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Cellular and Molecular Immunology > 7. Innate Immunity 2: Effector mechanisms > Flashcards

7. Innate Immunity 2: Effector mechanisms Flashcards

1
Q

How were macrophages discovered?

A

Some lava cells were pierced with thorns and something was observed slowly eating up the thorns. These turned out to be macrophages.

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2
Q

What is gout?

A
  1. A disease associated with an unhealthy and excessive lifestyle.
  2. The disease is based on immune dysregulation and overaction of the innate immune system.
  3. Uric acid deposits in the joint that activate the inflammasome and macrophages
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3
Q

What is uric acid?

A

It is derived from Protein, so excessive red meat consumption leads to a build-up.

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4
Q

What is the inflammasome role in diseases?

A

They are the common bases that link a wide variety of disease through over activation.

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5
Q

What are some diseases caused by inflammasomes?

A
  1. Crohn’s disease
  2. Gout and pseudogout
  3. Anthrax
  4. Autosomal dominant hereditary periodic fever syndromes. These are caused by gain of function mutations in the inflammasome.
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6
Q

What is the inflammasome?

A

A large cytosolic complex for autocatalytic activation of inflammatory caspases.

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7
Q

What are caspases?

A

proteases

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8
Q

What is caspase 1?

A

The caspases involved in inflammation. It is the most important caspase that forms part of the inflammasome.

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9
Q

What does the inflammasome lead to?

A
  1. Inflammation
  2. Lymphocyte activation
  3. Production of additional cytokines that mediate IL-1ß
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10
Q

What is the main function of the inflammasome?

A

To produce, activate and secrete IL-1ß

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11
Q

What are the 3 functions of the inflammasome?

A
  1. Release of IL-1ß
  2. Induction of pyroptosis
  3. Elimination of infected cells
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12
Q

Where are inflammasomes expressed?

A
  1. Macrophages
  2. Epithelial cells.
  3. Endothelial cells.
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13
Q

What does the release of IL-1ß cause?

A
  1. Fever
  2. Neutrophil influx
  3. T cell survival
  4. B cell proliferation and antibody production
  5. Polarisation of mainly Th1 but also Th2 and Th17 responses.
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14
Q

What is pyroptosis?

A
  1. A proinflammatory cell death that occurs in the cell the inflammasome forms in.
  2. Causes the release of alarmins, which are DAMPs.
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15
Q

What does the elimination of infected cells do?

A

Removes the disease and prevents it from spreading.

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15
Q

How many types of inflammasomes are in humans?

A

22

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16
Q

What are the 2 conserved inflammasome regions?

A

The adaptor and effector regions that homodimerise.

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17
Q

Where is the variation in the inflammasome?

A
  1. In the sensor regions
  2. These interact with stimuli
  3. Nod-like receptor domains interact with stimuli.
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18
Q

What is the most important inflammasome NLR?

A

Nlrp3

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19
Q

What does Nlrp1b detect?

A

bacillus anthracis lethal toxin

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20
Q

What does Nlrp3 detect?

A
  1. Microbial PAMPs
  2. Endogenous DAMPs
  3. Crystals like uric acid
  4. UVB radiation
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21
Q

What does Nlrc4 detect?

A

Bacteria such as:
1. Salmonella
2. Shigella
3. Psuedomonas aeruginosa

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22
Q

What does AIM2 detect?

A
  1. DNA viruses
  2. Francisella tularensis
  3. Listeria monocytogenes
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23
Q

How does UVB radiation activate the inflammasome?

A

It causes sunburn which is an inflammatory response.

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24
Q

How does a single receptor detect many different things?

A
  1. Nod-like receptors look for the down stream effects of the stimuli on the cell.
  2. This is effector-triggered immunity.
  3. We don’t really know how it works, but it somehow triggers the inflammasome.
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25
Q

How does Nlrp3 detect its stimuli?

A
  1. Recognises phagosomal destabilisation through phagosomal leakage.
  2. Recognises K+ efflux from the cells when pore-forming toxins from bacteria cause pores in the cell membrane.
26
Q

What are the 2 signals needed to activate the inflammasome?

A
  1. The priming signal
  2. The assembly signal
27
Q

What is the priming signal in inflammasome activation?

A
  1. Transcription of the components of the inflammasome.
  2. Caused by the stimulation of TLR4 through MyD88 and NF-kB
  3. Causes the transcription of Nlrp3 and pro-IL-1ß
28
Q

What is the assembly signal in inflammasome activation?

A
  1. An activator interacts with Nlrp3 which causes a conformational change to expose the PYD domain on the Nlrp3.
  2. This allows the oligomerisation of the PYD domains on the Nlrp3 and binding to PYD domain on ASC to form the inflammasome structure. The ASC forms long filament like structures.
  3. ASC is the adaptor and recruit procaspase 1 through its CARD domain.
  4. If you bring lots of procaspases together they activate each other through autocatalysis.
  5. Pro Gasdermin-D is also cleaved.
  6. Gasdermin-D assembles on the plasma membrane and forms pores.
  7. Through the pores IL-1ß exits the cell and water enters.
  8. This fills the cell with water and causes death by pyroptosis and releases of alarmins.
  9. Neutrophils come in and clean up the debris.
29
Q

What is a CARD domain?

A

caspase activation and recruitment domain

30
Q

How are the procaspases cleaved?

A

Through proximity induce autocatalysis

31
Q

What happen when Nlrp3 is inappropriately activated?

