Transcribed by Sofiya Khazanovich July 28, 2014

General Pathology Lecture 13 Shutting off the Immune Response by Dr. McCutcheon
Slide 1 Shutting off the Immune Response
McCutcheon: Weve spent the past month talking about how we get all of your immune system turned
on to get rid of pathogens. And thats a physiologic immune response. If you dont turn the immune
system off, that becomes, and this is an acute immune response, if you dont turn the immune system
off, then you have a chronic immune response and thats a pathologic immune response. So a lot of the
diseases that you deal with, or actually, the diseases that patients have that you will deal with the fact
that they have the disease, although you wont deal with the disease directly, are a result of a chronic
immune response more so than we original thought. The disease that you as dentists will be dealing
with that is a chronic immune response is periodontal disease. Decay has nothing whatsoever to do with
immunology, the rest of the stuff that goes on in the oral cavity has a lot to do with immunology.

Slide 2 Shutting off the Immune Response
McCutcheon: So you need to shut down the immune response. Youve got all these cells up and going,
theyre doing what theyre supposed to do, and then you need to shut it down. And what drives shutting
down is running out of pathogen. As long as you have pathogen there, you need to keep the immune
response going. And if it goes on too long it becomes a chronic immune response and then you have
periodontal disease. So once the pathogen drops, the immune system has done what its supposed to
do, and its time to get the immune system stopped because once youve run out of pathogen whats
left? Host. We dont want the immune system to do things to the host, cause its bad.

Slide 3 The Damage Done
McCutcheon: And so you get my fantastic animated cartoon of what happens when you have the
immune system doing what it does and you run out of pathogen. So this is what kind of epithelium?
Cuboidal epithelium. And here are my bacteria, and the bacteria are sitting on top of my cuboidal
epithelium, and here are my ROS or cytokines like TNF alpha. Then the thing about macrophages is they
are not antigen specific, they dont bind to epithelial cells, and direct their lytic molecules right onto the
spot on the cell, unlike T cells which are going to bind exactly to a virally infected cell and when they
release perforin and granzymes, the only possible membrane that perforin and granzyme can contact is
the cell the T cell is attached to. So macrophages and neutrophils, they release ROS and the ROS fall
where they fall. And so here we see a ROS thats fallen on a bacterium, theres a ROS protein, or thingy,
thats fallen on a bacterium, and these are fallen on epithelial cells. And who do the epithelial cells
belong to again? Host. So what you do is you end up killing whatever the ROS falls on, and if it falls on a
bacterium you kill the bacterium, and if it falls on a host, you kill the host. And you, at the end of the
immune response weve run out of bacterium, so what are those ROS going to fall on? Host. And the
thing about the macrophages, once it drops its ROS, its not done yet. So we got rid of the bacterium,
weve gotten rid of the host, but the macrophage is still there and its still secreting the ROS, and now
were out of bacterium, so what are we going to kill? Host. At this point in time, its really important to
start shutting down the immune response. There are three things that are really involved, so weve got
macrophages and weve got TH1 T cells, and if its a viral infection, weve got CD8 T cells, and those all
need to be stopped. Weve got our B cells that have been secreting massive amounts of plasma cells
that have been secreting massive amounts of antibody, we have lots and lots of antibody at this point in
time, and weve run out of pathogen for the antibody to bind to. And then, we have B cells, a lot more B
cells get recruited into an immune response than T cells do, and we continue to recruit B cells until we
stop that. So the three things we have to stop, we have to stop the activated cell mediated immune
response, we have to do something to get rid of the antibody and in the process we have to generate
large antigen antibody complexes. And then we have to stop B cells from being recruited. We have this
Transcribed by Sofiya Khazanovich July 28, 2014

system where the body generates antibodies against antibodies. So the part of the antibody that binds
the epitope is the idiotype. The part of the antibody that binds the epitope is the idiotype. And a plasma
cell, a single plasma cell lives about 30 days. And a single plasma cell can secrete enough antibody that if
you were to dry it down, you could see it without a microscope. Its the size of a grain of sugar. So its
tiny, but if you think about it thats a huge amount of a pure protein. And so each plasma cell secretes its
own specificity of antibody and that idiotype of which you have milligram quantities is something that
the immune system has never seen before. Because the specificity, the protein sequence of that part of
the antibody is unique from that B cell. And so what does the immune response do when it sees large
quantities of a protein that its never seen before? You make an antibody against it.

