Autoimmunity, Immune Tolerance

Question 1

2 hallmarks of autoimmune disease? (IMPT!!!)

Answer 1

1) Loss of immune tolerance to self antigens
2) Tissue damage or physiological dysfunction due to autoimmunity

Question 1

Define autoimmunity

Answer 1

Adaptive immune response specific for self antigens

Question 2

What are 2 rare single gene defects associated with autoimmunity?

Answer 2

AIRE: Autoimmune regulator

Foxp3: for Treg dvp, multi-organ autoimmunity

Question 3

Do we know the exact cause of autoimmune diseases?

Answer 3

No, we do not. However, it is likely due to:

1) Cumulative effect of multiple minor genetic variants
+
2) Environmental factors

Question 4

Why are women more prone to autoimmune conditions?

Answer 4

Systemic Lupus Erythematosus (SLE) an example.

related to female sex hormones.

Relationship to ovarian hormonogenesis?
-Incidence highest during reproductive years
-Declines around the menopause

Relationship to pregnancy?
-May relapse during pregnancy
-Symptoms may improve postpartum

Question 5

How does infection trigger autoimmunity?

Answer 5

Infections activate self-reactive lymphocytes

Question 6

Define immune tolerance

Answer 6

Mec that prevent autoimmunity, prevent adaptive immune response against specific self antigens

Question 7

What are 2 types of immune tolerance?

Answer 7

1. Central tolerance: immature lymphocytes undergo selection in Primary Lymphoid organs
2. Peripheral tolerance: mature lymphocytes under selection in Periphery

Question 8

What are 3 fates of T cells in Central Tolerance?

Answer 8

Useless TCR: lost
Useful TCR: preserved
Dangerous TCR: eliminated

Question 9

What is MHC restriction?

Answer 9

Both TCR-peptide and TCR-MHC contacts are required to stabilise interaction

TCRs without some ability to bind to self MHC would not be useful.

Question 10

What is neglect?

Answer 10

Immature T cells that fail to bind any self peptide-MHC complex in thymus will not receive enough signal to survive –> apoptosis

rationale: Non-functional T cells removed to avoid wasting resources & immune inefficiency.

Question 11

What is positive selection?

Answer 11

Select for lymphocytes that express TCRs with some reactivity for self peptide-self MHC, thus exhibit MHC restriction.

T cells expressing TCRs that bind with low to moderate affinity survive.

T cells expressing TCRs that fail to bind will not survive (neglect)

Question 12

What is negative selection?

Answer 12

T cells with receptors that bind to self peptide-self MHC complexes with high affinity will die by apoptosis

Question 13

What is the role of Autoimmune Regulator?

Answer 13

Causes transient expression in the thymus of extra-thymic tissue-specific antigens

Allows for negative selection of TCRs specific for self antigens that are normally not expressed in the thymus

Mutations in AIRE associated with autoimmune disease

Question 14

Role of thymus?

Answer 14

T cell precursors migrate to the thymus from the bone marrow. Within the thymus, immature T cells undergo further development, and are subject to positive and negative selection. Subsequently, the T cells that survive this process exit the thymus as mature but naïve T cells.

Question 15

How does dendritic cells mature?

Answer 15

recognition of Pathogen-Associated Molecular Patterns (PAMPs) by Pathogen Recognition Receptor (PRR) triggers maturation of dendritic cells

Question 16

What are 3 signals required by naive T cell activation?

Answer 16

1) Specific antigen signal (TCR:antigen-MHC complex)
2) Co-stimulation signal (B7:CD28)
3) Cytokines signal (IL2, etc)

Question 17

What happens in costimulation?

Answer 17

CD28 (T cell) bind to B7 (APC) –> upregulate IL-2, autocrine growth factor for T cell proliferation and differentiation

Question 18

What happens in signal 3 Cytokines?

Answer 18

IL-12 and IFN-γ → Th1 → more IFN-γ to activate M1 macrophage + cytotoxic T (intracellular pathogen, cell-mediated immunity).

IL-4 → Th2 → IL-4, IL-5, IL-13 to activate B cell (extracellular pathogen, humoral immunity).

