Self Tolerance Pt 1 Flashcards
What is tolerance?
Unresponsiveness to an antigen resulting from previous exposure to that antigen
What is tolerance not?
Unresponsiveness!
Unresponsiveness is the inability to respond to something, while tolerance requires exposure to the antigen, and it ANTIGEN SPECIFIC!
Antigens that induce tolerance are called what?
tolerogens
as opposed to immunogens
What is self tolerance?
Tolerance to normal body ‘self’ antigens
What is self tolerance mediated by? (2)
1) prevent maturation
2) prevent activation of self reactive cells
failure of any of the mechanisms of self tolerance can lead to immune responses to self antigens (=autoimmunity)
This is relevant also to allergy, autoimmunity, transplantation, and CANCER!
Things that are introduced orally usually generate tolerance better
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Innate immunity is non specific and _______ to self
unresponsive
Adaptive immunity is specific for antigen and is ______ of self
tolerant
Tolerance is a property of what immune system?
adaptive! (lymphocytes)
tolerance is antigen specific
Lymphocyte receptor repertoires are generated randomly, PRIOR to Ag exposure, and subject to clonal selection
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Ig and TcR gene rearrangements occur essentially randomly and independently in ever lymphocyte, generating a receptor repertoire that is capable of recognizing any possible antigen.
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What are mechanisms of Diversity of lymphocytes?
Random assortment of H and L chains (combinatorial diversity)
Multiple Germ-line genes (or gene segments)
Recombination of gene segments: Light chain and Heavy chain somatic gene rearrangements, also a type of combinatorial diversity)
Junctional diversity
- Imprecise recombination
- N (and P) region additions (H chain only)
Where is receptor diversity generated?
primary lymphoid organs
Self-tolerance is learned during development/differentiation, not genetically encoded!
Where does it start?
primary lymphoid organs….so bone marrow for b cells and thymus for t cells
Somatic hypermutation presents an additional problem in terms of self-tolerance for B cells… need another mechanism to monitor for self-tolerance outside of the primary lymphoid organs
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What is central tolerance?
Deletion/inactivation of self-reactive clones in the primary lymphoid organs… not 100% efficient (somatic hypermuation, and tissue specific antigens not found in the bone marrow/ thymus)
what is peripheral tolerance?
multiple mechanisms, different for B cells and T cells
Maintains tolerance to antigens that are not expressed in BM or thymus or not expressed until adult life (after puberty)
The Pre-B cell receptor - with surrogate light chain - has constitutively active signaling that says you…
made a good heavy chain and start making a light chain! - this is a survival signal
Immature B cell after the Pre-B cell has a different type of signaling that is a…
negative signal
if it recognizes a signal in the bone marrow, then that is most likely a self-antigen
the cell then undergoes apoptosis if the IgM on its surface is activated
this is clonal deletion (Death by apoptosis - primary central tolerance mechanism for B cells)
What are the B cell central tolerance mechanisms?
1) clonal deletion (Death by apoptosis) - primary mechanism
2) Receptor editing
3) clonal anergy
Central Tolerance in B cells:
If there is high avidity (multiple receptors are engaged on a B cell) for an immature B cell, what two things can occur?
Apoptosis through deletion
OR!
Receptor Editing in the bone marrow - expresses RAG gene again and allows for more DNA recombination to occur to change the V region
This will lead to a non-self reactive B cell in the peripheral tissues
Central Tolerance in B cells:
What if there is low-avidity for self-antigen recognition?
Here, the antigen is usually soluble rather than cell surface bound so you don’t have as much cross linking of receptors and as high of an avidity
Leads to reduced receptor expression, signaling is blocked (down regulates receptors)
Creates an anergic B cell (unresponsive in periphery)
these cells can sometimes be “rescued”
Peripheral Tolerance in B cells:
What if there is high-avidity self antigen recognition in the periphery for B cells? (2)
1) Deletion through apoptosis
2) functional inactivation - leading to anergy (unresponsiveness)
These two require NO T CELL HELP! - signal 1 but no signal 2
Peripheral Tolerance in B cells:
What if there is self-antigen recognition (low or high avidity) in the periphery?
Regulation by inhibitory receptors occurs!
this does require T cell help?
What are the three B cell peripheral tolerance mechanisms?
1) Lack of T cell help… unresponsiveness or apoptosis
2) clonal anergy?
3) inhibitory receptor engagement?
What three different selective processes do T cells undergo in the thymus? (selection/central tolerance)
1) survival signals via pre-TcR (checkpoint 1)
2) positive selection (checkpoint 2)
3) negative selection (checkpoint 3)
The pre-TcR receptor (beta and pre-alpha chain) have tonic signaling… required to go ahead to rearranging alpha genes (survival signaling)
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After Pre-T cell receptor stage, what happens?
The T cell becomes a double positive T cell and expresses both CD4+ and CD8+ receptors
this is where it differs from B cells - B cells only receive a negative signal at this stage but T cells receive pos or neg from here - this has to do with how T cells recognize their antigens
The T cells in your body are restricted to what?
Your MHC alleles!
That means that only .0001 percent of the T cells you make will have the proper criteria for your MHC alleles (there are like 10,000 diff MHC alleles in the population)
What does positive selection do for your T cells?
It weeds out the useless T cells that do not recognize your own MHC alleles
What is thymic education?
Your T cells learn to be restricted to the self-MHC type
Occurs in the thymus
What happens with weak recognition of the Class II/I MHC + peptide?
where does this occur?
Develops into mature CD4/CD8 depending on what recognized - positive selection!!
happens in the thymic cortex!!
What happens if there is a strong recognition of either class I/II with peptide?
where does this occur?
negative selection! apoptsis
occurs in the MEDULLA! (and cortex?)
what happens if there is no recognition of MHC +peptide?
apoptosis
failure of positive selection (death by neglect)
Thymic education results in a population of T cells biased towards recognizing self MHC found in thymus (MHC restriction). Positive selection!!!
Recogniction of MHC is the dominant mode of selection, the peptide is irrelevent
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positive selection determines if the cell becomes CD4 /CD8
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Positive selection happens where…?
What are the APC’s called there?
cortex!
called cortical epithelial cells
why class II APC’s are located in cortex?
Negative selection starts in the cortex but continues into the medulla
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Complete lack of positive selection (e.g. in Tap deficiency) results in what?
Bare lymphocyte Syndrome, lack of T cells
What happens specifically in absence of Tap and why?
Lack CD8+ cells because Tap is necessary for MHC Class I getting surface of cells
Developing T cells that pass checkpoint 2 (positive selection) go to checkpoint 3 (negative selection) —- medulla to cortex
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T cells that do not recognize self antigen in the medulla are allowed to exit the thymus
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Some T cells that do not recognize Ag in the medulla differentiate into….
T regs!
T regs exert their function (and can also be generated) in the periphery
APC’s in the medulla are bone marrow derived cells - Here engagement of T cell receptor results in death OR in some cases, creates Tregs - inhibitor of T cells
dont understand this mechanism as a scientific community
What are the two T cell central tolerance mechanisms?
Clonal deletion (death by apoptosis)
Clonal anergy
What is the T cell periphery tolerance mechanisms?
Clonal anergy
Inactivation via inhibitory receptors (originally thought to be mainly involved in dampening chronic inflammation, more important role in maintaining self-tolerance only just beginning to be widely appreciated)
For a T cell, we have signal 1 (APC) and signal 2 (?)
CD28 on T cell and B7 on APC
What happens if a T cell failures to get signal 2?
anergy!
unresponsive
Once a T cell gets two signals, it no longer requires signal 2 for effector function! only needed it for activation
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