MEDICATIONS THAT HAVE SIDE
EFFECTS THAT DON'T WORK FOR YOU,
SO YOU HAVE TO DISCONTINUE
THOSE, OR MEDICATIONS THAT MAYBE
WORK WELL FOR YOU BUT GET PULLED
OFF THE MARKET OR GET A BLACK
BOX WARNING BECAUSE SUDDENLY
THEY'RE KNOWN TO CAUSE CLOTTING
RISK.
SOME MEDS ARE NOT ADVISED TO BE
TAKEN LONG TERM LIKE PREDNISONE.
I'M VERY FORTUNATE IN THAT I WAS
ABLE TO START TAKING BENLISTA
INFUSIONS, I THINK THAT'S A
MONOCLONAL ANTIBODY.
I STARTED THAT IN 2019.
BUT AGAIN, GOING BACK TO THE
WORK, IT TAKES TIME OUT OF YOUR
DAY TO GO GET AN INFUSION, SIT
THERE FOR A COUPLE HOURS, AND
ALSO THE MEDICATIONS ARE VERY
EXPENSIVE, AND THAT PUTS A LOT
OF WORK THEN ON THE PATIENT TO
TRY TO FIGURE OUT HOW TO PAY FOR
IT, HOW TO ACCESS PATIENT
ASSISTANCE PROGRAMS AND TO WEIGH
RISK BENEFITS, PML, THE RISK OF
GETTING PML, IS THAT SOMETHING
YOU'RE WILLING TO TRADE OFF IN
EXCHANGE FOR MAYBE HAVING YOUR
DISEASE UNDER CONTROL.
SO AGAIN, IT'S A LIFETIME'S
WORTH OF WORK WHEN YOU GET ONE
OF THESE PREGNANCIES.
>> YOU WERE ON BENVISTA TO HELP
WITH SOME OF YOUR SYMPTOMS BUT
THAT CREATED IMMUNOSUPPRESSION
AND THEN WE ENTER THE COVID ERA,
SO HOW DID THAT AFFECT YOUR
DECISION-MAKING AND HOW TO MEET
THAT CHALLENGE?
>> WELL, I THINK EVERYONE HAD A
CERTAIN BASELINE OF CONCERN AND
WORRY DURING THE PANDEMIC AND
FOR SOMEONE WHO'S
IMMUNOSUPPRESSED, THERE'S AN
ADDED LAYER ON THAT CAKE.
WHEN VACCINES BECAME AVAILABLE,
I WAS CHOMPING AT THE BIT TO GET
ONE, BUT I KNEW I WOULD NEED TO
DO THAT RESEARCH ON MY OWN.
SO MUCH OF CHRONIC ILLNESS IS
MANAGED OUTSIDE OF A CLINICAL
ENCOUNTER.
THERE'S MONTHS THAT GO BY WHERE
YOU NEED TO BE EDUCATING
YOURSELF.
SO I DID A LOT OF WORK TO MAKE
SURE THAT AN MRNA VACCINE WAS
SAFE AND, OF COURSE, THEN SELF
ADVOCATING TO GET A BOOSTER WHEN
THOSE BECAME AVAILABLE, NOT ALL
IMMUNOSUPPRESSED PEOPLE FALL
INTO THE SAME BUCKET, AND SO
UNDERSTANDING THOSE GRADATIONS,
NAVIGATING THAT.
AND JUST THIS LAST WEEK, THE CDC
CAME OUT AND RECOMMENDED
POTENTIALLY A FOURTH SHOT.
SO YOU KNOW, THE LIST OF WORK
AND TASKS GOES ON.
>> SO LASTLY, JENNIFER, MAYBE
YOU CAN SAY JUST A WORD ABOUT
WHAT PARTICIPATING AND
CONTRIBUTING TO RESEARCH HAS
MEANT FOR ME.
I WANT TO SAY THAT I WAS JUST
THRILLED TO HAVE THE OPPORTUNITY
TO RECRUIT YOU TO OUR RESEARCH
TEAM EARLY ON.
YOU CONTRIBUTED SO MUCH BECAUSE
OF YOUR PERSPECTIVE AS A PATIENT
WHO WAS EXPERIENCING THIS
ILLNESS, AND I JUST HAVE REALLY
VALUED OUR RELATIONSHIP OVER
MANY OF THOSE YEARS.
SO MAYBE YOU COULD SHARE A
LITTLE BIT OF THAT WITH THE
AUDIENCE, AND THEN I THINK WE'LL
HAVE TIME FOR SOME QUESTIONS
BEFORE WE MOVE ON AFTER THAT.
>> THANK YOU.
WELL, AS YOU KNOW, I STUMBLED ON
YOUR RESEARCH STUDIES 23 YEARS
AGO AND ENROLLED, AND IT CHANGED
MY LIFE.
PERSONALLY, WHEN YOU GET A
DIAGNOSIS LIKE SYSTEMIC LUPUS
AND ARE TOLD NO CHILDREN AND ARE
TOLD, YOU KNOW, THAT YOU'LL HAVE
TO JUST LIVE WITH A HIGH RISK OF
STROKE, IT TAKES AWAY A LOT OF
HOPE.
AND I FOUND THAT TAKING PART IN
RESEARCH AS A PATIENT RESTORED
MY HOPE.
MY HOPE THAT THINGS WOULD
IMPROVE.
AND IT ALSO GAVE ME A SENSE OF
CONTROL THAT EVEN IF WE
DEPARTMENT HAVE A CURE, I COULD
HELP MOVE THE BALL DOWN FIELD IN
TERMS OF GETTING CLOSER.
PROFESSIONALLY AS A
COMMUNICATIONS PROFESSIONAL, I
CHANGED MY CAREER 23 YEARS AGO
TO FOCUS EXCLUSIVELY ON MAKING
RESEARCH MORE UNDERSTANDABLE,
MORE ACCESSIBLE TO PEOPLE, AND I
SPENT THE LAST 23 YEARS DOING
JUST THAT.
SO IT'S SOMETHING I REMAIN
COMMITTED TO.
IT IS NOT LOST ON ME THAT MY
TWIN DAUGHTERS ARE NOW THE SAME
AGE, 20, THAT I WAS WHEN I WAS
DIAGNOSED.
I KNOW THERE'S A GENETIC
COMPONENT AND I KNOW WE STILL
DON'T HAVE A CURE.
THAT SAID, I KNOW WE HAVE NEW
MEDICATIONS COMING OUT, RESEARCH
CONTINUES, AND MY HOPE IS THAT
AS MUCH AS COVID INVOLVES THE
IMMUNE SYSTEM, MAYBE BY CHANCE,
THIS PANDEMIC WILL LEAD TO
ADDITIONAL UNDERSTANDING OF THE
ROLE IMMUNE SYSTEM PLAYS IN
ILLNESS.
SO I REMAIN VERY OPTIMISTIC AND
AS COMMITTED AS EVER TO
RESEARCH.
>> GREAT.
WELL, THANK YOU SO MUCH FOR
SHARING YOUR STORY, AND I'M
GOING TO TURN THINGS OVER TO DAN
NOW, I THINK, FOR -- IN CASE
SOME QUESTIONS HAVE COME UP THAT
MAYBE YOU CAN ADDRESS AT THIS
TIME.
>> YES, THEUZ VERY , THANK YOU VERY MUCH,
BOTH JENNIFER AND LINDSEY FOR
THIS WONDERFUL, WONDERFUL
INTERVIEW.
FOR THE QUESTIONS, ANYONE IN THE
AUDIENCE WHO HAS A QUESTION FOR
JENNIFER, YOU JUST HAVE TO
SUBMIT THE QUESTION TO THE "SEND
LIVE FEEDBACK" OPTION IN THE
VIDEOCAST DISPLAY, AND MY
COLLEAGUE KENNY WILL FORWARD
THOSE QUESTIONS TO ME.
RIGHT NOW I DON'T SEE ANY IN THE
CHAT AT THE MOMENT, BUT
JENNIFER, MAYBE I CAN ASK A
COUPLE OF QUESTIONS WHILE WE'RE
WAITING FOR SOME TO COME IN.
SO THAT WAS REALLY A VERY, VERY
MOVING AND RIVETTING ACCOUNT OF
WHAT HAPPENED.
CAN YOU TELL US A LITTLE BIT
MORE ABOUT OVER THE COURSE YOUR
ILLNESS, WHAT ABOUT LUPUS HAS
HAD THE BIGGEST IMPACT ON YOUR
LIFE?
>> I THINK THE FACT THAT LUPUS
HAS SO MANY DIFFERENT -- IT'S
CHARACTERIZED BY FLARE AND
REMISSION, AND STRESS CAN CAUSE
THE DISEASE TO FLARE.
WHO AMONG US DOESN'T EXPERIENCE
STRESS?
AND SO I THINK ASIDE FROM
DEALING WITH SOME OF THE
PHYSICAL CHALLENGES AROUND
ARTHRITIS PAIN, WHICH CAN BE
SIGNIFICANT AND GET IN THE WAY
OF SORT OF ACTIVITIES OF DAILY
LIVING, THE FACT THAT ONE NEEDS
TO CONSTANTLY MONITOR EXPOSURES
TO SUN, I LIVE IN CALIFORNIA,
THAT CAN BE A CHALLENGE, STRESS,
BUT HOW DO YOU BALANCE THAT WITH
LIVING A FULL LIFE?
HOW DO YOU BALANCE THAT WITH
KNOWING THAT YOU COULD HAVE A
STROKE.
YOU JUST HAVE TO INTEGRATE IT
INTO YOUR LIFE.
IT'S LIKE AN UNWANTED GUEST THAT
MOVES IN, AND YOU JUST NEED TO
LEARN TO ACCOMMODATE IT.
SO I WILL SAY MENTALLY IT CAN
BE -- IT CAN TAKE A TOLL ON YOUR
MENTAL HEALTH, AND I HAD
PARTICULARLY EARLY ON, A
STRUGGLED WITH DEPRESSION,
TRYING TO FIGURE OUT HOW TO LEAD
THE LIFE I WANTED TO WHILE
HAVING THIS DISEASE.
>> YES, I CAN IMAGINE.
AT LEAST FROM MY RECOLLECTION,
YOU SAID THAT YOU WERE DIAGNOSED
AT THE END OF YOUR SECOND YEAR
OF COLLEGE, SO THERE WERE
PROBABLY SIGNIFICANT STRESSES
JUST IN TERMS OF EXAMS AND
VARIOUS DEADLINES THAT YOU HAD
AS PART OF COLLEGE AND I CAN
JUST IMAGINE PSYCHOLOGICALLY IF
YOU START TO THINK THAT THE
STRESS IS GOING TO INDUCE A
FLARE-UP, THEN YOU GET STRESSED
WORRYING ABOUT THE STRESS.
>> SPOT ON.
IT'S A VICIOUS CYCLE.
>> WHILE WE WERE TALKING,
SOMEONE HAS SENT US A QUESTION.
AND IT IS: HOW IMPORTANT IS TO
JENNIFER THAT RESEARCH BE HONEST
WITH ITS SUBJECTS?
GIVING YOU SOME FEEDBACK IN
TERMS OF THE RESULTS AND WHAT
THEY MEAN, WHETHER THEY BE
PROMISING OR NOT PROMISING.
>> IT'S ABC LIGHT ESSENTIAL ABSOLUTELY ES SENTIAL,
AND I WANT TO ACKNOWLEDGE
SOMETHING THAT DR. CRISWELL
SAID, WHICH IS THAT SHE SAW IT
AS A PRIORITY TO INVOLVE
PATIENTS IN RESEARCH, AND I
THINK WHEN PATIENTS ARE SEEN AS
CO-PARTNERS IN RESEARCH, I NOPA
CORY DOES I KNOW
PCORI DOES A GREAT JOB OF THE
MODEL.
PATIENTS ARE CAPABLE, THEY'RE
THE ONES LIVING WITH THE
DISEASE, THEY CAN HANDLE THAT
NEWS.
AND I THINK BEING HONEST BUT
HAVING AN EVOLVING RELATIONSHIP
WITH A PATIENT DURING THE STUDY,
NOT JUST RECRUITMENT BUT
FOCUSING ON RETENTION AND
INFORMATION, HAVING THAT OPEN
TRANSPARENT DIALOGUE IS
ESSENTIAL.
>> YES, I CERTAINLY AGREE WITH
THAT.
HOW ABOUT PATIENT ADVOCACY
GROUPS?
HAVE YOU BEEN INVOLVED IN THEM?
IT SOUNDS LIKE PROBABLY YOU
HAVE, AND WHAT IS THE ROLE OF
THAT, IN THE WHOLE PROCESS OF
LIVING WITH A CHRONIC DISEASE.
>> I WAS HEAVILY INVOLVED IN
PATIENT ADVOCACY GROUPS,
PARTICULARLY WHEN I WAS WORKING
ON DR. CRISWELL'S STUDIES
BECAUSE THEY CAN BE SUCH A RICH
SOURCE OF RECRUITMENT FOR
RESEARCH.
I CAN TELL YOU I SUBSCRIBE TO
MANY DIFFERENT LUPUS FOUNDATION
OF AMERICA, THE AUTOIMMUNE
DISEASE SOCIETY NEWSLETTERS JUST
TO SAY INFORMED.
I REFERENCE THE FACT A LOT OF
THE WORK FALLS ON PATIENTS, SO
ONE THING I'LL STRESS IS THESE
ADD VO
ADVOCACY GROUPS DO A GREAT JOB
OF COMMUNICATING IN PLAIN
LANGUAGE.
THAT IS THE EMPHASIS OF MY
PROFESSIONAL LIFE BUT IT IS
ABSOLUTELY ESSENTIAL TO HELP
PEOPLE BE ENGAGED BECAUSE IF YOU
CAN'T UNDERSTAND, YOU CANNOT BE
ENGAGED.
>> YES, AND A LOT OF TIMES THE
MEDICAL JARGON, EVEN IF THE
PHYSICIANS THINK THAT THEY'RE
SPEAKING IN PLAIN LANGUAGE, IT
MAY BE PLAIN TO THEM BUT NOT TO
ANYBODY ELSE.
CAN YOU SPEAK TO SOME OF THE
BIGGEST COMMUNICATION ISSUES
BETWEEN PATIENTS WITH LUPUS AND
PHYSICIANS?
>> JARGON.
I WILL SAY THIS, THE NUMBER ONE
PIECE OF ADVICE I CAN GIVE AND
HAVE GIVEN OVER THE YEARS AS A
PATIENT ADVOCATE IS TO NOT BE
AFRAID OR ASHAMED TO SAY I DON'T
UNDERSTAND, CAN YOU SAY THAT
AGAIN IN PLAIN LANGUAGE.
IT IS ABC ABSOLUTELY ESSENTIAL IF
YOU WANT A PATIENT TO BE ABLE TO
LEAVE YOUR OFFICE AND -- I HATE
USING THE WORD ADHERE, BUT TAKE
THE MEDICATION, GO GET THE TESTS
DONE, THERE HAS TO BE
UNDERSTANDING, THERE HAS TO BE
BUY-IN.
SO IF YOU DON'T HAVE A PROVIDER
THAT'S SKILLED IN PLAIN
LANGUAGE, DON'T BE AFRAID TO ASK
FOR THAT, AND ALSO EMPLOYING
TEACHBACK, SAYING AS A PATIENT,
HERE'S WHAT I HEARD YOU SAY, IS
THIS CORRECT, IS THIS WHAT I
NEED TO DO.
AND PROVIDERS SHOULD BE DOING
THAT AS WELL.
>> SO THOSE ARE VERY WISE PIECES
OF ADVICE.
SO WE HAVE A COUPLE MORE
QUESTIONS AND THEN I THINK WE'LL
MOVE THINGS BACK TO
DR. CRISWELL, AND THERE WILL BE
OPPORTUNITY AT THE END FOR
PEOPLE TO ASK QUESTIONS AS WELL.
BUT QUESTION NUMBER THREE IS
WHAT HAS BEEN THE VALUABLE
STRATEGY IN MANAGING THE IDEA
THAT YOU CANNOT ESCAPE SOMETHING
THAT IS INHERENT IN YOUR OWN
BODY.
HAVE YOU FOUND MEDITATION,
THERAPY OR SOMETHING ELSE
HELPFUL?
>> WE HAVE TOO MUCH STIGMA IN
THIS COUNTRY AROUND MENTAL
HEALTH, SO I HESITATE TO SHARE,
I SOUGHT THERAPY TO HELP ME
LEARN COPING MECHANISMS STO
LEARN TO BE AT PIECE WITH IT.
YOU CAN'T FIGHT SOMETHING THAT'S
IN YOUR BODY AND AVOID BEING
STRESSED AND DRIVEN TO THE
BREAK.
SO I HAD TO LEARN TO COPE AND
DEVELOP A MORE RESPECTFUL
RELATIONSHIP WITH THE DISEASE
HAS CERTAIN NEEDS, SOMETIMES I
HAVE TO PAUSE AND TEND TO THE
DISEASE'S NEEDS.
BUT IT DOESN'T MEAN THAT THOSE
NEEDS ARE PARAMOUNT AND OVERRIDE
WHAT I WANT TO DO.