Slide 4 Function of Idiotypic Regulation
McCutcheon: And so this is called idiotypic network regulation. And so this is the idiotype of an antibody
and so you get enough of any one kind of antibody that you will start making an antibody against the
idiotype, and anti means against. So we have an idiotype and then we make an anti-idiotype antibody,
and actually if you have enough of this, by the time youve mopped up all of the idiotype, if you have
enough of the anti-idiotype, you can make an anti-anti-idiotype,

Slide 5 Shutting off the Immune Response
McCutcheon: And so this is called idiotypic network regulation.

Slide 6 Image
McCutcheon: And so this is the idiotype of an antibody and so you get enough of any one kind of
antibody that you will start making an antibody against the idiotype, and anti means against. So we have
an idiotype and then we make an anti-idiotype antibody, and actually if you have enough of this, by the
time youve mopped up all of the idiotype, if you have enough of the anti-idiotype, you can make an
anti-anti-idiotype antibody. Now, the details are not important. But the point is, you have this massive
amount of antibody and theres nothing for it to bind. And so in order to not have it find something to
bind, because if it finds something to bind, whats it going to be binding to? Host. Were going to make
an antibody against it. And because antibodies, every antibody has a minimum avidity of 2, we could
make these really long chains of antibody binding to antibody binding to antibody binding to antibody.
And theres long chains of antibody binding to antibody binding to antibody can be bound by a receptor
for IgG on red blood cells, the red blood cells travel through what organ once a day? Spleen and whats
in the spleen? Macrophages. So the red blood cells go to the spleen, the splenic macrophages pull off
the antibody bound to antibody bound to antibody complexes and degrade them. And now weve
gotten the antibody out of the system. So the point of idiotypic network regulation is because at the end
of the immune response when weve run out of pathogen, each one of those plasma cells is secreting a
protein that the immune system can recognize as unique. If theres a high enough concentration if it we
need to mount an immune response against that. Well make an antibody against the antibody, and
then that allows us to create these large large large chains of antibody bound to antibody bound to
antibody. They can bind to FC receptors, IgG receptors on the red blood cells, and be carted off to the
spleen and be devoured by the macrophages. So were getting rid of all of that excess antibody so it
cant find something else to bind to because the something else is host.

Slide 7 How damage is caused
McCutcheon: So damage can happen in two ways, and we dont care about the left hand half of this
slide, because thats whats done by the pathogen. What we care about is the stuff that gets done by the
immune response. So when you have small antigen antibody complexes, really small ones, those end up
getting, when they travel through the renal epithelium in all of those loops and tubules and things, the
Transcribed by Sofiya Khazanovich July 28, 2014

really small antigen antibody complexes end up getting lodged in the renal epithelium, complement gets
activated against the antigen antibody complexes, and in the process it destroys the renal epithelium,
and when you destroy renal epithelium, you dont replace it with epithelium, you replace it with
connective tissue. And once youve replaced the renal epithelium with connective tissue, your kidneys
dont work anymore, and thats glomerular nephritis. Glomerular nephritis. And so you end up with
kidney damage. So one of the things that we need to do is we need to make our really small antigen
antibody complexes bigger, because once theyre bigger we can get rid of them. So another thing that
happens, so antibodies are specific, but specific doesnt always mean they can only bind one protein.
Sometimes they can bind a group of closely related proteins. And so, if you are one of the people, you
get infected with beta hemolytic strep, and your immune system makes an antibody and it turns out
that the antibody that binds to this particular epitope on the beta hemolytic strep, that epitope is only
one or two amino acids away from myocardium, so once you get that population of antibodies they can
go off and bind the heart muscle, and you get rheumatic fever. So here we have cross reactivity, where
the antibody that bound to bacteria can now recognize host heart muscle, and then the antibody
destroys the heart tissue, you replace the muscle with fibrous tissue and you have rheumatic fever. So
the immune system can do a lot of damage.

