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Recall, please, that we
were discussing last time

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the fact that the immune system
makes a wide diversity of antibody

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molecules. And, by the
way, a synonym for an

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antibody molecule
is an immunoglobulin.

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Recall that we used that word
very briefly. Another word we use,

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by the way, was the word antigen.
And, an antigen is a functional term.

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That was pretty funny. An
antigen is a functional term.

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An antigen is an agent that
provokes an immune response.

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And, the term antigen doesn't
really refer to any specific

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chemical structure. It
doesn't even have to be a

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protein. Antigen simply refers to
some chemical entity that creates

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some response from the immune
system. We also use the word in

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passing, epitope. And, an
epitope refers to a small

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region, for example, a protein
against which an antibody

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has developed reactivity. And
if you recall our discussion

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last time, a protein obviously
of some size has multiple distinct

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epitopes, each of which can be
recognized by a distinct antibody

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molecule. And,
for us, could we,

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I'm sorry if I got all
this political discussion

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started, thank you.
Thank you. An epitope,

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from the point of view of a
protein is an oligo peptide.

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So, a stretch of amino
acids of maybe ten, or 12,

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or 15 amino acids forms an epitope.
And therefore, you can imagine

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there are multiple epitopes
on the surface of a protein.

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In fact, antibodies can sometimes
recognize the internal parts of the

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protein because protein can
sometimes become denatured

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or degraded. Indeed, as
we will discuss shortly,

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proteins also become
cleaved into oligo peptides.

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These oligo peptides can come
from any part of the protein,

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to state the obvious, and therefore
there might be internal epitopes

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that exist in a protein that are
not normally exposed by the native

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protein. Recall that we were
dealing with the issue of how the

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immune system is able to create
a wide diversity of antibodies,

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immunoglobulins would share
in common a constant domain.

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And the constant domain is formed by
these invariant regions of the light

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and the heavy chains. We call
this the heterotetramer in

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contrast to the variable domain up
here which recognizes the antigen

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that initially provoked the
production of this antibody molecule.

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And, the immune system may at any
one point in time be making hundreds

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of thousands, maybe even millions
or tens of millions of distinct

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antibody species that differ
one from the other by the antigen

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recognition site here at this
part of the antibody molecule.

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And recall as well that
since these are proteins, the

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antigen-recognizing pocket
is itself an oligopeptide,

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which combined in some complementary
fashion to whatever antigen

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initially provoked the synthesis
of this antibody molecule.

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At the end of last time,
we discussed the fact that

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antibodies are made by B cells,
and the fact that in the disease of

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multiple myeloma, one
ends up with a monoclonal

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disease, that is to say,
one of a vastly heterogeneous

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population of B cells begins
to proliferate uncontrollably.

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And now, all of its descendants
make a single antibody species.

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And that single antibody species
consists once again of a heavy and a

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light chain, whose identity is
created by the antigen-recognizing

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pocket that it happens to carry.
And this begins to suggest a notion

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of clonal expansion. By
that, I mean the following.

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Let's imagine a scenario where we
start out with a naïve immune system

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where we have a whole
series of different B cells.

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And this series goes here from 1-15,
but in fact this could go from one

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up to a million. And
each of these antibody

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producing B cells, or
each of these B cells,

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has in principle the ability to
respond to a different antigen.

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Let's just imagine that. And
now, what we can imagine is

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that an antigen such as, for
example, poliovirus comes into

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the body, and it is recognized
by two different clones of these B

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cells. And that recognition, we
can imagine, acts as a mytogenic

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signal, a growth stimulatory signal
for these two particular clones and

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B cells. It almost acts as
if it were a growth factor.

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But of course, we're not talking
about growth factors here.

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We're talking about antigens,
including antigens brought into the

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tissue by a foreign infectious
agent. And therefore,

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the recognition of the antigen by
these two B cells may thereafter

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provoke their clonal expansion.
By that I mean to say that they

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will preferentially begin to
proliferate whereas all the other B

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cells, which are not in any way
responsive to that antigen will just

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sit there like bumps on
a log. And, if there is,

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therefore, clonal expansion,
now there will be a much larger

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number of cells in the immune system
that are capable of producing the

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antibody that recognizes
its provoking antigen.

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Again, recall that this
number may go up to a million.

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This is just a great simplification.
Now here, we use the word plasma

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cells. And in fact, if one
wants to get the nomenclature

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very proper, the plasma cells are
the products of B cells which mature

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into the antibody
producing plasma cells.

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They are very close on
the same lineage of cells,

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and what that means in the end
for us is if once there's an active

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immune response, there's
been the preferential

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expansion of certain sub-populations
of B cells and plasma cells,

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and other ones of them which don't
recognize these antigens just sit

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there are underrepresented in
the total population of cells.

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Still, the fundamental
question that we posed last time

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was the following.
If it's the case,

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and it happens to be that each
of these B cells makes an antibody

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having a distinct reactivity, a
distinct ability to react to one

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or another antigen how do they make
so many different kinds of antibody

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molecules. How do they know how
to do that. We argued that it's

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implausible that the amino acid
sequences of each antibody molecule

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are encoded in the germ line.
Why? Well, if there are indeed a

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million or even 100 million distinct
antibodies can be made by the immune

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system, clearly there
can't be 100 million genes,

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each of which is dedicated to
the production of a distinct

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antibody molecule. And the
solution to this puzzle was

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first worked out by Susumu Tonegawa
already more than 20 years ago who

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happens to be in our biology
department. And what he discovered

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was the following, that
the way that the antibody

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producing genes are organized
is really quite extraordinary

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and unusual. Here's the
heavy chain of the gene,

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and keep in mind that there's
a heavy and a light chain gene.

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The heavy and the light chain
genes are in different chromosomes.

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And therefore, the genes that are
responsible for encoding these two

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proteins, the heavy and the
light chain, they're on different

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chromosomes, and encode by
different genes. OK, so what Tonegawa

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discovered was the following,
that the variable region of an

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antibody molecule which is at its
end terminus is encoded by small

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segments of DNA that are carried
in one very large genetic locus,

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an immunoglobulin locus. And
what happens in humans is the

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following. There are in
humans rather than mice,

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this number should be 100 in humans,
there are 100 distinct V segments

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that are encoded in this antibody
locus. Each one is roughly the same

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size, and they're located
in a large tandem array.

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Similarly, there are in
humans 30 of these desegments.

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The numbers change here if
one goes from mouse to human,

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but that's irrelevant.
And, there are six of the J

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segments. And, much of
the antigen-recognizing

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capacity, much of the variable
region is encoded in the green and

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the blue region of the gene, and
the encoding happens as follows.