IT'S A LITTLE BIT OF A TRADEOFF
BUT I CAN TELL YOU 30 YEARS IN,
IT IS AN ONGOING PROCESS, AND
CAN STILL BE A STRUGGLE.
>> YEAH, THAT'S FOR SURE.
OKAY.
WELL, I'LL JUST ASK THE LAST OF
THE QUESTIONS NOW THAT'S COME
IN.
GIVEN THAT ELECTRONIC RECORDS
ARE COMMONLY AVAILABLE, WHAT DO
YOU SEE AS THE IMPEDIMENT TO
THEIR UNIFORM ADOPTION AND THE
NEED FOR THE PATIENT TO SHOULDER
THE RESPONSIBILITY TO TRANSFER
THEIR OWN RECORDS?
WHY CAN'T WE JUST HAVE A GOOD
ELECTRONIC MEDICAL RECORD SYSTEM
THAT IS UNIVERSALLY APPLIED?
>> SUCH A SIMPLE CONCEPT.
WE HEAR THE TERM
INTEROPERABILITY THROWN OUT A
LOT AND OCCASIONALLY YOU HEAR
PEOPLE SAY WE'RE THERE ALREADY.
I'M GOING TO USE AN EXAMPLE, I'M
GOING TO NAME A NAME HERE, AND
THAT'S HE PICK.
FOR EXAMPLE, MANY OF THE HEALTH
SYSTEMS ARE IN EPIC.
IN THE COURSE OF FOUR YEARS, I
WAS AT THREE DIFFERENT HEALTH
SYSTEMS, ALL USED EPIC.
AND MY RECORDS WERE NEVER FULLY
INTEGRATED BECAUSE IT IS AT THE
HEALTH SYSTEM LEVEL, THIS
HESITANCY TO PULL IN ALL OF THAT
DATA FROM HEALTH SYSTEM A WHEN
YOU'RE AT HEALTH SYSTEM B.
I UNDERSTAND IT'S TECHNICALLY
POSSIBLE BUT SHOULD A PROVIDER
BE SPENDING THEIR PRECIOUS TIME
DOING THAT?
SHOULD IT BE AT THE SYSTEM
LEVEL?
WE NEED SYSTEMS TO REALLY COMMIT
TO MAKING THAT EASIER THAT THAT
INFORMATION IS PRESENT SO DOCTOR
AND PATIENT CAN MAKE THE BEST
SHARED DECISIONS DURING THE
LIMITED TIME THEY HAVE TOGETHER.
>> YEAH, MAKING THE BEST USE OF
THEIR TIME BECAUSE IF YOU SPEND
ALL YOUR TIME FUMBLING AROUND
TRYING TO FIGURE OUT WHAT THE
RECORD SHOWS, THEN IT'S TIME TO
MOVE ON.
THAT'S NOT A GOOD SITUATION AT
ALL.
ALL RIGHT.
WELL, THAT'S IT FOR THE
QUESTIONS THAT WE HAVE.
JENNIFER, THANK YOU SO, SO MUCH.
I REALLY -- WE ALL REALLY
APPRECIATE YOUR BEING HERE AND
IT'S JUST SUCH A IMPORTANT
THING, ESPECIALLY WHEN WE'RE
TALKING ABOUT HUMAN ILLNESS TO
ACTUALLY HAVE -- TO PUT A FACE
ON IT.
SO THANK YOU SO, SO MUCH.
>> THANK YOU.
>> ALL RIGHT.
CAN YOU SEE MY SLIDES AGAIN,
EVERYBODY?
>> YES.
>> AND HEAR ME OKAY?
SO THANKS AGAIN, JENNIFER.
THAT WAS WONDERFUL.
SO AS I MENTIONED, THERE'S NO
PATHOGNOMIC TEST FOR LUPUS.
AND WHAT PHYSICIANS FACE WHEN
TRYING TO DETERMINE WHETHER
INDIVIDUALS HAVE LUPUS IS THEY
CONSIDER A LONG LIST OF
MANIFESTATIONS, CLASSIFICATION
CRITERIA, AND IN THE CASE OF
LUPUS, ALTHOUGH THESE HAVE BEEN
REVISED RECENTLY, THE WAY TO
DETERMINE SOMEONE MEETS CRITERIA
FOR LUPUS IS TO CONSIDER THESE
11 CRITERIA, AND THEN ASK THE
QUESTION, OKAY, WELL, HAVE AT
LEAST FOUR OF THESE BEEN
PRESENT?
AND IF SO, YES, THIS PERSON CAN
BE CLASSIFIED AT LUPUS, THEN IF
NOT, NO.
BUT IT'S EASY TO UNDERSTAND THE
GREAT HETEROGENEITY OF THE
DISEASE WITH SUCH WIDE RANGING
MANIFESTATIONS.
NOW I HIGHLIGHTED IN BOLD THE
MANIFESTATIONS THAT JENNIFER
HAD, SO SHE MET SEVEN OUT OF
THESE 11 BUT HAS NOT HAD ANY
EVIDENCE OF RENAL INVOLVEMENT
OVER 30 YEARS, FOR EXAMPLE, AND
HASN'T EXPERIENCED SOME OF THE
OTHER MANIFESTATIONS.
SO TREMENDOUS HETEROGENEITY AND
CHALLENGES FOR DIAGNOSIS.
SHE ALSO HAD LOW LEVELS LIKELY
RELATED TO THE VERY SERIOUS
PREGNANCY COMPLICATION THAT SHE
HAD, THE HELLP SYNDROME.
SO REALLY COMPLICATED DISEASE.
SO NOW WHAT ABOUT GENETIC
FACTORS?
SOME OF THE EARLIEST INSIGHT TO
THE IMPORTANCE OF GENETICS CAME
FROM TWIN STUDIES.
PICTURED HERE ARE TWO SETS OF
IDENTICAL TWIN GIRLS.
THEY'RE ACTUALLY VERY HEALTHY.
THEY HAPPEN TO BE JENNIFER'S
TWINS IN THE MIDDLE AND MY TWINS
ON THE OUTSIDE.
WE HAD TWINS ABOUT FOUR MONTHS
APART.
AND IT'S STUDIES OF CONCORDANCE
FOR DISEASE IN TWINS THAT GIVES
US SOME INSIGHT INTO THE
STRENGTH OF THE GENETIC
CONTRIBUTION TO LUPUS.
NOW, FOR LUPUS, LIKE MANY
COMPLEX DISEASES, THE
CONCORDANCE FOR THE DISEASE
AMONG IDENTICAL TWINS IS ONLY
ABOUT 20 OR 25%.
SO MUCH OF THE DISEASE RISK
RELATES TO NO KNACK FACTORS OTHER THAN
GENETICS.
THE CONCORDANCE FOR FRATERNAL
TWINS IS MUCH LESS, THE
CONCORDANCE AM SIBLINGS OF AN
AFFECTED INDIVIDUAL, EVEN
SMALLER.
NOW IN SPITE OF THE FACT THAT
GENETICS HAD A CLEAR-CUT ROLE,
IT WAS PAINSTAKINGLY SLOW TO TRY
TO IDENTIFY GENETIC FACTORS
UNTIL IT BECAME POSSIBLE TO
PERFORM GENOME-WIDE ASSOCIATION
STUDIES WHEN WE COULD LOOK AT
LARGE NUMBERS OF VARIANTS IN
WELL CHARACTERIZED SETS OF CASES
AND CONTROLS.
AND FOLLOWING THAT CAPABILITY,
THERE'S BEEN JUST AN EXPLOSION
OF THE IDENTIFICATION OF GENES
FOR LUPUS AND OTHER AUTOIMMUNE
DISEASES.
THIS IS A SNAPSHOT FROM A FEW
YEARS AGO TO SHOW YOU HOW
RAPIDLY PROGRESS OCCURRED.
THIS IS A META-ANALYSIS OF
ALMOST 6,000 LUPUS PATIENTS,
OVER 13,000 CONTROLS, ALL OF
EUROPEAN ANCESTRY IN THIS CASE,
IDENTIFYING 63 RISK SIGNALS.
AND JUST TO ORIENT YOU TO THIS
MAN
MANHATTAN PLOT, EVERY DOT ON THE
SLIDE IS A GENETIC VARIANT.
THE STRENGTH OF THE ASSOCIATION
WITH THE DISEASE IS SHOAP ON SHOWN ON THE
Y AXIS.
CONTRIBUTIONS FOR MANY, MANY,
MANY OTHER GENES.
SOME REALLY STRIKING FINDINGS
FROM THE EMERGING TB. WAS EMERGING STUDIE S IN
LUPUS AND OTHER DISEASES, IT WAS
POSSIBLE TO IDENTIFY A LARGE
NUMBER OF GENES IN A SINGLE
EXPERIMENT.
ALL OF THESE LOCI WERE IDENTIFY
JUST IN THE CONTEXT OF THAT
SINGLE STUDY, BUT MANY OF THEM,
MORE THAN HALF, WERE BEING
IDENTIFIED IN THE CONTEXT OF
GWAS STUDIES OF OTHER AUTOIMMUNE
DISEASES, EVEN THOSE WITH VERY
DIFFERENT CLINICAL
MANIFESTATIONS.
SO A LOT OF SHARED RISK ACROSS
VERY HETEROGENEOUS SETS OF
DISEASES.
ANOTHER VERY STRIKING FINDING
WAS THE THE EXTENT TO WHICH GENES
RELATED TO THE TOLL LIKE
RECEPTOR INTERFERON TYPE
1 SIGNALING PATHWAY, SIMPLIFIED
AND ILLUSTRATED HERE IN A SIMPLE
WAY ON THIS SLIDE, WERE BEING
IDENTIFIED IN GENETIC STU STUDIES.
VIRTUALLY EVERY GENE WAS
REPRESENTED HERE HAS BEEN
DEMONSTRATED TO BE ASSOCIATED
WITH LUPUS.
NOW I'M GOING TO HIGHLIGHT, I'LL
POINT OUT JUST A COUPLE,
INCLUDING STAT 4 OVER HERE AND
IRF-5, BUT VIRTUALLY ALL OF
THESE GENES HAVE BEEN ASSOCIATED
WITH THE GENETIC CONTRIBUTION TO
LUPUS.
NOW, I'VE BEEN TALKING ABOUT THE
HETEROGENEITY OF THE DISEASE.
STAPH 4, 1 OF THE VERY FIRST
GENES TO BE IDENTIFIED IN THE
LAST DECADE OR SO, PROVIDED US
WITH GREAT INSIGHT TO THE EXTENT
TO WHICH GENETIC VARIATIONS
WOULD VARY.
WE HAD THE OPPORTUNITY TO LOOK
AT THE STAT4 RISK VARIANT, FIRST
IDENTIFIED FOR RHEUMATOID
ARTHRITIS.
WE SAID, GEE, IS IT ASSOCIATED
WITH LUPUS?
IF SO, PERHAPS ESPECIALLY AMONG
PATIENTS WITH ARTHRITIS.
WELL, IN FACT, TRFS THERE WAS NO
ASSOCIATION WITH LUPUS FOR STAT4 BUT A VER Y STRONG
ASSOCIATION, LARGE, HIGH ODDS
RATIOS AMONG INDIVIDUALS WITH
RENAL DISEASE AND EARLY AGE OF
ONSET.
SO THAT GAVE US INSIGHT INTO THE
EXTENT TO WHICH GENES WOULD
INFLUENCE THE SPECIFIC
MANIFESTATIONS PRESENT.
SO WE OVER THE ENSUING YEARS
WERE ABLE TO REANALYZE GWA DATA
BROKEN DOWN FOO SUBSETS OF
DISEASES, TO TRY TO UNDERSTAND
THE GENETIC DIFFERENCES.
WHAT I'VE SHOWN HERE ARE TWO
MANHATTAN PLOTS NOW, FROM THREE
STUDIES WHERE WE'RE LOOKING JUST
AT DOUBLE STRANDED DNA POSITIVE
PATIENTS HERE AND ONLY A DOUBLE
STRANDED DNA NEGATIVE PATIENT
HERE, AND YOU CAN SEE THE
STRIKING DIFFERENCES IN THE
GENETIC CONTRIBUTION TO THESE
DISEASES.
HUGE MAC CONTRIBUTION, CRACKS
FROM STAT 4, VERY MODEST
ASSOCIATION WITH DOUBLE STRAND
NEGATIVE DISEASE.
WE ALSO LOOKED AT RENAL DISEASE.
HERE WE'RE ASKING ONCE YOU HAVE
LUPUS, WHAT ARE THE GENES THAT
ARE GOING TO INFLUENCE WHETHER
OR NOT YOU DEVELOP SIGNIFICANT
RENAL INVOLVEMENT, A REALLY
FEARED MANIFESTATION.
WHAT WAS SURPRISING HERE WAS THE
EXTENT TO WHICH THE GENES THAT
CONTRIBUTED TO DEVELOPMENT OF
NEPHRITIS ARE DISTINCT FROM
THOSE THAT INFLUENCE YOUR
OVERALL RISK OF LUPUS.
NOTICE THE VERY MODEST HLA
CONTRIBUTION, AND MANY OTHER
GENES THAT WEREN'T ON OUR RADAR
SCREEN FROM THE CASE CONTROL
STUDIES.
IT ALSO BECAME POSSIBLE TO ASK,
WHAT IS THE INFLUENCE OF THE
NUMBER OF RISK VARIANTS AN
INDIVIDUAL HAS INHERITED?
WHEN WE LOOKED AT INDIVIDUALS
ACCORDING TO THE NUMBER OF
ESTABLISHED RISK VARIANTS AND WE
ASKED, WHAT WERE THEIR DISEASE
CHARACTERISTICS, IT WAS
STRIKING, THE EXTENT TO WHICH
CERTAIN DISEASE MANIFESTATIONS
SUCH AS DOUBLE STRANDED DNA
ANTIBODIES, OTHER IMMUNOLOGIC
MANIFESTATIONS, RENAL DISEASE TO
A CERTAIN EXTENT, WERE INCREASED
AM
AMONG THOSE WITH A HIGH GENETIC
BURDEN, A HIGH NUMBER OF RISK
VARIANTS, WHEREAS OTHER
MANIFESTATIONS WERE NOT
INCREASED SIGNIFICANTLY AMONG
INDIVIDUALS WITH A LARGE GENETIC
RISK SCORE.
SO WE KNOW GENETICS IS NOT THE
ENTIRE ANSWER.
THERE'S BEEN A LONG HISTORY OF
STUDIES OF ENVIRONMENTAL FACTORS
THAT CONTRIBUTE TO THE DISEASE,
BUT RESEARCH IN THAT AREA IS
VERY CHALLENGING.
THAT IN PART HAS PROMPTED
INTEREST IN LOOKING AT EP GENIC
GENETIC FACTORS.
THESE ARE FACTORS THAT INFLUENCE
GENE EXPRESSION BUT DON'T
INVOLVE MODIFICATIONS TO THE DNA
NUCLEOTIDE SEQUENCE.
I'M GOING TO FOCUS ON DNA
METHYLATION BECAUSE OF ITS LINK
TO THE ENVIRONMENT.
BUT THE HOPE HERE IS THAT EB
GENETIC FACTORS HELP TO EXPLAIN
NOT ONLY THIS MISSING
HERITABILITY, NOT DEFINED BY
GENETIC RISK VARIANTS, BUT ALSO
HELP TO FILL OUT THE TOTALITY OF
THE CONTRIBUTION TO THE DISEASE.
THIS IS CONSISTENT WITH A
LONG-STANDING MODEL IN WHICH
GENETIC PREDISPOSITION OVER TIME
EVENTUALLY LEADS TO DISEASE IN
THE CONTEXT OF APPROPRIATE
ENVIRONMENTAL FACTORS, PERHAPS
MEDIATED BY EPIGENETIC
MODIFICATION.
SO WHY LOOK AT DNA METHYLATION?
WELL, IT HAS PROFOUND INFLUENCES
ON GENE EXPRESSION, AND IT'S
BOTH INHERITED AND ALSO AFFECTED
BY THE ENVIRONMENT.
DNA METHYLATION OCCURS AT THESE
SO CALLED GPC SITES, WHERE YOU
HAVE CYTOSINE FOLLOWED BY A
GUANINE.
IT INFLUENCES LEVELS OF GENE
EXPRESSION.
NOW THE VERY FIRST BACK TO TWINS
AGAIN, THE VERY FIRST
METHYLATION STUDY IN LUPUS WAS A
SMALL STUDY COMPARING DISCORDANT
IDENTICAL TWINS, FIVE SETS OF
IDENTICAL TWINS, DISCORDANT FOR
THE DISEASE, AND A SET OF FIVE
MATCH CONTROL INDIVIDUALS.
WHAT THE INVESTIGATORS DID HERE
A DECADE AGO NOW IS THEY LOOKED
AT 800 METHYLATION SITES ACROSS
THE GENOME AND THEY COMPARED
LEVELS OF DNA METHYLATION STATUS
BETWEEN THE TWO TWINS WITH AND
WITHOUT LUPUS AND THE HEALTHY
CONTROLS.
OVERALL, THE LUPUS TWINS HAD
MUCH LOWER LEVELS OF METHYLATION
GLOBALLY AND 50 GENES, MANY OF
WHICH HAVE ROLES IN THE IMMUNE
SYSTEM.
