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Module 204 MSK & Immune system > T1 L3 Innate immune defences and inflammation 2 > Flashcards

T1 L3 Innate immune defences and inflammation 2 Flashcards

1
Q

What are the functions of neutrophils?

A

Phagocytosis
Reactive oxygen and nitrogen species
Antimicrobial peptides

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2
Q

What are the functions of macrophages?

A 
Phagocytosis
Inflammatory mediators
Antigen presentation
Reactive oxygen and nitrogen species
Cytokines
Complement proteins
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3
Q

What are the functions of dendritic cells?

A 
Antigen presentation
Costimulatory signal
Reactive oxygen species
Interferon
Cytokines
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4
Q

What are the functions of natural killer cells?

A

Lysis of viral infected cells
Interferon
Macrophage activation

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5
Q

What are the 4 stages of phagocyte recruitment?

A

1) Rolling
2) Activation
3) Arrest / adhesion
4) Transendothelial migration

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6
Q

What is phagocytosis?

A

Capture and digestion of foreign particles

Performed by neutrophils and macrophages

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7
Q

What stimulates phagocytosis?

A

Opsonins

Phagocytic receptors

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8
Q

Give examples of some opsonins that trigger phagocytosis

A

Complement components
Collectins (mannose-binding lectin)
Antibodies

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9
Q

Give examples of some phagocytic receptors that trigger phagocytosis

A

Complement receptors
Fc receptors
Mannose receptors
Scavenger receptors

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10
Q

What initiates the active process of phagocytosis?

A

Binding to the pathogen

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11
Q

What are the steps of phagocytosis?

A

1) Macrophage receptors that recognise components of microbial surface
2) Microorganisms bound by phagocytic receptors on macrophage surface
3) Microorganisms are internalised by receptor-mediated endocytosis
4) Fusion of endoscope with a lysosome to form phagolysosome in which microorganisms are degraded

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12
Q

Describe the acidification of antimicrobial mechanism of phagocytes

A

Macrophage and neutrophil products:

  • pH around 3.5 to 4
  • Bacteriostatic or bactericidal
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13
Q

Describe the toxic oxygen-derived products

A

Macrophage and neutrophil products:

  • superoxide
  • hydrogen peroxide
  • singlet oxygen
  • hydroxyl radical
  • hypohalite
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14
Q

Describe the antimicrobial peptides of macrophage products

A

Cathelicidin

Macrophage elastase-derived peptide

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15
Q

Describe the antimicrobial peptides of neutrophil products

A 
Alpha-defensins
Beta-defensin
Cathelicin
Azurocidin
Bacterial permeability inducing protein
Lactoferricin
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16
Q

Describe how enzymes contribute to the antimicrobial mechanism

A

Macrophage and neutrophil products:

  • lysozyme
  • acid hydrolyses e.g. elastase and other proteases
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17
Q

Describe the competitors of antimicrobial mechanisms of phagocytes for neutrophil products

A

Lactoferrin (sequesters Fe2+)
Vitamin B12
Binding protein

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18
Q

What happens during NETosis?

A 
Activation of neutrophil 
Cell bursts
Nuclear chromatin is released from cells
Forms NETs
Traps microorganisms
Aids phagocytosis
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19
Q

Give examples of types of pattern recognition receptors

A

Toll-like receptors (TLRs)
NOD-like receptors (NLRs)
Rig-I like receptors (RLRs)
Cytosolic DNA sensors (CDS)

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20
Q

What are DAMPs?

A

Damage associated molecular patterns that are released from necrotic cells

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21
Q

What is the structure of the toll-like receptor?

A

Extracellular: LRR domain which is the site of pathogen binding
Cytosolic side: TIR domain conserved stretch of around 200 amino acids

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22
Q

Describe how toll-like receptors form functional hetero/homodimers

A

Convex surfaces of TLR-1 and TLR-2 have binding sites for lipid side chains of triacyl lipopeptides
Binding of each TLR to same lipopeptide will induce dimerisation which brings their cytoplasmic TIR domains into close proximity

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23
Q

What TLRs are on the surface?

A 
TLR-1
TLR-2
TLR-4
TLR-5
TLR-6
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24
Q

What exogenous products do cell surface TLRs recognise?

A

Mainly bacterial products:

  • lipopolysaccharide
  • flagellin
  • lipoteichoic acid
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25
Q

What endogenous products do cell surface TLRs recognise?

A

HSP70
Fibrinogen
Fibronectin

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26
Q

What TLRs are endosomal?

A 
TLR-3
TLR-7
TLR-8
TLR-9
TLR-10
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27
Q

What exogenous products do endosomal TLRs recognise?

A

Mainly recognise viral products

  • dsRNA
  • ssRNA
  • DNA
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28
Q

What endogenous products do endosomal TLRs recognise?

A

dsRNA
ssRNA
DNA

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29
Q

What genes does TLR signalling induce?

A

Genes that function in host defence

  • pro inflammatory cytokines
  • chemokines
  • MHC and co-stimulatory molecules
  • antimicrobial peptides and complement components
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30
Q

What are the 2 main pathways that TLR signals down?

A

MyD88 dependent pathway

Trif pathway

31
Q

What does the MyD88 pathway activate?

A

AP-1

NF-kB

32
Q

What does the trif pathway activate?

A

IRF family members which drive production of type 1 interferon

33
Q

What TLR adaptor proteins only use Myd88?

