Adventures in the Genomics of Inflammation – Daniel Kastner

Adventures in the Genomics of Inflammation – Daniel Kastner


Daniel Kastner:
Well, Gene [spelled phonetically], thank you very much for that kind introduction, and
thank you all for the opportunity to be here this morning. It’s really fantastic being
able to get acquainted with you all and talk with you about a topic that’s near and dear
to my heart, that being “Horror Autoinflammaticus: the Adventures and the Genomics of Inflammation.”
And of course, the term “horror autoinflammaticus” is sort of a takeoff on the term “horror autotoxicus,”
which was a term that was proposed by Paul Ehrlich back at the beginning of the 20th
century. He was one of the great early immunologists, who recognized the severe consequences when
the immune system turns against its host, and so Ehrlich coined the term “horror autotoxicus,”
and what we’re going to be talking about this morning, horror autoinflammaticus, is just
basically the turning against of the innate immune system of a part of the immune system
against the host, and so we’ll focus on that particular aspect of the immune system. But
anyway, I hope that over the course of the next three or four hours that I have with
you, that we can really get down to some details in terms of these fascinating autoinflammatory
diseases. So, in any event, I have nothing to disclose
in terms of commercial relationships, but probably the first thing, at least for some
of you, is to get down to the question of the systemic autoinflammatory diseases. What
are they, and why should you care? So, in any case, first of all, just in terms of the
definition, they are a group of disorders in which there are episodes of seemingly unprovoked
inflammation in the absence of high-titer auto-antibodies, antigen-specific T-cells,
or other features, cardinal features of the adaptive immune system, and no evidence of
infection. Despite the fact that there isn’t any strong evidence for the adaptive immune
system being involved in these diseases, they do really manifest dramatic systemic inflammation,
and I’ll just illustrate this on this slide. First of all, in the left-hand side, you can
see a laparoscopic view of the peritoneal cavity of a 7-year-old girl that we saw at
the NIH a few years ago who has TRAPS, the TNF receptor-associated periodic syndrome,
and this is one of the diseases that we will be discussing this morning. This child had
episodes of intermittent sterile peritonitis, and what you can see here are basically adhesions
that have formed because of the repeated episodes of sterile peritonitis. The next image is
the forearm of a young man from Kansas City who has PAPA syndrome. PAPA syndrome is pyogenic
arthritis with pyoderma gangrenosum and acne, and what you see here on his forearm is, in
fact, pyodermic gangrenosum, basically the breakdown of the skin and the infiltration
of the area with polymorphonuclear leukocytes. And this particular lesion, in the case of
this patient, actually, it took us a year to resolve this lesion in this patient. And
then, finally, the image on the right is from a patient with the — one of the newer autoinflammatory
diseases, the more newly recognized autoinflammatory diseases, and this is a patient with DIRA,
the deficiency of the IL-1 receptor antagonist, something that we published in the New England
Journal about three years ago, and I’ll be telling you about that in a little bit as
well. So anyway, as I mentioned, one of the important
aspects of these diseases is the fact that they are disorders of the innate immune system,
and just to remind those of you who aren’t thinking about immunology every day — if
there is any such person in this auditorium — but in any case, the adaptive immune system,
of course, is that part of the immune system where the players are lymphocytes. These are
a subset of the white blood cells and the receptors for various pathogens, receptors
that rearrange in the genome and somatically mutate, whereas the adaptive immune system
is that part of the immune system that’s a little bit more ancient in terms of its history
in organisms, and it’s the part of the immune system in which the myeloid lineage of cells
plays a more important role, and in which the receptors are actually hardwired in the
genome and do not somatically rearrange or mutate. Now, this slide here is just a table of at
least a number of the autoinflammatory diseases. It’s probably — the print is probably too
small for you to read, but I will just highlight the fact that there are a bunch of different
classes of diseases now that have been put under this rubric of autoinflammatory. The
first ones that were recognized were disorders that are hereditary periodic fever syndromes,
as Jean was alluding to in the introduction — diseases like familial Mediterranean fever.
But there are a host of other diseases that are also categorized as autoinflammatory,
such as the idiopathic febrile syndrome, Still’s disease in children, adult Still’s disease
in adults, various pyogenic disorders like PAPA syndrome that I mentioned earlier, granulomatous
diseases like Blau syndrome, and some would regard Crohn’s disease as being autoinflammatory.
Autoinflammatory disorders of the skin and bones such as DIRA; we’ll be talking about
a few of them. And then a host of other things, such as metabolic diseases like gout, that
we will talk about in a little bit. In any case, my exposure to autoinflammatory
diseases, and sort of the dawning of my interest in these diseases, actually happened when
I was a beginning fellow in rheumatology at the NIH back in 1985. I was 5 at the time,
of course, and I happened to see in our new-patient clinic this man, Sarkis, who was a man who
was referred to us with a mystery illness. And basically, at the time that we saw him,
he was in his early 20s, of Armenian ancestry, and he presented with a history of episodic
attacks of monoarticular knee or ankle arthritis since infancy. These would usually occur on
the order of once a month or so and would last for several days at a time. They would
be accompanied by fever and an erythematous rash over the involved joint, and he would
have massive effusions of his joints at the times that he would have these attacks. Between
the attacks, he was totally normal, and the attacks would resolve spontaneously. So, this
was someone who, in his early 20s, had probably had a couple hundred of these attacks over
the course of his life but had had actually no lasting damage of his joints, and when
he walked in to see us, he was between attacks and looked totally normal. And the question was, what does he have? Well,
actually, at the time that I saw him, I didn’t know what he had, either, just as a number
of other physicians who had seen him over the course of his life. But fortunately, there
was a fellow in the lab that I was working in who was from Israel, and he said, “Dan,
it’s obvious what this patient has. He has familial Mediterranean fever.” And sure enough,
we witnessed an attack, we aspirated some fluid from his joint, from his knee. He had,
like, a hundred thousand polys per cubic millimeter in the synovial fluid, which is typical for
the arthritis attacks of FMF. These patients will have an arthritis that looks like a septic
arthritis, essentially, so this is something that’s a cardinal feature of FMF, and at the
time that we saw him, it was already recognized. The colchicine is a fairly effective treatment
in preventing the attacks of FMF. We put him on colchicine, and essentially, he has done
well ever since, for the 27 or so years that it’s been since we first saw him. In any case, just to illustrate some of the
features of FMF, it’s a recessively inherited disease. It’s a disorder that is seen, as
the name implies, in individuals of Mediterranean ancestry. That means Jewish, Arab, Armenian,
Turkish, and Italian people. Recessive disease, attacks of fever that last on the order of
usually one to three days, sometimes a little bit longer with the arthritis. They can have
severe abdominal pain from sterile peritonitis; they can have sharp pleuritic chest pain from
pleurisy; they can have arthritis, as I described to you; they can have a skin rash as well.
