Regulation Of Lymphocytes

Question 1

Why is immune regulation important?

Answer 1

To avoid excessive lymphocyte activation and tissue damage during normal protective responses against infections

To prevent inappropriate reactions against self-antigens (“tolerance”)

Question 2

What is autoimmunity?

Answer 2

Immune response against self antigens

Question 3

What happens if immune regulation fails? (3 answers)

Answer 3

Autoimmunity

Allergy

Hypercytokinemia and sepsis - excessive immune response triggered by positive feedback loop

Question 4

What are the 3 signals required to license an immune response?

Answer 4

1. Antigen recognition
2. Co-stimulation
3. Cytokine release

Question 5

What is self limitation?

Answer 5

Preventing excessive immune response. Primary mechanism is through elimination of antigen removing the first signal for lymphocyte activation.

Question 6

What are the 5 steps of cell-mediated immunity?

Answer 6

1. Dendritic cell collects antigen from infected cells
2. MHC peptide TCR interaction
3. Naïve T cell becomes effector
4. Effector cell performs functions on MHC peptides on infected cell (cytotoxic T cell)
5. Effector pool contracts to memory cells

Question 7

What happens at the end of an immune response?

Answer 7

Resolution - no tissue damage, returns to normal. Phagocytosis of debris by macrophages.

Repair - healing with scar tissue and regeneration. Fibroblasts and collagen synthesis.

Chronic inflammation - active inflammation and attempts to repair damage ongoing.

Responses against pathogens decline as the infection is eliminated. Lymphocytes that lose their survival signals (antigens etc.) undergo apoptosis leaving only memory cells.

Question 8

Why is immunological tolerance important?

Answer 8

• All individuals are tolerant of their own antigens (self-tolerance); breakdown of self-tolerance results in autoimmunity.
• Therapeutic potential: Inducing tolerance may be exploited to prevent graft rejection, treat autoimmune and allergic diseases.

Question 9

What is central tolerance?

Answer 9

Central tolerance = destroy self-reactive T or B cells before they enter the circulation.

Lymphocytes that recognise self-antigens before maturation in the generative organs are eliminated (deletion) or made harmless.

Question 10

What is peripheral tolerance?

Answer 10

Peripheral tolerance = destroy or control any self-reactive T or B cells which do manage to enter the circulation.

Some B cells may change their specificity and some T cells develop into regulatory (suppressive) T lymphocytes.

Question 11

What is the function of AIRE (autoimmune regulator)?

Answer 11

AIRE is a specialised transcription factor that drives the negative selection of self-reactive T cells.

It does this by allowing the transcription of a wide range of organ-specific genes in the thymus. This produces proteins that are usually only present in other tissues in the thymus. T cells that bind strongly to self antigens are eliminated.

Question 12

What are the 4 main parts of peripheral tolerance?

Answer 12

Anergy, ignorance, deletion, regulation

Question 13

What happens to T cells in the thymus that cannot bind to any self-MHC at all?

Answer 13

Undergoes apoptosis by neglect since it no longer receives survival signals.

Question 14

What happens to T cells that bind to self-MHC too strongly?

Answer 14

Triggers apoptosis (negative selection)

Question 15

What happens to T cells that bind weakly to self-MHC?

Answer 15

GIven signal to survive (positive selection).

Question 16

What does it mean for a T cell to become anergic and how does it occur?

Answer 16

A T cell that is anergic is less likely to be stimulated in the future even if co-stimulation is present.

Naive T cells need co-stimulatory molecules from the antigen presenting cell to activate. If a naive T cell sees its MHC without appropriate co-stimulatory protein it becomes anergic.

Question 17

Role of Th1

Answer 17

Produces interferon gamma. Boosts intracellular immune response.

Question 18

Role of Th2

Answer 18

Produces il4, il5 and il13. Boosts anti-multicellular orgnaism response.

Question 19

Role of Tfh

Answer 19

Produces il21, resides in B cell follicles. It is essential for the generation of isotype-switched antibodies.

Question 20

Role of Th17

Answer 20

Produces il17 in autoimmune diseases such as arthritis. There are also other T helper cells named after the interleukin it produces for example Th9 and Th22 which produces il9 and il22 respectively.

Question 21

Role of Treg

Answer 21

Expresses transcription factor FoxP3. A mutation in this gene leads to IPEX which is a severe and fatal autoimmune disorder.

Question 22

What does IPEX stand for?

Answer 22

Immune dysregulation, polyendicrinopathy, enteropathy, X-linked syndrome

Question 23

What are the 2 types of Treg?

Answer 23

Natural Treg and Inducible Treg

Question 24

What is the difference between the two types of Treg?

Answer 24

Natural - develops in thymus and resides in peripheral tissues to prevent harmful reactions to self.

Inducible - develops from normal CD4+ T helper cells that are exposed to antigens in the periphery. May be generated in all immune responses to minimise collateral damage.

Question 25

When is Treg regulation especially critical?

Answer 25

Pregnancy - only mammals have Treg.

Question 26

Function of il10

Answer 26

Multifunctonal anti-inflammatory cytokine that acts on a range of cells and blocks pro-inflammatory cytokine synthesis including TNF, il6 and il8. It also downregulates macrophages.