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AI - Innate Immunity > Innate Immunity > Flashcards

Innate Immunity Flashcards

1
Q

What is innate immunity?

A

The ability of an organism to defend itself against microbes that it has not previously encountered.

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2
Q

What is innate immunity reliant on?

A

Receptors encoded in the germ line, that do not undergo recombination.

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3
Q

Is innate immunity conserved through all domains of life?

A

Yes - innate immune responses have been identified in bacteria. Similar signalling is used in plant and animal innate immunity.

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4
Q

What are the 3 stages of the response to an infection?

A

Immediate innate immunity, early induced innate immunity and adaptive immunity.

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5
Q

Describe immediate innate immunity.

A

Occurs in the first few hours of an infection, mainly acellular, bactericidal components of body fluids and physical defence barriers. Includes the complement system.

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6
Q

Describe early induced innate immunity.

A

Occurs during the first 4 days of an infection, involves the detection of microbes through recognition of PAMPs by specialised cells. Results in inflammation.

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7
Q

Describe adaptive immunity.

A

Depends on the innate response. Involves the clonal expansion of T and B cells, upon antigen presentation in the lymph nodes.

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8
Q

When did adaptive immunity emerge in evolution?

A

Later on - has almost exclusively been characterised in vertebrates.

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9
Q

When does the early induced innate response occur?

A

Once microbes breach the epithelia; through an open wound, or a bacterial adaptation that allows the bacteria to pass through the epithelium.

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10
Q

What does PAMP recognition result in?

A

Production of antimicrobial effectors, release of cytokines and chemokines that recruit other immune cells and initiation of the adaptive immune response.

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11
Q

Is the adaptive response required to eradicate an infection?

A

Not necessarily - the innate response may effectively kill the microbes.

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12
Q

What are PRRs?

A

Germ-line encoded pattern recognition receptors.

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13
Q

Where does variation come from in PAMP recognition?

A

Different macrophages have different abilities to express different PRRs and PRR expression can be tissue dependent.

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14
Q

What has evolution selected for in PRRs?

A

Receptors that can recognise PAMPs that are present in many microbes.

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15
Q

What are the key characteristics of PAMPs?

A

Present in many microbes, absent/masked in host cells, abundant in microbes, should be surface proteins.

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16
Q

Why must PRRs recognise multiple PAMPs?

A

It would not be efficient to have a receptor for each individual microbe species.

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17
Q

Give an example of a microbe we have evolved to detect specifically. Why does this occur?

A

Mycobacterium tuberculosis. Recognition of the unique long chain lipids in their outer membrane. Occurred because we have co-evolved with mycobacteria.

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18
Q

Why must PAMPs be absent/masked in host cells?

A

Prevents an immune response being triggered against host cells.

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19
Q

Why must PAMPs be highly abundant in microbes?

A

Means an immune response is triggered even if there is a low number of microbes present.

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20
Q

Why should PAMPs be surface proteins?

A

Easily accessed. It would be inefficient to have to rely on bacterial cell lysis for recognition.

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21
Q

Give examples of bacterial PAMPs.

A

LTA: Lipoteichoic acid (amphiphile polyanionic polymer), produced by gram positive bacteria.
LPS: Lipopolysaccharide (polysaccharide side chains and Lipid A), unique to gram negative bacteria.
Peptidoglycan: sugar and amino acid polymer, present near the surface of all bacteria.
LAM: lipoarabinomannan (glycolipid), and other lipids.
Galactan: polysaccharide (polymerized galactose)
Mycolic acid: fatty acid
Flagellin

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22
Q

Where are PRRs found in animal cells?

A

Cell surface, in the cytoplasm and in endosomes.

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23
Q

Give examples of cell surface PRRs.

A

TLRs, CLRs and PGRPs.

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24
Q

What are the domains in TLRs?

A

LRRs to detect PAMPs, and TIR domains for downstream signalling.

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25
Q

What are the domains in CLRs?

A

Extracellular carbohydrate recognition domain, cytosolic ITAMs for downstream signalling.