So, these are — these things are illustrated on this slide. This is an upright film of
the abdomen of a patient having a peritoneal attack of FMF, showing the air fluid levels.
My pointer doesn’t — isn’t very strong, but you can imagine that there are air fluid levels
there. A left pleural effusion in this chest radiograph on the lower left. Here, in the
center, you have a posterior pericardial effusion, and actually, asymptomatic pericardial effusions
are relatively common in patients with FMF. Up in the upper right, you can see a radiograph
of the hip in a patient with chronic arthritis of the hip. Usually, the arthritis of FMF
is a non-deforming, non-erosive arthritis, but in about 5 percent of untreated patients,
you can get this picture of a destructive arthritis. And then down in the lower right,
you have erysipeloid erythema, which is basically a reddish raised rash, usually on the dorsum
of the foot, the ankle, or the lower leg that occurs in these patients, a lot of times mistaken
as being an insect bite. Now, histologically, as I mentioned, these
patients have lots of polys in their synovial fluid or in their skin, if you were to biopsy
the skin, and really, the thing that was the most devastating manifestation of FMF before
colchicine therapy was systemic amyloidosis. Now, amyloidosis is a term that refers to
the ectopic deposition of protein in a number of different tissues in the body, and there
are different forms of amyloidosis, as many of you know, so that there is AA amyloidosis,
AL amyloidosis, transthyretin amyloidosis, and a host of other amyloidoses in which one
can have mutations and various proteins, a lot of them that are serum proteins. In the
amyloidosis of FMF, what is being deposited is serum amyloid A, which is an acute-phase
reactant which is produced by the liver during the inflammatory attacks of FMF, and a cleavage
product of SAA is what deposits in the kidneys and several other vital organs. And before
the advent of colchicine therapy in FMF, amyloidosis was actually a major cause of death in FMF
patients. Now, back in the mid-1980s, this was a fascinating
disease. It was a disease we didn’t know what caused it. It was a disease with dramatic
inflammation, and this was really at the advent, at the dawning of the Human Genome Project.
And so at that time, it was just becoming possible to map genes that cause human diseases
by basically comparing the inheritance of those diseases in families with the inheritance
of DNA markers, which were just being discovered at that time, of known chromosomal location.
So I thought that if others could be mapping and cloning the gene for diseases like cystic
fibrosis, why couldn’t Dan Kastner find the gene that causes FMF? And of course, the naiveté
of youth is a good thing. When you’re 5 years old, you know, these kinds of things are great. And so, fast-forward a little bit. This is
a HIPAA-approved photograph of a family that I visited in Israel. So, basically, in the
summer of 1989, I spent the summer with this guy here, Dr. Mordechai Pras, who ran a very
large FMF clinic in Tel Aviv. And he made available to me patients with FMF as well
as unaffected family members. In some cases, they couldn’t make it to the clinic, so we
went to them. And you can see, after getting informed consent — there’s a notebook with
the informed consent documents — everyone would roll up their sleeves and give blood.
We would have lunch, and it was a great thing. And here, this happens to be a family from
Akko, which is a northern coastal town in Israel. They are of Moroccan-Jewish ancestry,
and actually a consanguineous family. The parents in the family were first cousins to
one another, and you may note the strong intrafamilial resemblance between Mom and Dad in this family.
And then, also pictured here are several members of the family affected with FMF as well as
one of the members of the family up here in the upper left, our upper left, who’s totally
unaffected and turned out later, once we had the gene, not even to be a carrier for FMF. So, in any case, we did do what we set out
to do, which was to map the gene for FMF, and it turned out to be on the short arm of
chromosome 16, and then we became sort of the Genome Project for that area of the human
genome. This was back at the time when things were just really getting underway in terms
of the Genome Project, and so we developed fairly high-resolution maps of this region,
of — oh, that’s where it is — of — in the middle — high-resolution maps of this area
of chromosome 16, narrowed things down to about a 200 kV interval. There were 10 genes
that we had to figure out were encoded in that region, and of course, as our luck would
have it, it was the 10th of the 10 genes that we looked at that had mutations in it that
were, in fact, associated with inheritance of FMF. So, in any event, we did find, then,
a gene depicted here, MEFV, mutations in which cause FMF, and it encodes what was then a
predicted protein, shown here, which we call “pyrin,” after pyrexia. Now, at the time that we were actually at
the point of finding the gene, we were in a fight to the death with a French group,
a race to the finish line, and so this was actually in July of 1997, so 15 years ago.
And so we, and they, found the same gene. Fortunately, it was the same gene at the same
time, and we named the encoding — encoded protein “pyrin,” after “pyrexia” for fever.
The French group, being much more erudite than we, called it “Mare Nostrum” after “Mare
Nostrum” for the Mediterranean Sea. That was the Latin for the Mediterranean Sea. We chose
a name that would be relatively short, easy to pronounce, and perhaps easy to remember,
hoping that then — we didn’t know for sure that the French had something, but we figured
if they did, it would be good, at least in terms of what name would finally stick, that
our name would be one that would be easier to remember. So anyway, we called it “pyrin,”
after pyrexia. And at the time, it was a novel protein. It was a protein that hadn’t been
recognized before. And it turns out that the N-terminal 90 or so amino acids — at that
time, again, it was not known, but that domain turns out to be a domain that’s found in some
20 different proteins in humans that are involved in the regulation of inflammation and apoptosis.