Slide 8 Image
McCutcheon: So when we have somewhat, I mean this cells small, but theyre really larger, Im not quite
sure why its this small. So the somewhat larger antibody antigen complexes, they can be bound by
complement and decorated with C3B, and so erythrocytes also have receptors for C3B so they can cart
whatever is attached to the C3B to the spleen and the splenic macrophages then digest it. So red blood
cells are one of the primary players in mopping up excess immune response. They can bind to IgG, so
they can bind to the antibody complexes, they can bind to C3B, now red blood cells arent phagocytic,
they arent going to do anything with this except carry it around, but a red blood cell passes through the
spleen, once every 24 hours, and the spleen is full of macrophages that are hungry. So the splenic
macrophages can then get rid of the excess antigen antibody complexes, they can get rid of the excess
antibody antibody complexes, and that keeps those from doing damage elsewhere, primarily the
kidneys, but it can be in other tissues.

Slide 9 Shutting off the Immune Response
McCutcheon: There are cytokines, and the anti-inflammatory cytokines have their name anti-
inflammatory because they suppress the cell mediated immune response.

Slide 10 Cytokine Functions
McCutcheon: So IL-4, it can prevent differentiation of nave CD4 T cells and TH1 T cells, so at the end of
the immune response if you have a high IL-4, any T cells that are still proliferating, they wont
differentiate into any more TH1, so we stop making TH1 T cells. With IL-10 and IL-13, they can down
regulate activated natural killer cells. With IL-10 and IL-13, IL-4 can down regulate activated CD8 T Cell
activity. So you stop making CD4, TH1 T cells, you suppress any activated macrophages, you suppress
activated CD8 T cells, IL-10, IL-4, IL-13. IL-10 by itself can also suppress macrophage respiratory burst,
and cytokine secretion. IL-10 when it hits the activated macrophages, you stop the ROS production, you
stop the production of IL-1, IL-6, and TNF alpha. And then that stops during tissue damage. IL-13 with IL-
4 and IL-10 down regulates NK cell activity, and with IL-4 and IL-10 down regulates CD8 T cell activity.
TGF beta can inhibit B cell growth, TGF beta can inhibit macrophage activation. So these four cytokines
help suppress everything thats already going. In addition to the functions that they have to get B cells
activated. So they have two very different sets of functions. One is to get B cells to do their thing and the
other is stopping T cells, macrophages, and NK cells from doing their thing.
Transcribed by Sofiya Khazanovich July 28, 2014


Slide 11 Image
McCutcheon: So TH2 T cell, IL-10 suppress macrophage ROS, with IL-4 and IL-13 it can suppress CD8 T
cells, with IL-4 and IL-13 it can suppress NK cells, and IL-4 and IL-10 can prevent nave T cell activation.
So the TH2 cytokines suppress the CMI reaction.

Slide 12 Image
McCutcheon: And then the last thing is that nave B cells, in addition to the B cell receptor and
complement protein receptors, they have an IgG receptor. Nave B cells in addition to their B cell
receptor and complement protein receptors, they have an IgG receptor. Now, at the beginning of the
immune response is there any IgG around? No. So, the nave B cells at the beginning of the immune
response they bind through their antibody B cell receptor and complement receptor, and they do cross
linking and receptor mediated endocytosis, and off they go. After weve made a lot of antibody, and
weve gone through lots of rounds of somatic hypermutation, so the antibody is high affinity and its
staying attached to the pathogen, when the next round of nave cells comes along, you bind through the
B cell receptor but at the same time you bind through the IgG receptor because theres already IgG on
the pathogen. Originally the B cell binds through the nave B cell binds through the B cell receptor and
complement receptor and you get activation, later on in the immune response when the pathogen is
already decorated with IgG, the B cell will shut (I think this is what she says?) and then the next round of
nave B cells will bind but at the same time, the IgG thats already there will bind to the IgG receptor on
the B cell. And when the B cell binds to the B cell receptor and the IgG receptor at the same time,
instead of getting activation you get anergy. So later on in the immune response you already have IgG
coating the pathogen, the B cell receptor binds the IgG receptor binds to the IgG thats already on the
pathogen and instead of getting activation you get anergy. This point in the response, we dont need
new B cells. We have high affinity antigen being secreted by plasma cells, we have high affinity memory
cells, we dont need new B cells. So this prevents any new B cell from making a receptor and getting
started.

