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OK.  So I'm Claudette Gardel.
And I am in the instructor of this

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course.  And I've been asked to do
the second immunology lecture

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because Professor Jacks
is out of town.

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So he talked to you on Friday.
And he introduced the topic of

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immunology.  And he talked about the
cells that one finds in the blood.

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And these are the cells that are
important for immunology.

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They're responsible for the immune
response.  And he mentioned,

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I believe he mentioned mast cells
and macrophages and neutrophils and

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plasma cells and B cells and T cells.
And those are really the main

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players of immunology.
He also, no, no,

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no.  He also talked to you about the
incredible diversity,

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incredible, tremendous repertoire of
antibodies that we have that

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recognize variable,
based on their variable regions they

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can recognize a whole slew of
antigens.  OK?

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And this is like a graphic
depiction of an antibody.

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This is a hetero-dimer,
excuse me, tetramer.  And this

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diversity is a result of gene
rearrangement in the variable region

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of the antibody chains.
And so you heard VDJ recombination.

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So this is at the level of DNA
recombination.

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Similar to the gene rearrangement
that occurs in B cells that results

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in the diversity of antibodies,
T cells also have rearrangement for

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their variable region of
their T cell receptors.

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So we have a population of B cells
and T cells that can recognize a

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wide array of foreign antigens.
OK.  So this is immunology.  This

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is a topic that makes grown
scientists run away.

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And partly it is because there are
so many terms and so much jargon and

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it just seems so confusing to get it
all straight.  And it is.

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There is a lot of jargon.
So my goal in this lecture is to

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try and make you understand
conceptually what's going on.

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OK?  And I don't have handouts,
but I promise I will put this on,

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now, this isn't very helpful.  But I
will put this PowerPoint presentation

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on the Web.
And I have like tried to elucidate

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the main concepts of immunology,
which is so cool.  It is like such a

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cool topic.  OK?
So we're going to get through this.

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OK.  So what is immunology?  It's
how we fight infections.

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And what causes infections?
Pathogens.  So let's have a look

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and see what we're up against.
This is what we're fighting.  OK?

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There are parasites and funguses,

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fungi and bacteria and viruses.  And
they cause a whole slew of diseases.

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You've heard of some of them, right?
Smallpox we've heard of.

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Influenza.  We're going to study
AIDS.  We talked about polio a

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little bit.  We had cholera perhaps.
And tetanus we talked about.  And

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what must every pathogen do to cause
disease?  They must enter you.

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They want to live on you.
They want to grow on you.

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You are their food source.
So they want to enter you.  They

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want to evade the immune system,
which we're about to learn about.

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They want to colonize and multiply
and grow.  And then they want to

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spread to other hosts.
That's all they want.  Whether you

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get hurt in the process they don't
care.  They can cause disease three

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different ways.
Pathogens have basically three main

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strategies to cause disease.
They can cause disease from an

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extracellular point of view.
And so here I've drawn some,

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could you keep it down?  Some
epithelial cells.

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These little spots here are nuclei.
The pink represents damage.  So

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these pathogens can cause damage
without being in close proximity to

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the cell.  This is usually the
result of secreting a toxin.

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And this occurs with tetanus,
anthrax, gangrene.  Other pathogens

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have to be right up close to the
cell surface to cause disease.

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And this is true of the positive
agent of cholera.

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So they get up close and then they
can cause damage.

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And then there are others that are
intracellular.

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They actually get within the cell.
And this is true of many bacterial

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pathogens like chlamydia and the
causative agents of tuberculosis.

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And it's true of every single virus.
OK.  So we have developed

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strategies to deal with this.
And this strategy goes under the

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main umbrella called the immune
response.  And the immune response

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can be divided into two main parts,
innate or nonspecific and/or acquire

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adaptive and specific.
OK.  So this slide is actually my

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summary slide.
And it's going to blow you away a

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little bit, but by the end of the
talk you're going to understand it.

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OK?  So we're going to go through
it really quickly,

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you're going to like glaze over,
and then we're going to go through

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it.  Oops.  What happened?
Tom?  OK.  Oh, that was good.

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OK.  So the innate.
The innate response is composed of

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things that we have all the time,
natural barriers to the disease.

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They're always present,
it's a quick response, and it

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doesn't result in anything
long-lived.  The acquired or

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adaptive response takes longer.
And it's divided into two kinds,

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humoral and/or the other kind is
cell-mediated or sometimes it's

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called cellular and sometimes it's
called cell-based.

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This is why immunology is so
confusing.  Professor Jacks used the

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word cell-based.
And the main players of these,

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they're going to be shown here.  So
humoral has macrophages,

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helper T cells and B cells.
The main player of the cell-base is

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killer T cells.
This is the pathway that they work.

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You're going to learn about this in
detail.  Lysosome breaks up the

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antigen into epitopes.
It's presented on MHC-2 molecules.

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In the case of cell-based it's a
proteasome that breaks it up into

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epitopes presented on MHC-1
molecules.  And it's presented to

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the helper T cell by way of its
receptor which is associated with

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CD4 or to the killer T cell which
has a T cell receptor with an

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accessory protein called CD8.
The end result of the humoral

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response, antibodies
and memory B cells.

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The end result of the cell-based
response, memory T cells.

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That's it.  OK.  So that's what
you're going to know by the end of

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the lecture.  Here's the immune
response.  Excuse me.

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Here's the innate.  We're going to
discuss the innate.

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This is like an exploded diagram of
a human sort of.

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Now, I talked about pathogens and I
talked about bacteria being

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pathogens, but not all bacteria are
pathogens.  In fact,

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we are colonized by bacteria.
We are colonized by microbes.

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In fact, they outnumber us.  There
are ten to the thirteen cells that

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we have and there are ten to the
fourteen bacteria.

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They live on your skin.
They live in our large intestine.

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And this is a good thing, OK,
because they're commensals and they

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take up space to prevent real
professional pathogens from honing

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in on that space.
So commensals are beneficial.

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Plus we have this thing called skin.

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Skin is a good barrier.
It prevents us from looking like a

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piece of meat.
You know, it's tough.

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It's thick.  It's salty.
It has a low pH.  It's not exactly

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37 degrees.  It's a little bit
cooler.  Pathogens like to be at 37

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degrees.  It has fatty acids which
is sort of anti-microbial.

