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Respiratory Pharmacology > L2 - Innate response > Flashcards

L2 - Innate response Flashcards

1
Q

Innate immune response

A

Born with it rapid host defence against invading pathogens which occurs within minutes

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2
Q

Pattern recognition receptors

A

Act either b directly binding PAMPs, or interact with other receptors bound to PAMPs - recognition of pathogens

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3
Q

Pathogen-associated molecular patterns (PAMPs)

A

found on pathogens but not host cells, highly conserved structures expressed by large groups of pathogens

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4
Q

Damage-associated molecular patterns (DAMPs)

A

endogenous molecules created to alert the host to tissue injury and initiate repair
intracellular molecules released by cell necrosis or activation allowing injury

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5
Q

DAMPs proteins

A

heat shock proteins, high mobility group box 1 protein, fibrinogen, fibronectin, tenascin-C

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6
Q

DAMPs self-nucleic acids

A

mRNA, ssRNA, DNA, IgG-chromatin complexes

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7
Q

DAMPs proteoglycans, glycosaminoglycans

A

billycan, version, hyaluronic acid fragments

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8
Q

Damage chain reaction

A 
Harmful stimulus
Tissue damage
DAMPS
TLRs
Pro-inflammatory mediators
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9
Q

Pro-inflammatory mediators can…

A

cause further tissue damage leading to repeat of damage chain reaction

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10
Q

DAMPS can activate…

A

more DAMPs

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11
Q

harmful stimuli

A

pathogens, injuries, heat, autoantigens, tumours, necrotic cells

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12
Q

Extracellular detection

A

Diacyl lipopeptides
treacly lipopeptides
flagellin
LPs

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13
Q

Diacyl lipopeptides

A

TLR6/2

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14
Q

Triacyl lipopeptides

A

TLR1/2

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15
Q

Flagellin

A

TLR5

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16
Q

LPS

A

Tlr4, MD-2 and CD-14

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17
Q

Heat shock proteins

A

TLR2 and 4

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18
Q

High mobility group box1 proteins

A

TLR 2 and 4

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19
Q

mRNA

A

TLR3

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20
Q

ssRNA

A

TLR7 and 8

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21
Q

DNA

A

TLR9

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22
Q

IgG-chromatin complexes

A

TLR9

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23
Q

Fibrinogen

A

TLR4

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24
Q

Fibronectin

A

TLR4

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25
Q

Tanascin-C

A

TLR4

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26
Q

Biglycan

A

TLR 2 and 4

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27
Q

Versican

A

TLR2

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28
Q

Hyaluronicc acid fragment

A

TLR2/4

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29
Q

Endosomal detection

A

dsRNA, ssRNA and CpG DNA

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30
Q

dsRNA

A

TLR3

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31
Q

ssRNA

A

TLR7/8

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32
Q

CpG DNA

A

TLR9

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33
Q

TLR10

A

cell surface, ligand undetermined in human

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34
Q

Human TLR family

A

10 members which can be cell surface or inn the cytoplasm on endosomes

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35
Q

TLR signalling

A

TIR domains of TLRs interact with TIR domains of the adaptor proteins
phosphorylation cascades activate NF-KB and MAPKs allowing entry to the nucleus to drive expression of cytokine genes
IRF phosphorylation leads to nucleus localisation to drive expression of type 1 interferon genes to help control viral infections

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36
Q

Phosphorylation cascades activate…

A

NFKB and MAPKs which allows entry to the nucleus to drive cytokine gene expression

37
Q

IRF phosphorylation leads to…

A

localisation to the nucleus to drive expression of type 1 interferon genes to help control viral infections

38
Q

TLR4 is unique because…

A

it can use all 4 adaptor proteins

39
Q

Four main TIR adaptors

A 
MYD99
TRIF
TIRAP
MAL 
TRAM
40
Q

TLR4-TRIF signalling is…

A

initiated within endosomes

41
Q

NOD-like receptors (NLRs)

A

involved in sensing intracellular bacterial pathogens and DAMPs
and in regulation of inflammatory and cell death responses

42
Q

NOD-like receptor structure

A

characterised by presence of a conserved nucleotide-binding and oligomerisation domain (NOD)

43
Q

NLRs subdivided into…

based on….

A

4 subfamilies

N-terminal effector domains

44
Q

Gram positive bacterial peptidoglycan

A

bacterial cell wall

mainly NOD 2

45
Q

Gram-negative bacterial petidoglycan

A

periplasmic space,

mainly NOD1

46
Q

NOD activation

A

1 and 2 activated by recognitionn of specific motifs (mostly neuropeptides) present in PG

47
Q

NOD 1 recognises…

A

meso-diaminopimelic-acid containing PGN fragments, mainly gram-negative

48
Q

NOD2 recognises…

A

muramyl dipeptide, found in PGN of nearly all gram-positive and gram-negative organisms

49
Q

NOD1 and 2 are…

A

cytoplasmic proteins

dynamically traffic to intracellular membranes upon detection of PG derivatives

50
Q

NOD1 and 2 cause….