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There is a
combinatorial fashion the

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random fusion of V, D,
and J segments. There are

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specific, highly specialized enzyme
that will choose one specific V

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segment, one specific D segment,
and one specific J segment,

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ostensibly on a stochastic basis,
a totally random basis, and fuse

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them together. And
if that happens,

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and the intervening DNA
sequences are discarded,

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then right away we can see
that through the combinatorial

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mathematics that results from this,
there is the possibility for having

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100 times 30, which is 3, 00,
times six, which is already 180,

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00 distinct combinations encoding
the reading frame of this particular

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antibody molecule.
Here, I've just said V23,

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I guess, D7, J2. But again,
let's imagine, which is

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approximately the case, that
each of these combinations can

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be fused with roughly
equal probability.

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What happens subsequently, then,
is that this variable region

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sequence, which has been formed by
fusion, is then the transcript that

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comes from that is spliced to the
constant region which is towards the

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C terminus. So here,
when we talk about the V,

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D, and J segments, we're talking
about the segments that are encoding

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this portion. Here's this
portion of the antibody molecule.

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Keep in mind, from here on down,
we're talking about constant region

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segments which are not affected
by these combinatorial fusions.

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And, in the overhead I just showed
you, I was just talking about how

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the heavy chain gene is rearranged.
And what that results as a

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consequence is the following.
This is just another version of

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what I just showed you before,
where the V, D, and J segments

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become fused randomly to
one another creating a V, D,

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J fusion thing, which then by
splicing is fused to the constant

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region which here
is called C sub-mu.

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For reasons of why it's called
sub-mu I'll mention in a moment.

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And this is the actual messenger
RNA which then goes into the

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cytoplasm. And what we can
now imagine is the following,

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that when the immune system first
begins, it randomly fuses whole

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series of V, D, and
J segments together,

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and all kinds of combinations.
The same happens in both the heavy

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chain and the light chain,
although the light chain is slightly

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simpler. But that's
irrelevant for us

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conceptually. And then, we
end up having hundreds of

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millions of distinct V cells,
each of which has a different

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combination of heavy and light
chains because keep in mind the

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light chain genes are also
being rearranged combinatorially.

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They're also being fused. And
therefore, we can have 180,

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00 distinct heavy chains, and I
forget the exact number for the

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number of light
chains. It's a bit less,

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but we can multiply those two
combinations by one another because

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keep in mind that the gene encoding
the heavy chain here in its variable

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region, and the gene encoding the
light chain in its variable region

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are organized on
separate chromosomes. And,

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they're fused together. These
segments are fused together

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randomly. So, the
total number of antibody

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molecules we can make is 180,
00 distinct kinds of these.

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And, I've just slipped up in knowing
the total number of these that can

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be made, although we could figure
it out shortly if it were really

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important. But once again, the
number is in the many thousands.

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And therefore, overall, the
total number of distinct antibody

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molecules one can make on
the basis of this is this.

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Did I get the math right,
60 by 30, 18,000. It's 18,

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00. So, there's 18,000 distinct
of these that can be made,

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and the number of these, I
think, is closer to 10,000.

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I forget, but multiplied, let's
call it 10,000 for a moment.

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That's not the right number.
There's 10,000 different ones of

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these, and 18, 00 of
these that can be made.

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Multiply them together, and you get
the total number of combinations of

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antibody molecules it could make
because it is the case that the

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antigen recognition site
here is created cooperatively,

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collaboratively, by the heavy and
light chain. You had a question?

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So, the gene is rearranged, and
when the rearrangement occurs,

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on V segment is fused to one D
segment, is fused to one J segment.

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And all of the extraneous segments
that are between them have been

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deleted from the chromosome. So,
this leads me to a second point

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I wanted to make, and that
is that here we are dealing

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with a process of
somatic mutation.

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We talked about last time or the
time before last the fact that

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somatic mutation is generally a
process that can lead to cancer,

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i.e. the mutation of germ line
genes that are in one way or another

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corrupted by random
mutational processes. But here,

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I'm talking about a
somatic mutational process,

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which is highly directed and highly
organized, and focused on creating a

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series of rearranged genes that can
then serve as the template for the

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production of an antibody molecule.
So here, let's just look at this

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again. Here, I'll tell you,
there are many V genes. There are

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many D genes, and there are many
J genes. And, this is the embryonic

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DNA. After large segments of the
immunoglobulin locus are deleted,

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and then the surviving V, D, and
J segments become fused in the DNA

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directly to one another.
And when that happens,

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the resulting B cell DNA can be
transcribed, and via splicing create

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an mRNA where the region in between
the J's chain and the constant

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region chain called, here
C, is further deleted.

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So, each messenger RNA has one V,
one D, and one J segment together

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with a constant region segment.
There are yet other processes that

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further diversify how many different
variable regions can be encoded.

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One of them is the following.
It turns out that the process by

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which the V and D, and
the D and J genes are fused

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together, those segments are
fused together, is a bit sloppy.

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And therefore, sometimes the fusion
will occur creating a sequence of

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00:15:46,000 --> 00:15:50,000
nucleotides that has a nonsense
codon in. Sometimes it will create

224
00:15:50,000 --> 00:15:54,000
a coherent reading frame that
creates yet another kind of amino

225
00:15:54,000 --> 00:15:58,000
acid sequence there. And
therefore, this is not a highly

226
00:15:58,000 --> 00:16:02,000
ordered process in the sense that
these micro-architecture of the

227
00:16:02,000 --> 00:16:06,000
points with the V and the D, and
the D and the J are fused is a

228
00:16:06,000 --> 00:16:10,000
little bit chaotic. So
that creates even further

229
00:16:10,000 --> 00:16:16,000
randomization of the
nucleotide sequence. And then,

230
00:16:16,000 --> 00:16:21,000
finally, once this gene has been
created, there is a process which is

231
00:16:21,000 --> 00:16:27,000
called hypermutation, where
through mechanisms which are

232
00:16:27,000 --> 00:16:32,000
not well understood, the
nucleotide sequence of this

233
00:16:32,000 --> 00:16:38,000
region is actually
further changed.

234
00:16:38,000 --> 00:16:44,000
It's mutated by certain enzymes.
For example, there's an enzyme

235
00:16:44,000 --> 00:16:50,000
called cytidine deaminase, which
takes off the amine group off

236
00:16:50,000 --> 00:16:56,000
of the cytidines in that region,
and thereby effectively converts the

237
00:16:56,000 --> 00:17:02,000
C's in that coding region more
into having a T coding capacity.

238
00:17:02,000 --> 00:17:06,000
This happens somatically, and
here once again I'm talking

239
00:17:06,000 --> 00:17:10,000
about a further dimension
of diversification.