And so this actually became something that was more or less a key to understanding a
whole branch of regulation of the innate immune system. And that domain, I will tell you,
everyone refers to as “the pyrin domain,” not “the Mare Nostrum domain” — [laughter] — but “the pyrin domain.” So, the pyrin domain, it turns out, forms
the six alpha-helical structure, shown here in the upper left, and that structure is sometimes
referred to as a “death fold,” because it’s seen in death domains, death effector domains,
caspase recruitment domains, and pyrin domains. Now, pyrin domains are actually the most numerous
of these four families of domains. The interesting thing about this structure is it allows the
formation of a dipole, with positive charges being shown in blue here and negative charges
being shown in red. And the idea is that by forming this dipole, what happens is that
you can get, then, cognate interaction, self-self-interactions between pyrin domains. And so pyrin domains
of one protein can interact with pyrin domains of another protein, basically to allow for
intermolecular interactions and for various regulatory processes to happen in the cell. So, the pyrin domain of pyrin interacts with
a protein that is sometimes known as ASC: apoptosis-associated speck-like protein with
a CARD domain, which is why most people call it “ASC.” And ASC is a fairly small protein
that has a pyrin domain at its N-terminus and a CARD domain, which is also a domain
in the same death fold configuration, at its C-terminus. The CARD domain of ASC interacts
with the CARD domain of caspase one. And caspase one, some of you may know, is actually the
enzyme that catalyzes the conversion of pro-interleukin-1 beta to interleukin-1 beta. And interleukin-1
beta, IL-1, is one of the major mediators of fever and inflammation in humans. And so
this basically ties pyrin to the regulation of this process of IL-1 activation. We have generated mice over the course of
the years that have actually — that harbor mutations in them, in the mouse pyrin, that
are the same mutations as what we see in humans with FMF. And you can see on the left, here’s
a wild-type mouse, and then a littermate that has the V726A mutation. That’s one of the
FMF-associated mutations, substitution of the alanine for baline [spelled phonetically]
at position 726, and you may see here, that, in fact, this mouse has arthritis of its hind
paw, and if you section the joint, there’s lots of polymorphonuclear leukocytes in the
synovial fluid. Moreover, if you compare the peripheral blood leukocytes in the V726A bred
onto a wild-type background, there’s lots of — there’s a granular cytosis in these
mice. But if you breed it onto an IL-1 receptor knockout so that you’re blocking IL-1 signaling
in the mouse, that goes away. Now, you may say, well, we don’t treat mice,
so, so what? Well, so, I’ll tell you so what. So, in any case, back in, I think it was 2005
or something like that, we had this patient who was sent to us from the Mayo Clinic, who
was a man from Baghdad, Iraq. He was 18 years old at the time. He’s homozygous for the M694V
mutation at the FMF locus. Now, that’s the most severe, that’s the mother of all mutations
at the FMF locus, and patients that have that mutation, if they’re not treated aggressively,
can develop amyloidosis. And so at the age of 18, he actually did have systemic amyloidosis.
He had amyloid in his kidneys and had a creatinine, at the time that he came to us, of 3.5. He
had amyloid in his heart, which is actually relatively unusual for AA amyloid, but he
had it, and he had an ejection fraction of 37 percent. He had amyloid in his gastrointestinal
tract, which led him to have malabsorption and chronic diarrhea, and this is just all
illustrated on the images here. So, this is the glomerulus of the kidney, and you can
see when — it’s stained with Congo red. Looked at under regular light, it looks like this.
Under polarizing light, you can see the apple-green birefringence that’s typical for amyloidosis.
Stained with anti-AA monoclonal antibody, it shows up this way. Here is amyloid in his
duodenum, causing chronic diarrhea, malabsorption. Here’s amyloid in his heart; this is an anti-AA
stain. So anyway, given the fact that he had amyloid
in his GI tract, that he had chronic diarrhea, and that — actually, what happened was that
I went to give a talk up in Connecticut at a Wharton conference, and I got this message
at the end of the talk that I should call the ICU at the NIH as soon as possible. So,
I called the ICU. This guy had, while I was away, gone into renal failure and heart failure
and was in the ICU, and there was the question even as to whether we should support him because
of the fact that he had already such advanced amyloidosis, and what were we going to do
for him, and could we do anything like a kidney transplant for such a patient as this, because
this is a process that seemed irreversible. But, at that time, there was just beginning
to be the thought that amyloid is actually a dynamic process in which you have deposition
of whatever is the protein that’s being deposited as the form of amyloid, but there’s also a
resorptive process, and that if you could block the deposition of amyloid, that the
resorptive process would eventually lead to improvement in the patient. Well, we couldn’t treat him aggressively with
colchicine because he had diarrhea, and as many of you know, colchicine causes diarrhea.
So, what to do? Well, we were just beginning to see the light with regard to the connection
of pyrin with IL-1. So, we thought, well, maybe we should treat him with an IL-1 inhibitor,
which we did. And here, this is just on the Y axis, acute-phase reactancy, that the serum
amyloid A or the CRP [spelled phonetically], while he was on — at least in this image
— while he was on Anakinra, which is the IL-1 receptor antagonist, you can see that,
in fact, his acute-phase reactants were well-controlled. We had to stop it for a period of time because
he was septic. But in any case, we continued the treatment with him, and actually, his
amyloid has not totally gone away, but certainly much improved, so that at this point, his
ejection fraction is 55 percent; he’s able to eat pizza for lunch; he’s had a kidney
transplant; and here’s a picture of him, a recent picture of him. So, in fact, this has
been, for some patients, a lifesaving kind of thing. And there’s actually an article
that’s going to be coming out in the Annals of Internal Medicine, a study that we were
involved in at the clinical center, using a different IL-1 inhibitor, Rilonacept, in
a randomized placebo-controlled trial showing that Rilonacept is effective in the treatment
of FMF. That’s another IL-1 inhibitor. All right. So, in any case, let’s move on
to another disease. I think you’ve heard enough FMF for the morning. So, let’s talk about
another patient: Christina. Now, Christina was a patient that was referred to us at the
NIH while we were looking for the gene for FMF. And she was not of Mediterranean ancestry.
Instead, she was Irish. She was actually referred — her husband worked at the Irish embassy.
There was an Irish anesthesiologist at the NIH who called me up one day and said, “I
heard you’re working on familial Mediterranean fever.” I said, “Yes, that’s true.” “Well,
I’ve got something for you. I’ve got a patient with familial Hibernian fever — [laughter] — Irish fever.” So, I said, “All right.” So anyway, she came to the NIH, we saw her,
27 years old at the time. She had a 14-year history going back to age 13, I guess, of
three to five-week febrile episodes. Now, remember, I told you that the episodes of
FMF last on the order of one to three days, so this is way too long for attacks of FMF.
She had abdominal pain with her attacks, which of course, you can have with FMF, but she
had a couple of other things that you usually don’t see with FMF: periorbital edema and
a migratory rash. We saw her about one week after she had delivered a healthy baby boy,
and she was just going into an attack. During her pregnancy, she was totally attack-free,
and this is actually quite typical for the disease that I’m going to be telling you about.
