4. Innate defence Flashcards
what are the phagocytic cells?
Macrophages
Neutrophil
immature Dendritic cells
what is the phagocytic precursor?
Monocytes
what are tissue resident macrophages also known as?
Mononuclear phagocytes
What tissues do mononuclear phagocytes reside in?
Lymph node sinuses
small blood vessels
Endothelial cells of sinusoids of liver, spleen and bone marrow
alveoli
brain
What are neutrophils also known as?
Polymorphonuclear neutrophilic leukocytes
which phagocytes are short lived?
Neutrophils
when are dendritic cells phagocytic?
when immature and resident in the tissue
what do mature dendritic cells do?
migrate to the lymph nodes and act as APC to T cells
What are the 3 steps of phagocytosis?
- chemotaxis
- attachment and uptake
- microbicidal activity
what is the bacterial protein N-terminus used in chemotaxis to recruit phagocytes?
f-Met-Leu-Phe
what attracts monocytes to the site of infection in chemotaxis?
complement fragment C3a and C5a
chemokines
What chemokine is the macrophage inflammatory protein?
CCL3
What chemokine recruits neutrophils and T cells to the site of infection?
CXCL8 (IL-8)
What receptors do cells rely on to detect the chemotaxis gradient?
G-protein coupled receptors
what receptors do macrophages express?
PRRs that bind microbe components
complement receptors
lipid receptors
scavenger mannose
what are the phagocytic receptors on macrophages?
Dectin-1
mannose receptor
scavenger receptors
complement receptors - CR1, CR3, CR4
what does dectin-1 bind?
B-1,3-linked glucans on fungi
what does mannose binding receptor bind?
mannosylated ligands on bacteria, fungi and viruses
what do scavenger receptors bind?
anionic polymers
what do complement receptors bind?
inactivated C3b on bacterial surface
when does a macrophage initiate inflammation?
once a pathogen is phagocytosed
what do PRRs recognise?
pathogen-associated molecular patterns (PAMPS)
what PRR represent an evolutionary ancient host defence?
Toll- like receptors
What TLR recognises diacyl lipopeptides?
TLR2 and TLR6
What TLR recognises triacyl lipopeptides?
TLR1 and TLR2
What TLR recognises flagella?
TLR5
What TLR recognises lipopolysaccharides (LPS)?
TLR4
What TLR recognises dsDNA?
TLR3
What TLR recognises ssRNA?
TLR7 and TLR8
What TLR recognises methylated CpG DNA?
TLR9
What is the signalling cascade when TLR2 is bound?
- starts with MyD88
- MyD88 activates transcription factor NF-kB
- NF-kB moves to the nucleus and induces the expression of proinflammatory cytokines
what is MyD88?
a viral adaptor protein
give an example of a PRR in the cytoplasm
NOD2
What does NOD stand for?
Nucleotide binding oligomerisation domain
what does binding to NOD2 cause?
start of the NF-kB signalling cascade
do cytokines work locally?
yes
what cytokines trigger inflammation?
IL-1b and TNFa
what does IL-6 do?
acts on the liver to produce acute proteins like mannose binding lectin and C reactive protein
what is phagocyte oxygen independent killing?
using an acidic environment,
lysozymes,
antimicrobial peptides,
hydrolases
What is phagocyte oxygen dependent killing?
Respiratory bursts (important in neutrophils)
Oxygen-derived products (ROS)
superoxide
hydrogen oxide
singlet oxygen
hydroxyl radical
hypophalite
what is critical for oxygen dependent killing?
NADPH and O2 are oxidised by NADPH oxidase to form H2O2 and O radicals
what happens if a person lacks NADPH oxidase?
cannot make ROS
develop chronic bacterial infections
develop skin and liver granulomas
how does the superoxide ion contribute to oxygen dependent killing?
cause influx of K+ and H+ into phagocytic vesicles and lowers the pH.
causes a release of cathepsin G and elastase from granules which are activated by lysosomal proteases
how is NADPH oxidase assembled in the respiratory burst?
GP91is on the membrane of the neutrophil
associated with the cytoplasmic components and becomes a complex in the phagolysosome membrane
the enzymes in the primary granule can be activated in the phagosome
then start production of ROS
What are NETs?
Neutrophil extracellular traps
Include DNA histones, granules and proteins outside the cell to trap and kill bacteria
What are the 2 main viral components that trigger PRRs?
dsRNA triggers TLR3
unmethylated CpG DNA triggers TLR9
what type of signalling cascade does the viral components trigger?
To produce type 1 interferons
What are type 1 interferons?
antiviral effector molecules that effect the cells around then
what anti viral responses do type 1 interferons produce?
induce resistance to viral replication
increase MHC-1 expression and antigen presentation
activate dendritic cells and macrophages
activate NK cells
what is the purpose of the type 1 interferon antiviral state?
creates a fire-break
the virus cannot replicate in neighbouring cells to keep the infection local
what are natural killer cells?
large granular lymphocytes for early defence
derived from the common lymphoid progenitors
activated by type 1 interferons and cytokines
what is NK cells role in early immunity?
start killing the virus during the lag phase of adaptive immunity
How do NK cells scan healthy cells?
binds the activating receptor to the ligand
binds MHC1 to the inhibitory receptor
the inhibitory signal overrides the activation
how do NK cells scan infected cells?
the MHC1 is not expressed or expressed incorrectly
no inhibitory signal
NK cells activated and kill by triggering apoptosis
What do NK granules contain?
Perforin = helps deliver granule contents to the target cell
serglycin = a proteoglycan scaffold
Granzymes = granules associated enzymes like serine proteases that trigger host cell apoptosis
How do granzymes trigger apoptosis?
Granzyme B cleaves procaspase 3 to activate it
caspase 3 cleaves the inhibitor of caspase-activated DNase (ICAD)
CAD then triggers DNA degradation
