Immunologic tolerance Flashcards
What is important in order to have positive selection of immature T and B cells?
TCR or BCR have weak affinities to self-antigens
Where are T-cell “central” self-antigens found?
- Thymus
- expressed in periphery but brought to thymus by circulation
- Peripheral tissue-specific Ag expressed in thymic medullary epithelial cells under control of TF Autoimmune regulator (AIRE)
What stage does negative selection occur? (T cell)
Does the TCR show high or low affinity to central self-Ag in order for deletion to occur?
Double positive CD4+ CD8+
high affinity
Which cells mediate negative selection of thymocytes?
thymic DC
Macs
thymic medullary epithelial cells
(DC and Macs are bone marrow origin)
Where does negative selection of thymocytes occur?
Cortex-medulla junction (mainly)
Medulla
How does deletion occur for negative selection of thymocytes? (central tolerance)
Deletion by apoptosis
Autoimmune polyendocrine syndrome
- Mutation in AIRE gene
- Leakage in negative selection
- Affects endocrine organs: parathyroid gland, adrenal glands, pancreatic islets
Tolerance to “central” self Ag in B cells is induced where? in which stage?
Bone marrow
immature B cells
Does B cell have central tolerance mechanisms for high or low affinity to central self Ag?
BOTH
What is the mechanism for high affinity self Ag? (B cell)
Receptor editing
Clonal deletion
What is the mechanism for low affinity self Ag? (B cell)
Anergy
What happens during receptor editing?
Reactivate expression of Rag1 and Rag2 –> DNA rearrangement of Ig gene on k light chain - change specificity
What happens during clonal deletion?
Apoptosis
What is anergy?
reduced receptor expression
signaling block
basically, unresponsiveness to subsequent encounter of the self ag
What happens if autoreactive T cells escape negative selection?
become mature autoreactive T cells and exit thymus to the periphery
How are mature autoreactive T cells in the periphery kept under control?
- Anergy
- Deletion
- (Foxp3+) Regulatory T cells
Anergy in T cell peripheral tolerance is due to
Absence of costimulation
Anergy in T cell peripheral tolerance
Mechanism:
Down regulation of TCR expression : Cbl-b ubituitin ligase-mediated degradation
Induction of inhibitory receptors:
CTLA-4 – high affinity for B7 - competitive inhibition of B7:CD28 - inhibitory signal
PD-1 – affinity for PD-L1 or PD-L2. Block T cell activation or pro-inflammatory cytokine expression on APC
What causes a breach in T cell Anergy?
infection:
PAMPs interact with TLR –> APC (immature DC) express high levels of MHC II and costimulatory molecules (B7)
Deletion of autoreactive T cells in periphery
apoptosis by:
- mitochondrial pathway (activate Bim)
- Fas-FasL mediated –> activation-induced cell death (AICD)
What happens when Fas-FasL apoptosis is defective?
Autoimmune lymphoproliferative disorder (ALPS)
What can actively suppress activation of conventional CD4 T cells and CD8 T cells?
Treg
What offers best hope for curing autoimmune disease?
T reg
Types of Treg cells
- natural
- inducible