SO RESEARCH IN THIS AREA
PROGRESSED RAPIDLY, LOOKING AT
GREATER AND GREATER NUMBER OF
CPG SITES, 28,000 METHYLATION
SITES IN THIS STUDY, LARGER SETS
OF INDIVIDUALS WITH A SIMILAR
PATTERN.
SIGNIFICANTLY DIFFERENTIALLY
METHYLATED GENE REGIONS BETWEEN
LUPUS AND CONTROL INDIVIDUALS,
OFTEN HIGHLIGHTING GENES
RELEVANT TO THE IMMUNE SYSTEM
AND INFLAMMATORY PATHWAYS.
NOW THE BIGGEST OF THESE SO
CALLED EWA STUDIES WAS A SWEDISH
STUDY LOOKING AT 450,000 CPG
SITES.
72,000 -- 7200 DIFFERENTIALLY
METHYLATED SITES, MANY IN THE
TYPE 1 INTERFERON GENES, AND
MANY INFLUENCED BY GENETIC
VARIATION, AND SOME OF THOSE
GENES CORE CORRESPONDED TO RISK LOCI.
NOW WHAT ABOUT DNA METHYLATION
AND DISEASE MANIFESTATIONS?
I SHARED SOME WORK IN THE
GENETIC STUDIES SHOWING HOW
DIFFERENT THE GENETIC
CONTRIBUTION IS ACCORDING TO THE
CLINICAL MANIFESTATIONS.
WHAT ABOUT DNA METHYLATION
PATTERNS?
WE'VE NOW HAD THE OPPORTUNITY TO
PERFORM EPIGENOME-WIDE
ASSOCIATION STUDIES IN WELL
CHARACTERIZED INDIVIDUALS WITH
LUPUS SO THAT WE CAN ASK WHETHER
PATTERNS OF DNA METHYLATION ARE
DIFFERENT.
FOR EXAMPLE, BETWEEN INDIVIDUALS
WITH DOUBLE STRANDED DNA
POSITIVE DISEASE AND DOUBLE
STRANDED DNA NEGATIVE DISEASE.
THIS SLIDE SUMMARIZES RESULTS
FOR OVER 300 SUCH INDIVIDUALS.
WHAT'S BEEN STRIKING TO US IS
NOT ONLY THE NUMBER OF
STATISTICALLY SIGNIFICANT
METHYLATION DIFFERENCES BETWEEN
THESE SUBSETS OF THE DISEASE,
BUT THE NUMBER THAT HAD NOT --
THAT HIGHLIGHT GENE REGIONS THAT
WERE NOT ON OUR RADAR SCREEN
FROM GENETIC STUDIES, ALSO
PROMINENCE OF TYPE I INTERFERON
BETWEEN GENES, AND THE MODEST
CONTRIBUTION OF THE MHC REGION
COMPARED TO GENETIC STUDIES.
SO WE'VE LOOKED AT AUTO ANTIBODY
PROFILES, WE'VE LOOKED AT RENAL
DISEASE.
ONCE AGAIN, A VERY IMPORTANT
DISEASE MANIFESTATION, WE SEE
ALMOST 20 SIGNIFICANTLY
DIFFERENTIAL -- PATIENTS THAT DO
AND DON'T DEVELOP RENAL DISEASE.
IN THIS CASE, THE GENE REGIONS
THAT ARE DIFFERENTIALLY
METHYLATED HIGHLIGHT PATHWAYS
RELATED TO TISSUE HYPOXIA AND
TYPE 1 INTERFERON RESPONSES.
SO AS YOU CAN IMAGINE, TO
CONTINUE WORK IN THIS AREA, IT'S
CRITICALLY IMPORTANT TO HAVE
ACCESS TO DEEPLY PHENOTYPE
INDIVIDUAL.
FORTUNATE TO UTILIZE A DEEPLY
PHENOTYPED MULTIETHNIC COHORT
THAT WAS DEVELOPED THANKS TO
FUNDING FROM THE CENTERS FOR
DISEASE CONTROL AND PREVENTION
AND LED BY MY COLLEAGUES AT
UCSF, AND WE HAVE BEEN
CHARACTERIZING THESE INDIVIDUALS
FOR GENOME-WIDE GENETICS,
EPIGENETICS, AND OTHER OMICS TO
HELP US BETTER UNDERSTAND
HETEROGENEITY OF THE DISEASE,
INCLUDING GREATER INSIGHT INTO
THE RACE AND ETHNIC DIFFERENCES
IN THE DISEASE.
SO I'LL VERY BRIEFLY SUMMARIZE
SOME OF OUR WORK RELATED TO THE
CLUES COHORT.
WE DECIDED INSTEAD OF LOOKING
INDIVIDUAL DISEASE
MANIFESTATIONS, WE KNOW MANY ARE
CORRELATED WITH EACH OA THEY
CLUSTER TOGETHER.
SO WE CONSIDERED ALL THE ACR
CRITERIA AND THE SUBCRITERIA
THAT HAD BEEN CHARACTERIZED FOR
INDIVIDUALS AND WE ASKED WHETHER
THERE WERE NATURAL CLUSTERS OF
INDIVIDUALS BASED ON BE THESE
MANIFESTATIONS.
INDEED THREE CLUSTERS EMERGED
FROM THE DATA, WHICH WE HAVE
LABELED MILD BECAUSE OF THE
ABSENCE OF SIGNIFICANT INTERNAL
ORGAN INVOLVEMENT AND TWO THAT
ARE PRIMARILY DIFFERENT IN TERMS
OF HEMATOLOGIC MANIFESTATIONS.
SO BOTH HAVE SIGNIFICANT RENAL
INVOLVEMENT BUT THEY DIFFER IN
TERMS OF THE HEMATOLOGIC
MANIFESTATION.
SO THREE CLUSTERS OF INDIVIDUALS
BASED ON THE PATTERNS OF THESE
MANY MANIFESTATIONS.
SO THEN WE ASKED THE QUESTION,
WELL, DO THESE CLUSTERS DIFFER
IN TERMS OF THEIR METHYLATION
PATTERNS.
LOOKING GENOME-WIDE AND
ACCOUNTING FOR OTHER FACTORS
THAT WOULD INFLUENCE METHYLATION
STATUS, AGE, SPOKING STATUS,
CELL COMPETITION, ET CETERA, WE
FOUND -- ONCE AGAIN MANY OF
WHICH MAPPED TO THE TYPE
1 INTERFERON PATHWAY.
FORTUNATELY WE HAD ACCESS TO AN
INDEPENDENT COHORT THAT ALLOWED
US TO CONFIRM THESE ASSOCIATIONS
BETWEEN DNA METHYLATION STATUS
AND CLINICAL CLUSTERS.
NOW WE CAN ALSO LEVERAGE THIS
DATA BY MAPPING THOSE 256 SITES
TO GENES AND THEN PERFORMING
PATHWAY ANALYSIS.
THAT SORT OF ANALYSIS
DEMONSTRATES SIGNIFICANT
ENRICHMENT OF GENES ASSOCIATED
WITH INTERFERON TYPE
1 SIGNALING, ANTIVIRAL
RESPONSES, AND NUMEROUS
INFLAMMATORY PATHWAYS.
NOW ONCE AGAIN, AS I'VE
HIGHLIGHTED, MANY OF THE GENE
REGIONS HIGHLIGHTED METHYLATION
STUDIES ARE DISTINCT FROM THOSE
THAT WE SEE IN ASSOCIATION
STUDIES, GIVING US ANOTHER
PERSPECTIVE ON CONTRIBUTIONS TO
THE DISEASE.
SO NOW ONCE AGAIN I'VE BEEN
FOCUSING ON DNA METHYLATION AS
AN IMPORTANT CLUE TO THE
ENVIRONMENT FOR CONTRIBUTION TO
THE DISEASE.
WHY IS THAT?
PATTERNS OF DNA METHYLATION ARE
GENERALLY STABLE, BUT THEY CAN
BE INTERRUPTED.
FOR EXAMPLE, AS A RESULT OF
OXIDATIVE STRESS OR OTHER
ENVIRONMENTAL EXPOSURES.
AND THERE'S A LONG HISTORY OF
ENVIRONMENTAL TRIGGERS FOR
LUPUS.
AND IT'S VERY DIFFICULT IN THE
CONTEXT OF THESE EPIDEMIOLOGIC
AND OBSERVATION STUDIES TO
REALLY DEMONSTRATE CAUSATION,
NOT TO MENTION TO UNDERSTAND
UNDERLYING MECHANISMS.
SO THERE'S GREAT HOPE THAT
EPIGENETIC CHANGE WILL EXPLAIN
SOME OF THESE ENVIRONMENTAL
ASSOCIATIONS WITH THE DISEASE
AND THAT FURTHER ANALYSIS OF
EPIGENETIC PATTERNS WILL PROVIDE
GREATER INSIGHT INTO OTHER
ENVIRONMENTAL CONTRIBUTIONS TO
THE DISEASE.
AND IN FACT, THERE'S A LOT OF
INTEREST IN THIS AREA, AND A
NUMBER OF EXPOSURES THAT HAVE
BEEN IMPLICATED IN STUDIES OF
LUPUS HAVE NOW BEEN SHOWN TO BE
ASSOCIATED WITH DNA METHYLATION
CHANGES.
PROVIDING PROMISE THAT THIS IS
GOING TO BE AN INFORMATIVE AREA
OF FUTURE RESEARCH.
I WOULD DRAW YOUR ATTENTION TO
THIS REALLY NICE REVIEW OF THE
SUBJECT RECENTLY BY CHRISTINA
LINATA AND COLLEAGUES.
NOW LASTLY, I'VE ALLUDED TO THE
FACT THAT IT'S CHALLENGING TO
UNDERSTAND THE ENVIRONMENTAL
CONTRIBUTION TO THE DISEASE.
BUT THERE'S RENEWED INTEREST IN
THIS CONCEPT OF THE EXPOSOME
THAT'S MEANT TO REFLECT THE
TOTALITY OF EXPOSURES ACROSS THE
LIFE COURSE, INCLUDING ALL SORTS
OF EXTERNAL AND INTERNAL
EXPOSURES.
THE HOPE IS THAT BY
CHARACTERIZING THE EXPOSOME IN
HEALTH AND DISEASE, WE CAN HAVE
A MORE COMPREHENSIVE AND
ACCURATE WAY OF UNDERSTANDING
HOW THE ENVIRONMENT CONTRIBUTES
TO THE DISEASE INCLUDING THE
RELATIONSHIP TO EPIGENETIC
FACTORS.
SO WE'RE REALLY EXCITED ABOUT
THE FACT THAT THERE ARE NOW
NON-TARGETED APPROACHES TO VERY
COMPREHENSIVELY CHARACTERIZE THE
EXPOSOME IN LUPUS AND OTHER
AUTOIMMUNE DISEASES AND WE'RE
EXCITED TO SEE HOW THOSE
STUDIES, WHAT THEY TELL US ABOUT
THE DISEASE LUPUS.
SO LET ME JUST CONCLUDE MY
COMMENTS BY THANKING MY MANY
COLLEAGUES, ESPECIALLY JOANNE,
LISA, CHRISTINA, SHARON AND KIM
WHO CONTRIBUTED VERY IMPORTANTLY
TO THE STUDIES I MENTIONED, MY
LONG LIST OF OTHER COLLABORATORS
FROM AROUND THE WORLD, MANY
NON-PROFIT ORGANIZATIONS, AND
PERHAPS MOST IMPORTANTLY, THE
MANY PATIENTS WITH LUPUS AND
THEIR FAMILY MEMBERS WHO HAVE
CONTRIBUTED SO SIGNIFICANTLY TO
OUR RESEARCH AND PROVIDED SUCH
GREAT INSPIRATION, AND ONCE
AGAIN, THANKS TO JENNIFER FOR
SHARING HER STORY HERE TODAY.
>> WELL, KNEW THANK YOU SO MUCH,
DR. CRISWELL, FOR THAT FANTASTIC
PRESENTATION, AND AGAIN, THANK
YOU, JENNIFER, FOR BEING WILLING
TO TELL US A LITTLE BIT ABOUT
WHAT IT'S LIKE TO HAVE LUPUS.
SO AT THIS POINT, WE'LL TURN
THINGS OVER TO OUR SECOND
SPEAKER, DR. HOLLAND.
STEVE, TAKE IT AWAY.
>> ALL RIGHT.
THANK YOU VERY MUCH, DAN,
LINDSEY AND JENNIFER.
THAT WAS REALLY AN EXTRAORDINARY
STORY, BOTH FROM THE PATIENT
STANDPOINT AND FROM THE
SCIENTIFIC ONE.
AND I HOPE THAT THE STORY I'M
GOING TO SHARE WITH YOU TODAY IS
A LITTLE BIT COMPLIMENTARY TO
THAT, AND THAT I'M LOOKING
FORWARD TO GETTING FEEDBACK.
SO I WANT TO TALK A LITTLE BIT
ABOUT ANTICYTOKINE AUTO
ANTIBODIES.
LET ME REMIND YOU AT THE
BEGINNING, CYTOKINES, THOSE ARE
HOW CELLS TALK TO EACH OTHER.
WE USE DIRECT MESSAGING, TEXT,
BUT CELLS LIKE TO SEND OUT
PROTEINS THAT GO FROM ONE TO THE
OTHER AND BIND TO RECEPTORS,
THEN THEY TELL THAT CELL WHAT TO
DO.
THAT'S WHAT WE'RE GOING TO FOCUS
ON TODAY.
I HAVE NO DISCLOSURES AND MY
OBJECTIVE IS JUST THAT YOU COME
AWAY APPRECIATING THAT THIS IS
REALLY NIFTY.
SO LET'S JUST START OUT, THOUGH,
WITH JUST TRYING TO PUT US IN
CONTEXT.
SO THIS GRAPH LOOKS AT -- IT'S A
DPRAF OF HUMAN POPULATION.
YOU MIGHT BE WONDERING, WELL,
YOU KNOW, STEVE, HOW DO YOU KNOW
WHAT POPULATION LOOKED LIKE BACK
IN SOME OF THESE EARLIER
PERIODS, BACK IN HERE, AND
FRANKLY IT'S BECAUSE I ASKED DAN
AND HE WAS ABLE TO GIVE ME SOME
DIRECT INSIGHT.
BUT NOW THE QUESTION HERE IS,
WHAT IS THE ROLE OF ANTIBIOTICS?
THAT IS, WE THINK -- I'M AN
INFECTIOUS DISEASE GUY.
WE THINK ANTIBIOTICS ARE
IMPORTANT.
WHEN WERE THEY GIVEN?
IF I HAD YOU GUYS IN FRONT OF
ME, I WOULD ASK YOU WHICH IS THE
FIRST ANTIBIOTIC, AND THE VAST
MAJORITY OF YOU WHO HAVE BEEN
MARKETED MERCILESSLY WOULD SAY,
OH, IT'S PENICILLIN.
NO, IT'S NOT PENICILLIN.
THE VER FIRST ANTIBIOTIC IN A
CENTENNIAL THAT WENT WITHOUT
APPROPRIATE HERALD WAS REALLY
MADE IN 1909, AND IT WAS CALLED
SALVORSAN, DEVELOPED FOR THE
TREATMENT OF AFRICAN SLEEPING
SICKNESS.
UNFORTUNATELY, IT REALLY WAS NOT
VERY ACTIVE AGAINST THAT, AND IT
WOUND UP BEING USED AGAINST
ANOTHER SLEEPING SICKNESS KNOWN
AS SYPHILIS.
BUT IT TOOK 33 YEARS FROM THE
DEVELOPMENT OF SALVORSAN TO THE
DEVELOPMENT OF PENICILLIN, AND
ALONG THE WAY WERE THE SULFA
DRUGS.
I WANT TO EMPHASIZE THAT DESPITE
THE FACT THAT ANTIBIOTIC
DEVELOPMENT HAS ONLY BEEN AROUND
FOR 100 YEARS, OUR SPECIES HAS
BEEN GROWING IN NUMBER.
AND I THINK THAT TELLS YOU THAT
WE ARE ACTUALLY BUILT TO GO THE
DISTANCE, AND SO WHEN WE DON'T,
WE WANT TO WONDER WHY.
FOR THOSE OF YOU THAT ARE
INTERESTED, I GET NOTHING FOR
TELLING YOU BUT THIS IS A
FANTASTIC BOOK, THE DEMON UNDER
THE MICROSCOPE, AND I CAN'T SAY
ENOUGH GOOD THINGS ABOUT IT.
ABOUT THE DEVELOPMENT OF
ANTIBIOTICS AND HOW
EXTRAORDINARY IT WAS.
BUT LOOK, THE REAL QUESTION
HERE, THE EL VANT IN THE ROOM,
IF YOU WILL, IS WHY DO PEOPLE
GET SICK?
THAT'S REALLY WHAT WE WANT TO
KNOW.
WHETHER WE'RE DOCTORS, PATIENTS,
OR INVESTORS, WE WANT TO KNOW
WHY ARE PEOPLE GETTING SICK?
BECAUSE WE WEREN'T BUILT IN
ORDER TO GET SICK.
SO THE LENS I USE FOR THIS ARE
CALLED PRIMARY IMMUNE
DEFICIENCIES.
