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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
What endogenous products do cell surface TLRs recognise?
HSP70 Fibrinogen Fibronectin
26
What TLRs are endosomal?
``` TLR-3 TLR-7 TLR-8 TLR-9 TLR-10 ```
27
What exogenous products do endosomal TLRs recognise?
Mainly recognise viral products - dsRNA - ssRNA - DNA
28
What endogenous products do endosomal TLRs recognise?
dsRNA ssRNA DNA
29
What genes does TLR signalling induce?
Genes that function in host defence - pro inflammatory cytokines - chemokines - MHC and co-stimulatory molecules - antimicrobial peptides and complement components
30
What are the 2 main pathways that TLR signals down?
MyD88 dependent pathway | Trif pathway
31
What does the MyD88 pathway activate?
AP-1 | NF-kB
32
What does the trif pathway activate?
IRF family members which drive production of type 1 interferon
33
What TLR adaptor proteins only use Myd88?
``` IL-1R TLR5 TLR7 TLR8 TLR9 ```
34
What pathway does TLR1/2 use?
Myd88 | Mal
35
What pathway does TLR3 use?
Trif
36
What pathway does TLR4 use?
MyD88 Mal TRAM Trif
37
What is Waldenstrom macroglobulinaemia?
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
Why does the clinical status of children with MyD88 deficiency improve with age?
Compensatory effect of adaptive immunity or other innate immune mechanisms
39
What are the consequences of TLRs deficiency?
Herpes simplex encephalitis
40
What TLRs are involved in causing HIV?
TLR8
41
What TLRs are involved in causing sepsis?
TLR2 and TLR4
42
What TLRs are involved in causing tuberculosis?
TLR2 | TLR4
43
What TLRs are involved in inflammation of systemic lupus erythematous?
TLR7 TLR8 TLR9
44
What TLRs are involved in inflammation of Alzheimer's disease?
TLR2 | TLR4
45
What TLRs are involved in inflammation of atherosclerosis?
TLR2 | TLR4
46
What TLR agonist are used to treat genital warts?
TLR7
47
What TLR agonists are used to treat melanoma?
TLR7 ligand
48
What TLR agonists are used to treat allergy to ragweed pollen?
TLR9
49
What TLR antagonists are used to treat autoimmunity?
TLR7 | TLR8
50
What TLR antagonists are used in treatment of sepsis?
TLR4
51
What are NLRs?
Nucleotide-binding leucine rich (NLR) | Cytoplasmic pattern recognition molecules
52
What are the 2 major groups of NLRs?
``` NLRCs = NLR caspase recruitment domain NLRPs = NLR pyrin domain ```
53
What are 2 examples of NLRCs and what do they bind?
NLRC1 (NOD1) - bind iE-DAP | NLRC2 (NOD2) - binds muramyl dipeptide
54
What is a NOD2 gain of function mutation associated with?
Early onset sarcoidosis where granulomas develop in organs of the body
55
What is a NOD2 loss of function mutation associated with?
Susceptibility to Crohn's disease
56
What is NLRP3 activated by?
``` Cellular stress K+ efflux ATP Reactive oxygen species Lysosomal damage ```
57
What is the consequence of NLRP3 gain of function mutation?
Cryopyrin-associated periodic syndromes - Muckle wells syndrome - familial cold auto inflammatory syndrome
58
Describe Muckle Wells syndrome
Occurs spontaneously or triggered by cold, heat, fatigue or other stressors Symptoms: fever, rash, arthralgia, conjunctivitis, uveitis, sensorineural deafness, potentially life-threatening amyloidosis
59
Describe familial cold auto inflammatory syndrome
Triggered by exposure to cold | Symptoms: fever, urticarial rash with headache, arthralgia, conjunctivitis
60
How is muckle wells syndrome and familial cold auto inflammatory syndrome treated?
Anakinra (IL-1RA)
61
What activates the inflammasome?
Cellular infection or cell stress - uric acid crystals (gout) - asbestos - silica - amyloid beta (Alzheimer's) - Islet amyloid peptide (type 2 diabetes) - Hemozoin (malaria)
62
What does activation of the inflammasome lead to?
Cleavage of pro-IL-1 and pro-IL-18 to allow secretion
63
What are RIG-I like receptors?
Sensors of cytoplasmic RNA that signal to induce pro-inflammatory cytokines and IFN
64
Describe RIG-I
Binds to single-stranded RNA containing 5'-triphosphate
65
What does RIG-I recognise?
Flaviviruses (hepatitis C) | Orthomyxoviruses (influenza)
66
What does MDA5 recognise?
Long double-stranded RNA
67
Describe cytosolic DNA sensors
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
What is SAVI?
Autoinflammatory disease | STING-associated vasculopathy with onset in infancy
69
What is SAVI caused by?
Gain of function mutations in TMEM173 (gene that codes for STING)
70
What does SAVI cause?
Abnormal inflammation throughout body, especially in skin, blood vessels and lungs
71
What induces the acute phase response?
Cytokines such as TNF, IL-6, IL-1
72
What does the acute phase response induce?
Opsonisation / phagocytosis | Can activate complement pathway
73
How can we detect inflammation clinically?
Raised ESR and CRP which are characteristic of acute phase response

Module 204 MSK & Immune system (44 decks)

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