So my name is Rebecca Manno, and I'm a rheumatologist
at Johns Hopkins. So first I'd like to
thank the organizers for the invitation to be here,
and to talk about a very big, but very relevant topic,
which is autoimmunity. So, as I mentioned,
I'm a rheumatologist. I'm not an immunologist,
I'm a clinician. I take care of patients, and the
research that I do is clinical research, so I don't
have mice with arthritis. I don't work in a lab,
but I work with people. And I work with people
with autoimmune diseases. And I see this every single day. And I see how
devastating they can be. But I've also been
doing this for long enough that I see
how far we have come. And it's a great time
to be a rheumatologist. And I always tell
medical students and residents who are thinking
about, maybe what are some of the more glamorous
fields, cardiology and surgery. And maybe they haven't thought
about rheumatology before. But it's a great time
to be a rheumatologist. Because we understand more about
the immune system and more about the clinical phenotypes that
occur because of dysregulation of the immune system than
we ever understood before. And most importantly, we actually have treatments now,
whereas even 20, 30, 50 years ago, we didn't have
anything to offer our patients. We now have FDA
approved treatments. We have treatments
in the pipeline and a lot of discovery for how to manage some of these very
rare and not so rare diseases. So, once again, thank you for the invitation to speak
about autoimmunity. Autoimmunity is important,
why is it important? There's a whole lot more
of it now than there was. And if you look at the data
in terms of the epidemiologic studies that are looking
at autoimmune disease and the incidence and the prevalence, almost
universally there's an increase. There's some discrepancy as to
how much that increase is, if it's 3% or 5%, but universally
there has been an increase. And the reason for that,
why is there an increase, there's a lot of
discussion in the field. Maybe it's because
we're living longer, that may have something
to do with it. Just as you were hearing
about the increase incidents of cancers with age. Some of that may have to do with
all the autoimmune d as well. Some of it has to do with
the ability to detect autoimmune diseases. We're understanding more about
what our patients look like so we can identify them clinically. We have better biomarkers, and I'm gonna talk a little bit
about those serum biomarkers that help us in diagnostics and
in following our patients. But even if we take that
bias out of the picture, the fact that we understand
these diseases better, we're recognizing them better, the
incidence is still increasing. And without a doubt,
almost universally, whatever autoimmune disease
that you wanna talk about, these disproportionately
affect women, almost every single one,
with very, very few exceptions. So these are incredibly
important for women to be aware of, to understand something
about these toxic diseases. And that we start thinking about
in the future how to tailor our treatments specifically
towards women as well. So, before we talk about
autoimmunity we have to talk a little bit about the immune
system, what is it, what does it do? Obviously, we all need one. The goal of your immune
system is to protect you from the big and bad environment. And specifically, the microbes in the environment
that want to do you harm. So there's two big parts
of the immune system, so this is very basic immunology. There's the innate
immune system, this is your prehistoric
immune system. It's been around for
a really really long time. It comes after things
with a sledgehammer. And then there's your
adaptive immune system. And this is made of different
populations of cells, t-cells and b-cells. And this is a really
sophisticated part of your immune system. And it has come up with a whole
repertoire of cells that can recognize foreign antigens. Antigens are anything that
triggers an immune response. And the goal of this part
of the immune system, is if it finds a cell that's
infected with something, it notices it, and
it destroys it. There's also another part of
this adaptive immune system that can secrete things that are
called antibodies or proteins. And if it sees a foreigner
in the milieu of the host, these immune cells can
secrete these antibodies. The antibodies can attach on
to the bacteria or the virus, tell the rest of the immune
system, get this bug, and they destroy it. I'm making it sound very simple,
it's not. It's very sophisticated,
but it works. And most of the time
it works really well. And it protects us from all of
the microbes that are trying to do us harm in the environment. While your immune system is
developing, it becomes smart. And some of these
sophisticated t-cells and b-cells develop something
that's called tolerance, which is it
recognizes you as you. And it says, that's not
something that I want to destroy or that I wanna mess with. And so when your cells develop
tolerance, then they're not going to cause problems with
your own body's tissues. So what is autoimmunity? Autoimmunity is a misdirected
immune response. Where all of a sudden, or gradually over time these
t-cells, b-cells become reactive to yourself, become reactive
to self-host antigens. There's a breakdown in
the sophisticated system of tolerance. And now, your immune system