WHAT ARE THOSE?
SO THEY GO BY SEVERAL DIFFERENT
NAMES.
OF COURSE JUST TO KEEP EVERYBODY
GUESSING, INBORN ERRORS OF
IMMUNITY, THAT IS HOW DO WE
PROTECT OURSELVES FROM
INFECTION, SOMETIMES REFERRED TO
AS CONGENITAL
IMMUNODEFICIENCIES, BUT THE
POINT IS THESE ARE
IMMUNODEFICIENCIES THAT ARE NOT
DUE TO THERAPY FOR LUPUS OR
THERAPY FOR CANCER.
THEY'RE NOT DUE TO HIV.
THEY'RE NOT DUE TO HAVING GOTTEN
A TRANSPLANT.
THESE ARE THINGS THAT YOU WERE
BORN WITH.
AND THE STUDY OF THESE OVER THE
LAST SEVERAL DECADES HAS REALLY
EXPLODED.
YOU CAN SEE HERE THE RATE OF THE
INCREASE OF THE NUMBER OF
RECOGNIZED PRIMARY IMMUNE
DEFICIENCIES, AND YOU SEE THAT
THE RATE HAS GONE UP REALLY
DRAMATICALLY, WHY IS THAT?
WELL, PARTLY BECAUSE WE KNOW A
LOT MORE.
YOU'RE HERE, YOU'RE PAYING
ATTENTION, MAYBE.
BUT THERE'S ALSO BETTER
SEQUENCING AND THE ABILITY TO
SEQUENCE THE DNA, IT HAS REALLY
TRANSFORMED HOW WE THINK ABOUT
DISEASE.
LINDSEY JUST TOLD YOU ABOUT NOT
ONLY SEQUENCING DNA, BUT LACKING
THEN AT LOOKING
AT WHAT BINDS TO THE DNA.
THESE ARE EXTRAORDINARY
OPPORTUNITIES.
WE'RE DOING MUCH BETTER TREATING
PATIENTS.
THEY SURVIVE.
WE HAVE A CLANS TO FIGURE OUT
PROBLEMS, AND THEN WE HAVE A
CHANCE TO DISSEMINATE
INFORMATION.
I WANT TO POINT THIS OUT BECAUSE
IT'S REALLY CHANGED THE WORLD.
AND THAT IS, WHEN WE LOOK AT THE
PREVALENCE OF PRIMARY IMMUNE
DEFICIENCIES WORLDWIDE, WHAT YOU
SEE IS THAT THE RATE OF PRIMARY
IMMUNE DEFICIENCIES IN THE
UNITED STATES IS SOMEWHERE
BETWEEN 5 AND 10 PER 100,000.
THAT MAY SEEM LIKE A BIG OR
SMALL NUMBER DEPENDING ON WHO
YOU ARE AND WHERE YOU COME FROM,
BUT I WANT TO CONTRAST TO THE
CURRENT RATE OF MYCOBACTERIUM
TUBERCULOSIS INFECTION, T.B.,
THE GREATEST KILLER POTENTIALLY
OF ALL TIME, AND NOW IMMUNE
DEFICIENCIES ARE TWO TO THREE
TIMES MORE COMMON IN THIS
COUNTRY THAN TUBERCULOSIS.
IF YOU'RE A DOCTOR, THINK ABOUT
THE LAST TIME YOU SCREENED FOR
T.B. VERSUS THE LAST TIME YOU
SCREENED FOR AN IMMUNE
DEFICIENCY.
THE FACT THAT THE RATES ARE HIGH
IN THE UNITED STATES, IT'S NOT
BECAUSE OUR GENETICS ARE THAT
DIFFERENT THAN MOST OTHER
PLACES.
THIS IS BECAUSE WE'RE LOOKING
AND OTHER PLACES HAVE NOT GOTTEN
AROUND TO IT YET, BUT THIS IS
WHAT WE OUGHT TO CONSIDER THE
RATE IS AND IT'S GOING TO BE
GOING HIGHER AS WE DO MORE DNA
SEQUENCING.
SO THAT'S THE BACKGROUND I WANT
TO START WITH AND WHY AM I
TELLING YOU THIS?
BECAUSE MY PATIENT IS THIS
WOMAN.
WHO CAME HERE, WAS REFERRED TO
THE NIH BECAUSE SHE WAS
DESPERATELY ILL.
SHE WAS AT THAT POINT A
60-YEAR-OLD WHO HAD GROWN UP IN
VIETNAM, HAD SURVIVED THE WAR,
HAD COME OUT ON THE BOATS, HAD
LIVED THROUGH REFUGEE CAMPS, HAD
COME TO THE UNITED STATES WHERE
SHE ESTABLISHED A BUSINESS AND A
FAMILY AND WAS DOING GREAT UNTIL
SHE GOT INTO HER LATE LATE '50S AND
THEN REALLY STARTED TO LOSE
WEIGHT, HAD FEVERS, EVENTUALLY
WENT TO HER DOCTOR.
WHAT YOU SEE HERE ARE THESE
SPOTS ON HER CHEST.
AND THOSE SPOTS ARE TEEMING WITH
MYCOBACTERIA.
I'LL TELL YOU THAT IN A SECOND.
AND THEY'RE TEEMING WITH
MYCOBACTERIA BECAUSE SHE HAS
THESE INFECTIONS IN HER BONE
THAT ARE NOT ONLY DESTROYING THE
BONE, BUT THEY'RE THEN DRIVING
THEMSELVES OUT THROUGH THE SKIN.
AND PEOPLE SAID, WOW, THIS IS
BAD, AND WE DON'T KNOW WHY.
WHEN WE MET HER, WE SAID THIS IS
BAD, AND WE DON'T KNOW WHY.
SO WHAT ARE THESE MYCOBACTERIA?
IT WAS ALMOST 140 YEARS AGO THAT
ROBERT KOCH INVITED HIS FRIENDS
INTO HIS KITCHEN TO SHOW THEM
UNDER THE MICROSCOPE -- HE
INVITED THEM OVER FOR DINNER,
SHOW THEM UNDER THE MICROSCOPE
THE ORGANISM THAT HE THOUGHT
CAUSED TUBERCULOSIS.
WELL, OF COURSE ALL OF HIS
FRIENDS SAID ARE YOU CRAZY?
THAT'S WHY HE HAD TO COME UP
WITH THESE THINGS THAT
EVENTUALLY GOT CALLED KOCH'S
POSTULATES.
HOW DO YOU PROVE THAT WHAT YOU
THINK IS TRUE IS REALLY TRUE?
MORE IMPORTANT THAN THAT,
EVERYBODY SAID NO WAY WE'RE
HAVING DINNER AT BOB'S EVER
AGAIN.
WELL, OVER THE 140 YEARS SINCE
HE DISCOVERED THAT, WE'RE STILL
HAVING TROUBLE UNDERSTANDING WHY
PEOPLE GET TUBERCULOSIS.
THIS IS WHAT IT LOOKS LIKE UNDER
THE MICROSCOPE, AND THIS
CHARACTERISTIC SORT OF
RED-APPEARING BACTERIA IS REALLY
WHAT WE'RE AFTER.
WELL, IT TURNS OUT THAT M
TUBERCULOSIS IS AT THE VERY TOP
OF THAT PYRAMID OF PATHOGENESIS
OR VIRULENCE, IT'S A REALLY
NASTY BUG WHICH IS WHY EVERYBODY
KNOWS ABOUT IT.
AND THEN THERE ARE HUNDREDS MORE
MYCOBACTERIA.
AND YOU SEE HERE, I HAVE MADE A
FANCIFUL PYRAMID OF THE
NON-TUBERCULOUS MYCOBACTERIA,
BRILLIANT NAME, IT'S NOT
TUBERCULOSIS, THEREFORE IT'S A
NON-TUBERCULOUS MYCOBACTERIA.
I CAN'T TELL YOU WHERE THESE
NAMES COME FROM.
BUT THE NON-TUBERCULOUS
MYCOBACTERIA FOR THE MOST PART
DO NOT CAUSE SEVERE DISEASE.
IN FACT, THEY ONLY CAUSE SEVERE
DISEASE IN PEOPLE WHO HAVE MAJOR
SUSCEPTIBILITY FACTORS.
THOSE INBORN ERRORS OF IMMUNITY.
AND SO WHAT DO WE KNOW ABOUT
THESE?
SO WHAT WE KNOW IS THAT THE
ABILITY OF CELLS TO CONTROL
MYCOBACTERIA, AND JUST TO REMIND
YOU, ALMOST ALL OF THESE
ORGANISMS HERE ARE OUT IN THE
ENVIRONMENT.
M TUBERCULOSIS, THAT GETS SPREAD
MOSTLY HUMAN TO HUMAN.
THESE ORGANISMS ARE IN THE
ENVIRONMENT, AND YOU, I,
EVERYBODY GETS EXPOSED TO THEM
ALL THE TIME.
SO IF YOU'RE EXPOSED ALL THE
TIME, YOU BETTER HAVE A SYSTEM
IN PLACE THAT CONTROLS THEM.
AND THE GOOD NEWS IS, YOU DO.
HERE'S HOW IT WORKS.
THIS IS CALLED THE MACROPHAGE,
THIS LARGE CELL MACRO, BIG,
PHAGE, EATER, THE BIG EEGHT EATING
CELL THAT GOBBLES UP THE
MYCOBACTERIA.
AFTER THEY'RE INGESTED, THE CELL
MAKES INTERLEUKIN 12 WHICH BINDS
TO ITS RECEPTOR ON T-CELLS AND K
CELLS, AND THAT LEADS TO THE
PRODUCTION OF INTERFERON GAMMA,
WHICH THEN WORKS ON ITS RECEPTOR
ON ALL NUCLEATED CELLS IN THE
BODY, AND WHEN IT BINDS ITS
RECEPTOR, IT DOES A VARIETY OF
THINGS.
IT INCREASES TUMOR NECROSIS
FACTOR, WHICH IS A CYTOKINE THAT
MAKES FOR FEVER AND WEIGHT LOSS,
AND IT ALSO SIGNALS THEN THROUGH
OTHER MOLECULES TO LEAD TO THE
KILLING OF MYCOBACTERIA INSIDE
THE CELL.
AND 140 YEARS AFTER ROBERT KOCH
HAS IDENTIFIED THIS, WE STILL
DON'T KNOW EXACTLY HOW THE
MYCOBACTERIA ARE KILLED.
WE JUST KNOW IF YOU CAN'T DO THE
INTERFERON SIGNAL, YOU'RE IN
TROUBLE.
AND HOW DO WE KNOW THAT, BECAUSE
MUTATIONS IN ANY OF THESE GENES
AND SOME MORE LEAD TO SEVERE
DISSEMINATED MYCOBACTERIAL
DISEASE.
THEREFORE, IT'S ONE MAJOR
PATHWAY THAT DRIVES FROM
INGESTION OF MYCOBACTERIA TO
PRODUCTION OF IL-12 TO
PRODUCTION OF INTERFERON TO
SIGNALING THROUGH THE INTERFERON
RECEPTOR TO KILLING, AND
INTERFERON DRIVES FOR THE
PRODUCTION OF IL-12 SOME MORE.
SO IT'S A NEAT SYSTEM THAT
INTEROPERATES THROUGH THE
PRODUCTION OF CYTOKINES AND
THEIR SENSING BY RECEPTORS TO
LEAD TO THE KILLING AND CONTROL
OF MYCOBACTERIA.
NOW, OF COURSE THAT'S THE
SIMPLIFIED STORY.
BUT THAT'S NOT THE WHOLE STORY.
AND IT TURNS OUT THIS VACUOLE,
THIS CONTAINER INSIDE THE
MACROPHAGE ISN'T JUST DESIGNED
FOR THE CONTROL OF MYCOBACTERIA.
LOTS OF THINGS LIVE IN THERE.
FUNGI, BACTERIA.
SO HERE THEY ARE, HERE ARE THE
NON-TUBERCULOUS MYCOBACTERIA,
INCLUDING THE COMPLEX MY PATIENT
HAD, BUT THERE ARE OTHER
MYCOBACTERIA HERE.
MTB AND THIS OTHER ONE CALLED
BCG, AS WELL AS OTHER BACK BACTERIA
AND SOME FUNGI AND SOME VIRUSES.
SO THIS PATHWAY TURNS OUT TO BE
REALLY IMPORTANT FOR HOW WE
INTERACT WITH THINGS IN THE
ENVIRONMENT.
NOW, THIS TURNS OUT TO BE A
PATHWAY THAT WHEN THERE ARE
MUTATIONS IN IT MOSTLY SHOWS UP
IN CHILDHOOD BECAUSE, FRANKLY,
CHILDREN GET EXPOSED TO THINGS
EARLY ON, AND IF YOU GET A MAJOR
BREACH IN HOST DEFENSE, THEN YOU
GET SICK WHEN YOU ENCOUNTER IT.
SO MOST OF THESE DEFECTS START
EARLY.
SO NOW LET'S GO BACK TO OUR
PATIENT.
BECAUSE NO MATTER HOW YOU SLICE
IT, I MEAN, FOR REAL, 60 AIN'T
YOUNG.
AND SHE WAS FINE UNTIL SHE GOT
TO THAT LEVEL.
SO IF MOST OF THOSE GENETIC
DEFECTS START IN CHILDHOOD, AND
SHE'S GETTING SICK IN ADULTHOOD,
WHAT'S THE PROBLEM?
SO WHEN SHE CAME HERE TO THE
NIH, WE SAT DOWN AND SCRATCHED
OUR HEADS AND SAID, WELL, DOES
SHE HAVE A PROBLEM IN ANY OF
THESE GENES THAT WE'VE
IDENTIFIED BEFORE?
NO.
SO OUR PROBLEM WAS WHAT SHE HAD
LOOKED LIKE A GENETIC DISEASE,
IT ACTED LIKE A GENETIC DISEASE,
NO MATTER HOW MUCH DRUG THEY
GAVE HER, THEY COULDN'T GET HER
INFECTION UNDER CONTROL, BUT
IT'S COMING ON LATE LIFE.
AND WHEN WE TOOK THE CELLS IN
HER BLOOD AND ASKED THEM TO DO
AK BA TICS IN THE
ACROBATICS IN THE LAB, THEY WERE
FINE.
SO WHAT COULD REALLY BE GOING ON
HERE?
AND TO CUT TO THE PUNCH LINE,
WHAT SHE HAS IS AN ANTICYTOKINE
ANTICYTOKINE AUTOANTIBODIES.
THIS ONE ACTUALLY DIRECTED
AGAINST INTERFERON GAMMA ITSELF.
AND THIS ANTIBODY IS BINDING
INTERFERON, COMPLETELY BLOCKING
ITS ABILITY TO INTERACT WITHITY
RECEPTOR, AND, THEREFORE,
MIMICKING COMPLETELY THE
ABILITY -- MIMICKING COMPLETELY
THE CONDITION OF HAVING
INVITATION IN THE INTERFERON
GAMMA RECEPTOR.
SO AS WE STARTED INVESTIGATING
THIS CONDITION, WE REALIZED THAT
IT WAS BEING IDENTIFIED.
SO SHE WAS FROM VIETNAM.
HERE IS A REPORT OF A
25-YEAR-OLD WOMAN FROM THAILAND
WHO WAS LIVING IN GERMANY WHO
GOT ANOTHER MYCOBACTERIUM AND
THEN ANOTHER BACTERIA AND DIED.
25-YEAR-OLD WOMAN, PREVIOUSLY
HEALTHY.
ANOTHER REPORT OF A 57-YEAR-OLD
MAN WHO HAD TUBERCULOSIS,
ANOTHER NON-TUBERCULOUS
ORGANISM, AS WELL AS SOME
AUTOIMMUNE PROBLEMS, AND HE
DIED.
PREVIOUSLY HEALTHY MAN.
AND THEN ALONG THE WAY, WE WERE
COLLECTING PATIENTS WHO HAD
EXACTLY THE SAME PROBLEM, AND
WHAT WE FOUND WERE SIX WOMEN,
ALL FROM SOUTHEAST ASIA,
INCLUDING THE PATIENT I SHOWED
YOU, WHO HAD DISSEMINATED
MYCOBACTERIAL DISEASE, ALL OF
WHICH WERE EXTREMELY SEVERE.
SO WE SAID WAIT A MINUTE, THESE
PEOPLE ALL HAD ANTIINTERFERON
GAMMA AUTO ANTIBODIES.
BUT THEY'RE ALL SOUTHEAST ASIANS
OUTSIDE OF SOUTHEAST ASIA.
AND THE ANTIBODY THERE IS WHAT'S
CALLED IGG, THE MOST COMMON OF
THE ANTIBODY CLASSES THAT
COMBINE TO THESE THINGS, AND
THEY HAD A VARIETY OF PROBLEMS
LIKE THE ONES I'VE SHOWN YOU.
THEY HAD LOTS OF INFECTIONS.
WE REFER TO OPPORTUNISTIC
INFECTIONS THE INFECTIONS YOU'RE
NOT SUPPOSED TO GET UNLESS
YOU'RE PRETTY SICK.
THAT IS, THINGS FROM THE
ENVIRONMENT AREN'T USUALLY
SUPPOSED TO BE CAUSING YOU
DISEASE.
