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8. Frontiers of Biomedical Engineering: Cell Communication and Immunology (cont.)


Poziom:

Temat: Nauka i technologia

Professor Mark Saltzman: Okay, today we're going to
continue to talk about cell communication.
I'm going to talk about - take sort of the general concepts
that we talked about last time and talk about how they apply in
two physiological systems, the nervous system first and
then the immune system. This is a lead in to what we'll
talk about next week. We're going to start talking
about vaccines which is really sort of applied immunology:
trying to take immunological concepts and put them into
action or to engineer them in some way.
So, we'll talk about that next time.
I want to start with the nervous system.
This is a picture of a neuron, this particular neuron has been
filled with a fluorescent dye so that it's colored green.
I'm using it just to make the point, which you already know
about; that the nervous system is
complex in it performs a complex set of functions.
It's able to do that because there are cells like this
particular cell that have shapes that are suited to their
function. In this case the shape is -
there's a cell body in the center here so this is where the
nucleus is and where all the transcription,
production of proteins take place here.
Then around this cell body there's an elaborate set of
processes which extend out from the cell body,
and they go in various directions.
If you look throughout the nervous system you would find
cells that look different in different regions,
because of where they're situated in the brain.
But they'd all have some of these same features,
that is a cell body with many processes that meet in the cell
body. Now, what this enables these
cells to do is to communicate with very specific other regions
of the nervous system. So this cell,
wherever it's setting, wherever it is positioned
within the nervous system - let's say in the cortex
somewhere or the outside surface of the brain - is able to
communicate with a region of the brain that's in this direction,
a region in this direction, a region in this direction,
a region in this direction. So one way that neurons,
in particular, are able to communicate with
other cells in the nervous system,
share information, integrate information,
decide what to do next is that they are physically connected to
other different cells. Part of the complexity of the
nervous system is the complexity of this interconnection of
cells. Now, if we look at this
schematically and so again this is a schematic.
It doesn't represent any particular neuron in the body,
but just meant to represent functions that all of them have.
Here is the cell body up at the top of the diagram here.
You could distinguish between some properties of these
processes that extend out, in that most of them are what
are called dendrites. One of these processes,
a special one is called the axon.
The way this cell works as an information processing unit is
that the dendrites, which extend out in all these
different directions, are receiving information from
other cells which is integrated at the position of the cell
body. Then that information - that
integrated information - is passed onto another cell through
the axon. Information flows from the
dendrites, through the cell body, down the axon.
That's what this arrow at the right shows, the direction of
the flow of information. We're going to talk in some
detail, not a very high level of detail, but in some detail about
how this communication takes place between cells and how the
information is passed down one of these cells today.
Some terminology, some of which I've already
given you: cell body, dendrites, axons.
If this is the particular kind of axon that is 'myelinated',
then it might have a layer of a special substance called myelin
in sheathing the axon. That just allows information to
move more quickly from one end of the cell to the other.
That can be important because in some cases these processes
are very long. There are processes that go
from my nervous system, from my brain and spinal cord
out to the tips of my fingers that allow me to move muscles
there, or down to your toes.
So, these cells can be many, many feet long,
these processes can.
Well, the mechanism that the cell uses to transmit
information along itself, along this process which goes
from my brain to my fingers, for example,
is through an electrical signal called an action potential.
We're not going to talk about this is in great detail,
there's some detail in your book.
If you go on to take, particularly the course that's
offered here called Physiological Systems,
you'll learn a lot about action potentials and what the
mechanisms for generating them are,
but I'm only going to say a few words here to sort of orient you
in the subject. All membranes are electrically
charged. They carry a potential,
that is, if you could - if you had a tiny, tiny electrical
meter, you could one put one electrode
on one side of the cell membrane, on the extracellular
side and one on the intracellular side and measure,
you would measure a potential difference;
just like a battery you would measure a potential difference.
That potential difference is generated by the movement of
ions, principally sodium and potassium across the membrane.
Now, sodium and potassium don't ordinarily move across
membranes, they're charged molecules,
they can't dissolve, they can't permeate through a
cell membrane, but they go through because
there are channels that allow them to pass through in the
membrane. All cell membranes have
these channels within them, and under their resting
conditions sodium is moving from outside to inside,
potassium's moving from inside to outside.
Because there are ions moving back and forth,
there's a current that flows and there's a electrical
potential that's generated. Now, this is in the resting
state of all cells, there's some membrane potential
and neurons have this resting membrane potential also.