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Skin is good, yet some pathogens
have evolved systems to get through

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the skin.  For instance,
malaria gets in on a mosquito bite.

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Yersinia pestis, the causative
agent of bubonic plague which gets

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in on a flee bite.
OK.  So some can get through the

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skin.  And then,
of course, there are cuts.

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The eye is mostly sterile due to
lysozyme which is an enzyme that

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breaks down bacterial cell walls.
Your respiratory tract is

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surprisingly sterile considering
there are 500 to 1,

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00 microbes per cubic meter of air.
And as you're sitting here at rest

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in 10-250 breathing in about six
liters a minute,

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that translates to about 10,
00 microbes a day.  And why is this?

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But I just told you that your
respiratory tract is relatively

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sterile.  And that's because it's
lined with mucus which traps the

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microbes.  And the cells along the
respiratory tract have these little

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cilia that look like little
hair-like projectiles.

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And they're beating up,
constantly beating up the microbes.

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And they get to the back of your
throat and you swallow them.

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OK?  So you swallow them.  And then
the stomach, a sterile environment

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because of the low pH.
There are some microbes that can

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live in the stomach and they cause
ulcers.  Small intestine.

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Is that sterile or not?  Nobody
knows.  It's very sterile.

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It's a hostile environment.
It's full of bile.  If you can live

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there, like vibrio cholerae,
you'll be causing disease.  The

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large intestine.
Is that sterile?

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No.  No.  There are so many
bacteria in the large intestine that

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per gram of feces there's ten to the
eleventh bacteria.

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That's a one with 11 zeros after it.
So it's a lot of bacteria.

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And this is a good thing.  E.
coli secretes little vitamin K for

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us and there are commensals.
The bladder should be sterile.

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The kidneys should be sterile.  And
the flushing action of urine is

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constantly pushing down microbes
that might be wanting to infect us.

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OK.  Within the blood there are also
some innate components.

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One of them is the complement
system.  The complement system is a

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series of serum proteins that can
recognize nonspecifically many

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different bacterial pathogens.
And they come, and it's an

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enzymatic cascade,
and they land on the surface of the

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bacteria.  And then they can either
recruit other members of the immune

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system or they can actually
physically drill a hole in the

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bacteria and then kill it like a
little oil rig.

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And then there are macrophages which
I like to abbreviate this way,

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macrophage.  Macrophages are white
blood cells that engulf,

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they swallow, they phagocitize.
Phago means to eat.  Macro means a

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lot.  They eat a lot,
and they eat nonspecifically.

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They just swallow and take things
away nonspecifically.

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There are also interferons,
a component of the innate response.

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And that's interesting in that when
a cell is infected with a virus

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sometimes it will secrete.
And it knows it's infected.

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Sometimes it knows it's infected,
and sometimes it has the ability to

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secrete interferon.
And there are other cells that have

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receptors for interferon.
And when it's through a signal

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transduction mediated pathway they
go into an anti-virus state and they

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stop making protein and they start
cutting away RNAs.

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And so, actually, some of the bad
feelings that we have when we have

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flu is not really the flu virus.
It's the result of interferons

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being globally secreted in our body
and our cells sort of

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shutting down.  OK.
So here's the inflammatory response.

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OK?  And here we have a splinter.
This is a piece of wood coming in

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and look.  Oh,
look, it's coated with little

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bacteria.  OK?
And, actually,

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this experiment was done by
Mesnekoff many,

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many years ago where he took a
splinter and he put it in a starfish

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leg.  Leg?  You know,
one of those little projectiles of

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the starfish.  And he looked.
And he saw these cells trying to

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engulf, actually trying to engulf
the wood.  And that turned out to be

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the macrophage.
OK?  So he was actually the first

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person who discovered the macrophage.
So here we see the splinter

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penetrating the dermis.
And these cells here are called

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mast cells.  And they're full of
vesicles that secrete histamines.

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And the histamines cause the blood
vessel that's underlying to become

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more permeable such that the
macrophages and neutrophils,

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phagocytes can come to the area and
swallow the bacteria.

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So this is histamine,
these are the macrophages that are

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coming and swallowing.
And also you can see these little

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red dots are complement.
Those are the serum proteins that

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will come and land nonspecifically
on bacteria and lyse them.

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And the macrophage will also
secrete something we

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call cytokines.
Cytokines are signaling molecules

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that immune cells use.
And there is a whole array of

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cytokines and they have a whole
different variety of affects.

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Some cytokines have global affects
upon us.  They cause us to have

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fever and not feel too well.
OK.  So after the infection you'll

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notice the macrophage is swallowing
a dead, infected cell.

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They clean up.  And then these
cells with grow and

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will be repaired.
So this is the inflammatory response.

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The hallmark is redness and
swelling and heat.

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So now let's discuss the acquired
response.  The acquired takes longer.

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There was the humoral cell-mediated.
The end result of the humoral

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response are antibodies and memory B
cells.  The end response of

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cell-mediated are killer T cells.
We're going to talk about the

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humoral response right now.
And I'm going to give you an

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example of a disease.
This is vibrio cholerae.

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It's a bacterium that causes
cholera.  There are some places in

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the world where some people get
cholera.  And this person is

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suffering.  And the doctor has
squeezed her skin,

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and you can still see that the skin
is upright because she is severely

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dehydrated.  The disease is marked
by severe diarrhea that can lead to

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death within hours.
And they measure --

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What they do to treat cholera is
they measure the amount of diarrhea

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that happens, and that is the exact
amount that they replace in fluids.

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The lifecycle of the bacterium is
shown here.  You ingest contaminated

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food or water.
The bacteria get through the low pH

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of the stomach.
They swim through the mucus gel

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00:16:48,000 --> 00:16:52,000
overlying the small intestine
epithelial cells at which point they

217
00:16:52,000 --> 00:16:56,000
adhere.  And they start to elaborate
cholera toxin and other factors that

218
00:16:56,000 --> 00:17:00,000
allow them to colonize
and multiply.

219
00:17:00,000 --> 00:17:04,000
It's the action of cholera toxin
which causes the severe diarrhea,

220
00:17:04,000 --> 00:17:09,000
and it releases the vibrios into the
environment and the cycle continues.