She had a high white count, elevated acute-phase reactants, and had a history of responding
to corticosteroids, but not colchicine. So, she was not of Mediterranean ancestry. She
had these prolonged attacks. The attacks had manifestations that aren’t manifestations
that you usually see in FMF. And she responds to steroids, but not colchicine. And here
she is in the pedigree. And you can see that this looks more like a dominant pattern of
inheritance. She’s got three sisters who are affected, her mother is affected — well,
the maternal aunt isn’t, but then there’s a maternal cousin who is. So, what is this? And this actually had been
called — in the literature, there were a couple of cases reported, a family reported
— it had been called familial Hibernian fever because it had been described amongst the
Irish. And there even had been a hypothesis that perhaps the Irish are actually descended
from Jewish sailors who were a part of the Spanish Armada, which was shipwrecked, and
that they swam ashore in Ireland and actually intermarried with the Irish population and
introduced a dominant form of FMF into the Irish population. This was the thinking that
was going on at that time. Well, in any case, so, we had this patient,
and for a while we just took care of her and didn’t know what it was, and we didn’t have
the gene for FMF at the time. Once we found the gene for FMF, then we screened that gene
for mutations to see if there was some different kind of mutation that would cause a dominantly
inherited form of periodic fever. Nothing there. In the meantime, my former fellow,
Mike McDermott, a good Irishman, actually finished his fellowship at the NIH, took a
job over in London, and tracked down the original Hibernian fever family, and mapped the gene
in that family to the short arm of chromosome 12. In the meantime, we had approved several
other families with dominantly inherited fever, and so it did appear that there was this region
on chromosome 12, the short arm of chromosome 12 — and of course, the FMF gene is on chromosome
16, so it can’t be that gene — some gene on chromosome 12 that might be causing this.
Now, the region that Mike had mapped the gene to was much too large for us to, you know,
just look at a few candidates, and actually, Mike came back to my lab to do a sabbatical
to try to figure out what the gene was. So, at first, while we were trying to find
more families to narrow down the region, we subjected this interval of the genome to a
very important test: the embarrassment test. So the embarrassment test is, you look at
all the genes that are known in a given candidate region. You think about the phenotype. And
you think, well, what gene would it be that would be the most embarrassing that if we
spent five years looking for it, and then we found it by some, you know, positional
approach or whatever, and then people would say, well, we could’ve told you that at the
beginning. So, the gene in that interval that seemed to be — would be the most embarrassing
if it turned out to be it, was this one here: TNFRSF1A. And it’s the gene that encodes the
55-kilodalton receptor for tumor necrosis factor. Now, tumor necrosis factor is another
mediator of fever and inflammation in humans. There are three major mediators of fever in
humans: IL-1, TNF, and IL-6. So, this is TNF, the TNF receptor. There’s actually two TNF
receptors in humans: a 55-kilodalton TNF receptor that’s encoded here, and the 75-kilodalton
receptor that’s encoded on chromosome 1. The protein that’s encoded by this receptor is
shown here. It has four cysteine-rich domains, a transmembrane domain, and intracellularly,
a death domain. So, it’s actually a cousin of pyrin, you know, because remember, death
domains and pyrin domains are similar in structure. So, in any case, Mike McDermott and Ivona
Aksentijevich, one of the people in my lab, set out, then, to screen this gene for mutations.
They started, actually, in October of 1998, and on Thanksgiving Day — I have a very hardworking
group in my lab — they came in to check their electropherograms of their sequences, and
they found, on Thanksgiving Day — Thanksgiving Day — mutations in seven different families
with dominantly inherited fever in this gene. That was the discovery of this disease on
Thanksgiving Day, 1998. We had Thanksgiving dinner as a lab afterwards, at Ivona’s house,
actually. Anyway, the mutations that they found are mutations that disrupt this loopty-loop
structure. See, there’s a fancy folding structure of these cysteine-rich domains that basically
involves the formation of disulfide bonds. And the disulfide bonds essentially form between
cysteines. And if you have a mutation that substitutes something else for a cysteine,
the disulfide bond can’t form, and if the disulfide can’t — bond can’t form, it doesn’t
fold right. So, this thing doesn’t fold right because you have mutations that substitute
something else for the cysteines, such as, for example, C52F here, where you have a phenylalanine
instead of a cysteine at position 52. So, in any case, that, then, leads to this disease. Now, in the original — now, this is just
sweet irony — in the original Hibernian fever family, it was actually a family of mixed
ancestry — the one side of the family was Irish, the other side of the family was Scottish.
They were being seen at a center in Nottingham, England, and I guess that the group in Nottingham
figured that the fever must come from the hot-blooded Irish side of the family. But
in point of fact, when we knew what the gene was and what the mutation was, turns out it
came from the Scottish side of the family. So, it should’ve been Caledonian fever, not
Hibernian fever. But actually, at that time, with the seven families that we had, we had,
like, a Finnish family, so should it be, you know, Finnish fever or something like that?
Well, we decided, probably best, you know, just as a matter of international diplomacy,
to take the ethnic attribution out of the name, and so we came up — again, thinking
of short names that would be easy to remember and that people would quote — we came up
with the name TRAPS: TNF receptor-associated periodic syndrome. And so that’s what this disease is called
nowadays, and here are just some clinical images of patients with TRAPS. I already showed
you this one. This is the adhesions in the 7-year-old girl with repeated episodes of
peritoneal inflammation. This is pleural thickening in a middle-aged man with recurrent episodes
of pleurisy. This is the migratory rash of TRAPS, which is quite interesting. It’s a
rash that starts proximal and moves distally, oftentimes on an extremity. In this case,
this man has the rash on his inner thigh on this particular day that the picture was taken,
and then it might be on the knee the next day, the calf the next day, the foot the next
day. So, it moves down. It’s not spreading; it’s moving. And if you look by magnetic resonance
imaging, you can see that the inflammation actually goes down into the muscle compartment.
It’s not a myositis, though; it’s a fasciitis that these patients have. You can see there’s
conjunctivitis these patients have; they can have periorbital edema, and they can develop
amyloidosis. This is a kidney biopsy stained with an anti-AA monoclonal antibody. So, in any case, what causes this? We had
thought, at first, that the mutations led, and they do lead, to a problem of shedding
of TNF receptors off the cell’s surface. Retention of the TNF receptors would then lead to repeated
signaling through the receptors. That does happen, but it appears to have a rather minor
effect in terms of the inflammation. What actually is the problem in TRAPS is constipated
monocytes. So, in any case, what happens is that when these receptors misfold, there’s
a problem with the trafficking of the receptors from the endoplasmic reticulum to the Golgi
apparatus and then to the cell’s surface. So, if you compare what happens with wild-type
receptors in this transfection system, you can see that you get — the green is the receptor,
the red is just a marker for the Golgi, and you can see that there is colocalization of
the wild-type with the Golgi apparatus. But in the case of mutant receptor, you can see
that it just gets stuck in the endoplasmic reticulum. And you can see, actually, in cells
from patients — these are human patients with TRAPS — and you can see that there’s
a reception of TNF receptor intracellularly compared with wild-type. What that does is shown here on this slide.