Question 19

4 Mechanisms of Peripheral Tolerance

Answer 19

1. Ignorance: insuff signal 1
2. Anergy: signal 1 but no signal 2
3. Deletion
4. Regulation

Question 20

What is Ignorance in peripheral tolerance

Answer 20

Interaction bw TCR and MHC: self-peptide is too weak to cause activation of mature T cells in the periphery

Question 21

What is Anergy in peripheral tolerance

Answer 21

Naive T cell bind MHC: peptide receive signal 1 but not costimulation signal 2.

reasons:
1. immature DC (PAMP not triggered) –> exp low level of costimulation.

2. Non-APC: present MHC Class I but no costimulation.

• Anergised T cells remain unresponsive, even if they reencounter peptide-MHC & appropriate costimulatory later.

Question 22

Suggest 3 mec of anergy

Answer 22

Active process requiring transcription of anergy genes

• Some suggested mechanisms:

-Failure to activate IL-2 autocrine loop

-Abnormal signalling by TCR complex (modification / degradation of intracellular signalling proteins impedes activating signals)

-Ligation of inhibitory receptors

Question 23

What is deletion in peripheral tolerance?

Answer 23

Mature T cells that recognise self antigens can undergo apoptosis and so are deleted from the T cell repertoire

Question 24

2 mecs of T cell deletion

Answer 24

Mitochondrial pathway regulated by members of the bcl-2 family Death receptor pathway mediated by Fas – Fas ligand signalling. px with genetic defects in Fas, FasL dvp autoimmunity

Question 25

Best examples of Tregs? And what is their transcription factor?

Answer 25

CD4+ CD25+ T cells. Transcription factor: Foxp3

Question 26

How does Regulation happen?

Answer 26

Via Regulatory T cells inhibiting immune response

Question 27

How does Treg act out its function?

Answer 27

Possess strong TCRs that recognises SP-SMHC strongly, and act on self-reactive immune cells to suppress their activity Several possible mechanisms of action: * Cell-cell contact: Constitutive expression of CTLA4 on Tregs blocks and removes B7 from APCs * Soluble factors: Secrete inhibitory cytokines, e.g. TGF-β

Question 28

Mutation in foxp3 is associated with?

Answer 28

Multi-organ autoimmune disease

Question 29

Similarities and differences between CTLA-4 and CD28? (IMPT)

Answer 29

Similarities: - Both expressed on T cells - Both binds to B7 Differences: - CTLA4 not constitutive, comes up a few days after T cell activation, only constitutive in Treg - CTLA4 binds more strongly to B7 than CD28 - Interaction between CTLA4:B7 delivers negative signal while that between CD28:B7 delivers positive signal

Question 30

CTLA-4 on Tregs may inhibit T cell activation by:

Answer 30

-Sequestration of B7 on APC (by CTLA-4 higher affinity binding) -Downregulation of B7 on APC

Question 31

With respect to CTLA4 and PD1, how can cancer evade immunity?

Answer 31

-Upreg CTLA4 or PD1 on tumour specific T cells -Expression of PDL1 (LIGAND!) on tumour cells -recruit Tregs to inhibit

Question 32

How can we enhance T cell function with respect to CTLA4?

Answer 32

We can have Anti-CTLA4 antibody Depletes Tregs and block inhibitory effect of CTLA4 on effector t cell

Question 33

When is Programmed Cell Death Protein 1 expressed

Answer 33

induced after T cell activation, exp strongly in chronically activated T cells

Question 34

What is the role of PD-1 in immune checkpoint

Answer 34

- limit T cell mediated tissue damage during chronic infection - inhibit autoreactive T via mec of inhibiting TCR & CD28

Question 35

In what type of cells do we see Programmed Death-1 (PD-1). What are the effects?

Answer 35

In chronically activated T cells. Inhibits activation signalling from TCR complex (signal 1) and CD28 (signal 2)

Question 36

With ref to immune checkpoint, how do we enhance anti-tumour T cell response?

Answer 36

In immune checkpoint blockade: use Ab against CTLA-4, or PD-1, inhibit Treg & reduce inhibitory signals for T cell -->boost T cell response --> tumour regression