targets certain parts of you. One of the manifestations of
this may be the generation of autoantibodies. Now you've probably all had the
experience or known somebody who said I had the lupus test or
the rheumatoid arthritis test. And it's a blood test, and so does that blood test tell you
about an autoimmune disease? And the blood tests are, most of
the time, the blood tests that we're looking at,
are these autoantibodies. They're proteins that are made
by the immune system. And what we've learned about
them over the years, and as we're discovering more and
more, they help us understand where the dysregulation in
the immune system is occurring. From a clinician's standpoint,
they can be an incredible powerful marker of dysregulation
in the immune system, and cue me in to potential
problems down the road. Well, what we also know
about autoantibodies, and you've probably heard
of a few of them, ANA, double-stranded DNA,
anti-Ro, anti-La. I can go down a whole
list of them, and we're constantly
discovering more and more. What we know is that most of
the autoantibodies do not equal an autoimmune disease. But they're telling
us something, and we're finally starting
to listen, and we're starting to understand
what they're trying to tell us. They're telling us
there's a marker for the immune system
being dysregulated. And as we start to follow large
groups of individuals over time, and large groups of individuals
over time who have or don't have these antibodies. We can start to subset what
our patients with with autoimmune diseases, what
their clinical phenotypes are. And we can start to understand
what the natural history of their autoimmune disease may be. And most importantly,
how a particular therapy may or may not be effective based
on those autoantibodies. So, autoantibodies and those
blood tests that people order all the time and they think
about when they think about rheumatologists, are more
than just a marker. They're really telling us
about the pathophysiology of the disease. So, why does the immune
system become dysregulated? So, what happens? Well, we know that
there's multiple hits. So there isn't just one
thing that has to happen for the immune system to go awry. And what has become very,
very clear is there is absolutely a genetic component,
but that's not sufficient. Something else has
to happen as well. So there's lots and lots of data
about the genetic component. And one of the best examples of
this is in rheumatoid arthritis. So there's a genetic marker, which has been discovered in
rheumatoid arthritis, and it's something that's
called the shared epitope. And so we know that individuals
who have this genetic marker added an increased risk compared
to the general population for rheumatoid arthritis. And that was a really big
breakthrough in the world of rheumatoid arthritis, but we also know is that
it's not sufficient. So everyone with a genetic
marker does not go on to develop the disease. And we see this repeated time
and time and time again, whatever autoimmune disease
that you're talking about. There has to be a second hit. So what are some
potential second hits? So, the environment, toxins. There's certainly some toxins
that we know have been linked very, very strongly to
autoimmune disease, silica being one of them. We know that
medications can do it. We can see this in drug
reactions, where a medication is introduced into a person,
into the host environment. The immune system reacts to
it in a very pathogenic way, and we see the development
of an autoimmune disease. Those diseases are usually very
nice to take care of cuz you get rid of the drug and
things get better. What are other
potential triggers? UV light, so the sunlight can be
a trigger in the right host for the development of
autoimmune diseases. And then there's
the world of infections, this world of microbes that
we're constantly in battle with. And remember that's what
the job of the immune system, part of the job of the immune system is to protect us
from those microbes. And there are some infections,
specifically chronic infections that we know are constantly
stimulating the immune system. Infections like hepatitis C,
hepatitis B, HIV, that EBV as well. That are very closely linked with very discrete
immunologic phenotypes. So how does the immune
system become disregulated? And it's highly variable, but we know that you have
to have those two hits. We also know that
there's a delay. So when an event happens
it may be months, years before the patient
presents clinically. And we've learned this through
these auto antibody markers. So there's some very nice
work which has been done, it's been a few decades now
Where serum was collected in individuals who didn't have any
evidence of autoimmune disease. And they looked for
autoantibodies and they found these
people over time and said who develops
autoimmune disease? And we saw these beautiful
graphs that panned out, that showed us there can be a
big lag between the development of the autoantibody and
the clinical phenotype. And that's telling
us that there's this quiescent period and what's so
exciting about that is that it's an opportunity
in the future to intervene. And if we can understand what's
happening in that quiescent period between the immune system
being activated, the generation of autoantibodies and then
the presentation of the clinical phenotype of the patient,
we really can make a difference. We can do more than just