So, when you signal through the TNF receptor, when TNF signals through the TNF receptor,
what happens is TNF is actually a trimer in the bloodstream. The trimer of TNF binds to
three of the TNF receptors. It induces trimerization of the receptors. And when that happens, it
brings together, in close apposition, three of these death domains on the intracellular
side of the cell membrane, and that, then, engages a signaling complex that leads to
cytokine activation in the cell. When you have these mutant receptors, they actually
aggregate in the endoplasmic reticulum. And so there is actually then constitutive aggregation
of these death domains intracellularly, which leads to constitutive activation of the pathways
that lead to inflammation through the TNF receptor. So, that’s at least the major mechanism
of inflammation. Let’s now turn from FMF, from TRAPS, to three
other diseases — this is a threefer — that are caused by mutations in the same gene.
And this is one that’s really near and dear to my heart, because in fact, it turns out
that this gene encodes a protein that’s a cousin of pyrin. So anyway, so these three
diseases are sometimes known as CAPS: cryopyrin-associated periodic syndromes. So, the common feature
in these diseases is that these patients have fever, recurrent fever, with a hives-like
skin rash. It’s not true hives. They don’t have mast cells in these lesions. They don’t
have elevated levels of histamine in their bloodstream. It’s neutrophils, actually, that
are in these skin lesions. And there are three diseases. One of them is called FCAS: familial
cold autoinflammatory syndrome, or urticaria. It’s cold-induced hives and fever that these
patients will get. It’s dominantly inherited. The person, if they go out in the cold for
an hour or so, they’ll break out in hives and have a fever. If they walk into an air-conditioned
room, if they live in the South — and a lot of these people have moved to the South because
of avoidance of cold weather, basically — if they go into an air-conditioned room, they’ll
break out in hives, after an hour or so. And they feel lousy, and they have to actually
go to bed in order to recover. Second disease, that’s also caused by mutations
in the same gene, is a disease called Muckle-Wells syndrome. It’s not cold-induced, but the patients
get fever, they get the same hives-like rash. Actually, this patient here has Muckle-Wells.
They get arthritis, they can develop sensorineural hearing loss, and they can develop amyloidosis.
And then the most severe is a disease called NOMID: neonatal onset multi-system inflammatory
disease. In Europe, it’s called CINCA syndrome — chronic infantile neurologic cutaneous
and articular syndrome — and it is a disease in which there’s fever, hives-like rash, bony
overgrowth of the epiphyses of the long bones, and most devastating, CNS disease. These patients
develop basically a chronic, aseptic meningitis that leads to blindness, and deafness, and
mental disability. So, it’s a very severe illness and actually wasn’t thought to be
genetic at first because most of the patients who develop it have it as a spontaneous de
novo mutation and never have children of their own, so it was thought to be a sporadic disease
a few years ago. So, in any case, Hal Hoffman at the University
of California, San Diego, looking at some families with cold urticaria and Muckle-Wells,
mapped the causative gene to the long arm of chromosome 1. And in the candidate interval
— this was around 2000, 2001 — he found a predictive gene that had a pyrin domain.
So, he applied the time-honored embarrassment test to this region and decided that he would
screen the gene for mutations associated with these two diseases, and lo and behold, he
found that there were mutations in this gene in the so-called NACHT domain, which is just
a acronym and has nothing to do with falling asleep at night or anything like that. But
in any case, this protein has a pyrin domain at its N-terminus, it has a NACHT domain,
which is a protein interaction domain, in the middle, and a leucine-rich repeat domain
at its C-terminus. It can interact with ASC, that same protein that pyrin can interact
with, and it also can have a role in activating IL-1. Now, at the time that Hal was doing these
studies, we were seeing a patient with Muckle-Wells, and my colleague, Raphaela Goldbach-Mansky,
was seeing this young man from North Carolina named Jonathan. And Jonathan had been sent
to the NIH with possible Still’s disease, systemic-onset JIA, and here’s his picture
back 10 years ago or something like that. And here he is. I don’t know that you can
make the diagnosis of systemic-onset JIA from this picture. But there were some other features
that didn’t seem typical for Systemic-Onset JIA. He had a hives-like rash. He had papilledema.
He had some element of ventriculomegaly. And he had these knobby looking knees, which are
pathognomonic for NOMID. This appearance of the knees is what NOMID knees look like, or
CINCA, if you’re in Europe. So, Raphaela correctly diagnosed this patient as having NOMID, neonatal
onset multisystem inflammatory disease. And it was the two fellows who were on service
that actually catalyzed this discovery. So, these fellows had been seeing my patient,
with Muckle-Wells, and had been seeing Raphaela’s patient, with NOMID. And they said, well,
the skin rash of these two diseases looks very similar, are you sure that they’re not
the same disease? We said no, they’re not the same disease, why do you — haven’t you
been reading, you know? But they insisted, and so we thought, well, maybe they’re right.
Maybe there is some connection there. And, of course, the gene for Muckle-Wells had just
been identified by Hal Hoffman, so we knew what that was. So we decided, well, we’d check
it and see whether or not Jonathan, this patient with NOMID, in fact had mutations in this
gene, the gene that encodes this protein, cryopyrin. And so here’s Raphaela, the person
that saw Jonathan, and Ivona, who did the sequencing, and low and behold, what they
found was that, in fact, there was a mutation in cryopyrin in NOMID. And then, you know, this is one of these great
NIH stories. So, you know, we were telling people about this, you know, wasn’t it interesting?
And it happened that there was this guy, Sergio, from Argentina, who was a fellow up on the
11th floor, two floors up from us, who had brought a couple of DNA samples with him from
Argentina of NOMID patients, in the hopes there would be someone at the NIH doing studies
of the genetics of NOMID that he could then collaborate with. So, he gave us these samples,
after appropriate paperwork was done, and sure enough, they had mutations in this gene,
too. And it turns out that about half of the patients with NOMID have mutations in this
gene. The mutations are clustered in the NACHT domain, just as they are for the other two
diseases. And, in fact, the balls, the different colored balls, represent mutations associated
with the different diseases, and you can see they’re all clustered in the same region.