If you measured it for most cells it's about between -60 and
-90 millivolts. For this particular cell here
it looks like it's about -75 millivolts, so the inside of the
cell is a little bit more negative than the outside.
Now, what happens during an action potential is that that
membrane potential changes rapidly and it changes from
being negative to being more positive.
That change happens because something gets triggered in the
membrane, and what gets triggered is a voltage gated
sodium channel, which is shown here.
Now, remember we talked about these last time,
voltage-gated channels are channels that would allow the
passage of sodium, in this case,
but they can exist in two states, a closed state and an
open state. When an action potential is
initiated these ion channels go from their closed state to their
open state, when they open sodium can now pass through.
The balance of sodium movement relative to potassium movement
changes because there's this resting movement of all these
molecules anyway, but that balance changes
dramatically when these ion - when these gated ion channels
open. That results in a dramatic
change in the membrane voltage; the potential across the
membrane and that's shown here by this rapid rise in membrane
potential. Now, that rapid rise is
called depolarization and the membrane is said to be in a
depolarized state because it's less polarized or less
negatively charged - repolarized as negatively charged.
It's less negatively charged than it is in its resting state.
That happens, and if I was looking at a
region of membrane that was experiencing an action potential
I would see voltage change in just the way it's shown in this
graph here. Now, if that potential changed
and it stayed changed forever, then the cell would never go
back to its resting state. That would be - you could have
a cell that did that but that would be cell that could only
send one signal. It sends it's signal,
it's signal - the signal that it sends is this change in
voltage, and once it changes, maybe it's all done.
That would be a bad design for our nervous system where we want
to use cells over and over again,
so they're able to recover from this change in potential.
That's shown functionally here but recovery means that this
sodium channel becomes closed again.
Now, it's more complicated than that because it's not just
sodium channels that are involved,
there are potassium channels also, and the interplay between
sodium channels opening and potassium channels opening,
this is described in some detail in your book.
We're not going to talk about those details in the class here;
I want you to sort of understand this really at the
level that I've described it here.
There's a local change in the membrane, that local change
involves opening of channels that allow ions to pass through
regions where they couldn't pass through before,
that results in a change in voltage.
That voltage moves from one end of the cell to the other.
That action potential is initiated here up in this
region. This part of the cell becomes
depolarized because it gets the message that it's supposed to
depolarize because of all the inputs that impinge on these
dendrites. It's collecting information
from all these dendrites under the right series of signals the
cell body integrates all that information,
says time for me to fire an action potential.
That happens, the membrane potential changes
here, and the change in membrane potential here is so dramatic
that it changes the membrane potential here,
and here, and here, and that change of potential
flows down the surface of the axon,
eventually reaching this output region.
The flow of information is really a flow of electrical
potential and it goes in one direction only.
It goes from the region of the cell where the dendrites are
down through the axon. We're going to come back and
talk about the action potential a little bit more when we talk
about how the heart works, because the heart when its
contracting, the muscle cells also use action potentials to
initiate contraction. When we measure EKG's,
what we're measuring is the activity of all these cells
within our heart performing action potentials.
Now, in the heart action potential is moving from one
heart muscle cell to another over the surface of the heart.
In the brain, action potentials are moving
down processes, down a single cell process for
example. So action potentials are used
by tissues in different ways to send signals from one cell to
another or from one end of one cell to another end of the cell.
Does that make sense? We'll come back to this in our
example in the cardiovascular system when we're talking about
the heart and we'll talk about how to measure the collective
group of action potentials using EKG's.
You'll actually get to measure EKG's on each other during
section the week we talk about that.
Well, what happens when the signal gets to the end of the
axon? How do cells pass the signal
from themselves to the next cell?
In the heart it turns out that the cells of the heart are
electrically coupled together, so if an action potential moves
down this cell it directly moves into the next cell.
So, there's a continuum of electrical connection in the
heart that allows an action potential to sweep across the
surface of the heart and for the heart to beat in a coordinated
fashion. In the nervous system it
doesn't work that way. It doesn't work that way for a
variety of reasons, but the main reason is that you
want some decisions to be made at each space between two cells.
