induced innate immunity (exam 2) Flashcards
induced innate immunity
4hrs to 4 days after infection
new DNA transcription and protein synthesis
induced innate immunity involves the
recruitment of soluble effector molecules and effector cells to infected tissue
what is involved in the induced innate immune response?
resident effector cells
internal signaling
external signaling
recruited effector cells
induced complement pathways
internal signaling in induced leads to
gene expression changes
external signaling in induced leads to
cytokine production
PAMP
pathogen associated molecular pattern
structural feature on microbe surface
PRR
pattern recognition receptor
molecule on immune cell surface that recognizes and binds PAMPS
distinguish between self, non self and altered self
many microbial ligands are
carbohydrates and lipids not present on eukaryotic cells
receptors for microbial ligands
lectins
scavenger receptor
CR3, CR4
lectins
recognize carbohydrates
scavenger receptor
binds negatively charged ligands
including apoptotic human cells
CR3 and CR4
bind complement and microbial agents
binding of CR3 and CR4 triggers
receptor mediated endocytosis
other macrophage receptors
trigger cytokine release
Toll-like receptor, NOD-like receptor, RLR
Toll like receptor
several types, each specific for common elements of different microbial products
TLR4
recognizes LPS and other molecules on gram NEGATIVE bacteria
generates intracellular signals through cytoplasmic domain –> causes gene expression
TLR4 causes gene expression that triggers
induced innate immune responses and inflammation (inflammatory cytokines)
2 major types of Toll like receptors
- plasma membrane bound
- endosomal membrane bound
plasma membrane bound TLR
direct contact with EXTRACELLULAR pathogen
endosomal membrane bound TLR
sense mostly viral DNA and RNA (INTRACELLULAR)
released in extracellular environment and taken up by cells
When discussing TLR receptors, if there is an intracellular pathogen versus an extracellular pathogen you can expect
a different response since different receptors are triggered
NF-kB pathway
major role in innate and adaptive response
activation of nuclear factor kB –> antigen binding –> activation and nuclear translocation of NFkB into nucleus –> activates expression of genes –> inflammation
NEMO deficiency
genetic lack of IKK subunit
susceptible to bacterial infections
interferon pathway
response to viral infections, intracellular bacteria
IRF7/IRF3
IRF7 or IRF3 results in
synthesis and secretion of type 1 interferons –> infected cells will be killed
with TLR signaling, cells of the innate immune response can _____________ to different typers of _________
tailor response
pathogens
TLR response to extracellular bacteria
inflammatory cytokines
TLR response to viral
interferons
NOD-like receptors
recognize parts of cell wall from phagocytose bacteria
production of inflammatory cytokines
RIG-1 like receptors
recognize viral RNA
production of type 1 interferons
cytokines
small signaling proteins made in response to external stimuli
pro inflammatory cytokines secreted by MO
IL-1b
TNF-a
IL-6
IL-12
CXCL8 and CCL2
master regulator of inflammation
IL-1b
IL-12 induces
NK lymphocyte proliferation
chemokines
small proteins that attract specific leukocytes
chemokine follow a
concentration gradient (low to high)
chemokine recruit
neutrophil and monocytes to alter cell adhesive properties and guide neutrophils/monocytes along gradient
IL-1 inhibitors approved for clinical use
anakinra - IL-1 antagonist
canakinumab - neutralizes IL-1b
rilonacept - neutralizes IL-1a/IL-1b
at the site of infection, activated ___________ secrete __________
resident macrophages
inflammatory cytokines
TNF-a
stimulates vascular endothelial cells to make platelet activating factor
triggers bloot clotting
systemic infection
pathogen is disseminated throughout the body via bloodstream
septic shock
widespread clotting in capillaries, organ failure
people with a defective TLR
are at increased risk for septic shock
widespread TNF-a production
phagocytic cells
macrophages and neutrophils
macrophages
long lived
reside in tissues
immediate response
phagocytosis
neutrophils
short lived
circulate in blood
recruited by macrophages
neutrophils
granulocytes
polymorphonuclear leukocytes
short life span, constantly made in bone marrow
how many neutrophils enter the mouth and throat each day?
