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99 Cards in this Set

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What is the difference between central tolerance and peripheral tolerance?
Central tolerance is tied into the selection process

Peripheral tolerance is completely independent of selection because it happens outside of where the cells develop
Where does almomst everything happen in regards to early T cell development/maturation?
thymus
Where does extra-thymic T cell development occur?
gut
Where do the early thymic precursors come from?
blood
What are the 2 regions of the thymus and what occurs in each region?
cortex and medulla

cortex - all the early thymic development occurs here. Th cells go thru stages defined as DN1, DN2, DN3/4, pr-DP, DP, SP which goes into the thymic medulla and into the periphery

Medulla - late thymic development happens here; you have the cell either becoming single positive CD4+ or CD8+; the cells then integrate back into the capillaries and into the circulatory system
What occurs during the first positive selection step in maturation of T cells?
T cell is trying to determine if its receptor is functional. There is positive selection for the ability to react with Ag that has been presented on a MHC molecule

As the signal passes through the Ag receptor, it tells the T cell that this is potentially functional and its positively selected to go fwd. If it doesnt see that signal, the cell dies by apoptosis - death by neglect
What occurs during negative selection in the maturaion of T cells?
Deletion of T cells expressing Ag receptor that react strongly when engaged by self-Ag

this is the first step of central tolerance

Any Ab that reacts strongly with self-Ag is deleted

99% of the T cells that are generated get deleted. Only 1-2% goes to the periphery during thymic development
What is the second positive selection in the maturation of T cells?
This is where the cells are intstructed to become either CD4+ or CD8+
Where does a T cell precursor come from?
An early hematopoietic stem cell differentiates into a common lymphoid progenitor. From this cell comes a population of cells called early thymocyte precursors.

An early thymocyte precursor cell migrates through the blood and becomes the T cell precursor. The ETP is not committed completely to the T cell pathway - it still has the option of going through the B cell pathway, depending on the signal it receives. The T cell precusor goes into the thymic cortex and goes through stages -- DN1, DN2, DN3, DN4
What does double negative mean?
cell doesnt express either CD4 or CD8
What does double positive mean?
it expresses both CD4 and CD8
What does single positive mean?
Cell either expresses CD4 or CD8
What defines the following

DN1?
DN2?
DN3?
DN4?
DN1 - c kit expression, CD44 expression, but no CD25 expression

DN2 - all 3 markers expressed

DN3 - only CD25 expressed

DN4 - lose all of the markers

There is ordered expression of these molecules and during this process, there is TCR rearrangment
During what stage do you have expression RAG?
DN2
What is RAG?
recombination activating gene, which causes the initial rearrangement of TCR-beta chain. This is followed rearrangement of the TCR alpha chain.
Which chain undergoes rearrangement first: alpha or beta?
beta first, then alpha
What occurs during the DN4 stage?
the Pre-T(alpha) combines with the TCR beta chain to give what we call a functional TCR chain of an early TCR receiving positive selection signals

At this stage, if the cells do not receive a signal, it tells the cell that something is wrong and the cell will die.
If cells go from DN4 to DP, what is occurring in the cell?
upregulation of both CD4 and CD8

they now have a fully functional TCR alpha chain and Ag receptor. If the cell survives it's going to have that same receptor for the rest of its life
Cells go from DN to DP stage via...?
positive selection
DP cells undergo what type of selection?
negative
SP cells go through what type of selection?
positive
Describe what is occurring during the first positive selction?
The epithelial thymic medullary cells express MHC I and MHC II. They have within their Ag binding sites a peptide. These peptides are presented to T cells during selection. **If the T cell is unable to react to this completely, meaning it cannot bind/recognize the peptide presented by self MHC, it will undergo death by neglect
What occurs if they react with very high affinity to self-peptides?
cells will also die
What are 2 types of cells that expressed both in the medullary region and cortical regions of the thymus?
macrophages and dendritic cells
What is the major governing factor that dictates the T cell maturation through the thymus?
Signal strength
What is the instructive model of differentiation from double positive to single positive?
It suggests that you have DP cells. It a DP cell recognizes peptides in context of MHC class I, that cell down regulated CD4 and becomes CD8+ or vice versa
What is the stochastic model of differentiation from double positive to single positive?
This model suggests that the down-modulation of CD4 or CD8 is a RANDOM event. At that stage in the random event, if cells happen to bind to MHC class I and it down regulated CD4, it can mature into CD8

If it looks at the wrong MHC class at that time, the cell will die
What is immune tolerance?
the inability to respond to Ag stimulation or immunological unresponsiveness
Describe adult onset type 1 diabetes.
Those self-reactive T cells could be present for an individual's entire life, but they didnt see signs of diabetes until later in life. The reason for this is that there has been an activation of the T cell clone that is self-reactive. Until that time, T cell clone was maintained and silenced. The whole process of silencing is immune tolerance.
What is central tolerance?
this largely reflects early selection.