You want decisions to be made there so you need some
additional mechanism for decision making at the point of
contact between the axon of one cell and the dendrite of
another. Well, that specialized
region - now in this diagram here, this is the axon of one
cell, the first cell in a sequence
and that axon meets the dendrite of another cell at a special
region called a synapse. The synapse is just this
anatomical region of contact between two adjacent cells in
the nervous system. It varies in its structure
among cells of the nervous system but all synapses have
some properties in common. One is that there's a physical
space in between the two cells, so the axon of what's called
the pre-synaptic neuron, or the neuron that's bringing a
signal into the synapse, the axon terminal is physically
separated from the dendrite of the next cell.
That space is about 20 to 40 nanometers, it's not a very big
space, but it's a significant space.
It's called the synaptic cleft and it's filled with
extracellular fluid. Now, another thing that
you'd find if you looked inside the axon terminals of any of
these pre-synaptic membranes, you'd find lots of vesicles or
some membrane bound compartments that contain special chemicals
called neurotransmitters. Neurotransmitters are molecules
you've heard of like acetylcholine,
like dopamine, like serotonin.
They're small molecules that - whose principal function in the
body is to carry signals from one cell in the nervous system
to another. Now, how they carry signals is
that these neurotransmitters act as ligands.
When an action potential comes down this pre-synaptic axon,
when it reaches this point here,
it sets off the process of these vesicles dumping their
content into the synaptic cleft. This process,
which is shown schematically here, as a vesicle fusing with
the cell membrane and then dropping its neurotransmitter
only happens when an action potential reaches the end of the
axon. Neurotransmitter release is
stimulated by the electrical activity that reaches the end of
the axon. When these vesicles dump their
contents into the synaptic cleft, the concentration of
these ligands rise. Another characteristic of the
synapse is that the post-synaptic membrane,
the membrane of the cell which is going to receive the signal
has receptors on it. Those receptors,
some fraction of them, are specific for the ligand
that the pre-synaptic cell releases.
There's a lot of words here, long words, pre-synaptic,
post-synpatic, but pre, post,
you get the idea. Caitlin?Student:
Just curious; before the ligand perimeter
[inaudible] where are they
stored?Mark Saltzman: They're actually stored in these
vesicles and so--and they get into the vesicles in a variety
of different ways. In some cells they're recycled,
that is the cell is able to take up the neurotransmitter
after it's released and restore it,
but most often there are enzyme systems inside the pre-synaptic
membrane where those neurotransmitters are
synthesized. They're synthesized,
they're packaged into vesicles, and then they're just waiting.
If you could look inside a pre-synaptic axon terminal,
you would find one of the characteristics is that it's
loaded with these vesicles and they're just sitting there
waiting to receive an action potential so that they can
immediately dump their contents. One of the things you know
about the nervous system is its fast.
I decided to move, I can move right away.
So, in order to have fast transmission you do that by
transmitting electrical signals; that happens pretty quickly.
You turn on your lamp, it happens pretty fast because
current can flow very quickly through wire or through a
charged - a solution of ions. So, that process happens fast
but you also need this neurotransmitter release and
activation to happen fast so that you can have rapid
activity.
Now, in this cartoon here I've shown a variety of
different receptors just to show - just to remind you of the
different families of receptor molecules that could be involved
in receiving and translating a signal.
But in general, for each neurotransmitter that
released it there would only be one population of receptors
that's ready to receive it. In some cases it might be a
ligand-gated ion channel. Wouldn't that be convenient?
Because if it was a neurotransmitter activated ion
channel, what would happen when the neurotransmitter bound here?
It would generate an electrical signal because it would - you'd
open the ion channel and you would ion fluxes and you would
change the membrane potential in just the way I described for the
action potential. This is a mechanism by which an
electrical signal comes here, it gets translated into a
chemical signal, the chemical diffuses across
the gap and reinitiates a - an electrical signal in the next
cell and that's one way that it happens.
It can also happen in other ways, it could be a G-protein
coupled receptor which we talked about last time,
which indirectly activates another ion channel to start the
electrical signal. Why do this?
Well, one reason to do this is because on each post-synaptic
neuron there might be many axons coming together at once,
and each one might be generating a different kind of
signal, through maybe even different neurotransmitters.
Because this post-synaptic neuron is going to be receiving
different signals from different cells,
it's decision about what to do next, and the what to do next is
either create an actual potential or not create an
action potential. So, it makes a binary decision,
either I create an action potential or I don't,
but that decision could be based on many inputs,
not just on input from one cell.
It could be the integration of many different chemical signals.
