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Transcript of Immuno - Lec 14
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Cell-Cell Interaction in Generating
Effector Lymphocytes
Tamara ShoterZiad Al-Nasser
Thursday, 21/7/2011
20
14
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Immunology Lecture #14
Thursday, 21/7/2011
Done by: Tamara Shoter
The doctor started the lecture talking about the exam; its place,
time...Etc.
So, yesterday we were talking about the process of T-cell development
and we said that it occurs within the thymus gland. The earliest
thymocytes (Double negative cells, which express self-surface
molecules such as CD25 and CD44) enter the subcapsular zone, where
they start to mature. After that, they move further into the cortexwhere we have MHC antigens. Now, in the cortex, double negative cells
mature into double positive cells (CD4+ CD8+). Thymocytes' fate
depends on the ability of their receptors to recognize class I or class II
MHC molecules. Double positive (DP) cells that recognize calss I MHC
molecules will become CD4 + cells, while DP that recognize class II MHC
molecules will become CD8+ cells (this process is called Positive
Selection and it occurs in the medulla).
Notes:
1. T-cells that have high affinity for self-antigens are going to be
eliminated.
2. There's a mechanism called central tolerance related to the endocrine
gland, where all the tissues in our bodies supposed to be presented in
the thymus gland but it doesn't happen this way, so we have (?). The
auto regulatory immune gene can control this process with self-
restriction and if we have a mutation in this gene, then self tolerance or
self restriction is going to be affected and we call this
autoimmune polyendocrine syndrome I. ( Multiple endocrine organs
that have an autoimmune disease).
3. Some self-reactive cells may escape into the periphery and this will
cause the development of something called 'Peripheral Tolerance'.
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Also, if you don't have accessory molecules like CD28 which develops at
the periphery, then peripheral tolerance will develop (Not fully sure).
4. We talked about T reg (known as suppressor T cells) which produce
suppressive cytokines like; IL-10 and the transforming growth factorbeta (TGF-). As I said the gene that codes for that is called Foxp3.
Mutations in it will result in a multisystem autoimmune disease.
5. 95% DP cells never mature because they lack TCRs that can
appropriately recognize self-MHC.
T helper cells are divided to Th1 and Th2 cells based on the nature of the
infectious process or the mechanism of the immune destruction that we
need. For example, if we need to destroy virally infected cells or tumor
cells, we require Interferon-gamma (IFN-) which activates
macrophages that express class I MHC that is need for cytotoxic T cells.
Remember, tumour necrosis factor and interleukin 6 cause elevated
body temperature and isotype switching to (IgG) which acts as anopsonin. Macrophages produce interleukin 12 which stimulates the
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differentiation of Th0 to Th1 cells. The same thing here, we need other
types of antibodies we call them IgH (IgH means any antibody that's
not IgM, be it IgG, IgE ..Etc). Now, Interleukin 4 is produced by mast
cells which induce differentiationof Th0 cells to Th2 cells, which will
also produce interleukin 4 and interleukin 5, and interleukin 5 attracts
eosinophils.
We also talked about the gamma delta T-cell subset which represents a
small percentage (5%) of all T cells. The gamma delta T-cell receptor
can recognize certain peptide and non-peptide antigens without
processing and in the absence of MHC class I or class II molecules. These
cells help other T cells to activate macrophages, also they are involved
in the lysis of virally infected cells and they are a part of the first line of
defence. (Skin, gut mucosa..)
So here, in DiGeorge syndrome, the 3rd and 4th pharyngeal pouches
aren't developed. Therefore, the thymus and parathyroid glands will be
missing, of course patients with this syndrome will have a very low
number of T cells. However, the B cell count is normal .Since these
patients have T lymphocyte deficiency, they will be more susceptible to
viruses and tumours. There's a virus called Epstein-Barr (EB)virus that
binds to CD21 receptors present on the surface of B cells and this will
cause differentiation of B cells into antibody-producing plasma cells,
which in turn activate the CD8+ cells that are going to destroy infected
cells. Also, TNF and Il-6 cause elevated body temperature. See the
figure below:
http://en.wikipedia.org/wiki/Gammahttp://en.wikipedia.org/wiki/Delta_(letter)http://en.wikipedia.org/wiki/Gammahttp://en.wikipedia.org/wiki/Delta_(letter)http://en.wikipedia.org/wiki/Delta_(letter)http://en.wikipedia.org/wiki/Gammahttp://en.wikipedia.org/wiki/Delta_(letter)http://en.wikipedia.org/wiki/Gamma -
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Chapter 16 - Cell-Cell Interaction in Generating
Effector Lymphocytes
So now the B, T cells left the thymus gland and the bone marrow as
nave/ virgin lymphocytes and we need those to be primed in order to
stay in the secondary lymphoid organs as long as we want an efficient
immune system.
