Lecture 4 Flashcards
State and briefly describe the 2 types of effector mechanisms that innate immunity uses
Non-specific control: a reaction to a pathogen that occurs without the immune system having any clue what type of pathogen it is. ex. WBC thinks “that looks weird, Ill eat it”
Broadly specific control: slightly specific recognition of the pathogen ex. self or non-self ; and TLR combinations
State and briefly describe the 2 types of effector mechanisms that adaptive immunity uses
Humoral: B cells provide this mechanism, which involves attacking soluble things, with the help of antibodies
Cell-mediated: T cells provide this mechanism, which occurs attacks directed via cell-to-cell contact
(takes time for this to occur ; “you pay for it”)
True or False:
Innate immune responses recognize and respond to host molecules. explain.
True
It responds to host molecules that may be stressed, damaged, or dead
Innate immunity stimulates and controls tissue _______. what does it do to damaged cells?
remodeling
it also eliminates damaged cells
State the 3 main functions of Innate immunity
Initial host defense response: prevents, controls, or eliminates infection
Eliminates damaged cells/initiates tissue repair
Controls adaptive processes: creates signals based on the pathogen that influence the type of adaptive immune response
What is a nonspecific type of defense that occurs from a very strong release of cytokines that overflows out of the infected tissue and into the blood?
The cytokines can reach the brain and cause a fever or local rise in temperature at the infection site (in an effort to achieve a temperature that will kill the infecting pathogens)
Explain the relationship between PAMPs and PRRs. Be sure to mention why this is important for immunity.
PAMPs are pathogen-associated molecular patterns that have NO structural similarity with self Ags
PRRs are pattern recognition receptors used by phagocytes that can recognize PAMPs (toll-like receptors and mannose receptors)
This is how Innate immune cells determine self and nonself
What are Mannose-tailed glycans?
Mannose-tailed glycans: essential surface molecules of bacteria and viruses
(the same mannose receptor that the innate immune system uses to ID Mannose tails, will interact with several different microbes bc they all have the mannose tail)
What does “Germ-line encoded” mean?
Germ-line encoded: refers to sequences that are found in gamete producing cells
What is the significance of N-formylmethionyl peptide (fMet)? what happens if it is recognized by a polymorphonuclear cell?
fMet is present in prokaryotes but not present in eukaryotes
upon recognition of fMet, polymorphonuclear cells bind to the proteins that have fMet and use that to initiate phagocytosis.
Gram-positive, Gram-negative, and other microbe classes that are recognized by TLRs will activate what?
Inflammation
What is the main purpose of the Broadly specific identification via TLR’s? (there’s really 2 purposes to list here)
to determine if the pathogen is self or nonself AND whether it is intracellular, or extracellular
Explain the signalling of Extracellular TLR’s, beginning with the ligand, and ending with the “outcome”
Ligands interact with TLR’s on the surface of a cell
(Signalling pathway begins)
MyD88 adaptor protein signals the IRAK family of enzymes
IRAK signals TRAF
This activates genes in the nucleus which produces pro-inflammatory cytokine secretion
After a TLR is activated on a DC and the responsive antimicrobial genes are activated, what are 4 outcomes that can occur in an effort to combat the pathogen?
The DC cells influences the adaptive response, leading to cell-mediated immunity
The DC itself can have a direct antimicrobial response
the DC can signal for apoptosis of host cells (tissue injury)
The DC can initiate septic shock (tissue injury)
What are NOD-like receptors?
NOD-like receptors: (Nucleotide oligomerization domain) or NLR’s are a specialized group of intracellular proteins that control the activation of inflammatory caspases
Explain how NOD-like receptors activate inflammation
NLR’s act as scaffolding proteins that assemble signalling platforms that trigger NF-kB and MAPK (mitogen-activated protein kinase) signalling pathways
Inflammasome inflammation is induced by a wide variety of ______ stimuli that are often associated with infection, including microbial products, crystals, and a reduction in cytosolic K+ ions.
