This program is a
presentation of UCTV for educational and
non-commercial use only. I'm very excited to introduce
to this week Tony DeFranco. After spending significant
time going back and forth between East and West
coast I've learned tonight, he very wisely settled
on the West Coast in 1983, coming to UCSF. But he spent undergraduate
time at Harvard, and then he was at Berkeley
for graduate school, and then was at NIH, and
then came back out to UCSF. When I asked him how he
wanted to be introduced, he mostly very modestly said, please introduce me as a
teacher of immunology. Well, that is certainly an understatement
because he has been absolutely core to
the teaching programs not only of medical students, but of everyone here
learning immunology. Compared to my basic overview
that you got last week of clinical immunology with a
little bit of basic thrown in with just mostly
introduction and terminology. Tonight, you're set for the nuts and bolts of immunology
so that you can learn a little bit more
in depth and more precisely about
the immune system. I feel very privileged
that he's here tonight, and I'm going to turn you
over to Dr. DeFranco. Thanks, Dr. Gundling, and thanks for that
fine introduction. It's great to see
everybody here tonight. I gave a very similar talk about two weeks ago to another
group of medical students. That group is really busily studying for a really big exam. That's our second
year medical students and you all don't look nearly
as nervous as that group. Nuts and bolts are in the title and I hope you
don't get too afraid by that. I'm going to give you a
few nuts and a few bolts. But what I'm going to try
to mostly do is give you the principles and
use those nuts and bolts to illustrate the
key principles for how our immune system
helps protect us. Of course, I think most people, even before last week's lecture, knew that the immune system is to protect us from scary
things that want to eat us. No, not these scary things. These scary things. On the left, we have an electron micrograph
of a virus particles. This is the virus that causes AIDS, Acquired
Immunodeficiency Syndrome. This is a bacterium here. That's the bacterium that
causes tuberculosis. Over here, we have
a red blood cell that's got some parasites inside. Those are the parasites
that cause malaria. Those, of course, are the
three big killers worldwide. Infectious disease killers of people worldwide
along with influenza, we probably should include
that to be the big four. We're going to hear
something today about how the immune system protects us about these kinds of threats. Now, these are numbers from the US Centers for
Disease Control, the CDC, who keep
track of this thing. This is the number of types
of viruses and bacteria and fungi and worms and parasitic protozoa such as
the one that causes malaria. These are the number that cause serious disease in people. You can see, it's not
just a few things, but the immune system has
got to protect us from a continual barrage of
things that want to eat us. They don't eat us the way a
lion or an alligator would, but they want to make use of
our goodies and grow in us. That really should be
in the very big type, and then some other functions of the immune system I've listed here should be a
much smaller type. The immune system also promotes the normal functioning
of the body by helping clean up our
tissues and repair wounds. It helps remove abnormal cells, including the beginnings
of some cancers. This is now well established that the immune system
does cure cancer. To some extent, it prevents
cancers from coming up, and it's also in some clinical
settings does cure cancer. I'll talk about that
toward the end. Then this is the good. This is why we need
our immune system, and this is why
individuals who are born with a big malfunction
in their immune system, really are going to die in a
very short time unless we do some really drastic treatment. We have a lecture coming up on bone marrow
transplantation, which is one way that some of those diseases can
be completely cured. Which I think is
very exciting and some of that really was pioneered here at UCSF.
Some of those therapies. I don't know if anybody
saw the Chronicle, I think it was on Saturday. There was an article about
the pediatrics department here is working on getting faster diagnosis of those kinds of individuals
because the therapies, the bone marrow transplantation
works better if you catch the people before they
have serious infections. This is an ongoing area
that UCSF is a leader in. But then there's
also the bad part of the immune system and a
couple of the lectures are going to touch on that. Our immune system
sometimes confuses all of these bad guys for
things that are not so bad, like hay fever pollen and cat dander and
things like that, and can cause allergies, which is Dr.
Gundling's specialty. Even worse, it can mistake
some of our own components for foreign invaders and
cause auto-immune diseases. We're going to have
a lecture from Dr. Andrew Gross in our
rheumatology division about some of the exciting
new therapies that are coming online that make
use of this information, the understanding of the
immune system that I'm going to talk about today, to develop new
therapies for some of these very nasty
diseases where we really need a really strong
intervention. Then of course, another example
would be transplantation. If somebody needs a new kidney, or a new lung, or a new heart, or a new liver, we have immunological rejection
as one of the problems. Those procedures only became feasible when we
learned how to suppress immune responses enough to allow those organs to remain and not get destroyed by
the immune system. A slider to remind you of some of the things that Dr.
Gundling covered last week. First off, I just want to remind
you of the players. The Giants have pitchers and in fielders and outfielders
and a great catcher, what does the immune system have? The immune system has
sentinel cells that are sitting in the tissues waiting for an infection to come along, and there's really three types of immune cells sitting out there. A cell called the
dendritic cells, and I'll talk a little
bit more about them. This is a type of cell that immunologists are really
excited about right now. We're learning about
these dendritic cells as being very important players. There's the macrophage, which is also an important
player out in the tissues, and there's a cell
called a mast cell, which is important for
allergies and asthma, and also for protecting
us from worms and blood-sucking insects like mosquitoes and ticks
and things like that. Then these cells that are in the tissues waiting for an
infection to come along, when they find one, they call out for help
from their friends which are circulating
around in the bloodstream, and they come in two flavors. The cells that are good
at killing things, the phagocytes are good
at eating things and the granules are good
for killing things. You saw some movies of
neutrophils last week. Neutrophils, monocytes, and eosinophils would be the three types of
cells in this category. They're circulating around in the blood waiting
for an infection, and then they're going to
go into the infected tissue and help get rid
of that infection. Then we have our lymphocytes. These are what we call our
adaptive immune system. They are the B cells
that make antibodies, T cells that do
cell-mediated immunity. You heard a little
about these last time, and I'm going to go into these in a little bit more detail today. Some of these immunodeficiency
patients that really need a bone marrow transplantation are because they're missing
these components here. Although that therapy is
also being considered for defects in these kinds of cells
as well, genetic defects. Then finally, I heard that
you had some questions last week about a type of cell called the natural killer cell, and it's really good at
killing virus infected cells. It is more in this category
than in this category. But morphologically,
it's a lymphocyte, which is what does it look like in a light
microscope type of definition. Anyway, you'll hear a
little bit about this. One of the world's experts on natural killer cells
is Lewis Lanier, and he's going to be part of that bone marrow
transplantation lecture coming up in a couple of weeks. Those are the players. Let's then look at what happens
when we get an infection. Again, this is something that we
heard a little bit about, we're going to go into some
more detail about it tonight. The sentinel cells
in the tissues, and that would be the macrophages and dendritic
cells in this case, if we're talking about
a new infection. They would recognize the
microorganism that's coming in. Let's say you get a
cut in your finger and you get some
bacteria in there, or you breathe in
something and it gets past the barriers in the lung
and gets into the tissue, then we would be
having an infection, and then our cells in the tissue would be recognizing that. This process of recognition by these types of cells as
opposed to the lymphocytes, we call that innate immunity, and they utilize
evolved receptors that recognize broad
classes of microbes. They would recognize
that this is a virus, or this is a bacteria, or this is a worm. They recognize broad classes. They recognize molecules that are characteristic of broad
classes of organisms. Not necessarily pathogens,
but any bacteria, or any yeast, or any worm. Some small fraction of the bacteria in the world
are pathogens of people. Most of them are benign
and live in the soil, and help decompose
dead organisms, and so forth, they provide
a very beneficial role. Most of the bacteria are good, but then occasionally they are really ones that come
after us and are bad. These sentinel cells
in the tissue, the dendritic cells
and the macrophage, what happens when they