If you are following the development of the B cells & T cells and the
markers that will develop on their surface when they go to the
secondary lymphoid organs, we see that after they go to the secondary
lymphoid organs and interact with an antigen we see other markers that
are so important for the activation of those B or T cells.
We can see that the binding of the antigen -when it's carried by the
MHC antigens- to the receptor is providing me with one signal but you
need other signals, and those come from the accessory molecules and
those are so important; sometimes for cytokine function, for isotype
switching.
So the immune system will not be completed unless those accessory
molecules that I am going to talk about are there and perform their
function, if they are missing then we are going to be
immunocompromised .This is what I am going to talk about in Cell-Cell
Interaction In Generating Effector Lymphocytes.
We are talking about an antigen taken by an APC, processed, presented
to the surface and then binding to the B & T cells; this is one factor, wehave other factors/ signals that are going to be involved in the
secondary lymphoid organs.
Refer to the Over-view figure at the beginning of the chapter:
We can see here in the Fig. the antigen taken by an APC (through the T
helper cells), T helper cells will be activated & produce cytokines which
act on the B cell, B cell will be differentiated into a plasma cell that will
give AB. This process is called effector B-cell generation. We are talking
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about thymus dependent; this is the role of thymus (the process of
effector B cell generation in the involvement of T cell).
This is the activation of B cells. So it's not enough to bind the Ag to a B
cell, you require also the help of the thymus gland through CD4 by theproduction of cytokines to the B and to the differentiation to a plasma
cell.
The same thing here applies for T cytotoxic and the killing, it's not just
enough that the virus or the tumor Ag is presented to the T cytotoxic
cell through class-1 MHC Ag; this is one signal, the 2nd signal must come
also from a T helper cell.
We will see the cytokines that are going to be produced; sometimes if
the Ag presenting cell is already infected, certain viruses, extracellular
vaccines could be presented by class-1 MHC Ag to T helper. So both (?)
can provide cytokines through this process that will activate the CD8 to
change into an effector cell and then produce the cytolysin & kill the
target cell. (You better skip this paragraph).
So as you can see here (in the fig), in both* the T helper are required for
AB production or for killing process.
* Effector B cell generation & effector T cell generation.
T cell recognizes antigen that is only presented by an MHC Ag on
the APC (thymus dependent Ag). While B cell doesn't have to.
Co-stimulatory signals provided by the interaction with accessory
cells, so we require other signals beside the binding itself.
The outcome is plasma cells -as effector- that give me antibodyOR effector T cell either helper or cytotoxic. The helper will be
activated and act on the T cytotoxic activating it when this
cytotoxic is bound to the Ag of the surface of the cell that I need
to kill.
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Refer to Fig.16.1/Pg.121:
So this is what's happening; here a B cell, it has a B cell receptor and the
Ag is bound here (to the BCR) will be taken inside, bind to class-2 MHC
Ag and then be presented (so B cell acts as an APC) to the T-helper.Then the T-helper is supposed to be activated. Now -as I said- when this
is taking place we require other mechanisms for the production of
cytokines.
Now this stage of T cell activation, makes the T cell (the prime T we call
it) form other accessory molecules that are needed for the production of
cytokines and for the activation of the T helper cell that's going to work
on the B cell, that's going to differentiate into plasma cell, that giveantibodies.
Fig. 16.2/Pg.121:
Look for example:
This is Lymphocyte Functional Antigen on T cell that's going to
bind to the ICAM-1 on APC.
CD28 & CD80(B7); this interaction is so important to tell you thatthis stage is a thymus dependent.
