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80 Cards in this Set

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  • Back
Define tolerance:
The specific unresponsiveness of the human immune system to its own self antigens.
What components of immunity exhibit tolerance?
All of them
-innate (no PRRs on self cells)
-Cell mediated - Tcells
-Humoral - Bcells
How is Tcell tolerance different from Bcell?
Tcell tolerance is LONG lived
Bcell tolerance is short lived
Bcell tolerance less complete
Bcell tolerance quiescent in absence of Tcell help
How does the immune system avoid recognizing self?
Well, it doesn't really; there is always the initial point where developing cells must bind self antigen on APCs in generative organs.
What are 2 ways by which immune cells can remain tolerant?
What is an immunogenic antigen?
One that stimulates proliferation and differentiation of a cell upon recognition
What is a tolerogenic antigen?
One that causes the cell that recognizes it to become either anergic or apoptotic.
What is a nonimmunogenic antigen?
One that is ignored by lymphocytes even tho they bear specific receptors for it
What are 3 factors that determine how an immune response to an antigen will develop?
1. Nature of Ag-spcf lymphocyte
2. Nature of the antigen
3. How Ag is displayed
What are 3 factors that determine whether an antigen will induce tolerance?
-Immunologic maturity of the person in whom the Ag resides
-Antigenic structure/dose
-Immunosuppressive therapy
Who is most immunologically tolerant based on maturity?
Elderly and neonates
What antigenic structure and dose is most capable of being tolerated?
-Simple structure
-Very high or very low dose
What does immunosuppression do to tolerance?
Enhances it
Are our body's self antigens normally tolerated or ignored?
Is it possible to induce tolerance of antigens that are causing autoimmune disease?
Where are 2 categories of places where immune cells can see self antigen?
1. Central (generative organs)
2. Peripheral (lymph)
What is central tolerance?
The deletion of lymphs that STRONGLY recognize self antigens present in the generative organs.
What type of selection achieves central tolerance?
Neg selection
What is required for neg selection?
Pos selection - the cells do have to bind to self antigen at least a little.
What happens to the naieve cells that survive neg selection in generative lymphoid organs?
They go out into peripheral circulation.
Are ALL self antigens present in the generative organs?
No; some are just out in the periphery
What is peripheral tolerance?
The deletion or anergy of lymphs that recognize self Ag in peripheral tissues.
What are the two ways that central tolerance is not complete?
1. A small subpopulation of lymphs ESCAPE neg selection
2. Not all self peptides are present in generative organs
How are the cells that strongly bind self antigen during negative selection killed?
By apoptosis of unknown mechanisms.
What antigens are higher in concentration in the thymus; those that induce positive, or negative selection?
Those that cause negative selection (bind strongly).
What is the result of a defect in central tolerance?
Many Tcells mature and exit the bone marrow, capable of binding self antigen!
What are the earliest cells in lymphocyte maturation?
Pro-B or Pro-T cells
What are the 5 steps in lymphocyte maturation?
1. Proliferation
2. Pre-B/T Ag receptor expression
3. Proliferation
4. Ag full receptor expression
5. Pos and Neg selection
What is the first thing expressed on a T or Bcell surface?
HALF of the cell receptor; one chain of it.
What happens after the expression of a pre-lymphocyte receptor during maturation?
The cell proliferates
Once a small clonal population of cells expressing the pre-B/T Ag receptor has expanded, what is the next step in maturation?
Expression of the complete antigen receptor
What are the cells in the thymus that express self peptides to achieve central tolerance?
Thymic medullary epithelial cells
What is the gene that regulates this expression of self antigens?
the AIRE gene
What is AIRE?
Autoimmune regulator
What disease results from mutations in the AIRE gene?
What is APECED?
PolyEndocrinopathy with
Candidias and
Ectodermal Dysplasia
What is the general result of AIRE mutations?
Lack of negative selection of self-reactive Tcells in the thymus.
What are the 3 main manifestations of the antibodies that result from APECED?