3x10^9
_________ of neutrophils is the first step in inflammatory response
arrival
neutrophils die within
hours of entry into tissue
(this is why pus is at infected wounds)
neutrophils have
surface receptors for inflammatory mediators
ligand/receptor interactions (for neutrophils) induce
expression of adhesion molecule
expression of ligands for adhesion molecules on vascular endothelial cells in capillaries near infection
extravasation
migration from vessel to tissue
steps of extravasation of neutrophils
- neutrophil is slowed down by VEC
- tight binding
- diapedesis
- migration to center of infection in tissue
tight binding step of extravasation
weak interactions, chemokines induce stronger ones
neutrophil stops rolling
diapedesis step of extravasation
neutrophil squeezes between adjacent VEC and reaches basement membrane
migration to center of infection in tissue (extravasation)
driven by gradient (CXCL8)
homing
all WBCs leave the blood and migrate to infected tissue
what determines where and when homing occurs?
cytokines and chemokines
target identification of neutrophils on pathogens
phagocytic receptors for microbial products
complement receptors for opsonized microbes
NADPH oxidase
produces superoxide radicals consuming O2 which removes H ions and produces hydrogen peroxide
fusion of phagosomes with neutrophil granules
NADPH oxidase raises pH of phagosome activating antimicrobial peptides
fusion of phagosome with lysosomes (neutrophils)
acid hydrolases finish the job, then the neutrophil dies
chronic granulomatous disease
defect in NADPH oxidase
no respiratory burst
leads to chronic bacterial/fungal infections
neutrophil extracellular traps
trap and kill pathogens
systemic effects of inflammatory cytokines in innate immunity
induce fever
produce acute-phase response
induce fever
act on hypothalamus and muscle
fat cells generate heat
helps fight infections
name of molecules that induce fever
pyrogens
acute phase proteins
change spectrum of soluble plasma proteins made by liver cells
mannose binding lectin
binds carbohydrates of bacteria, viruses, fungi, protozoans
triggers lectin pathway
how does mannose binding lectin not attach to human cells?
it can attach only to repetitive structures on pathogens
C reactive protein (CRP)
binds phosphocholine of bacterial and fungal cell walls
triggers classical pathway in absence of antibody
serum amyloid A protein
induces inflammatory cytokine production in macrophages
fibrinogen
blood clotting
localizes pathogen and prevents spread
lectin pathway
binding of MBL to bacterial surface
cleaves C4 and C2
genetic deficient in MBL
can result in severe meningitis
common
classical pathway
binding of C1 to C reactive protein on pathogen activates protease
cleaves C4 and C2 –> opsonization
which pathways of complement need to be induced
lectin and classical
the main complement pathway at the start of infection
alternative
type 1 interferons
made by any human cell infected with virus
interfere with viral replication
how do type 1 interferons alert the area that there in an infection?
they signal neighboring cells to prepare
alert immune cells
make virus infected cells targets for NK cells
forms of type 1 interferons
IFN-b and IFN-a
synthesis of interferons is induced by
viral infection or binding to a signaling receptor since dsRNA is not found in healthy human cells
what type of fashions can interferons act in?
paracrine and autocrine
interferon response
induce resistance to viral replication in all cells
increase expansion of ligands for receptors on NK cells
activate NK cells to kill virus infected cells
plasmacytoid dendritic cell
produces huge amounts of type 1 interferon
found in blood and lymphoid tissue
NK cells
5-25% of lymphocytes
against intracellular infections
migrate from blood to tissue in response to inflammatory cytokines
functions of NK cells
kill infected cells (stimulated by IFN-a,b)
produce cytokines (stimulated by IL-12)
what type of cytokine does NK cells produce?
IFN-g which activates macrophages
NK cells interact with
dendritic cells
suppress or activate them depending on sufficiency of innate response
how do NK cells kill infected human cells?
inducing them to die via apoptosis
ligands on NK cells
inhibitory and activating receptors
type of ligands on healthy cells
more inhibitory over activating
when NK cells are ________ they outnumber dendritic cells and _______ the dendritic cells
abundant
kill
when NK cells are scarce, they signal the dendritic cells and
initiate the adaptive immune response