221
00:17:09,000 --> 00:17:13,000
And some of you had in your signal
transduction the action of cholera

222
00:17:13,000 --> 00:17:18,000
toxin where it like turns on the
alpha protein in the intestinal cell

223
00:17:18,000 --> 00:17:23,000
causing high levels of cyclic AMP
which results in chloride ions and

224
00:17:23,000 --> 00:17:28,000
salt followed by water going into
the lumen of the small intestine.

225
00:17:28,000 --> 00:17:32,000
A person can die in as little as
eight hours due to the action of the

226
00:17:32,000 --> 00:17:36,000
toxin, and yet it's absolutely
treatable with oral hydration.

227
00:17:36,000 --> 00:17:41,000
And yet still 50,000 people die
each year because it can take up to

228
00:17:41,000 --> 00:17:45,000
40 liters of liquids to restore
hydration.  And sometimes it takes

229
00:17:45,000 --> 00:17:50,000
place in areas where there's not
water or for some reason small

230
00:17:50,000 --> 00:17:54,000
babies cannot take in the water.
Without treatment 70% will die.

231
00:17:54,000 --> 00:17:59,000
With treatment less
than 1% will die.

232
00:17:59,000 --> 00:18:03,000
Now, there are some places in the
world where cholera is endemic.

233
00:18:03,000 --> 00:18:07,000
People get it and they get treated
with oral rehydration.

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00:18:07,000 --> 00:18:12,000
And once you get it you don't get
it again.  You will have developed

235
00:18:12,000 --> 00:18:16,000
long-lived immunity to cholera.
And this long-lived immunity is a

236
00:18:16,000 --> 00:18:21,000
result of the humoral response.
So the next slide will show you the

237
00:18:21,000 --> 00:18:25,000
two key members,
actually three key members of the

238
00:18:25,000 --> 00:18:30,000
humoral response dealing
with a pathogen.

239
00:18:30,000 --> 00:18:34,000
So here we have a macrophage,
here we have a B cell.  And look,

240
00:18:34,000 --> 00:18:39,000
this little red dot could be a
pathogen, it could be an antigen,

241
00:18:39,000 --> 00:18:43,000
and it's about to be engulfed by the
macrophage and it's about to be

242
00:18:43,000 --> 00:18:48,000
recognized on the surface,
it's about to be recognized by the

243
00:18:48,000 --> 00:18:53,000
variable region of the antibody
which is on the surface of this B

244
00:18:53,000 --> 00:18:58,000
cell.  This is the B cell.
This is macrophage.  OK.

245
00:18:58,000 --> 00:19:02,000
So the macrophage swallows it and it
goes into an endosome.

246
00:19:02,000 --> 00:19:06,000
It endocytosis it or phagocytosis.
It could be a phagosome or an

247
00:19:06,000 --> 00:19:10,000
endosome it's called.
The B cell does exactly the same

248
00:19:10,000 --> 00:19:15,000
thing.  It brings it in on the
antibody.  And so it's also in an

249
00:19:15,000 --> 00:19:19,000
endosome or phagosome.
And see this little circle here?

250
00:19:19,000 --> 00:19:23,000
That's a lysosome.  Do you remember
lysosome?  We had them early.

251
00:19:23,000 --> 00:19:27,000
This is not lysozyme which is the
enzyme that's in the tears that

252
00:19:27,000 --> 00:19:32,000
break down cell walls.
No.  This is an organelle that is

253
00:19:32,000 --> 00:19:36,000
found in cells,
and it's full of degradative enzymes,

254
00:19:36,000 --> 00:19:41,000
proteases, nucleases,
lipases.  And it just fuses with the

255
00:19:41,000 --> 00:19:46,000
phagosome and chews it up into
little itty bitty pieces.

256
00:19:46,000 --> 00:19:50,000
And these little itty bitty pieces
are loaded onto these molecules

257
00:19:50,000 --> 00:19:55,000
called MHC class II molecules.
And they display little eight or

258
00:19:55,000 --> 00:20:00,000
nine amino acid snippets of what was
just chewed up.

259
00:20:00,000 --> 00:20:05,000
The only two cells in the body that
make MHC-2 molecules are the

260
00:20:05,000 --> 00:20:10,000
macrophages and the B cells.
And who are they displaying it to?

261
00:20:10,000 --> 00:20:15,000
Well, there's this third cell right
here.  It's the helper T cell.

262
00:20:15,000 --> 00:20:20,000
And the helper T cell recognizes
the MHC-2 class molecule in

263
00:20:20,000 --> 00:20:25,000
conjunction with the epitope by
virtue of its T cell receptor.

264
00:20:25,000 --> 00:20:30,000
OK.  And here are some helper T
cells.

265
00:20:30,000 --> 00:20:33,000
Here's either a macrophage or a B
cell.  This sort of looks like a B

266
00:20:33,000 --> 00:20:37,000
cell.  It's an antigen presenting
cell of which there are only two

267
00:20:37,000 --> 00:20:41,000
kinds, B cells and macrophages,
and they have MHC class II.  OK.

268
00:20:41,000 --> 00:20:45,000
Here's another way of looking at it,
pathogen engulf.

269
00:20:45,000 --> 00:20:48,000
There's the phagosome or endosome.
It looks like the lysosome is

270
00:20:48,000 --> 00:20:52,000
already fused.
It's broken up into little

271
00:20:52,000 --> 00:20:56,000
fragments.  Peptide fragments are
called epitopes.

272
00:20:56,000 --> 00:21:00,000
They're loaded onto MCH class II
molecules.

273
00:21:00,000 --> 00:21:04,000
Presented to the helper T cell.
And now, look, here's the T cell

274
00:21:04,000 --> 00:21:08,000
receptor.  It has an accessory
protein.  The helper T cell

275
00:21:08,000 --> 00:21:13,000
receptor's accessory protein
is called CD4.

276
00:21:13,000 --> 00:21:23,000
OK.  So, now, remember the helper T

277
00:21:23,000 --> 00:21:30,000
cell is going to bind to the
macrophage?  And it's going to --

278
00:21:30,000 --> 00:21:35,000
Only if it recognizes the epitope in
conjunction with MHC-2.

279
00:21:35,000 --> 00:21:40,000
And should that happen the
macrophage sends out some cytokines,

280
00:21:40,000 --> 00:21:45,000
special cytokines that causes the
helper T cell to also send out

281
00:21:45,000 --> 00:21:50,000
cytokines to itself and causes it to
clonally expand.