-Endocrine gland problems
-Liver problems
-Skin problems
Where do thymocytes enter the thymus?
At the corticomedullary junction
Where do thymocytes go initially in the thymus?
To the cortex
What type of thymocytes are found in the subcapsular region and cortex?
Double negative immature thymocytes
What type of thymocytes are found in the corticomedullary region?
Double positive immature thymocytes
What type of thymocytes are found in the medulla?
Mature single positive thymocytes
Where does negative selection occur in the thymus?
In the medulla
What is required for a NORMAL response of a Tcell to a specific antigen in peripheral lymph organs?
-MHC presentation of Ag
-B7 costimulation of CD28
What will happen if a Tcell in a peripheral lymphoid organ recognizes Ag on an APC that lacks B7?
The Tcell will go into a state of anergy.
What if that anergic Tcell is REstimulated with an APC presenting the same Ag, but now has B7?
It will remain anergic and nonresponsive.
What will happen if a peripheral APC presents Ag and has B7, but now the Tcell is expressing CTLA4 instead of CD28?
It will induce an unchangeable state of anergy.
What is the reason for a Tcell expressing CTLA4 instead of CD28?
We don't know.
In what state will Tcells be if APCs in the periphery have high levels of B7?
Tcells will express CD28
In what state will Tcells be if APCs in the periphery have low levels of B7?
Tcells will express CTLA4
What is the alternative way to achieve periphal tolerance besides anergy?
Tcell deletion
One more thing about anergy; what stimulates high levels of B7?
ok back to Tcell deletion
What are two types of proteins expressed on Tcells that deal with cell death?
1. Death receptors
2. Apoptotic proteins
If a CD4+ Thelper cell is repeatedly activated by self antigens, what will result?
Expression of Fas on some of the clones, and FasL on others
What is the result of Fas/FasL upregulation?
Cellular apoptosis
What proteins increase in surface expression in response to Antigen recognition?
What proteins increase in surface expression in response to 2nd signal activation?
So what happens if the 2nd costimulatory signal is missing?
Only pro-apoptotic proteins are expressed so the Tcell undergoes apoptosis.
What are the 3 ways by which peripheral tolerance is achieved?
1. Anergy
2. Deletion
3. Tsuppression
What cells achieve T cell suppression?
Tregulatory cells
Where do Tregs develop?
In the thymus
How do Tregs develop in the thymus?
By recognition of self antigen by immature double pos thymocytes (in the corticomedullary area)
Why do Tregs develop?
Because of their TCR-MHC avidity
How do Tregs work?
They blunt the activation of mature Tcells by contactdependent or independent mechanisms.
What is the Contact-dependent pathway for Treg suppression of Tcell activation?
Binding of the Treg to the Tmature cell induces inhibitory signaling, maybe CTLA-4
What is the contact-independent pathway for Treg suppression of Tmature activation?
The Treg cells secrete high levels of TGFb and IL-10, which inhibits Tcell activation.
Are tolerogenic self antigens present in generative organs?
Are tolerogenic self antigens presented along with second signals?
No; as a result it leads to Tcell anergy or apoptosis.
How long do tolerogenic antigens persist in the generative organs?
Throughout life
Why would we want tolerogenic self antigens to persist for life?
Because it's the REPEATED stimulation of Tcells with self antigens that induces deletion.
Are immunogenic, foreign antigens present in generative organs?
Where are immunogenic, foreign antigens concentrated?
In peripheral lymphoid organs.
Are immunogenic, foreign antigens presented with second signals?
Why is it good that immunogenic, foreign antigens are presented with 2nd signals?
It promotes lymphocyte survival and activation!
How long do immunogenic, foreign antigens persist?
Usually short lived - you want the immune system to eliminate them!
What type of antigen results in clonal DELETION of Bcells?
Surface antigen
What type of antigen results in clonal ANERGY of Bcells?
Soluble antigen
What type of antigen results in clonal IGNORANCE of Bcells?
Low concentrations of soluble antigen.