CD154 (CD40L) is going to bind to CD40 on the APC. This binding
makes the cytokines that are needed for isotype switching; so if
this binding is not formed only the B cell will produce the IgM (as
if it's thymus independent).
* We have a syndrome regarding this called X-linked hyper IgM
syndrome; the patient keeps producing IgM and doesn't produce IgGand you know how important the IgG is for opsonization, neutralization
and the high affinity of Igs and so on -while the IgM has a low binding
affinity.
So this syndrome results from the missing of CD154, and how can we
treat those? By Gene Therapy; we have to introduce the gene that's
missing so the isotype switching is going to take place.
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*All these interactions occur when you have an APC in the paracortical
area of the lymph nodes.
*If any of the up-mentioned receptors is missing then we become
immune compromised.
Fig. 16.7/ Pg.125:
These are the differences between TH1 and TH2, we talked about that:
TH1: interferon- and the tumor necrosis factor-
responsible for fever, & IL-6 as well as IL-10. IL-4 & IL-5 not
produced here.
TH2: IL-4 & IL-5 and no INF- & TNF- .
Fig. 16.4/ Pg.122:
Look here into the complete picture that I was telling you about; class-2
presenting the Ag to the T helper providing the 1st signal. CD3 is so
important in the T helper for the passage of the signal. And then the
CD28 & the CD80 (B7) the same thing; give me an indication that this is
thymus dependent. And we talked about the CD40L and the CD40 that
will give a signal here for the isotype switching as well.
For B cell activation, it's not enough just to bind the Ag to BCR, this
gives you just one signal & you require other signal as we said many
times. This all doesn't happen in the bone marrow it happens when the
cell is primed; when the cells go to the secondary lymphoid organs &
meet the APCs in the interaction. This is naturally what should happen.
The explanation of stimulated or primed B & T cells in the secondary
lymphoid organs is that the APCs are present in the secondary lymphoid
organs so now what comes from the bone marrow or the thymus gland
(Nave or virgin lymphocytes) are going to be stimulated there.
The DC could produce cytokines, for example IL-12 for the
differentiation of TH1 &TH2, those they make the HEV to produce the
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selectins & the addressins & those are important for the stoppage of
these lymphocytes & the passage through the assigned areas in the
secondary lymphoid organs; the paracortical region or the follicular
region.
The adhesion molecules communicate through the cytokines, so the
cytokines are also important for the adhesion molecules to develop.
* The function of T helper cells is cytokines production; interleukins &
other cytokines.
* T helper 2 activation usually leads to antibody production of the IgE
type and others (IgH: IgA, IgD, IgE), while IgG comes from T helper 1
and functions in opsonization.
* T helper 1: cell mediated immunity, interferon gamma, isotype
switching to IgG, then IL-6 and tumor necrosis factor.
B cell can present Ag to TH cell by class-2 MHC Ag. Those you see
between the APC at one side & the B or T cell on the other side we call
them the immunological synapse.
So when we talk about the immunological synapse, we are talking
about the Ag presented with class-2, ICAM-1, CD40, CD80 (B7) & on the
other side we have the receptor & the CD4, LFA-1, CD28, CD40LThis relationship in the synapse is VERY important in isotype switching.
So, what about Cd40 and Cd28? We said before that presentation with
class II MHC antigen to the receptor will provide just one signal, the
other signal should come from the accessory molecules in the synapse
as we said. These 2 signals will stimulate T helper cells to produceinterleukin 2 which induces the differentiation of B cells. Also,
interleukin 2 acts on a receptor called interleukin 2 receptor (Will be
explained in details later on). Remember that interleukin 2 is the major
cytokine needed for growth and differentiation, if it's not developed, we
will be severely immunocompromised. And in order for interleukin 2 to
be produced we need all the accessory molecules, so one signal here
isn't enough. The co-stimulatory receptor-ligand pairs CD40-Cd154
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(CD40L) and CD80 (B7)-CD28 act synergistically to enable T-H cell
differentiation.
Hyper-IgM syndrome results from mutations in the CD154 gene, here
there will be no isotype switching to igG.
Here, the doctor is talking about figure 16.6 on p.124, just follow the
arrows. He added that cytokines are important for the development of
memory cells.