see these agents? Well, they realize that they
are in limited number and they won't be able to
really take care of the problem all by themselves, they got to call out to their
friends in the bloodstream. The way they do that is
by secreting proteins. They secrete proteins
that then go and diffuse over to the
neighboring cells and to the neighboring blood vessels
and cause those cells to now bring in the
cells from the blood. These proteins that are made
by immune cells and act on other cells, we call cytokines. Cyto for cell, and kine because
it induces an action on the part of the cell that
it's acting on, so cytokines. The cytokines are really
important in immunology. I'm going to mention them again and again in this lecture. I'm not going to give you the
names of too many of them, the actual nuts and bolts. We know of about 50 cytokines. We don't even make our
second-year medical students, and the people who write
the board exam questions, don't make them learn the names of all 50 of those cytokines. They have to learn
about a dozen of them. I'm going to mention about
three or four or five tonight, so you're not going to
get quite as many as our second year medical students. But you're going to hear
about some more from Andrew Gross because
some of them are targets of new therapeutics. We'll talk about cytokines
and what they do. These cytokines go over to
the neighboring blood vessel, the blood vessel cells then respond to that. What do they do? They put adhesion molecules,
sticky molecules, on their surface that's
facing the bloodstream for this white blood cells
in the bloodstream to attach and then
come into the tissue. I'll explain how that
works in just a minute. They're going to attract
circulating immune cells to the site of the tissue. This is a very efficient system. The cells recognize
the infection, they say to the
neighboring blood cells, "Bring in some help." The blood vessels
bring in some help, and here it comes. The blood vessels also
allow fluid from the blood. This is the cellular help. They also allow the
fluid to come in with proteins that are put
directly protective as well, such as antibody molecules that you heard about last time. I'll talk in a lot more detail tonight about antibody molecules. In general, this
response of bringing in immune cells and bringing
in fluid from the blood, we call this inflammation. Everybody is familiar
with inflammation. You'd get a cut in your skin, you get bacteria in there, it swells up, it's red, it hurts. The definition of an
inflammation was made by the ancient Romans. We've known for many years. You've all experienced
inflammation. What I'm telling you is
inflammation is good. We think of inflammation as bad, in this context,
inflammation is good. It's doing what it's supposed to. It's getting the immune system there to fight the infection. When inflammation
is bad, however, is when it's prolonged and chronic then you
get tissue damage. Those immune cells
that are coming in, their goal is to kill the
bacteria, kill the fungi, kill these other things
that are trying to eat us, and they're going to
cause some damage to the underlying tissue if
we give them the chance. That's where inflammation is bad, is when it's prolonged
and chronic. This is just an illustration of the process I
just went through. This is the tissue side. This is the layer
of cells that line the blood vessel called
the endothelium. This is the bloodstream here. We've got our white blood
cells flowing through here. On the interstate, they're going through it
70 miles an hour. Out here in the tissue
we got these bacteria. Our sentinel cells
are recognizing those bacteria, they're
secreting cytokines, and I've listed two
cytokines on this diagram, interleukin-1, IL-1 and TNF. Among about the 50 cytokines, about 35 of them or so have a systematic name
called the interleukin-1, interleukin-2 all the way
up to interleukin-35. That's good for being systematic, but it's hard to remember them. What does interleukin-22
do again? We immunologists
struggle with that. They originally named interleukin because it was thought that they're being secreted by one immune cell and acting
on another immune cell. We now know it's more
complicated that they can act on non-immune cells, like blood vessel
cells as shown here. That's when the name was changed from interleukin to cytokine. But instead of calling them
cytokine-1, cytokine-2, cytokine-3, we've stayed with the interleukin 1, 2, 3, etc. About the other 15 all have names that were too popular to give up. This one, for example, the TNF, that stands for tumor
necrosis factor. Now, put yourself in the place of the scientist who discovered
tumor necrosis factor. He had this thing
that he found that he injected into a mouse
that had a tumor, and the tumor cells
all died rapidly by a process of cell
death called necrosis, which is what happens if you
starve the blood supply. The cells don't get any
blood then they die by necrosis. It's a violent death. It's also what
would happen if you take blood cells and stick them in a glass of water and they would blow up because
there's no salt around. He had dollar signs
and visions of fame flash before his eyes when he gave this
molecule this name. Turns out, you can't
use it to treat cancer. You cannot give people TNF. The reason you can't give
them TNF is because this happens too much and you
get inflammation too much, you go into shock, very bad news. However, somebody is
making money from TNF, but by doing the
opposite, by blocking it. This is really good for some nasty inflammatory diseases such as rheumatoid arthritis, then blocking TNF can be
a very good therapeutic. You're going to hear
more about that from Dr. Gross in a couple of weeks. IL-1 and TNF. It turns out we have
therapeutics that block TNF, they are good for some diseases. Therapeutics that block IL-1, they're good for
some other diseases, not quite as many diseases, so they're not making as
much money from that. Somebody got the bright idea. What if we block both
of them at once? That clinical trial
stopped really fast because the people
got severe infections. These two cytokines have overlapping functions and
if you block them both, you have bad news, but
you can block one of them and there's a therapeutic value that
you can get from that. Our host sentinel cell
sees the bacteria, secretes TNF and IL-1 that
acts on these blood vessels, they put up several
adhesion molecules. This one here grabs the leukocytes as they're
coming by and they start rolling on the
endothelium instead of zipping by 70 miles an hour, they get on the off-ramp and say, "Do I want to exit or not?" Whether they want
to exit or not is determined by this
little green ball here, which we call a chemokine, because it's a kine means
that the cells respond to it. The kine refers to
the cells responding, and the chemo is
referring to the fact that there's a chemical
that it's attracting cells. Basically, what the
chemokine does is it controls which immune cells come into that site
of inflammation. The reaction started here is
determining which chemokine, which is determining which
blood cell is coming in. The immune system has the ability to customize the response, and we'll talk a little
bit more about how that happens a little bit
later in the talk. You can customize the
response to fight the type of infection that is
being sensed here. The type of chemokine determines what blood cell comes in. If this cell sees the right chemokine
that it can respond to, then its other sticky molecules, adhesion molecules
become more sticky. It then stops, instead
of rolling along, it stops and then it
squeezes through between the endothelial cells and comes in here and then
helps fight the infection. That's that sequence of events
to get inflammation going. As I indicated there, the neutrophil is the immune
system's first responder. If we have an infection
with bacteria or fungus, yeast type a cell, it's the neutrophil
that's going to come in and do the heavy lifting. Neutrophils are typically the
first cells that come in, they are really good
at killing things. They make a lot of
nasty chemicals, including bleach molecule. Basically, what we use as bleach is one thing that
the neutrophil makes. They're very good at
killing microbes. They can also damage
tissue in the process. If you get an infection, you'll probably notice
you get some pus, and a lot of that is due to the dead neutrophils
that are coming there. The neutrophils make
nasty chemicals. They're very short-lived cells, because they make
these nasty chemicals it's not good for
their own health, but they come in and they
fight the infection. Because they don't
live very long, they need to be continually replenished from our bone marrow. This is, again, another
medical correlation here, is that, if we have
a situation where the bone marrow is not putting out blood cells adequately, the first place we feel
that would be two things, the red blood cells and anemia, and the other thing would be the neutrophils and getting more infections or more
severe infections, if we don't have
enough neutrophils, because the neutrophils
have got do this all the time because
we're always getting some bacteria or fungus getting in there whether
we got to kill off. Some chemotherapies for cancer treatment
have this problem, and luckily, we have a couple of cytokines that make the bone marrow produce
more neutrophils, and so since they've come
online as therapeutics, that's helped cancer patients
getting chemotherapy to do better that we can boost their neutrophils back up
to where they should be. The neutrophils, now, because
they're pretty nasty, this basic inflammation generally doesn't bring in
neutrophils for very long, maybe about a day,
and then it switches, and the next cell
up is the monocyte. The neutrophil comes
in first and then we start making
different chemokines on the blood vessel
