Lecture 4: Innate Immunity Flashcards
PAMPs
Pathogen associated molecular patterns
No structural similarity with self Ags
PRRs
Patter recognition receptors
Cell receptors that recognize PAMPs
Phagocytes, PRRs and fMet
Phagocytes have PRRs to distinguish self from non-self
These can help phagocytes bind proteins starting with fMet, and use them to control motility and initiate phagocytosis.
fMet is present in prokaryotes but not eukaryotes
Endosomal TLRs respond to
Only to nucleic acids
Which TLR recognizes lipoproteins
2
Which TLR recognizes LPS
4
T or F: One pathogen is recognized by one TLR
False. One pathogen can be recognized by multiple TLRs
ssRNA viruses recognized by which TLRs
dsRNA recognized by which TLRs
7, 8
3
Unmethylated CpG-rich DNA recognized by TLR
9
Gram-positive bacteria recognized by which TLRs
1, 2, 6, 9
Gram-negative bacteria recognized by which TLRs
4, 5, 9
Fungi recognized by which TLRs
2, 9
Protists recognized by which TLRs
2, 4
TRIF dependent signaling
TLR3 uses only the adaptor protein TRIF to activate NF-kB and IRF transcription proteins
MyD88/TRIF dependent signaling
TLR4 uses both MyD88 and TRIF to activate NF-kB and IRF transcription proteins
MyD88 dependent signaling
TLRs 1, 2, 5, 6, 7, 8 and 9 use only the adaptor protein MyD88 to activate transcription factors NF-kB and IRF
TLRs are expressed where
Immune cells including monocytes, neutrophils, macrophages and DCs
TLR dependent signaling pathways activate __ which results in
NF-kB and IRF which results in transcription of pro-inflammatory genes
What controls the adaptive T-cell immune response
Cytokine IL-12
How can activation of TLRs be detrimental to host
Can contribute to tissue injury by inducing apoptosis
Can lead to septic shock
TLR4 complete complex on macrophage surface
TLR4, MD2, CD14 and LPS on macrophage surface
TLR4 first steps in function
MyD88 binds TLR4 and activates IRAK4 to phosphorylate TRAF6, which leads to phosphorylation and activation of IKK
TLR4 second set of steps
IKK phosphorylates IkB, leading to its degradation and the release of NF-kB, which enters the nucleus
TLR4 third set of steps
NF-kB activates transcription of genes for inflammatory cytokines, synthesized in cytoplasm and secreted via ER
NLRs
NOD-like receptors- intracellular proteins
Play critical role in regulation of the host innate immune response
NLRs act as ___
They control __
Scaffolding proteins that trigger NF-kB and MAPK signaling pathways
They control the activation of inflammatory caspases
NLRs respond to _____&_____ by
PAMPs and DAMPs, by binding other proteins and forming an inflammasome
Inflammasome activates
Caspase-1
Caspase-1 function
Cleave inactive precursor forms of cytokines IL-1B and IL-18
Secreted forms of these cytokines drive inflammation
Inflammasome activation induced by
Variety of cytoplasmic stimuli associated with infections and cell stress
-Microbrial products, crystals, reduction in cytosolic K+ concentrations
NLRP3 senses
Many DAMPs and PAMPs including uric acid crystals, aluminum hydroxide and ATP
Pyroptosis
Form of programmed cell death induced by inflammasome. Macrophages and DCs (but not neutrophils and other cell types) are affected.
Scavenger receptors are important for
Tissue remodeling after collateral damage due to inflammation and infections
Cellular domains of SRs
SRCR (Absent in SR-AII)
Collagen-like domain
alpha-helical coiled-coil domain (absent in MARCO)
Collagen-like domain function
Implicated in the binding of polyanionic ligands
What type of receptors are SRs
PRRs- Pattern recognition receptors
SR-AI, SR-AII and MARCO are all expressed on ___ and mediate
Macrophages
Mediate recognition/phagocytosis of microorganisms via recognition of PAMPs
What would happen to an SR knock-out mouse
It would have increased susceptibility to infection
Carbohydrate (mannose) receptors
Member of Lectin family
Recognize microbial mannose
Trigger secretion of cytokines
Mannose receptor on phagocytes is involved in
Phagocytosis of microbes
Causes of inflammation
Increased blood supply to area
Increased capillary permeability
Influx of neutrophils, monocytes, macrophages
Distortion of homeostasis and loss of function
DAMPs will activate
NF-kB
Examples of DAMPs that activate NF-kB
HMGB1
Uric acid
HSPs
Defensins are
Small cationic peptides with cationic and hydrophobic sequences
Defensins produced by, synthesis is stimulated by
Neutrophils, NK cells and cytotoxic t cells
Stimulated by cytokines/microbes
Defensins have direct or indirect toxicity to microbes
Method of action?
Direct toxicity
Insert into and disrupt function of microbial membrane
Defensins can regulate
Activation of immune cells involved in inflammatory responses
Cathelicidins- what produces it, what stimulates production
Produced by neutrophils
Production stimulated by microbes/cytokines
Cathelicidens bind
LPS to neutralize it
NK cells respond to ___ secreted by ___
IL-12 secreted by macrophages
NK cells release ___ which
IFN-y which activates macrophages to kill phagocytized microbes
NK cell activating receptors
KIRs- activate PTKs (protein tyrosine kinases), trigger killing of cell
NK inhibitory receptors
Recognize class I MHC molecules on normal cells, therefore inhibiting the killing of that cell
NK cell killing method
Releases perforins, which perforate enemy cell membrane
Granzymes enter cell and degrade enzymes, triggering apoptosis
Macrophage engulfs and digests cell