282
00:21:50,000 --> 00:21:55,000
OK?  So many more of these helper T
cells are around.

283
00:21:55,000 --> 00:22:00,000
So here we go.  It's found the
macrophage.

284
00:22:00,000 --> 00:22:04,000
It becomes activated.
It becomes in an activated state.

285
00:22:04,000 --> 00:22:09,000
It clonally expands but it still
remains in its sort of activated

286
00:22:09,000 --> 00:22:14,000
state.  And should it encounter a B
cell that has swallowed the exact

287
00:22:14,000 --> 00:22:19,000
same antigen or pathogen and is
displaying the exact same epitope

288
00:22:19,000 --> 00:22:24,000
then it causes the B cell to do
something through the action of

289
00:22:24,000 --> 00:22:29,000
cytokines.  So here it's finding the
B cell.  It has the exact

290
00:22:29,000 --> 00:22:34,000
same epitope.
And it sends these cytokines and it

291
00:22:34,000 --> 00:22:40,000
causes the B cell to clonally expand
into memory B cells and also to

292
00:22:40,000 --> 00:22:45,000
differentiate into plasma B cells
that are now secreting the antibody

293
00:22:45,000 --> 00:22:51,000
that originally recognized the
surface of the bacterium or the

294
00:22:51,000 --> 00:22:57,000
antigen.  And now these are now
being secreted into the blood or

295
00:22:57,000 --> 00:23:02,000
wherever they are.  OK.
Here it is again,

296
00:23:02,000 --> 00:23:06,000
helper T cell recognizes the B cell,
sends a signal, clonal expansion.

297
00:23:06,000 --> 00:23:10,000
The ones where the antibodies remain
on the surface are called memory

298
00:23:10,000 --> 00:23:14,000
cells.  Now they're in greater
abundance.  Some of them

299
00:23:14,000 --> 00:23:18,000
differentiate into these cells that
have lots of endoplasmic reticulum

300
00:23:18,000 --> 00:23:22,000
because they're synthesizing a
secreted protein.

301
00:23:22,000 --> 00:23:26,000
Now it's secreted and it's called
antibody.  So we've got all these

302
00:23:26,000 --> 00:23:30,000
secreted antibodies and all these
memory T cells, excuse me, B cells.

303
00:23:30,000 --> 00:23:35,000
And this is the reason why the
secondary response is greater.

304
00:23:35,000 --> 00:23:41,000
OK?  So the first time you
encounter a pathogen or an antigen

305
00:23:41,000 --> 00:23:46,000
it takes a while and it's not as
great the magnitude of antibodies.

306
00:23:46,000 --> 00:23:52,000
But the second time, because we
have all those extra memory cells

307
00:23:52,000 --> 00:23:58,000
around, it's much quicker and it's
also a greater magnitude.

308
00:23:58,000 --> 00:24:01,000
Now, if some of you were observing
that there are these things called

309
00:24:01,000 --> 00:24:05,000
IgM and IgG.  Well,
this refers to different classes of

310
00:24:05,000 --> 00:24:09,000
antibodies.  And there are different
classes.  IgM are the ones that are

311
00:24:09,000 --> 00:24:13,000
sort of on the surface of the B
cells.  They're sort of still

312
00:24:13,000 --> 00:24:16,000
tethered at some point.
And then as they become plasma

313
00:24:16,000 --> 00:24:20,000
cells they actually have secreted
antibodies.  And there are different

314
00:24:20,000 --> 00:24:24,000
classes depending upon what fluids
the antibodies will be found in.

315
00:24:24,000 --> 00:24:28,000
For instance, IgG is the
predominant antibody

316
00:24:28,000 --> 00:24:32,000
found in the blood.
IgA is found in some mucouses and

317
00:24:32,000 --> 00:24:37,000
tears and mother's milk.
So babies don't have any immune

318
00:24:37,000 --> 00:24:43,000
system, but if they're nursed they
get the IgA from their mother.

319
00:24:43,000 --> 00:24:48,000
And, actually, it goes into their
small intestine and just goes right

320
00:24:48,000 --> 00:24:53,000
across into their bloodstream.
So it actually helps them because

321
00:24:53,000 --> 00:24:59,000
it takes the babies a while to
develop antibody-making systems.

322
00:24:59,000 --> 00:25:04,000
IgE is an antibody that has been
implicated in allergic responses.

323
00:25:04,000 --> 00:25:09,000
Do you remember the mast cells that
have those ready pockets of

324
00:25:09,000 --> 00:25:14,000
histamine ready to like secrete out
and cause like a ray of affects?

325
00:25:14,000 --> 00:25:19,000
Well, they also have receptors for
IgE.  And so some of us have

326
00:25:19,000 --> 00:25:24,000
allergies, right?
And when we have allergies we

327
00:25:24,000 --> 00:25:30,000
develop IgE to ragweed
or cat dander.

328
00:25:30,000 --> 00:25:36,000
And as a result,
if we're exposed to this antigen we

329
00:25:36,000 --> 00:25:42,000
can have this reaction involving IgE
in mast cells resulting in histamine

330
00:25:42,000 --> 00:25:48,000
release.  And if it's very bad then
it can actually result in

331
00:25:48,000 --> 00:25:54,000
anaphylactic shock.
OK.  So antibodies,

332
00:25:54,000 --> 00:26:00,000
you know, we have a whole production
of antibodies made.

333
00:26:00,000 --> 00:26:04,000
But how do they actually fight
disease?  What do they do?

334
00:26:04,000 --> 00:26:09,000
So we've got them floating in our
blood?  How do they rid ourselves of

335
00:26:09,000 --> 00:26:13,000
the infection?
Well, they do it three ways.

336
00:26:13,000 --> 00:26:18,000
OK.  Remember vibrio cholerae?
It wants to get to the intestinal

337
00:26:18,000 --> 00:26:22,000
epithelium to cause disease.
Here's a bacterium here.  Here are

338
00:26:22,000 --> 00:26:27,000
antibodies that are specific to the
surface of vibrio cholerae,

339
00:26:27,000 --> 00:26:32,000
this bacterium here.  It is coated
with this furriness of antibodies.

340
00:26:32,000 --> 00:26:37,000
Can it touch the tissue?
No it cannot.  It is sterically

341
00:26:37,000 --> 00:26:42,000
hindered from getting to its surface.
And this would be true of a toxin,

342
00:26:42,000 --> 00:26:47,000
too, of a toxin, a protein toxin.  A
toxin is coated with antibodies.