Slide 13 Image
McCutcheon: So how does all of this work? So, we had our first pathogen be it naturally occurring or
vaccinated, you notice that it takes somewhere over five days before we start seeing an antibody
response to that first induction of a pathogen. It takes six or seven days before you really start making
antibody. So we have this antibody response and it goes up and up, and then starts to drop off. If you
have a second exposure to that pathogen be it a vaccine or be it the same virus that you already fended
off once, notice here it takes about 24 hours to immediately start, and the other thing is the antibody
levels never go away. You maintain an antibody response, and thats when they draw blood to see what
your titers are, thats what they're looking for. So as long as you have antibody against that pathogen its
not going to be able to infect you again. And if you are infected again, theres less than 24 hours you
have this immediate and huge spike in the amount of antibody that you get. So these are your memory
B cells at work. Pathogen is infected, under 24 hours you have a very large amount of antibody
produced, a lot of that will be neutralizing antibody so now the pathogen cant bind and infect, its high
affinity antibody so the antibody will stay bound and that will allow macrophages and neutrophils to
opsonize, NK cells can do ADCC, pathogen can be picked up on red blood cells, you can decorate it with
complement or pathogen can be picked up with IgG receptors on the red blood cells, carted off to the
spleen. So you may be infected but youre not going to be sick because the antibody is there, its an
immediate response, its a very high affinity response, and its a massive response. You get a lot of
antibody. But just because you get an antibody to this pathogen that youve already seen doesnt mean
that youre going to have this kind of response to something new. Something new is always going to
Transcribed by Sofiya Khazanovich July 28, 2014

start out exactly like this. If you get two things at the same time, and you have antibody against one and
have never seen the other, you have to go through the entire immune response for that second thing in
order to end up at this point. So its a specific response, if you have H1N1 which is a flu type, you have
antibody against H1N1 but you wont have antibody against H2N7. So you make the antibody against
that pathogen if the mutation in the pathogen is where the antibody bound then we have to start from
scratch and do it all over again. So the driving principles of shutting off the immune response are
decreasing antigen density, you have cytokines Th2 cytokines that suppress the TH1 cells, you make an
anti-idiotype antibody to mop up all the excess antibody against the pathogen that doesnt have
anything to bind to, and that also helps turn small immune complexes into larger immune complexes
that can be carted off to the spleen where they're degraded by the macrophages, and then high affinity
antibody thats already bound prevents activation of nave B cells. You ready?

Question and Answer Session
Thats it. I will answer any questions about anything in the course.

Question: Something about the last slide, asking for clarification.
Answer: Antigen density is what drives shutting off the immune response. TH2 cytokines suppress TH1
cells, activated TH1 cells. Or the cells that are activated by the TH1 pathway. So macrophages,
neutrophils, CD8 T cells, NK cells, and you prevent differentiation of more TH1. You get rid of those.
Idiotypic network regulation causes antibodies to be made against species of antibodies that are in high
concentration. So you have antibody that binds to antibody and you mop up all of the excess antibody
so it cant find something else to bind to, it gets carted off to the spleen and eaten by the macrophages,
the red blood cells do the carting the macrophages do the eating. That also allows you to go from really
really small antigen antibody complexes to larger antigen antibody complexes that can be bound by C1,
you decorate those with C3B, red blood cells also have receptors for C3B, so you can cart those antibody
pathogen complexes off to the spleen where theyre eaten by the macrophages. And high affinity IgG
thats already bound to the pathogen will prevent activation of nave B cells because nave B cells have
an IgG receptor, and the antibody on the pathogen will bind the IgG receptor and instead of activation
you get anergy.

Question: Cant tell what is being asked.
Answer: Yes, along with TGF beta.