SO THEY WERE SEVERE,
DISSEMINATED AND FATAL.
SO WE BEGAN TO WONDER IF THESE
ANTIBODIES ARE ASSOCIATED WITH
DISSEMINATED NON-TUBERCULOUS MY
COBACK
MYCOBACTERIAL INFECTIONS IN
SOUTHEAST ASIANS OUTSIDE OF
SOUTHEAST ASIA, WHAT'S GOING ON
IN SOUTHEAST ASIA?
SO I WAS LUCKY ENOUGH TO HAVE
READ AN ARTICLE BY A GIFTED
INVESTIGATOR FROM THAILAND, AND
SHE REPORTED 59 PATIENTS IN
THAILAND WHO HAD ALL OF THESE
OPPORTUNISTIC INFECTIONS.
BACTERIAL, FUNGAL, VIRAL, AND
MYCOBACTERIA, BUT NONE OF THEM
HAD HIV.
THAT IS, THEY LOOKED LIKE THEY
HAD SEVERE HIV DISEASE, BUT THEY
DIDN'T.
WE REALIZED WHEN WE PUT TWO AND
TWO TOGETHER THAT WE WERE
PROBABLY DEALING WITH THE SAME
THING.
SO WORKING WITH SARAH BROWN WHO
WAS THEN IN MY LAB AND PETER
BURBELO, WE PUT TOGETHER A TRIAL
TO GO TO THAILAND AND TIE TAIWAN TO
TRY AND FIGURE OUT WHAT WAS
GOING ON.
I'M JUST GOING TO IDENTIFY HERE
FOR A MOMENT, WHAT WERE THE
GROUPS OF INDIVIDUALS WE SOUGHT
OUT?
WE HAD PEOPLE WHO HAD
DISSEMINATED NON-TUBERCULOUS
DISEASE, PEOPLE WHO HAD OTHER
OPPORTUNISTIC INFECTIONS,
VIRUSES, FUNGI, OTHER BACTERIA,
OTHER OPPORTUNISTIC INFORECASTS
WITH OR WITHOUT NON-TUBERCULOUS
DISEASE.
AND THEN BECAUSE THIS QUESTION
ABOUT WE THINK THAT THESE
MYCOBACTERIA ARE ALL IN A
SPECTRUM, SO WHAT'S THE
RELATIONSHIP BETWEEN THE
NON-TUBERCULOUS MYCOBACTERIA AND
TUBERCULOSIS?
SO WE HAD PATIENTS WITH
DISSEMINATED TUBERCULOSIS AND
PULMONARY TUBERCULOSIS, AND THEN
PEOPLE WHO WILL WERE DONORS IN A
BLOOD BANK WHO I THINK, FOR OUR
PURPOSES, WE'RE GOING TO SAY ARE
NORMAL.
WE PUT TOGETHER THIS GROUP OF
INDIVIDUALS AND THEN WE DECIDED
TO MEASURE, ACTUALLY WE MEASURED
41 CYTOKINES AT THE TIME BECAUSE
PETER HAD A BRILLIANT ASSAY HE
DEVISED THAT LET US DO THAT ON
TINY VOLUMES OF PLASMA, BUT HERE
I'M ONLY SHOWING YOU THE RESULTS
FOR THE ANTIBODY AGAINST
INTERFERON GAMMA, BECAUSE THAT
TURNED OUT TO BE THE MOST
IMPORTANT OF THE ONES THAT WE
IDENTIFIED.
AND SO WHEN WE PUT THIS GROUP
TOGETHER, DISSEMINATED DISEASE
VERSUS EVERYTHING ELSE, WHAT WE
SAW WAS THAT THE PEOPLE WHO HAD
DISSEMINATED DISEASE WITH EITHER
NON-TUBERCULOUS OR OTHER
OPPORTUNISTIC INFECTIONS, THE
VAST MAJORITY OF THEM HAD
EXTRAORDINARILY HIGH LEVELS OF
ANTIBODIES AGAINST INTERFERON
GAMMA.
FASCINATINGLY, THOSE WHO HAD
TUBERCULOSIS EITHER DISSEMINATED
OR ISOLATED TO THE LUNG, THEY
DIDN'T.
SHOCKING.
ABSOLUTELY SHOCKING.
I'LL SAVE YOU ANY EFFORT NOW, I
DON'T KNOW WHY.
BUT I WOULD ARGUE THAT IT'S
BECAUSE TUBERCULOSIS AND THESE
NON-TUBERCULOUS ORGANISMS ARE
NOT THE SAME.
BUT IT WAS HIGHLY ASSOCIATED
WITH AN ANTIBODY AGAINST INFEAR
ON -- THAT WAS MIMICKING THE
PROBLEM WHEN YOU MUTE RECEPTORS.
WHAT DID IT LOOK LIKE?
THESE PEOPLE WERE REALLY, REALLY
SICK.
YOU CAN SEE THIS MAN HAD TWO
INFECTIONS GOING ON AT THE SAME
TIME.
A DISSEMINATED FUNGAL INFECTION
AND A DISSEMINATED MYCOBACTERIAL
INFECTION.
THIS WOMAN HAD HUGE LYMPH NODES
DUE TO SALMONELLA, WHICH IS A
BACTERIA.
HERE YOU CAN SEE THIS YOUNG MAN
HAD AN INFECTION IN HIS BONE
WITH CRYPTOCOCCUS, WHICH IS A
FUNGUS, AND THIS YOUNG WOMAN HAD
EXTENSIVE SKIN DISEASE.
SO ALL OF THESE IN PEOPLE WHO
HAD HIGH LEVELS OF ANTIBODY
AGAINST INTERFERON GAMMA.
THE FIRST POINT HERE IS THAT
THESE ANTIBODIES THAT COME ON
LATE IN LIFE MIMIC GENETIC DUS
ORDERS AND YOU CAN SEE, I THINK,
EXACTLY WHY.
THEY TAKE OUT A CRITICAL SIGNAL
MOLECULE THAT'S IN EXACTLY THE
SAME PATHWAY AS ALL THE OTHER
DEFECTS THAT HAD BEEN
IDENTIFIED.
SO THEN I THINK ALL OF US, AS 16
SHANT HUMANS, SPEND A LOT OF
TIME SAYING WHY, WHY ME, WHY
NOW, WHY THIS PROBLEM?
AND THAT WAS THE QUESTION THAT
PEOPLE TURNED TO NEXT.
SO WHY DID THESE PEOPLE START TO
GET THESE PROBLEMS, AND WHY WERE
WE FINDING IT SO FREQUENTLY IN
PEOPLE THAT ORIGINATED IN
SOUTHEAST ASIA, BUT NOT IN THE
VASTLY LARGER NUMBER OF PEOPLE
IN THE COUNTRIES THAT
SURROUNDING THEM.
SO A REALLY GIFTED GROUP IN
TAIWAN BEGAN TO LOOK INTO THIS
AND THEY FOCUSED ON THE HLA
MOLECULES.
NOW YOU MAY HAVE SEEN THAT
COMING UP IN LINDSEY'S DATA,
THAT BIG -- THE HIGHEST PEAK
THAT SHE HAD FOR MOST OF HER
GENOME-WIDE ASSOCIATIONS WAS IN
THE MHC COMPLEX.
AND SOME OF THOSE MHC MOLECULES,
THIS IS WHAT THEY DO.
THEY COME TOGETHER IN A LITTLE
CLUSTER, AND THEY FORM A VERY
SPECIAL POCKET, AND ONLY
SPECIFIC KEYS CAN FIT INTO THE
POCKET THAT THEY FORM.
AND WHAT THEY IDENTIFIED IN
PATIENTS WHO HAD THESE
ANTIINTERFERON AUTO ANTIBODIES,
WERE TWO PARTICULAR MOLECULES
THAT GO INTO MAKING UP THOSE
POCKETS OF THE HLA COMPLEX.
THAT WAS SORT OF FASCINATING IN
AND OF ITSELF.
THEY WENT ON TO SAY, OKAY, WHY
IS THAT PARTICULAR SET OF
MOLECULES OCCURRING?
REMEMBER, THOSE MOLECULES ARE
MAKING THE CAPACITY TO BIND ONLY
CERTAIN THINGS.
WELL, WHAT WAS THE CERTAIN THING
THEY BOUND?
IT TURNS OUT THAT THAT BINDING
POCKET MADE BY THOSE MOLECULES
CORRESPONDS TO THE LAST AMINO
ACIDS OF THE INTERFERON GAMMA
MOLECULE.
AND EVEN MORE INTERESTINGLY,
THAT LAST PART OF THE INTERFERON
GAMMA MOLECULE HERE SHOWN IN RED
TURNS OUT TO BE IDENTICAL TO
ANOTHER GENE THAT SHOWS UP IN A
FUNGUS CALLED ASPERGILLUS.
WELL, HERE YOU SEE IN THIS
TABLE, THIS IS THE AMINO ACID
SEQUENCE OF INTERFERON GAMMA.
THIS IS THE AMINO ACID SEQUENCE
OF THIS GENE CALLED NOC2 IN AS
PER JILL US.
THOSE AUTHORS SAID WAIT A
MINUTE, HERE'S WHAT WE THINK IS
GOING ON, WE THINK HUMANS ARE
INHALING, OR MAYBE EATING,
ASPERGILLUS, AND THAT THEY
THEN -- THEIR IMMUNE SYSTEM
RECOGNIZES THIS PROTEIN IN
ASPERGILLUS CALLED NOC2.
YOU THEN MAKE AN ANTIBODY
AGAINST THAT PROTEIN NOC2, BUT
THAT ANTIBODY AGAINST
NOC2 CROSS-REACTS AGAINST
INTERFERON GAMMA, AND NOW THAT
ANTIBODY IS BLOCKING THE
INTERFERON HERE IN THE GREEN,
AND THEN CAUSING THIS PROBLEM OF
INTERFERON GAMMA DEFICIENCY DUE
TO AN ANTIBODY.
AND THEY SHOW THAT THIS MADE
SOME SENSE BECAUSE THEY COULD
ACTUALLY TAKE THE MOLECULE
INTERFERON GAMMA TO TAKE OUT
THAT PART THAT WAS BEING
RECOGNIZED BY THE ANTIBODY AND
THEN THE INTERFERON WORKED ALL
OVER AGAIN.
SO HERE THEY'VE CHANGED IT FROM
A DIE MONDAY TO DIAMOND TO A TIER DROP.
WHETHER THIS IS EXACTLY THE
EXPOSURE THAT LEADS TO MOLECULAR
MIMIC RE, I DON'T KNOW, BUT IT
CERTAINLY MAKES SENSE AND IT'S
CLEAR THAT JUST AS LINDSEY WAS
TALKING ABOUT, ABOUT
ENVIRONMENTAL EXPOSURES, THIS IS
AN ENVIRONMENTAL EXPOSURE THAT
COULD BE DRIVING AN IMMUNE
REACTION THAT THEN LEADS TO
SEVERE DISEASE.
ONCE YOU UNDERSTAND THE DISEASE,
YOU CAN CHANGE ITS COURSE.
SO ONCE WE IDENTIFIED THAT THESE
PATIENTS WERE GETTING SICK
BECAUSE THEY HAD AUTO ANTIBODIES
AGAINST INTERFERON GAMMA, AND WE
KNOW THAT ANTIBODIES ARE MADE BY
B CELLS, THEN WE REALIZE THAT WE
COULD GO AND WHACK THOSE B CELLS
AND MAKE THEIR ANTIBODIES GO
DOWN.
SO IN FACT, HERE WAS THE LEVEL
OF ANTIBODY BEFORE TREATMENT,
AND HERE'S WHAT HAPPENS TO
ANTIBODY DURING TREATMENT, AND
THEN HERE'S WHAT HAPPENS AFTER
TREATMENT.
AS FURTHER PROOF THAT THIS IS
REALLY IMPORTANT, THIS IS THE
PATIENT WHOSE SLIDE I SHOWED
YOU, WHO HAD THE SPOTS ON HER
CHEST.
WHEN WE STOPPED GIVING HER THE
DRUG TO TAKE OUT THE B CELLS,
HER LEVELS WENT UP, SHE HAD A
CLINICAL RELAPSE, THAT IS, HER
INFECTIONS CAME BACK, AND WE HAD
TO GIVE TO HER AGAIN AND THEN
EVERYTHING RESOLVED AND WENT
AWAY.
SO THIS ARE A FASCINATING
EXAMPLE OF WHAT WE REFER TO AS
GENETICS, GENDER AND GEOGRAPHY.
GENETICS IS OBVIOUS BECAUSE
YOU'VE GOT THE HLA ASSOCIATION.
THE GENDER IS FAST FASCINATING
BECAUSE THE VAST MAJORITY OF
PEOPLE OUTSIDE OF SOUTHEAST ASIA
WHO HAVE BEEN IDENTIFIED ARE
WOMEN.
WHEREAS IN SOUTHEAST ASIA, THE
RATES BETWEEN MEN AND WOMEN ARE
GENERALLY THE SAME.
AND GEOGRAPHY, BECAUSE IT'S ONLY
PEOPLE WHO ARE BORN THERE IN
SOUTHEAST ASIA FOR MOST PART IN
WHOM THIS HAPPENS.
PEOPLE OF THE SAME ETHNICITY
BORN ELSEWHERE DON'T SEEM TO BE
AS SUSCEPTIBLE.
IT'S CLEARLY GOT GENETIC
COMPONENTS AND I THINK WE CAN
TREAT IT.
SO THAT'S AN EXAMPLE, ONLY ONE
EXAMPLE OF AN ANCYTOKINE AUTO
ANTIBODY CAUSING A DISEASE THAT
MIMICS A MENDELIAN DISEASE.
NOW THE NEXT QUESTION IS, WELL,
OKAY, THAT'S A RARE SET OF
PROBLEMS.
IS THIS INVOLVED IN COMMON
PROBLEMS?
DOES THIS OCCUR OUTSIDE OF THOSE
PRIMARY IMMUNE DEFICIENCY-LIKE
DISEASES?
DO THESE OCCUR IN MORE COMMON
DISEASES?
SO HARKING BACK TO WHAT LINDSEY
WAS TALKING ABOUT, WE WORKED
WITH SARTHAK GUPTA AND HARRY
MOTSOUPOULOS TO SAY OKAY, WHAT
ABOUT THE -- ARE THESE AUTO
BODIES OCCURRING THERE AND IF
SO, ARE THEY IMPORTANT?
SO JUST REMIND YOU THAT LUPUS
OCCURS IN ABOUT ONE-TENTH OF 1%
OF THE POPULATION.
BUT THAT'S A BIG NUMBER WHEN
YOU'RE TALKING ABOUT 330 MILLION
PEOPLE.
RHEUMATOID ARTHRITIS, ABOUT 1%,
AND SLOW SJOGREN'S, UP TO 3% OF THE
U.S. POPULATION.
SO THESE ARE BIG TIME DISEASES.
AND WE PERFORMED A SIMILAR
EXPLORATION.
TRYING TO IDENTIFY ANTIBODIES
AGAINST CYTOKINES IN PATIENTS
WHO HAD THOSE DISEASES.
SO WHAT DID WE FIND?
AND I'M JUST GOING TO BRIEFLY
HIGHLIGHT THIS.
WE FOUND ACTUALLY THERE WERE A
FAIR NUMBER OF ANTIBODIES
AGAINST INTERFERONS AND OTHER
CYTOKINES IN THIS POPULATION.
SO HOOR THE BLACK HERE THE BLACK BOXES AR E THE
NORMAL RANGE IDENTIFIED THROUGH
ESSENTIALLY NORMAL VOLUNTEERS OR
BLOOD BANK CONTROL, AND ANYTHING
OUTSIDE OF THOSE BLACK BARS IS
ELEVATED.
AND IN FACT, THERE WERE A FAIR
NUMBER OF ANTIBODIES AGAINST
INTERFERONS AS WELL AS AGAINST
OTHER CYTOKINES.
THEN THE QUESTION WAS, OKAY, IS
THAT CLINICALLY IMPORTANT?
WITHOUT GOING INTO HOW THEY MAKE
UP THESE SCORES, THERE IS THIS
OPPORTUNITY TO LOOK AT PATIENTS
WITH LUPUS AND LOOK AT THEIR
BLOOD AND SAY OKAY, WHAT GENES
ARE TURNED ON?
AND IT'S IN GENERAL THOUGHT THAT
LUPUS IS A DISEASE OF INTERFERON
ALPHA, OR TYPE I INTERFERON
ACTIVITY, OR AT LEAST THERE IS A
LOT OF INTERFERON ACTIVITY IN
IT, AND SO WE LOOKED FOR WHAT
WERE THE SIGNATURES FOR THAT.
AND SO IT TURNS OUT THAT IF
YOU'RE BLOCKING INTERFERON
GAMMA, THE LEVEL OF INTERFERON
ALPHA SIGNALING GOES UP.
AND WE'VE ACTUALLY SEEN THIS IN
THE GENETIC CONDITIONS AS WELL.
IF YOU BLOCK ONE, THE OTHER ONE
IS INCREASED.
