L14. Problems with the Innate Response in Health and Disease Flashcards
What happens upon injection of Interleukin 1?
Evoke the cardinal signs of acute inflammation
What does the term interleukin mean? What do the interleukins do?
It is a protein produced by leucocytes
It mediates cross talk between different types of leucocytes
What are some of the responses to IL-1?
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
What is the inactive pre-cursor form of IL-1?
IL-1b - a large portion: extension of the N terminus
How is inactive IL-1b activated into IL-1?
By the action of an enzyme called Interleukin-1 converting enzyme (ICE) otherwise known as caspase 1.
It cleaves the precursor
What is the NOD-like receptor family?
A group of molecules that are closely associated with the activation of caspase 1 (ICE)
What is Familial cold Urticaria?
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.
Describe the activation of caspase 1
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
What is the large protein complex aggregate that activates caspase 1 called?
The inflammasome (because it activates inflammation)
What is gout?
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.
What is Anakinra and how does it work?
It is an IL-1 receptor antagonist
It is successful in preventing gout attack
What is an absolute contraindications to using Anakinra? Why is this so?
Neutropenia: because lack of neutrophils and lack of IL-1 leads to high susceptibility to bacterial infections.
What are some factors that are able to activate the inflammasome?
Pore-forming toxins
Cholera toxins
Bacterial and viral genomes
Fungi
Because of the very potent effects of IL-1 on multiple systems, its activation requires very high regulation. How does the body achieve this?
Activation of the inflammasome requires TWO SIGNALS
What are the 2 signals required to activate the inflammasome?
- The activators mentioned in a previous question: toxins, pathogenic genomes
- Transcription of the inactive form of IL-1 (priming)
How is the priming step of inflammasome activation achieved?
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
How many times can this second signal of induced pre-IL1 be activated?
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)
Why is pyroptosis a step in this process?
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.
Describe the pathogenesis of Salmonella infection
- Salmonella enters via ingestion
- Enters epithelial cells into an intracellular vacuole and hides from the immune system
- Recognition of flagellin (TLR5) leads to inflammasome activation and caspase 1
- The release of IL-1 from this cell causes cell death and release of bacteria at the same time
- Neutrophils are able to clear the bacteria
How is metabolic syndrome associated with inflammasome activation?
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