that attract now the monocytes instead
of the neutrophils. The beauty of the monocyte
is it's bipotential. It can either be a good
killer like a neutrophil, not quite as good
as a neutrophil, but it can still be pretty good, or it can clean up the mess
and help us repair the damage and get back to
normal healthy tissue and not being all red
and swollen anymore. What controls
whether the monocyte is going to fight or
going to clean up? Cytokines. Whatever cytokines are getting made when the
monocyte gets in there, if we've already gotten
rid of the infection, the cytokines shift over and we get the ones that
promote wound healing. If the bacteria are
still multiplying, we haven't gotten them all yet, then the cytokines are getting produced by the other cells in the tissue are going
to be the ones to tell the monocyte
to keep fighting. The monocytes comes in, it's sort of, "What's going
on guys? Tell me what to do." It can respond to cytokines
to do what we want it to do. Now, as I said, the neutrophils make a
lot of nasty things. Another important
principle about how we kill microbes is
that we eat them. Our neutrophils,
and our monocytes, and our macrophages, and our dendritic cells are
really good at eating things. That's a process that
we call phagocytosis. Phagocytosis means one
cell eating something, in this case, eating
something big. The definition of phagocytosis
is something big, at least a bacteria size. That would be eating a microbe. The neutrophils and
the monocytes can do this to some extent
on their own but it's really greatly helped along
if we make antibodies against that bacteria or that virus
or that fungus particle. If we coat that microbe with some soluble
immune components, can be some innate
components work this way, but for sure, antibodies are
really, really good at this. Now, our phagocytes really will eat them much faster and much better and kill
them much better. That's the cooperation of the circulating phagocytes
that act early with antibodies which are going
to get produced a little bit later against things that we
don't kill off right away. Now, I think this is a
pretty important point here. Those things I gave
you from the list, I just gave you the numbers,
I didn't give you the names. Those things that
cause human disease, mostly, and I think there's probably very
few exceptions to this. Almost all of them cause disease because they're good at evading the immune
system killing them. They have figured out ways to avoid getting killed
by the immune system. Microbes that cause illness in healthy people either
resist phagocytosis or resist killing inside
the phagocytes or have some other related
strategies to get by. Some good examples of the latter, some of them get taken
up by the phagocytes, but then they keep the phagocyte from killing them somehow. A couple of good examples
of that are Salmonella, which is a common cause
of food poisoning, and also causes Typhoid
fever if you have a breakdown in the water supply. Another great example would be Mycobacterium tuberculosis, the organism that causes TB. Tuberculosis, as I said, it's one of the big four. It's a huge threat to human health in many
parts of the world. Although it's not a terrible
problem in this country, there are people who get infected in this country as well. It's just much less, but in many parts of the
world, it's a big threat. An example of an organism
that evades this principle here of the antibodies coating
it and making it really easy for our phagocytes to
eat them up and kill them, an example of one that evades that is Streptococcus pneumoniae, which is a bacteria
that is important cause of severe bacterial pneumonia. This one, it changes
its outer surface so that if you make antibodies against Streptococcus pneumoniae, it's got a lot of very
close cousins that your antibodies won't
recognize that slight variant. There's lots and lots
of really close cousins of Streptococcus pneumoniae. We've tried to help this along
because we have a vaccine. One of the main vaccines
for this takes 23 of these different
variants and puts them all together and
immunizes people. That takes care of about
90 percent of the cases, there's still about
10 percent that are relatives that are
enough different that these antibodies don't help. But it does help about
90 percent of the time. Now, other examples
of common organisms that change their coat so that the antibodies don't work again and protect us from
a second infection, influenza virus is another flu, is another example of that. Another common example would be the common cold, rhinoviruses. Again, come in about 100
different varieties. Eventually, you will have
had almost all of them, but it takes a while before
you've had that many colds. Unfortunately. Yeah. Our
adaptive immunity is good, but the bugs can figure
out ways to evade it. That's a good transition
for me now to talk about the B cells and antibodies and the T cells and
cell-mediated immunity. They're part of what we
call adaptive immunity. We've been talking so far
mostly about innate immunity, the ability of our neutrophils and monocytes and dendritic cells and macrophages to directly
recognize infectious agents. Adaptive immunity uses a
completely different strategy. Innate immunity,
those innate cells, they just have a bunch of different receptors
that recognize very conserved elements
of whole classes of organisms and are hard
for those organisms to change because it's part
of their lifestyle, certain aspects of
their cell wall, if it's a virus, most viruses have RNA as their genetic material and
when they replicate their RNA, they make a
double-stranded RNA that the two strands paired
against each other, we can detect that
double-stranded RNA. It's hard for the virus to change how it replicates its
genetic material. There aren't very
many viruses that can directly avoid doing that. There are a few viruses that have switched
to using DNA as their genetic material
but most of them use RNA. Anyway, that's how the
innate immunity does. Adaptive immunity uses a
completely different strategy. Here now instead of
all of the cells having a dozen
different receptors, each of which it recognizes
broad classes of organisms, our T cells and B cells, each one uses a similar molecule
but slightly different. So it can recognize a
different pathogen. We'll have one cell in 10,000 that will recognize
influenza virus, one cell in 10,000 that will recognize rhinovirus
that causes colds, one in 10,000 that will recognize the organism that causes
tuberculosis, etc. That's all before
we get infected. When we get infected, those ones that can respond, they expand up and we
get more of them so that there's now enough to
help fight the infection. Adaptive immunity uses a
very different strategy. It starts out with
each cell having one receptor and being able to recognize one type of thing, one individual
rather than a broad class but then you have to expand those up to
make them useful. Now, there are some
other points here which I'm going to
come to in a minute. The way in which this works for the B
cells and the T cells, is that they do it
at the DNA level. They start out with their ability to recognize
these pathogen molecules. The gene encoding, those
recognition elements exist in pieces spread out across the DNA
of one chromosome. Then as part of the development of each individual B-cell, it picks one of these several 100 elements, and sticks them next
to one of these, in this example, four elements. Some of the genes have three different
types that come together, some of them have two
that come together. I'm just trying to be
very schematic here, but any given individual
B-cell as it develops, it picks at random
one of these 1, 2, 3 up to several 100. It puts it next to
one of these four, you're getting a multiplication to give you the number
of possibilities. This example I have
given you only get up to a few 100 different
possibilities, but it turns out, there are
various mechanisms that are a little more complicated
than I want to get into, but we can get up to
millions and billions of possibilities for our
B-cells and T-cells. Really, our B-cells and T-cells can recognize
almost anything. There were studies done by an American by the name of
Landsteiner in the 1930s. He made lots of organic
chemicals and tested the immune system's ability to make antibodies against them. Really, whatever he made, he was able to get antibodies
against pretty much. The B-cells and the T-cells, they can recognize
whatever we throw at them. As I mentioned, these cells
start out pretty rare because we've got each of which
recognize different things. The principle here is that
once we get an infection, those B-cells and those T-cells, which can recognize
with their receptors, can recognize molecules
of the infectious agent, they multiply many times
to expand their number, and then some fight
the infection, others are left in
reserve as memory, and that's one of the
main reasons that we don't get nearly
as sick the second time around is that we have
more of those lymphocytes. Instead of one in 10,000, we have one in a 100 or several in a 1,000,
we have a lot more. That's what vaccines do, vaccines give us a fake infection that gives us more of
that immunological memory and antibodies so that if we get the real infection,
we're more prepared, our adaptive immunity doesn't
take as long to get going, it gets going faster, it beats back the infection
faster before we get as sick. Adaptive immunity is
very important in a first infection and it's
even better in a second, it learns from the
experience of the first. It changes how many cells
there are waiting around for the infection to give us more of those to be able
to respond faster. I've illustrated that a little
bit in this slide here. This is now lymphocytes, these happen to be T-cells, based on the shape
