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here as nih, and we recognize that the biggest audience that we have are ph.d. students, postdocs, a whole smattering of people, many of whom never studied pathology or histology, some never took biochemistry. so what this clinical

investigator does is talk in like scientific american terms, you know? things that any intelligent person can grasp on, the purpose of this whole course is to excite, it's not to have you fill a notebook full of things that somebody is going to ask

you to memorize. so things like changing epidemiology, how do we know when somebody has what we're talking about, and where do things stand, somewhat low key, and why that individual happens to be here at the nih spending their productive years doing the

research that they do. the second speaker is usually a leading basic scientist who relates what do we really understand in a reductionist sense, molecular, whatever sense, what's really going on with this disease, what do we know, and what are the

challenges? and the emphasis is on challenge, because most of the people who come here take this course. they know all the current technology, they know a good bit of genomics, informatics, they know a great deal about it.

but they know very little about human disease. what it looks like, what it feels like. they know words. at any rate, i don't want to belabor this point but i hope you get the message. and you're all welcome, of

course, to go to the website and you can download the program for the year, all the powerpoints, and all the references which are up to date and usually has one or two good reviews of the topic, and some cv information about the speakers, and many times people in the audience

contact the speakers and sometimes striking things have happened. postdocs have even changed laboratories, which has gotten back to me as maybe not -- at any rate, today apparently we have an added feature which we don't normally have, and that is

this session is being filmed by the discovery channel. this is part of a relationship with the clinical center as part of the effort to make the public more aware of the incredible things that go on here. but in general, i don't think the public is very aware of the

amazing things that go on here. we're constantly having friends who are not in science but very accomplished in their observe field, you ask them what's the nih, and they tell you it's a big building where they hand out money. they have no idea of what goes

on here. one other brief announcement. now this has all been changed and if you go to the schedule, these changes that i'm mentioning are already there, so there's nothing new. but due to some confusion, we had to change things around so

today's topic, atopy, is today on the 16th, and on the 23rd, jeff cohen is going to talk about shingles, herpes s zoster, and some really incredible progress and advances being made in that very serious disease. then the program scheduled on the oral microbiome, meet cell

biology, and periodontal disease, which was originally to be on the 16th, will be on the 29th of march. that's all in the program so you don't have to do anything about it. okay. i just want to say one or two

other words. today's topic is one that i think represents several major interfaces in medical research. a lot of what we do in medicine starts out with epidemiology. people argue whether epidemiology is a hard science at times or -- but it gives a

clue as to where to go. but the media don't necessarily take that broad view of epidemiology. they treat it as fact. and the reader treats it as fact. so we're readers. so one of the things i hope we

will have some consideration in, are we living at a time when allergic diseases, atopic diseases, are almost like an epidemic? is asthma really an epidemic disease now? are the risks of asthma, if you're born by cesarean section,

really significantly different if you're born by vaginal delivery? there are a whole host of these epidemiologic considerations that reach the public media, and i think we have an opportunity today with two experts in this field to hear their opinion

about some of this and help put it into some perspective. because it's the public image that often drives a political image, a budgetary influence and all sorts of things which may have nothing to do with the underlying science. so we are very fortunate because

we have two experts who are going to be speaking with us, and i guess, josh, you're going to speak first, okay? so josh milner is chief of the genetics and pathogenesis section of the laboratory of allergic diseases in the niaid. he's a graduate of the albert

einstein college of medicine. that was my home turf for 30 years. so he's a prized graduate. at any rate, josh is a leading immunologist whose attention has been directed toward trying to understand sometimes rare disorders of allergy and atopy

at the genetic level, the genomic level, and mechanistically what do those genes do, is all of this a t cell business, is ige the common denominator for all kinds of -- all kinds of things like that. so josh is going to begin and discuss that.

and then our second speaker is a relatively newer arrival on the nih campus. pamela guerrerio, who got her m.d. and ph.d. from john johns hopkins, and she is interested in genetics. she's trained in pediatrics, got a fellowship in allergy and

immunology at hopkins, and her work is concerned also with basic mechanisms and trying to understand what's going on, particularly with regard to food allergy, one of the more common kinds of allergies about which i as a layman find totally confusing when i read much of

what's said in the lay press and people speaking about things that they don't know the hard science of. so we're very grateful to all of you, particularly to you folks who have come and been willing to tell your story. everybody here is involved in

science in some way or another. except for the photographer, perhaps. photographers these days have ph.d.s in molecular biology sometimes so i have to be careful. at any rate, so this is all, you know, sort of within the family.

your privacy is completely respected, people will hear your voice, they will not see your face, and we welcome you very much to share with us what you have learned about your disease, because that's really where it starts. okay?

so josh? >> all right. so we're very excited that our family is with us. sharon, brian, stephanie and scott. sandra, sorry. apologies, sandra. see, i met her for the first

time today. so -- and these are three generations. and they're going to just give us a flavor of a number of the things that have been going on with scott, who was a patient who was brought to our attention a number of months ago, and who

will really serve as the anchor for all the things that we're going to be talking about, at least i'll be talking about for the rest of my talk. so stephanie, if you could just give us a flavor of what you first noticed and how things played out with respect to

scott's allergies. >> okay. well, scott has always been our conundrum child. when he was about 2, we took him in to have him evaluated for autism because he just seemed a little off compared to the other kids.

and they diagnosed him with sensory integration disorder. and then from there, we also noticed that whenever he had eggs, he would get really sick, and then he had eczema in the different -- on his arms and legs and things like that, so we saw a dermatologist who sent us

to a an allergist and he had the scratch testing done, and they said he was allergic to eggs and dogs. very allergic to dogs. golden retriever would lick his face and his whole face would blow up. so he has always had issues with

allergies. >> what kind of thing would happen when he would eat the eggs? >> he would throw up. as soon as he would have egg, within 20 minutes, he would throw it up. if he touched egg, even if it

was just, like, baking with grandma and grandma touched an egg and then she would touch his food and he would touch his food and then touch his face, his whole face would swell up. >> and what other kinds of things happened with respect to him eating?

did he have difficulty eating -- >> sometimes when scott would eat, he would choke a lot. and we always just thought that what he had was a small esophagus because his dad and his grandfather always said that they had small esophaguses, so taking medicine, like pill form

or eating certain things, he would have a lot of difficulty swallowing it. >> would that cause pain also? >> absolutely. so he was -- we always called him our expert vomiter because he could vomit. if he just knew how to get it

up, if needed, he could always make himself throw up. >> were there any other things so besides you mentioned the behavioral differences that you noticed, were there any other things that didn't seem to you to be as related to allergy that you noticed as well?

we had him tested for adhd, we had him -- we even spent a couple thousand dollars to have him tested educationally for processing, all sorts of stuff, because there was just something always a little off, so he was diagnosed with adhd, more of the add, more than the hyperactivity

part. and with his eczema getting really, really bad, it also led to depression, where he just was a very unhappy person, in fact, a couple years ago, we went on vacation out of the country, and his eczema got so bad, it was like head to toe he was red,

that he didn't want to come out of the hotel room. so it was the most miserable vacation in a tropical paradise because he didn't want to come out, and when we did go to the grocery store in that country, they all thought he had like some kind of -- what was the

virus they thought? chickunguya. they were all looking at him funny because he was so red. >> anything with his skeletal system that you noticed that was different? >> a few years ago, during one of his checkups, his doctor said

his spine was curved, so now he sees a orthopedic doctor and has to wear a back brace at night for scoliosis. >> scott, i understand you can do some interesting things with your joints as well. could you share one of them? very quickly, without getting

everybody -- can you do anything with your thumbs or your fingers or make a sound with them or anything like that? >> um, like this? >> do that again. i don't know if you can hear it, but -- scott can make joints pop in and out.

so okay. and dad, did some of the things that went on with scott ring any bells for you? >> yeah. i told my wife that there's no question of paternity with him. you could tell, he had a lot of the same traits as i do and as

my father had. and so the allergies are all allergic to a lot of the same things as far as shell fish, seafood, nuts, even chicken, nobody's allergic to chicken. we're allergic to chicken. so there's a lot of food allergies on my side of the

family. and again, as stephanie mentioned, the assumption that we had a narrow esophagus because we had problems with do doing -- swallowing issues and then doing scopes, those were difficult whenever we had upper endoscopies.

and so there was just an assumption that we had -- we'd all have the same allergies and we'd all have the same throat issues, and it's just something we have to deal with and we have to live with and that there's nothing really we could do about so it's sad that we passed it on

to scott. >> and sandra, you would say hadsaid you also noticed some things bothin, even just an hour ago, you pointed out some extra things. >> right. i think i probably came to the realization first that it was eoe, because just the way he

threw up was like the way grandpa did with all that mucus, and then scott had depression a year ago, and brian had depression about that same time, when he was that same age. we all got into therapy together and stuff like that. so that's what i know.

