Immunological Tolerance Flashcards
1
Q
What is Immunological tolerance?
What is the Immune system tolerant to?
A
Immunological tolerance refers to the mechanisms by which lack of immunological reactivity is induced and maintained
- Self
- Harmless antigens such as food or environmental ag
- Commensal microbiota
2
Q
Where is self-tolerance induced?
A
- induced in the central lymphoid organs
- Bone marrow (B cells) - nursing cells facilitate this
- Thymus (T cells) - thymocytes
- maintained in the periphery
3
Q
How does T-cell Self-tolerance occur?
- what is the outcome
A
- during random somatic gene rearrangement to create many variable regions, the b cells and t cells have to go through maturation
- the many T cells go through Double Positive MHC restriction–> Negative selection - tolerance induction
- this screens for self recognising receptors
- only cells that have appropriate antigen receptor affinity and is presented in self MHC complexes complete their maturation and form the peripheral T Cell pool outcome is
- they are called Naive T cells
- self MHC restricted and self tolerant
4
Q
How does B-cell self-tolerance occur?
(3)
A
- B cells are tested in the bone marrow for self-recognition. If they recognise self they are removed by
- Deletion: if immature b-cell recognises very common Ag (such as MHC) on BM stromal cells leads to apoptosis
- Anergy (paralysis of function): if immature b cells recognise self Ag –> No Ab cross-linkin –> anergy
- They can also have Receptor Editing
- can rearrange the V(D)J sequence to form an alternative BCR
5
Q
What are the peripheral organs/ tissues for T cell migration?
A
- Lymph nodes
- Spleen
- GALT: Gut Associated Lymphoid Tissues
6
Q
Explain Thymic Involution
- what is it
- when does it occur
- what is the effect on immunity?
A
- The human thymus is fully developed before birth and increases in size during puberty
- Thymus is most active in the young and it atrophies with age
- It progressively shrinks (fat replaces areas where thymocytes existed)
- Degeneration is complete by the age of 30, but residual thymic activity persists until advanced age
- The reduced production of T-cells does not completely impair immunity. Once established the repertoire of the T-cells is long-lived
7
Q
What factors is Negatively selected for and positively selected for in T cell maturation
A
- double negative for CD3-, CD4-, CD8-
- double-positive for CD3+, CD4+, CD8+
- this all happens in the cortex
- as they move into the medulla they latch onto dendritic cells to differentiate between CD4+8- and CD8+4-
- any cells that bind strongly to self cells are negatively selected
8
Q
What is Positive and Negative selection in terms of self-cells
A
Positive Selection
- Retention of thymocytes expressing TcR that are RESTRICTED in their recognition of antigen by self MHC
- TCRs unable to recognise self-MHC –> Apoptosis i.e. selection of the USEFUL
Negative Selection
- Removal of thymocytes expressing TcR that recognise self-antigens presented by self MHC - elimination of harmful T cells
- the binding needs to be modest
9
Q
How can the thymus express all self-antigens?
How do we become self tolerant to antigens expressed by specialised tissues?
- clinical significance?
A
- Promiscuous gene expression in medullary thymic epithelial cells mirrors the peripheral self
- this uses Autoimmune regulator (AIRE)
- Mutations of AIRE lead to autoimmune polyendocrinopathy with candidiasis and ectodermal dysplasia (APECED), also called autoimmune polyendocrine syndrome (APS-1)
- In mice if this is knocked out –>: failure to express many self-antigens in the thymus and expression of autoantibodies
10
Q
What is Split tolerance?
A
- many pathways of immunity are interdependent, they do not all need to be tolerised.
- For example, tolerised T cells will not activate autoreactive B cells.
- Without this help from CD4 T cells, the B cells will not be activated.
11
Q
What are the mechanisms of peripheral Tolerance?
(4)
A
- IGNORANCE: lymphocytes fail to recognise or respond
- CLONAL ANERGY: binding of ag 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
12
Q
What is Clonal Ignorance?
