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.