Clinical Applications:
There's a disease called Leprosy ( ), it's caused by
Mycobacterium leprae. This disease affects the terminal (?), so you
are going to have nodules and paraesthesia. They have noticed that if
you have (?) infection, then lepromatous leprosy results, and if you
have a localized infection we call that tuberculoid leprosy. In
lepromatous leprosy, Th2 cells are going to be activated (Note:
Mycobacterium tuberculosis activates Th1 cells which will
activatemacrophages..), antibodies will be produced (IgE type)
which have no effect, so patients usually die. Now, in tuberculoid
leprosy, small amounts of Th1 cells will be activated and interferon
gamma, interleukin 6, and TNF will be produced, these cytokines will
activate macrophagesEtc. (Note: Patients with tuberculoid leprosy
have a positive skin test reaction) Also, patients can fully recover
from this disease and they become immune to this bacterium.
Refer to page p.126, Acid-fast bacilli are present in all parts of thebody in lepromatous leprosy.
Refer to p.127, here is a patient with hyper IgM syndrome, he's
immunocompromised because IgM antibodies have low affinity and
no memory. So patients with this syndrome require gene therapy.
Remember, the molecule that is missing here is CD154 or CD40L (L
stands for ligand).
http://en.wikipedia.org/wiki/Mycobacterium_lepraehttp://en.wikipedia.org/wiki/Mycobacterium_lepraehttp://en.wikipedia.org/wiki/Mycobacterium_leprae -
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You can see how the cooperation is going to take place for the killing
process as well. Now, activation of CD8 T cells in order to develop
effector functions requires: (1) First signal: An antigen presented by
class IIMCH molecules. (2) Second signal: Interleukin 2 which we can
get from the same virus that has been trafficked through the
extracellular pathway or from T helper cells. (Note: We always require T
helper cells in the thymus-dependent mechanism, to provide us with
interleukin 2).
Notes:
1. In multiple scelrosis, sheaths around the axons will be destroyed byTh1 cells. We notice that during pregnancy Th2 are going to be
activated, so more antibodies will go to the baby. (Pregnancy reduces
the activity of this disease Beneficial effect). Th1 and Th2 can't be
activated at the same time; if we activate Th1 cells, we suppress Th2
cells and vice versa, we can use that in the treatment of autoimmune
diseases.
2. We talked about conjugate vaccines against Streptococcus
pneumoniae and Haemophilus influenzae B. The polysaccharides of
these encapsulated bacteria stimulate thymus-independent antigens,
resulting in the production of IgM antibodies only , so no memory cells
will develop and there will be no isotype switching. So, how are going to
deceive our immune system? We get the polysaccharide antigen and
mix it with a protein. The protein component of the conjugate can then
be processed and presented on the surface of B cell associated with
MHC class II molecules; this complex is going to be recognized by T
helper cells which in turn will produce cytokines needed for the
production of memory cells.
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Chapter 17 Immunological Memory
After Initial exposure to a certain antigen, memory cells will be formed
and they will stay in our bodies for a long period of time. On a
subsequent exposure (Secondry exposure) to the same antigen, there
will be a more rapid and higher affinity immunological response and
these memory cells will be released. Refer to figures (17.1, 17.2) They
are very important. You have to remember that vaccines are used to
create memory cells for pathogens before we encounter them. Also,
there are qualitative and quantitative differences between naive cells
and memory cells (Will be explained later on). Keep in mind that a single
vaccine results in production of small amounts of memory cells, that'swhy it's important to give booster shots from time to time in order to
achieve full immunity. (Since, the length of survival differs from one
memory cell to another). One significant characteristic of memory cells
is that they have anti-death genes antibodies which will neutralize the
effect of death genes, so they can survive for a long period of time.
Note:
The expression of L-selectin (CD62L), the receptor that facilitates
homing to peripheral lymph nodes in T memory cells is variable,
because they are already activated, so they do need to go lymphoid
tissues. Effector T cells low; because they aren't needed anymore,
they are ready for action. Navie T cells High; because we need them
to bind and go to the assigned areas.
Done!
I'd like to give a shout-out to my dearest friend; Mai Mazen. Thanks a
bunch for helping me with this lecture :]
Tamara Shoter