240
00:17:10,000 --> 00:17:14,000
One of the dimensions diversification,

241
00:17:14,000 --> 00:17:18,000
first of all, the V and the J
chains rearrange independently,

242
00:17:18,000 --> 00:17:22,000
randomly, and stochastically.
Secondly, the joining of the

243
00:17:22,000 --> 00:17:26,000
segments is a bit sloppy.
And thirdly, there is somatic

244
00:17:26,000 --> 00:17:30,000
hypermutation. There's
an enzyme like this which

245
00:17:30,000 --> 00:17:34,000
is actually an actively mutagenic
enzyme which fiddles around with

246
00:17:34,000 --> 00:17:38,000
some of the C's in this portion
of the gene, thereby further

247
00:17:38,000 --> 00:17:42,000
diversifying the coding ability
of the immunoglobulin gene that's

248
00:17:42,000 --> 00:17:46,000
encoded by the cell. And what
this means is the following,

249
00:17:46,000 --> 00:17:51,000
that if we imagine this scheme
here where each of these B cells

250
00:17:51,000 --> 00:17:56,000
recognize it's a different antigen,
initially there may be 100 million

251
00:17:56,000 --> 00:18:01,000
distinct B cell clones that are
created, each the consequence of a

252
00:18:01,000 --> 00:18:06,000
different random mutation.
That happens early in the

253
00:18:06,000 --> 00:18:10,000
development of the immune system.
Thereafter, there are certain

254
00:18:10,000 --> 00:18:14,000
selective processes there at play.
One important selective process is

255
00:18:14,000 --> 00:18:18,000
the elimination of B cells that
have failed to make nicely rearranged

256
00:18:18,000 --> 00:18:23,000
antibody molecules.
What do I mean by that?

257
00:18:23,000 --> 00:18:27,000
I told you how sloppy the V,
D, J joining is. And therefore,

258
00:18:27,000 --> 00:18:31,000
many of these joinings could create
reading frames that are incoherent

259
00:18:31,000 --> 00:18:35,000
with stop codons in the
middle. And therefore,

260
00:18:35,000 --> 00:18:39,000
those cells which happen to have
created antibody molecules which are

261
00:18:39,000 --> 00:18:43,000
highly mutant and clearly
structurally defective are

262
00:18:43,000 --> 00:18:46,000
eliminated. So, one
prerequisite for the survival of

263
00:18:46,000 --> 00:18:50,000
these B cells early in the
development of the immune system is

264
00:18:50,000 --> 00:18:54,000
that they've learned how to make
functional heavy and light chains.

265
00:18:54,000 --> 00:18:58,000
If they don't, they're right away
wiped out. They're eliminated.

266
00:18:58,000 --> 00:19:02,000
Here's another very important
prerequisite for survival,

267
00:19:02,000 --> 00:19:06,000
that these B cells don't make
antibodies that react with antigens

268
00:19:06,000 --> 00:19:11,000
that are native to the body's own
tissues. What do I mean by that?

269
00:19:11,000 --> 00:19:15,000
Well, one of the wonders of the
immune system is the following,

270
00:19:15,000 --> 00:19:20,000
that it can recognize foreign
antigens that are brought into the

271
00:19:20,000 --> 00:19:24,000
body from the outside including,
for example, the epitopes on the

272
00:19:24,000 --> 00:19:29,000
surface of polio virus particle.
It can recognize many different

273
00:19:29,000 --> 00:19:33,000
viruses, surface antigens present
on the surface of bacteria,

274
00:19:33,000 --> 00:19:38,000
and fungi, and all kinds
of other infectious agents.

275
00:19:38,000 --> 00:19:43,000
But importantly, the immune
system also sees hundreds

276
00:19:43,000 --> 00:19:48,000
of millions of different epitopes
of the proteins that are present

277
00:19:48,000 --> 00:19:53,000
endogenously, native proteins
in our tissues. A priori,

278
00:19:53,000 --> 00:19:58,000
the native proteins, what's
called our own self-proteins,

279
00:19:58,000 --> 00:20:03,000
are perfectly qualified
to function as antigens.

280
00:20:03,000 --> 00:20:07,000
And yet, the immune system rarely
develops strong reactivity against

281
00:20:07,000 --> 00:20:12,000
them. Thus, the immune system has
the ability to recognize self versus

282
00:20:12,000 --> 00:20:16,000
non-self. What do I mean
by self versus non-self?

283
00:20:16,000 --> 00:20:21,000
Self are the body's own native
proteins, which are in principal

284
00:20:21,000 --> 00:20:25,000
conceivably antigenic. Non-cell
are foreign invaders that

285
00:20:25,000 --> 00:20:30,000
bring strange
epitopes into the cell.

286
00:20:30,000 --> 00:20:35,000
And what happens is that B
cells, which make antibodies, that

287
00:20:35,000 --> 00:20:41,000
recognize native proteins in our
tissues are, if things are working

288
00:20:41,000 --> 00:20:46,000
well, rapidly eliminated early in
the development of the immune system.

289
00:20:46,000 --> 00:20:52,000
What happens if that elimination
fails to occur properly?

290
00:20:52,000 --> 00:20:58,000
If it fails to occur, one has
the process of autoimmune disease.

291
00:20:58,000 --> 00:21:04,000
And, there are multiple
autoimmune diseases.

292
00:21:04,000 --> 00:21:08,000
Type one diabetes, early
onset diabetes happens when

293
00:21:08,000 --> 00:21:12,000
the immune system recognizes
antigens that are present in the

294
00:21:12,000 --> 00:21:16,000
islet cells in the pancreas that
make insulin. Rheumatoid arthritis,

295
00:21:16,000 --> 00:21:20,000
which inflicts a large portion of
the elderly, happens when the immune

296
00:21:20,000 --> 00:21:24,000
system recognizes antigens that are
present normally in the cartilage in

297
00:21:24,000 --> 00:21:28,000
our joints. Lupus happens when,
it's an autoimmune called lupus

298
00:21:28,000 --> 00:21:32,000
which is often fatal,
happens when the immune system

299
00:21:32,000 --> 00:21:37,000
recognizes proteins in
many different tissues.

300
00:21:37,000 --> 00:21:41,000
And once again, in
all of these cases,

301
00:21:41,000 --> 00:21:45,000
there is a breakdown of the
mechanisms governing immune

302
00:21:45,000 --> 00:21:49,000
tolerance. And what do I mean by
tolerance? I mean the mechanisms

303
00:21:49,000 --> 00:21:53,000
whereby the immune system
tolerates native antigens,

304
00:21:53,000 --> 00:21:57,000
but is conversely intolerant
of foreign antigens.

305
00:21:57,000 --> 00:22:01,000
The word intolerant is not used in
immunology, but I'm just using it

306
00:22:01,000 --> 00:22:06,000
for the sake of explanation here.
So, immune tolerance is a very

307
00:22:06,000 --> 00:22:10,000
important area of current
immunological research.

308
00:22:10,000 --> 00:22:14,000
We don't really understand why
we don't have much more autoimmune

309
00:22:14,000 --> 00:22:18,000
disease than we do. And by
the way, only listed two or

310
00:22:18,000 --> 00:22:22,000
three of the most common kinds of
autoimmune diseases that happen with

311
00:22:22,000 --> 00:22:26,000
the mechanisms that normally
guarantee immune tolerance failed.

