L14. Problems with the Innate Response in Health and Disease

Question 1

What happens upon injection of Interleukin 1?

Answer 1

Evoke the cardinal signs of acute inflammation

Question 2

What does the term interleukin mean? What do the interleukins do?

Answer 2

It is a protein produced by leucocytes

It mediates cross talk between different types of leucocytes

Question 3

What are some of the responses to IL-1?

Answer 3

Pyrogenic (induces fever)
Neutrophilia (increased neutrophil production and activation)
Cellular proliferation
Fibroblast proliferation and increased collagen production
Increase metabolism
Activation of T cells and B cells

Question 4

What is the inactive pre-cursor form of IL-1?

Answer 4

IL-1b - a large portion: extension of the N terminus

Question 5

How is inactive IL-1b activated into IL-1?

Answer 5

By the action of an enzyme called Interleukin-1 converting enzyme (ICE) otherwise known as caspase 1.

It cleaves the precursor

Question 6

What is the NOD-like receptor family?

Answer 6

A group of molecules that are closely associated with the activation of caspase 1 (ICE)

Question 7

What is Familial cold Urticaria?

Answer 7

A disease where people suffer the acute inflammatory response after exposure to the cold.

It was caused by a single mutation in Cryopyrin, which was found to be a NOD-like receptor. This mutation led to the unregulated and over activation of the caspase 1 leading to over activation of IL-1 and hence increased inflammatory activation.

Question 8

Describe the activation of caspase 1

Answer 8

It is a very complex pathway.

Activation of a NOD-like receptor leads to a series of complex protein activations and interactions. These proteins then AGGREGATE into a large protein complex.

This complex is then able to autocatylase and activate caspase 1

Question 9

What is the large protein complex aggregate that activates caspase 1 called?

Answer 9

The inflammasome (because it activates inflammation)

Question 10

What is gout?

Answer 10

Consumption of purine rich food produces proteins normally excreted by the kidneys.
However over consumption or disturbed excretion leads to accumulation of proteins which precipitate in the joints.

These crystals cause destruction and heavy inflammation.

They bind to NOD3 receptors leading to the cascade and inflammasome production and caspase 1 activation.

Question 11

What is Anakinra and how does it work?

Answer 11

It is an IL-1 receptor antagonist

It is successful in preventing gout attack

Question 12

What is an absolute contraindications to using Anakinra? Why is this so?

Answer 12

Neutropenia: because lack of neutrophils and lack of IL-1 leads to high susceptibility to bacterial infections.

Question 13

What are some factors that are able to activate the inflammasome?

Answer 13

Pore-forming toxins
Cholera toxins
Bacterial and viral genomes
Fungi

Question 14

Because of the very potent effects of IL-1 on multiple systems, its activation requires very high regulation. How does the body achieve this?

Answer 14

Activation of the inflammasome requires TWO SIGNALS

Question 15

What are the 2 signals required to activate the inflammasome?

Answer 15

1. The activators mentioned in a previous question: toxins, pathogenic genomes
2. Transcription of the inactive form of IL-1 (priming)

Question 16

How is the priming step of inflammasome activation achieved?

Answer 16

Not all cells have inactive IL-1b present. This needs to be induced. This can be achieved by:
TLR recognition and pro-inflammatory mediators and NOD like receptors
These signals converge onto the NFkB and increase gene transcription of the IL-1b

Question 17

How many times can this second signal of induced pre-IL1 be activated?

Answer 17

Only ONCE because once this begins to be expressed, it is a signal for the cell death. Inflammasome production leads to PYROPTOSIS (inflammatory cell death)

Question 18

Why is pyroptosis a step in this process?

Answer 18

Because once IL-1 produced and activated, it has to get out of the cell, and there is no mechanism for this except for cell suicide (pyroptosis) to let it out.

Question 19

Describe the pathogenesis of Salmonella infection

Answer 19

1. Salmonella enters via ingestion
2. Enters epithelial cells into an intracellular vacuole and hides from the immune system
3. Recognition of flagellin (TLR5) leads to inflammasome activation and caspase 1
4. The release of IL-1 from this cell causes cell death and release of bacteria at the same time
5. Neutrophils are able to clear the bacteria

Question 20

How is metabolic syndrome associated with inflammasome activation?

Answer 20

Lipid derived mediators are released in adipocyte death and form crystals in the tissue.

Macrophages recognise the crystals and they are sensed by NOD like receptors to activate the inflammasome.

Inflammaton ensures leading to a low grade inflammatioi of the fatty tissue

IL-1 is able to increase insulin resistance leads to compensation by increased insulin production = type 2 diabetes. The insulin resistance can also lead to hepatocyte dysfunction and liver damage.

The crystals can also deposit in the intima leading to atherosclerosis