IL-1 Family in Immunity Overview

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Questions and Answers

What is the primary characteristic of sterile inflammation that demonstrates a divergence from caspase-1 dependent mechanisms?

Presence of fever, elevated IL-6 and increased hepatic acute phase proteins with caspase-1 deficiency. (correct)

Reduced neutrophil infiltration.

Increased hepatic acute phase protein production in caspase-1 deficient mice.

Absence of fever and elevated IL-6.

What role does proteinase-3 play in the context of IL-1β and IL-18?

It inhibits the activation of both IL-1β and IL-18 precursors.

It processes the IL-1β precursor intra-cellularly.

It contributes to the processing of both, IL-1β and IL-18 precursors extracellularly into active forms. (correct)

It only processes the IL-18 precursor, while another enzyme processes IL-1β.

Besides proteinase-3, which of the following proteases has NOT been reported to process the IL-1β precursor extracellularly?

Granzyme A

Matrix metalloprotease 9

Cathepsin G (correct)

Elastase

What is a typical finding in IL-1β deficient mice that distinguishes them from their wildtype counterparts?

Specific differences in response to challenge, for example, local inflammation from a subcutaneous turpentine injection. Signup and view all the answers

Why is the release of the IL-1β precursor from neutrophils not unexpected, given their nature?

Neutrophils are short-lived cells, dying soon after emigration, releasing their intracellular stores. Signup and view all the answers

Which cytokine has been found to be elevated in the postictal period of patients with recurrent seizures?

IL-6 Signup and view all the answers

In patients with recurrent temporal lobe epilepsy, at what point during a seizure has elevated IL-1β been observed?

Intracellular ictal period Signup and view all the answers

What is the name of the severe seizure disorder where anakinra has been administered with resulting cessation of seizures?

Febrile infection-related epilepsy syndrome Signup and view all the answers

In the context of macrophage activation syndrome (MAS), anakinra is primarily used for patients with which condition?

Systemic juvenile idiopathic arthritis (sJIA) only Signup and view all the answers

What triggers the assembly of the inflammasome components with inactive procaspase-1?

A decrease in intracellular potassium levels. Signup and view all the answers

What was the primary outcome that was measured in the randomized, placebo-controlled trials of anakinra in septic shock?

28-day mortality Signup and view all the answers

According to the re-analysis of a septic shock trial data, which of the following is NOT a typical feature of macrophage activation syndrome (MAS)?

Hypoglycemia Signup and view all the answers

What effect does increased IL-18BP concentration have on the availability of IL-37?

It decreases the availability of IL-37. Signup and view all the answers

What is the role of the P2X7 receptor in the context of inflammasome activation?

It opens the potassium channel, leading to a decrease in intracellular potassium. Signup and view all the answers

Which of the following is NOT a pathway for processed IL-1β to exit the cell?

Release through direct activation of calcium channels. Signup and view all the answers

What is observed when mice are injected with low doses of IL-18BP in a model of rheumatoid arthritis?

Reduced inflammation. Signup and view all the answers

In the anakinra vs. placebo study for MAS in adults with septic shock, what percentage of those treated with anakinra survived after 28 days?

65.4% Signup and view all the answers

What is pyroptosis?

A caspase-1-dependent form of cell death. Signup and view all the answers

What happens to the anti-inflammatory properties of IL-18BP as its dosage increases?

They are lost. Signup and view all the answers

What was the hazard ratio for death observed in patients with MAS treated with anakinra compared to placebo in the study?

0.28 Signup and view all the answers

What is necessary for the mature IL-1β to exit the cell, in addition to the pathways mentioned?

An increase in intracellular calcium. Signup and view all the answers

How does IFN-γ affect the gene expression and synthesis of IL-18BP?

It increases gene expression and synthesis of IL-18BP. Signup and view all the answers

Which of the following is a characteristic of 'familial cold autoinflammatory syndrome'?

Constitutional symptoms, fevers, and elevated acute phase proteins after cold exposure Signup and view all the answers

The influence of IFN-γ on IL-18BP gene expression is an example of what type of biological process?

Negative feedback loop. Signup and view all the answers

Which of the following is a characteristic of the caspase-1 enzyme?

Caspase-1 is activated by a decrease in intracellular potassium. Signup and view all the answers

Which treatment has been shown to lead to elevated levels of IL-18BP in patients?

Treatment with IFN-α for hepatitis. Signup and view all the answers

In the skin, how does IL-27 function in relation to inflammation?

It acts through a negative feedback loop for inflammation. Signup and view all the answers

Which receptor is directly activated by ATP which leads to a fall in potassium?

The P2X7 receptor. Signup and view all the answers

What role does natural IL-18BP play during a common viral infection such as Molluscum contagiosum?

It neutralizes human IL-18. Signup and view all the answers

What was the median progression-free survival in patients who experienced a CRP reduction of 40% or greater?

104 months Signup and view all the answers

Compared to the overall survival of patients who did not experience a 40% reduction in CRP, what was the overall survival of those who did?

Not Reached. Signup and view all the answers

Since its introduction in 2002, how many patients are estimated to have received anakinra?

150000 Signup and view all the answers

What is a safety benefit attributed to anakinra?