It is the negative selection of immature lymphocytes by clonal deletion of self reactive clones during development. This occurs by induction of programmed cell death (apoptosis)
What is one disease in which there is a defect in central tolerance?
Addison's disease

it is a reaction to the adrenal cortex so there is a reduction in the production of cortisol
What is AIRE?
autoimmune regulator - transcription factor

It is known as the master regulator for ectopic expression of peripheral tissue-restricted Ags in stromal cells of the thymic medulla

These Ags that have no reason to be in the thymus, other than for Ag selection are only expressed because of this transcription factor
What is APECED?
autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy

Triad of symptoms:
1. Chronic mucocutaneous candidiasis
2. Hypoparathyroidism
3. Adrenal insufficiency
What c'some is the AIRE gene localized to?
21
What are 3 factors that regulate central tolerance?
Avidity, Affinity, Co-stimulation
What is affinity?
intearction with an Ag and Ag receptor

Affinity is the strength of a single binding site between 2 molecules. It looks at the quality of the interaction
What is avidity?
interaction b/w Ag:MHC and Ag receptor

the strength of binding between a single binding site of a molecule and a ligand influenced by both affinity and valency of interactions

Quantity or number of interactions

You can have a lower binding strength but quantity of binding could overcome the quality of binding
What is the fxn of co-stimulation?
Co-stimulatory signals enhance signal strength
Describe B cell development.
Happens in the bone marrow and re-circulated cells through the circulation (unlike T cells)

ProB -> PreB -> immature B -> naieve B cell --> mature B
The immature B cell is most sensitive to what type of selection?
Negative selection and therefore central tolerance
Describe the immature B cell.
It has a fully functional Ag-receptor: an Ig molecule that is either a kappa or lambda chain

Cross linking of this Ag-receptor by antigen either leads to activation or death

Cross-linking in an immature B cell - leads to death

Cross linking in a mature B cell - leads to activation
What are 3 processes for central tolerance?
Deletion - strong self reactive cells die and disappaer

Anergy
Receptor editing
What is anergy?
functional inactivation of a cell - that cell suddenly becomes unable to respond to Ag
What is receptor editing?
This is what a B cell does in a way to rescue itself.

Where there is a strong deletion signal, befire it dies, the cell tries to go back and rearrange its second light chain functionality. It tries to revise the receptor in order for the B cell to go back into the periphery. This is a process that causes on chain to get inactivated and the second get activated

At this stage you have reactivation of the recombination machinery: RAG1 and 2
What is clonal deletion?
If a stromal cell in the bone marrow has a strong interaction with the immature B cells, this leads to death of the B cell
What is the difference between clonally ignorant B cells and anergic cells?
Clonally ignorant B cells are seeing Ag in the context of soluble Ag. They are somehow silenced, but you can reactivate them pathogenically in the periphery.

Anergic cells, however, cannot be reactivated.
Why are not all self reactive T/B cells not deleted during development?
1. Need for a peripheral repertoire that will protect from pathogens
2. Peripheral tissue specific Ags not expressed in thymus
3. Expression of new Ags occurring as a result of tissue damage
4. Expression of specific endopeptidases that modify peptides in the thymus
5. Positive selection of specificities that enxhibit weak self-reactivtiy but with the propensity for pathogenic autoreactivity
What is peripheral tolerance?
control of autoreactive T and B cells in the periphery
What are some factors that regulate peripheral tolerance?
1. Co-stimulatory molecules (signal 2)
2. Cytokines (signal 3)
3. Inhibitory molecules
4. T-regulatory cells
5. Dendritic cells
What is the role of signal 2 in tolerance?
A TCR recognizing Ag sees signal 1

Signal 2 is co-stimulation through CD28, which enhances the response. CD28 recognizes another molecule on the Ag presenting cell called B7.

If you lack this co-stimulation, it causes anergy and/or apoptosis. There is a molecule called CTLA4, which is expressed inducibly for turning down response. If you express CTLA4 as a soluble form, it binds to B7 and blocks the ineraction b/w CD28 and B7 causing anergy in activated cells
What is the difference between LAD1 and LAD2?
LAD1 - due to integrin deficiency