A 
IL-1R
TLR5
TLR7
TLR8
TLR9
34
Q

What pathway does TLR1/2 use?

A

Myd88

Mal

35
Q

What pathway does TLR3 use?

A

Trif

36
Q

What pathway does TLR4 use?

A

MyD88
Mal
TRAM
Trif

37
Q

What is Waldenstrom macroglobulinaemia?

A

Rare type of non-Hodgkin lymphoma
B cells make large amounts of IgM which causes excess bleeding, Vision problems and headaches
Lymphoma cells proliferating in bone marrow can cause anaemia, neutropenia and thrombocytopenia

38
Q

Why does the clinical status of children with MyD88 deficiency improve with age?

A

Compensatory effect of adaptive immunity or other innate immune mechanisms

39
Q

What are the consequences of TLRs deficiency?

A

Herpes simplex encephalitis

40
Q

What TLRs are involved in causing HIV?

A

TLR8

41
Q

What TLRs are involved in causing sepsis?

A

TLR2 and TLR4

42
Q

What TLRs are involved in causing tuberculosis?

A

TLR2

TLR4

43
Q

What TLRs are involved in inflammation of systemic lupus erythematous?

A

TLR7
TLR8
TLR9

44
Q

What TLRs are involved in inflammation of Alzheimer’s disease?

A

TLR2

TLR4

45
Q

What TLRs are involved in inflammation of atherosclerosis?

A

TLR2

TLR4

46
Q

What TLR agonist are used to treat genital warts?

A

TLR7

47
Q

What TLR agonists are used to treat melanoma?

A

TLR7 ligand

48
Q

What TLR agonists are used to treat allergy to ragweed pollen?

A

TLR9

49
Q

What TLR antagonists are used to treat autoimmunity?

A

TLR7

TLR8

50
Q

What TLR antagonists are used in treatment of sepsis?

A

TLR4

51
Q

What are NLRs?

A

Nucleotide-binding leucine rich (NLR)

Cytoplasmic pattern recognition molecules

52
Q

What are the 2 major groups of NLRs?

A 
NLRCs = NLR caspase recruitment domain
NLRPs = NLR pyrin domain
53
Q

What are 2 examples of NLRCs and what do they bind?

A

NLRC1 (NOD1) - bind iE-DAP

NLRC2 (NOD2) - binds muramyl dipeptide

54
Q

What is a NOD2 gain of function mutation associated with?

A

Early onset sarcoidosis where granulomas develop in organs of the body

55
Q

What is a NOD2 loss of function mutation associated with?

A

Susceptibility to Crohn’s disease

56
Q

What is NLRP3 activated by?

A 
Cellular stress
K+ efflux
ATP
Reactive oxygen species
Lysosomal damage
57
Q

What is the consequence of NLRP3 gain of function mutation?

A

Cryopyrin-associated periodic syndromes

  • Muckle wells syndrome
  • familial cold auto inflammatory syndrome
58
Q

Describe Muckle Wells syndrome

A

Occurs spontaneously or triggered by cold, heat, fatigue or other stressors
Symptoms: fever, rash, arthralgia, conjunctivitis, uveitis, sensorineural deafness, potentially life-threatening amyloidosis

59
Q

Describe familial cold auto inflammatory syndrome

A

Triggered by exposure to cold

Symptoms: fever, urticarial rash with headache, arthralgia, conjunctivitis

60
Q

How is muckle wells syndrome and familial cold auto inflammatory syndrome treated?

A

Anakinra (IL-1RA)

61
Q

What activates the inflammasome?

A

Cellular infection or cell stress

  • uric acid crystals (gout)
  • asbestos
  • silica
  • amyloid beta (Alzheimer’s)
  • Islet amyloid peptide (type 2 diabetes)
  • Hemozoin (malaria)
62
Q

What does activation of the inflammasome lead to?

A

Cleavage of pro-IL-1 and pro-IL-18 to allow secretion

63
Q

What are RIG-I like receptors?

A

Sensors of cytoplasmic RNA that signal to induce pro-inflammatory cytokines and IFN

64
Q

Describe RIG-I

A

Binds to single-stranded RNA containing 5’-triphosphate

65
Q

What does RIG-I recognise?

A

Flaviviruses (hepatitis C)

Orthomyxoviruses (influenza)

66
Q

What does MDA5 recognise?

A

Long double-stranded RNA

67
Q

Describe cytosolic DNA sensors

A

1) Double-stranded DNA from viruses activates cGAS
2) Produces cGAMP from ATP and GTP
3) cGAMP or other bacterial-derived cyclic dinucleotides bind to STING dimer on ER membrane which activates its signalling
4) STING activates kinase TBK1 which phosphorylates IRF3, which enters nucleus and induces expression of type 1 interferon genes

68
Q

What is SAVI?

A

Autoinflammatory disease

STING-associated vasculopathy with onset in infancy

69
Q

What is SAVI caused by?

A

Gain of function mutations in TMEM173 (gene that codes for STING)

70
Q

What does SAVI cause?

A

Abnormal inflammation throughout body, especially in skin, blood vessels and lungs

71
Q

What induces the acute phase response?

A

Cytokines such as TNF, IL-6, IL-1

72
Q

What does the acute phase response induce?

A

Opsonisation / phagocytosis

Can activate complement pathway

73
Q

How can we detect inflammation clinically?

A

Raised ESR and CRP which are characteristic of acute phase response

Module 204 MSK & Immune system (44 decks)

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