Short duration of action Signup and view all the answers

In animal studies involving live bacteria, what was the effect of anakinra treatment in comparison to a vehicle?

Greater survival with anakinra Signup and view all the answers

What was a key finding in MAS patients treated with anakinra compared to placebo?

Survival benefit in a subgroup Signup and view all the answers

Compared to untreated persons, how much higher can reactivation of latent Mycobacterium tuberculosis be in patients receiving anti-TNF-α therapies?

25 times higher Signup and view all the answers

What is a characteristic of Mycobacterium tuberculosis reactivation in patients treated with anti-TNF-α therapies?

Disseminated form Signup and view all the answers

What was the original name of IL-18 before it was purified from mouse livers?

IFN-γ-inducing factor Signup and view all the answers

Which of the following is NOT a characteristic of the IL-18 precursor?

Has a signal peptide Signup and view all the answers

What is the molecular weight of mature, active IL-18 after processing?

17,200 Signup and view all the answers

Which enzyme is directly responsible for cleaving the IL-18 precursor into its mature form?

Caspase-1 Signup and view all the answers

In what type of cells is the IL-18 precursor found in healthy subjects, according to the text?

Blood monocytes and epithelial cells of the GI tract Signup and view all the answers

Which of the following best describes the relationship between IL-18 and IL-1β?

They share structural similarities but have significant biological differences Signup and view all the answers

What percentage of the IL-18 precursor remains unprocessed inside the cell after caspase-1 activation?

Over 80% Signup and view all the answers

What does the text suggest about the genes of IL-18 and IL-37?

They share similar intron-exon borders, suggesting a close association. Signup and view all the answers

Study Notes

Overview of the IL-1 Family in Innate and Acquired Immunity

The interleukin-1 (IL-1) family of cytokines and receptors is unique in immunology due to its shared functions with Toll-like receptors (TLRs).
The IL-1 family is primarily associated with innate immunity, playing a crucial role in inflammation. Innate immunity is used by 95% of living organisms for survival.
Inflammation, while a host defense mechanism, can be detrimental if uncontrolled.
IL-1 family members trigger innate inflammation through IL-1 receptors. TLRs trigger inflammation in response to bacteria, viruses, nucleic acids, and damage-associated molecular patterns (DAMPs).
Some IL-1 family members, like IL-1α and IL-33, also function as DAMPs.
IL-1 family members can also play a role in acquired immunity.

The IL-1 Family of Cytokines and Receptors

There are 11 members of the IL-1 family of cytokines and 10 members of the IL-1 family of receptors.
Most members lack a signal peptide, are not readily secreted, and are found as precursors in the cytoplasm.
A conserved consensus sequence (A-X-D) is present in most precursors.
Precursors often contain a specific cleavage site that is essential for proper function, like the caspase-1 cleavage site in the IL-1β precursor.
The IL-1 family of receptors includes both signaling and decoy receptors.

IL-1α

IL-1α is a dual-function cytokine, meaning it has both intracellular and membrane-bound functions.
IL-1α has a nuclear localization sequence which causes it to shuttle between the cytoplasm and nucleus.
The nuclear form acts as a transcription factor.
Extracellular IL-1α can be found on the membrane of certain cells, particularly monocytes and B lymphocytes.
In a necrotic state, the IL-1α precursor acts as a DAMP.

IL-1β

IL-1β is primarily induced in disease states.
Its production is often triggered by microbial products through TLR ligands.
The inactive precursor form of IL-1β resides in the cytosol until processing by the NLRP3 inflammasome and caspase-1.
Caspase-1 cleavage is essential for its activity and secretion.

IL-1 Receptor Antagonist (IL-1Ra)

IL-1Ra is an important inhibitor of IL-1 signaling, effectively blocking IL-1α and IL-1β activity.
Anakinra is a clinically used recombinant form of IL-1Ra used to treat autoimmune diseases and autoinflammatory conditions.
There are clinical trials showing its use to treat heart disease, multiple myeloma, and other disorders.

IL-33

IL-33 is an alarmin belonging to the IL-1 family.
It has both intracellular and extracellular functions, and can be found in the nucleus and cytoplasm.
Nuclear expression is involved in limiting inflammation.

IL-18

A crucial cytokine for innate immunity, particularly for Th1 responses. It can be processed via caspase-1, similar to IL-1b.
IL-18 plays a role in host defense against infections.
It can play a part in multiple conditions like heart disease and inflammatory bowel disease, among others.

IL-37

IL-37 is unique in that it has both pro- and anti-inflammatory properties.
Its high levels are usually linked to inflammation and autoimmunity.

IL-36

The IL-36 subfamily has multiple ligands that bind to the IL-1R6 receptor.
Often expressed in the skin for inflammatory conditions like psoriasis and skin infections.

IL-38

Discovered later, IL-38 is emerging as an anti-inflammatory cytokine, often negatively correlating with disease severity.
It plays a role in autoimmune diseases such as SLE, and other conditions.

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Description

This quiz explores the IL-1 family of cytokines and their pivotal role in both innate and acquired immunity. It covers their functions, mechanisms of action, and their interactions with Toll-like receptors. Delve into the complexities of inflammation and the significance of these cytokines in immune responses.