Because of that, because they're not directly
wired together but because there is - are decisions and
integrations occurring at each junction,
the potential operation of the nervous system becomes diverse.
So, you have both the diversity in the physical connections,
any one cell is potentially contacting lots of other cells.
You have a diversity in the chemical changes that occur as a
result of any of those connections.
That's what leads to some of the complexity of function of
the nervous system. I want to talk about the
immune system for the rest of the time here.
Again, the point today is not for you to understand in detail
all these mechanisms but to understand how those basic
concepts we talked about last time,
basic concepts of cell communication if arranged in the
right kinds of ways can lead to complex outcomes.
That was the point I was trying to illustrate in the nervous
system. In the immune system you could
think of it as an even more complex set of outcomes that
occur. The outcomes that occur are
protective outcomes in general. Our immune system's function is
to keep us healthy in the face of an environment where there
are lots of things that could potentially harm us.
The study of immunology is the study of mechanisms that your
body uses to protect itself from - mainly from foreign pathogens
like viruses and bacteria. Some words that are useful
in this discussion, a 'host'.
A host is the organism that you're interested in defending
and it could be you or me or some typical person.
'Foreign' is, then, any molecule or set of
molecules or substances that are foreign to the host,
they don't belong there; it could be foreign proteins
from a virus, could be foreign elements from
a bacterium, it could be that one of your
cells has become mutated, is now abnormal and so doesn't
belong in you anymore. It's foreign,
it's not part of the host or not a normal part of the host.
So, all those things would be considered foreign.
We're going to use this special word "antigen," and
antigen has a very particular meaning.
Its molecules are pieces of molecules often derived from
foreign pathogens which stimulate an immune response.
So, antigens are molecules or pieces of molecules that
stimulate an immune response. Any molecule can be an antigen;
the food that you eat is full of antigens, microbes that try
to live in your body are full of antigens.
Pieces of your own cells are antigens as well.
They're just antigens that belong to you and so you don't
normally mount an immune response to antigens that are
part of you. We'll talk about how that
happens a little bit as we go through here.
Generally, you think about the immune
system protecting against different classes of pathogens
and several classes of pathogens are shown on this table.
So, you're familiar with some of these bacteria like
salmonella, or the micro bacterium that causes
tuberculosis are shown here. Viruses, you know about viruses;
variola, we're going to talk about next week which causes
smallpox, influenza, which causes the flu and HIV of
course which cause AIDS are some examples.
Fungi which don't often cause infections in people with
healthy immune systems but can under some circumstances,
and can be tremendous problems in patients that have weakened
immune systems. Parasitic organisms like
protozoa and worms which are - which can cause terrible
diseases. Malaria is one that causes much
disease worldwide. Schistomiosis,
which is a worm that lives in river waters,
causes terrible diseases that are still prevalent in many
parts of the world. So, just an introduction to
the classes of potential foreign invaders that our immune system
tries to defend us against. Because it's working to defend
us against many different kinds of potential assaults,
the immune system has a diverse repertoire of responses that it
uses in the face of these assaults.
One kind of response is called the innate response and innate
means that it's present from the beginning.
So, this is an immune response that doesn't have to be
activated and we're used to thinking about immune responses
that have to be activated. You get a vaccine for chicken
pox, it gets injected, and sometime later you're going
to be protected against it. Or you get a cold,
the cold virus takes hold, the viruses start replicating
inside of you and it takes some time for immune system to gear
up to eliminate it, so we're used to thinking about
responses that take some time. But innate responses are there
from the very beginning and they can fight foreign--against
foreign pathogens immediately. It's mainly--these
functions are mainly performed by a set of cells called
macrophages, neutrophils and natural killer
cells, which are circulating throughout your body all the
time, ready to destroy anything that
they recognized as not part of you.
So, that's the innate response. We're not really going to say
much about that here, there's a little bit about in
the book. If you go onto study immunology
you'll learn that this is one of the most important and rapidly
evolving areas of the study of immunology.
In fact, the people who have been most important in
understanding how the innate immune system works are people
here at Yale.
The immune system that we're used to thinking about is
called the adaptive immune system, and the adaptive immune
system does just that. It changes or adapts in
response to an insult or a threat.
So, this is the kind of immune response that gets activated
only when it's needed. Then it will stay activated for
some period of time, and eventually disappear again.
There are two types of adaptive immune responses and they're
called humoral immune responses. Humoral comes from the term
humours and it used to be that we thought about disease as
being caused by the balance of humours in our blood.