of this molecule, but they're each a
different color here, and that is supposed to represent the fact
that they each have a little bit different
shape and they can recognize a different pathogen. We start out with many
different possibilities, now, because of the way
this is generated, the B-cells and the T-cells, they are randomly bringing these gene segments together. It turns out, not only can they recognize any molecule
we can synthesize, or any molecule that a
pathogen can throw at us, but they also recognize
our own molecules as well. That is the downside that
comes with the good side, the bad with the good. That's the reason when we have an autoimmune disease
or an allergy against food or against cat
dander or against pollen, our immune system, our B-cells and T-cells have made a mistake, they've made an immune response
when they shouldn't have. In most of us, we make
that decision correct so often that we don't notice that we ever make any mistakes, we do make mistakes
at small levels, all of us do,
certainly, not rare, but only in a few percent of people do those
mistakes get made badly enough that it becomes a disease or a
really bad nuisance. Now, I guess probably,
for allergies, it would be higher
than the few percent, that would be probably, many of us experience allergies in springtime and
things like that, but the point is that we randomly generate
these lymphocytes. We then have to have a way of trying to get rid of
the ones that are bad. Part of that is done
during their development, they go through a phase in their development where if they contact their antigen,
they're inactivated. That's illustrated here, some of the colors
have dropped out, the point of that is that our self molecules
are always there, whereas infections are not
there and then appear. We have a timing device. The cells are developing
all the time, the ones that develop
before the infection, well, if we're going to see that
infection in the future, they could just develop, they wouldn't see our
self molecules, they would make it to
the mature stage, and now when we get the
infection, they can respond. The ones that saw ourselves, our self is there all the time, it would be there during
the immature phase, and a lot of those
cells would die off. That is one of the
mechanisms which we get rid of the
self reactive cells, it's not the complete mechanism, and I'll come back
later in the talk to other mechanisms that
the immune system uses. This is one of the
important mechanisms, but there's also a subsequent
mechanism that occurs. Some cells sneak past that
checkpoint and then we have to silence them later to
avoid auto-immune disease. If we get an infection,
in this example, we're getting an infection
with a virus that is seen by this cell here with
the orange receptor, and so those cells expand. The other colors don't expand, they stay the same in number, but we give more of these. Now, at this state, if we get infected again
with this orange pathogen, well, we've got a lot more
cells to deal with it. We call that clonal selection. This would be referred to as a clone of cells that came from the original mother cell divided many times and gave
rise to a clone of cells. They're all identical
or nearly so. Again, vaccination
works by generating memory T-cells and
memory B-cells. Also, the cells that
make antibodies, the B-cells during
an immune response, some of them become antibody
secreting factories and make large
amounts of antibody, during an immune response, some of those can become
very long lived cells, and continue to make
antibody for many years, certainly, up to a
decade, if not longer. We don't know completely
how long they live, but certainly, for a decade, they slowly go down over time. We have antibody right there, right at the beginning when the pathogen comes back to
deal with it right away. I've been talking
about antibodies. What I want to do for the
next five or so minutes is, probably, more like ten
minutes, I want to tell you a little bit more in
detail about antibodies. You all have heard
about antibodies, but let's talk about
some details so you understand a little bit
better how they work and how we can use
them in therapeutics. As a person, I can make millions or billions of
different antibodies, but any one B-cell is only
going to make one antibody. That's because it
rearranged its DNA, each B-cell did
that individually. Now, the molecule,
I want to define another term here that
immunologists always use, antigen. Antigen is what an
antibody recognizes. That's an easy way, we have to have a word for what does an antibody binds to, it binds to the antigen. The name antigen comes
from the fact that the antigen generates the
production of the antibody. We inject an antigen into
ourselves or into an animal, our immune systems produce the antibody against
that molecule, they generate an
antibody response. It's a circular definition. An antigen is something
that causes you to make an antibody
that recognizes it, that's where the name comes from. Then by analogy, we call it when a T cell recognizes
also an antigen, although T cells don't
make antibodies, but by analogy, we call
that antigen as well. Now, as I mentioned, we have many B cells in our body and each B cell is making a little bit
different antibody. But when we have, let say, a flu virus come in, we have different
B cells that will make an antibody recognize different parts of
that flu virus. It's not just one B cell
that's getting activated, it's a handful or 100 or maybe even 1,000
B cells are getting activated and each expanding in number and then
each making antibody. Each of those is a clone, but it's many clones because there were many
different B cells to start with, each of which made a
different antibody. We call that antibody polyclonal, and I'm going to distinguish
that in a minute from a monoclonal antibody
which we use in therapy, so this is a clone. Now, another important
principle here is that B cells are often
helped by T cells. Although T cells do
cell-mediated immunity and B cells make antibody, they also work together
and I believe you've got a movie of that last
week from Dr. Gundling. That's the T cells helping the B cells
to make antibodies. When that happens, the B cells make a
higher quality antibody. What will happen in
an immune response is actually some B cells will go
off and make some antibody quickly on their own and that's an antibody that sticks a little bit
to the pathogen, but not really well,
sticks a little bit, so we want to get some
of that out there fast, just to help right away. But some of those B cells, they're going to take the more long-term
investing strategy, they're going to collaborate
with the T cells, and they're going to
make better antibody. They're going to go
through a process in which they introduce mutations
and then pick out the one, the mutants that have the highest affinity
for the antigen. There's a slow, but
ultimately useful process in which we make higher-quality
antibodies that bind more strongly to the pathogen and therefore are
more protective. We make some lower-quality
antibody quickly, they help out right away and then we take some
of our B cells and we invest them in a long-term bond and
at the end of the day, we have higher-quality product. The B cells and the T
cells see antigen in a fundamentally different
way, as I'm going to explain. But yes, the way this
works is that T cell has to see the same
virus or bacteria or whatever that the
B cells sees and only if they both are against the same molecular antigen, perfect, the same particle or, it doesn't have to be
exact, immunologists would usually use antigen to
refer to a single molecule. But in a virus
particle, there are several types of
molecules in there, and this will work for two different molecules in
the same particle as well. Now, we call this the germinal center response and you don't need
to remember that. But the key point is
that this gives you these long-lasting
antibodies secreting cells that go to the bone
marrow and they secrete antibody for years
and years and years. This makes sense if
you think about it, that B cells that make
the quick response, that's not as sticky, but it's going to
help a little bit, we don't worry about, we just make that those cells only make antibody
for a short time, but the ones that get the T cell help and make the really high-quality antibody, those are the ones we want, those antibody secreting cells
to last a long time and to really help us over time so that when that
pathogen comes back, we've got the best quality
antibody to fight it. Almost all the vaccines
work by this principle of producing this
high-quality antibody that you're cranking
out all the time. At least 25 of the 27 licensed vaccines
work by that mechanisms, there is a little bit of
argument about the last two, but almost all the vaccines
work by this mechanism here, this is what we know how to do. Now, I want to say that
actually this understanding of immunology was put to use in the 1990s to develop
improved vaccines. It turned out some of the
vaccines against some bacteria were using a type of antigen which could not
engage the helper T cells, and so you only got the quick
low affinity response that was only protective for a short period of time
because you didn't keep making those antibodies
six months later. It was found that those vaccines in very young children
were not protective, it was only protecting
against half, when the trials were done, the number of cases of that disease only went
down by about half, not more as you would see
with other good vaccines. They said, "Well, wait a minute, this vaccine doesn't have any way to activate
the helper T cell, let's add that in there." That's a type of vaccine
called the conjugate vaccine. Those came into
being in the 1990s. Those are a case where this
basic understanding of immunology has been applied
