28 - Self/Non-Self Discrimination

Question 1

Central tolerance

Answer 1

Removing autoreactive lymphocytes during development of these cells (in thymus, bone marrow)

Question 2

Mechanisms used to induce tolerance 
1
2
3
4

Answer 2

– To delete (eliminate the problem) - Central tolerance
– To anergize (switch off the problem) - Peripheral
– To ignore (ignore the trigger) - Peripheral
– To regulate (contain the problem) -Peripheral

Question 3

Central mechanisms of B cell tolerance

Answer 3

Deletion, anergry

Question 4

Peripheral B cell tolerance

Answer 4

Ignorance, anergy, death

- Lack of co-ordinated T cell help

Question 5

Is B cell or T cell tolerance more effective?

Answer 5

T cell

Question 6

Effect of B cell encountering soluble self protein in the periphery

Answer 6

Anergy

Question 7

Effect of B cell activation without T cell costimulation

Answer 7

Differentiate to short-lived IgM+ plasma cell

Form of tolerance -> without cognate CD4+ help, autoreactive B cell can only do so much damage

Question 8

T cell development in the thymus

Answer 8

Early T-lineage precursor
Pro T-cell (rearrange beta chain, express with surrogate light chain)
Double negative thymocyte
Double positive thymocytes (rearrangement of alpha chain)
Positive selection (can bind self-MHC)
Commit to either CD4 or CD8, depending on either recognising MHCI or II

Question 9

T cell positive selsction

Answer 9

Only thymocytes that express TCRs capable

of recognising self-MHC are selected to survive

Question 10

T cell negative selection

Answer 10

Thymocytes expressing TCRs that bind too strongly to a self antigen presented on MHC will undergo apoptosis

Question 11

Transcription factor responsible for ectopic presentation of self antigens in the thymic medulla

Answer 11

AIRE (autoimmune regulator of expression).
Involved in T cell maturation (negative selection).
Expresses tissue-specific antigens (EG insulin)

Question 12

Cells that express AIRE transcription factor

Answer 12

Thymic epithelial cells.
If a TCR can detect these antigens, they undergo apoptosis.
Either detect these on the surface of thymic epithelial cells, or thymic epithelial cells die, are phagocytosed by DCs, which then present self-antigens.

Question 13

Mechanism of T cell anergy

Answer 13

Without DC costimulation, T cells become antergic

Question 14

Role of immunosuppressive T cells

Answer 14

Treg release TGFb, IL-10, which are immunosuppressive

Question 15

nTregs

Answer 15

Natural Tregs.

Develop in the thymus to be nTregs

Question 16

iTregs

Answer 16

Induced Tregs
Naive CD4+ T cells activated in the presence of TGFb become iTregs.
– Secrete immunosuppressive cytokines - IL-10 and TGFb
– Express CTLA4 and inhibit co-stimulation
– Release molecules that create a ‘suppressive’ environment

Question 17

CTLA4

Answer 17

Present on the surface of B cells.
Binds to CD80/CD86 with a higher affinity than CD28.
Negatively regulates activated T cells by inhibiting co-stimulation.

Question 18

Two broad classifications of autoimmune disease

Answer 18

Organ-specific

Systemic

Question 19

Disease that arises when AIRE is defective

Answer 19

APECED
Multi-system autoimmunity
Loss of central tolerance

Question 20

Disease from defect in Foxp3 gene

Answer 20

IPEX.

Loss of Tregs and peripheral tolerance mechanism.

Question 21

Transcription factor for Treg differentiation

Answer 21

Foxp3

Question 22

Two examples of T-cell-mediated autoimmunity

Answer 22

Type I diabetes.

MS

Question 23

MS aetiology

Answer 23

CD4 T cells specific for myelin antigens promote an
inflammatory response and degrade the myelin
sheaths covering nerve axons

Th1 and Th17 responses are detrimental
Th2 responses associated with remission
Dysregulation of Tregs has been associated with MS

Question 24

How can self antigens be recognised?

Answer 24

Recognition of self antigen in the presence of inflammation (death of self cells, release of internal antigens)

Question 25

Example of molecular mimicry autoimmunity

Answer 25

Streptococcal infection response directed against Strep M protein.

Persisting anti-M protein lymphocytes can autoreact with antigens of cardiac valves.