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2.1 Molecular Immunology > Greg - Pattern Recognition Receptors > Flashcards

Greg - Pattern Recognition Receptors Flashcards

1
Q

What specificity does the innate immune system have?

A

It knows what is a fungus, a bacteria, a parasite etc

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2
Q

How does the innate immune system have some specificity?

A

The innate system can recognise structural components that don’t change over long periods of time e.g. LPS

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3
Q

What four things must an APC do in order to initiate an immune response?
(4)

A

Leave the tissue by downregulating adhesion molecules so it can release from tissue and move into fluid

Upregulate MHC

Upregulate costimulatory molecules

Secrete cytokines

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4
Q

What is the “Danger Model” of the immune system?

A

The innate immune system has evolved to recognise signals that indicate that infection or tissue damage is happening

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5
Q

Who came up with the “Danger Model”?

A

Polly Matzinger

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6
Q

What does PRR stand for?

A

Pattern Recognition Receptors

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7
Q

What are the two classifications of PRRs?

A

PAMPs
DAMPS

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8
Q

What are PAMPs?

A

Pathogen associated molecular patterns

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9
Q

What are DAMPs?

A

Damade/danger associated molecular patterns

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10
Q

Where are the three places PRRs can be located?

A

Anchored in the cell membrane

Inside cells located in endosomes/lysosomes or in the cytosol

Secreted from the cell

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11
Q

Give an example of a receptor anchored in the cell membrane

A

Toll-like receptors

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12
Q

Give an example of a receptor anchored in the cell membrane

A

Toll-like receptors

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13
Q

Give two examples of receptors found in the cell

A

Nod-like receptors

Rig-I-receptors

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14
Q

Give two examples of receptors secreted from cells

A

C-reactive protein

Mannose binding lectin

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15
Q

What are DAMPs?
(2)

A

Molecules often derived from tissue damage that cause host cells to undergo necrotic death

Harmful Molecules and or contents of the cell that spill out of the cell when they die via necrosis

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16
Q

What is cell necrosis?

A

Unorganised death of a cell

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17
Q

Give some examples of DAMP
(7)

A

gDNA fragments
Chromatin components
Mitochondrial DNA
Uric acid crystals
Heat shock proteins
Products of complement activation

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18
Q

What does the deposition of uric acid crystals lead to?

A

Goitre

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19
Q

How many TLRs do humans have?

A

Humans have 11 but the 11th is not active

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20
Q

Describe the basic structure of a TLR
(5)

A

Extracellular pattern recognition zone

Intracellular TIR domain

Single pass through membrane

Horseshoe shaped

18-25 motifs made of 20-29 amino acids rich in leucine

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21
Q

What is the TIR domain?
(4)

A

Cytoplasmic signalling domain

Toll-Interleukin-1 Receptor

Present in TLRs and IL-1B receptors

Contains 3 highly conserved amino acid sequences called boxes, 1, 2 and 3

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22
Q

What two types of receptors are TIR domains found on?

A

TLRs

IL-1B receptors

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23
Q

What happens when TLRs bind their ligand?
(2)

A

They are induced to dimerize

Most are homodiners of a single polypeptide

24
Q

Give a TLR that forms heterodimers

A

TLR2

25
Q

Give two heterodimer options for TLR2

A

TLR1 with 2
TLR6 with 2

26
Q

What does TLR 7 detect?

A

Viral single stranded RNA

27
Q

What does TLR 10 detect?

A

We don’t really know, could be vestigial

28
Q

What does TLR 9 detect?

A

CpG -> cysteine followed by guanine (not really found in humans but a lot id found in pathogens)

29
Q

Describe the relationship between TLRs, their location and their function

A

TLRs on the outside of the cell tend to detect bacterial and fungal PAMPs

TLRs that detect viral PAMPs are found inside the cell in endosomes and lysosomes

30
Q

What is unique about TLR4?

A

It can move between the inside and outside of a cell

31
Q

What TLR detect LPS?