312
00:22:26,000 --> 00:22:30,000
And therefore, these B cells
survive are ones that make

313
00:22:30,000 --> 00:22:34,000
functional antibodies and those
whose antibodies do not recognize

314
00:22:34,000 --> 00:22:38,000
self-antigens. They are
permitted to survive,

315
00:22:38,000 --> 00:22:43,000
and once again, we imagine
that those that happened to make

316
00:22:43,000 --> 00:22:47,000
antibodies that recognize particular
foreign antigens undergo or enjoy

317
00:22:47,000 --> 00:22:52,000
clonal expansion. During
the development of the

318
00:22:52,000 --> 00:22:57,000
immune response, there is
a further diversification

319
00:22:57,000 --> 00:23:02,000
of the antigen-recognizing domain
of the protein by hypermutation.

320
00:23:02,000 --> 00:23:06,000
And therefore, descendants
of these initially

321
00:23:06,000 --> 00:23:11,000
developed cells, which
have begun to expand because

322
00:23:11,000 --> 00:23:16,000
they make an antibody, may
develop antibody molecules that

323
00:23:16,000 --> 00:23:21,000
are even more able to bind avidly
to the antigen. It could be that

324
00:23:21,000 --> 00:23:25,000
initially, these antibody-producing
cells make antibody molecules that

325
00:23:25,000 --> 00:23:30,000
bind nicely to the antigen but
not really avidly. Avidly means

326
00:23:30,000 --> 00:23:35,000
really tightly. And,
that's enough to get their

327
00:23:35,000 --> 00:23:39,000
clonal expansion going, but
during the process of clonal

328
00:23:39,000 --> 00:23:44,000
expansion, this hypermutation
creates further variants of these

329
00:23:44,000 --> 00:23:48,000
cells, further mutates their
antibody producing genes so that

330
00:23:48,000 --> 00:23:53,000
some of the descendants of
these cells will produce antibody

331
00:23:53,000 --> 00:23:57,000
molecules that bind even more
tightly and specifically to the

332
00:23:57,000 --> 00:24:01,000
provoking antigen.
And when that happens,

333
00:24:01,000 --> 00:24:05,000
the quality of the antibodies
is improved progressively.

334
00:24:05,000 --> 00:24:09,000
Now clearly, the somatic
hypermutation once again,

335
00:24:09,000 --> 00:24:13,000
it's a random hypermutation. And
those clones of cells in which

336
00:24:13,000 --> 00:24:16,000
the hypermutation created less
effective antibodies will not have

337
00:24:16,000 --> 00:24:20,000
their proliferation stimulated.
Those clones of cells whose

338
00:24:20,000 --> 00:24:24,000
antibodies make more and more
tightly binding antibodies will

339
00:24:24,000 --> 00:24:28,000
preferentially have their
proliferation stimulated.

340
00:24:28,000 --> 00:24:32,000
And as a consequence, they
will now be the ones that are

341
00:24:32,000 --> 00:24:37,000
favored to yield the plasma cells
that produce large amounts of

342
00:24:37,000 --> 00:24:42,000
antibody molecules. So, we
have now this very unusual

343
00:24:42,000 --> 00:24:47,000
and very interesting way by which
B cells and plasma cells are able to

344
00:24:47,000 --> 00:24:52,000
create a wide diversity
of antibody molecules. Now,

345
00:24:52,000 --> 00:24:56,000
one of the interesting things,
actually, is the fact that this

346
00:24:56,000 --> 00:25:01,000
constant region contains
one of a variety of distinct

347
00:25:01,000 --> 00:25:06,000
constant regions. Initially,
when one produces the

348
00:25:06,000 --> 00:25:10,000
first immune response, the
first immune response as we said

349
00:25:10,000 --> 00:25:15,000
before produces a constant
region which is called CM,

350
00:25:15,000 --> 00:25:20,000
and I had the right overhead
this morning. Ah, here it is.

351
00:25:20,000 --> 00:25:24,000
Here's the way the genes
are actually rearranged.

352
00:25:24,000 --> 00:25:29,000
Here's the rearranged V, D,
and J, and here's the splice to

353
00:25:29,000 --> 00:25:34,000
the constant region. And
downstream are a whole series of

354
00:25:34,000 --> 00:25:40,000
constant region segments.
What's the first one: CM.

355
00:25:40,000 --> 00:25:45,000
I told you about that before.
Thereafter, C sub delta, C sub

356
00:25:45,000 --> 00:25:51,000
gamma-3, gamma-1, gamma-2,
gamma-8, and so forth.

357
00:25:51,000 --> 00:25:57,000
And therefore, the initial
event can create an ig-mu, an IgM

358
00:25:57,000 --> 00:26:02,000
antibody molecule. The
mu region creates an IgM.

359
00:26:02,000 --> 00:26:07,000
Later, as the immune
response develops further,

360
00:26:07,000 --> 00:26:13,000
this mu segment may become deleted.
And now, the splice may occur to a

361
00:26:13,000 --> 00:26:18,000
delta or a gamma change. And
therefore, if the intervening

362
00:26:18,000 --> 00:26:23,000
constant region is changed, you
might get what's called an IgG.

363
00:26:23,000 --> 00:26:28,000
An IgG is an immunoglobulin
which is produced when this

364
00:26:28,000 --> 00:26:34,000
antigen-recognizing region becomes
spliced down to here or here by

365
00:26:34,000 --> 00:26:39,000
virtue of the deletion of
these intervening constant

366
00:26:39,000 --> 00:26:44,000
region segments. What's
the purpose of what's called

367
00:26:44,000 --> 00:26:48,000
class switching? Because
these are different classes

368
00:26:48,000 --> 00:26:52,000
of antibodies, because
they have different

369
00:26:52,000 --> 00:26:56,000
functions. Note importantly that
when this class switching occurs,

370
00:26:56,000 --> 00:27:00,000
it has no effect on the
antigen-recognizing site of the

371
00:27:00,000 --> 00:27:04,000
antibody molecule. Rather,
it affects the constant

372
00:27:04,000 --> 00:27:08,000
region of the antibody molecule.
Well, how does that work? The

373
00:27:08,000 --> 00:27:13,000
initially made antibody molecule,
I told you, is IgM. And in fact, if

374
00:27:13,000 --> 00:27:18,000
you look at the structure of IgM,
it looks like this. Here's, let's

375
00:27:18,000 --> 00:27:22,000
say, a B cell, and the IgM
molecule is actually not

376
00:27:22,000 --> 00:27:27,000
secreted into the extra
cellular space like a soluble

377
00:27:27,000 --> 00:27:33,000
antibody molecule. Here's
what IgM looks like from very

378
00:27:33,000 --> 00:27:39,000
schematically IgM has our
standard antigen-recognizing site,

379
00:27:39,000 --> 00:27:45,000
but IgM is embedded in the plasma
membrane of the B cell exactly the

380
00:27:45,000 --> 00:27:51,000
way that a growth factor receptor is
embedded in the plasma membrane of a

381
00:27:51,000 --> 00:27:57,000
B cell. But keep in mind that I
just said that this IgM molecule has

382
00:27:57,000 --> 00:28:03,000
an antigen-recognizing domain up
here, which is exactly the way we

383
00:28:03,000 --> 00:28:10,000
described it before. So, the
antigen recognition is not

384
00:28:10,000 --> 00:28:16,000
affected by whether we
have an IgM molecule here.

