Biology 1A - Lecture 32: Reproduction




Uploaded by UCBerkeley on 14.11.2012

Transcript:
>>INSTRUCTOR: Okay. Let's go. It's really hard coming back today. It's felt
to me like last Friday we could have ended the semester and it's especially hard because
I wasÊ last week I was so excited about the immune system and I learned everything, and
then I'm so over that now, on the weekend I was trying to read up on the osmoregulation
and kidneys and, you know, this is so last week, but we're going to finish adaptive immunity,
and then on Friday, we'll talk about osmoregulation. So, we had discussed these main issues in
adaptive immunity verses innate immunity so you have this tremendous specificity, you
have self tolerance for distinguishingÊ it's this self verses nonself question really comes
up here and then you have this remarkable memory response that re exposure to disease
and antigen will provoke a much faster and stronger response.
We talked about the different kinds of players the lymphocytes, the T cells, B cells and
natural killer cells that arise from the bone marrow and then, interacting with antigen
presenting cells, some of which we recognize from the innate immune system.
So, then we talkedÊ discussed the molecular basis of diversity in terms of the somatic
gene rearrangements that occur for both B cells and T cells to makeÊ so that each clone
of T cell or B cell makes a specific kind, a specific flavor of its specificÊ of a specific
receptor. So, I say, a cloneÊ ah.
What do we mean when we talk about a cellular clone?
We're talking about one cell and all of the cells that descend from it, okay.
So, in the development of T cells and B cells, there's many different cells in the bone marrow
for each of these, and each one of these undergoes its specific set of gene rearrangements and
then those are essentially unchange as that cell proliferates or in some cases, is selective
against and dies, okay. So these are clones of cells.
All of the descendants from a single cell, there are two different kinds of receptors,
the B cells make antibodies, through gene rearrangements and the T cells make T cell
antigen receptors, not antibodies. But they're similar in that they both have
variable reasons, generated by gene rearrangements. One copy of the genes rearranges and makes
a functional receptor, the other copy of the gene then, on the other chromosomes is silenced.
So that each clone is only making a specific type of flavor of receptor.
Whether it's a T cell or a B cell. So, now, I think we're to the point where
we can talk about the molecular basis of self recognition.
How go you distinguish self from nonself in the adaptive immune system? And the key to
this is to know that all nucleated cells express, on they're surface, on the membrane surface,
a complex of proteins called a major histocompatibility complex, or MHC.
So, all nucleated cells in your body. So the only exception is, red blood cells.
Right. So, there are so manyÊ there are different
proteins in the complex, and many different allelic variance of each of those proteins,
so that each person in this room has his or her own unique MHC complex.
Okay. Unless, any identical twins?
That would be theÊ so you and your twin would probably have the same MHC complex proteins.
Okay. That you inherited from your parents.
Okay. So these are amazingÊ people initially started
to study these in terms of tissue rejection from graphing or implants, transplants and
then they realized from that their importance in the immune system, and now this molecular
basis of individuality is realized to extend much further, people have done things like
study the influence of MHC diversity ordinary mate preferences, okay.
And the way thisÊ one sort of experiment they do is take sweat pads and put them under
the underarms of some guys, okay. And then offer these as ode rants to women
and see how they respond. Positively, negatively to different odors.
And it was discovered, I'm told, I haven't really read this data carefully, I'm told
that people tend to have a preference for more diverse molecularly diverse MHC complex
proteins. That's for the odors associated with the individuals
with more divergent MHC complexes. So this could be a way of using ourÊ you know, subliminal
odor detection capabilities in avoiding inbreeding too much.
Okay. So, this is also an interesting example of
the inherent sexism, it seems toÊme, in that it pervades all of ourÊwork, right? It's
the automatic way they did this was to make male scents, offer it to females, I haven't
heard about it being done the opposite way, but it could be. And certainly, the interesting
to know for people who are not interested in those of the opposite sex whether they
would also have innate preferences based on MHC odors, but there's lots of probabilities
there. But we're mainly interested in they're functions in the immune system.
There's this MHC class 1 and class 2, slightly different complexes of MHC proteins. MHC 1
class is on all cells, except red blood cells. Class 2 MHC complexes are on the antigen presenting
cells. Okay. So, that's one wayÊ so, if you're going to
distinguish self verses nonself, self is MHC, your MHC molecules and we have to figure out
some way of recognizing that. The other key process in molecular self recognition
is that you have clonal selection in both the B cell and T cell development, youÊ after
you make all of these combinatorial gene rearrangements to make the antibodies receptors and the T
antigen receptors, there's clonal selection against certainÊ (No sound).
Lines of cells. Okay. And this happens in two different ways.
In the B cells, it's fairly straightforward, the developing B cells interact with antigen
presenting cells, that are presenting host proteins, okay.