A

TLR4-TLR4 homodimer

32
Q

Describe the movement of TLR4

A

TLR4 can move from the plasma membrane to endosomes/lysosomes after ligand binding

33
Q

How is LPS detected?
(4)

A

LPS binds to CD14 which associates to the MD2 of TLR4

LPS binding protein (LBS) delivers LPS to CD14

Complex formed from MD2, TLR4, CD14, LPS

Cytolines may then be released, MHC expression might be increased

34
Q

Describe the TLR signalling pathway of detection
(4)

A

Complex of TLR 4, MD2, CD14 and LPS is assembled on macrophage surface

MyD88 binds TLR4 and activates IRAK4 to phosphorylation TRAF6 which leads to phosphorylation and activation of IKK

IKK phosphorylates Ik(kappa)B which leads to the degradation and release of NFkappaB which enters the nucleus

NFkappaB activates transcription of genes for inflammatory cytokines, which are synthesised in the cytoplasm and secreted via the ER

35
Q

List the molecules in the receptor signalling pathway

A

Complex of TLR 4, MD2, CD14 and LPS

MyD88

IRAK4

TRAF6

IKK

Ik(kappa)B

NFkappaB

NFkappaB

Cytokines

36
Q

What are protein kinases?

A

Enzymes that can add phosphate groups to certain amino acids in proteins

37
Q

What are the most common targets for kinases?

A

Serine/threonine or tyrosine

38
Q

Explain what happens when there is extracellular recognition of LPS?
(6)

A

The TIR domain of TLR4 binds to a similar TIR domain of the adaptor protein MyD88 and forms a protein bridge to bring other molecules together

MyD88 has another ‘death’ domain where it recruits IRAK4 (a protein kinase)

IRAK4 has a death domain as well which is what binds to MyD88

IRAK4 is activated and it phosphorylates IRAK1

IRAK1 binds and phosphorylates TRAF6

This complex dissociates from receptor and leads to the activation of IkappaB kinase

39
Q

What activates IRAK4?

A

The death domain of IRAK4 binds to the death domain of MyD88

40
Q

What does activated IRAK4 do?

A

It phosphorylates IRAK1

41
Q

What does IRAK1 do?

A

IRAK1 binds and phosphorylates TRAF6

42
Q

What does TRAF6 do?

A

IRAK1 TRAF6 complex dissociates from receptor and leads to the activation of IkappaB kinase

43
Q

How does IRAK1/TRSF6 complex lead to the activation of IkappaB
(4)

A

The complex dissociates from the receptor which phosphorylates and activates IKK via kinase cascade

IKK phosphorylates IkB

IkB dissociates from NFkB

NFkB moves into nucleus where it directs the activation of genes for cytokines, adhesion molecules and other proteins that expand and intensify the APC effector functions

44
Q

List the results of TLR-induced changes in gene expression
(4)

A

Surface expression of co-stimulatory molecules

Cytokine secretion

Chemokine secretion

Migration of dendritic cells

45
Q

Give some examples of co-stimulatory molecules

A

B7
(CD80/CD86)

46
Q

List five pro-inflammatory cytokines

A

IL-6
TNF-a
IL-1B
CXCL8
IL-12

47
Q

What does IL-6 do?
(2)

A

Causes fever

Induces acute-phase protein production by hepatocytes

48
Q

What does TNF-a do?
(4)

A

Activates vascular endothelium and increases vascular permeability -> increased entry of complement and cells to tissues -> increased fluid drainage to lymph nodes

Causes fever

Causes mobilization of metabolites

Shock

49
Q

What does IL-1B do?
(6)

A

Activates vascular endothelium

Activates lymphocytes

Causes local tissue destruction

Increases access of effector cells

Causes fever

Causes production of IL-6

50
Q

What does CXCL8 do?

A

Chemotactic factor that recruits neutrophils and basophils to site of infection

51
Q

What does IL-12 do?

A

Activates NK cells

52
Q

What cytokines cause fever?

A

IL-6
TNF-a
IL-1B

53
Q

What cytokine induces acute phase protein production?

A

IL-6

54
Q

What cytokine mobilises cells and fluid in inflammation?

A

TNF-a

55
Q

What cytokine produces IL-6

A

IL-1B

56
Q

What cytokine activates natural killer cells?

A

IL-12

57
Q

What cytokine acts as a chemotactic factor for neutrophils and basophils?

A

CXCL8

2.1 Molecular Immunology (19 decks)

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