385
00:28:16,000 --> 00:28:22,000
Only the location of the antibody
molecule, and as I'll show shortly,

386
00:28:22,000 --> 00:28:28,000
the function of this antibody
molecule is affected by this IgM.

387
00:28:28,000 --> 00:28:34,000
Later on, descendants of this B
cell will mature into those that

388
00:28:34,000 --> 00:28:40,000
secrete IgG molecules
into the plasma.

389
00:28:40,000 --> 00:28:44,000
So, here's a maturation
that's going on. But look here.

390
00:28:44,000 --> 00:28:48,000
Once again, the antigen-recognizing
domains of this IgG are unaffected

391
00:28:48,000 --> 00:28:53,000
by this conversion. Here,
the constant region is

392
00:28:53,000 --> 00:28:57,000
tethering the antibody
molecule to the plasma membrane.

393
00:28:57,000 --> 00:29:02,000
Here's the
antigen-recognizing sites.

394
00:29:02,000 --> 00:29:06,000
After this maturation occurs, the
secreted IgG molecules, which go

395
00:29:06,000 --> 00:29:10,000
into the solution, have
identical antigen-recognizing

396
00:29:10,000 --> 00:29:14,000
sites, but now they're
soluble proteins. Well,

397
00:29:14,000 --> 00:29:19,000
you'll say, why does the
immune system do that?

398
00:29:19,000 --> 00:29:23,000
And, it goes back to an overhead I
showed you just moments ago in which

399
00:29:23,000 --> 00:29:27,000
there was a puzzle implicitly
created by the image on the overhead.

400
00:29:27,000 --> 00:29:32,000
And here it is. Let's
look at this for a moment.

401
00:29:32,000 --> 00:29:37,000
What detail is now explained in
this scheme? What detail is now

402
00:29:37,000 --> 00:29:43,000
explained? I told you that B
cells can be stimulated by certain

403
00:29:43,000 --> 00:29:48,000
antigens. Let's imagine that each
of these B cells made only secreted

404
00:29:48,000 --> 00:29:53,000
antibody, OK, instead of making cell
surface antibody because the cell

405
00:29:53,000 --> 00:29:59,000
surface antibody, which is
being made in this scheme,

406
00:29:59,000 --> 00:30:04,000
is actually the IgM molecules.
Let's say this B cell over here is

407
00:30:04,000 --> 00:30:08,000
making an antigen.
I'll just draw it as,

408
00:30:08,000 --> 00:30:12,000
there's the antigen, is making
an antibody against this antigen,

409
00:30:12,000 --> 00:30:16,000
and it's secreting antibody against
this. And I'd just argue that the B

410
00:30:16,000 --> 00:30:21,000
cell that makes good antibody is
favored. It has its proliferation

411
00:30:21,000 --> 00:30:25,000
stimulated, right? That's
what we talked about.

412
00:30:25,000 --> 00:30:29,000
But if this B cell sends all
of its antibody into the plasma,

413
00:30:29,000 --> 00:30:34,000
how is it going to know that
it's making a good antibody?

414
00:30:34,000 --> 00:30:38,000
It can't because all of the antigen
recognition is happening by the

415
00:30:38,000 --> 00:30:43,000
secreted antibody. So,
what happens with the IgM

416
00:30:43,000 --> 00:30:48,000
molecules. The first antibody
molecule this produced is IgM.

417
00:30:48,000 --> 00:30:52,000
And, it stays tethered to the
plasma membrane of the B cell.

418
00:30:52,000 --> 00:30:57,000
It's a transmembrane protein,
and it functions much like a

419
00:30:57,000 --> 00:31:01,000
growth factor receptor.
That is to say,

420
00:31:01,000 --> 00:31:05,000
when the antigen binds out here,
there are signals that are radiated

421
00:31:05,000 --> 00:31:09,000
into the cell that induce the
proliferation of this cell.

422
00:31:09,000 --> 00:31:13,000
And now, these cells that produce
the antigen-recognizing IgM

423
00:31:13,000 --> 00:31:16,000
molecules on their surface can now
have their proliferation stimulated.

424
00:31:16,000 --> 00:31:20,000
That solves the puzzle here
which is created by this scheme.

425
00:31:20,000 --> 00:31:24,000
If all these B cells just made
secreted antibody like this,

426
00:31:24,000 --> 00:31:28,000
then there would be no way to
encourage their proliferation

427
00:31:28,000 --> 00:31:32,000
because there would be no way
of telling this B cell you're

428
00:31:32,000 --> 00:31:36,000
doing a good thing. Keep
making more of these antibody

429
00:31:36,000 --> 00:31:40,000
molecules. Here, the
antigen-recognizing capability

430
00:31:40,000 --> 00:31:44,000
is embedded in the plasma membrane.
And when an antigen binds this, the

431
00:31:44,000 --> 00:31:49,000
IgM molecule's organized so that now
growth stimulatory signals are sent

432
00:31:49,000 --> 00:31:53,000
into the cell which cause this
cell to begin to proliferate,

433
00:31:53,000 --> 00:31:57,000
producing more IgM containing
cells which are further stimulated

434
00:31:57,000 --> 00:32:01,000
to proliferate. And
ultimately after this has gone

435
00:32:01,000 --> 00:32:05,000
on for a while, there is
a class switching which

436
00:32:05,000 --> 00:32:09,000
deletes the IgM region of the
gene chain region, and causes a

437
00:32:09,000 --> 00:32:13,000
conversion to IgG. Again,
the conversion from here to

438
00:32:13,000 --> 00:32:17,000
here doesn't change the
antigen-recognizing capability of

439
00:32:17,000 --> 00:32:21,000
these two antibodies. It
just makes a cell surface

440
00:32:21,000 --> 00:32:25,000
transmembrane protein or
a secreted protein. (pause)

441
00:32:25,000 --> 00:32:37,000
No, the VDJ choice
happens in the

442
00:32:37,000 --> 00:32:41,000
nucleus. It's a fusion of different
DNA segments, and when it's

443
00:32:41,000 --> 00:32:46,000
transcribed, that fused VDJ is now
spliced to a constant region segment.

444
00:32:46,000 --> 00:32:50,000
The choice of VDJ is a fusion
of DNA segments. It happens in

445
00:32:50,000 --> 00:32:55,000
chromosomal DNA. It results
in the deletion of all

446
00:32:55,000 --> 00:32:59,000
the segments that aren't used.
So, all that's left in the

447
00:32:59,000 --> 00:33:04,000
immunoglobulin locus of a B cell is
a DNA segment encoding V fused to a

448
00:33:04,000 --> 00:33:09,000
DNA segment encoding D, fused
to a DNA segment encoding J.

449
00:33:09,000 --> 00:33:13,000
So now, you have a new somatically
mutated immunoglobulin gene,

450
00:33:13,000 --> 00:33:18,000
lest there be any residual
confusion about that. So,

451
00:33:18,000 --> 00:33:22,000
you see the elegance of
this class-switching thing.