Question: Again, cant tell what the question is.
Answer: It depends on the antibody, if its a lock and key specific, no, it will only bind what its going to
bind to. If its one of the broader specificities, possibly. Usually vaccine B has no relationship whatsoever
to vaccine A, and so no. But thats the reason, if you have the flu the reason you dont get the flu the
next year is because even though one set of antibodies is going to get knocked out, you have other
antibodies that bind to other epitopes on that flu virus that didnt mutate so you will still be covered. So
the idiotype is the part of the antibody that binds the epitope. So most of the antibody has the same
amino acid sequence as all other antibodies except for the part of the loops and thats the idiotype. And
so that particular amino acid sequence and tertiary structure will be unique for the antibody secreted by
each separate plasma cell, and if the antibody is bound to the pathogen there wont be much of it left
and we dont care about it. Its when you have the plasma cells that were generated at the very end of
the response, and theyre secreting antibody and theres no pathogen for it to bind to, and now you
have this massive amount of protein with this unique amino acid structure, B cells will recognize that
and make an antibody against that. The purpose of it, the details are not important, the purpose of
Transcribed by Sofiya Khazanovich July 28, 2014

idiotypic network regulation is getting rid of the antibody so it cant go off and bind something else
which is host.

Question: Cant tell.
Answer: So HLA polymorphism, polygenism is the fact that you have different loci that have protein
products that have almost identical structure and the same function. Polymorphism is changes in the
nucleic acid sequence that cause changes in the amino acid sequence, so although the function of each
of the proteins is the same, there are subtle structural differences. Many shapes.

Question:
Answer: The first time you see a pathogen, you do what weve just spent this month talking about.
Eventually you end up with an antibody response, whether its a bacteria or a virus, you end up with
antibodies. So first of all, one of the things you can do, the immune system is specific enough so that you
can draw blood from a person and you can do an antibody titer and if that person has never seen that
pathogen youre not going to have any antibodies against that. So you have this background of 0,
effectively speaking. So you go through what weve just gone through this month, and now you have an
antibody, you have antibodies and its not, the background isnt 0 anymore, youre always going to have
antibodies against that, if its a naturally occurring infection, youll have antibodies for 60 or 70 years.
Eventually old peoples memory cells die off, and thats one of the reasons that when you start hitting
your 7
th
decade, your immune system isnt very good, cause youve lost some of the immunity that you
generated as a kid. If you vaccinated against things, vaccines are incredibly important against pathogen
that will kill you, but they dont work very well compared to a natural immune response so you need to
be vaccinated about once every 10 years, cause you dont get good memory. In the event of a naturally
occurring pathogen, you make this immune response and now you end up with an amount of antibody
thats in the blood and youre always going to have that antibody until you get really old. If you have a
re-exposure to that pathogen, first of all you have antibody against it, so rather than the virus being able
to infect a bunch of epithelial cells, the antibodies neutralize the virus, they cant infect, so they dont
get into the system in the first place and thats the end of them. Antibodies against bacteria, the
antibody will bind to the parts of the bacteria that the bacteria needed to attach or infect or to secrete
toxins, the antibody will bind to the toxins so the toxins cant infect, so thats neutralization, but also
these are high affinity antibodies so once they bind they stay stuck. And that means that the dendritic
cells or the macrophages or the neutrophils or whatever happens to come along that has an IgG
receptor can kill off whatever the antibody is attached to. So the bacteria instead of getting in there and
being able to replicate, they get there and they get killed, and thats the end of that. So youre
constantly being re-infected with things you have antibody against, and the reason you dont know that
youre constantly being re-infected with thinks is cause you dont get sick. Youve got the antibody, they
do what they're supposed to do, and the pathogen gets eliminated before it can start causing damage.

Question: With the repeated responses, does the level of antibody always go back to the same?
Answer: No, if you have enough exposure, youll its not an infinite increase, but the second and the
third it will go up a bit. And it does eventually, 30-40 years out, start to drop back down.

