Week 9 - Immune Regulation

Question 1

Loss of Tolerance

Answer 1

Has life threatening consequences
Loss of tolerance to self
- destruction of self tissues
- autoimmune disease
Loss of tolerance to innocuous non-self
- e.g. inhaled antigen such as pollens
- allergy

Question 2

Development of Tolerance

Answer 2

Development of tolerance to cancer
Development of tolerance to pathogens

Question 3

How does the Host Avoid Destruction by T and B Cells?

Answer 3

Central tolerance
Avoidance/barriers/ignorance
- skin
- sequestration of antigen
Regulation/suppression
- by regulatory cells
Destruction (deletion)
- clonal deletion
Incapacitation
- turn off reactive cells
Skewing
- become a different cell

Question 4

Central Tolerance

Answer 4

Primary lymphoid organs (bone marrow and thymus)
E.g.
- self antigen in BM or thymus -> deletion of high affinity self Ag lymphocytes
- lymphoid maturation of clones weakly responsive to self Ag

Question 5

Peripheral Tolerance

Answer 5

Secondary lymphoid organs (lymph nodes and spleen)
E.g.
- self antigen in peripheral tissues -> regulation or anergy of self Ag specific lymphocytes
- immune response to foreign Ag

Question 6

Central B Cell Tolerance in the BM

Answer 6

Works by:
1. Deletion
- death by apoptosis
2. Anergy
- long term inactivation
3. Receptor Editing
- reactivation of V(D)J recombination
- B cell with receptor for non-self antigen

Question 7

Central T Cell Tolerance

Answer 7

Works by:
1. Death by Neglect
- no TCR interation with self antigen in MHC on thmyic epithelial cells or dendritic cells -> apoptosis
2. Negative Selection
- double positive TCR - high affinity for self antigen -> apoptosis
3. Positive Selection
- single positive TCR - low affinity for self Ag -> migrate to LN and spleen

Question 8

Regulation of Peripheral Autoreactive T Cells

Answer 8

1. Ag Sequestered -> clonal ignorance
2. APC, MHC/Ag + Costimulation -> autoimmunity
3. APC, MHC/Ag with No Costimulation -> clonal anergy
4. Suppression

Question 9

Cells that Suppress the Immune Response

Answer 9

CD4+CD25+ regulatory T cells (Treg)
CD4+ Th2 cells
CD4+ Th3 cells
M2 Macrophages
Myeloid derived suppressor cells
Immature dendritic cells

Question 10

Regulatory T Cells (Tregs)

Answer 10

CD4+ CD25+ (IL-2 receptor a chain)
FoxP3+ (forkhead box P3 = nuclear transcription factor)
- master regulator in the development of regulatory T cells
Mediated by cytokines:
- transforming growth factor beta 1 (TGFb-1)
- IL-10

Question 11

Role of Cytokines in Suppression

Answer 11

IL-10 inhibits functions of APCs: IL-12 secretion, B7 expression
TGF-B inhibits T cell proliferation
IL-4 inhibits actions of IFN-g
IL-10, TGF-B inhibit macrophage activation

Question 12

Immature Dendritic Cells

Answer 12

Express low levels of MHC I / II, co-stimulatory molecules (CD40, CD80, CD86)
Not activated in a ‘dangerous setting’ (won’t drive T cell responses) - take up self antigen
Do not activate effector T cells
Secrete IL-10
Directly responsible for inducing Tregs
Prevents autoimmunity

Question 13

NK Cell and Dendritic Cell Association

Answer 13

Activate each other
DCs express ligands for NKp30
NK cells can kill (immature) DC
Stop DCs from activating T cells

Question 14

M1 Macrophages

Answer 14

Pro-inflammatory
Anti-microbial
Anti-tumour function
Phagocytes
Present antigen to T cells
Activate T cells

Question 15

M2 Macrophages

Answer 15

Wound healing, angiogenesis
Promote tumour growth
Reported to be in tumours
Present antigen to T cells
Suppress T cell function

Question 16

What Parts of the Body Can the Immune System Not Recognise Self Antigens?

Answer 16

Brain
Eye
Testis
Uterus (fetus)

Question 17

Sympathetic Opthalmia

Answer 17

Antigens hidden (sequestered) from the immune system
Injury in one eye shows up in other healthy eye
Mediated by T cells

Question 18

Sympathetic Opthalmia Steps

Answer 18

Trauma to one eye results in release of sequestered intraocular protein antigens
Released intraocular antigen is carried to lymph nodes and activates T cells
Effector T cells return via bloodstream and encounter antigen in both eyes

Question 19

Damage Associated Molecular Patterns

Answer 19

DAMPs are nuclear or cytosolic self proteins
Released when tissues are injured
Examples:
- high-mobility group box 1 (HMGB1) - TLR2 and TLR4
- DNA not in nucleus or mitochondria -TLR9
- damaged RNAs - TLR3

Question 20

Checkpoint Molecules

Answer 20

Negative immune regulatory molecules
Prevent excessive inflammation and dampen responses that could induce autoimmunity
Mostly target T cells
Tumour cells take advantage of these pathways to inactivate anti-tumour T cells

Question 21

How do Checkpoint Molecules Work?

Answer 21

Programmed cell death protein-1 (PD-1) is expressed on activated T cells
Programmed cell death ligand (PD-L1) on APCs
APC binds T cells with this ligand -> inhibits T cell proliferation

Question 22

Checkpoint Molecule - Adenosine

Answer 22

Naturally occurring purine nucleoside
From breakdown of adenosine triphosphate (ATP) = primary energy source for cells
Ectonucleoside triphosphate diphosphohydrolase-1 (CD39)
- converts adenosine triphosphate (ATP) to adenosine diphosphate (ADP)
- converts ADP to adenosine monophosphate (AMP)
Ecto-5’-nucleotidase (CD73)
- converts AMP to adenosin

Question 23

Effects of Adenosine Binding to A2A and A2B Receptors - T cells

Answer 23

↓ T cell proliferation
↓ T cell cytokine production

Question 24

Effects of Adenosine Binding to A2A and A2B Receptors - DCs

Answer 24

Prevent DC maturation
↓ DC pro-inflammatory cytokines
↑ DC suppressive cytokines