Lecture 19 - Immunologic Tolerance and Immunology Flashcards
What is immunologic self tolerance and how is it generated?
L19 S3
Unresponsiveness to an Ag, typically self Ags.
It is generated from negative selection in the thymus
Differentiate between central and peripheral tolerance?
L19 S4
Central tolerance:
-occurs in primary lymphoid organs upon generation of novel BCR/TCRs in immature lymphocytes
Peripheral tolerance:
-occurs in peripheral lymphoid organs in mature lymphocytes
What are the possible outcomes of self reactive lymphocytes in central tolerance and peripheral tolerance?
L19 S5
Central tolerance:
- deletion
- BCR editing
- development into T reg cells
Peripheral tolerance:
- anergy
- deletion
- suppression by T reg cells
What transcription factor regulates expression of tissue restricted antigens in the thymus and what cells are these presented on?
L19 S7
AIRE which is expressed in medullary thymus epithelial cells
How do Treg cells regulate immune response and what cell types do they inhibit?
L19 S8;14
- they constitutively express IL-2R allowing them to keep IL-2 from effector T cells
- the constitutively express CTLA-4 allowing them to bind DCs earlier than effectors
Cells:
- inhibits effector T cell activation
- inhibits CTL activity
- inhibits B cell activation
What cytokines/signals regulate Th17 and induced T(reg) cells?
L19 S15
TGF-β:
-required by both during Ag recognition
IL-6:
- stimulates Th17 differentiation
- inhibits T(reg) differentiation
IL-2:
-aids in development and necessary for survival of T(reg)
What are the components that activate B cell peripheral tolerance?
L19 S17
CD22:
-inhibitory receptor for B cells
Lyn:
-phosphorylates CD22, activating it
SHP-1:
-phosphorylase which inactivates immune signals
*defects in these results in autoimmunity
What combination of BCR signaling and BAFF signaling is responsible for B cell maturation?
L19 S18
High BCR signaling/low BAFF signaling:
-deletion
Low BCR signaling/high BAFF signaling:
-maturation
What factory is responsible for breaking central tolerance when defective and why?
L19 S25-26
AIRE
- stimulates expression of tissue-restricted Ags (TRAs)
- if these are not expressed, T cells are not tested for reactivity to self-Ags9
What factors cause T-cell anergy?
L19 S30
- absence of costimulation (CD28 engagement)
- stimulation of CTLA-4
What diseases are associated with CTLA-4 polymorphisms?
L19 S34
Autoimmune diseases:
- type 1 diabetes
- Graves’ disease
How are natural T(reg) cells formed and what is characteristic of them?
L19 S38
- formed in thymus
- positively selected from strong TCR interaction with self-antigen but survives due to anti-apoptotic molecules
Characteristics:
- CD4+
- CD25+ (IL-2Rα)
- CTLA-4 expressed at high levels
- FOXP3+
What are methods of preventing autoimmunity?
L19 S43
Immunologic ignorance:
-physical separation of Ag from T cells
Deletion:
-T cells express Fas (CD95) which stimulates FasL+ cells to undergo apoptosis
Inhibition:
-CTLA4 (CD152) binds CD80 and inhibits T cell activation
Suppression:
-T(reg) cells produce inhibitor cytokines such as IL-10 and TGF-β
What genetic factors are associated with autoimmunity?
L19 S47
Typically complex, polygenic traits that increase susceptibility.
MHC genes have the strongest association
What mechanisms allow for some microbial infections to trigger autoimmune responses?
L19 S49
Molecular mimicry:
- bacterial Ags are similar to self-Ags
- e.g. streptococcal Ag can mimic cardiac myosin
- e.g. MS resulting from Epstein-Barr Ag which is similar to myelin basic protein
Bystander activation:
-activation of auto reactive lymphocytes due to massive activation of naïve cells and release of cytokines
Release of sequestered self-Ags:
-lysed host cells release self-Ags that lymphocytes are not checked for self-reactivity with