Question: So dendritic cells break up viruses and whats the point isnt it good enough
Answer: So we have a virus, pick a virus of your choice. So you have the chicken pox virus, and it gets in
your cells and starts to replicate. And its going in your cells and its replicating, and were putting chicken
pox peptides on HLA class I. And so what kind of T cells do we activate? CD8 T cells, and what do CD8 T
cells do? They kill things. So the CD8 T cell can kill the virally infected cells. The CD8 T cell kills this virally
infected cell, the CD8 T cell kills that virally infected cell, the CD8 T cell kills this virally infected cell, but
Transcribed by Sofiya Khazanovich July 28, 2014

this virally infected cell right here, that lyses. So now we have another 50,000 copies of the virus that
have just been released into the extracellular space, and they bind to 40,000 new epithelial cells. So the
CD8 T cell can kill the virally infected cells, but we just had four more virally infected cells that lysed
before the CD8 T cell got there, and no we have 100,000 new virally infected cells. Tell me how Im going
to make this stop. So how do we stop the virus from infecting the cell? CD4 T cells do not recognize
virus. What can recognize the virus when its in the extracellular space? Antibodies. Any antibodies. How
do we get antibodies, where do they come from? B cells, ok? How do we activate a B cell? TH2 T cells,
what kind of a T cell is a TH2 T cell? CD4 T cell. How do we activate CD4 T cells? Peptide at MHC Class II.
So why does the dendritic cell have to present on both MHC Class I and MHC Class II? Because to get rid
of intracellular pathogens you have to have antibodies. The CD8 T cells can kill the virally infected cell,
but nothing can prevent other cells from being virally infected, so youre just going to keep the
destruction going. The antibody are what can prevent the uninfected cells from being infected, and to
get antibody you have to activate B cells, to activate B cells you have to have TH2 T cells, to activate TH2
cells you have to have peptide presented on HLA Class II. Now for extracellular pathogens you dont
have peptide on HLA Class I. Its only ever in the vesicle, never in the ER. So CD8 t cells do nothing. They
come by, they check out because they get recruited the check out the peptide on MHC Class I on those
dendritic cells, but what kind of peptide is on MHC Class I on a dendritic cell thats not virally infected?
Host. So the CD8 T cells are unactivated and they dont do anything. The dichotomy is really between
intracellular vs. extracellular because for an intracellular response you have to have all of your cells, you
dont need complement except for C3B. For an extracellular response you need all of your cells except
CD8 T cells, and you use all of complement. This is a critical point. Thats a good question and its a
critical point. Does everybody think they understand it?

Question: If you dont have a costimulatory signal, whats the point in having the HLA molecules, they
cant
Answer: There are time when a T cell is binding to HLA Class I on a host cell and we dont want
activation. So if the T cell happens to be binding on HLA Class I on an islets of Langerhans cell, the
peptides that are going to be presented are insulin peptides. We dont want T cells to recognize insulin
peptides, because if they do what will that CD8 T cell do to that islets of Langerhans cell? It will kill it.
What happens when you kill off enough islets of Langerhans cells? You get diabetes. And so the way we
prevent the CD8 t cells from being activated is that islets of Langerhans cells have no B7. So the T cell
receptor binds, theres no costimulatory signal, so you anergize that T cell, cause we dont want it to
ever be able to bind because we never want T cells to be able to recognize insulin peptides.

Question: So when it does recognize it, as in diabetes?
Answer: Actually diabetes happens because youve gotten CD4 T cells that then turn on the CD8 T cells.
Its interesting but theres a class II correlation for diabetes.

Question: So when does isotype get changed and how does your body know what kind of which one
they want.
Answer: Isotype switching occurs in cells that are differentiating to plasma or memory cells, and what
happens is that the cytokine that binds, that will isotype switch to a different isotype, it does so by
deleting the intervening constant regions. If youre going to isotype to an IgG, you delete the IgM and
IgD region and the next thing you transcribe on is an IgG I forget the subtype. If youre going to isotype
switch to an IgA you delete everything until you get to the IgA and then you transcribe on the IgA
constant region.

Question: So do you always start with IgM?
Transcribed by Sofiya Khazanovich July 28, 2014

Answer: You always start with IgM, its not until IL-4 or IL-10 or TGF beta bind that you can isotype
switch to other things.

Question: Something about IgM and IgD
Answer: IgM is primarily the secreted form, weve only just recently discovered that IgD gets secreted,
and not very much of it. So once you switch out of those two, then its usually the IgGs that get
produced.

