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?

<p>Specific differences in response to challenge, for example, local inflammation from a subcutaneous turpentine injection. (A)</p> Signup and view all the answers

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

<p>Neutrophils are short-lived cells, dying soon after emigration, releasing their intracellular stores. (C)</p> Signup and view all the answers

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

<p>IL-6 (D)</p> 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?

<p>Intracellular ictal period (D)</p> 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?

<p>Febrile infection-related epilepsy syndrome (C)</p> Signup and view all the answers

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

<p>Systemic juvenile idiopathic arthritis (sJIA) only (C)</p> Signup and view all the answers

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

<p>A decrease in intracellular potassium levels. (D)</p> 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?

<p>28-day mortality (A)</p> 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)?

<p>Hypoglycemia (A)</p> Signup and view all the answers

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

<p>It decreases the availability of IL-37. (C)</p> Signup and view all the answers

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

<p>It opens the potassium channel, leading to a decrease in intracellular potassium. (A)</p> Signup and view all the answers

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

<p>Release through direct activation of calcium channels. (B)</p> 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?

<p>Reduced inflammation. (A)</p> 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?

<p>65.4% (C)</p> Signup and view all the answers

What is pyroptosis?

<p>A caspase-1-dependent form of cell death. (B)</p> Signup and view all the answers

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

<p>They are lost. (C)</p> 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?

<p>0.28 (C)</p> Signup and view all the answers

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

<p>An increase in intracellular calcium. (C)</p> Signup and view all the answers

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

<p>It increases gene expression and synthesis of IL-18BP. (B)</p> Signup and view all the answers

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

<p>Constitutional symptoms, fevers, and elevated acute phase proteins after cold exposure (A)</p> 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?

<p>Negative feedback loop. (C)</p> Signup and view all the answers

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

<p>Caspase-1 is activated by a decrease in intracellular potassium. (B)</p> Signup and view all the answers

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

<p>Treatment with IFN-α for hepatitis. (D)</p> Signup and view all the answers

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

<p>It acts through a negative feedback loop for inflammation. (D)</p> Signup and view all the answers

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

<p>The P2X7 receptor. (B)</p> Signup and view all the answers

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

<p>It neutralizes human IL-18. (B)</p> Signup and view all the answers

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

<p>104 months (D)</p> 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?

<p>Not Reached. (C)</p> Signup and view all the answers

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

<p>150000 (D)</p> Signup and view all the answers

What is a safety benefit attributed to anakinra?

<p>Short duration of action (A)</p> Signup and view all the answers

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

<p>Greater survival with anakinra (C)</p> Signup and view all the answers

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

<p>Survival benefit in a subgroup (B)</p> 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?

<p>25 times higher (D)</p> Signup and view all the answers

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

<p>Disseminated form (B)</p> Signup and view all the answers

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

<p>IFN-γ-inducing factor (D)</p> Signup and view all the answers

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

<p>Has a signal peptide (C)</p> Signup and view all the answers

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

<p>17,200 (A)</p> Signup and view all the answers

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

<p>Caspase-1 (B)</p> Signup and view all the answers

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

<p>Blood monocytes and epithelial cells of the GI tract (D)</p> Signup and view all the answers

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

<p>They share structural similarities but have significant biological differences (A)</p> Signup and view all the answers

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

<p>Over 80% (B)</p> Signup and view all the answers

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

<p>They share similar intron-exon borders, suggesting a close association. (A)</p> Signup and view all the answers

Flashcards

Protein processing

The process by which a protein is broken down into smaller, active fragments. This is often done by specific enzymes called proteases, which cleave the protein at specific sites.

Neutrophils

A type of white blood cell that plays a crucial role in the immune system. Neutrophils are the first responders to infection and inflammation, engulfing and destroying invading pathogens.

Sterile inflammation

An inflammatory response that is triggered by non-infectious stimuli, such as sterile injury or tissue damage. This response is characterized by the activation of immune cells and the release of inflammatory mediators.

Interleukin-1 beta (IL-1β)

A potent pro-inflammatory cytokine that is produced by immune cells, mainly macrophages and neutrophils. IL-1β plays a crucial role in the initiation and amplification of inflammatory responses.

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Caspase-1

An enzyme responsible for cleaving and activating IL-1β. Caspase-1 is an important mediator of inflammatory responses and is activated in response to infection or injury.

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NLRP3 Inflammasome

A protein complex that activates caspase-1, leading to the processing and release of pro-inflammatory cytokines, such as IL-1β.

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Pyroptosis

A type of cell death that occurs during inflammation, triggered by the activation of caspase-1.

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Pro-IL-1β

The precursor form of the pro-inflammatory cytokine IL-1β.

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P2X7 Receptor

A receptor on the cell surface that is activated by ATP and triggers a decrease in intracellular potassium levels.

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Familial Cold Autoinflammatory Syndrome

A condition characterized by recurrent episodes of inflammation triggered by cold exposure.

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IL-1β Release Mechanism

The process by which IL-1β is released from the cell after being processed by caspase-1.

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Sources of IL-1β

Organs or cells that produce and release IL-1β.

