3. Cellular mechanisms of innate immunity Flashcards
what are PAMPs
conserved molecular features shared by related groups of microorganisms
recognized by PRRs
what are PRRs
receptors that recognize PAMPs (and DAMPs) - foreign material that appears on microorganisms but are lacking in host cells
genetically encoded and inherited through germ line
what is non-clonal expansion of PRRs
immune cells express multiple PRRs
macrophages express receptors that enable them to…
take up microbes by phagocytosis
phagolysosomes of macrophages
contains a lysosome and AMPs
become acidified
produces superoxide and NO radicals to kill pathogens
what are the 5 families of PRRs
TLRs
lectin receptor
scavenger receptor
cytosolic innate receptor
opsonin receptor
characteristics of the lectin receptor
bind carbohydrates: sulfated sugars and polysaccharides
prompts phagocytosis
e.g. mannose receptor (CD206)
characteristics of the scavenger receptor
binds negative charged ligands: sulphated polysaccharides and LTA (G+) and LPS (G-)
prompts phagocytosis
e.g. SR-A and SR-B
characteristics of the cytosolic innate receptor
binds intracellular PAMPs: DNA, dsDNA, cyclic dinucleotides
inhibits pathogen growth
prompts WBC recruitment to kill infected cells
e.g. RIG-1 (viral RNA) and cGAS (DNA)
characteristics of the opsonin receptor
binds pathogens or foreign molecules tagged with opsonins
prompts phagocytosis
e.g. complement receptors (CR3, CR4) and Fc receptor
what happens when cytokines cause blood vessels to dilate and alter endothelial cells
neutrophils and monocytes are guided by chemokines to enter the infected tissues
characteristics of TLRs
vital roll in the innate immune response
induce key signalling events for mounting robust defense against pathogens
evolutionarily conserved
ligands are specific to hosts and are not expressed on human cells
which TLRs are intracellular and participate in antiviral immunity
TLR 3, 7, 8 and 9
which TLRs are extracellular and participate in antibacterial immunity
TLR 1-2, 2-6, 4, 5,
what are the 3 characteristics all TLRs share
leucine rich repeats
ITRs
the overall C form
TLR-4 signalling pathway to produce pro-inflammatory cytokines (apply to most TLRs)
TLRs dimerize*
recruit IRAK 1 and 4 which activate TRAF6
TRAF6 is polyubiquitinated which activates TAK1
TAK1 associates with IKK which leads to the phosphorylation of IkB
IkB is degraded, releasing NFkB into the nucleus as a TF for cytokine gene expression
what does the TF KFkB induce?
the expression of pro-inflammatory cytokines
TLR signalling to produce interferons: TLR3 pathway
TLR3 in endosome binds dsRNA and signals TRIF and TRAF3 to induce IFN gene expression via IRF3
TLR signalling to produce interferons: TLR7 pathway
TLR7 in endosome binds ssRNA and signals via MyD88 to induce IFN gene expression via IRF7
what are DAMPs
Damage-associated molecular patterns
derived from host cells (including tumor or dying cells)
recognized by PRRs
cytosolic innate immune receptors recognize different ligands by different strategies, match the ligands to their recognition strategy (RIG1, MDA5, cGAS, NOD1, NOD2)
RIG1 - triphosphate dsRNA
MDA5 - dsRNA
cGAS - DNA
NOD1 - iE-DAP
NOD2 - MDP
what are cytokines and their functions
signalling molecules which promote immune cell activation
bind to cytokine receptors on immune and non-immune cells
activate innate and adaptive immunity
involved in inflammation
many are members of the Interleukin (IL) family
which cytokines are inflammatory
TNF-a
IL-1
which cells secrete inflammatory cytokines
macrophages
which cytokines are signalling
IL-2, IL-4, IL-10
IL-12
IL-17
IFN-y
IFN-a/-B
TGF-B
which molecule is a chemokine
CXCL8 (IL-8)
which cytokines function in T and B cell activation
T = IL-2
B = IL-4
which cytokine is anti-inflammatory
IL-10
What is the function of INF-a and INF-B
