Immune Tolerance and Autoimmunity Flashcards
What is autoimmunity?
Adaptive immune response specific for self-Ags
What is an auto-antigen?
Ag targets in autoimmunity
What are auto-reactive cells?
Immune cells that respond to auto-Ags
What are auto-antibodies
Abs that target auto-Ags
What are the 2 hallmarks of autoimmunity?
1) Loss of immune tolerance to self-Ags
2) Tissue dmg/physiological dysf(x)
What are the 3 broad factors that cause a loss in self-tolerance?
1) Genes
a) single gene defects
- AIRE (-ve selection in thymus)
- Foxp3 (T regs)
b) multifactorial
- aetiology for majority of autoimmunity diseases
- environmental + genetics
c) MHC allele linked
- ankylosing spondylitis and HLA-B27
2) Sex bias
- 10x incidence of SLE in F
3) Infection
- microbial Ags similar to self-Ags
What is central tolerance?
The selection process through which surviving lymphocytes do not exert effector f(x) to self-Ags
Why is central tolerance needed?
VDJ recombination can produce lymphocytes that bind very strongly to self-MHC and self-Ag and hence have a high chance of eliciting autoimmunity (inducing apoptosis in normal cells)
How are T lymphocytes selected for central tolerance?
via negative selection where T cells with TCRs that bind to self-MHC-self-peptide with very high affinity under apoptosis
What is the role of Autoimmune Regulator (AIRE) in central tolerance?
They cause transient exp. of extra-thymic tissue specific Ags in the thymus.
Does central tolerance involve immature or mature lymphocyte?
Immature
What is peripheral tolerance?
The processes by which mature T cell activation is controlled to prevent autoimmunity.
What are 3 signals in T cell activation?
1) TCR binding to peptide MHC
2) Co-stimulation (eg. CD28-B7, CD40-CD40L, 4-1BB-4-1BBL)
3) Cytokines (eg. IL-2→CD8, IL-12→Th1, IL-4→Th2)
What are the 4 mechanisms of peripheral tolerance?
1) Ignorance (no signal 1)
2) Anergy (Signal 1, no signal 2)
3) Deletion (recognition of self-Ag → no co-stimulation)
4) Regulatory T cell inhibition
How does ignorance contribute to peripheral tolerance?
T cells with TCRs that have peptide-self-MHC interactions too weak don’t activate
(useless T cells → can never cause autoimmunity)
How does T cell anergy contribute to periphery tolerance?
It ensures that T cells that bind to immature APCs or Non-APCs do not receive co-stimulatory activation to be activated.
What happens in an anergised T cell?
- It is an Ag-dependent process that causes anergy gene transcription
- T cells don’t differentiate into effector cells
- remain unresponsive (even w subsequent signal 1 & 2)
What are the 3 mechanisms of T cell anergy?
1) Failure to activate IL-2 autocrine loop
2) Abnormal TCR-complex signaling
3) Ligation of inhibitory receptors
What are the 2 major pathways in T cell deletion?
1) Mitochondrial (regulated by BCL-2)
2) Death receptor (meditated by Fas-FasL)
How is a T cell deleted through mitochondrial and death receptor upon recognition of self-Ag?
Apoptosis
T regs are ____ dependent T cells possessing TCRs that _____ recognise self-peptide-self-MHC and suppress self-reactive immune cell activation.
IL-2
strongly
Which gene is crucial to Treg function?
FOXP3
How do Treg cells inhibit immune cell activation?
1) Cell-cell contact (CTLA-4 exp.)
2) Soluble factors (inhibitory cytokines eg. TGF-ß)
What are 2 immune checkpoint axes?
PD-1/PD-L1
CTLA-4/B7