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26
Q

Where are TLRs found?

A

Cell surface, and within endosomes.

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27
Q

Why are TLRs found in endosomes?

A

Allow detection of bacteria within phagocytosed material.

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28
Q

What are PGRPs?

A

Peptidoglycan recognition domain (modified amidase). Found in invertebrates.

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29
Q

What is amidase?

A

An enzyme used by all animals to degrade peptidoglycan on the surface of gram negative bacteria, and to remove any peptidoglycan present once the bacterium has been killed.

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30
Q

Which PRRs can be cytosolic?

A

NLRs and PGRPs.

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31
Q

What domains are found in NLRs?

A

LRRs to recognise PAMPs, and NOD domains for downstream signalling.

32
Q

What are the specialised immune cells that express PRRs?

A

Macrophages, neutrophils and dendritic cells.

33
Q

Describe the role of macrophages.

A

Act as surveillance cells in all tissue types and act as direct antimicrobial effectors. Most important innate immune cells for initial detection of infection.Stimulated to become pro-inflammatory upon infection.

34
Q

Describe the role of neutrophils.

A

act as antimicrobial effectors, to kill pathogens. Recruited by cytokine release from activated macrophages.

35
Q

Describe the role of dendritic cells.

A

Primarily act as surveillance cells, and activate adaptive immunity. Able to collect antigens and take them to lymph nodes for presentation, via MHC Class II, to cells of the adaptive immune response.

36
Q

What transcription factors are switched on downstream of PRR activation?

A

NFkB and AP-1 - both must be activated for there to be an effective immune response.

37
Q

What transcription factors are switched on downstream of PRR activation during viral infection? And what do these upregulate?

A

IRF3 and IRF7 - results in upregulation of IFNy.

38
Q

Why are NFkB and AP-1 important?

A

Account for all of the transcriptional changes that occur following microbe detection.

39
Q

What domains are found in NFkB?

A

Rel homology domain (DBD and dimerisation) and a transactivation domain.

40
Q

How is NFkB initially expressed?

A

As an inert complex, bound to an inhibitory protein - means NFkB is held in the cytosol.

41
Q

How is NFkB activated?

A

Upstream signalling results in cleavage of the inhibitory protein, allowing NFkB to be translocated into the nucleus.

42
Q

What family of transcription factors does NFkB belong to?

A

Rel

43
Q

Describe the structure of AP-1.

A

c-fos/c-jun heterodimer - where dimerisation is mediated by leucine zippers in the two monomers.

44
Q

How is AP-1 activated?

A

MAPK phosphorylation of the activation domains in c-fos/c-jun.

45
Q

What are the transcriptional targets of NFkB and AP-1?

A

Cytokines, antimicrobial effectors and other regulatory proteins.

46
Q

What is the theory of macrophage differentiation and how was this discovered? Why may this be untrue?

A

Monocytes in the blood are stimulated by various cytokines and inflammatory signals trigger the differentiation of macrophages into different types of macrophages, with defined different functions according to cytokine release.
It was discovered by taking monocytes from blood and giving them different cytokine cocktails to drive differentiation. However, this method cannot give an indication if this is how macrophage differentiation works in the body.

47
Q

What is known about macrophages and monocytes in vivo?

A

It is true that there are macrophages in tissues, and most of these are not derived from monocytes but are instead are put there during embryonic development, and are from a separate cell lineage to those that derive from monocytes.
It is true in vivo that upon exposure to microbial protein, monocytes do change and become more like macrophages and go into tissues.

48
Q

Give examples of pro-inflammatory cytokines.

A

IL-1B, IL-12, IL-23 and TNFa.

49
Q

Give examples of anti-inflammatory cytokines.

A

IL-10, TGFB, IL-1Ra.

50
Q

What is the function of pro-inflammatory cytokines?

A

Involved in the activation of immune responses, and also drives immune responses in non-immune tissues.

51
Q

What is the function of anti-inflammatory cytokines?