>> so scott came here and we tried to get his eczema more under control, and while he was here, we talked about issues of swallowing. so can you just give us an idea or even scott, does your skin feel better after all that was done?

and what did we do about your throat? did you take a specific medicine? >> yes. >> and then they had to do an endoscopy to look in to see if there was anything wrong to begin with, and they said there

was, and you went on the medicine for a while, and remind me, how many foods can you eat right now, how many different foods do you eat? >> i'm really not sure. >> is it somewhere around five? >> more than that. >> oh, more than that.

>> maybe about five to 10 foods. >> so there are five to 10 foods that you eat, period. and because it's hard to swallow and because of the concern for so after you went on the medicine, then what happened with your swallowing? >> um, it got better.

>> yeah? so is it easier to eat now? >> you are looking forward to the possibility of having 11, 12 or 13 different kinds of food? >> okay, great. and mom, how was that experience for you? >> it's been -- you know,

whenever we would get a prescription, he would ask for it in liquid form, he hated anything in pill form because it was always so hard to swallow, and now he doesn't throw such a fit if he has to take a pill. if he gets a headache, he doesn't get up sell the about

having to take advil because he can swallow it now and it's not such a big deal as it was before. >> so between the skin and his swallowing, would you say his quality of life has improved? >> oh, absolutely. it's like he's finally happy and

it's so nice having a regular kid again instead of one who just wants to hide in his bedroom and want nothing to do with anybody, he's seeking out friends again, having friends over, he's not hiding. it's such a relief to have like a regular kid again, like all my

other friends, instead of having one that wants nothing to do with anyone. >> well thank you very, very much for your talk. [applause] so our family gave us a good number of bits of information that hopefully i'll be able to

refer back to as i'm talking, and both in terms of the allergies that we sort of know about and perhaps some elements that we didn't necessarily think had to do with allergic disease. so the outline that i'm going to go through is first of all try to define an allergy, i don't

think that will happen in a short period of time, but we'll try to define an allergy, how they happen, how we treat them. again, this is just the highlights, this will just be scratching the surface. we'll ask why do we have now that dr. arias mentioned if

they are and why they're on the increase, and then finally get into the way that we're beginning to approach these questions from a genetic point of view and ask how our ability to understand genetics, which now in this day and age is so fundamentally different than it

was even 10 years ago, we could get insights we thought we would never have, so we'll give a few chams of thosexamples of thosewe're taking care of here and again how our family might fit into that. so what are allergies? we can break them down into immediate type of allergies and

chronic allergies. cloayou can say, i'm allergic to school, right? i'm allergic to shopping. that's the sort of thing we need to get a little more precise about it to talk about it. so anaphylaxis, when someone drops their blood pressure and

their throat begins to close, that's the most severe form of allergy. that's what scares us. that's what can kill people. breaking out into hives within four hours of a food or drug, that's a pretty classic manifestation.

getting hay fever. that was probably the first description in lay terms, hay fever, it was -- they were getting sick from hay, but actually what it was was they were having an allergy to hay and now everything else that's in the air.

lots of asthma attacks but not all asthma attacks are allergic. something called the oral allergy syndrome. i can guarantee you there are folks in here who thought they didn't have too many allergies but sneezed a lot during the fall or the spring, then

suddenly found when they found a raw mango or banana or some sort of raw fruit that their mouth started to burn or they got hives. that's actually our immune system being tricked into thinking that you're seeing pollen, when all it is is that

you're eating a raw feut. fruit. if you cook it, it was all better. and vomiting after eating a food. if it tasted really bad, you might just puke from that, but there are allergic reactions

which would cause you to rejurnlregurgitate the food immediately. then there's the chronic kinds of allergies, causing a chronic inflamed state that is sort of there all the time. allergies can make it a little bit worse or better but you

don't have a response just like that. iyou're not having an immediate reaction to the food, you're having difficulty swallowing because allergies to all sorts of things have created an inflammatory state in the esophagus, which is actually not

so different than that chronic inflammatory state that the skin can have in eczema, which would be another example of a chronic there's something called -- because i know we run into this all the time, protein proctocolitis, when you see blood in a baby's diaper because

he's having cow's milk or mom is having cow's milk and breast feeds the child, and this is very scary to the parents. it's called an allergy, it's not really using the same machinery as all as most other kinds of allergies, bur but certainly the parents will say my child cannot

have milk or my child cannot have eggs. the nice thing there is that after about a year of age, you grow out of it and it has nothing to do with breaking out into hives or any other severe but it's very important because people will call that an

something that i want to describe also is remodeling. you know you remodel your house, over time things change a little bit. that's what happens also when you have an allergy, the inflammation actually changes the room that the allergy is

happening in. so in your lungs, remodeling actually makes it that you start to lose progressively your lung function. so in fact also when you get allergic rhinitis, when you get hay fever, that also can change over time and be fundamentally

different even if you're no longer exposed to the aler gin. things which are not allergies are lactose intolerance, celiac disease when people can't have wheat, that's just a different arm of our immune system. almost all drug reactions are not allergy, but yet when you

look on a patient's chart or when you look in your own chart, you will find a whole list of things which we'll call allergies just because they don't know what it is, it was scary the first time, let's not try it again. but allergies are a specific

response to allergens, which we can all discuss what that means that, type of response is not what most drug allergies are. reflux or heartburn because you're having chocolate or something like that is not for the most part allergies, getting joint pain from eating things,

these are different parts of the immune system which are being activated. and importantly, at least half if not more of food allergies, when a mom or dad comes in and says this child is terribly allergic to milk, 50% of the time we find out that was not

the case. something happened, we know something happened, but that allergy was for sure happening in our child is actually not present. 50% of the time. other types of allergic symptoms.

just old-fashioned hives. what did you do? nothing. i was walking and i broke out into hives. stress is a great way to break out into hives. chronic itching with no explanation, probably parts of

the allergic immune system are being activated. getting in your face or in your skin, although also just being embarrassed, that can happen, but also where there's no real trigger and you can get in the face. certain kinds of abdominal pain

will happen because your allergic immune system is doing stuff do you even though you weren't eating something to which you were allergic at that time. and indeed am drop i a drop inyour blood pressure, that's an flax cyst,anaphylaxis, we'll explain why that thats in

a second. you can be pretty sure within four hours of eating a food, your throat starts to close, you can be pretty sure that that was an allergy, or if your nose starts to run and you wheeze at the same time every single year, or every time you go to that

house, your nose starts to run, exception can be your in-laws, then when that happens, that's who is likely to be your allergic immune system that's acting. it's not going to be happening all the time. this picture is a great

representation of hives. now, when do we start asking questions? wait a minute, i don't think this is an allergy. how many folks have this either for themselves, for their child, because of one reaction to something, their doctor doing

their best did 300 different tests for allergies or tested them to about 100 things on their back and said guess what, you're allergic to milk. you read that report while you're having pizza and yogurt and having a cup of milk or something like that.

you should be skeptical that you're allergic to something when you're sitting there and eating it without a problem. so often unfortunately we go on fishing expeditions to find out what we're allergic to when really i always say, if you can't tell me what you're

allergic to, chances are i can't tell you what you're allergic to, and that is a pretty good rule to have to avoid getting stuck with tests that say things that don't make a lot of sense. these are some of those tests. on the top are skin prick testing, where a little bit of

that allergen has been very carefully put together and standardized. there are actually volunteered throwt who standardize the strength of the allergen for the fda, they are the designated people that go quick like that, and if it stays within a certain

size, it's good, if it's too small, they'll have to have it again, if it was too big, that means it was too potent. there are people, that's their job, and again, these tests are there to determine whether or not you're allergic, and one way is to introduce it into your

skin. i should point out about 50% of the time that someone has a positive food allergen, it's raw. so you only do that test if you really, really think that it's a -- and you don't do that test if you're just trying to guess

what it is. why that is, we don't know supervisor, supervisor well. again, those tests -- where it can actually predict for you, where i can say, this test level -- 50% chance or an 80% chance of failing a challenge with that particular food.

