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>> Poly Matzinger: I'm going to take you through 65 years
of immunological theory in one diagram,
to show you how we differ from the older
models, and how we stand on top of some
of them, all right? So, the self-non-self
model was invented in 1953 by a guy
named Macfarlane Burnet in Australia.
And, if you look at that model in modern
terms, what he said was that the B-cells
and the killer cells -- the effector arm of
the immune system -- work by recognizing
non-self. What he said was that a B-cell
has on its surface a whole bunch of
copies -- we now know that it's about a
hundred thousand -- of the antibody that
it's going to later make. And, early in
life, all the B-cells, whose antibody can
see one of your own components, are
deleted. So, the only ones that are left
are the B-cells that can see foreign.
Killer cells are the same. They don't
recognize viruses purely, but what they
recognize are virus components. Pieces
displayed on the surface of infected
cells. And he said that those killers are
also -- the ones that can see self, like
your own kidney, your own heart -- are
deleted early in life, and the only ones
that are left are the ones that see
foreign. That was '53. That got a Nobel
Prize, and it lasted until 1969,
when Peter Bretscher and Mel
Cohn, at the Salk Institute in San Diego,
modified it. And they modified it by
adding another cell and another signal.
The signal that Burnet had suggested, we
call Signal 1, boringly. And that is
that, when a B-cell sees, say, a virus, the
binding of its antibodies gives it a
Signal 1. And Burnet said that was
enough to get it to divide and start
making antibody. Peter Bretscher and
Mel Cohn
said, "No, no. This isn't going to work." And
the reason they said that was that, in
the mid-60s, it was discovered that, when
B-cells do see a virus -- flu, HIV, whatever --
not only do they divide to make a small
army and start pumping out 2,000
antibody molecules per second, they also
mutate. In fact, they hypermutate. They
mutate a lot. And we think the reason is
that a B-cell that has very weak binding
to a virus, when it mutates, will generate
a few B-cells that have very high
binding -- strong binding -- and therefore
better antibodies. But, in the process of
all that mutation, you can imagine that
some B-cells would now mutate and be
able to see self. So, if the immune system
discriminates self from non-self, how can
you do that if you remove all your non-self
reactive B-cells but then, by
hypermutation, creates some more? So, what
they suggested was that it takes two
cells to create an immune response. If
you have two cells, both seeing the same
virus, and both mutate, it will be a rare
day when they both mutate to see the
same self-protein. So, if you require two
cells to make an immune response, you
would very rarely have autoimmunity.
Actually, they wanted to require three.
But, the problem with that is that the
frequency of B-cells for any one foreign
protein is about one in a million. So, if
you needed three cells to start an
immune response, you would need 10^9
-- which is a million times a million,
times a million -- B-cells to make an
immune response. We don't have that many
cells. So they settled on two, all right?
So, they invented -- this is how you made a
logical theory happens, hey? -- they
invented another cell that they called a
"helper," that we we, today, call a "T helper."
And they suggested that the T helper
needs to see the same foreign body as
the B-cell and that, in fact, if the B-cell
sees, let's say, the virus and gets
Signal 1
without a second signal from the
helper, Signal 2, that they called "help,"
the B-cell would die. So, a B-cell
that mutates to become autoreactive, if
it doesn't get help, will die. If there is
a helper that can see that same foreign
protein, you will get an immune response.
In fact, we know, now, that that's true, and
that, in fact, the B-cell takes in the
virus, breaks it up into little pieces,
displays it on the surface in special
schlepper molecules called MHC, and that
is seen by the T helper, that gives the T
helper Signal 1, it then gets activated,
gives the B-cell Signal 2, and voila! You
get an immune response, okay? That was
1969. That lasted until
1973. In 1973, back in Australia, Lafferty
and Cunningham modified the model, yet
again, by adding another cell and another
signal. And the problem they were dealing
with was that T helpers seemed to be
more responsive to the molecules of
another human than they are to the
molecules of a mouse, or a dog, or a monkey.
And yet, a mouse, a dog, or a monkey ought
to be more foreign to a human helper
than another human. So, there seemed to be
some kind of species-specificity going
on, here. And so, to deal with that, they
added another cell and another signal.
They added what they called an "accessory
cell," and today we call an
"antigen-presenting cell," "macrophage," or
"dendritic cell." And they suggested that
the helper cell itself needed a second
signal, and that, without that second
signal, it couldn't make a response. And
that it got the second signal from the
accessory cell. So, what they said was, the
macrophage -- or the dendritic cell; the APC --
breaks up the foreign body into little
pieces, displays it on its surface where
it can be seen by the helper, that gives
it Signal 1; if it also gets a second
signal that they called "co-stimulation,"
you get an immune response.
Now, that was 1973. What happened for the
next 13 years was that "help" was studied.
You could get NIH grants to study help.
I bet you could get MRC grants to study
help. And presenting cells were totally
ignored, until 1986, when Jenkins and
Schwartz, at the National Institutes of
Health in DC, found by accident that, if
you allowed the presenting cells to
degrade the virus and put its pieces on
the surface, and then you fixed it into a
little billiard ball, it would not
stimulate an immune response. You needed
an active, happy, presenting cell in order
to give the second signal, co-stimulation.
That was '86. And, one then has the
question, why did it take 13 years? After
1986, presenting cells and co-stimulation
became a huge topic in immunology. I
would say a third of the immunology labs
around the planet studied it. Why did it
take 13 years? Here's the reason. We
scientists have our own failings, right?