343
00:26:47,000 --> 00:26:52,000
It cannot get to a receptor and
cause ill effects.

344
00:26:52,000 --> 00:26:57,000
OK.  So now we've got these
antigens and bacteria and they're

345
00:26:57,000 --> 00:27:02,000
coated with antibodies.
Opsonization.  This is derived from

346
00:27:02,000 --> 00:27:08,000
a Greek word which means seasoning
on food like salt and pepper.

347
00:27:08,000 --> 00:27:13,000
So here's a pathogen.  It's coated
with antibodies.

348
00:27:13,000 --> 00:27:19,000
In comes a macrophage and swallows
it up.  Now, the macrophage would

349
00:27:19,000 --> 00:27:24,000
devour this thing anyway without the
antibodies.  But it might be slower.

350
00:27:24,000 --> 00:27:30,000
It might be a little pokey.  When
you have --

351
00:27:30,000 --> 00:27:34,000
It's like seasoning on food.
When you have antibodies it's going

352
00:27:34,000 --> 00:27:39,000
to do it voraciously.
And why is that?  It's because the

353
00:27:39,000 --> 00:27:44,000
variable region binds to the
bacterium or the pathogen or the

354
00:27:44,000 --> 00:27:49,000
antigen.  What's sticking out is the
constant region of the antibody.

355
00:27:49,000 --> 00:27:54,000
No matter what's on the variable
region the constant region is the

356
00:27:54,000 --> 00:27:59,000
same.  So the macrophages have
receptors that recognize this

357
00:27:59,000 --> 00:28:04,000
constant region and they zip it up
and they swallow it.

358
00:28:04,000 --> 00:28:08,000
Likewise antibody triggers the
complement system,

359
00:28:08,000 --> 00:28:12,000
so although the complement system
might come in slowly,

360
00:28:12,000 --> 00:28:16,000
when it sees antibodies bound to a
bacterium it comes in and it does

361
00:28:16,000 --> 00:28:21,000
its little oil drill thing instantly.
OK.  So that's how antibodies

362
00:28:21,000 --> 00:28:25,000
prevent disease.
Here's a picture of the macrophage

363
00:28:25,000 --> 00:28:29,000
with its receptors.
This end of the molecule of the

364
00:28:29,000 --> 00:28:34,000
antibody is called FC.
So the receptor is called the FC

365
00:28:34,000 --> 00:28:40,000
receptor.  And it just coats it and
brings it in and ingests it.

366
00:28:40,000 --> 00:28:46,000
OK.  So we've got antibodies as a
result of the humoral response.

367
00:28:46,000 --> 00:28:51,000
Would they be affective in
preventing a toxin from binding to a

368
00:28:51,000 --> 00:28:57,000
surface if we had antibodies against
that toxin?  You bet.

369
00:28:57,000 --> 00:29:03,000
It's very good for pathogens that
cause extracellular disease

370
00:29:03,000 --> 00:29:08,000
away from the cell.
It's very good for toxins,

371
00:29:08,000 --> 00:29:12,000
extremely good.  What about
preventing cholera again?

372
00:29:12,000 --> 00:29:16,000
Can it prevent a pathogen from
binding to a surface,

373
00:29:16,000 --> 00:29:20,000
an adherent bacterium?
Yes.  We just showed you it did.

374
00:29:20,000 --> 00:29:24,000
Sterical hindrance.  But what about
the case of viruses or other things

375
00:29:24,000 --> 00:29:28,000
that are intracellular,
that cause disease from within,

376
00:29:28,000 --> 00:29:32,000
would antibodies be effective there?
Only if they were caught before they

377
00:29:32,000 --> 00:29:37,000
got in.  But once they're in they're
protected from macrophages.

378
00:29:37,000 --> 00:29:41,000
They're protected from antibodies.
They're in a nice, warm,

379
00:29:41,000 --> 00:29:46,000
nutrient-rich environment.
They're looking pretty good.

380
00:29:46,000 --> 00:29:51,000
And many professional pathogens
have opted for this tact.

381
00:29:51,000 --> 00:29:55,000
So what we've done is we've
developed the other wing of the

382
00:29:55,000 --> 00:30:00,000
immune system called cell-mediated
to deal with intracellular

383
00:30:00,000 --> 00:30:05,000
pathogens.
And these are the stars of the

384
00:30:05,000 --> 00:30:09,000
cell-mediated or cell-based or
cellular system.

385
00:30:09,000 --> 00:30:14,000
And they are called killer T cells.
And they are the coolest cell in

386
00:30:14,000 --> 00:30:18,000
your body.  They're like the
Terminator, you know,

387
00:30:18,000 --> 00:30:23,000
Arnold Schwarzenegger,
the Terminator.  And so they go

388
00:30:23,000 --> 00:30:28,000
around and they like will protect us.
So let's show you this.  OK.

389
00:30:28,000 --> 00:30:32,000
This thing that looks like a
suitcase is my drawing of let's say

390
00:30:32,000 --> 00:30:36,000
an epithelial cell that has been
like sandblasted away.

391
00:30:36,000 --> 00:30:41,000
OK?  One side of it is sandblasted
away so we can look in.

392
00:30:41,000 --> 00:30:45,000
Oh, look, there's its nucleus and
there's its endoplasmic reticulum.

393
00:30:45,000 --> 00:30:50,000
And what are these things on the
surface of the cell?

394
00:30:50,000 --> 00:30:54,000
Well, it's called MHC class I
molecule and it's presenting and

395
00:30:54,000 --> 00:30:59,000
epitope of eight to
nine amino acids.

396
00:30:59,000 --> 00:31:04,000
All nucleated cells in the body.
Every cell in your body that has a

397
00:31:04,000 --> 00:31:09,000
nucleus is presenting MHC class I
molecules on their surface,

398
00:31:09,000 --> 00:31:17,000
presenting epitopes on MHC class I.

399
00:31:17,000 --> 00:31:23,000
And where did these epitopes come
from?  They come from proteins that

400
00:31:23,000 --> 00:31:29,000
are found in the cytoplasm.
At some point routinely proteins

401
00:31:29,000 --> 00:31:35,000
are channeled through this organelle
called a proteasome.