You could have good humours and you could have bad humours and
if those humours, whatever they are,
got out of balance then you got sick if you had too many bad
ones compared to good ones. Humoral refers to immunity
in the blood and it's immunity that's in the blood in the form
of antibodies. We're going to talk a lot about
antibodies over the next week or so, but antibodies are
specialized proteins that, as you know,
are designed to bind to antigens or foreign molecules
inside the body. I'll say more about that in a
minute. The humoral immune response
involves antibody production and antibodies are made by a subset
of cells called B-cells.
The other part of the adaptive immune system is the
cell mediated immune system and this is an immune where - that
doesn't involve antibodies but involves cells that are
activated in response to a foreign antigen and that utilize
cellular means to get rid of it. Usually the cellular means that
they get rid of is that instead of an antibody being produced,
you activate a population of cells that will specifically go
and hunt down the foreign antigen,
or more commonly, cells that contain the foreign
antigen. Now, why do you need a cell
mediated immune response if you have an antibody response?
We'll talk about that in a few minutes.
We're going to - one of the reasons why you'll see why cell
mediated responses are important is because antigens can appear
in your body in different ways. The way that they appear in
your body tells the immune system something about where
they came from. We'll learn more about that in
a moment, but basically it allows the immune system to
distinguish between viral and bacterial pathogens,
and respond appropriately depending on the type of
pathogen that's there. The main effector cells in
cell mediated immunity, the cells that do the main
business are called T-cells. Now, T-cells are also involved
in humoral immunity but they're not the end result.
The end result in humoral immunity is B-cells producing
antibodies, the end result, or the molecules that carry out
the function in cell mediated immunity are T-cells,
either - let me talk about different types of T-cells in a
moment, but either cells that are called CD4+ cells or CD8+
cells. Why do you have these different
kinds of responses? The reason is that because of
the ways that different microorganisms take - the ways
the different microorganisms reproduce and damage cells and
tissue within your body, you need different ways to
respond to them effectively. Think for a minute about
what happens if you get infected with a virus.
Now, a virus is not capable of reproducing on its own,
so if you got a virus into your body somehow and it didn't enter
any of your cells, it would cause no damage
because it could not reproduce. It's reproduction of the virus
and passage of that virus onto new cells which causes the
problems with disease that we associate.
They often kill the cells that they infect, and that's a
problem with viruses. A virus isn't troublesome until
it infects a host cell and when it infects a host cell it
becomes troublesome because it takes over some of the host
machinery for DNA synthesis, transcription,
and translation and starts making more viruses and this
happens largely in the cytoplasm of the cell.
How is your immune system going to recognize that this
virus is there causing bad results if it's living inside of
a cell and doing all its business inside a cell where
antibodies can't get to it? Antibodies are outside of cells
circulating in your extracellular fluid.
Well, the way that your immune system recognizes it is that all
the cells of our body express a molecule on their surface,
a membrane protein called the MHC1 complex.
MHC1 is a word, MHC stands for major
histocompatibility complex and it's one of the things that
distinguishes my cells from your cells,
from your parents cells, from your roommates cells.
Each one of our cells - one of the things that distinguishes
them is the kind of MHC molecules that all of my cells
make. It's what makes my cells my
cells, and your cells your cells.
It's the reason why you can't do organ transplants between
people that aren't immunologically matched.
If you take an organ from one person and put it in another,
if their MHC molecules don't match then the immune system
recognizes - the immune system of the host recognizes 'this is
not the right MHC for me' and the immune tries to destroy
those cells. One of the functions of MHC is
to indicate which cells belong inside your body,
which cells don't. The other thing that it
does is that when a virus is inside these cells making its
proteins, some of those proteins get
processed or digested into small fragments that are themselves
antigens. Those antigens get expressed
together with MHC1. One of the other things that
MHC1 does, in addition to marking yourselves as your own,
is that it's capable of making combinations with all the
different molecules that are present inside the cell and
expressing them on the surface, and sort of showing them to the
outside world. It's showing them to the
outside world in combination with MHC1.
The immune system, some cells of the immune
system, in particular this class of T-cells called CD8 cells have
receptors which recognize MHC1. They're capable of
recognizing MHC1 together with foreign antigens.
When these CD8 T-cells see your MHC1 together with an antigen
that doesn't belong in you, it creates an immune response.