We have no idea why one mutation causes one of these diseases, and another mutation the
other disease. The pyrin domain is almost invariant, and
leucine-rich repeat domain seldom has mutations either. And so this — the gene encodes this
protein cryopyrin, pyrin because it has a pyrin domain, cryo, because at least some
of the patients have cold-induced symptoms. And cryopyrin forms a macromolecular complex,
and this is actually something that if you’re taking boards or whatever, you probably ought
to know. The macromolecular complex is called the inflammasome. And the inflammasome, you
don’t need to know all the components of the inflammasome, but it is, basically, a complex
that’s involved in the activation of IL-1 beta. It’s one of several complexes that can
activate IL-1 beta. So you have this inflammasome, and basically the mutations that are associated
with these diseases are in the NACHT domain, and they’re activating mutations that turn
on this process all the time, constitutively. So, we reasoned that if IL-1 is turned on
all the time in these patients, just like I told you about the patient from Bagdad,
Iraq, that we decided to treat with Anakinra, we decide that we would do a trial of Anakinra
in NOMID, because this is a devastating disease. And we thought that if there was something
that really deserved some attention, it was this disease. On the left hand side of the
image here, you can see how IL-1 ordinarily signals. You can think of IL-1 as blue bubbles,
just for purposes of this discussion. And IL-1 has to bind the two chains of its receptor
in order to signal. The green, type one IL-1 receptor, and the purple, IL-1 receptor accessory
protein. It has to engage both of those receptors in order to deliver a signal. In all of us,
we have something called IL-1 receptor antagonist, which is basically a protein that can bind
to the type 1 receptor, but doesn’t bind to the accessory protein. So, it competes with
IL-1 to bind to its receptor, and basically, it can bind but it doesn’t signal. So, it’s
basically a way of turning off signaling by IL-1. And it’s something that normally happens
during inflammation in people, is that you get IL-1 receptor antagonist levels going
up in the bloodstream, at least, in part, as a homeostatic mechanism to tone down the
inflammation. There’s a recombinant form of this that’s
known as Anakinra, or Kineret, the trade name. And so, anyway, we did a trial of Anakinra
in NOMID, and, essentially, the results are shown here; it was published in the New England
Journal in 2006. Within two or three days, the hives-like skin rash goes away completely.
The conjunctivitis goes away completely. Within three months, this white here, this is the
chronic aseptic meningitis. This is a MRI, with a flare image, and, basically, all of
the white is inflammation and you can see it’s gone, basically, within three months.
The arrow points to the cochlea, this is a fiesta image of the head, and this is cochleitis.
This is what leads to deafness in these patients, and cochlear inflammation goes away as well.
So, anyway, this has been a very effective treatment for NOMID. So now we have a little quiz here, and we’ll
go a little bit more quickly through the other diseases, because we have several other diseases
to talk about, and only 14 minutes to do it in. So anyway, here’s your quiz. So, could
this be NOMID? So, here is a patient, a 9-month-old child from Canada, who is referred to us with
these total — this total body pustular rash. And here’s the hair, so this is the fold of
the neck; it’s pustulars all over the body. The patient had a multifocal osteomyelitis,
aseptic osteomyelitis, and you can see here some of the punched-out lesions the arrows
are pointing to throughout the body. And then the patient also had evidence of vasculitis.
So, from what I told you about NOMID, is this NOMID? No, of course not, because the skin
lesions of NOMID are hives-like, not pustulars. Because the bone lesions of NOMID are overgrowth
of the epiphysis of the long bones, the knobby looking knees, not multifocal recurrent osteomyelitis,
and I didn’t say anything about vasculitis in NOMID. So, this was not NOMID. We were
asked is this NOMID? Just given the pictures, we said no, it’s not. We actually did sequence
for mutations and cryopyrin, didn’t find any. But, the referring physician from Canada was
an obstinate character, and so he treated the patient with Anakinra anyway, and this
is what happened. So, here’s the child before treatment, and you can see pustulars on the
face. Within three days, this child is starting to shed his skin, you can see he’s kind of
smiling here. And within a week he’d shed nearly all his skin, pustulars went away completely,
and the multifocal osteomyelitis resolved within two or three months. So, what is this?
What could this be that basically responds to an IL-1 receptor antagonist, but it’s not
NOMID? Well, again, this important test, the embarrassment test, once again, comes to the
rescue. So we were thinking, well, okay, so here’s a patient who responds to the IL-1
receptor antagonist. So what gene would be the most embarrassing, that if it turned out
to be it, and we hadn’t looked at it first, which one should we look at first? Well, of
course it’s the gene that encodes the endogenous IL-1 receptor antagonist. So, we looked at that, and lo and behold,
what we found was that this patient was homozygous for a two-base-pair deletion in the coding
region of the IL-1 receptor antagonist gene. That’s almost too good to be true. Homozygous
for the same two-base-pair deletion, how could that be, you know? So, we sequenced the parents;
sure enough, the parents were carriers for it. The kid really is homozygous for the two-base-pair
deletion. And then of course, we took a better history, and it all became clear when we learned
that the patient was from Newfoundland. And so, basically, the explanation there, of course,
is that Newfoundland is an island off the eastern coast of Canada, and many of the current
residents of Newfoundland are descendants of settlers who came to Newfoundland, actually,
200 years ago. And they are at least, you know, distantly related to one another, in
the sense that there’s a founder population there. And so probably one of the early settlers
to Newfoundland had this mutation, just as a heterozygous would have no symptoms associated
with it, but it just happened that the two parents both were carriers for this, and then
the child was as well. We now know that there are other mutations
in this gene, for example, a stop codon amongst people living in the bible belt of the Netherlands.
There’s another mutation that we see in the Middle East, yet another mutation in Northeastern
Puerto Rico that are associated with this phenotype. And so we, again, thought that
because there are mutations in the same gene associated with a particular phenotype, we
would give this disease a name, and the name that we have given it is DIRA, the deficiency
of the IL-1 receptor antagonist. Again, adhering to the naming conformity of short, easy to
pronounce, and easy to remember. So, in any case, this table just summarizes the comparison
of NOMID with DIRA. Different genes are involved. The functional consequences for NOMID, it’s
activation of the inflammasome. For DIRA, it’s decreased inhibition of IL-1. Different
skin rashes, different bone manifestations, different CNS involvement as well. And then, finally, the last of these monogenic
diseases, and maybe we’ll curtail things a little bit, so as not to get into the lunch
hour, but, in any case, this disorder that we’ll talk about, just briefly, is PAPA syndrome.