A

Limit the damage caused by infection, help tissue repair or restrain immune activity once an infection has been eradicated.

52
Q

Give an example of a cytokine that can be pro and anti-inflammatory.

A

IL-6

53
Q

Give the main functions of cytokines.

A

Facilitate the recruitment of other immune cells. Alter the activity of other immune cells. promote the physiological responses to infection, in non-immune tissues.

54
Q

Give the role of IL-8.

A

mainly produced by macrophages, but also produced by dendritic cells. Key signal for neutrophil recruitment.

55
Q

Give the role of TNFa.

A

acts upon the vascular endothelium, affecting cell adhesion protein expression, and affects cell to cell junctions. Drives vascular permeabilization.

56
Q

Give the role of IL-12 and IL-23.

A

act upon naïve T cells to give a Th1 response and pro-inflammatory cytokine secretion.

57
Q

Give the role of IL-1.

A

mainly produced by macrophages. Enhances immune responses, and induces acute-phase protein secretion from the liver.

58
Q

Give the role of IL-6.

A

produced by macrophages and dendritic cells. Enhances immune responses, and induces acute-phase protein secretion from the liver. Can promote fever.

59
Q

Give a pro-inflammatory cytokine that drives NFkB expression.

A

IL-1B

60
Q

Why must IL-1B activity be tightly controlled?

A

To prevent uncontrolled fever.

61
Q

How is secretion of IL-1B and IL-18 controlled?

A

By inflammasomes.

62
Q

Why is inflammasome activation a two-step process?

A

Requires sensitisation of TLRs to microbial products, leading to expression of pro-IL-1β, as well as removal of any pathogen-mediated negative regulation of inflammasome formation.

63
Q

How do NLRs activate caspase 1?

A

Through a CARD domain or an adaptor with a CARD domain, e.g. ASC.

64
Q

Give the role of IL-1B.

A

promotes inflammation, cellular extravasation and upregulates chemokine, and cytokine production.

65
Q

Give the role of IL-18.

A

upregulates chemokine production, induces production of IFN-γ, and stimulates macrophages, and helps to inhibit growth of intracellular bacteria by stimulating trafficking to lysosomes.

66
Q

How are IL-1B and IL-18 released from cells?

A

Through caspase 1 dependent membrane channels. Pro-IL1B must be cleaved by caspase 1 before secretion.

67
Q

Which inflammasome is best well characterised?

A

NLRP3

68
Q

What are DAMPs? What does their detection result in?

A

Danger signals that activate innate immunity. Result in formation of the inflammasome through activation of NLRP3.

69
Q

Give examples of DAMPs sensed via the inflammasome.

A

cytosolic DNA, uric acid crystals (released by necrotic cells)

70
Q

Give examples of DAMPs sensed by TLRs.

A

released mitochondrial products from dying cells, free heme (typically released from haemoglobin), HMGB1 (nuclear protein released from dying cells).

71
Q

Give examples of DAMPs sensed via dedicated receptors.

A

ATP (detected by CD39) and adenosine

72
Q

How can microbes affect DAMP detection?

A

Direct modification - proteases released by pathogens can cleave host proteins.
Indirect modification - toxins released by pathogens induce host cell death, resulting in release of DAMPs from the apoptotic host cell, e.g. the Diphtheria toxin.

73
Q

What are the two antimicrobial mechanisms in drosophila?

A

Humoral response – inducible production of antimicrobial peptides in the fat body, which bind to bacteria in circulation and kill them.
Cellular response – hemocytes phagocytose microbes and attempt to kill them. Equivalent of macrophages in humans.

74
Q

What is the main difference between human and drosophila immune responses?

A

Humoral response is activated in the fat in drosophila and can detect microbes through TOLL and PGRPs.

75
Q

Give evidence for the importance of innate immunity in drosophila.

A

Immunocompromised mutants cannot clear infection as there is no antimicrobial response. Wildtype drosophila can clear infection in 7 hours.

AI - Innate Immunity (3 decks)

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