hall eng can be eat the food, let me watch you and see if you have a reaction or here, inhale the allergen and see if it causes you to wheeze, stick it up your nose, see if it starts to make you sneeze. i didn't have one just now. excuse me.

and those are all ways that we can test them. actually those are the more real life ways we can challenge someone. the gold standard for diagnosing a food allergy is to watch someone eat that food. that's the gold standard.

interestingly, it only works if i don't know what the food is that i'm giving you and you don't know. you don't know what food you're getting. because believe it or not, if one of us knows, then the accuracy of that test stunk.

tells you how much the brain can mess with the allergic immune system and that's something we'll discuss in a little bit. on the bottom is a thing called patch testing. that's if you're looking for something that gives you something called contact

dermatitis. you get a rash right above a belt buckle because nickel will give you an allergy. for those whom that's an epiphany, no problem, i'll charge you later, but nonetheless, there are contact things which by touching your

skin cause inflammation. they're not really allergy, they're not quite -- obviously you're not gonna anapha lax to those things you're having contact to and you can't really test them by doing a skin prick, you actually put them on the skin, it takes 48 hours and it

takes about that long to have a response to if you're going to have a response to it. so that's patch testing and it has limited value. how do there's allergies happen? again, these are just the highlights. you have the obligatory picture

of somebody sneezing. so i dp. e. ge. the antibody ige which is here, we have antibodys that can fight infections, we have antibodies that coat the lining of our gut like iga, and ige, its purpose is not 100% clear in humans.

it's not 100% clear. but we know whether i what itcan do is cause a pretty bad allergic reaction. so we take a cell called a mast cell. the mast cell contains within it all sorts of things that when the mast cell releases

everything inside, causes allergic inflammation and allergic reaction. the most famous one is histamine. histamine is inside of a mast cell and it's released immediately and that's what you take an antihistamine for.

is histamine. the blue is the histamine. i'm not a graphic artist but bear with me. so on the surface of the mast cell is a receptor that can recognize ige and ige specifically. the bottom end of ige.

down here. is what it recognizes, just like op the otheon the other end ofthe ige is what it's specific for. in this particular case, we've got you're allergic to peanuts, this is not drawn to scale. you're allergic to peanuts and when peanut comes along, and you

happen to have ige antibodies specific for that peanut, then the reaccep receptors signal andthat causes the mast cell to release what's inside of it. that's classic immediate hypersensitivity. you already have those antibodies, they're sitting on

the mast cell, you're then exposed to the allergen and you have the immediate reaction because they've been released. when histamine acts on your blood vessels, it can cause them to become -- cause the skin and the whole area to become swollen.

they're swollen because the blood vessel has become leaky and because it's dilating. so fluid is rushing out, it becomes leaky, and also actually the diameter of that vessel increases, so that lets more blood go in, that's where the inflammation, that's where the

redness comes from, that's where the swelling comes from, and then other mediators that are in there are acting on nerves that are right there and those nerves are detecting those mediators and it's causing you to scratch, causing you to itch. so that's where, depending on

where that is, you can get hives in the skin or itchiness, if it's in your nose, it will cause you to sneeze because you're getting inflammation there, if it's in your lungs, it will cause you to wheeze. your nose could run, if it's in your belly it could cause you to

vomit, if it happens very quickly, and if all of your blood vessels are dilating and becoming leaky at the same time in your body, your body cannot keep the pressure up, that's anaphylaxis. we give antihistamines to block the histamine from blocking

locally, we giveconstrictors from sudafed to make the blood vessel tighter. there is a drug that is not terribly effective in most cases bull there arbut there arecertain areas where giving a mast cell stabilizer that can stop the mast cell from releasing even if

it's being tickled. there is a drug which actually blocks the ability of ige to get to the mast cell, so it can block the ige from ever getting to the mast cell, and it can be very effective in treating asthma and in treating chronic urticaria, chronic hives.

then antigenic tolerance. being exposed to the thing you're allergic to in the right way can make you no longer allergic to it. that's what allergy shots are. dr. guerrerio is going to explain a little more about that, making you more tolerant

to whatever it is. so that's an acute allergic reaction, the i ge. oand you have those responses immediately. then there's allergic inflammation. this is the chronic state that can happen that can cause that

eczema, that can cause chronic asthma, that can cause ee owe si know fill icky sof jiets, and a bunch of players are present. here's our mast cell with the immediate reaction, but things likely start here with a dendritic cell and a th2 cell, a helper t cell that makes a

certain set of cytokines, of messengers, to other cells that say go initiate an allergic why that th2 cell decides to become a th2 cell, it was naive, it was a freshman in college, it didn't know what it liked, it took some music, some literature, but it's deciding to

become an allergic cell? that's obviously an active area of research right now. but it graduates and it becomes a th2 cell and it makes the types of messengers that create the environment for allergy. they can create the environment for allergy by making a cell

make ige antibodies as opposed to other kinds of antibodies that can produce the allergy. it can produce il5, gets into the esophagus. all sorts of things can be released. gata3 is a transcription factor that's the master regulator of

th2 cells, and i circle it ohm because there are now drugs that target gata3 that if trails can actually prevent allergy or treat allergy. another type of mediator released from mast cells also -- we can block those as well and they prevent some of the

inflammation that you can see. so again, some of the things that get released lead to chronic allergic issues, and the other things that get released lead to acute allergic issues. for the most part, things start right here, where your t cell which was naive decided that you

should be a t cell specific for that allergy and cause an allergic reaction to that allergen. corticosteroids, so i told you all the different ways you could treat reactions but the truth is, is that the most famous way to treat an allergy is

corticosteroids. it used to be called, i think, adrenal factor. and it was noticed almost 100 years ago that it didn't stop at allergic reaction but it would prevent future allergic and it acts on a whole variety of mediators chronically, to

prevent allergic issues. the problem is, you can't stay on them because it doesn't work super well, and actually an inhaled corticosteroid for a brief period of time that scott was on made his esophagitis go away. allergen comes through and makes

itself a th2 cell right here that releases all sorts of master regulators that can get ige made, that can recruit all sorts of other cells to come in. scratching itself can release something called tslt. can yoyou can actuallyupregulate a molecule which will turn on your

immune system actually by acting on the dendritic cell just by scratching. so we often say, if you could stop someone who has eczema from scratch beinging, it's thescratching alone that's 90% of the disease, it's the scratching. part of it is because the actual

scratching turns on your allergic immune system. there was probably some bug that was a good idea to scratch, and we don't see that bug anymore, and so we're left with this system that makes us have an we'll touch on that. when things get inflamed enough

in the area, you don't need the allergen there anymore. you can have inflammation just from being exposed to the bacteria that are always in our skin, that are always around in our nose. they alone can promote this allergic inflammation without

having to see the allergen anymore. so it has to be treated differently. that's microbial talk, causing the trouble. now -- oh, wait a minute, doctor. you gave me a wonderful list of

drugs. i took antihistamine, all these other things, and i am still itching. the bottom line is no matter what allergists say, we really don't always know exactly what the story is, so there's much more room for us to advance the

science. why do we have allergies? well, it's been thought classically that parasites, worms, since they're too big for any cell to gobble them up, you have to spend a bunch of things at them to kill them. so it would kill those parasites

or cause your digestive system to expel those parasites. that's the classic thoughts for why we have what's called a type 2 or an allergic response. but we can have responses to all sorts of other things. the classic idea was that we had to fight some sort of bug, you

had to release all of these different things that causal erg to fight that bug. there's been a bit of a complementary theory that's been put forth which is that it's not just about fighting the parasites, but it's also about getting rid of foreign bodies.