If something doesn't fit into your model,
you ignore it. And co-stimulation didn't
fit into the self-non-self model, and
here's why. If you think that the immune
system functions by discriminating self
from non-self, cells that are specific,
meaning they can see one thing, are
useful. The helper cell can be the cell
that governs immunity, because you can
remove the helpers that see self. The
presenting cell doesn't discriminate
between self and non-self. It picks up
anything. They clean up wounds, they pick
up anything. They pick up viruses,
bacteria, fungus, allergens, everything. The
presenting cell cannot discriminate self
from non-self. So, if that's the cell that
starts an immune response, how does the
immune system recognize self from
non-self? So, it was ignored for 13 years.
And then it was rediscovered. And then
immunologists had a problem. And then,
for three more years, they had a problem,
and then Charlie Janeway solved it, sort
of, by suggesting that the presenting
cell itself can discriminate self from
non-self in a funny way. That bacteria,
not viruses, bacteria, are so
evolutionarily distant from humans that
we could have genetically-encoded,
selected over time, receptors for
bacterial proteins. The most important
thing he said was the presenting cell is
normally off. You turn it on when it sees
a bacterium -- an evolutionarily distant
non-self -- and that was cute, because it put
co-stimulation, which is only made by
activated APCs, back under the control
of a self-non-self signal. But Ephraim
and I said to Charlie, "But, wait a minute,
Charlie, the immune system rejects
transplants. Most well done heart
transplants are not covered in bacteria,
right? It can cause autoimmunity, and it
can sometimes reject a tumor. So, there no
bacteria there. How does the immune
system work against those things?" And
Charlie said, "Oh, no problem. Transplants
are a modern invention. We didn't evolve
to deal with those. And tumors and
autoimmunity tend to kill you late
enough in life that you've already had
your kids, and so evolution doesn't care."
And we said, "You know what? If you want to
make a model that describes what the
immune system does, you have to describe
what it does. Not just what you think it
evolved to do, but what it does. And it
does reject transplants, and it does give
us autoimmunity, and it can reject a
tumor. So how do you deal with that?" And
so, what we did is we followed tradition.
We added another cell and another signal,
and this is it. There are no more cells
you can add, all right? Because what we
brought into this conversation was every
tissue of the body. And we said, if you
have a tissue made up of cells, and the
cells are healthy, and happy, or if they
die a normal death, and get scavenged by
their neighbors -- which is what happens
when cells die a
normal death -- everything's fine. But,
should a cell get virus-infected, or
damaged and blown open, it will release
alarm signals. And that those alarm
signals are what the presenting cells
are really waiting for. And that that's
what starts an immune response. It's the
alarm signals from damaged tissue, not
the recognition of foreignness. The
bacterium comes in and does no damage,
you don't respond. We have plenty of
bacteria in our guts, our skin, etc, that
we don't make immune responses to. They're
not doing damage. So, here we follow
tradition. We've added another cell and
another signal, and it turns out that if
you take that one more step with me, you
fall off a cliff. And you stand in a
different place. And you look at the
immune system from a different point of
view. And when you look at the immune
system from that point of view, it turns
out that you can explain almost
everything it gets right and almost
everything it gets wrong. Ao here's a
list. We're not gonna have time to do the
whole list. You can explain why you don't
reject yourself at puberty, why lactation
is not a problem, why fetuses are not
rejected -- and we'll come back to that -- why
transplants are rejected, why tumors are
not rejected, why you get
graft-versus-host disease, why there are
parasites like Filaria, which is the
worm that makes elephantiasis. It lives
in the lymphatic vessels in intimate
contact with the immune system, and,
usually, you don't make an immune
response. And it doesn't explain why you
get allergy or asthma, and that doesn't
bother me. And, the reason it doesn't
bother me is that allergy and asthma are
a problem in a different universe of
question. What do I mean by that? Here's what
I mean. So, the immune system has to deal
with two questions: 1) do I respond or
not, when faced with something? That's what
we're talking about here. Do I respond or
not? The second question, once you decide
to respond, what kind of response do I
make? How do I know
to make the right response to fight a
worm, or the right response to fight a
virus? And allergy and asthma are a
problem in that question. Allergens are
dangerous. Der p 1, which is the main
allergen in house dust mite, is a
protease that attacks the surface
epithelium of the lung, and also attacks
B-cells. Bee venom is not innocuous.
So, the danger model says that the
reason an allergen is an allergen is
that it either is dangerous itself, is
packaged with something that's dangerous,
or mimics an endogenous alarm signal. Why
some people make IgE to allergens and
other people make IgG, and are not
allergic, is a question of the second
question, which is what kind of response
do I make? What kind, rather than weather.
So, let's stay with weather, because we
don't have time to do everything. But the
short answer is, you don't reject your
fetuses because they don't look
dangerous. You do reject transplants
because they look dangerous. And you
don't reject tumors because they don't
look dangerous. That's Immunology 101-A
as seen from the danger model. Now, one
minute, when I teach this to grammar
school kids, I give them the following
scenario. I say, if you think about the
body as a community, the self-non-self
model suggested that the white blood
cells that are part of your immune
system are like cops -- American cops -- they
go around shooting any foreigner they
meet, and they define a foreigner as
anybody they hadn't already met by the
time they finished high school.
The danger model says that, no, no. If you
think of the body as a community, right,
the immune system is more like firemen.
They sit in their fire houses playing
cards until somebody rings an alarm. And
it doesn't matter if the alarm is wrung
by a member of the community or a
traveling salesman, which is not allowed
in the other community, or an immigrant --
they only respond when there's an alarm.
And, unlike the cops, they have more than
one way of responding. If it's a cat up a
tree, they bring a different truck from
if it's a three alarm fire. So, that's the
difference between the self-non-self
model and the danger model. I hope you
enjoyed the talk. Thank you very much.
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