And any B cells thatÊ whose receptors bind too strongly to the host proteins are either
killed or prevented from dividing further, okay.
So those don't play a role if you'reÊ if you're lucky. Okay.
So, negative selection on the B cells. In the T cells, it's a little more complicated.
The T cells have first a positive selection for cells that can recognize MHC class proteins.
Okay. And we'll see why that's important. Later.
And then there's a negative selection from among those that pass the first test, there's
a negative selection again, against those that bind too strongly, for if the T cells,
it's sort of like a Goldilocks thing you to be able to recognize MHC proteins, you can't
interact with them too strongly. Okay.
Questions? So, just an overview and we'll go through some examples for a little bit
more detail. What you see is an antigen is exposedÊ is
presented invading the host, and you have some sort of engulfment, and that gets the
proteins in the antigen get digested and put onto the surface of these antigen presenting
cells, and then they can be recognized by a form of T cell, based on they'reÊ the interaction
of the T cell with theÊ with the invader protein that's put on the surface, okay.
And then these T cells, well they don't do anything themselves, but they activate other
aspects of the immune system, they tendÊ they can stimulate B cells that would recognize
that same antigen. They can stimulate cytotoxic T cells and they
can generate memory cells. So this will become clearer as we go through it.
But for both the activated B cells and the activated T cells you have memory cells, that
hang around that are specific for that initial antigen, and so if that antigen comes again,
these memory cells are ready to respond much more quickly and strongly to the second presentation.
Okay. Around basically, the theme we're going to
develop is that the B cells work by secreting antibodies, primarily, and that theÊ so that'sÊ
against antigens that are out in the plasma free. But that once a invader virus, or bacteria
gets inside host cells and they're you're dependent on the cytotoxic T cell system to
defend against intracellular pathogens, okay. So, this is called: The humoral response and
the cellular response. All right then.
So the B cells, they make these multiple flavors of B cell receptors, antibody receptors, and
they based on chance or actions the combination ofÊvariable region gene sectors, may generate
an end on this receptor. Here by the little triangle that interacts really well with a
particular part ofÊsome molecule on the pathogen. Okay.
And that's called: The epitope. So that tight fit in indicated there and you
can seeÊthat it would not fit here, okay. So once if that lock and key gets activated,
then this B cell becomes stimulated to form two different kinds of cells, first it'll
generate these plasma cells, and the plasma cells are, you can see in this cartoon it's
got an very extensive endoplasmatic reticulum and golgi apparatus, these are protein secreting
machines, 2,000 antibody molecules per minute can be secreted into the plasma from these
cells, once they're activated. And so then they can interact with any other copies of
the antigen that are present in the system. So, they proliferation of that B cell clone,
once it's activated, the plasma cells make lots of secreted form of the antibody, and
then you have these memory cells, some of the other B cells so there's lots of proliferation of that activated
B cell clone to make plasma cells and memory cells.
Okay. Questions?
And they're all making essentially the same receptor.
So, the other thing, again to reinforce this idea of antigen receptor specificity, you've
got different antibodies from different B cell clones and you can see that these different
shapes would interact with different portions of the molecule, okay.
Of different antigens, okay. So now look at this for a second and can anybody see a mistake
that was made in this figure? By the artist.
Ha? I could do this at the clicker question, so
but I didn't. Yes?
>>STUDENT: [Indiscernible] >>INSTRUCTOR: Brilliant. Antibody A has two
different receptor, two different variable regions and that's not supposed to be the
case. Each receptor makes a singleÊ each antibody molecule has a single kind of receptor
on both ends. Okay. So this should beÊ if this is a trianglely
one and then this should also be trianglely. Cool.
I don't know if I want to share a kitchen with you, but I think you have the makings
of a good scientist. So, that's all rightÊ never mind.
Little too much self analysis there. And you know, I saw it too. Right. And nobody
wants to share a kitchen with me. So, anyway, clonal selection.
So you have these different molecules thatÊ different B cells expressed different form
antibody, and it's only the one that gets activated by antigen that gets stimulated
to proliferate and make memory cells and antibody secreting plasma cells, okay.
So this is clonal selection, okay. And these are the cells that have already survived the
initial negative selection against cells that are making host specific antibodies. Have
I got you confused on that now? All right.
So here's a picture of one of these plasma cells it's really pretty, huh?
Great big nucleus, huge endoplasmatic reticulum, it's just specialized for making the RNA from
those antibody genes and translated in the ER and then secreting it, okay, into the medium.
So we have seen that the B cells bind directly to intact antigens, either in solution or
on the surface of a cell. So they recognize things outside.
In contrast, now we're moving onto the T cells the T cells require that the antigen be processed
and presented as part of an MHC complex. This self identity molecular complex, okay.