402
00:31:35,000 --> 00:31:39,000
They get threaded through and they
get broken up into eight or nine

403
00:31:39,000 --> 00:31:44,000
amino acid snippets,
and they get loaded onto MHC class I

404
00:31:44,000 --> 00:31:48,000
molecules in their final stages of
being transported to the membrane.

405
00:31:48,000 --> 00:31:53,000
And who are they presenting, these
MHC class I molecules to?

406
00:31:53,000 --> 00:31:57,000
They're presenting them to killer T
cells by way of the

407
00:31:57,000 --> 00:32:02,000
T cell receptor.
Now, although most of the epitopes

408
00:32:02,000 --> 00:32:08,000
that are presented on these MHC
class I molecules are derived from

409
00:32:08,000 --> 00:32:13,000
your own proteins,
host proteins.  Any killer T cell

410
00:32:13,000 --> 00:32:19,000
that could have recognized a host
protein, in conjunction with the

411
00:32:19,000 --> 00:32:25,000
MHC-1 molecule,
has been eliminated early in

412
00:32:25,000 --> 00:32:30,000
development.
Early in development if there is

413
00:32:30,000 --> 00:32:35,000
recognition.  That killer T cell has
been targeted for apoptosis and dies.

414
00:32:35,000 --> 00:32:40,000
And this is true with B cells,
too.  So if they have an antibody on

415
00:32:40,000 --> 00:32:45,000
their surface that can recognize a
self protein they are eliminated.

416
00:32:45,000 --> 00:32:50,000
And this is called clonal deletion.
So what is left in our blood are

417
00:32:50,000 --> 00:32:55,000
only killer T cells that can
recognize foreign epitopes in

418
00:32:55,000 --> 00:33:01,000
conjunction with the MHC
class I molecule.

419
00:33:01,000 --> 00:33:05,000
And so if the cell is infected,
and it is because I drew in these

420
00:33:05,000 --> 00:33:10,000
chlamydia, and if some of these
proteins are chlamydia proteins and

421
00:33:10,000 --> 00:33:15,000
they are being presented on these
MHC class I molecules,

422
00:33:15,000 --> 00:33:19,000
and the right killer T cell with the
receptor that comes by and

423
00:33:19,000 --> 00:33:24,000
recognizes it,
if recognition occurs two things

424
00:33:24,000 --> 00:33:29,000
happen.  OK.  Here's the killer T
cell.  Here's the MHC-1 with the

425
00:33:29,000 --> 00:33:34,000
chlamydia epitope or a
pathogenic epitope.

426
00:33:34,000 --> 00:33:37,000
A foreign epitope sitting right
there.  The killer T cell says oh,

427
00:33:37,000 --> 00:33:41,000
my God.  We have a cell that's
infected.  Maybe there are other

428
00:33:41,000 --> 00:33:45,000
cells that are infected.
I've got to make more of me.

429
00:33:45,000 --> 00:33:48,000
And it clonally expands to make
more of itself with the exact same T

430
00:33:48,000 --> 00:33:52,000
cell receptor that's going to
recognize this epitope.

431
00:33:52,000 --> 00:33:56,000
It also punches a whole in the cell
using perforin.

432
00:33:56,000 --> 00:34:00,000
It secretes this thing called
perforin.

433
00:34:00,000 --> 00:34:04,000
It punches a hole in the cell.
And if that's not good enough,

434
00:34:04,000 --> 00:34:09,000
it also secretes something called
granzyme B which causes this cell to

435
00:34:09,000 --> 00:34:13,000
undergo apoptosis.
So it like double kills it.

436
00:34:13,000 --> 00:34:18,000
OK?  And here's like another
picture of it.

437
00:34:18,000 --> 00:34:23,000
So here's the virus.
The proteins are loaded onto MHC

438
00:34:23,000 --> 00:34:27,000
class I molecules.
The killer T cell recognizes it by

439
00:34:27,000 --> 00:34:35,000
way of its T cell receptor.
And its successor protein is CD8.

440
00:34:35,000 --> 00:34:47,000
OK.  Here's the infected cell.

441
00:34:47,000 --> 00:34:52,000
Here is the killer T cell.  There's
the CD8.  This is perforin which is

442
00:34:52,000 --> 00:34:57,000
going to puncture a hole in the
infected cell.

443
00:34:57,000 --> 00:35:02,000
It figures it better kill this cell
now and save the rest of the body.

444
00:35:02,000 --> 00:35:06,000
It decides to sacrifice the infected
cell.  And here's granzyme that

445
00:35:06,000 --> 00:35:11,000
causes apoptosis.
And this cell then ends up looking

446
00:35:11,000 --> 00:35:16,000
like this with holes punched in it,
cytoplasm streaming away and starts

447
00:35:16,000 --> 00:35:24,000
to undergo apoptosis.

448
00:35:24,000 --> 00:35:30,000
And it makes more of itself.
So you end up with an army of

449
00:35:30,000 --> 00:35:37,000
memory killer T cells that are going
to recognize this exact pathogenic

450
00:35:37,000 --> 00:35:43,000
epitope.  Here's a killer T cell.
Here's an infected cell.  And

451
00:35:43,000 --> 00:35:53,000
here's a movie.

452
00:35:53,000 --> 00:36:00,000
Remember I said Terminator,
right?  OK.  There's the T cell.

453
00:36:00,000 --> 00:36:03,000
There's the cytoplasm streaming away.
And look it.  It just keeps going.

454
00:36:03,000 --> 00:36:07,000
It doesn't stop.  It just keeps
going.  Punching away.

455
00:36:07,000 --> 00:36:11,000
Wasn't that awesome?  Let's do it
again.  OK.

456
00:36:11,000 --> 00:36:28,000
That is so cool.

457
00:36:28,000 --> 00:36:32,000
Yup.  OK.  And they're on our side,
you know.  This is the army we have

458
00:36:32,000 --> 00:36:37,000
going in our blood.
It's just awesome.  It's just

459
00:36:37,000 --> 00:36:45,000
awesome.  OK.

460
00:36:45,000 --> 00:36:50,000
OK.  So this is the T cell receptor.
This is found in both helper T

461
00:36:50,000 --> 00:36:56,000
cells and killer T cells.
Notice it has a variable region.

462
00:36:56,000 --> 00:37:02,000
Early in its development the T cell
precursor actually has

463
00:37:02,000 --> 00:37:07,000
both CD4 and CD8.
And it's immature at this point.