Cytoplasmic
SR’s are ____ complexes of type II transmembrane _____.
trimeric
polypeptides
SR’s are a group of receptors that mediate the uptake of oxidized lipoproteins. Where do these oxidized lipoproteins come from and why is this important they are cleaned up?
the oxidized lipoproteins are the “dead bodies” from the war on the pathogens
They must be cleaned up because they can lead to atherosclerosis
State the function of the following circulating effector cells
Neutrophils
Macrophages
NK cells
Neutrophils: early phagocytosis and killing of microbes
Macrophages: Efficient phagocytosis and killing of microbes AND secretion of cytokines that stimulate inflammation
NK cells: Lysis of infected cells and activation of macrophages
State the function of the following effector proteins
Complement proteins
Mannose-binding lectin (Collectin) proteins
C-reactive protein (pentraxin)
Complement proteins: Killing of microbes, opsonization of microbes, and activation of leukocytes
Mannose-binding lectin (Collectin) proteins: Opsonization of microbes, activation of complement (lectin pathway)
C-reactive protein (pentraxin): Opsonization of microbes, activation of complement
State the function of the following Cytokine
TNF, IL-1, Chemokines
TNF, IL-1, Chemokines: Inflammation
State the function of the following Cytokine
IFN -alpha, -beta
IFN -alpha, -beta: Resistance to viral infection
State the function of the following Cytokine
IFN - gamma
IFN - gamma: Macrophage activation
State the function of the following Cytokine
IL-12
IL-12: IFN-gamma production by NK cells and T cells
State the function of the following Cytokine
IL-15
IL-15: Proliferation of NK cells
State the function of the following Cytokine
IL-10, TGF-beta
IL-10, TGF-beta: Control of inflammation
explain the steps involved when PRR’s trigger phagocytosis
- the microbe binds to the PRR’s in the phagocyte membrane, and a phagosome is formed via invagination of the membrane
- Once inside of the phagocyte, the phagosome fuses with a lysosome
- NOS (Inducible nitric oxide synthase) and ROS (reactive oxygen species) then destroy the microbe
Compare what toll-like receptors and mannose-receptors recognize AND what they both do when they detect their ligands
Toll-like receptors sense PAMPs and mannose-receptors sense mannose-tailed glycans (essential to the surface of bacteria and viruses)
Both of these PRR’s produce cytokines, Reactive oxygen intermediates (ROI’s), and induce phagocytosis of the microbe
Compare endosomal to cell surface TLRs (include what they respond to)
endosomal TLR’s are located in endosomes and respond ONLY to nucleic acids
cell surface TLR’s are located on the cell’s surface (membrane) and recognize products of extracellular microbes (PAMP’s)
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR1: TLR2 heterodimer
Ligand: Lipopeptides and GPI
Cell it’s found on: Monocytes, DC’s, Eosinophils, Basophils, and Mast cells
Location: PM
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR2: TLR6 heterodimer
Ligand: Lipoteichoic acid and Zymosan
Cell it’s found on: Monocytes, DC’s, Eosinophils, Basophils, and Mast cells
Location: PM
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR3
Ligand: Double-stranded viral RNA
Cell it’s found on: NK cells
Location: endosomes
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR4: TLR4 homodimer
Ligand: Lipopolysaccharide
Cell it’s found on: Macrophages, DC’s, Mast cells, and Eosinphils
Location: PM
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR5
Ligand: Flagellin
Cell it’s found on: Intestinal Epithelium
Location: PM
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR7
Ligand: Single-stranded viral RNA’s
Cell it’s found on: Plasmacytoid DC’s, NK cells, Eosinophils, and B cells
Location: Endosomes
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR8
Ligand: Single-stranded viral RNA’s
Cell it’s found on: NK cells
Location: Endosomes
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR9
Ligand: Unmethylated CpG-rich DNA
Cell it’s found on: Plasmacytoid DC’s, B cells, Eosinophils, and Basophils
Location: Endosomes
For the following TLR, state it’s Ligands, the types of cells that feature this specific TLR, and if it is endosomal or in the plasma membrane (PM)
TLR10 homodimer and heterodimers with TLR1 and 2
Ligand: Unknown
Cell it’s found on: Plasmacytoid DC’s, Basophils, Eosinophils, and B cells
Location: Unknown
Out of TLR’s 1 through 9, which of them are endosomal and therefore detect intracellular pathogens? (the rest detect extracellular pathogens)
3, 7, 8, and 9
Describe where the following components of the signalling pathway for extracellular TLR’s fit into the system
IRAK
MyD88
NF-KB
TRAF6
MyD88: (myeloid differentiation primary response gene 88)is an adaptor protein that ,when stimulated by extracellular TLR’s, activates IRAK
IRAK: (Interleukin-1 Receptor-Associated Kinase) activates TRAF
TRAF: (TNF Receptor Associated Factor 6) Inactivates IKB and activates MAPK kinases
NF-KB: is a “pro-inflammatory cytokine secreting gene” that is activated when TRAF stimulates the MAPK kinase pathway that translocates the NF-KB gene
Which specific TLR’s (4 of them) use the MyD88 adaptor protein to activate the transcription of NF-KD factors? which of these are endogenous and which are membranous?