A
  1. The basis of lots of immunopathology.
  2. Random gain of function mutations leads to cryopyrin-associated periodic syndrome.
  3. These lead to unprovoked hyperactivation of the inflammasome when there is no autoantibodies or self reactive T cells.
  4. This is autoinflammatory disease.
32
Q

Mutations in the inflammasome that lead to disease: Nlrp3

A
  1. Gain of function mutation in Nlrp3
  2. Rashes triggered by prolonged cold exposure.
  3. Found through whole genome sequencing
33
Q

Mutations in the inflammasome that lead to disease: A20

A
  1. A 20 is an inhibitor of NF-kB
  2. A loss of function mutation leads to the inability to inhibit NF-kB.
  3. This causes the overproduction of IL-1ß.
  4. Symptoms include systemic inflammation, arthritis, ulcers, ocular inflammation, and sterile abscesses.
34
Q

What are sterile abscesses?

A

A conglomerate of immune cells that form a lump

34
Q

What is the clinical application of knowing the cause of inflammasome diseases?

A
  1. We know IL-1ß is the driver of inflammation.
  2. We can treat these diseases using anti-IL-1ß antibodies or by blocking the IL-1ß receptor
35
Q

What are some chronic inflammatory diseases that could be treated using an IL-1ß blockade?

A
  1. Gout and psuedogout
  2. Atherosclerosis
  3. Alzheimer’s disease
36
Q

What are macrophages?

A

Large multifunctional mononuclear phagocytic cells

37
Q

What did we think macrophages only were?

A

immune cells, but actually, they have lots of housekeeping roles

38
Q

How do macrophages present antigens?

A

They express MHC class 2 and professionally present antigens.

39
Q

What cells do macrophages share a lineage with?

A

Dendritic cells

40
Q

What house keeping functions do macrophages have?

A

Maintaining the tissue homeostasis of other tissues.

41
Q

What cells are most macrophages derived from?

A

Monocytes

42
Q

What is the mean turnover time of acute macrophages?

A

7 days

43
Q

What do tissue resident immune macrophages control?

A

The onset and resolution of inflammation.

44
Q

What are housekeeping macrophages?

A
  1. Lived longed macrophages
  2. derived from the embryo yolk sack
  3. They have many functions to maintain tissue homeostasis.
45
Q

How were housekeeping macrophages discovered?

A
  1. By studying people with tattoos
  2. Macrophages eat the ink of tattoos as they heal.
  3. Macrophages were found with ink in them up to 10 years after the tattoo was done.
  4. This showed there were long lived macrophages in the body.
46
Q

What are microglia?

A
  1. Macrophages in the brain
  2. They move from the yolk sack to the developing brain early in development before the blood brain barrier forms.
  3. They reside in the brain forever and undergo proliferation themselves.
  4. Their main function is synaptic pruning to promote memory functions.
47
Q

What is the function of gut macrophages?

A

They help with the muscle contraction through the gut to keep food moving.

48
Q

What are Kupffer cells?

A
  1. Macrophages in the liver
  2. functions include immunosurveillance and detoxification.
49
Q

What are Alveolar macrophages?

A
  1. Macrophages in the lungs
  2. Immunosurveillance and dealing with inhaled particles
50
Q

What is the polarisation of macrophages?

A

It is the acquisition of the different development states through environmental signalling.

51
Q

What are the 3 state of immune macrophages?

A
  1. Classical
  2. Alternative - wound healing
  3. Alternative - regulatory
52
Q

Development and functions of classical macrophages

A
  1. They are the result of IFNg exposure.
  2. These produce lots of reactive oxygen species due to up regulation of enzymes that produce them.
  3. This makes them very good at killing things.
  4. They up regulate MHC2 for antigen presentation
  5. They produce inflammatory cytokines like TNF or IL-1ß.
53
Q

Development and functions of Wound healing macrophages

A
  1. They are a result of IL-4 and IL-13 exposure.
  2. They are important in tissue repair.
  3. Upregulation of Arginase to make ECM components.
  4. Deposit ECM in the wound to help it close.
54
Q

Development and functions of regulatory macrophages

A
  1. They are a result of IL-10, immune complex and apoptotic neutrophil signals.
  2. These are anti-inflammatory.
  3. They trigger the resolution of inflammation through TGFß and Tregs.
55
Q

What signals activate classical macrophages?

A
  1. Innate activation by PRR
  2. Humoral activation by antibody FcR and complement - complement receptor.
56
Q

How does the metabolism of L-arginine show the difference in macrophage function?

A
  1. In classical macrophages, L-arginine is converted to Citrulline and NO by NOS2 to be in the phagosome.
  2. In wound-healing macrophages, L-arginine is converted to ornithine and proline by arginase1. These are major parts of the ECM that are needed for wound healing.
57
Q

How do macrophages interact with adaptive immunity?

A

When the lungs are infected with TB, macrophages are recruited. The macrophages then interact with T cells, which release IFNg. This causes a strong activation of macrophages needed for the mycobacterium infection.

58
Q

How does the innate immune system interact with the adaptive?

A
  1. Cytokines
  2. Complement
  3. Dendritic cells
59
Q

How does the adaptive immune system interact with the innate?

A
  1. Cytokines
  2. Antibodies
60
Q

How did an experiment show co-evolution of macrophage deficiencies?

A
  1. 4 children had an acute response to a bird mycobacterium that doesn’t normally infect humans.
  2. These kids all lacked the IFNg receptor so the macrophages are not very strongly activated.
61
Q

Key concepts of this lecture.

A
  1. The inflammasome is an intracellular innate signal response system.
  2. Macrophages and neutrophils are rapidly recruited to the local microenvironment.
  3. Integrated innate and adaptive immune activation regulates the progress of an immune response.

Cellular and Molecular Immunology (17 decks)

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