dust gets into your eye if you itch, you get that dust out of your eye. if tears get made t will the dust out of your eye. if you swallow a toxin, if you have a quick reaction to it, you'll throw it up before that toxin gets into your body and

messes with your brain. it's an interesting theory, we don't have proof for it but it's an interesting theory. there's a very interesting example, there was actually a drug being given for cancer that on the very first dose of getting that drug, people were

having anaphylaxis. and it's not making any sense. you should have that drug moshdrug more than once to ever have an allergic reaction, you need to see it twice almost always. there were a group of people having anaphylaxis every time they got the drug.

interestingly, this only happened in virginia, north carolina and a little bit westward at the beginning. so that's interesting, it was only happening when a bad batch was getting into the -- that's not what it was. every person who said they had

the allergic reaction, at some point in time someone was paying attention and heard them say that they were allergic to meat. they were all allergic to meat. and what it turned out is that meat had in it a certain glycosylated -- a place where sugar is put on a protein, it

has in it this glycosylation which we don't have, and it caused an ige response to the meat and that's what the antibody was made in a cell that made that glycosylation event, that put that sugar on the protein. and what carried that

glycosylation around from the meat to the person was a tick, a lone star tick, which was only around in virginia, north carolina and westward. and so having an allergic reaction to the tick was probably a good idea. because if the tick is there and

you scratch it immediately, it can't give you whatever tick-borne virus that you might get. if it sits there for a long time, you might get sick. so it's an advantage to notice and have an allergic reaction to that tick.

the disadvantage is you might not be able to eat meat and you can't have this drug that could save your life for cancer. so it's nonetheless a really interesting story where here, we have an allergy to protect us from a tick from actually causing a problem.

another way that's been shown is that if you get these things, can you have an allergic reaction to a bee sting, there's no doubt about it, but actually the venom from the bee sting is what usually kills smaller animals. it's not an allergic reaction.

what's killing them. there's actually some very interesting data that you need to have that ige, and only that allergic antibody will work to go and bind up bee venom after that first sting that if you got stung by six bees later on, the ige would bind it up and you

would not have a fatal venom reaction, a toxic reaction, not an allergic reaction. so it's there to protect us even though we can also have allergies to bee venom. so those are pretty interesting examples of why we might need to have those allergies but for

some reason it goes awry. why are they on the increase? yes, we hear about more on the web and yes, hearing about it on the web gives people allergies, no doubt about it. but nonetheless, it is definitely treul that as time has passed, there are more of

almost every type of allergy that we have. and the big reason that everybody gives is the hygiene hypothesis. we avoid the bug that we used to get when we were younger and keeping our immune system occupied with those bugs

prevented us from having our immune system do the things that causal ergs. so we don't like hand washing, we like the kid wallowing in dirt. another thing that has happened because we're afraid of allergies is we stop introducing

solid foods when babies were young. and dr. guerrerio will discuss that avoiding those solid foods when babies were younger actually made it worse. we got morale erg morale moreallergies because we were avoiding foods when babies were young.

we're exposed to the wrong foods, the wrong chemicals, if the dir is in the middle of new york city, it might not contain the right bugs to keep you from having allergies. then there's something else about western lifestyle that i thought was important to point

out. i had a patient say that to me, dear doctor, xanax is the most wonderful antihistamine i've ever taken. now, they then produced a paper that showed that the drug actually might inhibit mast cells, okay, fine.

but the chances are that's not how it was working. the chances are, is that the stress was being mitigated. their stress was being mitigated and that's why they weren't having as bad a reaction. stress now is different than stress was, let's say, a

thousand years ago. i actually love this comic from "the new yorker." everything was better when everything was worse. there are things that got us much more stressed a thousand years ago than the things that get us stressed now.

but it seems to be it's the things that get us stressed now that cause the allergic irissues. so being eaten by a sabre tooth tiger was not nearly as stressful as having to go to your mother-in-law's house. i keep harping on that. i love my mother-in-law.

anyway. and so getting up here and speaking is worse than an electric shock, according to a recent study, where they shocked mice, or they shocked people, oh, my goodness, they shocked people, or they made them get up and give a speech, just like

this. and they looked at the intestinal permeability in the people who were shocked, versus the people who had to give a speech, and there was increased intestinal permeability basically like ibs, okay? pain in the belly from being

nervous from the speech. but not from the shock. those are two very different kinds of stressors. but only one of them seems to cause the kinds of problems that you might see. and it actually -- there is reason to believe that it's mast

cells that are mediating this permeability. because mast cells can actually be exposed to certain types of steroids that make them release what's inside them very easily. and the reason why we think this is here is the person giving a speech, this is their intestinal

permeability right here. if i give them chrome lin, which stabilizes those mast cells and preeivets them from releasing what's inside, their guts are no longer as permeable. so not only have the bugs changed, but the things that stress us out have changed too,

and that may also be contributing to our eiler jik diaphysis. all right. the microbiome analogy, again, these are the types we see, discuss them at length. i just thought this was interesting, i went to school

with this woman and she's written about the dirt cure, growing healthy kids with foods straight from soil. i'm sure it's the bacteria that's on there. how do genetics contribute to allergy? let's get into some examples of

how we can study the genetics of allergy to learn about the genetic immune system. here's one thing i'd like to throw out there as a possibility for why allergies are increasing, and that; well, the genes for allergies were always there, we just changed our

environment. the genes were always there. allergies would have always run in families, but we had to leave the farm. you got off the farm, we were exposed to the same type of bugs, and that is what brought out those genes which would lead

to allergy. there's not new genetic diseases, or when taylor swift moves from country music to pop music, same thing. same thing. now, the skin and the skin barrier, thank you, scott, for laughing, i appreciate that.

the skin barrier is supposed to be this nice water-tight barrier that keeps things out and keeps the water in. it doesn't just sit there. it's dynamic. it's turning over all the time. that's why we shed skin, that's why we don't lose our skin after

shedding our skin, it's always turning over. and there are these little pieces of glue throughout the skin or pieces of brick which the glue sticks to that keeps the skin as nice and waterproof at preventing things from going in.

and actually if you bring up the ph you by certain types of soaps or detergents, that actually makes this glue eat itself and fall apart. well, there are genes, tons of genes that control this glue. there are genes that, again, they make the brick, there are

genes that make the glue, there are genes that eat the glue, such as proteases, and then there are inhibitors of the gene protein products which eat the glue so as to not eat the glue all the way through. one of those genes, for instance, is lekti, which eb

codes for spink35 which is one of the inhibitors of proteases. if you don't have that gene, then the glue eaters can go to town, and this is what it looks like. that patient is missing the one gene in spink5. another gene that's in there is

something called phalagren, it's part of the brick, and when it's mutated across the common population, it might be only 50 people in the world with spink5 mutations, but in the common population, mutations in filaggrin are quite common and having them increases

substantially your risk for developing eczema. one thing that we can do then, a lesson we can learn from that is that we need to protect that barrier as much as possible. so this is not scott, this is someone else, who we treated by literally creating a barrier for

them. we give them a bath, it gets them moist, we put steroids on it, we put other types of things like vasoline and wrap them up like a mummy. after that, for a week, they come out looking like the gerber baby because we've improved

their barrier, and it let them get better on their own because then this is bad eczema, let's just put it that way, and for like a year, it can stay pretty decent. just by getting that barrier back in shape. it has nothing to do with the

immune system. it only has to do with the structure of our skin. getting an eczema infection when you also have eczema is interesting. it seems to be a genetic disease. you have mutations and something

called the interferon gamma receptor 1. if you're completely missing it, you die of viral infection. but if you just have it not working as well, you get eczema herpeticum. that's a specific gene that would you actually target to

prevent eczema herpeticum as opposed to just saying, that kid happened to have bad eczema and happened to get eczema we don't have to say anymore, it just happened to happen. there are a number of disorders which we've begun to study where one gene mutating -- mutating

one gene led to allergies. it also leads to lots of other stuff. so we get clues from those other things, like scoliosis, or depression, or behavioral differences, that give us a clue that it mit -- i'll just mention very quickly a couple that we've

found. plaid. antibody deficiency and immune disregulation. the way that we solved the problem was that the baby's nose thank goodness got better after three years, but that same baby, if you put water on his skin,

caused a hive as it evaporated off of his skin. so the tear caused a hive or just screeching out a spong of water right on the back immediately caused a hive. they had allergy to cold. there were other issues that led to that nose leagues you're

lookinleagues, but theanswer iseverybody is allergic to cold. the problem was these patients said i thought it was normal to itch when it's cold. doesn't everybody itch why it's cold? that's why nobody ever figured out that there was something

running in their family that was a specific gene that led to this entire syndrome. so they can get immune defish vees, they can get autoimmunity or nothing but the cold allergy. and that's what threw people off. we learned a lot about signaling

just from studying these patients with bad allergies and the mechanism, we can talk about it another time. another disease here where they got terrible allergies, bad infections, neurologic issues, delays, scoliosis and other problems, we're hearing a theme,

although this is not at all what's going on with scott, and they can have a number of problems in their laboratories, these are two different families that have it. here is scoliosis and bad eczema in one of the patients. his mutation was in a gene

called pgm3 which controlled glycosylation. i know most people here are ph.d.s, nonetheless, now we had to learn about glycosylation because the patients were showing us something that is important about a specific pathway.

