Mechanisms of tolerance

Question 1

What does immunological tolerance refer to?

Answer 1

Mechanisms by which lack of immunological reactivity is induced + maintained.
Tolerance is antigen specific.
Immunological equilibrium:
balancing lymphocyte activation (reactions against pathogen) + tolerance regulation (no response to self + other harmless antigens).

Question 2

How do T cells recognise antigens?

Answer 2

Express TCR / CD3 (+ CD4 or CD8)

Recognise self MHC I / II + peptide antigen

Question 3

Tolerance to self antigens is induced in which structures?

Answer 3

Central lymphoid organs + maintained in periphery

Question 4

The specificity of TcR in the immature repertoire is also random and will include cells with receptors that are…?

Answer 4

Self antigen recognition -> harmful, negatively select
Useless -> neglect
Foreign antigen recognition -> useful, positively
select.

Question 5

Which cells form the peripheral T cell pool?

Answer 5

Only cells that bear antigen receptor with appropriate affinity for peptide presented in self MHC complexes that complete maturation.
Naïve T cells -> self MHC restricted + self tolerant

Question 6

Where does thymic development occur?

Answer 6

Thymic stroma (epithelial cells + connective tissue) provides microenviroment for T cell development + selection.
Thymic epithelial nurse cells in cortex support positive selection. 
Medullary epithelial cells support negative selection.
Thymocytes associated with epithelial cells as they develop in thymus.

Question 7

Outline the screening system

Answer 7

Discrete forms of selection
Positive selection -> retention of thymocytes expressing TcR that are restricted in recognition of antigen by self MHC i.e. selection of useful.
Negative -> removal of thymocytes expressing TcR that recognise self antigens presented by self MHC i.e. selection of harmful.

Question 8

Outline positive selection

Answer 8

T cells from bone marrow negative for CD4, CD8, TCR: double negative -> somatic rearrangement of genes encoding for b + a chains of TCR and expression of both CD4 + CD8 (small non-dividing cortical thymocytes, short life-span) -> double positive.
Thymocytes express TCR
Thymocytes able to recognise self MHC expressed on surface of cortical epithelial cells survive.
Induction to survival, differentiation, maturation (long-lived cells). those who cannot undergo apoptosis.
MHC restriction

Question 9

Outline negative selection

Answer 9

Dendritic cells + macrophages at cortico-medullary junction are APC expressing MHC I + MHCII molecules + present self-peptides to T cells.
Modest binding of dendritic cells -> modest binding -> lives.
/ strong binding -> possible auto-immunity -> apoptosis.
Tolerance induction

Question 10

Which gene is an autoimmune regulator and what are the consequences of a mutation to this gene?

Answer 10

AIRE
Autoimmune polyendocrine syndrome (APS-1).
Mouse knockout -> failure to express many self antigens in thymus + expression of autoantibodies.

Question 11

What is peripheral tolerance and what happens when there is a breakdown?

Answer 11

Tolerance being induced + maintained outside thymus

Auto-immunity/allergy -> immune system responds to self or environmental antigen.

Question 12

What are the mechanisms of peripheral tolerance?

Answer 12

Ignorance -> lymphocytes fail to recognise or respond
Clonal anergy -> binding of antigen makes lymphocyte unresponsive.
Suppression -> interaction with suppressor cells / cytokines to inhibit lymphocytes responsiveness.
Clonal exhaustion -> continued stimulation by persistent antigen may ‘wear out’ responsive cells.

Question 13

What are unresponsive B cells?

Answer 13

Auto-reactive B cells can be present without being able to be activated if there is no help available.
If help is provided (e.g. injecting auto-ag coupled to immunogenic foreign carrier), B cells will mount an immune response -> split tolerance.

Question 14

What is clonal ignorance?

Answer 14

Self reactive lymphocytes fail to recognise or respond to some self antigens in periphery. cells neither die nor become anergic.

Question 15

What causes clonal ignorance?

Answer 15

Antigens anatomically sequestered from immune system -> T cells can’t reach cells bearing antigen -> tissue grafts placed in these sites aren’t rejected.
Immunologically privileged sites -> eye, testis, uterus / placenta, allow foreign graft survival.
If sequestred antigen is released -> autoimmunity can result.

Question 16

What is sympathetic ophthalmia?

Answer 16

Physical trauma in one eye can initiate autoimmune response to both eyes -> blindness in both damaged + undamaged eyes

Question 17

What is induction of anergy / clonal anergy?

Answer 17

Binding of antigen makes lymphocyte unresponsive.

Presentation without co-stimulation CTLA-4 signalling

Question 18

What are the consequences of knockout of CTLA-4 in mice and heterozygous mutation in humans?

Answer 18

Immune dysregulation -> lympho-proliferation, multi-organ inflammation

Question 19

What is the function of anti-CTLA-4 antibody?

Answer 19

Blocks CTLA-4 + prevents inhibitory signals.

Blocking CTLA-4 promotes tumour rejection -> CTLA-4 Limits immune responses to tumours -> tumour immunotherapy.

Question 20

What is the function of treg cells?

Answer 20

Maintains peripheral tolerance through suppressive mechanisms.
suppresses activation of effector responses + critical for regulating homeostasis + tolerance to self antigens.

Question 21

What is absence of T regulatory cells associated with?

Answer 21

CD25 (IL-2Ra) constitutively expressed by Treg cells:
consumes IL2 to limit expansion of Teff.
depletion of CD25(+) CD4(+) T cells leads to autoimmunity.
FOXP3 transcription factor:
critical for TReg activity and development
mutations in FOXP3 gene cause IPEX -> Immunodysregulation, Polyendocrinopathy + Enteropathy, X-linked syndrome] -> systemic autoimmunity in first year of life.

Question 22

What are the clinical applications of treg cells?

Answer 22

Strengthen self-tolerance in autoimmune disease.
Induce tolerance to non-self-antigens in organ transplantation, GVHD + allergy.
Induce tumour immunity in cancer patients.

Question 23

What is activation-induced cell death?

Answer 23

Repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of activated cell.
Elimination of T cells specific for abundant peripheral antigens -> clonal exhaustion (expression of inhibitory receptors on exhausted T cells).

Question 24

What are the properties of antigens?

Answer 24

Molecular weight -> smaller, soluble, not-aggregated favours tolerance. large, aggregated, complex molecules favours immunogenicity.
Dosage -> very small or large favours tolerance intermediate favours immunogenicity.
Routes of administration -> oral, intratracheal, orbital exposure can activate T cells to secrete tregs.

Question 25

What is hypersensitisation immunotherapy?

Answer 25

Using small amount of allergens (food, pollen) to induce antigen specific tolerance.
Continuous administration of allergen, rather than elimination, to promote development + maintenance of tolerance.