So, what theÊ what happens is that the antigen is pathogen is somehow taken in, interacts
with the host cell, whichÊ if it's lucky and survives the interaction, degrades some
of thatÊ the pathogen proteins, and then these get chopped up into peptides and then
a associated randomly with MHC molecules then that are put onto the surface. And this all
has to happen on the inside. You can't have an MHC molecule on the surface that binds
a soluble peptide. Okay. It has to happen intracellularly. And then what happens is
the T cell antigen receptor interacts both with the MHC molecule, and the specificity
comes from the interaction between the T antigen receptor and the antigen that's presented.
So, the model that's used is sort of a hot dog in a bun. Rearranger.
The MHC molecule has this sort of cleft in its extracellular portion and you line a peptideÊ
I should have looked upÊ I don't know how long these are, they're not super long, so
I don't know that. How long have these peptides are on average
that get laid out here and presented to the outside world. So the MHC complex and the
antigen process together inside the cell and put onto the outside. Okay.
For recognition by T cells. Okay.
So, this slides sort ofÊ everybody knows this anyway.
The point is you have this response to the initial presentation of antigen, you generate
antibodies, and then because of the memory cells in both the B and the T systems, a secondary
response to the same antigen gives you this huge response and the specificity selectivity
is indicated by the fact that you can present a different antigen at the same time and that
still evokes just the initial smaller response, okay.
So, this secondary response is not a global activation of the immune system, but rather
memories for a very specific antigen that was seen before.
So, here we see an antigen presenting cell, this could be a dendritic cell, a macrophage
or a B cell, that presents this chunk of antigen pathogen associated protein on the surface
of an MHC class 2 molecule, okay. And thisÊ these helper T cells have the antigen
receptor that's looking for a specific epitope, based on the variability of the T antigen
receptor domain. It also has a conserved receptor, CDC molecules that allow it to interact with
the MHC class, and that's why we have to have this initial positive selection the T cells
cannot function unless they are able to recognize these MHC molecules on the surface, okay.
So, that's why there's a dual selection in the development of T cell lineages.
So, once thisÊ these two conditions have been met, and activated T cell canÊ it releases
chemical signals that stimulate B cells that would react with the same antigen, again it's
a completely different receptor, right? These areÊ the B cell antibody receptors
and the T antigen receptors are made in independent cell lines by independent sets of gene rearrangements,
but they can still interactÊ be interacting with the same pathogen, slightly different
parts. So, this might be activating it sees the T
cell, helper, T cell and so it gets stimulated and then to go through the B cell process.
And generate humoralÊimmunity. And these in parallel with that, the helper
cell can activate a different class of T cells called cytotoxic T cells that would also interact
with this antigen and these are active killer cells that generate the cellular mediated
immunity. And then finally, we see also the production
from this of memory T cells. Okay.
So, this cytotoxic T cellÊ these are sort of good guys.
They go along and they are looking for, again, the antigen that's specific to their receptor
that they've generate and they also have these accessory proteins that look for class 1 MHC
molecules. And these are the ones that are on any cell
in the body, except red blood cells. So, if you have an infected cell that has
generated some of this antigen and put it in its MHC complex, the cytotoxic T cell says
you're infected, you will die. So, what happens, upon this activation, if
it sees a class 1 MHC molecule with that antigen, it secretes a poor forming molecule called:
Porphyrin that generates poser in the cell surface that would be pretty bad. It also
in and of itself, in terms of leakage of components and depolarization etc., it also secretes
enzymes called granzymes for some reason. And together, these granzymes proteolyse cell
proteins inside the cell that trigger this infected cell to undergo apoptosis and therefore
stop making the pathogen. Yeah?
>>STUDENT: [Indiscernible] >>INSTRUCTOR: Could I please explain the difference
between class 1 and class 2 MHC molecules. So, they're just slightly different versions.
They're multi protein complexes. Many of the components are the same. And a
few are different. That'sÊ that's pretty much all I know there's
a picture of it in the book. But that's the functional thing that you need
to know, right? So that different with kinds of cellsÊ sorry, all cells are making the
MHC type 1, except red blood cells, and MHC type 2 is made by the antigen presenting cells,
dendritic cells, macrophage cells and so these T cell accessory proteins that are shown in
pink, these are CDC 4, CDC 8 sorts of proteins they're the ones that allow the T cell to
distinguish between class 1 and class 2. That's sort of the limit of my knowledge.
>>STUDENT: [Indiscernible] >>INSTRUCTOR: If they see a class 1 molecule
with itsÊ the antigen, that's a signal to kill it. Okay.
And then these are released and they can go onto kill again.
Yes? >>STUDENT: [Indiscernible]
>>INSTRUCTOR: Yeah. The question is whether theÊ whether the
virus particles that might be inside of a
cell are
also inactivated byÊ (Lost sound and GP).
>>INSTRUCTOR: First they're out there in the circulation.
So they'll bind to the antigen, for example it could be a virus particle, they can coat
the virus particle, that's a process that was named opsonization.