LAD2 - due to transport of fucose residuse and you do not get good selectin binding as a result
What are monokines?
cytokines produced by monocytes
What are lymphokines?
cytokines produced by lymphocytes
What are Interleukins?
cytokines produced by lymphocytes and acted on by lymphocytes -- this was found to be FALSE. They can be produced by many cell types and act on many cell types.
What are Interferons?
important in ctonrolling viral infections and augmenting the immune response
What is the function of gamma interferon?
hypes of macrophages to become more phagocytic and start immune function
What are colony stimulating factors?
molecules that help differentiation of immune cells as they come from pleuripotent stem cells to the immune precursors, myeloid and lymphoid
What are chemokines?
involved in maturation of cells, chemoattraction, as well as wound healing
What are growth factors?
cytokines involved in stem cell differentiation and other fxns
What does it mean for a cytokine to be pleiotropic?
Each cytokine mediates more than one function; one cytokine mediates different functions on different cells depending on the cell type it it interacts with or the signals it has gotten before the interaction
What does it mean for cytokines to be redundant?
There is an overlap in function. example - IL6 is important in acute phas response, generates production of acute phase proteins from the liver, and is a potent growth factor for B cells
What does it means for cytokines to be synergistic?
If you treat with one cytokine, you get one resopnse. If you treat with another cytokine, get another response. If you treat with both of the cytokines together, you will see more than an additive response.
What does it mean for a cytokine to be an antagonist? Give an example.
Need to rev up the immune system when you encounter a pathogen, but also turn down the immune system once the pathogen has been removed to get rid of the cells you don't need and keep the memory cells.

Example - TGF-beta
--this is an anti-inflammatory cytokine. It is produced immediately as immune response has turned on; acts as a feedback loop to temper the immune response to the amount of pathogen that is there to be eliminated
What are the cytokine properties?
1. low molecular weight proteins or glycoproteins
2. Multimeric in form
3. Synthesized in active and inactive forms - they may have to be activated by cleavage from enzymes that will cleave off a peptide that is critical to blocking their active site or conformational change of their function; some sit on the surface of the cell to mediate leukocyte trafficking.
4. Secretion is brief and self-limiting
5. Active at low concentrations
6. Signal cells by binding to specific receptors on target cells
Why do cytokines not need to be activated for long periods of time?
Production of cytokines if for local actions. Cytokines interact closely with cells that need to be turned on or off. Cytokines don't need to be produced for long periods of time because they can end up in circulation and become like a hormone in the body and it would activate many T cells all over the body.
Describe cytokine receptors.
Each cytokine has its own receptor, but there is not just one receptor for each cytokine. Receptors are multichain complexes and signaling through these receptors require a number of different events.

Structural features that differentiate the receptors
What are the different structural features of a multichain receptor?
1. cognate receptor - a single extracellular subunit that binds cytokine

2. Signaling receptor - a signaling chain that transduces into the cell

Signaling receptor can be paired with different cognate receptors which allows you to get specificity with the different cytokines, but use the same signaling mechanism. This creates redundancy within the system
What is the generalized mechanism of cytokine function?
alpha chain cognate receptor - binds the cytokine

beta chain signaling receptor - allows signal transduction

Once the complex is together with cytokine bound, it becomes activated and intracellular Jak kinases can become activated. Jaks are good at phosphorylating sequences on receptor subunits as well as themselves. Jaks can also phosphorylate additional molecules that can be recruited to complex.

Intracellular STAT phosphorylation - causes STATs to homodimerize and then be transported to nucleus and serve as transcription facotrs that bind to promoters of different genes that the particular cytokine is involved in regulating.
Describe autocrine signaling and give an example.
cytokines act on on the cell that produced them.

IL2 - a good T cell growth factor; when T cells get their first and second signals, they make and release IL2. IL2 then binds IL2 receptors located on the same T cell that released it to drive growth and proliferation.
Describe paracrine signaling and give an example.
Released from a cell and acts on a neighbor.

Interferons - when infected with viral infection, cells are stimulated to produce interferons. binds to receptors on neighbors to prime them to handle a viral infection
Describe endocrine signaling and give an example.
Acting systemically like hormones

TNF-alpha and IL1 can be produced in high enough concentration to get into bloodstream. It binds to receptors in the brain where thermal regulation occurs and you develop a fever
What is Stem Cell Factor?
there are cytokines help retain stem cells in this capactiy to continue to develop
What is the fxn of IL-7?
critical cytokine for development of T and B cells

w/o IL7 - you dont get T and B cells.
What is the fxn of colony stimulating factor?
Required for myeloid progenitors to develop into basophils, eosinophils, neutrophils, and macrophages

Macrophage colony stimulating factor for monocytes

Granulocyte colony stimulating factor - for neutrophils
What is the function of IL3, IL5, and IL6?
aid in development into myeloid subsets for fighting off infection, in innate immunity
What is role of IL7 in B and T cell development?
Early in development, B cells are interacting with bone marrow stromal cells that feed them signals. If they do not interact with c-Kit, they do not develop to express the IL7 receptor. Pro-B cells have to express the IL-7 receptor to move into Pre-B cell stage to rearrange their genes and put Igs on the surface of the B cells. Without IL-7, you are stunted at the Pro B cell stage you never develop
What is the role of IL1, TNF, IL6, interferons?
involved in innate immunity to drive initial inflammatory responses, make it easier for macrophages and neutrophils to get into sites of infection, turn cells on to recognize the viral infection and take the appropriate steps to limit viral replication, but this does not mean they are not also involved in adaptive immunity.