NK cell activation, prevention of viral replication
(remember how NK cells are most important innate cells in anti-viral immunity)
which cytokine functions in peripheral tolerance
TGF-B
what is the JAK-STAT pathway
a pathway which cytokine receptors use for rapid signalling to induce gene transcription
basis of the JAK-STAT pathway
- cytokine receptors contain JAK on their cytoplasmic domain
- cytokine binding dimerizes the receptors bringing together the cytoplasmic JAKs, they activate each other and phosphorylate the receptor
- STATs bind to receptors and are phosphorylated by JAKs
- STATs form dimers, these dimers translocate to the nucleus to initiate cytokine gene transcription
what are some important cytokines produced by macrophages (and DCs) in response to bacterial products
IL-1B: increase vascular permeability (inflammation)
TNF-a: increase vascular permeability (inflammation)
IL-6: increase antibody production
CXCL8 (IL8): recruit neutrophils
IL-12: activate NK cells
which cytokines increase vascular permeability so that neutrophils can enter the endothelium
IL-1B and TNF-a
what are the 4 steps leukocytes must undergo to accumulate in a blood vessel
tethering
rolling
activation
firm adhesion
what are cell adhesion molecules
proteins that hold cells together
exists as a pair of complementary receptors: one is present on the neutrophil and its partner on the tissue
4 types of cell adhesion molecules
selectins: bind carbohydrate groups on neutrophils
glycoproteins: bind to selectins
integrins: bind to other proteins
iCAMs: bind to integrins
adhesion molecules involved in leukocyte interactions: selectins
bind to carbohydrate groups on neutrophils
bound by glycoproteins - sialyl-lewis-x and PSGL-1
tissue distribution = activated endothelium
weak adhesion allows leukocyte rolling
adhesion molecules involved in leukocyte interactions: integrins
bind to cell-adhesion molecules and extracellular matrix
bound by iCAMs, iC3b and fibronectin
wide tissue distribution
strong adhesion allows diapedesis
steps in leukocyte migration into tissues
rolling adhesion
tight binding
diapedesis
migration
3 proteins affected in the interferon response to viral infection and their protective mechanisms
PKR: inhibits protein synthesis
RNase L: destroys RNA in the cell (RNA is in many viral genomes)
p53: induce apoptosis
autocrine response of interferons from a virus infected cell
- interferon response by IFN-B (PKr, RNase L, p53) when it binds to type-1 interferon receptor on same cell
- causes IRF7 tp enter cell and allow transcription of IFN-a genes to produce other effects
paracrine response of interferons from a virus infected cell
interferon response on uninfected cell AND induce NK response from NK cells (release perforins and granzymes)
what components of NK cells are responsible for cell death and how?
perforin: punches holes in the membrane of cells
granzymes: induce apoptosis
what are the 2 kinds of receptors on the surface of NK cells
- activating: NKG2D, 2B4
- inhibitory: CD94:NKG2A
what are some malfunctions in innate immune cells and what they lead to
macrophages = persistent infections
neutrophils = granulomas
recurring viral infection = NK cells
systemic vs local release of TNF-a
same activity but different outcomes
local = removal of infection by adaptive immunity
systemic = death
which PRRs work in extracellular recognition
TLRs and lectin receptor
PRRs in cytosolic recognition
NLRs (anti-bacterial)
RLRs (anti-viral)
PRRs in endosomal recognition
TLR-3, 7, 8 and 9
what is the difference in outcome of intra and extra cellular TLRS
intracellular: mostly leads to interferon production
extracellular: mostly leads to cytokine production
what do each of the extracellular TLRs bind
2-6: lipopeptides
1-2: lipopeptides
5: flagellin
4: LPS
what do each of the intracellular TLRs bind
3: dsRNA
7: ssRNA
8: ssRNA
9: CpG DNA