SO IT TURNS OUT IF YOU WERE
BLOCKING INTERFERON GAMMA, YOUR
SCORE FOR INTERFERON ALPHA
ACTIVITY WAS HIGHER, SUGGESTING
POTENTIALLY WORSE LUPUS.
IN CONTRAST, THERE WERE OTHER
PEOPLE WHO HAD AUTO ANTIBODIES
AGAINST INFEAR ON INTERFERON ALPHA.
IF THEY HAD AUTO ANTIBODIES THAT
BLOCKED INTERFERON ALPHA, THAT
ACTUALLY MADE THEIR DEGREE OF
LUPUS SIGNIFICANTLY LESS IN
TERMS OF THE SCORING SYSTEM.
SO THIS SUGGESTS THAT
EPIGENETIC, AS IT WERE,
MODIFIERS OF LUPUS SCORES AND
LUPUS SEVERITY THAT OFTEN DON'T
GET TAKEN INTO ACCOUNT.
OKAY.
SO NOW WHAT ABOUT NOW THAT WE'VE
TALKED A LITTLE ABOUT RARE
DISEASE, ABOUT MORE COMMON
DISEASE, WHAT ABOUT REALLY
COMMON DISEASE?
WHAT ABOUT GOES ON IN PANDEMIC
DISEASE?
SO IN THIS REALLY ELEGANT STUDY
DONE, THEY WENT TO NORTHERN
ITALY TO OBTAIN SAMPLES FROM
PEOPLE WHO HAD SEVERE COVID-19
DISEASE.
AND THIS WAS LIKE ICU
SEVERE-SEVERE.
IN THE GENETIC PART OF THE
STUDY, WHAT YOU FOUND IS IF YOU
LOOK AT ONLY 13 GENES AROUND THE
RESPIRATORY SYSTEM AND HOW THE
VIRUSES RESPOND, THAT IS, CAN
YOU SENSE THE VIRUS, CAN YOU
RESPOND TO THE VIRUS BY MAKING
INTERFERONS, ONLY ABOUT 3 1/2%
OF PEOPLE HAD MUTATIONS IN GENES
AROUND THAT.
THAT IS, THEY HAD MONOGENIC
PROBLEMS THAT PREDISPOSE THEM TO
GETTING SEVERE COVID-19 DISEASE,
BECAUSE THEY COULD EITHER NOT
SENSE OR NOT RESPOND TO
INFECTION.
HERE YOU SEE SENSING AND HERE
YOU SEE THE INTERFERON RESPONSE.
AND THAT CORRESPONDED TO THIS
TYPE OF PROBLEM.
SO IF YOU LOOK AT THOSE PEOPLE
WHO HAD MUTATIONS IN KNOWS GENES
IN PEOPLE WHO WERE EITHER VIRAL
SENSING OR RESPONSE, AND YOU
LOOK AT THE LEVEL OF INTERFERON
ALPHA IN THEIR BLOOD, WHAT YOU
SEE IS THAT IF YOU CAN'T SENSE
THE VIRUS OR YOU CAN'T MAKE THE
INTERFERON, THEN, IN FACT,
YOU'VE GOT NO INTERFERON ALPHA,
TYPE I INTERFERON, DETECTABLE IN
YOUR BLOOD.
THIS IS WHAT THE NORMAL LEVEL
LOOKS LIKE IN PEOPLE WHO ARE
GETTING SICK WITH COVID-19.
SO THAT MAKES GOOD SENSE.
INTERFERON IS IMPORTANT IN
CONTROLLING VIRUSES.
THESE PEOPLE CAN'T DO THAT,
THEREFORE, THEY'RE GETTING SICK.
BUT IT TURNED OUT THERE WAS
ANOTHER SET OF PEOPLE WHO HAD
SEVERE DISEASE, WHO ALSO DIDN'T
HAVE DETECTABLE INTERFERON IN
THEIR PERIPHERAL BLOOD.
THIS TAKES US RIGHT BACK TO THE
BEGINNING BECAUSE THIS LOOKS
LIKE A GENETIC DISEASE, THIS ACT
LIKE A GENETIC DISEASE, BUT IT'S
COMING ON LATE IN LIFE.
AND THE IN VITRO CELLULAR
BEHAVIOR IS NORMAL.
SO WHAT'S GOING ON HERE?
WELL, YOU'VE ALREADY GUESSED IT.
THESE PEOPLE HAVE AUTO
ANTIBODIES, NOW NOT AGAINST
INTERFERON GAMMA, AGAINST
ANOTHER INTERFERON CALLED EITHER
ALPHA OROMAY GA.
OR OWE MAY TBA.
OMEGA.
WHAT THIS IS SHOWING IS A LOT OF
PEOPLE WHO ARE LIFE-THREATENING
COVID-19 DISEASE WHO DIDN'T HAVE
MUTATIONS HAD THESE AUTO
ANTIBODIES AGAINST INTERFERON
ALPHA OR INTERFERON OMEGA.
THE RATE OF THOSE ANTIBODIES WAS
MUCH HIGHER IN THOSE WITH
LIFE-THREATENING DISEASE
COMPARED TO THOSE WHO WERE
ASYMPTOMATIC OR HEALTHY
CONTROLS.
AND THOSE ANTIBODIES BLOCKED ALL
OF THE SIGNAL.
SO YES WE HAD PROBLEMS IN SOME
OF THE GENES IN A SMALL NUMBER,
BUT ALMOST THREE TIMES AS MANY
PATIENTS AS HAD GENETIC PROBLEMS
HAD ACQUIRED PROBLEMS THESE AUTO
ANTIBODIES.
NOW IT'S STILL A LITTLE UNCLEAR
WHAT IS CART AND WHAT IS HORSE.
IN STUDIES DONE HERE, WE KNOW
THERE IS A VERY DYNAMIC RATE TO
THESE.
THEY GO UP A LITTLE BIT EARLY IN
THE DISEASE, AND THEN OVER THE
COURSE OF TIME, THESE ANTIBODIES
FALL BACK DOWN TO THE NORMAL
LEVEL.
SO THEY ARE DYNAMIC AND SO
THEY'RE GOING TO BE CHANGING
OVER THE COURSE OF DISEASE.
LASTLY, ONCE YOU LIGHT THE FUSE,
IT'S HARD TO KNOW WHAT GOES OFF.
THIS IS DR. CRISWELL'S ALMA
MATER.
IF YOU LOOK AT THE CHANGE IN
AUTO ANTIBODIES IN PEOPLE WHO
HAVE BEEN INFECTED OVER THE
COURSE OF THEIR HOSPITALIZATION,
WHAT YOU SEE IS BEING INFECTED
WITH COVID-19 CAN TRIGGER THE
DEVELOPMENT OF AUTO ANTIBODIES
AGAINST A VARIETY OF MOLECULES,
INCLUDING INTERLEUKINS,
INTERFERONS, AND OTHER
CYTOKINES.
SO THIS IS BOTH SOMETHING THAT
IS AFFECTED BY HAVING AUTO
ANTIBODIES, AND MAY BE
GENERATING AUTO ANTIBODIES.
OKAY.
SO I'M DONE WITH THE
EXPOSITIONAL PART AND I WILL
JUST SAY HERE I HAVE MERCIFULLY
SPARED YOU FROM HEARING ABOUT
ANYTHING OTHER THAN JUST
INTERFERON GAMMA AND THE TYPE
1 INTERFERONS.
BUT THAT'S NOT BECAUSE THERE'S
NOTHING ELSE TO SAY.
AND THERE ARE AUTO ANTIBODIES TO
A VARIETY OF OTHER CYTOKINES AND
THOSE ARE MODIFYING AND CAUSING
DISEASE HAVE NOT YET BEEN SORTED
OUT.
SO THESE ANTICYTOKINE AUTO
ANTIBODIES ARE ACQUIRED INNATE
AND ADAPTIVE IMMUNE DEFECTS THAT
ARE DYNAMIC, THEY CAN HAVE
ON-TARGET AND OFF-TARGET
EFFECTS, AND WE CAN TREAT THEM,
AND I AM SURE THAT THEY CAUSE
MORE DISEASE THAN WE THINK.
SO SO WE START TALKING ABOUT
GENETICS AND WE WOUND UP TALKING
ABOUT EPIGENETICS.
AND SO I JUST WANT TO REMINE REMIND YOU
THERE'S GENOTYPE AND THERE'S
PHENOTYPE.
GENOTYPE MOSTLY SAYS THE SAME,
BUT PHENOTYPE CHANGES WITH TIME,
EXPOSURE, ENVIRONMENT, AND I
DARE SAY WITH SATISFACTION.
SO I JUST WANT TO STOP AND
ACKNOWLEDGE MY EXTRAORDINARY
COLLEAGUES HERE.
LINDSEY ROSEN, CHRISTA, SARAH,
AND LEE HAVE REALLY BEEN THE
ONES DRIVING OUR AUTO ANTIBODY
WORK AS WELL AS MANY
COLLABORATORS THAT HAVE BEEN
INVOLVED ESPECIALLY FOR THE
COVID WORK WITH GIGI, HELEN AND
ALA INSURING A.
OUR TERRIFIC COLLABORATORS IN
THE DENTAL INSTITUTE IN ATHENS,
IN THAILAND, AND IN THE HUMAN
GENOME PROJECT, AND THEN OUR
COLLABORATORS IN NIAMS,
DR. CRISWELL, THIS IS NOT FOR
YOUR BENEFIT, BUT I WILL JUST
SAY THEY HAVE BEEN EXTRAORDINARY
COLLABORATOR, DR. GUPTA, AND
OTHERS AS WELL.
AND SO I WILL STOP THERE AND I
LOOK FORWARD TO A CHANCE TO
INTERACT OVER QUESTIONS.
>> WELL, THANK YOU SO MUCH,
DR. HO LAND, HOLLAND, FOR THAT
SPECTACULAR TALK.
SO AT THIS POINT, WE WILL GATHER
TOGETHER OUR VARIOUS PRESENTERS.
JENNIFER AND DR. CRISWELL AND
DR. HOLLAND, AND DR. ARIAS IS
HERE ON THE SCREEN TOO.
AND WE'LL JUST ENTERTAIN
QUESTIONS THAT WE HAVE AND
ACTUALLY WE HAVE GOTTEN A BUMPER
CROP OF QUESTIONS.
I DON'T EVEN KNOW IF WE'LL BE
ABLE TO GET THROUGH ALL OF THEM,
BUT CERTAINLY FOR THE ONES THAT
WE DON'T GET TO, WE CAN ALWAYS
ADDRESS THEM TO THE SPEAKERS
LATER ON AND GET BACK WITH YOU
WITH THE ANSWERS.
SO ONE QUESTION THAT COMES UP
THAT REALLY TIES TOGETHER THE
TWO TALKS HAS TO DO WITH THE
WHOLE ISSUE OF TYPE
1 INTERFERONS, AND THE FACT THAT
TYPE 1 INTERFERONS PLAY AN
IMPORTANT ROLE IN AUTOIMMUNE
DISEASES LIKE LUPUS, BUT ARE
ALSO IMPORTANT IN TERMS OF
RESISTANCE TO CERTAIN BACTERIAL
INFECTIONS.
AND SO THE QUESTIONER WANT TO
KNOW WHETHER IN PATIENTS WITH
LUPUS OR PERHAPS WITH OTHER
AUTOIMMUNE DISEASES, ARE THEY
MORE RESISTANT TO CERTAIN VIRAL
INFECTIONS?
AND THIS COULD REALLY BE
ADDRESSED BOTH TO DR. CRISWELL
AND TO DR. HOLLAND.
>> I'LL START AND STEVE MAY WAN
TO ADD.
THE RELATIONSHIP IS FASCINATING,
AND YOU KNOW, CHANGES OVER TIME,
INFECTIOUS THREATS IN THE
ENVIRONMENT HAVE PROBABLY
INFLUENCED OUR GENETICS IN SUCH
A WAY THAT IT'S RESULTED IN
PREDISPOSITION TO AUTOIMMUNE
DISEASES, SO REALLY COMPLICATED
RELATIONSHIPS BETWEEN AUTOIMMUNE
DISEASES AND INFECTION.
IN TERMS OF LUPUS AND VIRUSES,
THE MOST NOTABLE ASSOCIATION IS
SIGNIFICANT EVIDENCE THAT
CERTAIN VIRUS INFECTIONS CAN
TRIGGER THE ONSET OF LUPUS.
THE STRONGEST DATA IS FOR
EPSTEIN-BARR VIRUS, THE VIRUS
THAT CAUSES MONONUCLEOSIS.
THERE ARE ALSO CASE REPORTS OF
OTHER VIRUSES SUCH AS THE
VARICELLA VIRUS THAT CAUSES
CHICKEN POX AND SHINGLES, FOR
EXAMPLE, TRIGGERING THE ONSET OF
LUPUS.
JENNIFER DIDN'T MENTION BUT A
YEAR OR SO BEFORE SHE DEVELOPED
LUPUS, SHE HAD CHICKEN POX, AND
ONE MIGHT WONDER WHETHER THAT
MIGHT HAVE CONTRIBUTED TO
TRIGGERING HER DISEASE.
SO I'M NOT AWARE OF SUBSTANTIAL
EVIDENCE THAT'S SUGGESTIVE THAT
ONCE SOMEONE DEVELOPED LUPUS
THAT THEY'RE PROTECTED FROM
VIRUS INFECTIONS, BUT STEVE MAY
HAVE ANOTHER PERSPECTIVE ON THAT
QUESTION.
>> OKAY, WELL, LET'S SEE WHAT
STEVE HAS TO SAY.
>> I WOULD NEVER DISAGREE WITH
LINDSEY, AND I DON'T HERE.
I THINK, YOU KNOW, THE
LITERATURE ABOUT INFECTION
SUSCEPTIBILITY IN A LOT OF THE
AUTOIMMUNE DISEASES IS HEAVILY
AFFECTED BY TREATMENT.
SO STEROIDS CLEARLY INCREASE THE
RISK OF INFECTION.
MANY OF THESE OTHER DRUGS
INCREASE THE RISK OF INFECTION.
ONE OF THE FASCINATING THINGS IS
THAT IN ALMOST ALL OF THE PRIME
RYE
PRIMARY IMMUNE DEFICIENCIES,
WHERE YOU'VE GOT A LOT OF
INFECTION SUSCEPTIBILITY, IT'S
COUPLED TO THE INCREASE IN THE
RATE OF AUTO AUTOIMMUNITY.
EXACTLY WHY THAT IS, I DON'T
KNOW, BUT I WOULD CERTAINLY
DEFER -- I THINK THAT LUPUS, PER
SE, IS NOT AN INFECTION
AGGREGATING DISEASE.
IT MAY BE TRIGGERED BY AN
INFECTION BUT THEY DON'T GET
MORE BACTERIAL INFECTIONS IN THE
ABSENCE OF THERAPY THAT I'M
FAMILIAR WITH.
>> AND JUST FOLLOWING UP A
LITTLE BIT ON WHAT LINDSEY HAD
RAISED THE QUESTION OF WHETHER
PERHAPS THE SELECTION FOR
RESPONSIVENESS TO CERTAIN
PATHOGENS MIGHT INCREASE THE
FREQUENCY OF VARIANTS THAT
INCREASE IMMUNE RESPONSIVENESS,
INTERFERON PRODUCTION OR
WHATEVER, IS THERE ANY DIRECT
EVIDENCE OF THAT, LINDSEY, THAT
YOU KNOW OF IN TERMS OF STUDIES
OF GENOME STRUCTURE, LOOKING FOR
LARGE HAPLOTYPES, LET'S SAY THAT
WOULD BE ASSOCIATED WITH
PARTICULAR VARIANTS OF
INTERFERON-RELATED GENES IN THE
GENERAL POPULATION?
>> I'M AFRAID I'M NOT AWARE OF
DIRECT EVIDENCE, BUT THERE ARE A
NUMBER OF VERY ATTRACTIVE
THEORIES THAT WOULD CONNECT
THOSE TWO THINGS.
FOR EXAMPLE, THERE'S A GENETIC
RISK VARIANT, A FUNCTIONAL
VARIANT, PNTP22 ASSOCIATED WITH
MANY AUTOIMMUNE DISEASES AND HAS
VERY STRIKING VARIATION IN
ALLELE FREQUENCY WITHIN EUROPE,
FOR EXAMPLE, WITH VERY HIGH
FREQUENCY IN THE NORTH, LOW
FREQUENCY IN THE SOUTH, FOR
EXAMPLE, .
AN ATTRACTIVE HYPOTHESIS IS THAT
PATTERN, DIFFERENCE IN ALLELE
FREQUENCY, REFLECTS AN
INFECTIOUS DISEASE -- PERHAPS
THE PLAGUE THAT WENT THROUGH
EUROPE AND RESULTED IN SELECTION
FOR CERTAIN VARIANTS THAT
PROTECTED AGAINST DISEASE THAT
HAVE AS A CONSEQUENCE NOW
AFRICAN AMERICAN AN
INCREASED RISK OF AUTOIMMUNE
DISEASES.
I'M NOT AWARE OF THE SORT OF
EVIDENCE THAT YOU ALLUDED TO,
DAN.
ONCE AGAIN, PERHAPS STEVE IS
AWARE OF SOME EVIDENCE ON THAT
FRONT.