to making new vaccines. Just to step back a little bit, I would say that where we stand with
vaccines right now is we have some
really good ones, some ones that are sore cells, and some ones that
just don't work. The three big ones
that I mentioned, AIDS, tuberculosis, and malaria, we don't have their
vaccines there obviously. There's a lot of thinking
that we need to really apply, we need to learn more
about the immune system and apply it to our
vaccines because what we've learned to do is this kind of immunology and what we
need to do is to learn, probably to boost
the cell-mediated component of immunology better in order to get vaccines against the things where
we don't have them now. I'm an apple guy, but I have
to give credit to Bill and Melinda Gates
Foundation is really spearheading the effort to develop these new vaccines, particularly for
things like malaria, which are problems in
third-world countries. Now, I want to show you
some molecules here. This is what an
antibody looks like if we look at the
actual structure. I've got one version on the left, and one version on the right. The version on the
left shows all of the atoms in the antibody, the antibody is in
purple and the antigen, which is a viral
protein is here in red. In this diagram here, every atom is shown
by a little ball, and the size of the ball
depends on which atom it is, whether it's a carbon or
a nitrogen or a hydrogen. Anyway, what you can see
here very clearly, I think, is how close the fit is between the antibody
and the antigen. The antibody mimics the antigen in its shape and that allows
it to stick to it tightly, like a hand in a glove
or a key in a lock, those are some analogies
people like to use. Now, that's what we will learn from looking
at this picture. What we learn from looking
at this picture, now, what this shows is
not all of the atoms, but just the traces, the path of the protein molecule. Protein molecule is
a long thin molecule with amino acids stuck
together, many, many, many. Two protein parts
stuck together here, there are about 200
amino acids each. This is tracing out from
the beginning to the end. It's a linear molecule in
terms of the sequence, but it folds up into
a compact shape. Now, what I want to
illustrate here is that this part of the antibody and
this part of the antibody, they are very similar from
one antibody to the next, so the shape of antibodies is very similar from one
antibody to the next. What is different is
these little loops up here at the end that
make the part that actually contacts the antigen. We get all of them, not all, but almost all of the variation occurs out in these loops. The structure is very similar, but the actual part that touches the antigen varies a lot from one antibody to the next because the variation
goes into those loops. This is a case where the detailed
structure lets us see the principle of how
the whole system works. Yes, each B cell makes
a different antibody, but they're not that
different from each other, they're very similar
to each other, except in those loops. Only the loops are different
and it's the loops that give a very exquisite
hand-in-glove type of fit. Now, actually, this is just a piece of the
antibody molecule, it's about a third. It corresponds to this
part here in this diagram. An antibody has two equal parts that each bind the same antigen because one antibody
molecules made by one cell and one cell
just makes one antibody, so the two halves are identical and can each bind to the antigen. Then this back-end
is going to help the antibody be useful
to the immune system, it's a tag for the other
cells in the immune system. Then in the middle, we
have a flexible part, this allows the antibody, if you can imagine
my two hands of the part that grab
onto the antigen, and my shoulders are the
flexible part we call the hinge, the value of that is that
my two hands can grab on to that virus particle regardless of its geometry
because if I have to, I can do like this or I can do like this or I
can do like this. I have a lot of flexibility in my ability to latch
on with both hands. Again, that makes for
a tighter binding, I can grab on more tightly if I use both hands than
if I just use one. Now, the other point
I want to make from this slide is that we make actually five types of antibodies that differ primarily down here, which is the part that the
immune system uses to latch on to help do other business
such as phagocytosis, the phagocyte taking up the
antibody coated bacteria. That's illustrated here. Antibodies can help
in several ways. They can help by just
gumming up the works. This is called neutralization, where we have a virus particle, the antibody binds to the virus particle and now that virus can't
get into the cell anymore because we've grabbed onto the part that it needs
to get into the cell. Now, that virus particle
we can destroy it, our phagocytes can eat it
up and chop to pieces, but it can't even infect
our cells in the meantime. This is the holy grail if you're trying to make a vaccine
against the virus, you'd love to make a vaccine that makes an antibody
that neutralizes, that can really just directly prevent the virus from entering. However, an important
part of antibodies, as I said, is connect
to the phagocytes. If the antibodies in this
case they're coating of bacterial particle, that lets the phagocyte eat it
up much more easily. Here, we've got an eosinophil which is good against defense
against parasitic worms. Here's a worm, it should
be much bigger than that, this is obviously a
worm that's got to say, a few thousand cells
compared to one cell here, so it should be 1,000
times bigger but if you'll ignore the artistic
license there, if it's got antibodies on it, then the eosinophil is going to secrete its granule contents, which make nasty
things that are going to kill that worm if we do
that up and down its length. Then there's some other
mechanisms as well. But you can see that the antibodies can work
directly or they can work together with our immune
cells to help protect us. Few other quick comments
about antibodies. Vaccines cause us to
make our own antibodies, we call that active immunity. That is good because it's going
to last a very long time. The tetanus vaccine,
we're supposed to get boosted every 10 years, so slowly your amount of antibodies go down
over a 10-year period, you want to boost them
up every 10 years. Now, the disadvantages it takes a week or two weeks to
make some good antibodies. If I may needs some
antibodies right away, they just got bit by a snake. What are we going to do? We can give them antibody, we can inject the antibodies
into them so that the antibodies can
just float around and grab the snake venom
and inactivate it. That's the alternative then, we call that passive immunity. The advantages is fast. The disadvantage is not
going to last very long. Antibodies in the blood
have a half-life of about three weeks so within a couple months
they're pretty much gone. Examples where we would
use that would be if somebody gets exposed to tetanus and has not
been immunized, hepatitis A, there's
now use of vaccine. But about 10 years ago I got a hepatitis A shot when
I was visiting India, for example, that was
antibody against hepatitis A, that was passive immunity. Protection against snake venom, and also the mother
imparts this type of immunity to newborn. When in utero, there is transfer of antibody
across the placenta. That's our most important
passive immunity is what we get from our
mother and help us through those first
few months of life. Finally, I want to
mention that as we said, that the antibodies taken
from a person or an animal, such as these examples, those would be
polyclonal antibodies. They would be made by the progeny of a number of different B cells. But we can also make
monoclonal antibodies. We can take a single B cell, we can immortalize it and
then have it turn into antibody secreting factories in the laboratory and
make lots of antibody. Then the advantage of
that, we can use that for as a therapeutic or diagnostic. The advantage is that
they're all identical, enhance very
standardized, and we can, know what they're going
to do time after time. Whereas these products
really have to be carefully tested and make sure it's good in
that kind of thing. One, I think really big change is that in the last 10 years, we're getting new
therapeutics based on monoclonal antibodies
that are coming and getting approved by the FDA and it's I would say on the order of 3-5 new ones every year and I don't mean me
too types of therapies. I mean novel therapies
where it's a new target is a new indication
and so I think this is a really exciting time
for the field of immunology. We're seeing it translated
into new therapeutics. The key to this was the monoclonal antibody
technology got discovered in around 1970. But this really is taken hold in the last 10 or 15 years
and that's because we've learned in the meantime to make those antibodies as similar to human antibodies as possible, they were originally
made in mice. The problem was if you injected a mouse monoclonal
antibody into a person, our immune system would see
that as foreign and make an antibody and then we'd get rid of that
as a therapeutic. That still happens with
these new generation, but in a much smaller
percentage now, less than one percent typically. That was the key breakthrough and that's why we now have a
lot of these coming online. This is just a very short
representative list. These are two molecules
here that are used in cancer immunotherapy
for breast cancer and for B cell lymphomas. These are made by Genentech, which is in South San Francisco, and I don't own any
Genentech stock. I should say happy to say, but probably would have
made a lot of money on it. But these are two
that are made by a local company
that was started by a UCSF faculty member,