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Febrile Infection-Related Epilepsy (FIRE) Syndrome

A syndrome characterized by severe seizures, often triggered by a fever or infection, and frequently seen in children.

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Anakinra

A drug used to block the effects of IL-1, a pro-inflammatory cytokine. It is effective in treating conditions like FIRE Syndrome and Macrophage Activation Syndrome (MAS).

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Macrophage Activation Syndrome (MAS)

A life-threatening complication that can occur in patients with certain autoimmune diseases like sJIA and AOSD. It involves uncontrolled activation of macrophages, leading to widespread inflammation.

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Systemic Juvenile Idiopathic Arthritis (sJIA)

A rare but serious disorder characterized by a persistent fever, joint pain, and inflammation, mainly affecting children.

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Adult-onset Still’s Disease (AOSD)

A similar condition to sJIA, occurring in adults, characterized by prolonged fever, joint pain, and inflammation.

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Disseminated Intravascular Coagulation (DIC)

A rare and serious condition characterized by widespread blood clotting in small vessels (microvascular thrombosis), leading to organ damage.

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Prothrombin Time (PT)

A measure of the body's ability to control bleeding. It is measured by analyzing the time it takes for a blood sample to clot.

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Anti-TNF-α-blocking therapies

A group of medications that block the action of Tumor Necrosis Factor (TNF), a molecule involved in inflammation. They are used to treat various autoimmune diseases.

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Progression-free survival

The time it takes for a disease to progress or worsen.

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Overall survival

The time a patient lives after diagnosis of a disease.

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C-reactive protein (CRP)

A protein in the body that is a marker of inflammation. Higher levels are usually associated with infection or inflammation.

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Host defense against infection

The ability of an organism to defend itself against infections.

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IL-18 and IL-1β: Similarities and Differences

IL-18 is a cytokine similar to IL-1β, but with distinct biological roles. Both are initially synthesised as inactive precursors without signal peptides, requiring processing for activation.

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Presence of IL-18 Precursor

The IL-18 precursor, a larger inactive form of the cytokine, is present in various cells, including blood monocytes and epithelial cells of the digestive tract.

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Processing of IL-18 Precursor by Caspase-1

The IL-18 precursor (24,000 molecular weight) undergoes processing by caspase-1, a crucial enzyme, to become the active, mature IL-18 (17,200 molecular weight).

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Activation of Caspase-1 for IL-18 Processing

Similar to the activation of IL-1β, procaspase-1 is first converted to active caspase-1 by the NLRP3 inflammasome, a protein complex involved in inflammation.

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Release and Fate of Processed IL-18

After being cleaved by caspase-1, mature IL-18 is released from the monocyte/macrophage. However, over 80% of the precursor remains unprocessed within the cell.

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IL-18 and IL-1β: Constitutive Presence

Unlike IL-1β, the IL-18 precursor is found in healthy individuals and in healthy mice, but inactive pro-IL-1β is not found in these conditions.

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IL-18 and IL-1β: Sources and Cell Types

Unlike IL-1β, which is mainly produced by macrophages and neutrophils in response to inflammation, the precursor of IL-18 is found in blood monocytes and epithelial cells of the gastrointestinal tract.

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Role of IL-18 in Inflammation and Immune Responses

IL-18 plays a key role in promoting inflammation and immune responses. It acts as a pro-inflammatory cytokine, contributing to the body's response to infection and other challenges.

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IL-18BP and IL-37 interaction

IL-18BP binds IL-37, reducing its availability as an anti-inflammatory cytokine. This can lessen IL-37's ability to control inflammation.

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Negative Feedback Loop

A negative feedback loop is a regulatory system in which a change in a variable triggers a response that counteracts the initial change, ultimately restoring the variable to its set point. For example, high IL-18 levels trigger an increase in IL-18BP, which then reduces IL-18 levels.

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IFN-γ's effect on IL-18BP

IFN-γ is an immune signaling molecule that is known to induce production of IL-18BP. This is an example of a negative feedback mechanism, as increased IFN-γ leads to increased IL-18BP, which in turn reduces IL-18 signaling.

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Viral infections and IL-18BP

Viral infections can trigger the production of IL-18BP as a natural response to control inflammation and prevent excessive immune activation. This is a way of regulating the immune system during an infection.

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IL-27's dual role

IL-27 is a cytokine with both pro- and anti-inflammatory properties, and can act as an anti-inflammatory by stimulating the production of IL-18BP.

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IL-18BP's anti-inflammatory mechanism

IL-18BP can act as an anti-inflammatory cytokine by reducing the levels of IL-18, which is a potent pro-inflammatory cytokine. This helps to control inflammation and prevent excessive immune responses.

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IL-18BP in disease states

IL-18BP levels are often measured in various disease states to assess the inflammatory response. This helps to understand the role of the IL-18/IL-18BP pathway in different diseases.

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Regulation of IL-18BP production

IL-18BP can be regulated at the level of gene expression. For example, IFN-γ stimulates the production of IL-18BP, leading to increased levels of the inhibitor.

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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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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.

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