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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
Tanascin-C
TLR4
26
Biglycan
TLR 2 and 4
27
Versican
TLR2
28
Hyaluronicc acid fragment
TLR2/4
29
Endosomal detection
dsRNA, ssRNA and CpG DNA
30
dsRNA
TLR3
31
ssRNA
TLR7/8
32
CpG DNA
TLR9
33
TLR10
cell surface, ligand undetermined in human
34
Human TLR family
10 members which can be cell surface or inn the cytoplasm on endosomes
35
TLR signalling
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
36
Phosphorylation cascades activate...
NFKB and MAPKs which allows entry to the nucleus to drive cytokine gene expression
37
IRF phosphorylation leads to...
localisation to the nucleus to drive expression of type 1 interferon genes to help control viral infections
38
TLR4 is unique because...
it can use all 4 adaptor proteins
39
Four main TIR adaptors
``` MYD99 TRIF TIRAP MAL TRAM ```
40
TLR4-TRIF signalling is...
initiated within endosomes
41
NOD-like receptors (NLRs)
involved in sensing intracellular bacterial pathogens and DAMPs and in regulation of inflammatory and cell death responses
42
NOD-like receptor structure
characterised by presence of a conserved nucleotide-binding and oligomerisation domain (NOD)
43
NLRs subdivided into... | based on....
4 subfamilies | N-terminal effector domains
44
Gram positive bacterial peptidoglycan
bacterial cell wall | mainly NOD 2
45
Gram-negative bacterial petidoglycan
periplasmic space, | mainly NOD1
46
NOD activation
1 and 2 activated by recognitionn of specific motifs (mostly neuropeptides) present in PG
47
NOD 1 recognises...
meso-diaminopimelic-acid containing PGN fragments, mainly gram-negative
48
NOD2 recognises...
muramyl dipeptide, found in PGN of nearly all gram-positive and gram-negative organisms
49
NOD1 and 2 are...
cytoplasmic proteins | dynamically traffic to intracellular membranes upon detection of PG derivatives
50
NOD1 and 2 cause....
DNA transcription, pro-inflammatory cytokines, chemokines
51
Assembly of inflammasomes
causes caspases to form Caspases cleave to form pro-cytokines releases cytokines into the environment
52
RIG-I-like receptors
three members the detect viral RNA in the cytoplasm | detect single stranded viruses but infect cells to produce dsRNA
53
Retinoic acid-inducible gene 1
5'-triphosphate short dsRNA influenza A and respiratory syncytial virus
54
Melanoma differentiated gene 5
long dsRNA with no end specificity replication intermediates rhinovirus
55
LGP2
laboratory of genetics and physiology 2 | very high affinity for a dsRNA
56
RLR signalling
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
IPS-1
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
LGP2 function
acts as a positive regulator in RIG-I-mediated and MDA-5 mediated virus recognition
59
Induced innate responses
cytokines, chemokines, acute phase response and adhesion molecules
60
IL-1B
activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells
61
TNF-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
IL-6
lymphocyte activation, increased antibody production
63
CXCL8
chemotactic factor recruits neutrophils, basophils and T cells to the site of infection
64
IL-12
activates NK cells, induces differentiation of CD4 T cells into TH1 cells
65
IL-1B induces
fever and IL-6 production
66
TNF-a induces
fever, mobilisation of metabolites and shock
67
IL-6 induces
fever and acute-phase protein production
68
Leukocyte production
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
Selectins
bind carbohydrates, initiate leukocyte-endothelial interaction
70
Selectin location
activated endothelium and platelets
71
Integrins
bind to cell-adhesion molecules and the extracellular matrix
72
Integrins location
in monocytes, neutrophils, macrophages, natural killer cells, dendritic cells and T cells
73
Immunoglobulin superfamily
have various roles in cell adhesion | ligand for integrins
74
Immunoglobulin superfamily location
activated and rested endothelium, activated leukocytes and dendritic cells
75
Acute phase liver
produce acute phase proteins, activation of complement opsonisation
76
acute phase bone marrow endothelium
neutrophil mobilisation leading to phagocytosis
77
acute phase hypothealamus
increased body temp | decreased viral and bacterial replication, increased antigen presenting and increased specific immune response
78
acute phase fat and muscle
protein and energy mobilisation allows temp increase | decreased viral and bacterial replication, increased antigen processing, increased specific immune response
79
Acute phase dendritic cells
TNF-a stimulates migration to lymph nodes and mutation | initiation of adaptive immune response
80
Anti-viral infection response cascade
IRFS --> IFNa/B --> STAT1, STAT2 and IRF9
81
IRSE
interferon stimulated response element | made u[ pf STAT1, STAT2 and IRF9
82
IRSE results in ( 5 parts)
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
IRSE induces resistance to viral replication
activates genes that cause the destruction of mRNA, inhibits translation of viral proteins and some host proteins
84
Antagonists in PRR targeting
block ligand binding or protein-ligand complexes to receptors interfere with adaptor molecules of common signalling pathways
85
Antagonists development
includes small molecules, oligonucleotides, peptises, proteins and antibodies
86
antagonist side effects
can potentially repress protective mechanisms
87
agonists in PRR targeting
adjuvant effect promoting protective responses e.g. interferons with anti-virals immune stimulators
88
Agonist side effects
can potentially enhance inflammation
89
Main challenge in PRR targeting
reducing excessive inflammation without affecting the innate immunity

Respiratory Pharmacology (17 decks)

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