Herbert Boyer. Then some of these are used
for inflammatory diseases blocking immune responses
and here's one that's used for coronary disease
just as some examples. I wanted to say a few words about cell-mediated
immunity and then I want to finish off by the
news you can use, some thoughts about
what do we know about the immune system
that we can apply to our everyday lives? I've got a few slides
on that at the end. I want to switch over to
cell-mediated immunity. The T cells recognize, instead of recognizing an
antigen in its normal form, the way it would be sitting
in a virus particle, the way it would be sitting on a bacterial cell cell surface. Instead of that, the T
cell recognizes a piece of a pathogen the immune system is extracted out of that
pathogen and displays. A piece, and we
call it a peptide, which means it's a short
piece of a protein. The advantage of that is that the T cell can do what
an antibody can't do. An antibody can only see a pathogen when it's
outside of cells. Antibodies are
secreted from cells, they float around on the
outside of our cells. However, T cells can see those pathogens when they're
hiding inside our cells. Those bacteria that get into the phagocytes and keep the
phagocytes from killing them, the T cell can see that. The virus, when it
infects a cell and the cell is now producing
virus particles, well our antibody can act against the virus particles
that get released. But the T cells can see this infected cell and they
can kill the infected cell. The T cells are very
complimentary to the B cells. They see the antigen or
pathogen when it's inside our own cells and they can
root it out and get rid of it. The way they do that is they see little pieces of the antigen that our immune cells extract from antigen and put it onto our
own proteins that display it. Now our T cells
come in two types. The T cells to recognize antigen, which is up at this peptide, bound to one of our own proteins, they use a molecule very similar, to the antibody molecule. We call it the T cell
antigen receptor, or TCR for short. It's very similar type of
molecule that's got the loops and it's very parallel system, it looks very similar. However, it's never secreted, it's always on the
surface of the T cell, the T cell never secretes it. It doesn't float around. It's always stuck to
the T cell and that's because the T cell is
always acting locally. The antibody can act
all over the body. The T cells only acting
locally because it's going after the
infected cell so it doesn't want to get away from the fact that I'm here and you're here and I'm
going to attack you. That's the idea of the T cell. There are two types of T cells. There are the killer T cells, their purpose is to kill
virus infected cells, and there are the helper T cells, and their purpose is to secrete cytokines to direct the
action of other immune cells. The helper T cells are the
cells that are infected by HIV and get depleted, and that's when we get
the immunodeficiency for the acquired
immunodeficiency syndrome, is when our CD4 T cells get too few to
protect us anymore. If you know anybody with AIDS who is on antiretroviral therapy, their doctor will take
some of their blood, send it to the lab,
and measure the number of helper T cells in the blood. If that's falling
instead of rising, then that means the virus is getting resistant to
that drug and I better switch them to another
drug because once that number falls
below a certain level, they're going to start getting
all sorts of infections, and that's when life becomes threatened in
those individuals. The helper T cells are
needed to protect us by secreting cytokines and boosting our immune responses
from other cells. The cytotoxic or killer
T cells instead of CD4, they have a molecule called CD8. The CD4 and CD8 are
molecules on the surface. They play important roles
in the function and that allows us to distinguish cytotoxic T cells
from helper T cells. This is just a picture
of what I just told you. The killer T cell kills
the virus infected cell. It sees a peptide from
the virus that is displayed by a protein
of the infected cell. In other words, the infected cell take some of these proteins of the virus that it's
making inside, chops them into pieces, sticks them onto this protein, sticks the protein
on the surface. Even though the virus is not putting its own proteins
on the surface, this cell is putting that piece of the virus on the surface, the killer cells sees
that and it kills. It secretes toxic
molecules that make holes and induces cell to die. This won't necessarily
kill the viruses that have already assembled and haven't yet been released. But the point is
that you want to cut off the factory that is
producing new virus, they block the virus that's already been
released with antibodies. The killer cells and the antibody work in a
complementary fashion. Helper cell is a little
more complicated. Here what happens
is that instead of the pathogen molecule being
made inside the cell, now the immune cell is taking
it up from the outside by phagocytosis or endocytosis, so related process with
smaller molecules, and then that cell chops it into bits, takes those peptides, sticks them on a very
similar molecule but a slightly different molecule
that binds those peptides. This type of molecule takes peptides that the cell
brought in from outside. This type of peptide
binding molecule takes peptides that were
made inside the cell. Some elaborate cell
biology that matches the peptide to the type of binding molecule
that's going to bind it. That's illustrated
here that we have two types of peptide
binding molecules, and they look like hot dog bun. It's got this part, this part, and it's hard to see the
three-dimensionality. This is sticking out and
this is in the back. It's a table with two
sausages on the surface here, and then the peptide
goes in the middle. We have two of these types. The red type, what
we call class 1, is going to pick up the peptide
that's made by the virus inside the cell and stick
that on the surface, and the blue one we call class 2, it's going to take a peptide
that was brought into the cell from outside
by phagocytosis, then we chop that
pathogen into pieces, load the peptide on, and then stick it
back on the surface. The T cell is interacting with cells that are displaying
peptides for it to see. There's a cooperation
between the cell, it's got the peptide
and the T cell that can then visualize that because it's displayed outside for it. That's very different
than antibody. The antibody just binds directly to the
pathogen molecule. Here we have elaborate
process for finding these, not letting the virus hide it inside. We're not going
to let it hide it. We're going to show it out
there so that it can be seen. Now, one more point before I
go to the immunology you can use is that immune responses are tailored to the
type of infection. I already mentioned
this a little bit. We can have a microbe infection or we can have a virus infection. We can have an
extracellular microbe or an extracellular microbe like the TB microbe or the Salmonella
food poisoning microbe. We can have the location. The immune system can specialize to immune response in the
lung versus in the gut. There's some different properties to the immune responses. Worms and biting insects
versus microbes would make a different type
of immune response against the worms and
the biting insects, then against the microbes. Defense against most microbes is antibodies and the phagocytes. We've already gone over
that in a bit of detail. We get a neutrophil
rich inflammation, and that can be prolonged
by the helper T cells. Normally, I said that you get neutrophils first
and then monocytes. Some circumstances, the
helper T cells will prolong the neutrophils
and keep bringing them in. That's of course a more
destructive type of inflammation. But sometimes,
that's what happens. Normally, it would switch over
to monocytes within a day. Defense against the
microbes that can survive and replicate inside phagosomes. Now, here it's
mostly the monocytes and macrophages
they're surviving in. Because remember, the neutrophils came in for the first day, after that, the
monocytes came in. A lot of times what
happens is these things gain a foothold in the
monocyte or the macrophage. It doesn't really
do them any good to get a foothold in the neutrophil, because a neutrophil dies
in a day or two anyway. They're not going to
stay there very long. But the macrophages
are long lived cell. If you can establish an
infection in a macrophage, it can stay there
for quite a while. That's what happens with
tuberculosis and salmonella. The defense against
this type of infection is what we call type 1 immunity, and the helper T cells then specialize to detect
these infected cells, they release cytokines
that promote killing by the macrophages. Defense against
viruses, I think we've already covered this,
the early defenses, the innate mechanisms that
restrict the replication of the virus that would be primarily a cytokine
called interferon, one of the first cytokines
that was discovered, interferon, and it's called interferon because it
interferes with virus growth. It makes cells able to resist the replication of
viruses to some extent. That's our early defense
and that's really critical, and then adaptive
immune defense comes in and we make
neutralizing antibodies, and we have the killer T cells. I think we've covered that. Then finally what we
haven't really covered very much is defense against
worms and biting insects. This is a different type of immunity called type 2 immunity. Here the helper T cells, do two types of things, they promote a different
type of antibody called IgE, which works together
with a mast cells, and another type of cell called the basophil to strengthen our barriers at the scan and