452
00:33:22,000 --> 00:33:27,000
Now there's yet other constant
region segments that are used for

453
00:33:27,000 --> 00:33:31,000
other purposes. For
example, when you have

454
00:33:31,000 --> 00:33:36,000
allergies, there's an
activation of the igE antibodies.

455
00:33:36,000 --> 00:33:41,000
When you have secreted antibody
production in the colon,

456
00:33:41,000 --> 00:33:46,000
igA is used more for that.
So, different ones of these

457
00:33:46,000 --> 00:33:51,000
constant regions are used for
different immunological applications.

458
00:33:51,000 --> 00:33:57,000
The IgM molecule, as I've
said, is used here just as a

459
00:33:57,000 --> 00:34:02,000
way of telling the B cell that it's
done well by making the right kind

460
00:34:02,000 --> 00:34:07,000
of antigen-recognizing site.
The real business of creating

461
00:34:07,000 --> 00:34:11,000
antibodies is the soluble antibody
production, the immunoglobulins,

462
00:34:11,000 --> 00:34:15,000
or the gammaglobulins because the
vast majority of antibodies floating

463
00:34:15,000 --> 00:34:20,000
around the blood plasma are
in fact IgGs. The IgMs are,

464
00:34:20,000 --> 00:34:24,000
as implied by this, actually just
largely tethered to the surface of

465
00:34:24,000 --> 00:34:29,000
cells. So, this really
is an extraordinary,

466
00:34:29,000 --> 00:34:33,000
elegant way of creating essentially
hundreds of millions of different

467
00:34:33,000 --> 00:34:37,000
antigen-recognizing domains each
created collaboratively between a

468
00:34:37,000 --> 00:34:42,000
heavy and a light chain. And
once these antigen-recognizing

469
00:34:42,000 --> 00:34:46,000
domains are created through
changes in DNA structure,

470
00:34:46,000 --> 00:34:50,000
then they can be used for different
immunological applications,

471
00:34:50,000 --> 00:34:55,000
driving B cell proliferation,
secreting soluble antibodies that

472
00:34:55,000 --> 00:34:59,000
are used to neutralize
virus particles in the blood,

473
00:34:59,000 --> 00:35:03,000
or if they're hyperactive to create
allergic reactions or to create

474
00:35:03,000 --> 00:35:08,000
immunity in certain regions
of the gut and so forth.

475
00:35:08,000 --> 00:35:12,000
So, this class switching doesn't
change the antigen-recognizing

476
00:35:12,000 --> 00:35:17,000
capability. It just changes the
utilization of how already-developed

477
00:35:17,000 --> 00:35:21,000
VDJ segments and their
antigen-recognizing capability are

478
00:35:21,000 --> 00:35:26,000
exploited by cells
of the immune system.

479
00:35:26,000 --> 00:35:30,000
Now, one thing that's not really
clear by all this is how all this

480
00:35:30,000 --> 00:35:35,000
develops at the cellular level
because what I've talked about until

481
00:35:35,000 --> 00:35:40,000
now is called humeral immunity.
Well, we talk about somebody having

482
00:35:40,000 --> 00:35:44,000
a good sense of humor. But
the actual original meaning of

483
00:35:44,000 --> 00:35:49,000
the word humor in Latin was fluids
that were fluxing through your body,

484
00:35:49,000 --> 00:35:54,000
and were responsible for
your different mood states.

485
00:35:54,000 --> 00:35:58,000
So, if you were depressed or
there just was a national election,

486
00:35:58,000 --> 00:36:03,000
there would be black fluids,
black humors coursing through

487
00:36:03,000 --> 00:36:08,000
your blood. And if you
were in a good mood,

488
00:36:08,000 --> 00:36:13,000
there were other humors
coursing through your blood.

489
00:36:13,000 --> 00:36:19,000
And that leads through this
etymology to the term of humeral

490
00:36:19,000 --> 00:36:24,000
immunity, which is to
say the soluble immunity,

491
00:36:24,000 --> 00:36:29,000
i.e. the production of
soluble antibody molecules.

492
00:36:29,000 --> 00:36:34,000
But I will tell you that there's
a second arm of the immune system

493
00:36:34,000 --> 00:36:40,000
which is equally important, and
that's called cellular immunity.

494
00:36:40,000 --> 00:36:44,000
And, to make a long story short,
and we'll elaborate it on Monday

495
00:36:44,000 --> 00:36:48,000
briefly. Cellular immunity is
largely created when you have a kind

496
00:36:48,000 --> 00:36:52,000
of immune cell that's called a cell
rather than the B cells we've been

497
00:36:52,000 --> 00:36:56,000
talking about until now, which
is able, and this cellular

498
00:36:56,000 --> 00:37:01,000
immunity is among
other things, cytotoxic.

499
00:37:01,000 --> 00:37:07,000
And, it can recognize a second cell
over here. Here's a second cell.

500
00:37:07,000 --> 00:37:13,000
This is its target cell because the
second target cell is displaying on

501
00:37:13,000 --> 00:37:20,000
its surface certain antigens. So,
antigens are being displayed on

502
00:37:20,000 --> 00:37:26,000
the surface of the target cell.
I've indicated them here as just

503
00:37:26,000 --> 00:37:32,000
little, blue strokes. And the
T cell is able to recognize

504
00:37:32,000 --> 00:37:36,000
these antigens on the
surface of this cell here,

505
00:37:36,000 --> 00:37:41,000
and is able to kill this cell
through a series of interesting

506
00:37:41,000 --> 00:37:45,000
mechanisms. This doesn't involve
the intervention of soluble antibody

507
00:37:45,000 --> 00:37:50,000
molecules. Here, we're
talking about one cell

508
00:37:50,000 --> 00:37:55,000
recognizing another, and
it turns out to be very

509
00:37:55,000 --> 00:37:59,000
important for antiviral defenses.
I've told you one way by which

510
00:37:59,000 --> 00:38:03,000
antiviral defenses are achieved.
Soluble antibody molecules are

511
00:38:03,000 --> 00:38:07,000
secreted into the blood plasma like
IgGs. They recognize an epitope on

512
00:38:07,000 --> 00:38:11,000
the surface of a virus particle.
They glom onto that epitope on the

513
00:38:11,000 --> 00:38:15,000
surface of the virus particle,
and they neutralize the virus

514
00:38:15,000 --> 00:38:19,000
particle. And,
that's very important.

515
00:38:19,000 --> 00:38:23,000
We started out in our discussion
of poliovirus talking about that.

516
00:38:23,000 --> 00:38:27,000
But this also turns out to be very
important. Why is it important?

517
00:38:27,000 --> 00:38:31,000
For the following reason: when
this cell, let's say this cell is

518
00:38:31,000 --> 00:38:35,000
infected by poliovirus
on the inside.