slow down these diseases, we can solve them. Getting back to the example
of rheumatoid arthritis, I think it's a nice example once
again, can have the genetics but you have to have something else. So I told you about the shared
epitope in rheumatoid arthritis which was a very big discovery. We also have auto-antibodies
now for rheumatoid arthritis. Anti-CCP antibody,
which is very specific for rheumatoid arthritis. But what we also have learned is
more about the environment and the environmental influences
on the immune system. An enlarged epidemiologic
studies when they look to say, whose got the shared appetite,
whose got this auto antibody and what really increases your
risk of developing an auto immune disease if you have
two those things, smoking. The risk associated with smoking
for developing rheumatoid arthritis, I don't think
anybody could predict. We all know smoking is bad for
lots and lots of reasons but this really spoke to us as
saying there's something very unique about the environment
that that changed the risk ten-fold for the development
of rheumatoid arthritis. So how does the immune system
becomes disregulated, and the analogy I like to use when
I'm explaining it to my patients is what I call
the campfire analogy. So if you want to
build a camp fire, you have to have wood, right? So you make the pile of wood,
okay? And you can soak that pile of
wood in gasoline, but you're still not gonna have a campfire,
you need to have a spark. So something has to light it,
and you can think of the wooden self as being the
genes that you were born with. You can think of the gasoline
that maybe you pour on the fire as something in the environment
that sets the stage, but then you have to have the spark. And maybe that's an infection,
and maybe that's a drug, we're not sure but
now you've got the campfire. But also remember with many of
our auto immune diseases these are not a self limited process
these become chronic diseases. So something has to
continue to feed that fire. Cuz otherwise it will burn out,
and now you have gotta
rebuild the camp fire. But something is a continuous
source of antigen to stimulate the immune
system on and on and on. And so maybe that is
a chronic infection, maybe that is
a chronic exposure, maybe that is the target tissue
of whatever the immune system is responding to that is the fuel
that continues to feed the fire. So, why are these autoimmune
diseases increasing? Why are we seeing more of them? And as I mentioned before, I don't think anyone
is really sure. No one can say,
this is exactly it. And that's probably because
it's complicated, and there's multiple influences. But there's a lot of
interesting thought so certainly the aging population, many of our auto-immune diseases
do occur in older individuals. Certainly we see autoimmunity
in children as well but it's rare compared to adults. And many of our diseases, if we
look at the age distribution, it's shifted towards fifty and older, there's some
variability there. There's a really interesting
body of literature that's continuing to grow called
the hygiene hypothesis, which you've probably heard
about or read about and it's all over the popular press. Which is maybe we're
being too sterile, maybe we aren't
exposing ourselves and our children to enough of
the microbes in the environment. Because we know when
we look at mice, and there's a lot of differences
between mice and humans. But if we look at mice and we keep them in a sterile
environment, there's actually higher risks of certain types
of autoimmune diseases. And interesting, there's a whole
growing body of literature in terms of parasites that in
individuals where parasites like hookworms are very, very common
there's a lower incidence of autoimmune diseases. So there's something about this
interaction between the immune system and microbes that
we don't understand yet. The microbiome In terms of all
of the bugs that is in your GI tract in particular is
a very hot area of research and investigation. And I'll tell you how how
interesting it has become at the American College of
Rheumatology annual meeting last year they had an entire two
hour session just dedicated to the microbiome and
how to sequence out bacteria in stool and how different it
is in different populations. It's different in people who
have Crohn's disease compared to people who have lupus compared
to people who don't have autoimmune diseases. There's something to it. We don't understand enough about
it but the more that we are able to have sophistication
measuring techniques, such as we were just hearing
about, with gene sequencing, now we're able to actually look at
these microscopic particles and try to understand what
the patterns are. And maybe this is going
to be a key to why we see a difference between women and
men in auto immunity and I think that there's a growing
body of evidence that suggests that may be the case. Cuz certainly, hormones have
something to do with it. But if that was all that it took
in terms of that differential between men and women, then we
would never see any autoimmune disease in men and that's not
the case, it's just less common. But maybe it's the interaction
between our microbiome and the hormones and
other environmental triggers. But you're starting to see
the layers of complexity when you're dealing
with the immune system. So autoimmunity and cancer, Dr.