>> STEVE IS SHAKING HIS HEAD
KNOW, BUT THIS IS JUST, I GUESS,
AN OPPORTUNITY FOR MORE RESEARCH
FOLLOWING UP ON THAT PTPN
22 VARIANT, PRANCE PERHAPS THERE'S
SOMETHING MORE THERE THAT CAN BE
FOUND, BUT IT'S A VERY
FASCINATING IDEA THAT PERHAPS
THAT HIGH FREQUENCY IN NORTHERN
EUROPEAN POPULATIONS IS THERE
FOR A REASON OF SOME SORT.
ALL RIGHT.
WELL, NOW THAT I'VE PICKED ON
DOCTORS HOLLAND AND CRISWELL,
NOW IT'S TIME TO GO BACK TO
JENNIFER.
SHE THOUGHT SHE WAS OFF THE HOOK
BUT THAT HOOK IS A PRETTY BIG
ONE HERE.
AND SO HERE IS A QUESTION FROM
CATHY.
THE QUESTION IS, HOW MUCH DOES
DIET CONTRIBUTE TO FLARE-UPS IN
THE BODY, AND WHAT ARE THE FOODS
YOU ENJOY TO ALLEVIATE SWELLING
IN THE BODY?
I GUESS THAT I COULD ADD ANOTHER
QUESTION TO IT.
I WAS TRYING TO THINK UP
QUESTIONS JUST IN CASE NOBODY
ASKED ANY QUESTIONS, SO THERE'S
THE VITAMIN D DEFICIENCY ISSUE
ASSOCIATED WITH AUTOIMMUNITY,
AND WOULD A DIET RICH IN DAIRY
PRODUCT LIKE ICE CREAM, WOULD
THAT, PERHAPS, HELP WITH AN
AUTOIMMUNE DISEASE?
>> WELL, AS SOMEBODY WHO ENJOYS
ICE CREAM BUT IS ALSO LACTOSE
INTOLERANT, IT'S A FASCINATING
QUESTION AND I WILL SAY THAT
FOR -- I'VE HAD G.I. CHALLENGES
AS FAR BACK AS MY TEENAGE YEARS.
THEY PERSIST.
AND FOR YEARS, MY DOCTORS
INCLUDING MY RHEUMATOLOGISTS HAD
SUGGESTED A GLUTEN-FREE DIET
POTENTIALLY.
I DID GO GLUTEN-FREE, GOSH,
PROBABLY WELL OVER A DECADE AGO.
THAT DID HELP.
I FOUND THAT GOING LOW FODMOP,
SUGARS THAT CAN BE HARD TO TIE
TIE-DYE
DIGEST, THEY CAN FERMENT IN THE
GUT, THAT IN ADDITION WITH BEING
BLUE 10-FREE
GLUTEN-FREE HAS HELPED.
I'VE NOT NOTICED A CORRELATION
WITH MY ARTHRITIS, THOUGH, AND I
WOULD LEAVE TO DRS. CRISWELL AND
HOLLAND TO MAYBE COMMENT ON
THAT.
>> BEFORE THEY DO, SO WHAT ARE
YOU LEFT TO EAT IF YOU'RE
AVOIDING ALL OF THESE THINGS?
>> THERE'S PLENTY LEFT TO EAT,
AND FORTUNATELY WE'RE IN AN AGE
NOW WITH THESE HAN TEE HANDY APPS ON OUR
IPHONES WHEN FACEED WITH A PLATE
OF SOMETHING DELICIOUS, YOU CAN
TYPE IN THAT FOOD AND SEE HOW
COMFORTABLE YOUR NEXT 24 HOURS
WILL BE SHOULD YOU PARTAKE.
>> HOPEFULLY THE APP ON YOUR
PHONE ALLOWS YOU TO EAT
SOMETHING, THOUGHMENT
>> YES.
NO, I'M CERTAINLY -- I DON'T GO
WITHOUT, I'LL SAY THAT.
>> ALL RIGHT.
WELL, LET'S SEE IF DR. CRISWELL
OR DR. HOLLAND HAVE ANYTHING TO
ADD TO THOSE COMMENTS.
>> STUDIES OF DIET AND YOU
AUTOIMMUNE DISEASE ARE
CHALLENGING FOR A NUMBER OF
REASONS, STUDY DESIGN ISSUES, ET
CETERA.
I'VE BEEN INTERESTED TO SEE SOME
IMPRESSIVE DATA IN TERMS OF THE
QUALITY OF THE STUDY COMING OUT
OF THE OSTEOARTHRITIS
LITERATURE, IMPLICATING CERTAIN
DIETS THAT THEY CHARACTERIZE
DIETS IN TERMS OF WESTERN DIET
VERSUS PRUDENT DIET BEING MORE
LIKE THE MEDITERRANEAN DIET, AND
OVER YEARS OF OBSERVATION WITH
IMAGING STUDY, ET CETERA,
OSTEOARTHRITIS PROGRESSED MORE
RAPIDLY AMONG INDIVIDUALS WHO
WERE CONSUMING A HIGH WESTERN
DIET COMPARED TO THOSE WITH THE
PRUDENT DIE E I WAS IMPRESSED
THAT WAS NOT FULLY EXPLAINED,
ONLY PARTIALLY EXPLAINED BY
WEIGHT AND BMI.
SO I THINK THERE IS STILL A LOT
TO LEARN IN TERMS OF DIET AND
ARTHRITIS AND OTHER
MANIFESTATIONS OF LUPUS.
>> ALL RIGHT.
WELL, THAT'S VERY INTERESTING.
I'LL HAVE TO LEARN ABOUT THIS
PRUDENT DIET AT SOME POINT.
DR. HOLLAND, DO YOU HAVE
ANYTHING TO ADD TO THAT?
>> AS LONG AS THERE'S COFFEE IN
THE DIET, I DON'T REALLY CARE.
SO I THINK WHAT WE'VE -- I DON'T
KNOW ANYTHING ABOUT THE
SPECIFICS OF THE DIFFERENT
DIETS, BUT THE WORK BEING DONE
OVER THE LAST DECADE OR SO IN
MICROBIOME HAS REALLY SHOWN A
PROFOUND EFFECT OF DIET ON
MICROBES AND MICROBES ON
IMMUNITY, EVERYTHING FROM IMMUNE
REACTIVITY TO CANCER.
AND I THINK IT'S REALLY HARD TO
SORT THOSE TWO APART, AND
CERTAINLY I LOOK FORWARD TO IT
BEING WORKED OUT MORE CLEARLY.
BUT I THINK WE SHOULD BE HUMBLE
ABOUT THE FACT THAT WHAT WE
CONSUME CLEARLY ACTIVATES OUR
COMPONENTS, WHETHER IT'S ABOUT
LACTOSE OR LACK TASTE LACTASE OR DIFFEREN T
BACTERIA, AND THOSE ARE
COMPLICATED STUDIES TO DO
BECAUSE THERE'S SO MUCH BACTERIA
IN THE ENVIRONMENT AND SO ON.
BUT THEY'RE CRITICALLY IMPORTANT
STUDIES TO DO, AND I THINK OUR
INSTITUTE AND MANY OTHERS ARE
REALLY COMMITTED TO TRYING TO
DISSECT OUT THOSE RELATIONSHIPS.
>> STEVE, I'M SO GLAD YOU
MENTIONED THE MICROBIOME AND IT
REMINDS ME ALSO THERE'S SOME
INTERESTING WORK FOR EXAMPLE
RELATED TO THE TREATMENT OF
RHEUMATOID ARTHRITIS AND
METHOTREXATE IS A DRUG WHERE THE
MICROBIOME INFLUENCES METABOLISM
OF THE DRUGS TOO, SO THAT'S
ANOTHER COMPLICATING FACTOR.
SO I AGREE THAT'S A REALLY RICH
AREA FOR FUTURE RESEARCH.
>> YEAH.
I MEAN, LIKE SO MANY THINGS,
IT'S SOMETHING THAT WE TOOK
LARGELY FOR GRANTED.
WE ASSUMED THAT YOU WERE PASSING
THAT STUFF OUT, IT WASN'T OUR
PROBLEM.
WELL, WE WERE WRONG.
SO IT WILL KEEP US BUSY FOR
QUITE A WHILE.
>> YES INDEED.
SO HERE'S A QUESTION FOR
DR. CRISWELL.
SORT OF HARKENING BACK TO HER
TALK.
ARE TWINS WHICH BOTH HAVE LUPUS
MORE PRONE TO HAVE THE SAME
CLINICAL MANIFESTATIONS THAN
RANDOM LUPUS PATIENTS?
>> THAT'S AN INTERESTING
QUESTION.
AS YOU CAN IMAGINE, THERE AREN'T
A LOT OF LARGE TWIN STUDIES IN
LUPUS, BUT SMALL STUDIES THAT
EXIST SUGGEST THAT THERE IS NOT
A LOT OF CONCORDANCE IN TERMS OF
THE SPECIFIC DISEASE
MANIFESTATIONS AMONG LUPUS
TWINS.
SO YOU MIGHT EXPECT THAT THE
DISEASE FEATURES WOULD BE VERY,
VERY SIMILAR, BUT THEY AREN'T AS
SIMILAR AS ONE MIGHT EXPECT,
WHICH ONCE AGAIN POINTS TO
EPIGENETIC FACTORS AND
EPIGENETIC DIFFERENCES BETWEEN
TWINS WILL INCREASE OVER THE
COURSE OF THEIR LIFETIME WITH
TIME, OR DIFFERENCES IN
EXPOSURES, CHANCE EVENTS, THAT
PROBABLY PLAYS AN IMPORTANT ROLE
TOO.
SO IT'S AN INTERESTING QUESTION.
THANKS FOR POSING THAT.
>> YEAH, AND YOU MENTIONED THE
QUESTION OF EPIGENETIC
EXPOSURES.
I KNOW THAT CIGARETTE SMOKING
HAS BEEN IMPLICATED AT LEAST IN
SOME AUTOIMMUNE DISEASES.
WITH THE DECREASE IN CIGARETTE
SMOKING IN THE GENERAL
POPULATION, HAS THERE BEEN ANY
CHANGE IN FREQUENCY OF
AUTOIMMUNE DISEASE, AT LEAST AS
OF YET?
>> I THINK ONE OF THE STRONGEST
ASSOCIATIONS FOR SMOKING IN
AUTOIMMUNE DISEASE IS PROBABLY
RHEUMATOID ARTHRITIS, WHERE THE
LUNG AND EXPOSURES THROUGH THE
LUNG INCLUDING CIGARETTE SMOKERS
ARE REALLY IMPORTANT IN TERMS OF
TRIGGERING THE DISEASE AND
CONTRIBUTING TO DISEASE
MANIFESTATIONS, AND THAT
PROBABLY EXPLAINS SOME OF THE
VARIATION IN RISK AROUND THE
WORLD, BUT THERE'S SO MUCH ELSE
THAT CONTRIBUTE TO THE DISEASE,
I THINK IT'S HARD TO
DEFINITIVELY SAY.
BUT CLEARLY SMOKING IS A MAJOR
CONTRIBUTOR TO RHEUMATOID
ARTHRITIS.
IT'S ALSO BEEN ASSOCIATED WITH
DOUBLE STRANDED DNA AUTO BODY --
IN LUPUS.
AND THERE'S SOME OTHER SIMILAR
SORTS OF EXPOSURES.
PROXIMITY TO MAJOR HIGHWAYS HAS
BEEN ASSOCIATED WITH RISK OF
AUTOIMMUNE DISEASES INCLUDING
RHEUMATOID ARTHRITIS AS WELL, SO
THE PARTICULATE POLLUTION PLAYS
A ROLE.
>> JUST MAJOR HIGHWAYS IN
GENERAL, NOT SOME PARTICULAR
MAJOR HIGHWAY.
>> THE ONE CLOSEST TO YOUR
HOUSE, DAN.
THERE'S SOME REALLY COOL STUDIES
THAT LOOK AT DISTANCE TO MAJOR
ROADWAYS AND IT HAS DEMONSTRATED
STRONG ASSOCIATION.
>> MY GOODNESS.
ALL RIGHT.
WELL, HERE'S ONE FOR
DR. HOLLAND.
HAVE YOU LOOKED AT ANY
CORRELATION BETWEEN ANCYTOKINE
ANTIBODIES AND LONG COVID?
CAN IT BE USED AS A PREDICTOR OF
DISEASE AS PATIENTS ARE ADMITTED
TO HOSPITAL WITH COVID?
>> ASK ME IN A COUPLE OF MONTHS.
>> ALL RIGHT.
WELL, WE WILL.
OKAY.
SO LET'S SEE.
HERE IS ONE THAT PROBABLY COULD
BE ADDRESSED BY EITHER
DR. HOLLAND OR DR. CRISWELL.
CAN YOU COMMENT ON RECEIPT
LAITION RISK OR BENEFIT BETWEEN
LUPUS AND OTHER AUTOIMMUNE
DISEASES AND COVID VACCINATION?
>> IF YOU HAVE AN AUTOIMMUNE
DISEASE, IT'S IMPORTANT TO
RECEIVE A VACCINATION.
THERE ARE COHORT STUDIES THAT
ARE LOOKING AT VACCINATION
RESPONSE, WHICH OF COURSE CAN BE
DIMINISHED IN THE SETTING OF
TREATMENT AND IMMUNOSUPPRESSION.
SO THAT'S ONE OF THE CHALLENGES
ASSOCIATED WITH AUTOIMMUNE
DISEASE AND IMMUNOSUPPRESSANT IS
THE CORY SPONS TO
THE CORE RESPONSE TO
VACCINATION.
UNLESS ABLE TO SPEAK TO
DIFFERENCES IN ADVERSE EVENTS,
FOR EXAMPLE, AMONG LARGE NUMBERS
OF VACCINATED INDIVIDUALS WHO DO
AND DON'T HAVE AUTOIMMUNE
DISEASE, STEVE IS PROBABLY IN A
BETTER POSITION TO ANSWER THAT
ONE.
>> I DON'T THINK I'VE SEEN TOO
MUCH THAT SUGGESTS TO ME THAT
DISEASES LIKE LUPUS ARE BEING
EXACERBATED BY VACCINATION.
IN CONTRAST, I THINK MOST PEOPLE
THAT HAVE SORT OF TWITCHY IMMUNE
RESPONSES IN GENERAL GET INTO A
LOT MORE TROUBLE WITH INFECTION
THAN THEY GET WITH THE VACCINE.
THERE'S NO QUESTION THE VACCINE
IS AN IMMUNE ACTIVATOR, AND
THERE'S NO QUESTION THAT PEOPLE
FEEL LOUSY AND ALL THAT STUFF,
WHICH IS EVIDENCE THAT IT'S
WORKING.
BUT THE VIRUS INFECTION CAN
REALLY TRIGGER MUCH MORE SEVERE
REACTIONS.
I THINK THAT STUDY FROM THE
GROUP AT SAN FRANCISCO THAT WAS
THE LAST DATA SLIDE I SHOWED
SUGGESTS THAT THIS INFECTION,
THAT THE VIRUS INFECTION CAN
TRIGGER QUITE A BIT OF AUTO I
MAWN YOU
AUTOIMMUNE REACTIVITY.
THE QUESTION OF WHICH ONE DOES
IT TRIGGER, WHICH ONE PERSISTS
AND WHICH ONE BECOMES MORE
SYMPTOMATIC, THAT'S A MUCH MORE
COMPLEX QUESTION AND WHAT WE'RE
TRYING TO DO IS LOOK IN LONG
TERM PATIENTS TO SEE EXACTLY
WHICH AUTO ANTIBODIES ARE COMING
UP.
I DON'T THINK IT WILL BE AROUND
THE AUTO INTERFERON AUTO
ANTIBODIES, BUT THESE ARE ALL
GOING TO BE IMPORTANT FACTORS IN
SOME OF THE LONG-TERM SEQUELAE
OF COVID-19.
>> YES, YES, YES, I THINK THAT'S
A VERY GOOD POINT.
AND GOING BACK TO JENNIFER'S
STORY, IF I'M REMEMBERING
CORRECTLY, A YEAR BEFORE SHE WAS
DIAGNOSED WITH LUPUS, SHE HAD
CHICKEN POX, I GUESS IT WAS.
SO THERE, A VIRAL INFECTION, NOT
THAT SHE RECEIVED A VACCINE A
YEAR BEFORE DEVELOPING LUPUS.
BUT CERTAINLY THAT'S AN
IMPORTANT POINT, AND JUST THE
WHOLE IDEA OF THE TYPE
AND DEGREE OF STIMULATION OF THE
IMMUNE SYSTEM THAT MIGHT BE
ASSOCIATED WITH THE DEVELOPMENT
OF AN AUTOIMMUNE DISEASE.
OKAY.
SO NOW WE HAVE -- WE JUST HAVE A
WHOLE BUNCH OF QUESTIONS HERE.
HERE'S ONE.
IS THERE ANY EVIDENCE FOR
CERTAIN VIRUSES TRIGGERING
GASTROINTESTINAL INFLAMMATORY
DISEASES LIKE CROHN'S DISEASE?