464
00:37:07,000 --> 00:37:13,000
It doesn't know what it is yet.  It
has both.  And then as it develops

465
00:37:13,000 --> 00:37:18,000
it has only one left.
So if it remains with the CD4 it is

466
00:37:18,000 --> 00:37:24,000
a helper T cell.
If it has a CD8 in its final

467
00:37:24,000 --> 00:37:30,000
differentiated state it
is a killer T cell.

468
00:37:30,000 --> 00:37:35,000
And it's this accessory protein that,
actually that's it,

469
00:37:35,000 --> 00:37:40,000
that's what causes it.
And so if we look up close and

470
00:37:40,000 --> 00:37:45,000
personal at an MHC receptor,
this could be MHC-1 or MHC-2.

471
00:37:45,000 --> 00:37:51,000
This accessory protein could be CD4,
CD8.  So if it's MHC-1 the accessory

472
00:37:51,000 --> 00:37:56,000
protein is CD8.
If it's MHC-2 the accessory protein

473
00:37:56,000 --> 00:38:02,000
that fits MHC class
II would be CD4.

474
00:38:02,000 --> 00:38:09,000
So now I'm hoping that this will

475
00:38:09,000 --> 00:38:13,000
become a little bit more clear for
you.  So the innate response had

476
00:38:13,000 --> 00:38:18,000
lysozyme, the mucus,
ciliary ladder, skin and complement,

477
00:38:18,000 --> 00:38:23,000
and macrophages and mast cells.  It
doesn't last very long.

478
00:38:23,000 --> 00:38:27,000
And it's really not completely
effective in, you know.

479
00:38:27,000 --> 00:38:32,000
It wouldn't really work that alone.
We'd need the acquired and adaptive

480
00:38:32,000 --> 00:38:37,000
response which takes a couple of
weeks the first time.

481
00:38:37,000 --> 00:38:42,000
And so the humoral response and the
cell-mediated or cellular or

482
00:38:42,000 --> 00:38:46,000
cell-based response.
The humoral response has the

483
00:38:46,000 --> 00:38:51,000
macrophage that first engulfs the
antigen and the B cell that

484
00:38:51,000 --> 00:38:56,000
recognizes the antigen through its
specific tethered on its surface

485
00:38:56,000 --> 00:39:01,000
antibodies.  Both of them engulf it,
break it down and present to the

486
00:39:01,000 --> 00:39:06,000
helper T cell.
The cell-based response involves

487
00:39:06,000 --> 00:39:11,000
killer T cells.
So inside the macrophage and the B

488
00:39:11,000 --> 00:39:16,000
cell a lysosome comes over,
it fuses with the endosome, breaks

489
00:39:16,000 --> 00:39:21,000
it into epitopes which get loaded on
MHC class II molecules.

490
00:39:21,000 --> 00:39:26,000
Inside every nucleated cell in our
body we have a proteasome that is

491
00:39:26,000 --> 00:39:31,000
breaking anything that's found in
the cytoplasm onto epitopes.

492
00:39:31,000 --> 00:39:35,000
And if the cell is infected those
are going to get broken into

493
00:39:35,000 --> 00:39:40,000
epitopes and loaded on MHC-1
molecule to be hunted down by killer

494
00:39:40,000 --> 00:39:45,000
T cells.  This is recognized by a T
cell receptor with an accessory

495
00:39:45,000 --> 00:39:50,000
protein CD4.  This one's recognized
by a T cell receptor with an

496
00:39:50,000 --> 00:39:55,000
accessory protein that's CD8.
See, it's not so hard, right?

497
00:39:55,000 --> 00:40:00,000
It seems a little bit wordy, but
conceptually --

498
00:40:00,000 --> 00:40:04,000
So the T cell causes the blood,
the B cell to clonally expand.  Some

499
00:40:04,000 --> 00:40:09,000
of them become plasma cells which
secrete antibodies.

500
00:40:09,000 --> 00:40:14,000
Some of them become long-lived
memory B cells.

501
00:40:14,000 --> 00:40:19,000
The killer T cell,
recognizing an infected cell,

502
00:40:19,000 --> 00:40:24,000
will secrete perforin to punch holes
in it, granzyme B to kill

503
00:40:24,000 --> 00:40:30,000
it through apoptosis.
And it also creates lines of memory

504
00:40:30,000 --> 00:40:36,000
killer T cells such that the next
time we see the same pathogen,

505
00:40:36,000 --> 00:40:43,000
if any, we're ready.  OK.  So, now,
if we didn't have the mechanism to

506
00:40:43,000 --> 00:40:50,000
make antibodies or T cell receptors,
what if we only had the innate

507
00:40:50,000 --> 00:40:56,000
response?  And there are people who
don't have the acquired

508
00:40:56,000 --> 00:41:02,000
or adaptive response.
Oh, excuse me.

509
00:41:02,000 --> 00:41:08,000
These are other terms.
And they're called the ìbubble boyî.

510
00:41:08,000 --> 00:41:13,000
Have you heard of the bubble boy?
They have to live inside a bubble,

511
00:41:13,000 --> 00:41:19,000
basically a plastic shell that's
completely sterile.

512
00:41:19,000 --> 00:41:24,000
They either don't have B or T cells
or they don't have any antibody or T

513
00:41:24,000 --> 00:41:30,000
cell variation.
And so the innate response is not

514
00:41:30,000 --> 00:41:35,000
quite good enough.
And so, on the other hand,

515
00:41:35,000 --> 00:41:40,000
sometimes you can have an overactive
immune response.

516
00:41:40,000 --> 00:41:46,000
For instance, you could have killer
T cells or even antibodies that

517
00:41:46,000 --> 00:41:51,000
recognize or start to recognize host
proteins.  And this happens.

518
00:41:51,000 --> 00:41:57,000
And the end result of this is
autoimmune disease.

519
00:41:57,000 --> 00:42:02,000
So here's an example of an
autoimmune disease that's caused by

520
00:42:02,000 --> 00:42:07,000
killer T cells that have now started
to recognize beta cells in the

521
00:42:07,000 --> 00:42:13,000
pancreas as being infected and they
kill them.  And the beta cells in

522
00:42:13,000 --> 00:42:18,000
the pancreas are cells that respond
to levels of glucose in your blood.