IL1 and IL6 give co-stimulatory signals to T and B cells to differentiate into appropriate effector cells
What is the role of IL2?
involved in development of T cells. T cells divide into subsets depending on the antigen and environment they are in and they produce characteristic cytokines

TH1 - drive cell mediated immunity that activates cytotoxic T cells

TH2 - cytokines produced to augment humoral immunity such as the development of B cells and B cell isotype switching
What is the role of Gamma Interferon?
produced largely by T cells and natural killer cells are involved in the activation of macrophages

Once you have an adaptive immune response going, you have T cells producing gamma interferon and that feeds back to activate macrophages to clear pathogens
What are the types of Type 1 interferons? What are their roles?
Alpha and Beta

both are produced by all cell types; producting is induced by viral infection and other pathogen

Functions:
1. interested in increasing MHC 1 molecules
2. Shut down the cell by producing RNAses DNAses, and proteases that are generated inside the cell to chew up viral proteins, DNA, and RNA
What is the role of Type 2 Interferon?
produced by activated T cells (Ag-activated)

1. Very good at inducing MHC class II expression because it will serve as a potent activator of macrophages
2. Promote B and T cell proliferation
What is the acute phase response? What cytokines are involved with it?
critical aspect in dealing with bacteria

Metabolic response to an organism to eliminate invading pathogens and prevent ongoing tissue damage that occurs --innate response is non-specific and kill anything in path to get rid of pathogen

mediated by TNF-alpha, IL1, IL6, IL8 and interferon gamma
What is the role of TNF-alpha?
Production induced by LPS and made by macrophages and many other cell types

LPS bind to macrophage Toll like receptor 4 or if it has peptidoglycan in it, it will bind to toll like receptor-2. This activates macrophages and neutrophils.

TNF-alpha induces pro-inflammatory cytokines and production of colony stimulating factors at teh beginning of the immune resopnse to generate additional cells that can eliminate the pathogen

They are critical for the initiation for acute phase response (fever) and induce the adhesion molecule expression making it easier for phagocytic cells to get into sites of infection
What is the role of IL1?
produced by macrophages and other cell types locally

Enhance T cell proliferation and B cell growth and induced expression of cytokines, continue the acute phase response.
Where are acute phase response proteins generated? What induces their production?
liver by hepatocytes

induced by IL1
What is the role of IL6?
produced by macrophages and other cell types

major inducer of acute phase protein production

Major growth factor for B cells; WITHOUT IL6, you are not going to have a good adaptive immune response
What are the acute phase proteins?
1. Host defense proteins increase
2. Protease inhibitors
3. Anti-oxidant molecules
Give examples of host defense proteins.
C-reactive proteins - levels are usually low in healthy individuals but in response to infection, get an increase in hepatocyte production of these proteins. They bind antigens and activate complement. They are important in phagocytic clearance of invading pathogens. They are killing cells or marking them for destruction.
Give examples of protease inhibitors.
Way to limit damage to your own tissues since a low of different molecules are being produced

C1 inhibitor blocks the classical pathway of the complement system

Alpha- 1 proteinase inhibitor - broad blockage of active sites
Give examples of anti-oxidant molecules.
Neutrophils produce ROS that can damage own tissue

Haptoglobin and Ceruloplasmin scavenge these molecules and limit damage to host proteins
How are chemokine families classified?
cysteine motifs
Where are chemokines expressed?
primary and secondary lymphoid organs due to their trafficking functions
What happens if you are missing IL2?
T cells are dependent on IL2 for activation, growth and proliferation after Ag binding. If you dont have IL2, you basically knock T cells down.
What do TH1 cells produce?
cytokines that aid in cell-mediated immunity

IFN gamma and IL2
What do TH2 cells produce?
aid in Ab production, B cell growth, and regulate isotype switching in B cells

IL4, IL5, and IL6

for isotype switching TGF-B for IgA and IL4 for IgE
Describe cytokine therapy in regards to chronic myeloid leukemia.
IFN-alpha so disease can be in remission
Describe cytokine therapy in regards to rheumatoid arthritis.
soluble TNF-alpha receptor therapy

side effect is that you may develop Multiple Sclerosis

TNF is considered a pro-inflammatory cytokine, but may have some anti-inflammatory effects involved in tolerance and prevent the development of MS
What is used in therapy for MS?
IFN-beta
What would you use procrit for?
to boost RBC levels in patients with chemotherapy