in the gut and in the lungs. At the barrier between the
outside and the inside, the epithelial layers, will
strengthen that barrier. Also these type 2 helper T cells, they attract eosinophils
to the site of infection which are very
good at attacking worms. Some manifestations
of type 2 immunity, which you probably don't like, would be things like sneezing, coughing, itching,
diarrhea, tears. What these things all have
in common is we're trying to get rid of stuff. We're trying to blow it out. We're trying to wash it out. Diarrhea, were trying to
wash it out that end. Coughing, we're trying to
blow it out by coughing. We just had somebody coughs. That's your immune system
trying to get rid of something. Now, the reason we don't
like that is because we live in a world that doesn't have very many parasitic worms, and so our immune system, the one theory that you're
going to hear about from Dr. Boucher in one of
the other lectures in this mini Med school is that one of the theories
that has a lot of support is that our immune system gets bored with not having
enough worms to deal with. It goes after pollen and cat
dander and things like that, which if we had worms
and other nasty stuff, we would just ignore that stuff, we would concentrate on
the important stuff. That's called the
hygiene hypothesis. You're going to hear about
that from Dr. Boucher. I've left you with a big problem, actually is a big problem that immunologist don't
fully understand. This is one of the
really active areas in immunology research right
now, including at UCSF, and that is how did the
B cells and T cells know what's an
infection and what's pollen and cat dander and the food you ate that you
had never eaten before? The answer is that, that's a very complicated thing, but I can give you at least
some of what we understand. One thing is that endorse
innate recognition mechanisms, the dendritic cells
and macrophages, the sentinel cells recognizing bacterial cell walls
and things like that. They then put molecules on their surface that promote
T cell activation, so that innate recognition of microbe is translated
into promoting the T cell activation
by putting molecules on the surface of
those innate cells, particularly the dendritic cells. We call this process something
called co-stimulation. The co being, the stimulation
would be the antigen, and this molecule that the dendritic cell is making in response to it
recognizing an infection. It's saying I see an infection, I'm going to tell a T cell
I've seen an infection. I know this is an infection. That's one of the most
important principles. We now have a therapeutic that directly attacks
that co-stimulation, directly blocks that
co-stimulation to try to suppress T cell in some nasty
immune diseases. Another mechanism we have is something called the
regulatory T cells. Some of those CD4 T cells make cytokines that promote
immune responses. Some of them are now going to be the stop T cells instead
of the go T cells. They're going to make cytokines that slowdown immune responses, that inhibit immune responses. We call that type of cell
a regulatory T cell. The rare individuals have defects in the ability can't
make any regulatory T cells. They get horrible
autoimmune disease of all their organs
at a very young age, is a very horrible disease. Luckily, only a very few
people ever experienced that. But we really need these
regulatory T cells. Again, they arise
during development. When they see self-antigen
during development, instead of being gotten rid of, they actually stay around and suppress the immune
responses later. Then finally, that's
what I just said, the defects in making
regulatory T cells is very bad. This is another area that's a research area that we have
some people at UCSF doing, can we harness regulatory
T cells for therapies? Can we take a person's
regulatory T cells, expand them in the laboratory, and then put back where
there's now more of them, and now maybe they can block an immune response in
a very specific way? Instead of just blocking
all immune responses, maybe we can block
just the rejection of that kidney transplant. That's a very exciting
area for the future. Quick couple of comments
about chronic inflammation. Sterile inflammation,
we mostly talked about the innate immune system
responding to actual microbes, but it also responds
to just tissue damage. That really, I think, is a strategy that we use because some pathogens
have figured out how to not be seen by the recognition of bacterial
cell wall components, etc. Just if we have tissue damage, that will induce some
inflammation on its own. Many of you probably experienced
this with sore knees and sore elbows after doing too much basketball or
something like that. Chronic inflammation,
if an antigen persists, then you can get chronic inflammation because
it's driven by the T cells. This is true in
autoimmune diseases and some allergic
diseases as well. There is speculation
and I think there's some evidence is
becoming now very well accepted in
atherosclerosis field that inflammatory processes
participate in the progression of
atherosclerosis, and I can talk about that more if people
are interested afterwards, and then this is now
more speculative. There's something in the
Alzheimer's disease may also probably not be
initiated by inflammation, but propagated and made
worse by inflammation. There's a lot of hope
that maybe we could learn to ameliorate these things a little bit and hold off some of these diseases and not let
them progress as much. That's an exciting
thing for the future. The immune system in cancer,
as I mentioned before, there's good evidence that
the immune system removes early cancerous cells in many cases and reduces
cancer incidence. The immune system is
actually used to cure some leukemias together
with chemotherapy, and this is a process called the graft versus leukemia effect. When bone marrow
transplantation is done, we use bone marrow from
a different individual, and then they leave
the T cells in there, and then they can attack
the residual cancer cells. There are some side
effects to that, but this is very commonly used, including at UCSF now
because it really does work and that is the
immune system killing off the residual cancer cells. We have some man-made killing cancer cells with
monoclonal antibodies. I mentioned that before. Then there are ongoing
efforts to boost the patient's own T cells to
react against their cancer, and there's been some
real progress in recent clinical
trials on that front, but there's still a long way
to go for that, I think. Anti-inflammatory therapies,
some of you may have, well, probably all of you are involved with this
one way or another, or maybe many of you anyway. Many of you probably have
taken aspirin and ibuprofen. They're good painkillers, but they're also
anti-inflammatories. They're used to inhibit
inflammation as well as pain. Now, they'll work when the inflammation
is not too strong. If it's too strong, then you got to go
with the bigger guns, the glucocorticoids
steroids like cortisone, and the more potent
versions of that. They were developed
originally in the 1950s, and they were really
life-changing for people who had severe inflammatory diseases
like rheumatoid arthritis. They're very effective
immunosuppressive drugs and anti-inflammatory drugs, but the problem is they have very significant side effects
of long-term use. We've been trying to
find better agents, and then you're going
to get a whole lecture on the newer biologics, monoclonal antibodies, and related molecules to block the inflammatory cytokines. These are really very effective, not every patient, but in the
patients that they work in. They worked really quite well. You'll hear about that
in another lecture. Last three slides. Keeping your immune system
in good working order. Now, we're getting into the areas where the immunologists have, it's more speculation
and less hard fact, but let me give you a few things. Nutrition and the immune system, you'll hear a lot about
nutrition and the immune system. I'll tell you my opinion. It's very clear that
real malnutrition, if you're really so
poor that you're not getting enough calories or not getting enough protein, your immune system
will suffer from that. That's what we call
macronutrients. If you don't getting enough
calories or enough protein, your immune system won't
function as well as it should. There are some micronutrients
that are important, some of the vitamins
are important. A normal, diverse diet
would do that fine. You don't need to take
vitamin supplements unless there's something
about your diet. You're not getting your
vegetables or what have you. Then finally, you'll sometimes see a lot in the news
about fish oils. Fish oil is anti-inflammatory, that is pretty well established. You have to take a
fairly high amount of it to achieve that effect. But fish oil is one of those things that
will be anti-inflammatory. That has to do with the
fact that inflammation is regulated by a variety of lipids, and we're now changing the
lipids that are present. So we're changing a little bit the balance between
pro-inflammatory lipids, which would be blocked also by ibuprofen and aspirin
to some extent. Again, if you take enough
of them and which again, speak to your doctor about that. I'm not telling you
how much to take. But there's also
anti-inflammatory lipids, so the thinking is the
fish oil helps boost the anti-inflammatory lipids
and protects us in that way. It reduces the chronic
inflammation in that way. Again, if it's
fair, this would be a case where it's
relatively mild, I think not a really
strong inflammation. Stress and the immune system is another popular topic. We actually have a
lecture for this, for our medical students. What I can tell you is that chronic stress
and I really mean, over several year
