L2 - Innate response Flashcards
Innate immune response
Born with it rapid host defence against invading pathogens which occurs within minutes
Pattern recognition receptors
Act either b directly binding PAMPs, or interact with other receptors bound to PAMPs - recognition of pathogens
Pathogen-associated molecular patterns (PAMPs)
found on pathogens but not host cells, highly conserved structures expressed by large groups of pathogens
Damage-associated molecular patterns (DAMPs)
endogenous molecules created to alert the host to tissue injury and initiate repair
intracellular molecules released by cell necrosis or activation allowing injury
DAMPs proteins
heat shock proteins, high mobility group box 1 protein, fibrinogen, fibronectin, tenascin-C
DAMPs self-nucleic acids
mRNA, ssRNA, DNA, IgG-chromatin complexes
DAMPs proteoglycans, glycosaminoglycans
billycan, version, hyaluronic acid fragments
Damage chain reaction
Harmful stimulus Tissue damage DAMPS TLRs Pro-inflammatory mediators
Pro-inflammatory mediators can…
cause further tissue damage leading to repeat of damage chain reaction
DAMPS can activate…
more DAMPs
harmful stimuli
pathogens, injuries, heat, autoantigens, tumours, necrotic cells
Extracellular detection
Diacyl lipopeptides
treacly lipopeptides
flagellin
LPs
Diacyl lipopeptides
TLR6/2
Triacyl lipopeptides
TLR1/2
Flagellin
TLR5
LPS
Tlr4, MD-2 and CD-14
Heat shock proteins
TLR2 and 4
High mobility group box1 proteins
TLR 2 and 4
mRNA
TLR3
ssRNA
TLR7 and 8
DNA
TLR9
IgG-chromatin complexes
TLR9
Fibrinogen
TLR4
Fibronectin
TLR4
Tanascin-C
TLR4
Biglycan
TLR 2 and 4
Versican
TLR2
Hyaluronicc acid fragment
TLR2/4
Endosomal detection
dsRNA, ssRNA and CpG DNA
dsRNA
TLR3
ssRNA
TLR7/8
CpG DNA
TLR9
TLR10
cell surface, ligand undetermined in human
Human TLR family
10 members which can be cell surface or inn the cytoplasm on endosomes
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
Phosphorylation cascades activate…
NFKB and MAPKs which allows entry to the nucleus to drive cytokine gene expression
IRF phosphorylation leads to…
localisation to the nucleus to drive expression of type 1 interferon genes to help control viral infections
TLR4 is unique because…
it can use all 4 adaptor proteins
Four main TIR adaptors
MYD99 TRIF TIRAP MAL TRAM
TLR4-TRIF signalling is…
initiated within endosomes
NOD-like receptors (NLRs)
involved in sensing intracellular bacterial pathogens and DAMPs
and in regulation of inflammatory and cell death responses
NOD-like receptor structure
characterised by presence of a conserved nucleotide-binding and oligomerisation domain (NOD)
NLRs subdivided into…
based on….
4 subfamilies
N-terminal effector domains
Gram positive bacterial peptidoglycan
bacterial cell wall
mainly NOD 2
Gram-negative bacterial petidoglycan
periplasmic space,
mainly NOD1
NOD activation
1 and 2 activated by recognitionn of specific motifs (mostly neuropeptides) present in PG
NOD 1 recognises…
meso-diaminopimelic-acid containing PGN fragments, mainly gram-negative
NOD2 recognises…
muramyl dipeptide, found in PGN of nearly all gram-positive and gram-negative organisms
NOD1 and 2 are…
cytoplasmic proteins
dynamically traffic to intracellular membranes upon detection of PG derivatives
NOD1 and 2 cause….
DNA transcription, pro-inflammatory cytokines, chemokines
Assembly of inflammasomes
causes caspases to form
Caspases cleave to form pro-cytokines
releases cytokines into the environment
RIG-I-like receptors
three members the detect viral RNA in the cytoplasm
detect single stranded viruses but infect cells to produce dsRNA
Retinoic acid-inducible gene 1
5’-triphosphate
short dsRNA
influenza A and respiratory syncytial virus
Melanoma differentiated gene 5
long dsRNA with no end specificity
replication intermediates
rhinovirus
LGP2
laboratory of genetics and physiology 2
very high affinity for a dsRNA
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
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
LGP2 function
acts as a positive regulator in RIG-I-mediated and MDA-5 mediated virus recognition
Induced innate responses
cytokines, chemokines, acute phase response and adhesion molecules
IL-1B
activates vascular endothelium, activates lymphocytes, local tissue destruction, increases access of effector cells
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
IL-6
lymphocyte activation, increased antibody production
CXCL8
chemotactic factor recruits neutrophils, basophils and T cells to the site of infection
IL-12
activates NK cells, induces differentiation of CD4 T cells into TH1 cells
IL-1B induces
fever and IL-6 production
TNF-a induces
fever, mobilisation of metabolites and shock
IL-6 induces
fever and acute-phase protein production
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
Selectins
bind carbohydrates, initiate leukocyte-endothelial interaction
Selectin location
activated endothelium and platelets
Integrins
bind to cell-adhesion molecules and the extracellular matrix
Integrins location
in monocytes, neutrophils, macrophages, natural killer cells, dendritic cells and T cells
Immunoglobulin superfamily
have various roles in cell adhesion
ligand for integrins
Immunoglobulin superfamily location
activated and rested endothelium, activated leukocytes and dendritic cells
Acute phase liver
produce acute phase proteins, activation of complement opsonisation
acute phase bone marrow endothelium
neutrophil mobilisation leading to phagocytosis
acute phase hypothealamus
increased body temp
decreased viral and bacterial replication, increased antigen presenting and increased specific immune response
acute phase fat and muscle
protein and energy mobilisation allows temp increase
decreased viral and bacterial replication, increased antigen processing, increased specific immune response
Acute phase dendritic cells
TNF-a stimulates migration to lymph nodes and mutation
initiation of adaptive immune response
Anti-viral infection response cascade
IRFS –> IFNa/B –> STAT1, STAT2 and IRF9
IRSE
interferon stimulated response element
made u[ pf STAT1, STAT2 and IRF9
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
IRSE induces resistance to viral replication
activates genes that cause the destruction of mRNA, inhibits translation of viral proteins and some host proteins
Antagonists in PRR targeting
block ligand binding or protein-ligand complexes to receptors
interfere with adaptor molecules of common signalling pathways
Antagonists development
includes small molecules, oligonucleotides, peptises, proteins and antibodies
antagonist side effects
can potentially repress protective mechanisms
agonists in PRR targeting
adjuvant effect promoting protective responses e.g. interferons with anti-virals
immune stimulators
Agonist side effects
can potentially enhance inflammation
Main challenge in PRR targeting
reducing excessive inflammation without affecting the innate immunity