a specific pathway which told us about a gene that prevents pgm3. and what it does is it preeivets actuallpreventsactually puttingsugars on proteins. it's low inside the cell and what's really important about finding this is that we can fix

it by putting in more of the sugar. and actually there's a clinical trial happening roit now to supplement these patients with with -- glucosamine, and there's patients with this genetic disorder being treated because we found the gene.

and the question, of course, is how many other patients are out there. was that not as severe of a mutation but enough to cause problems with the pathway and causal erg. could that be a new way to look at allergy.

finally, so in addition to the allergies that we saw with scott, there was one thing that was a little bit different. he had a high triptase, one of the mediators you find being released by mast cells. it's stable so you can measure it for a while, it usually goes

back down after an allergic his triptase was up all the and it's also up in his dad. if we could draw it in grand dad, we'd find it up in his grand dad as well. because what he had was something called f familial hypertryptasemia.

it can lead to a variety of symptoms of mast cells constantly emptying out what's inside and other issues which don't make quite as much sense. so recurrenting and itching and swelling like angioedema. hypermobile joints or scoliosis, which we heard about,

anaphylaxis, eczema, asthma, food and drug allergy, which we heard about, episodic pain in the belly, ibf, colitis, which we heard about in the family, tachycardia, palpitations, anxiety and depression, pain, fatigue and brain fog. but there's nothing wrong with

the bone marrow, there's no mast cells that are going crazy in the bone marrow. you can actually get them to by just putting their arms on a vortex, please don't try this in the lab, god knows what you put on that vortex. this is just an comparable ofexample of what

that hypermobility can look and this runs in the family. we only found it because we happened to draw triptase in a few original families. this one family initially, then we said, huh, who knew that having a high trip tryptase. so we kept asking folks and

drawing their tryptase and we found more, we found more. this is a partial that we found about 50 families, we have 150 patients, and they all have the same issue of having a high tryptase, many of the estimates this family has just described to you, and actually it runs as

a monogenic, autosomal dominant trait. what's also interesting about that is that it tushe turns out4 1/2% of the population has always had a high level at baseline. that's just where we decided to make the cutoff. it turns out a huge percentage

of those folks have many of the sicts we discussed. maybe not every one of them is as severe but lots of them have the same types of symptoms just for having the high trip taste. what we're fairly sure about in the lab is that every single one of them carries exactly the same

gene causing it. so by getting to the bottom of this familial inheritance of something that we just felt was totally sporadic, we thought that the eczema was sporadic, we didn't think it had anything to do with the scoliosis or the depression or the fact that dad

and grand dad had issues with swallowing or with their bellies, families like them and many other families, we found that there really is just a single gene causing this issue very commonly. it's not a rare disease. last thing i wanted to mention,

my mentor for four years was dr. bill paul, who many of you may have heard of, i'm sure many of you have to use his textbook for fundamental immunology, he passed away just a few months ago. he was like a father to me. and bill paul's claim to fame

for those who don't know is just that he discovered il-4. the cytokine that mediates allergies, it's fundamentally important for making an allergy to happen, he called it b cell growth factor. this is the original paper in jem in 1982, he described il-4,

and that was the basis for enormous amounts of research no into the fundamental reason why we have allergy, and i just put it up there because in the past year, we've had -- in fact, several years, we've had trials come out that show that by blocking a receptor for il-4, we

can block some of the most severe allergic dpeez diseases that are not able to be treated in any other way besides perhaps terrible immune suppression with steroids, and that all becomes, because of the bench work of dr. paul, from 30 years ago. so i will leave it at that.

these are some of the wonderful folks who work with me, and are just absolutely fantastic colleagues. and i will answer any questions. >> so my question is in regards to a variety of allergies, specifically somebody who's allergic to pollen is not as

allergic to pollen as somebody else. what are the causes of that other than genetics? >> so there can be genetics, there can be environment, there could be the type of bacteria that person a lived with is different than the type of

bacteria person b lived with, and importantly, there's something called imprinting in the immune system, where something during a critical window, and we don't know exactly when that is, when you got exposed to that poll ep, en, either it made it more or less

likely that you would have a severe reaction to. maybe you had a virus at the time you were exposed and it was different if you didn't have that virus when you were first exposed. so it could be critical early life events, it just happened to

be you were on the wrong bus at the wrong time in that time, in addition to the genetic explanation. >> so what's the relationship between allergy and autoimmunity? >> ah. so very important question, and

actually it gets confused very often by patients. autoimmunity, we define for the most part is the body's immune system attacking itself. allergies, for the most part, we believe is the body's immune system and really specifically the allergic arm of the body's

immune system attacking something foreign. response to yourself? we're still not sure. does eczema actually cause t cells to have an allergic response to skin? people have said maybe that's a possibility.

but that tends to be the fundamental distinction. both foreign versus self, and the type of the immune system that's causing the inflammation. >> are you -- maybe pamela is going to talk about this, but do you want to say something about asthma as an allergic disease?

>> so asthma can be an allergic disease and it can be a thing of its own. it's hypersensitivity of the lungs, of the lung lining, of the airways, and allergens can trigger it but other things can trigger it as well. so the result is the same when

you're wheezing, but the trigger can be very different. it does not have to just be an allergen that causes it. but getting allergic, it's the same way getting allergic to -- your nose to the food allergy. >> i'm just wondering -- so you use tryptase as a marker but

it's also an enzyme. are you thinking that something that maybe the mast cells are releasing are then damaging the -- >> yes, that's a great point. how do we put together there are allergies going on, you have scoliosis, you can pop your

joints in and out, how do you put those things together? first we thank the patients and the genetics are pointing that to us. that's step one. but step two is indeed, tryptase and a lot of things like it that get released from mast cells can

eat away or change the collagen. it's been going on your entire life, it could change the fundamental way your joints and your bones get made. >> so if you would maybe catch it early enough, possibly you can prevent some -- >> potentially, right, if we

could target that gene specifically, perhaps all those issues would not happen. would that stop everything that's going on in this family? can't really be sure yet, but we'll have to try. >> so where does allergy appear in the phylogenetic tree?