So, here is very severe cystic acne on the back of one of our patients with PAPA syndrome.
And it’s caused by mutations in this gene, PSTPIP1, which actually encodes a protein
that’s a pyrin binding protein. And so it just goes to show how mutations in all different
aspects of this pathway of regulation of IL-1 can actually lead to different inflammatory
diseases. So, in this case, actually PSTPIP1 binds to pyrin, and, in fact, the disease-associated
mutations are associated with increased binding of PSTPIP1 to pyrin, which leads to increased
IL-1 production and other cytokine production. So this schematic is just a depiction of IL-1
activation, some of the steps in IL-1 activation. And what I’ve shown you is that, depending
on where in the pathway you’re looking, if you’re mutating pyrin, you can have this erysipeloid
erythema skin rash. If you’re mutating PSTPIP1, you can get pyoderma gangrenosum. If you’re
mutating a NLRP3, you get these urticarial-like skin rashes. If you’re mutating the IL-1 receptor
antagonist, you get this total body hives-like rash. So, in any case, there’s a number of different
diseases that are all caused by mutations in this pathway. And, in fact, DIRA is the
prototype for a group of diseases in which receptor antagonist are mutated, and just
one that was published in the New England Journal a year or so ago, is a disease now
called DITRA, deficiency of the IL-36 receptor antagonist. And basically, IL-36 signals in
a similar way to IL-1, with a binding of two chains of a receptor, and a receptor antagonist
that only binds to one chain, and those patients get a form of pustular psoriasis. Now maybe I’ll just finish up by indicating
to you that, in fact, these pathways that I’ve told you about, that we’ve learned about
through these monogenic diseases, are pathways that are important in some much more common
genetically complex diseases. So that we now know that monosodium urate, for example, activates
the inflammasome. And that at least some of the inflammation in gout is due to excessive
IL-1 production, and, in fact, there have been successful studies of IL-1 inhibitors
in gout. Type 2 diabetes, actually is another disorder, genetically complex, that has an
IL-1 component to it. It turns out that islet cells of the pancreas synthesize IL-1 beta,
induced by hyperglycemia. IL-1 beta is actually toxic to islet cells, so hyperglycemia causes
islet cells to make IL-1, which causes them, basically, to commit suicide, which then leads
to further hyperglycemia. So that, actually, if you treat patients with Type 2 diabetes
with an IL-1 inhibitor, as shown in this paper in the New England Journal from a while ago,
glycemic control is actually improved. And then, probably the most common of these
diseases, atherosclerosis. So, atherosclerosis has, as I think many of you recognize, an
inflammatory component, and if one looks at mouse models of atherosclerosis, here is cholesterol
deposition in a wild-type mouse, but if one knocks out various components of the inflammasome
NLRP3, which is cryopyrin, ASC, or IL-1 knockouts, these mice do not develop atherosclerosis.
Now, you might say that’s great for the mice, but, in fact, there is a trial, the Cantos
Trial, that is going on right now. It’s a trial that Novartis, the maker of monoclonal
antibody against IL-1, canakinumab or ilaris. And this is a trial 17,200 patients, who have
had myocardial infarction, treating them either with placebo, or with three different doses
of this anti IL-1 antibody. And the outcome, what they’re looking for as the primary outcome,
is the number of second cardiac events, effectively, in these patients, with the idea that blocking
IL-1 will prevent recurrent cardiac events. Just the drug for each patient that’s getting
active drug, is about $100,000 dollars a year, so that for 17,200 patients, you’re talking
about a trial that’s a billion-dollar trial. So, definitely, these pathways are important,
or thought to be important, we believe they’re important, in common diseases. Well, we don’t have time to talk about CANDLE,
which is another interesting new disease that we’re working on, or about PLAID; this is
another disease we’ve published in the New England Journal earlier this year. We’ll just
flip through these slides. Or about a disease that’s coming out next month in the American
Journal, or about Behcet’s disease, either. But you see, these are all things that maybe
would get you to invite me back some other time for another talk, for part two of this.
So I’ll just, you know, go through these slides, you know, some very interesting associations
along Marco Polo’s silk root, but you’ll have to hear the next installment to know about
that. And here’s just a, maybe to finish up, a pie
diagram of some almost 1,900 patients that we have studied genetically at the NIH, in
our autoinflammatory diseases clinic. And the interesting thing is that in only about
a third of them, do we have a genetic explanation; in two-thirds of them we don’t. Now, not all
of them probably have a Mendelian disease, but this just highlights the point that there’s
plenty more to be found amongst these patients, and that there’s, I think, still a rich source
of patients for study, and that we can learn a lot from these patients. So just to summarize, the autoinflammatory
diseases manifest constitutive or easily triggered innate immune activation. Mendelian autoinflammatory
diseases provided important insights into the regulation of inflammation. IL-1 beta
activation protein misfolding, and well, we didn’t talk about proteasome dysfunction,
but take my word for it, are three mechanisms of Mendelian autoinflammatory disease. Based
on the demonstration of an important role for the inflammasome and their pathophysiology,
a number of common disorders such as gout, type 2 diabetes, and atherosclerosis have
been shown to have an autoinflammatory component. And again, for the next talk, genome-wide
association, and next-gen sequencing studies allow the identification of susceptibility
loci for the more common but genetically complex autoinflammatory disorders. Here is just the
cast of characters that really made all this happen. And, of course, the clinical center
of the NIH, where we carried out most of these studies. So, anyway, it is now one minute to 9, and
I apologize for talking a little bit over, but hopefully you’ve learned at least a little
bit. Thanks a lot. [applause] Male Speaker:
I hope you come back for part two. I wanted to ask you a question about amyloidosis. As
a rheumatologist, I treat a lot of inflammatory disease and I rarely see amyloidosis. So,
number one, am I preventing amyloidosis by treating inflammation, and number two, how
do you tell who’s at risk for amyloidosis [inaudible]? Dan Kastner:
Yeah, those are both great questions. So, we do believe that the more effective treatments
for inflammatory disease have led to a reduced frequency of amyloidosis. Certainly, chronic
infectious diseases, things like tuberculosis, were common causes of amyloidosis back in
the age before there were effective treatments for Tuberculosis. And we see less amyloidosis
associated with things like rheumatoid arthritis, as the biologics have become more widely used.