Before people really knew what it was. This can interfere with the virusÊ ability
of the virus to infect cells, for example. And it can alsoÊ so, sorry, that's neutralization.
Opsonization is when it coats somethingÊ and that can trigger then the macrophage to
engulf the pathogen. I apologize for this lapse. So neutralization,
opsonization. Nice to have some words that you can memorize
for the final exam, right? And then, the other thing that happens is
these antibodies when they're bound is they can activate the complement system, remember
that complex of 25 or 30 proteins that interacts to sort of in a biochemical cascade that's
sort of like blood clotting that can then generate the complement proteins when activated
generate membrane attacking complexes that pores that allow ions and water to he quill
rate across the host membrane, leading to its death hopefully.
So, here's where we've been, we have this humoral antibody mediated response that involves
B cells. B cells that are survived this initial clonal
selection against self recognition, then they can beÊ there's another clonal select activation
by when they see particular antigen that they're antibodies recognize.
They then are triggered to proliferate, and differentiate into plasma cells that secrete
antibodies, and memory B cells that remain on guard against the second appearance of
that antigen. Okay.
So, the B cells are interacting directly with antigens in solution or on the surface of
pathogen cells survivors, porticals. So then you this cell mediated immune response, involving
the T cells that defense against intracellular pathogens, and also, cells that are screwed
up by cancer if you're lucky. Not if you'reÊ not that you're lucky to have
the cancer, if you're lucky your T cells will kill them and you'll never know you had cancer.
So, here, again, you can have the helper T cells that activate cytotoxic T cells recognizing
the same antigen, these cytotoxic T cells will kill host cells that are infected and
presenting that antigen and they also generate a setÊ a class of memory cells toÊspeed
the and strengthen the response to a subsequent exposure.
Whoa. iClicker question.
First, are there anymore questions on the immune system?
iClicker question. B cells and T cells are different or how?
T cells have nuclei, T cells express MHC molecules but B cells don't. There are memory cells
in the B system but not the T system. Or B cells secrete antibodies and T cells
don't. Okay.
So 30 seconds. Ah, a minute.
This is the end of the lecture. 15 more seconds.
Okay. And stop.
Let's take a look. So, what's the answer?
>>STUDENT: [Indiscernible] >>INSTRUCTOR: Huh?
[Laughter] >>INSTRUCTOR: E? Okay. Fine.
Very good. So, now, now, look everybody makesÊ so let's
think about this. B, C, T cells express MHC molecules, B cells
don't. Every cell in your body expresses MHC molecules
except the once that don't have a nucleus, right. I mean even red blood cells express
very low levels of MHC molecules but they're residual they're like 1% and they're not usually
enough to trigger an immune response. Okay.
And for C, there are memory B cells but not memory T cells.
Gosh. We said that a few times in the lecture, but
maybe not quite enough. Okay. I'm glad nobody chose DÊ oh, I see,
you fell for my joke. Oh, man!
All right. So, what is thatÊ since we have a couple
of minutes we can talk a little bitÊ how cool it is that our red blood cells don't
have nuclei and don't have MHC complex. What does that mean? That means that you can
take blood from another person and have a transfusion without necessarily getting an
immune response right? So if it was blood translations, would be
essentially impossible for us if we had nucleated red blood cells that expressed MHC complex.
So what the blood typing? There are still molecules on the surface of red blood cells.
And there are theseÊ so there's A B and 0 types.
And here you can getÊ these are different versions of the gene, you can get 1 from your
mother 1 from your father. So you can have AA, A 0, AB, BB, BO, that's back to that MHC
thing, or 00, okay. So, ifÊ now in the immuneÊ so if you're
expressing both of these antigens on your red blood cells, then yourÊ then your own
immune system will not make antibodies against them, right?
So, no anti-A, or anti-B, because those antigens will have been selected against, okay.
So anybody that makes antibodies against these proteins will have been selected against in
the development of the B and T system. Okay.
So, in contrastÊ so then you can take blood from anybody because you don't make antibodies
against either of these antigens, okay. In contrast if you're just making the A type,
protein, you'll have antibodies against B. So, then you can take A blood but not B blood.
B blood would provoke immune response. Same thing for BÊ now O, the O donors don't
make either of these A or B proteins, so they don't makeÊ so they make antibodies against
both A and B. Okay.
So, if you take a type O person and give them either A or B or AB blood, they're going have
an immune response and that would be very bad, right?
Okay. So, theseÊ but on the other hand, since they're
not making either of these antigens, you can give they're blood to anybody.
Okay. So, O is the universal donor, AB is the universal
acceptor. A and B are the in betweens, and because this
O is sort of a neutral, the AÊ this is ourÊ what do you call it? Recessive phenotype.
All right. Stop there.
On Friday, we will start the kidney. And hopefully, finish it.