Nelson touched on this, and it's something as a rheumatologist
I think about all of the time. We've known about the
relationship between the immune system and cancer for
decades and decades. There's certain autoimmune
diseases where this became very, very obvious. So dermatomyositis is
an autoimmune condition that can affect the skin and
it can effect the muscles and it's driven by the immune
system causing weakness in the muscles and
it can cause a skin rash. And what became very clear,
this is well described even back when the disease
was first described, was that people with
this autoimmune condition had a markedly increased
risk of cancer. As we started to follow
individuals over time, we saw that the risk of cancer
increased around that five year time frame when
individuals are diagnosed. And this gets back to this
idea that your immune system, yes it's designed to protect you
from viruses and bacteria and the external world. But it's also trying to
protect you from cancers. We all make cancer
cells every day, but your immune system
gets rid of it, notices those genetic defects
and gets rid of those cells. But a cancer can also stimulate
the immune system and sometimes maybe the cancer grows,
stimulates the immune system, the immune system's successful,
It eradicates the cancer but the autoimmunity
continues to propagate. And so this observation
in dermatomyositis of the proximity between
the development of cancer and an autoimmune disease then
started investigators looking at other autoimmune diseases and
said well why would that happen? And in scleroderma was some
really amazing breakthrough research. It actually, from our division,
that found that the antigen in certain tumors,there was an
autoantibody that was targeted specifically against
that antigen. And so
the link between scleroderma and particular autoantibodies,
remember those serum tests I was telling you about before
being a marker for the development of a malignancy,
has now been confirmed. And so this link between
the immune system and cancers is a close one. And I think you're gonna
continue to hear more and more about it cuz once again it
gives us another opportunity to solve these diseases. The immunotherapy
to treat cancer, as Dr Nelson was just talking
about, is a very interesting and very, very, exciting world. And from a rheumatology
perspective, it's interesting in
a couple of ways. And one way, it gives us an
insight into the immune system because with some of these
medications that are being used to successfully treat cancers by
harnessing the immune system and targeting that cancer,
some of the casualties of that can be the development of
autoimmune phenomenon. And as we start to understand
that relationship closer, it may give us some insight then into
our other autoimmune diseases. So what does
autoimmunity look like? So what does it look like? And there's a whole host
of autoimmune diseases. You can go through every single
organ system in the body and I can come up with
a autoimmune disease. In the skin, we have psoriasis. In the liver we have
autoimmune hepatitis, primary biliary cirrhosis. In the gastrointestinal system
we have Crohn's disease and ulcerative colitis. The musculoskeletal system,
we have rheumatoid arthritis, scleroderma myositis. And what they all share,
although they all look very different, is this disregulation
in the immune system. But although we've grouped each
one of these diseases as their own disease, I think we're going to start to
see more similarities between them as we understand
more about the genetics. And as we understand more
about this feed forward loop as we learn about
the triggers for autoimmunity. So how do we treat
these diseases? So in 2016 right now,
how do we treat these diseases? I told you that it's a great time to be a rheumatologist
because we have treatments. So the easiest way to treat them
is if we know what the trigger is, if we know what has
sparked the campfire. If it is a known infection we
can treat the infection, and we have wonderful treatments
now for hepatitis C. We've gotten very good
treatments for HIV and hepatitis B and that can really
turn off the immune response and you can solve the disease. If we know what the toxin is,
we can get rid of it. And many times that'll take
care of the autoimmune disease. The problem is that for
many of the diseases, we don't know what is
driving that feed forwardly. But what we do know is
the pattern in which the immune system is responding. And if it is responding
with certain cytokines, which are proteins made
by the immune system, and we now have therapies which
are called biologic therapies. You see them advertised on
TV all of the time, yes. But what's unique about these
therapies, as compared to our previous approach to
many autoimmune diseases, which was shut
the immune system down. Hit it with a sledgehammer. But now we're trying to
target particular pathways. And we have a whole host of
biologic agents that block IL-6, that block TNF-alpha,
that deplete B cells, that JAK-STAT inhibitors,
all these different pathways. What's interesting is that
you'll see many of these different pathways may be used
to target a particular disease, which once again tells you
about the layers of complexity. But what's exciting is that
by blocking these pathways, by developing molecules
that target those pathways, we can make our patients better,
so much better. And we can change the course of
the disease, and that is really the objective, is to obtain
disease modifying therapies. Not just to quiet it, not just
to make someone feel better, we want that, too. But we wanna change
the course of the disease. We wanna prevent damage from
the immune system that's continuing to propagate. And with some of the new
therapies we think that we can actually do that. We're not so brave as to say
that any of these therapies are what we call rheumotocytal, the rheumatostatic that
they can stop the disease. But they can change
the course of the disease. So in summary, the immune
system really is your friend. You want your immune system. You want it to be healthy and
happy, and do all the things that
it's supposed to do. But it certainly can go awry. There's some things that
you can change, and a whole lot of things
you can't change. You can't change
your genetic makeup. The things that we all can do
in terms of, that we can change, avoiding the toxins, no smoking,
having a healthy lifestyle, having a healthy nutrition, those are the things
that we can change. And then, of course,
being a part of the medical community as we continue to
learn about these diseases and learn about immune
disregulation. Thank you for your attention. >> [APPLAUSE]