523
00:42:18,000 --> 00:42:24,000
So you have like a candy bar, you
eat a meal, there are high levels of

524
00:42:24,000 --> 00:42:29,000
glucose in your blood.
The beta cells secrete insulin so

525
00:42:29,000 --> 00:42:33,000
that your entire body,
the cells in your body will make

526
00:42:33,000 --> 00:42:38,000
glucose receptors to take that
glucose out of the blood and utilize

527
00:42:38,000 --> 00:42:42,000
it.  So if you don't have beta cells
because they've been killed by the

528
00:42:42,000 --> 00:42:47,000
killer T cells you don't make
insulin and you get diabetes.

529
00:42:47,000 --> 00:42:51,000
Let's see.  What other autoimmune
diseases?  Lupus is an

530
00:42:51,000 --> 00:42:56,000
autoimmune disease.
Sometimes you can have antibodies

531
00:42:56,000 --> 00:43:02,000
that recognize the myelin sheath,
the cells that make up the myelin

532
00:43:02,000 --> 00:43:08,000
sheath, and then those cells are
destroyed.  And that results in

533
00:43:08,000 --> 00:43:13,000
multiple sclerosis.
So these are autoimmune diseases,

534
00:43:13,000 --> 00:43:19,000
when the immune system goes wild or
goes bad.  OK.

535
00:43:19,000 --> 00:43:25,000
So I've just sort of built up the
immune system as being really great

536
00:43:25,000 --> 00:43:30,000
and wonderful.
But some of you might have questions

537
00:43:30,000 --> 00:43:35,000
and some of you are thinking,
well, you know, gee, I've had the

538
00:43:35,000 --> 00:43:40,000
flu twice.  My roommate has had
strep throat a couple of times.

539
00:43:40,000 --> 00:43:45,000
What gives?  What's with this
secondary response,

540
00:43:45,000 --> 00:43:50,000
this acquired response?
Well, pathogens, some pathogens,

541
00:43:50,000 --> 00:43:55,000
it's an ongoing war, have developed
strategies to overcome our immune

542
00:43:55,000 --> 00:44:01,000
system.  And that's why we use
antibiotics to kill them sometimes.

543
00:44:01,000 --> 00:44:05,000
OK?  And they're nasty,
you know, and they grow fast and

544
00:44:05,000 --> 00:44:09,000
they mutate.  And they can develop
ways of getting around our immune

545
00:44:09,000 --> 00:44:13,000
system.  For instance,
this is a picture of Bacillus

546
00:44:13,000 --> 00:44:17,000
anthracis.  It has developed this
enormous polysaccharide capsule that

547
00:44:17,000 --> 00:44:21,000
absolutely prevents it from being
phagocytosed by macrophages.

548
00:44:21,000 --> 00:44:25,000
Without the capsule it is
absolutely harmless.

549
00:44:25,000 --> 00:44:29,000
It absolutely requires the capsule
to cause disease, as

550
00:44:29,000 --> 00:44:34,000
well as a toxin.
That's the only thing it needs,

551
00:44:34,000 --> 00:44:40,000
a toxin that is on a plasmid and in
a capsule.  Or,

552
00:44:40,000 --> 00:44:46,000
let's say we develop antibodies to
neisseria gonorrhea,

553
00:44:46,000 --> 00:44:51,000
or we develop antibodies to malaria.
What they do, these pathogens, some

554
00:44:51,000 --> 00:44:57,000
of them very clever ones,
is they say OK, antibodies are

555
00:44:57,000 --> 00:45:02,000
recognizing things on my surface.
I know.  I'll just change my surface.

556
00:45:02,000 --> 00:45:06,000
And they'll change their surface.
They'll put up a different protein

557
00:45:06,000 --> 00:45:10,000
for phase variation or they'll
mutate.  And the antibodies are so

558
00:45:10,000 --> 00:45:15,000
specific that they cannot recognize
this mutated protein,

559
00:45:15,000 --> 00:45:19,000
and it's like we're getting it again
for the first time.

560
00:45:19,000 --> 00:45:24,000
And this actually happens with
cholera.

561
00:45:24,000 --> 00:45:29,000
So in places where it's endemic,
people get it once, they develop

562
00:45:29,000 --> 00:45:34,000
long-term resistance,
and then 20 to 40 years suddenly

563
00:45:34,000 --> 00:45:39,000
adults start getting cholera again.
Actually, I'm not even sure it

564
00:45:39,000 --> 00:45:44,000
happens that quickly.
The last one happened in the late

565
00:45:44,000 --> 00:45:49,000
1990s where it just started wiping
out adults.  And so whole clinics

566
00:45:49,000 --> 00:45:55,000
had to be developed in town squares
for oral rehydration.

567
00:45:55,000 --> 00:46:00,000
And what had happened was that the
bacterium, the vibrio cholerae

568
00:46:00,000 --> 00:46:06,000
bacterium changed one sugar residue
on its surface.

569
00:46:06,000 --> 00:46:11,000
Just one little sugar changes.
A fructose turned into a mannose,

570
00:46:11,000 --> 00:46:17,000
right?  And that was it, because
that was what the antibody

571
00:46:17,000 --> 00:46:22,000
recognized.  So now new antibodies
have to be made to that one so

572
00:46:22,000 --> 00:46:28,000
people will get it twice.
There are some bacteria that make

573
00:46:28,000 --> 00:46:34,000
proteases that are designed to cut
our antibodies in half.

574
00:46:34,000 --> 00:46:39,000
So horrible.  So they just go in
there and they just secrete these

575
00:46:39,000 --> 00:46:44,000
proteases, and the antibodies have
just like degraded.

576
00:46:44,000 --> 00:46:49,000
Let's see.  Some pathogens can
survive phagocytosis.

577
00:46:49,000 --> 00:46:54,000
They send out little messages that
prevent the lysosome from coming

578
00:46:54,000 --> 00:47:00,000
over, and they live
in the phagosome.

579
00:47:00,000 --> 00:47:03,000
And, oh, I'm going to be leaving you
on a sad note,

580
00:47:03,000 --> 00:47:07,000
ha?  But, all right,
do we have any questions?

581
00:47:07,000 --> 00:47:15,000
Do we have any questions?

582
00:47:15,000 --> 00:47:18,000
No?  Perfectly clear?
OK.  You can go.