period being stressed, a caregiver for a spouse who has Alzheimer's disease or for a child who has leukemia, something like that where
you're really stressed a lot for a substantial
period of time, that has detrimental effects on immune function,
but it's complex. It really depends, and again, these things will correct. There are some circumstances
where chronic stress will affect your ability
to fight infections. Mind over matter is a
very popular topic. What I can tell you is there is some science that
relates to this. There is a nerve that controls the heart beat, the vagus nerve. It also enervates many
of the immune organs, and it does modulate immune responses up and
down to some extent, it won't totally shut
off an immune response, but it can influence
it up or down. When people do clinical trials, you really want to do something to account for something
called the placebo effect, and that is if
somebody is getting a pill that they think
is going to help them, they actually will get
better with some diseases. That's called a placebo effect. If you're doing a clinical
trial for a new therapy, you have to give half the people something that's the same pill, but one of them has got the real pill and
one of them is not the real pill and
neither the patient nor the doctor really knows. That's called a double-blind
placebo-controlled, and you really need
to do that with immune system
diseases because they have a substantial placebo
effect in some cases. I think there is some
mind over matter when it comes to the mind and
the immune system. It's not something
you can necessarily use except that maybe
try to be less stressed. Aging and the immune system, I think this is something
where a good diet and trying to keep yourself healthy is going to help
your immune system. It is well established
that as people get old, they don't respond
as well to vaccines, but it's quite variable
from person to person. Some people show
that immune aging, other people not so much. We don't really know
all the details, but it would be a good guess that a healthy lifestyle is good
there and then vaccination. I want to say a few
words about vaccination. I really appreciate your
willingness to stand around. But I should have put this in earlier
because this is maybe the most important thing
I want to say today and that is in terms of keeping your immune system
in good working order, there's one thing
that we for sure no works and that is vaccination. Not every vaccine works, but a lot of the vaccines we have work really,
really quite well. What we don't have, we need
new vaccines for some things, but the ones that we have
that work really do work. Childhood vaccination, again, get the advice
of your doctor, but I really think
vaccinating children is the right answer, and I think there's a lot of fears being spread
on the Internet, which really just are not true. There are British
physician claimed, this as more than
a decade ago that mercury preservatives in
vaccines caused autism. This has been
completely disproven. There's even people
who think that this was fraud to start with, and it wasn't just bad science, but he may have had
an extra grind. But in any case, it's
clearly not true. The one that had a little
bit of truth was there was a small incidence of side
effects from the old DPT, which is the diphtheria,
tetanus, and pertussis. Pertussis is whooping cough. That vaccine, the formula
used prior to 2002, did have high fever. It's uncommon, but not really
all that rare side effect. It really had to be monitored. The new formulation has
much less problem there. It's a more purified version of the pertussis that does not
cause nearly as much fever. This is something
that's gotten quite a bit better, but nonetheless, there's a lot of fear
surrounding this, and whooping cough
has been making a comeback among
unvaccinated children. It's a very nasty disease. If you have any little children
at home or grandchildren, this is my advice. Don't believe the fears on the Internet about
these vaccines. Finally, vaccines aren't
just for children, they're for us as well. Few things, tetanus booster, you should get a tetanus
booster every 10 years. The best advice is that, do it when your
birthday has a zero. So 40, 50, 60, then it's easy to remember
when the 10 years comes up. Because who can remember when you had that tetanus vaccine last? Every 10 years really,
that's great advice. You don't want to get tetanus, I guarantee you. Flu vaccine. Yes, for most people, influenza can be
life threatening, particularly as people
get older in life. Most of the guidelines say 50 and older really should
get vaccinated every year. Then it changes its coat so
that the antibodies that we make against this year's
influenza won't help us very much against some of the strains that are
circulating the next year. Each year, they try
to figure out what the most important flu
that's circulating is, make the antibody against that. They're all very close
cousins of each other. Those of you traveling
to foreign countries, vaccination may be helpful. Plan ahead and I can recommend
from personal experience, the city of San Francisco
Health Department has an adult immunization
and travel clinic, which is really excellent. Also, you can check out the Center for Disease Control website that will tell you what part of the
world you're going to, what vaccines you
should be thinking about maybe to help you there. Then as we get older,
even if we don't travel, there's two vaccines that
are specifically aimed at people getting near retirement age or
after retirement age. That would be the shingles
vaccine, which is basically, if you had chicken
pox as a young child, that can come back as you get older and your immune
system wanes a little bit. It never went away
completely and you can get a very painful
condition called shingles. This vaccine's been shown
to ameliorate that greatly. There's another one
called Pneumovax. That's against that Streptococcus pneumoniae that you had. It's got 23 different cousins stuck in that vaccine and it protects
really quite well. Again, this is something. Ask your doctor, but if
you're 60 and older, you might want to
consider these things. I really thank you
for your patience, and I will stay, and
take your questions. The question is, how do we immortalize an antibody producing cell to
make monoclonal antibodies? There's two ways. The way that was
discovered in early 1970s and for which the Nobel Prize was awarded to a man in England, Cesar Milstein and George Kohler, two men in England. That was they would take a
cell that came originally from a cancer of an antibody
producing cell in which they had manipulated in the
laboratory to lose its own antibody producing genes, and then they would fuse it with a B cell so that the B cell
in the fusion part though, the one cell gave
you immortal growth, the other cell gave
you the antibody genes to make the antibody you wanted. That was the original method
and then more recently, there's direct DNA cloning method of pulling out antibodies and screening through to find
the ones that you want. There's two methods now. There's the fusing two cells or just going straight
in and pulling out the DNA and expressing
it in a new cell. The question has to do with autoimmune disease called lupus. The long form is systemic
lupus erythematosus. That's an autoimmune disease
that preferentially hits women usually in their 20s, and 30s, and 40s when it starts and then it's
never really goes away. You just try to keep it
at bay as best you can. I understand there's a
new therapeutic that was just approved for this last week and we're going to get Dr. Andrew Gross in one of
the future lectures, and that is he sees
lupus patients. He'll give you all
the up-to-date thing. What I will tell you is that for most of the
autoimmune disease, we don't know what triggers it. There's a generally thought, and you're going to hear
this for allergies as well, is that there's a genetic
susceptibility which is complex and we all have lots of genes that influence
our immune response, it's a little bit this way
and a little bit that way. If we get the wrong combination, then we would be susceptible to a particular autoimmune disease, and then there's some trigger. The trigger is thought to be probably some
infection or another. It's a combination of
genetics and some trigger. That would apply to all
the autoimmune diseases. In the case of lupus, the disease manifestations are primarily due to antibodies. Bacterial spores. Does immune system
recognize bacterial spores? Yes, it does. Now, so the outside of that is a really
thick carbohydrate and so the antibodies
can recognize it, but the T cells really can't
recognize it very well. Again, that what
I was mentioning, the conjugate vaccines, what was done was to take those, that coat of a bacteria and the original vaccine was just to use the
carbohydrate part. Because it was known
that the antibody to the carbohydrate was protective, but by coupling it to something that T cell could
see some protein component, you can then get
this higher quality. Question's why would the virus in a virus infected cell allow the immune system to take
a peptide and stick it onto that MHC molecule,
the HLA molecule? That's because that's
what we're trying to do, it's not what the
virus is trying to do. We have a machinery
that's doing this all the time with our own peptides. But then that we're already
tolerant to those because we've developed in the presence of those peptides all along. It's when the new
peptides show up that the killer T cells can get activated and can come and kill. Now, there are some viruses
that do block that process. I don't know if people have
heard of cytomegalovirus. Cytomegalovirus is a virus that specifically
blocks that process. CMV, exactly. CMV is a virus that
blocks that process. Most viruses can't block it, but that's one that does.
Lecturing begins @5:00