- how does it work
- give examples of where this is present
A
- self-reactive lymphocytes fail to recognise or respond to some self-antigens in the periphery cells neither die nor become anergic
- Self -reactive T cells sometimes ignore ag
- antigens are anatomically sequestered from the immune system: T cells cannot reach cells bearing the ag
- Tissue grafts placed in these sites are not rejected
-
Immunologically privileged sites
- (eye, testis, uterus/placenta)
- Immune-privileged sites allow foreign graft survival (allows transplants)
- if sequestered ag is released autoimmunity can result (e.g. anti-sperm Abs in vasectomised males have)
13
Q
Explain how the Eye anterior chamber is an immune-privileged site
- how can this be compromised
- what is the result of this being compromised?
A
- normally self-antigens in this site are not exposed to the immune system
- physical trauma in one eye can initiate an autoimmune response to both eyes
- this can cause blindness in both eyes
- Sympathetic ophthalmia
14
Q
What is Sympathetic Ophthalmia?
A
- normally self-antigens in this site are not exposed to the immune system
- physical trauma in one eye can initiate an autoimmune response to both eyes
- this can cause blindness in both eyes –> sympathetic ophthalmia
15
Q
What is Clonal Anergy?
A
- the presentation of an ag without costimulation or in the presence of a negative inhibitor signalling CTLA-4
16
Q
Explain the opposing functions of CD28 and CTLA-4
A
- in clonal anergy CTLA-4 receptors interact with B7 and act as an inhibitory signal when naive t cells bind to APC
- this results in restimulation of the APC, however, it is now expressing costimulators
17
Q
What are Checkpoint blockades?
- what is the clinical significance of this?
A
- removing the immune suppression action of CTLA-4 with anti-CTLA-4 antibody
- used to promote tumour rejection as CTLA-4 limits the immune response to tumours
18
Q
Where is CTLA-4 expressed?
A
- expressed on responding T cells
- and Regulatory T cells
19
Q
How is the Suppression of peripheral immune response carried out?
A
- T regulatory cells suppress the activation of effector responses and are critical for regulating homeostasis and tolerance to self-antigens
- they expressed CTLA-4 receptors
20
Q
What is the role of T regulatory cells?
- what is the clinical significance of them?
- linked factor?
A
- CD25 (IL-2Ra) is constitutively expressed by Treg cells
- Consumes IL2 creates competition and limits the expansion of T eff.
- depletion of CD25(+)CD4(+) T cells leads to autoimmunity
-
FOXP3 Forkhead/winged-helix transcription factor
- critical for TReg activity and development
- Mutations in FOXP3 gene cause IPEX [Immunodysregulation, Polyendocrinopathy and Enteropathy, X-linked syndrome] a fatal autoimmune disorder characterised by systemic autoimmunity in the first year of life
21
Q
How could T regulatory cells be used in therapeutic treatments?
A
- strengthen or re-establish self-tolerance in autoimmune disease
- induce tolerance to non-self-antigens in organ transplantation, GVHD and allergy
- Induce tumour immunity in cancer patients
22
Q
Explain Activation-Induced Cell Death (AICD)
(Clonal Exhaustion)
A
- Repeated stimulation of T lymphocytes by persistent antigens results in death by apoptosis of the activated cell
- due to the expression of Fas and FasL
- Elimination of T cells specific for abundant peripheral antigens: Clonal exhaustion (expression of inhibitory receptors on exhausted T cells, e.g. CTLA-4, PD-1)
- HIV, expression of receptors can indicate disease progression
23
Q
Explain the applications of Hyposensitisation Immunotherapy
A
- using small amount of allergens (food, pollen) to induce antigen specific tolerance
- continuous administration of the allergen, rather than its elimination, to promote the development and maintenance of tolerance
- Oral/sublingual desensitisation immunotherapy for peanut allergy holds promise for the control of allergy
