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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.