>> i don't -- bill used to tell me this and i don't know the answer to it right now. it goes -- there is ige in lower beings as well. i don't remember which. i want to say -- i can't remember. i don't remember how far back it

goes. >> i'm not asking whether fish have asthma, but what i mean is, is there something comparable in the reptile -- >> i mean, mast cells are old. mast cells are very old. so some form of it probably is. >> what are things that are not

allergies that we commonly call allergies, like say reflux or something like that, how do those -- what systems are changed in those, and would you still see an allergist? >> good question. so it's going to be hard for you to know beforehand, before you

go to the allergist who tells you thanks for coming but you didn't need to see me. maybe your doctor, your primary doctor would know. if you're getting reflux, chances are an allergy is probably not causing it. in some cases it could be

possible but most of the time it's not. or if you're having those belly papers and alpaperbellypainswhen you're eating wheat, it's more of an autoimmune problem, it might be a rheumatologist that might take care of it. often it's the primary care

doctor who is aware of the different types of reactions you can have, what looks more like an allergy and what more doesn't look like an allergy. the reap it matters is the management is completely dirn and what you need to even worry about is completely different if

it's not being caused by an >> are there any efforts to -- is there a way to think of reprogramming these iges to not -- >> so dr. grair ro guerrerio isgoing to discuss that, but when we get allergy shots, we believe we're getting a different part of the

immune system to attack the allergen and box out the ige to use a basketball term. i think we should proceed with dr. guerrerio and there will be time afterwards for more questions for dr. milner. >> so as josh has alluded to, pathogenesis of allergic disease

really seems to involve both a genetic predigs position as well as exposure to several environmental or lifestyle factors. we know that variations in certain genes involved in different arms of our immune system, both adaptive and innate

immunity, as well as the intestinal and skin barrier, can all predispose to allergic disease, including asthma and food allergy and eczema. however, several environmental factors including microbial exposures, vitamin d insufficiency, and timing and

route of food introduction can also play an important role. in order to maintain toltolerance, the new system not only has to tell the difference between self protein seproteins and non-selfproteins, it also has to tell which are harmful and which are innocuous, and those include the

environmental allergens. this is an issue at all barrier sites relative to allergic disease, it's really no small issue. for example, the human intestine is exposed to over 30 kilograms of food protein each year and it has to know not to react to all

that exposure, which is all foreign. the answers that we still don't completely understand the mechanisms by which tolerance to these innocuous antigens develop. but in the case of oral tolerance, food antigens are

thought to be taken up across the lumen of the small intestine, where they're transferred to these dendritic cells marked by cd103. these cells then go to a lymph node called the mesenteric lymph node. the t cells that are still in

school as josh was alluding to. in the presence of certain factors, these cells turn into a type of immune cell called a t regulatory cell that specifically recognize that particular food. and these t regs, as they're known, are able to suppress an i

meunl response to that food when you're reexposed to it, so when you eat the food again, you have these t regs in your gut that prevent your body from reacting to it. the mechanisms that we still don't yet completely understand, some failure in this process can

lead to the development of these allergic th2 effector cells, and these are the cells that then promote ige protection, they cause the recruitment and activation of all those other inflammatory cells important in allergic responses like mast cells and eosin fills and

basophils. for the longest time, tgf beta has been realized as one of the most important players in the development of toll rants. we don't really know if that's relevant to humans. until very recently. we recently had the opportunity

to ask what will alterations in tgf beta signaling may play in the pathogenesis of allergic so patients with -- syndrome have indications eb coding the receptor, this is what tgf beta binds. lds is a relatively rare connective tissue disease and

was initially characterized by hypertelorism, the patients develop cleft palate and they have a split or bifid uvula and also develop arterial tore teu os it, aneurysm and dissection. they're also at highly increased risk at developing nearly all forms of allergic disease.

we found just under a third of them had been diagnosed with eczema, over 40% with hay fever and seasonal allergies, just under 40% with asthma, almost a quarter with food allergies, and 10% with e eosinophilic esophagitis. consistent with their allergic

allergic -- they're pretty well within the normal range, the majority of the patients also had increased eosinophils in their blood. so as i showed you in that picture earlier, one the most important cells that's involved in the development of tolerance

are t regulatory cells. we quantitated their frequency in blood in people who have allergic disease but don't have any known genetic disorder, and as you can see here, we actually found more t regs in people with -- as well as people with allergic disease who didn't have

a genetic syndrome compared to their age matched controls. this increase was primarily in those t regs that expressed only moderate levels of a protein called fo. p3 which i fox p3. this is not at all what we were expecting. clearly our patients were

showing a loss of tolerance. we thought about one possibilities, one that the increase was a compensatory response to all the allergic inflammation in these patients. the second possibility is that the t regs just weren't working right.

one of the hallmarks of a t regulatory cell is that they don't -- by other t cells. however, we found that all subsets of t regs in our patients with lds as well as people with allergic disease who do not have lds produce the allergic cytokine il13, and this

was not seen in non-allergic controls. we also saw an increase in another type of inflammatory cytokine called il-17 but do not see an increase in interferon gamma, which is really involved in different types of immune responses, the opposite or

conversion of allergic disease. these data suggested that each though allergic people, including those with lds, may have more t regs, these tr eggs could be promoting rather than inhibiting allergic our study with this rare disease has also taught us that

mutations in just a single pathway, the tgf beta pathway, may be sufficient to predispose to allergic disease, and we think that could have really important therapeutic implications for allergic disease which has such a complex etiology.

one of the things missing from this picture that we think is very important in the development of tolerance are microbes, again not drawn to scale. so while there are fewer of these in the small intestine, the large intestine is home to

over 100 trillion bacteria, comprised of over a thousand different species. and now there's more and more data that these bacteria play a very important role in not only the development of tolerance but disease as well. germ-free mice completely lack

bacteria, so all of this has bacteria that normally live in our skin and gut and really throughout, really everywhere, but these mice have none of they have no commensal bacteria. and these germ-free mice actually spontaneously develop high ig levels.

they get worse anaphylactic reactions, and things you mace a mouse -- they get a asthma, they have more information in their lux thalungs and that mice thatare born and bred under other conditions. however, if you call on these germ free mice with a mixture of

bacteria, specifically during the neonatal period, you can actually prevent this dedisposition for them to develop allergic disease. the rise in prevalence of allergic disease over the last few decades has really been coincident with certain changes

in our diet. more and more suggesting these dietary changes would be eliminating bacteria that normally live in our gut in a way that's promoting our current westernized diet is not only high in sugar, but it's also very high in fiber.

this single dietary change -- for developing allergies. so they did a study in mice where they took adult mice and they put them on either a low fiber diet which contained only .3% fiber compared to mice on normal mouse food, so that contains about 4% fiber.

then what they do is they actually have the mice breathe in, and that induces inflammation in the lungs that's very similar to asthma. so when they do this, they found that mice on the low fiber diet showed much more inflammation in their lungs than mice on normal

mouse food. these mice had more eosinophils in their lungs which is what we see very similar to people with asthma and they had higher i.d. levels. they also had, again, more indications of an allergic response, higher of these

il-4 cytokines, il5, il-13, as well as il-17. and fortunately, the foreignimportantly so simply putting a normal mouse on a low fiber diet was enough to give that mouse worse asthma. so they asked is this somehow affecting the bacteria that formally live in the gut?

we know it very much shapes the commensal bacteria that live in the buys. as we can see here, there was a dramatic reduction in the number of bacteria from the family, and expansion in firmicutes. it turns out there's bacteria from this phyla very, very good

at preventing dietary fiber into a metabolite called short chain fatty acids, so they measure the concentration of these short chain fatty acids and found they were lower in the mice with the low fiber diet, so then they thought maybe the decrease in short chain fatty acids is why

these mice on the low fiber diet are more likely to develop worse so to ask that question, they took mice, again adult mice, all of them on a normal diet and they gave half of them a type of short chain fatty acid propionate around the other half saline.

then they made them allergic with house dust mites. the mice that were injected with the short chain fatty acid seems to have less inflammation in their lungs, there was significant decrease, and they also had lower ig levels. so this suggested that simply

altering the amount of one bacterial ma tab light is enough to prevent -- allergic disease. gpr41, by doing that, it was increasing the production of dendritic cells in the bone marrow, they were going back to the lung where they were less able to really induce this

allergic-type response. is there any evidence that this in humans can predispose them to allergic disease. there are many studies suggesting many of the early life events that increase the risks of developing allergic tease later in life very much

are likely to alter our intestinal microbiome, including early exposure to antibiotics, so babies that are exposed to antibiotics prenatally or shortly after birth tend to be at higher risk for developing those born by c-section tend to have a microbiota that very much

resembled the mom's skin rather than her vaginal floor a, and we know these babies are also more prone to developing allergies. children who grew up on a farm and are exposed to farm animals tend to be protected against allergies compared to those that grow up in an urban environment.