The immune response is directed at killing this cell.
The notion is, if there's something foreign
that's being produced inside this cell,
then that cell must have been corrupted in some way and it has
to be gotten rid of. It could have been corrupted
because a virus was inside of it so it was making foreign
proteins. That's making the cell look
foreign because some of that foreign protein is on the
surface with MHC1. It could be foreign because
it's become malignant. Maybe it got mutated and its
making the wrong kinds of proteins;
cancer cells often do that. So, those wrong proteins get
presented on MHC1 and your immune system can kill the cell
because it's a tumor cell. This is a way for the immune
system to recognize things that are going wrong inside the cell
protected from antibodies.
Other kinds of microorganisms reproduce and
cause tissue damage in a different way.
If you get bacteria under your skin, if you get a cut and
somehow that cut gets - bacteria gets inside there,
the bacteria can reproduce on their own.
They're fully functional organisms that can reproduce on
their own, and they can start growing outside of any cell and
that's what they do, they live extracellularly.
Well, your innate immune system tries to get rid of them.
The innate immune system composed of neutrophils and
macrophages; these are cells that are
crawling around your body all the time ready to eat bacteria.
When they do that they can actually engulf the bacteria in
a process called phagocytosis and break the bacteria down into
antigens. Then those antigens get
expressed with MHC just like they did in all the other cells
inside the host, but particular cells of the
innate immune system have a different kind of MHC called
MHC2. When T-cells recognize a
foreign antigen that's combined with MHC2, they know that that
antigen must have come from one of these professional phagocytic
cells digesting bacteria or some other extracellular invader.
Because this antigen gets expressed in the context of
MHC2, your immune system responds differently.
Now, there's a lot of words here, I mean there's a lot of
words, there's a lot of abbreviations,
there's a lot of players. The details are not
particularly important to us. Some of them are in your book
and I hope you read about them because it's really interesting,
but the main points are that for us here that this is a very
elaborate of cell communication that is - has the same essential
characteristics that we talked about last time in that there
are receptors that are presenting signals which now
other cells receive. Those receptors are more
complicated than the ones we thought about before.
The ligands are more complicated than the ones we
thought about before. The reason for that complexity
is because your immune system needs to be able to respond to
all the potential foreign invaders that we could
encounter. It's not just a limited number
of things that might happen, and so it's evolved these sort
of mechanisms in order to allow it to respond to a wide variety
of potential molecules, and to respond in the same way
- in a coordinated way that somehow knows where those
foreign molecules came from. Importantly,
is able to distinguish foreign molecules from your own
molecules. So, read about this but please
don't worry about all of the details because the details
aren't so important for what we're going to talk about.
He says that and then he shows an even more detailed
picture, but what I want to show you on this slide is just the
simple part of it. I talked last time about MHC -
on the last slide about MHC1. So, this is a cell that's
infected with a microorganism, it's infected with a virus,
let's say it's infected with influenza virus.
That virus is reproducing inside cells of your respiratory
tract. You've got the flu,
you've got influenza in your upper respiratory tract,
your cells are making more influenza.
That gets presented in the context of MHC1 on cells within
your body. Immune cells recognize it,
and they recognize it by a very special form of receptor-ligand
interaction where the ligand is MHC1 with the foreign antigen
and the receptor is a receptor called the T-cell receptor
complex. T-cell receptor complex is able
to recognize on one population of T-cells, able to recognize
MHC1, together with foreign peptides,
on another type of T-cell able to recognize MHC2 with other
types of foreign antigens. What happens when that
recognition takes place is that your immune system gets
activated, and the activation that happens usually involves
two things. It involves proliferation,
which we talked about last week.
So, when the right signal is received, the right T-cell finds
your host cell with a foreign virus in it,
the first thing that happens is that this T-cell becomes
activated and it starts reproducing,
making more copies of itself. So, reproduction,
proliferation, cell growth happens and then
those cells become more differentiated.
They become more mature and they mature into,
in this case, they mature into cytotoxic
cells,
and cytotoxic means 'cyto' - cell, 'toxic' - killing,
they mature into cells that are capable of killing other cells.
You don't want to generate a lot of cells that just start
killing every cell inside your body.
Here's where the intelligence of the immune system comes in,
is that these cytotoxic T-cells that are generated only kill
cells that have this signal on it.
They only kill cells that have the signal which stimulated
them. So, they don't start killing
all the cells in your respiratory system;
they only kill the cells that are harboring the virus.
