Immunological Tolerance

Question 1

What is Immunological tolerance?

What is the Immune system tolerant to?

Answer 1

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

Question 2

Where is self-tolerance induced?

Answer 2

• induced in the central lymphoid organs
  
  • Bone marrow (B cells) - nursing cells facilitate this
  • Thymus (T cells) - thymocytes
• maintained in the periphery

Question 3

How does T-cell Self-tolerance occur?

• what is the outcome

Answer 3

• 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

Question 4

How does B-cell self-tolerance occur?

(3)

Answer 4

• 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

Question 5

What are the peripheral organs/ tissues for T cell migration?

Answer 5

• Lymph nodes
• Spleen
• GALT: Gut Associated Lymphoid Tissues

Question 6

Explain Thymic Involution

• what is it
• when does it occur
• what is the effect on immunity?

Answer 6

• 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

Question 7

What factors is Negatively selected for and positively selected for in T cell maturation

Answer 7

• 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

Question 8

What is Positive and Negative selection in terms of self-cells

Answer 8

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

Question 9

How can the thymus express all self-antigens?

How do we become self tolerant to antigens expressed by specialised tissues?

• clinical significance?

Answer 9

• 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

Question 10

What is Split tolerance?

Answer 10

• 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.

Question 11

What are the mechanisms of peripheral Tolerance?

(4)

Answer 11

• 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

Question 12

What is Clonal Ignorance?

• how does it work
• give examples of where this is present

Answer 12

• 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)

Question 13

Explain how the Eye anterior chamber is an immune-privileged site

• how can this be compromised
• what is the result of this being compromised?

Answer 13

• 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

Question 14

What is Sympathetic Ophthalmia?

Answer 14

• 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

Question 15

What is Clonal Anergy?

Answer 15

• the presentation of an ag without costimulation or in the presence of a negative inhibitor signalling CTLA-4

Question 16

Explain the opposing functions of CD28 and CTLA-4

Answer 16

• 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

Question 17

What are Checkpoint blockades?

• what is the clinical significance of this?

Answer 17

• 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

Question 18

Where is CTLA-4 expressed?

Answer 18

• expressed on responding T cells
• and Regulatory T cells

Question 19

How is the Suppression of peripheral immune response carried out?

Answer 19

• 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

Question 20

What is the role of T regulatory cells?

• what is the clinical significance of them?
• linked factor?

Answer 20

• 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

Question 21

How could T regulatory cells be used in therapeutic treatments?

Answer 21

• 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

Question 22

Explain Activation-Induced Cell Death (AICD)

(Clonal Exhaustion)

Answer 22

• 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

Question 23

Explain the applications of Hyposensitisation Immunotherapy

Answer 23

• 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