519
00:38:35,000 --> 00:38:39,000
It turns out, interestingly enough,
that the cell has a way which we'll

520
00:38:39,000 --> 00:38:44,000
discuss of processing poliovirus
polypeptides, viral polypeptides,

521
00:38:44,000 --> 00:38:48,000
and displaying them on the
cell surface. In other words,

522
00:38:48,000 --> 00:38:53,000
the cell can chew up some poliovirus
proteins, put them to the outside,

523
00:38:53,000 --> 00:38:57,000
and tell the outside world, these
are the kinds of the proteins that

524
00:38:57,000 --> 00:39:02,000
are being made right
now inside of me.

525
00:39:02,000 --> 00:39:06,000
You the immune system can't really
look through the plasma membrane so

526
00:39:06,000 --> 00:39:10,000
I'm going to tell you this is
what's going on inside of me.

527
00:39:10,000 --> 00:39:14,000
There are poliovirus proteins
being made as we speak.

528
00:39:14,000 --> 00:39:18,000
On the outside of the cell,
these are displayed even though

529
00:39:18,000 --> 00:39:22,000
poliovirus replication is recurring
exclusively inside the cell.

530
00:39:22,000 --> 00:39:26,000
A cytotoxic T cell here may
recognize these antigens on the

531
00:39:26,000 --> 00:39:30,000
surface of the poliovirus infected
cell, and proceed to kill the cell.

532
00:39:30,000 --> 00:39:34,000
Why is that interesting or important?
Because the cytotoxic cell will

533
00:39:34,000 --> 00:39:39,000
kill the virus-infected cell while
the virus infection is still in full

534
00:39:39,000 --> 00:39:43,000
swing. And therefore, by
killing the virus-infected cell,

535
00:39:43,000 --> 00:39:48,000
it will abort the entire
bioreplication cycle because the

536
00:39:48,000 --> 00:39:53,000
virus won't have enough time to
replicate or proliferate inside the

537
00:39:53,000 --> 00:39:57,000
infected cell before it happens.
It's preemptively killed by the

538
00:39:57,000 --> 00:40:02,000
cytotoxic T cell. And in
fact, this way of eliminating

539
00:40:02,000 --> 00:40:08,000
viral infections from our body is
as important and often more important

540
00:40:08,000 --> 00:40:13,000
than the neutralization of soluble
virus particles in our plasma.

541
00:40:13,000 --> 00:40:18,000
And all that gets now to have us
focus increasingly on the mechanisms

542
00:40:18,000 --> 00:40:24,000
by which antigens are recognized and
processed so that the immune system

543
00:40:24,000 --> 00:40:29,000
can begin to respond to them.
So, I want to get into that now,

544
00:40:29,000 --> 00:40:35,000
into the aspects in which we
look at the cellular arms of

545
00:40:35,000 --> 00:40:41,000
the immune system. The most
important thing initially

546
00:40:41,000 --> 00:40:47,000
in the immune response is that
let's say poliovirus particle is

547
00:40:47,000 --> 00:40:54,000
recognized and digested by certain
phagocytic cells of the immune

548
00:40:54,000 --> 00:41:00,000
system. What's a phagocytic cell:
a cell that is able to gobble

549
00:41:00,000 --> 00:41:06,000
up other things. So, a
well-known phagocytic cell is

550
00:41:06,000 --> 00:41:10,000
a macrophage. And there you
can see the term phagocyte,

551
00:41:10,000 --> 00:41:14,000
macrophage. Phagos means
to chew up or to swallow,

552
00:41:14,000 --> 00:41:19,000
so macrophage might see a particle
like this surround that particle,

553
00:41:19,000 --> 00:41:23,000
and then internalize that
particle and digest it,

554
00:41:23,000 --> 00:41:27,000
let's say a poliovirus particle.
Macrophage could envelop a

555
00:41:27,000 --> 00:41:32,000
poliovirus particle
and internalize it.

556
00:41:32,000 --> 00:41:36,000
It could do the same thing
with a bacteria. Here,

557
00:41:36,000 --> 00:41:40,000
we'll use as an abbreviation
for macrophage this.

558
00:41:40,000 --> 00:41:44,000
So, that's macrophage.
There are yet other even more

559
00:41:44,000 --> 00:41:48,000
important phagocytic cells of
the immune system that are called

560
00:41:48,000 --> 00:41:52,000
dendritic cells. Now, these
cells gobble up whatever

561
00:41:52,000 --> 00:41:57,000
happens to be around
them. They don't care.

562
00:41:57,000 --> 00:42:02,000
They are promiscuous sewer,
gutter trollers. Whatever happens

563
00:42:02,000 --> 00:42:08,000
to be around, they will gobble
up whatever happens to be around.

564
00:42:08,000 --> 00:42:14,000
They'll put it inside of them,
and now they do something really

565
00:42:14,000 --> 00:42:19,000
interesting. The dendritic cells,
the macrophages, the phagocytic

566
00:42:19,000 --> 00:42:25,000
cells, they don't digest the
internalized particles down to amino

567
00:42:25,000 --> 00:42:31,000
acids. They digest the virus
particle down to oligopeptides.

568
00:42:31,000 --> 00:42:37,000
Usually if 10, 12, 14 amino
acids long: very important.

569
00:42:37,000 --> 00:42:43,000
So they don't make amino acids.
They make oligopeptides. Why are

570
00:42:43,000 --> 00:42:49,000
they doing this digestion?
Because these cells are

571
00:42:49,000 --> 00:42:55,000
exhibitionists and they want to show
the rest of the world what they've

572
00:42:55,000 --> 00:43:02,000
just swallowed up. It's
really important to them.

573
00:43:02,000 --> 00:43:07,000
Go figure. So,
what do they do?

574
00:43:07,000 --> 00:43:12,000
They take these oligopeptides that
they've just internalized and they

575
00:43:12,000 --> 00:43:17,000
put them on the cell surface via
molecules which are called MHC class

576
00:43:17,000 --> 00:43:23,000
2. MHC class 2 is the name of
these molecules, and these are cell

577
00:43:23,000 --> 00:43:29,000
surface receptors. And,
these MHT C class 2 molecules

578
00:43:29,000 --> 00:43:35,000
have included in them an
oligopeptide that has just been

579
00:43:35,000 --> 00:43:41,000
produced by the proteolytic cleavage
of an internalized infectious agent,

580
00:43:41,000 --> 00:43:47,000
let's say. And so, the macrophage
has many of these MHC class 2

581
00:43:47,000 --> 00:43:53,000
molecules on its surface, and
it displays to the outside world

582
00:43:53,000 --> 00:44:00,000
what it has just captured in
terms of these oligopeptides.

583
00:44:00,000 --> 00:44:05,000
And these oligopeptides are, by
the way, roughly the size of an

584
00:44:05,000 --> 00:44:10,000
epitope. Therefore, this
macrophage is just so excited.

