Lecture15: Immunologic Tolerance and Autoimmunity Flashcards
Central tolerance is induced in immature self-reactive lymphocytes in the ____
primary lymphoid organs
Peripheral tolerance is induced in mature self-reactive lymphocytes in
peripheral sites
Recogniction of self Ags by immature T cells in the thymus leads to _____ and ____
- Death of the cells by negative selection
- the development of Treg cells that enter peripheral tissues
What is AIRE?
is only expressed in thymocytes and it is responsible for making the protein fragments for all body cells to help with negative selection
Central Tolerance for T cells takes place in the
Thymus
Thymocytes that show no affinity at all (nonfunctional thymocytes) undergo
apoptosis
during the central tolerance only thymocytes that are activated below a certain threshold are _____
- positively seleted and migrate into periphery as mature T cells
- most become CD4+ and CD8+ but a small percentage of T cells on the upper end of the affinity/activation curve express FoxP3 and develop into natural CD4+CD25+CTLA4+ Treg cells
___ are key mediators of peripheral tolerance
- Treg cells
- may inhibit T cell activation by APCs and inhibit T-cell differentiation into CTLs
- may prevent T cells from providing help to B cells in production of Abs
iTreg Cells
- Induced Treg cells are formed in the periphery
- FoxP3 expression can be induced by naive CD4+ cells in viroro by antigen recognition and the presence of TGF-beta (note this only occurs if IL-6 is not present and if it is present then induces expression of Retinoic acid receptor (RAR) and Th17 differentiation)
Central B cell Tolerance
- Immature B cells that recognize self Ags in the bone marrow with high Avidity have two outcomes
- die by apoptosis
- undergo receptor editing and change the spcificity of their BCR
- This repleacent of the IgL-chain genes occurs until non-self recognizing receptors are produced or the cell dies
- Weak recognition of self Ags in bone marrow may lead to anergy (funcitonal inactivation) of the B cells
Peripheral B cell Tolerance
- Mature B cells that recognize self Ag in peripheral tissues in the absence of Th cells may be rendered funcitonally unresponsive or die by apoptosis
- The CD22 inhibitory receptor is phosphorylated by Lyn and then rectruits SHP-1 tyrosine phosphatase attenuating BCR signaling
- Therefore, defects in Lyn tyrosine kinase, SHP-1 tyrosine phosphatase, and the CD22 inhibitory receptor lead to autoimmunity
AIRE deficieny causes
autoimmune polyendocrine syndrome
Decreased clearance and imparied tolerance induction by apoptotic cells can lead to autoimmunity and is caused by deficiency in
complement C1q and C4
The AIRE regulates the expression of
Tissue-restricted Ags (TRAs)
If a T cell recognizes a self Ag without costimulation, The T cell
- becomes unresponsive to the Ag because of a block in signaling form the TCR complex. Blocking may be the result of
- Recruitment of phosphatases to TCR complex
- activaiton of ubiquitin ligases that degrade proteins
- Engagement of inhibitory receptors CTLA-4
- anergic T cells remains viable but is unable to respond to the self Ag