this one is a little more controversial but there's some evidence that infants that are breast fed may also be protected against allergies compared to those that are formula-fed. that's been attribute today a couple different things. it's known that breast milk

contains different factors that can affect the growth of different species of bacteria in the gut, and breast milk itself can actually contain organisms that can influence the initial colonization of the baby's gut. there's been a few studies showing that children who grew

up in families with a pet, they can't really be just any pet, it's really specific for a dog, may be protected against and then finally, there's data from the database that's sort of a cross-sectional look across the united states, both children and adults, and they found that

higher levels of antimicrobial agents, including one called try cloa san, in your urine, is associated with an increased likelihood of being exposed. triclosan is found in hundreds of bacterial products. there's a very good chance you'll see it in your

toothpaste, bacterial soaps, we're exposed to these things every day. so one of the largest studies to really look at this reesery laition ship between the microbiome in an infant and their subsequent development came from canada, it was the

canadian healthy infant longitudinal study or child study. this was a multi- -- basically they just recruited 300 infants born in the general population, at birth, and then they followed them through their first five years of life.

when the infants turned one year of age, they divided them in four different groups, those who considered atopic and wheezing, they had a positive skin test toality least one of the most common food or environmental allergens, and wheezing, they had to have a doctor-diagnosed

episode of wheezing sometime within their first year of life. then there were kids that just had atopy so only positive skin test but never wheezing. those that have only wheezed and the controls who had neither of those. they collected stool from all of

these infants at three months and again at one year of age. from other study, we know infants in this category are very high risk at developing asthma later in life, and in this study, this group had almost a 20 fold higher risk of having asthma, being diagnosed

by a doctor at age 3, than those in the control group. and that really reply kailted what we already knew. however, this was a great opportunity to really ask, were there differences in the microbiome of these infants at three months compared to the

and that's what this data is showing here. so this is a way to look at what bacteria are present in the fecal matter from infants that lead to these different groups. this is from fecal matter at three months of age, and when you just first take a look at

it, just looking at the colors that are there, there was really no striking difference in the types of bacteria that were the overall composition was the same. but when you looked more closely, there were very big differences between the quantity

or the number of bacteria, relatively quantity of bacteria in the controls and the atopic -- group. perhaps even more interesting, this difference was only present at three months. when they looked at one year of age, there were no differences

at all between these four different groups of patients. so whatever effect the microbiome is having on the child's subsequent risk of vemmindeveloping allergicdisease seems to be happening very early. i'm glad i knew that now and not

when i was pregnant. so we talked earlier how short chain fatty acids can influence a child's risk of developing allergies, so they measured the concentration of these in those fecal samples from kids and r. in the atopic wheeze group as compared to controls.

as can you see, they did see a significant decrease in acetate, there are no differences in the other two that they measures, but i think what the study really showed us is that again, the composition of the intestinal micro boy ohm verymicrobiome very early in life may actually be able to

predict that child's risk of developing allergic disease years later. as you can imagine, this has generated a lot of interest in trying to find ways to manipulate the microbiome, by using probiotics. the strict definition is that

probiotics are living microorganisms which upon ingestion of certain numbers exert health benefits that go beyond general nutrition. and the most of the probiotics that have been used in clinical trial so is far have really used bacteria that are similar to

those you find in a normal healthy human intestine. so it's things like bifidobacterium and lactoba si lactobacillus. it's known that different the colon have different abilities to induce the development of those t

regulatory cells which we think are so important and tolerant. in part by increasing the levels of il-10 and tgf beta. other bacteria tend to be good and -- that might promote tolerance, and bacterial products can repair our gut barrier and enhance iga

production, which we think may be protective. however, the results of most probiotic studies for allergic disease have really produced very dismal results. in fact, i don't know of any study where probiotics, when given as a mono therapy, the

only therapy, postnatally after the child is born has had any benefit in either preventing or treating any allergic disease. there have been a few studies when moms were given the probiotic while she was pregnant and while she was breast feeding, and they gave the baby

a probiotic as soon as possible. there may be a very small benefit in terms of preventing the child's risk of eczema. but the results of these studies have been conflicting and the benefits so small that there really is just not u.ssufficient data at this point to really

recommend routine use of these agents. so why is this? why have they not been effective? we think the microbiome is so important, why aren't the probiotics working? one is that we may just not be

using a high enough dose. most of those studies, they didn't actually show that they were actually changing the composition of the microbiome when they gave the probiotic. but who knows what those bacteria were even alive or even able to compete with the

bacteria that were normally present in the infant's gut. a second possibility is that we're simply using the wrong bug. so maybe we should be using things like clo clostridia, more active in promoting tolerance. another procedure that you've

heard about in recent years is something called fecal micro boy owe tmicrobiota transplant. so basically you administer fecal material to a patient either through an n g-tube, a tube that goes down their nose and in their stomach or during a colonoscopy.

so this was initially used to treat antibiotic resistant c. difficile infection, and there was just recently a randomized control trial showing efficacy for the specific indication and it's now used quite commonly. i am not aware of any published

trials where they use this for allergic disease, but there is a lot of interest in this and i'm sure we're going to hear more about it in the coming years. as we can see in this picture, the composition and the diversity of the microbiome changes dramatically with age,

from birth to adulthood. some of the most drastic changes in diversity occur when we introduce solid foods at some time within the first year of age. what's really not clear, however, is whether earlier or later introduction of solid

foods can help prevent allergic the recommendations regarding infant feed practice have changed dramatically over the last few years. in 2000, the american academy of pediatrics recommended that parents wait until their infant turns at least 3 years of age

before introducing some of the more allergenic foods like peanuts or fish, particularly if they were at high risk for developing food allergy. in 2008, however, they completely retracted that recommendation in part because there was no evidence that

withholding foods was actually curbing the sharp rise in allergic disease that was occurring during this time period. for example, the prevalence of peanut allergy was only .4% in 1997. and just 10, 11 years later

that, had more than tripled. currently over 2% of children have peanut allergy and it is the number one cause of anaphylaxis and death related to food allergy in the united states. so around the time they changed the recommendation, there were a

few studies coming out that suggested that maybe we got it wrong, really complietly wrong. so in 2008, detroit and colleagues in the u.k. showed that the prevalence of peanut allergy among jewish children living in london, where it was standard practice for parents to

avoid peanuts until their child was 3 years old, was 10 times higher than among jewish children living in israel, where irts common practice for infants to get exposed to peanuts within the first few months of life. almost all in israel have peanuts by the time they're six

months old. there were similar results seen for milk allergy, the prevalence of milk allergy was only .05% among infants who had at least some exposure to cow's milk within the first two weeks of life compared to 1.75% if the infant wasn't exposed until

after three months of age. and they saw similar rates with egg allergy in australia. here the odds of developing egg allergy were 1.6 to 3.4 fold higher if the child was first exposed to egg after 10 months of age compared to at 4 to 6 months of age.

so to rigorously ask and answer this question introducing peanuts into a child's diet could prevent development of peanut allergy, they did the loop study. the learning early about peanut allergy study. this was a randomized trial

performed and a single site in the u.k., where they enrolled infants 4 to 11 months of age. these were kids that were very high risk for developing peanut they had to have severe eczema, egg allergy or both of those. at the baseline visit, when they enrolled the infants they skin

prick tested them to peanut just to see where they stood. i think surprisingly, a number of those infants were already sensitized to peanuts. they already had ige to poe nuts. they weren't eating them at this age, but already a group of

them, almost 100 of them, had ige to peanuts even though they had a negative challenge to peanuts. the rest of the infants were negative. infants in both the groups were then randomly assigned to either peanut consumption where they

were told to eat at least six grams of peanut protein divided over three meals every week, or strict peanut avoidance, where they were to avoid all contact, any exposure to peanut whatsoever. they had to do this for five years, until the child turned

5 years of age. this is a long study. the children in that consumption group for the most part ate the snack food called bomba just like they were eating in israel. this is a snack food that's made of puff corn and peanut, looks a lot like a cheeto.

those that didn't like it consumed peanut butter. so in primary outcome in this study was challenge proven peanut allergy at 5 years of and i think the results were really more dramatic than anyone could have anticipated when we started with this study.