SO WOULD THERE BE ANY EVIDENCE
THAT VIRUSES -- NOW OF COURSE
CROHN'S DISEASE IS MAYBE NOT
EXACTLY IN THE CATEGORY OF
LUPUS, BUT ANY THOUGHTS WITH
REGARD TO ENVIRONMENTAL EXPOSURE
IN CROHN'S DISEASE?
>> I WOULD JUST SAY FOR CROHN'S,
IF WE LUMP INFLAMMATORY BOWEL
DISEASE TOGETHER, IS THERE
EVIDENCE FOR INFECTIONS BEING
IMPORTANT TRIGGERS?
OH, YEAH.
I THINK THE EVIDENCE IS MUCH
STRONGER FOR ULCERATIVE COLITIS
THAN FOR CROHN'S, BUT THE
EVIDENCE FOR MICROBIOME EFFECT,
THE EVIDENCE FOR CHANGES IN
INFLAMMATORY BOWEL DISEASE RATES
BY LOCATION, IS VERY, VERY
STRONG.
NOW IT GETS CONFUSING AS WE WERE
TALKING ABOUT EARLIER, WE'VE GOT
VARIABLES ALL BEING MOVED AROUND
ET AROUND
AT THE SAME TIME.
PATHOGENIC MICROBES, COMMENSAL
MICROBES, VIRUSES, ALL OF THESE
ARE HAPPENING IN ALL OF US ALL
THE TIME, SO TRYING TO SORT OUT
WHICH ONE IS THE CAUSAL ONE IS
HARD, BUT I WOULD -- I THINK
THAT WE'D ALL AGREE THAT
ENVIRONMENTAL INFLUENCES ARE
CRITICALLY IMPORTANT IN THE
RATES OF INFLAMMATORY BOWEL
DISEASE, AND WHAT EXACTLY IT IS
THAT'S BEEN CHANGING OVER THE
LAST 50 YEARS, THE RATES OF
INFLAMMATORY BOWEL DISEASE AT
LEAST IN THE WESTERN WORLD WENT
THROUGH THE ROOF.
THAT'S NOT AN EVOLUTIONARY
EFFECT, THAT'S AN ENVIRONMENTAL
EFFECT.
BUT WHICH ENVIRONMENTAL EFFECT,
I'M NOT SURE YET.
>> ALL RIGHT, WELL, THANK YOU
FOR THAT.
OKAY.
SO NOW WE HAVE A QUESTION COMING
BACK TO JENNIFER, IF SHE'S READY
FOR TAKING ANOTHER QUESTION
HERE.
SO THE INTERROGATOR FIRST THANKS
YOU FOR SHARING YOUR STORY.
DO YOU HAVE SUGGESTIONS FOR HOW
WE CAN DO, WE AS HEALTHCARE
PROVIDERS CAN DO A BETTER JOB
COMMUNICATING THE RESEARCH
OPPORTUNITIES AVAILABLE FOR
PATIENTS.
IT SOUNDS LIKE YOU ARE AN
EDUCATED CONSUMER BUT THERE ARE
MANY WHO DO NOT UNDERSTAND HOW
TO NAVIGATE CLINICAL TRIALS AND
RESEARCH OPPORTUNITIES.
>> I WILL SAY I'VE CERTAINLY
BECOME AN EDUCATED CONSUMER, BUT
IT IS MY -- I MAKE A LIVING
TRANSLATING CLINICAL CONTENT
INTO PLAIN LANGUAGE.
IT SHOULD BE DONE, PERIOD.
ESPECIALLY IF YOU WANT TO REACH
PATIENTS.
I THINK HAVING INFORMATION COME
FROM A TRUSTED SOURCE IS A HUGE
ADVANTAGE, AND THAT CAN BE FROM,
FOR EXAMPLE, HOW I ENROLLED IN
DR. CRISWELL'S STUDIES, MY
RHEUMATOLOGIST SUGGESTED THAT.
SO UTILIZING A NETWORK OF
PROVIDERS TO SUPPORT RESEARCH
AND ENCOURAGE PATIENTS.
ANOTHER WAY TO DO THAT WOULD BE
THROUGH PATIENT ADVISORY GROUPS.
I SEE A LOT OF RECRUITMENT
HAPPENING NOW VIA SOCIAL MEDIA,
FACEBOOK, ET CETERA, THOSE WERE
DIRECT MAIL CAMPAIGNS.
THAT WAS HIGHLY IMPERSONABLE.
MY FAVORITE RECRUITMENT TACTIC
IS TO HAVE ENROLLED PATIENTS GO
OUT AND SPEAK TO A FRIEND WHO
HAS LUPUS OR MAYBE THROUGH A
CHURCH GROUP, PEOPLE WHO ARE
TRUSTED WHETHER IT'S SOMEONE
WITH A CONDITION OR SOMEONE IN
THE COMMUNITY, AND I KNOW BACK
WHEN DR. CRISWELL AND I WERE
WORKING TOGETHER, WE SPENT A LOT
OF TIME IN SMALL TOWNS AROUND
THE COUNTRY GOING TO LOCAL
SUPPORT GROUPS SO THAT PEOPLE
COULD MEET HER FACE-TO-FACE, ASK
QUESTIONS, AND THEN WE WOULD
ENROLL THOSE WHO ARE INTERESTED.
SO I THINK TRUST STILL REMAINS
SORT OF THE FOUNDATION FOR A
ROBUST ENROLLMENT CAMPAIGN.
>> ABSOLUTELY.
THANK YOU FOR THAT VERY
INSIGHTFUL COMMENT.
SO HERE'S A VERY HARD NOSED,
TOUGH QUESTION FOR DR. CRISWELL.
WHY IS IT USEFUL TO HAVE A
BLANKET DIAGNOSIS OF LUPUS GIVEN
THE HETEROGENEITY IN GENETIC AND
EPIGENETIC ETIOLOGY IN CLINICAL
MANIFESTATIONS?
WHY EVEN USE THE WORD LUPUS
ANYMORE?
THAT'S WHAT THE QUESTIONER WANTS
TO KNOW.
>> YEAH, THAT'S -- YOU KNOW,
THAT'S A GREAT QUESTION AND
THERE'S THIS PHRASE, ARE YOU A
LUM PER OR A SPLITTER.
SO THAT'S DEFINITELY LUMPING AS
OPPOSED TO SPLITTING.
SO MY HOPE IS THAT WITH GREATER
UNDERSTANDING OF THE UNDERLYING
CAUSES, WE CAN SPLIT INTO
HOMOGENEOUS SUBSETS.
AND THAT'S AN OVERARCHING GOAL
OF ETIOLOGICAL STUDIES, JE NE TI
GENETICS, EPIGENETICS.
TO THE EXTENT THOSE ARE --
BIOLOGY, THAT'S GOT TO BE
RELATED TO THERAPEUTIC
APPROACHES, RESPONSE TO
TREATMENTS, OUT COME.
BUT THESE ARE -- MOST HUMAN
DISEASES ARE COMPLEX.
IT IS REALLY DIFFICULT TO DEFINE
THE APPROPRIATE ETIOLOGIC GROUP
WHEN YOU'RE TALKING ABOUT A
COMPLEX DISEASE.
NOW YOU'RE TALKING ABOUT A
SINGLE GENE DISORDER WITH 100%
PENETRANCE, THAT'S ONE THING.
BUT GARDEN VARIETY LUPUS IS VERY
DIFFERENT.
SO THESE CRITERIA EXIST BECAUSE
THERE'S A LOT OF CORRELATION
WITHIN INDIVIDUALS IN THESE
MANIFESTATIONS, SO THEY SEEM TO
CO-OCCUR, THEY CO-OCCUR IN
FAMILIES BS SO THEY'RE RELATED,
AND THERE ARE SOME SIMILARITIES
IN RESPONSE TO THERAPEUTIC
APPROACHES ACROSS FOLKS WITH
THESE DIFFERENT MANIFESTATIONS.
BUT I APPRECIATE THE QUESTION
BECAUSE I THINK WHERE WE NEED TO
GET IS A GREATER UNDERSTANDING
OF THE MOLECULAR BASIS AND
BETTER DEFINITIONS OF DISEASE
THAT RELATE TO THERAPIES.
>> IF I MAY JUMP IN, I JUST WANT
TO SAY THAT WHAT DR. CRISWELL
JUST SAID, IF WE CAN GET THERE,
IT WOULD AVOID SITUATIONS LIKE
THE ONE I EXPERIENCED, WHERE,
WE'LL KNOW IN A YEAR WHETHER
YOU'LL MAKE IT OR NOT.
THAT KIND OF UNKNOWN, EVERYONE
FALLS IN ONE BUCKET, I HOPE THAT
WE CAN GET THERE AND I THINK
FROM A PATIENT EXPERIENCE
STANDPOINT, I THINK THERE ARE
DISTINCT ADVANTAGES TO
CONTINUING DOWN THE PATH OF
UNDERSTANDING WHAT BUCKETS
EXIST.
>> SO THAT MAYBE 10 YEARS FROM
NOW, 20 YEARS FROM NOW OR
WHATEVER, WE'D BE ABLE TO SPLIT
A LITTLE BIT, ANYWAY, RATHER
THAN LUMP EVERYTHING.
THAT'S WHAT YOU'RE INTENDING TO
SAY, IS THAT RIGHT?
>> I WOULD CERTAINLY HOPE SO.
>> AND CERTAINLY, THERE'S EVERY
REASON TO BELIEVE GIVEN ALL THE
THINGS THAT YOU GUYS HAVE TALKED
ABOUT THAT THERE WILL BE
OPPORTUNITIES TO MAKE SOME OF
THOSE DISTINCTIONS.
SO HERE IS A QUESTION FOR
DR. HOLLAND.
AND THIS IS A QUESTION, I'M SURE
HE'LL TURN THIS RIGHT BACK ON
ME, BUT THIS IS A QUESTION FROM
MARK IN THE AUDIENCE, WHO WANTS
TO KNOW, DR. HOLLAND, IS THE IBS
DENSE
INCIDENCE OF ENVIRONMENTALLY
INDUCED REACTIONS DIFFERENT NOW
THAN, SAY, 150 YEARS AGO?
>> YOU KNOW, I WAS GOING BACK
THROUGH MY ROLODEX TO SEE WHAT I
WAS DOING ON THAT DAY, BUT I
THINK I LOOK PRETTY GOOD
ACTUALLY, BECAUSE YOU KNOW, I
THINK THIS IS A REALLY IMPORTANT
QUESTION, AND LET ME JUST SAY,
NUMBER ONE, I ACTUALLY WASN'T
THERE, BUT NUMBER TWO, THE
PROBLEM IS THAT WE'RE ONLY AS
GOOD AS THE RECORDS WE HAVE.
AND I THINK MOST OF US BELIEVE
THAT THINGS LIKE INFLAMMATORY
BOWEL DISEASE, ALLERGIES, PEANUT
ALLERGIES, I THINK MOST OF US
BELIEVE THOSE THINGS ARE
INCREASING IN FREQUENCY OVER THE
LAST FEW DECADES.
I REMEMBER I WAS AT A MEETING IN
ZAMBIA JUST A COUPLE YEARS AGO,
AND ONE OF THE IMMUNOLOGISTS
FROM ZIMBABWE WAS COMMENTING
OTHER THE FACT THAT OVER THE
LAST 10 YEARS, HE HAD SEEN
ALLERGIES TO THINGS HE HAD NEVER
SEEN ALLERGIES TO BEFORE.
PEANUTS, POTATOES, THINGS THAT
WERE STAPLES OF THE ZIMBABWE
DIET THAT HAD NOT BEEN CAUSING
TROUBLE UP UNTIL SOMETHING
CHANGED.
NOW WHAT THAT WAS, I DON'T KNOW
IF IT'S TOBACCO OR TWINKIES OR
WHAT, BUT IT'S SOMETHING THAT
WE'VE GOT HERE AS WELL.
SO I THINK THAT THE CHANGES OVER
THE LAST 150 YEARS ARE HARD TO
SORT OUT.
THE CHANGES OVER THE LAST 30
YEARS ARE EASIER TO SORT OUT,
AND THEY'RE QUITE DRAMATIC, AND
I THINK THIS IS WHERE WE'RE ALL
HAVING TROUBLE FIGURING OUT IS
THIS A MICROBIOME CHANGE, IS
THIS AN INGESTION CHANGE OR
MAYBE THOSE ARE ONE AND THE
SAME.
MAYBE IF YOU EAT A LOT OF
TWINKIES, YOUR MICROBIOME, MAYBE
IT'S TWINKED.
SO I THINK WE'RE ALL GOING TO
HAVE TO SORT OUT OVER THE NEXT
FEW YEARS EXACTLY WHAT ARE THOSE
EXPOSURES THAT ARE LEADING TO
THIS.
BUT IT'S CLEARLY ENVIRONMENTAL,
WE JUST DON'T KNOW WHICH PART OF
THE ENVIRONMENT IT IS.
>> THAT'S A VERY GOOD POINT.
VERY GOOD POINT.
SO I THINK WE'RE GETTING CLOSE
TO THE END HERE, BUT HERE'S A
GOOD QUESTION FOR DR. CRISWELL.
WHY IS THERE A PREDOM NAPTLY PREDOMINANTLY
FEMALE PREDISPOSITION TO DEVELOP
LUPUS?
>> YES, AND IT'S VERY STRIKING.
ONE OF THE MOST STRIKING AMONG
THE AUTOIMMUNE DISEASES.
AND THERE ARE SEVERAL LINES OF
EVIDENCE THAT IMPLICATE HORMONAL
FACTORS INCLUDING WHEN LUPUS
TENDS TO OCCUR OVER THE COURSE
OF THE LIFETIME IN RELATION TO
HORMONAL FACTORS.
THERE ARE GENES ON THE X
CHROMOSOME THAT HAVE BEEN
IMPLICATED IN LUPUS, BOTH FROM A
GENETIC STANDPOINT AN AN
EPIGENETIC STANDPOINT.
ALONG THOSE LINES, ONE OF THE
TYPES OF STUDIES THAT I FIND
MOST INTERESTING ARE STUDIES OF
FOLKS THAT HAVE ABNORMAL
KARYOTYPES, ABNORMAL SEX
CHROMOSOME STEREOTYPES.
FOR EXAMPLE, INDIVIDUALS WITH
TURNER SYNDROME, XO OR KLEIN
FELTER'S XXY, AND IN THOSE
INDIVIDUALS, THEIR RISK FOR
LUPUS RELATES TO THE NUMBER OF
COPIES OF THE X CHROMOSOME THEY
HAVE, NOT NECESSARILY THEIR
GENERAL PHENOTYPE.
SO KLEIN FELDER, MORE COMPARABLE
TO LUPUS, TURNER SYNDROME
FEMALES HAVE DECREASED RISK OF
LUPUS MORE SIMILAR TO MALES.
SO CLEARLY, TOESAGE OF GENES ON
THE X, WHETHER IT'S BECAUSE OF
INHERITANCE OF ADDITIONAL COPY
OF THE X OR PROBLEMS WITH X
CHROMOSOME INACTIVATION ARE PART
OF THAT EXPLANATION.
A TOUGHER QUESTION MIGHT BE
WHY -- NOT ALL AUTOIMMUNE
DISEASES SHOW THIS FEMALE
PREDISPOSITION, BUT ANYWAY, I
THINK BETWEEN HORMONAL FACTORS
AND GENES ON THE X CHROMOSOME
THAT GOES A LONG WAY TO EXPLAIN
THE FEMALE PREDOMINENCE FOR
LUPUS.
>> YES, INDEED.
WELL, AT THIS POINT, WE ARE DOWN
TO OUR LAST MINUTE AND
20 SECONDS OF THE TWO HOURS, AND
SO I THINK THAT AT THIS POINT,
WE SHOULD PROBABLY BRING THINGS
TO A CLOSE.
I AGAIN WANT TO THANK JENNIFER
FOR MAKING HERSELF AVAILABLE.
THIS HAS REALLY BEEN FANTASTIC,
HAVING THE VOICE OF A PATIENT
HERE TO REALLY PUT EVERYTHING IN
PERSPECTIVE.
I THANK DR. CRISWELL FOR A
WONDERFUL LECTURE AND
DR. HOLLAND FOR A WONDERFUL
LECTURE, AND ALL THREE FOR
ENTERTAINING QUESTIONS AND
REALLY BEING VERY NIMBLE IN
THEIR APPROACH TO ALL OF THE
DIFFERENT QUESTIONS THAT HAVE
BEEN POSED TO US.
SO WITH THAT, I THINK WE'LL CALL
TO A CLOSE.
THANK YOU AGAIN VERY, VERY MUCH.
THANK ALL OF THE PARTICIPANTS,
THE AUDIENCE, THE QUESTIONERS,
AND WE LOOK FORWARD TO A WHOLE
NEW AUDIENCE THAT WILL BE
VIEWING THIS OVER THE COURSE OF
THE NEXT WEEKS IN THE VIDEOCAST.
SO AGAIN, THANK YOU ALL VERY
MUCH.
HAVE A GOOD EVENING, 'ER ONE,
AND EVERYONE,
AND WE'LL LOOK FORWARD TO SEEING
EVERYONE BACK AGAIN NEXT TUESDAY
AFTERNOON.
THANK YOU.
>> AND THANK YOU, DAN.
>> BYE-BYE.