They know that these cells are harboring the virus because
those cells have foreign antigens on their MHC1.
Does that make sense? In the same way cells get
activated but these are different cells,
these are T helper cells that get activated by MHC2.
Helper cells don't become cytotoxic cells but they help B
cells become antigen producing - antibody producing cells.
So, this kind of recognition leads to an effect.
What's the effect? Cell killing.
This kind of recognition leads to another effect,
what's the effect? Antibody production.
Why are antibodies useful for bacteria?
Because bacteria are outside of cells and when antibodies bind
to them they can neutralize them.
They can't always neutralize viruses because the viruses are
predominantly inside cells. That's why you need two kinds
of immune responses. We're going to talk a lot
about antibodies, we're going to talk about
antibodies in section, and at the end of the course,
our last section meeting every year we get together and we talk
about which sections did you think were useful and which
parts - which sections were not so useful.
The section when you do today is always the most popular
section of the year, you'll know why after the
section, and you can tell me afterwards if you think you
figured out why. It involves thinking about
antibodies and how to use antibodies and technology.
Well, let me just say for the rest of time where do
antibodies come from naturally? They come from B-cells,
they come from B-cells that are activated with a specific
antigen. The antibodies that are
produced from these B-cells are also specific for the antigen.
An antigen expressed in the context of MHC stimulates your
immune system. One of the results of that
stimulation is that B-cells - a particular subset of B-cells -
gets activated. What happens when they're
activated is they start to reproduce, they make more and
more, and more B-cells. Those B-cells also mature,
they differentiate and that's what's shown on this slide here
is the differentiation of those immature B-cells into mature
B-cells. What do immature B-cells do?
They just wait, they wait for their time,
they wait until you are in danger from a particular
antigen. When you get exposed to that
particular antigen they say, 'I'm on, it's my time'.
They differentiate, they make many copies of
themselves - I'm sorry they proliferate,
they make many copies of themselves, and then they
differentiate into antibody production machines.
The antibodies they make are all specific to the antigen that
stimulated them. That's shown here,
a B-cell gets stimulated, matures into an antibody
producing factory. Antibodies look like this,
they're big proteins, if you looked at them under a
microscope or if you looked at them in cartoons they're shaped
like the letter Y. One part of them is all common.
The parts at the end of the Y's are variable.
What's variable about them is that they bind to a specific
antigen. They bind to the antigen that
stimulated their production. So, I have a bacteria
infection, stimulates my immune system, I start making
antibodies that bind to an antigen specific to that
bacteria. Won't help me against other
bacteria, but only against the one that I've got.
How do they recognize it? Because at the end of the Y,
there's a special region of the antibody, the antigen-binding
region, that is highly tuned for
binding to the antigen that stimulated them.
We're going to talk more about now how to use antibodies
in section today. One of the beautiful things
about antibodies is that one your immune system is able to
make antibodies against all the thousands,
ten thousand, hundred thousand different
pathogens that you'll come into contact with in your lifetime.
So, our bodies are capable of making antibodies that are tuned
for all the potential antigens that we come into contact with,
That's amazing that we have this capacity to respond and you
respond only when needed. From a technological
perspective, antibodies are incredible tools because
antibodies are molecules that are specifically designed to
bind to a particular antigen or a particular chemical.
What if you could manufacture antibodies?
Don't worry about how they work in the immune system,
but what if you could manufacture antibodies then you
could make a chemical, an antibody,
that is capable of binding to a specific other chemical and you
could use that for things. It turns out you can use
that for lots of things, you can use it to detect the
presence of small amounts of chemicals anywhere.
We'll talk about how to use antibodies in that fashion later
today in section. Questions?
One last word of encouragement, I'll say it again,
there's a lot of words in this chapter,
there's a lot of concepts, focus on the things that I
talked about in class not the details,
the basic concepts. Focus on the concepts of
receptors and ligands. I wanted to show you this slide
here on the homework. I realize that this thinking
about antigen, antibody combinations and the
mathematics of how strongly an antibody binds to a specific
antigen, is maybe something that's new
to you. There's - this diagram comes
directly from your book, from one of the boxes in the
book which describe how you analyze antibody interactions.
If you have questions about this I hope that you've already
taken advantage of the teaching fellows or come up after class,
I'd be happy to try to answer your questions now if you have
time as well. See you in section.
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