if you look at that cohort of infants who were initially negative, had a negative skin test of peanuts, you can see the prevalence -- almost 14%. 14% of those kids went on to develop peanut allergy compared to only 2%. you look at the cohorts -- they

were well on their way to developing a peanut allergy, those who ate peanuts, who are in the consumption group, were three fold less likely to develop peanut allergy. and where you look at what's called a protocol analysis, we only look at kids who are doing

exactly what they were told to do, you could see almost nobody who was in the consumption group went on to develop peanut this group followed both skin prick test responses to peanuts as well as peanut-specific ige levels over the course of the study, and one of the things

that i found really interesting is that peanut ige tended to increase over the five years in both the peanut avoid dance and in thavoidance andpeanut kuhnsumtion group, however it was only the true peanut con sthawms had -- compared to those who were tolerant, which is shown in

blue. ne also measured the levels of igg specific for peanuts, and that's because there is data that igg, specifically igg-4, may be able to inhibit ige muted responses through two different mechanisms. for one, there's igg can compete

with ig for binding to the allergen and two, this ig binds to inhibitory receptors on mast cells and bay sew sphil phil baybasophils and can -- they found much higher levels in the group that was eating peanut compared to those that were avoiding. it may be one mechanism that

accounts for why these children are more tolerant. i think overall, though, the results of the leap study really i think have taught us that early introduction of food and specifically peanut may be able to effectively prevent the development of peanut allergy in

infants that are high risk for developing the disease. whether this is true for other foods and whether these kids will remain non-allergic is still something that i think is an open question. very exciting results at least from this one study.

so somebody asked the question, well, what if i already have an allergic disease, is there any way we can go back and re-establish tolerance after you've had the allergy? and i think one very old strategy that attempts to do just that is something called

allergy immunotherapy, or you might know it as allergy shots. physically with allergy shots, those that haven't had them, you get injections of an allergen extract, initially these are given every week and then they're sort of spaced out to every two weeks and sometimes

longer, but they're given over a period of three to five years. and this really has been remarkably effective at treating symptoms of hay fever and allergic rhinitis. almost 70 to 80% of people who complete a full course of allergy shots show improvement

in their symptoms. the mechanisms behind that improvement is again back to our t reg pla r regulatory cells,thought to suppress ease effector cells that promote allergic responses and that in turn prevents the activation of other effector cells important in allergic

responses. these t regulatory cells can also produce high amounts of il-10, and this can cause switching from primarily ige to igg, and specifically igg-4, which may have a blocking effect. so the concept of immunotherapy

is certainly not a new treatment. allergy shots for grass pollen allergy were given at just the turn of the century. since then, we've learned a lot more about the me ca mechanismsby which allergy rm immune therapy might improve symptoms, but --

has really come to light. they did actually try allergy shots for peanut allergy in the early 1990s, however, this led to very severe side effects, including one fatality. so that halted research into immunotherapy for food allergy for some time until, again, very

recently when newer strategies for delivering the allergen that caused fewer side effects had been developed. so i told you with allergy shots, the allergen is given under the skin, given subcutaneously. however, with subling wall

immunotherapy or slit, the patients dispense a premeasured amount of an allergen solution under their tongue and hold it there for a few minutes before the idea with slit is that there are lots of cells in your oral mucosa that can promote tolerance.

and so if we target that area, you can use lower doses of allergen and that might have fewer side effects. this has been used in experimental trials for food allergy, but there is also what's called a glass tablet, they're using it to treat grass

oral immunotherapy is another strategy. this is really mostly been studied for food allergy and it's probably the most promising treatment we have for food allergy currently. but with oit, we actually fied the skidfeedthe kids whatthey're allergic

to. you start with really, really tiny doses and then over the course of weeks to months, you gradually build up the dose that they're getting. oit has been been studied for milk, egg and peanuts. sides effects are extreme legal

common and that's why we start again with very low doses. most of the side effects have the mild usually oral itching or g.i. upset, but we certainly see anaphylaxis and when a patient enrolls in this type of study, we're very clear that your child is going to react and

potentially react very severely, so this has really only been done in medical settings. the good news is that the majority of patients, maybe as many as 70 to 80% of patients that complete oit, are able to eat more of the food that they're allergic to at the end

of the study than they were at the beginning. however, the majority of those kids also regain reactivity if they stop eating the food. sometimes just after a week. and that's very worrisome to us because it may be easy to eat things like milk every week, but

if you get a g.i. virus where you're vomiting and you can't eat, we worry about those kids a lot and will they redevelop their allergy. so we have a lot more work to really optimize the in order to really achieve what we would call lasting tolerance.

so to summarize then, allergic disease at a fundamental level seems to result from an inability or defect in either establishing or maintaining tolerance to these innocuous antigens that are in our epidemiologic studies suggest that several early life

theeivets are known to increase allergic disease later in life very likely may do so by altering the microbiome that normally lives in our gut. and then finally, allergen immunotherapy is a time proven treatment for allergic rhinitis and we're hopeful it will be

helpful for other forms as well including food allergy in coming thank you. >> the introduction of bee honey versus bee pollen and what is more effective at mitigating hay fever. i know it's pretty specific, but --

>> it's really have interesting. i think the idea is qh you're doing bee honey like that, you're actually doing immunotherapy. because what the bee honey actually contains is poll en, so you're actually getting some exposure to the pollen, so if

it's a question whether bee honey or doing pollen therapy -- the imthank you know therapy would because you're just getting a larger dose of that poll enand we think a larger dose may be needed to truly generate tolerance. >> thank you.

and also, is it possible to have contact dermatitis in one mucosal surface but not another? >> it's really different than an al eerg. most of the time it's going to be through the skin though you can see it in other mucosal sites as well.

you think of it as a skin reaction rather than a mucosal >> i'm just curious, you're talking about the cellular level. is there any connection with the brain and what it recognizes? >> yeah, i mean, i think that's an area that we really have a

lot more to learn about, all our systems talk to each other, and there's no doubt that mediators that are produced by immune cells are acting on the brain, okay, and perhaps the other way around, that when we have emotion, that leads to changes in metabolites in our body --

>> when you're talking about stress -- >> exactly, and that goes back on our immune system. so there's a lot of crosstalk between those systems so i think we are just at the beginning of understanding how that works. >> i have the a question about

why peanuts. is there stg about peanuts or eggs, is there something that they do to the bacteria in the gut around them or is it something about a protein sequence? so that's a big question, is why are some foods allergenic and

some aren't. when you look at the class of foods that are allergens, they have several things in common. they tend to be water-soluble, they tend to be resistant to heat and digestion, and in some cases, they resemble hellman's parasite.

some allergens also resemble activators of our innate immune system. when you look at a group of allergens as a whole, those are some features that they all hold in common. so what's interesting is what the most common food allergens

are different in different parts of the world. i don't know that that is so much a difference that -- let me give you an example. peanut allergy is common in the united states but rare in israel. in israel, sesame allergy is

very common. is that a difference in exposure or environment? i suspects it's more to environmental differences than it is to fundamental differences in the food. >> i think it's interesting historically, we talked about

this actually last week when the topic was the microbiome and inflammatory bowel disease. historically, metchnikoff, who sort of started all this, pointed out that it was not possible to alter the composition, now this is 100 years ago, so they weren't doing

all these fancy separations, but his point was it was impossible to alter the composition of the fecal bacteria by the oral route route. now probiotics in a capsule are easy to sell, but i look, maybe you can answer this, i hope, i don't know of any evidence that

i'd seen that any oral probiotic really does anything substantial to the floor a. flora. metchnikoff did experiments, he could prolong well-being in rabbits by giving them the, quote, probiotic by the rectal route, not by the oral route.

now you can't sell that to the commercial markets these days, but it may be coming. >> would you comment about this, because i think it's a serious misleading view that an oral probiotic is going to do anything. >> i agree with everything you

say. it certainly hasn't been effective, and again, there are several reasons for that. whether they survive the gut, you know, i think is a whole question. and again, it could be dose. i think it really points to how

important it is when we're doing these probiotic trials to really show that we've had an impact on the mithe microbiota. the question is does the bacteria need to be alive or signal the immune system in that way that augments the protective response, an i think that's more

of an open question as well. so there's people interested in the fecal microbiota transplant, where you're transplanting them where they need to be, they should survive, they're in an environment where they're used to living, and maybe that will be more effective than trying to

take a pill orally. any other questions? if not, i want to thank you both on behalf of all of us.

dog allergies

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