Question: Why do we isotype?
Answer: Why do we isotype switch, anybody? You change the function. The binding end is the binding
end is the binding end and the binding end binds and thats all it does. If we want different functions we
have to change the constant region, and thats the isotype switching. So IgM activates complement, IgG
does neutralization, opsinization, ADCC and complement activation, IgE does mast cell granulation, IgA
neutralizes different functions. IgA gets stuck in extracellular or bodily fluids outside the cells, host. So
tears, saliva, sweat. So it can neutralize things before they can become pathogenic.

Question: ?
Answer: You dont have to know this but, so gamma delta T cell receptors actually look like antibody
when you crystallize them, theyre structurally very different from an alpha beta T cell receptor. Gamma
delta T cells and CD5 or B1 B cells live in the tissues, B1 B cells dont need TH2 t cells to be activated,
gamma delta T cells dont need antigen presenting cells to be activated, gamma delta T cell receptors
can bind to any structure like a CD5 or conventional B cell. So they live in the tissues, theyre first
responders, although they're antigen specific so they will only bind to a limited number of structures
compared to an alpha beta T cell or a conventional B cell. But theyre immediate responders, they're in
the tissue, they start doing what they're doing, the B cells secrete low affinity IgM antibody but it only
takes one IgM to activate complement. The gamma delta T cells secrete first pro-inflammatory cytokines
and then anti-inflammatory cytokines later in their response.

Question: Can you please explain the TH1 and TH2 with STAT and
Answer: IL-12 binding to the IL-12 so you have these activated proliferating T cells that have IL-4 and
IL-12 receptors. If IL-12 binds to the IL-12 receptor, you turn on a JAK STAT pathway that eventually
gives you Tbet. Tbet then causes the secretion, the translation of gamma interferon, and the gamma
interferon receptor. And so gamma interferon gets secreted by the T cell, it binds to the gamma
interferon receptor, and that causes second messenger signaling through STAT1. And then STAT1 causes
more Tbet and it also causes signaling and more gamma interferon and gamma interferon receptors,
and IL-12 receptors, and then STAT4,is it 4? STAT4 is activated through the signaling through the various
*something* receptors and that helps maintain the Tbet phenotype and then you also have another
transcription factor thats going to turn on the rest of the pro-inflammatory cytokines.

Question: ?
Answer: And for those of you who are secretly thinking do I really have to know the functions of the
cytokines, my answer is is there a question on the study guide that asks that? And if the answer to that
question is yes, then whats true about the functions of cytokines? Theyre on the test. Thats a good
answer.

Question: ?
Answer: TH17 cells secrete TH17 family cytokines that can both promote disease and promote health.
When IT-reg and TH17 cells play a role, and they're all relatively new so we dont have this that well
Transcribed by Sofiya Khazanovich July 28, 2014

sussed out yet, but so you have your immune response, TH1s are doing their thing, TH2s are doing
their thing, pathogen goes away. No IT-regs, no TH17 cells. You have your immune response, TH1 T cells
are doing their thing, TH2 T cells are doing their thing, pathogen isnt going away. So now all of the
sudden you have, if the TH1 cells are doing their thing and so TH2 cells are secreting TGF beta, if you
have excess TGF beta, you still have pathogen, and you dont have a lot of IL-6 or IL-21, youre going to
get IT-regs and those are going to start suppressing the CD4+ T cells. If you have excess TGF beta and
you still have this strong pro-inflammatory response with lots of IL-6, then youre going to end up driving
activation into a TH17 cell, and youre going to come up with this new family of cytokines that does
many of the things that pro-inflammatory cytokines do because the pro-inflammatory cytokines werent
working, so you have this new set of cytokines that gets secreted to try and clear the pathogen. So these
two cells come in when the classical TH1/TH2 didnt work. And so especially the IL-17 family, you might
try thinking of them as bridging cytokines between an acute and chronic inflammatory response. The
TH17s show up when you have high amounts of both IL-6 and TGF beta. So youre not clearing the
pathogen with the TH1/TH2 response.