So, I do think that aggressive treatment, and that’s certainly what we do with the periodic
fever syndrome patients, is that we really aggressively treat their underlying inflammation
to the point that we want to normalize their acute phase reactants. Now, in terms of who’s at risk for amyloidosis,
that’s also an excellent question. Now, it’s probably been looked at most systematically
in patients with FMF. And so, in FMF, certainly the mutations that are associated with more
severe disease, as you might expect, are associated with a higher probability of amyloidosis.
Males, for some reason, are associated with a higher risk of amyloidosis. Noncompliance
with treatment, associated with a higher risk of amyloidosis. There is a polymorphism in
the amyloid locus actually, that is associated with a higher risk of amyloidosis, probably
because it prevents the normal degradation of the amyloid protein. And then, the most captivating of all association,
is that it depends on where you grow up as to what your chances of getting amyloid are,
at least with FMF. Armenians who grow up in Armenia, for example, have about a 25 percent
risk of developing amyloidosis by the time they’re 30. Armenians in the United States,
with the same spectrum of mutations, even if not treated with colchicine, have less
than 1 percent risk of developing amyloidosis. And there was a big study done by Isabelle
Touitou, published in “Arthritis and Rheumatism” a few years ago, that looked at country of
origin as being really one of the major predictive factors in whether or not you get amyloid.
And people who come from countries where infant mortality is higher, and therefore, we think
the health care availability may be lower, have a higher risk of developing amyloid for
reasons unknown, but that seems to be the case. Male Speaker:
[inaudible] Dan Kastner:
Say it again? Male Speaker:
So populations that use [inaudible], if they were to move away from it, how long would
Mother Nature take to extinguish those [inaudible]? Dan Kastner:
Well, let’s — so, we do think, and I didn’t have time to talk about this, that, at least
at one time, there may have been a selective advantage for mutations at the FMF locus.
And, in fact, if you look at the carrier frequency for mutations in this gene, in Mediterranean/Middle
Eastern populations, it’s incredibly high. It’s like one in three to one in five. Now,
if you contrast that with the carrier frequency for cystic fibrosis, which is the most common
lethal recessive disease in Caucasians in North America, one in 20; so this is incredibly
high, one in three to one in five. And there’s been a lot of speculation as to whether there
might be, or might have been, some infectious agent that was selecting for these mutations
over the centuries. So far, at least in various epidemiologic studies and studies of experimental
animals, we haven’t figured out what that agent would be. Male Speaker:
[inaudible] Dan Kastner:
Apparently not, no. Male Speaker:
Is the Amyloid you have referenced to anything related to what you see in outsiders? [inaudible]
My second question is that colchicine is so inexpensive; does it have use in the broad
spectrum of the diseases that you mentioned? Dan Kastner:
Yes. So, both excellent questions. With regards to the amyloid of Alzheimer’s disease, it’s
a different protein that is being deposited. A beta, as opposed to AA, so it is a different
chemical process, although it does appear, there are some studies that would suggest
that IL-1 does play some role in the pathogenesis of even the amyloidosis in Alzheimer’s disease.
So, that’s an area still under study, as to whether or not maybe that would help in some
way. But, the thing is, all amyloid looks the same under the microscope when you stain
it with Congo red. It all gets this, if you look at it under polarizing light, this apple-green
birefringent appearance to it. But it’s, you know, different proteins that are being deposited,
but probably there’s some final common pathway that makes them, you know, misfold and deposit
in that way, so that’s an interesting question. Now the question as to whether or not colchicine
would have a role in treating some of the other amyloidoses, that’s something that one
could consider. There was the thinking, back in the old days, that colchicine might be
effective in FMF, even if you can’t prevent the attacks, that it might still prevent the
amyloidosis. Colchicine does prevent the amyloidosis of FMF. But, it appears that that’s related
to its ability to prevent the inflammatory attacks of FMF. So, it’s not that it has an
anti-amyloidagenic effect; it has an anti-inflammatory effect in that disease. Which then leads to
less burden of SAA in the blood, and less to deposit, so we don’t think that it’s because
it has a direct effect on amyloid deposition. As far as the cost of colchicine, just a word
about that, as some of you may know, colchicine used to be available as several generic forms
in the United States, and then, because of some well-intentioned legislation, it turned
out that if a maker of a drug like that, which had never undergone appropriate clinical trials,
if a maker of the drug went through certain tests with the FDA, they could then get exclusive
license and put all of the other companies out of business. So there’s a company, Union
Pharmaceuticals, that did just that, using gout as the prototype, and so, essentially,
at this point, there’s only one form of colchicine that is available in the United States, the
trade name of it is Colcrys, and it’s made by this company, Union Pharmaceuticals. And
the cost of colchicine has now gone up from roughly 10 cents a tablet to $5 a tablet,
which will persist for the length of time that they have an exclusive license on this. And again, this was something that was well-intentioned,
you know, in the idea that this would encourage further rigor in terms of the testing of agents
that had never been subjected to the scrutiny of modern trials. But, you know, it’s ended
up sort of causing this issue with regard to cost of the drug, and actually, Colcrys
itself, we’ve seen in some of our patients, is perhaps milligram per milligram, or .1
milligram to .1 milligram, a little bit less effective than the — some of the other generic
forms. And so, in fact, one has to make dose adjustments in the patients when they switch
from their generic to Colcrys. So, an interesting thing, sort of a quasi- political, medical-political
kind of issue I guess. Male Speaker:
Is there a dark side to [inaudible] in terms of risk and infection? Dan Kastner:
That’s a great question, Gene. So we don’t see a lot of problems, but, certainly, the
TNF inhibitors are a lot more associated with opportunistic infections, with microbacterial
infections, with fungal infections, than IL-1 inhibitors. We do see some increase in risk
of upper respiratory illnesses, but at least at the doses that we give for these diseases,
no, we do not see — and part of the problem is, the thing with these patients, is that
they have a very hyperactive innate immune system, and so what we’re doing, treating
them with the IL-1 inhibitors, is sort of bringing it back to normal. In a lot of cases,
parents of kids with these diseases will say that everybody else in the family will get
a cold or the flu, and this child, who’s not been treated yet, doesn’t. They may get their
recurrent fever syndrome, but they don’t get colds and flus. When we treat them with IL-1
inhibitors, or whatever other biologic, then they no longer have their periodic fever episodes,
but they, like the rest of us mortals, begin to get colds and flus like anyone else. Male Speaker:
That’s going to be very hard to follow. Thank you very much for coming in today. Dan Kastner:
Thanks, Gene.

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