A

DNA transcription, pro-inflammatory cytokines, chemokines

51
Q

Assembly of inflammasomes

A

causes caspases to form
Caspases cleave to form pro-cytokines
releases cytokines into the environment

52
Q

RIG-I-like receptors

A

three members the detect viral RNA in the cytoplasm

detect single stranded viruses but infect cells to produce dsRNA

53
Q

Retinoic acid-inducible gene 1

A

5’-triphosphate
short dsRNA
influenza A and respiratory syncytial virus

54
Q

Melanoma differentiated gene 5

A

long dsRNA with no end specificity
replication intermediates
rhinovirus

55
Q

LGP2

A

laboratory of genetics and physiology 2

very high affinity for a dsRNA

56
Q

RLR signalling

A

ligand binding induces conformational changes and oligomerisation of RLRs to activate the signalling partner IPS-1 on mitochondrial membranes
IPS-1 activates signalling cascades leading to activation of IRDs and NFKB and the expression of interferon and cytokine genes
LGP2 functions as a positive regulator in RIG-I-mediated and MDA-5-mediated virus recognition

57
Q

IPS-1

A

activated through ligand binding to RLRs on mitochondrial membranes
activates signalling cascades leading to activated of IRDs and NF-kB and the expression of interferon and cytokine genes

58
Q

LGP2 function

A

acts as a positive regulator in RIG-I-mediated and MDA-5 mediated virus recognition

59
Q

Induced innate responses

A

cytokines, chemokines, acute phase response and adhesion molecules

60
Q

IL-1B

A

activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells

61
Q

TNF-a

A

activates vascular endothelium and increases vascular permeability, which leads to increased entry of IgG, complement, and cells to tissues and increased fluid drainage to lymph nodes

62
Q

IL-6

A

lymphocyte activation, increased antibody production

63
Q

CXCL8

A

chemotactic factor recruits neutrophils, basophils and T cells to the site of infection

64
Q

IL-12

A

activates NK cells, induces differentiation of CD4 T cells into TH1 cells

65
Q

IL-1B induces

A

fever and IL-6 production

66
Q

TNF-a induces

A

fever, mobilisation of metabolites and shock

67
Q

IL-6 induces

A

fever and acute-phase protein production

68
Q

Leukocyte production

A

adhesion molecules are induced on circulating immune and endothelial cells
they coordinate movement of cells into infected tissues where phagocytosis and killing tajes place

69
Q

Selectins

A

bind carbohydrates, initiate leukocyte-endothelial interaction

70
Q

Selectin location

A

activated endothelium and platelets

71
Q

Integrins

A

bind to cell-adhesion molecules and the extracellular matrix

72
Q

Integrins location

A

in monocytes, neutrophils, macrophages, natural killer cells, dendritic cells and T cells

73
Q

Immunoglobulin superfamily

A

have various roles in cell adhesion

ligand for integrins

74
Q

Immunoglobulin superfamily location

A

activated and rested endothelium, activated leukocytes and dendritic cells

75
Q

Acute phase liver

A

produce acute phase proteins, activation of complement opsonisation

76
Q

acute phase bone marrow endothelium

A

neutrophil mobilisation leading to phagocytosis

77
Q

acute phase hypothealamus

A

increased body temp

decreased viral and bacterial replication, increased antigen presenting and increased specific immune response

78
Q

acute phase fat and muscle

A

protein and energy mobilisation allows temp increase

decreased viral and bacterial replication, increased antigen processing, increased specific immune response

79
Q

Acute phase dendritic cells

A

TNF-a stimulates migration to lymph nodes and mutation

initiation of adaptive immune response

80
Q

Anti-viral infection response cascade

A

IRFS –> IFNa/B –> STAT1, STAT2 and IRF9

81
Q

IRSE

A

interferon stimulated response element

made u[ pf STAT1, STAT2 and IRF9

82
Q

IRSE results in ( 5 parts)

A

dendritic cell and macrophage activation
induces chemokine to recruit lymphocytes
activates NK cells to kill virus-infected cells
increased MMC class I expression and antigen presentation of viral proteins - facilitates recognition and susceptibility to cytotoxic T cells
induces resistance to viral replication

83
Q

IRSE induces resistance to viral replication

A

activates genes that cause the destruction of mRNA, inhibits translation of viral proteins and some host proteins

84
Q

Antagonists in PRR targeting

A

block ligand binding or protein-ligand complexes to receptors
interfere with adaptor molecules of common signalling pathways

85
Q

Antagonists development

A

includes small molecules, oligonucleotides, peptises, proteins and antibodies

86
Q

antagonist side effects

A

can potentially repress protective mechanisms

87
Q

agonists in PRR targeting

A

adjuvant effect promoting protective responses e.g. interferons with anti-virals
immune stimulators

88
Q

Agonist side effects

A

can potentially enhance inflammation

89
Q

Main challenge in PRR targeting

A

reducing excessive inflammation without affecting the innate immunity

Respiratory Pharmacology (17 decks)

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