585
00:44:10,000 --> 00:44:16,000
It's like a little kid who
has just found something,

586
00:44:16,000 --> 00:44:21,000
so excited to show the world what
it's just found and gobbled up and

587
00:44:21,000 --> 00:44:26,000
processed. And over here is a class
of cells which are called T helper

588
00:44:26,000 --> 00:44:32,000
cells. And the T helper
cells are interesting in their

589
00:44:32,000 --> 00:44:38,000
own right, right? The T
helper cells have evolved

590
00:44:38,000 --> 00:44:45,000
through a mechanism that is similar
to and parallel to the evolution of

591
00:44:45,000 --> 00:44:52,000
the B cells. As a consequence,
there are many different kinds of T

592
00:44:52,000 --> 00:44:59,000
helper cells. Each one, so
TH-1, TH-2, TH-3, each of which

593
00:44:59,000 --> 00:45:07,000
displays on its surface
a T cell receptor.

594
00:45:07,000 --> 00:45:12,000
What kind of T cell receptor does it
display? A T cell receptor that has

595
00:45:12,000 --> 00:45:18,000
gone through exactly the same kind
of hoops that the antibody genes

596
00:45:18,000 --> 00:45:24,000
have gone through. That
is, each T cell expresses on

597
00:45:24,000 --> 00:45:30,000
its surface an antigen-recognizing
receptor just like the IgM molecule

598
00:45:30,000 --> 00:45:36,000
except it's made by T cells and
it's created by these stochastic

599
00:45:36,000 --> 00:45:41,000
processes of fusing DNA segments.
So, each of these T cells,

600
00:45:41,000 --> 00:45:45,000
and again, there are millions
of them, has a different T cell

601
00:45:45,000 --> 00:45:49,000
receptor with a different
antigen-recognizing capability.

602
00:45:49,000 --> 00:45:54,000
And here's what happens
in the immune system.

603
00:45:54,000 --> 00:45:58,000
Let's imagine, as
I say every year,

604
00:45:58,000 --> 00:46:03,000
that we're in a Middle Eastern
bazaar, and that Middle Eastern

605
00:46:03,000 --> 00:46:07,000
bazaar, here are all the shops on
the sides on the sides of this long

606
00:46:07,000 --> 00:46:12,000
bazaar. It's sometimes
called a shuk or a suk.

607
00:46:12,000 --> 00:46:16,000
And here we're going to have a
macrophage or a dendritic cell

608
00:46:16,000 --> 00:46:20,000
moving through the bazaar.
Hanging out in front of the stores

609
00:46:20,000 --> 00:46:24,000
are a whole bunch
of T helper cells.

610
00:46:24,000 --> 00:46:36,000
Business
is slow,

611
00:46:36,000 --> 00:46:40,000
so all these T helper cells
are just hanging out in front,

612
00:46:40,000 --> 00:46:44,000
and as is not the custom in this
region, let's pretend all the T

613
00:46:44,000 --> 00:46:48,000
helper cells are girls just for
the heck of it. It doesn't make any

614
00:46:48,000 --> 00:46:52,000
difference. And each of these T
helper cells is displaying its own T

615
00:46:52,000 --> 00:46:56,000
cell receptor which has arisen
through stochastic mechanisms and

616
00:46:56,000 --> 00:47:00,000
which recognizes a
different oligopeptide.

617
00:47:00,000 --> 00:47:04,000
And here we have now the macrophage
coming through like a vendor,

618
00:47:04,000 --> 00:47:09,000
a street vendor, saying, look girls,
look at the epitope I just gobbled

619
00:47:09,000 --> 00:47:13,000
up and produced.
Isn't it great? And,

620
00:47:13,000 --> 00:47:18,000
it's using its MHC class 2 molecules
to present, it's like hands,

621
00:47:18,000 --> 00:47:22,000
presenting the epitopes. It's
flogging them like a street vendor,

622
00:47:22,000 --> 00:47:27,000
and it walks down through this
bazaar, and each of the T helper

623
00:47:27,000 --> 00:47:31,000
cells, they're congregating
along the sides of the road,

624
00:47:31,000 --> 00:47:36,000
and most of them say
look at this drip.

625
00:47:36,000 --> 00:47:40,000
Look at the garbage he's selling
us today. I am totally uninterested.

626
00:47:40,000 --> 00:47:44,000
He was here last week
with some other chump too.

627
00:47:44,000 --> 00:47:48,000
Let's hope he disappears quickly.
And meanwhile the macrophage or the

628
00:47:48,000 --> 00:47:52,000
dendritic cell is very anxiously
trying to find someone who has even

629
00:47:52,000 --> 00:47:56,000
the slightest bit of
affection or respect for him.

630
00:47:56,000 --> 00:48:00,000
And this goes on
for a long time.

631
00:48:00,000 --> 00:48:06,000
And finally, the macrophage
finds a T helper cell over here.

632
00:48:06,000 --> 00:48:13,000
So, here's the T helper cell, and
it turns out that by coincidence

633
00:48:13,000 --> 00:48:19,000
the T helper cell has on here
surface a T cell receptor that

634
00:48:19,000 --> 00:48:26,000
recognizes the epitope that
the macrophage is peddling.

635
00:48:26,000 --> 00:48:34,000
So, here's the macrophage.
Macrophage has on its surface this

636
00:48:34,000 --> 00:48:42,000
oligopeptide held by the MHC class
2 hands. So, here's the peptide.

637
00:48:42,000 --> 00:48:51,000
And this T cell receptor which
I'll abbreviate TCR recognizes,

638
00:48:51,000 --> 00:49:00,000
binds strongly to the epitope that's
being flogged by the macrophage.

639
00:49:00,000 --> 00:49:04,000
And this is, I will tell you
honestly, love at first sight.

640
00:49:04,000 --> 00:49:08,000
She says, oh, I can't believe it.
You're selling an epitope that I

641
00:49:08,000 --> 00:49:12,000
just happen to love.
This is very exciting.

642
00:49:12,000 --> 00:49:17,000
And all the other T helper
cells say, oh my God,

643
00:49:17,000 --> 00:49:21,000
what does she see in him? And
she gets all excited because

644
00:49:21,000 --> 00:49:25,000
there's a direct complementarity.
In fact, to tell the truth, the T

645
00:49:25,000 --> 00:49:29,000
cell receptor recognizes not only
the epitope but also the surrounding

646
00:49:29,000 --> 00:49:34,000
amino acids in the fingers
of the MHC class 2 molecule.

647
00:49:34,000 --> 00:49:38,000
It's this constellation of things
that's recognized by the T cell

648
00:49:38,000 --> 00:49:43,000
receptor and gets this T
cell receptor really excited.

649
00:49:43,000 --> 00:49:47,000
And what does she do? Well,
we can't talk about everything

650
00:49:47,000 --> 00:49:52,000
because this is polite company.
But most important for what she

651
00:49:52,000 --> 00:49:56,000
does is she begins to
proliferate like mad. Well,

652
00:49:56,000 --> 00:50:01,000
you know, cells have a limited
repertoire of behavioral routines.

653
00:50:01,000 --> 00:50:05,000
Next time we're going to figure out
how this leads to an immune response.

654
00:50:05,000 --> 00:50:10,000
So, we're going to be on
[intention? all weekend.