TLR’s 1,2,4, 5, 6, 7 and 9
Plasma membrane: 1, 2, 4, 5 and 6
Endosomal: 7 and 9
Which adaptor protein(s) does TLR 4 and TLR 3 use?
TLR3 uses the TRIF adaptor protein to activate NF-KB and IRF (interferon response factors)
TLR4 can use either adaptor (TRIF or MyD88) to stimulate either pathway
TLR’s 7 and 9, which are endosomal, use which adaptor protein to trigger which pathways?
They use MyD88 to stimulate both NF-KB and IRF (both pathways)
What is the TIR-domain?
The Toll/interleukin-1 receptor is an intracellular signalling domain that is found in MyD88, interleukin-1 receptor, and TLRS
Compare the outcomes of the NK-KB and IRF signalling pathways.
they both result in the transcription of pro-inflammatory genes
Which cytokine controls the adaptive T cell immune response?
IL-12
True or False:
TLR’s trigger pathways the directly kill the pathogen. explain.
True
Name 2 ways in which the functions of TLR’s can be detrimental to the host
tissue injury (which induced apoptosis)
their functions can lead to septic-shock (has life-threatening symptoms)
Give the definition of necrosis and state what it generates
Necrosis: “dirty death” a passive, catabolic cell death in response to external toxic factors
Necrosis generates DAMP’s (Damage Associated Molecular Proteins)
What type of reaction is inflammation?
inflammation is an innate reaction
State the 5 potential outcomes of an inflammation reaction.
- an increased blood supply to the affected area (redness/heat)
- an increased capillary permeability that causes leaking from the blood vessels (swelling and pain)
- A massive influx of neutrophils
- an arrival of monocytes/macrophages (16-48 hrs)
- Distortion of the homeostasis and loss of function
The following DAMPs all activate which pathway? describe the following DAMPs as well.
HMGB1
Uric acid
HSPs
They all activate the NF-KB pathway
Describe HMGB1 and state the receptor for it
HMGB1 (High mobility group box 1): a protein that is passively released during necrosis
RAGE is the receptor for HMGB1 proteins
Describe what an inflammasome is
NLRs (a group of 14 receptors) respond to cytosolic PAMPs and DAMPs by binding to other proteins and forming a signalling complex known as an inflammasome
Explain the relationship between Inflammasomes and caspase-1
inflammasomes activate caspase-1, which is a protease enzyme
caspase-1 functions to cleave inactive cytoplasmic precursor forms of IL-1Beta and IL-18, into their active form
What do secreted forms of IL-1Beta and IL-18 do after they have been cleaved by Caspase-1?
They are proinflammatory cytokines that drive the process of inflammation
What is NLRP3 and what does it do?
NLRP3 is a sensor that detects DAMPs and PAMPs
uric acid, aluminum hydroxide, ATP released from mito, and bacterial products all have what in common?
They are all DAMPs or PAMPs that NLRP3 can detect (these are just the bolded examples, it can detect much more)
Define Pyroptosis. why is this process important?
an inflammatory form of programmed cell death that is stimulated by inflammasomes. (macrophages and DCs are the cells that die while neutrophils are unaffected)
pyroptosis causes the release of inflammatory mediators including IL-1Beta, IL-18, TNF, IL-6, and IL-8
What is important about the following extracellular structural domains?
SR cysteine-rich (SRCR) domain
Collagen-like domain
Alpha-helical coiled-coil domain
they are all extracellular domain structures that SR’s (scavenger receptors) seek out and save (recycle)
State the 3 different type of SR’s that make up the scavenger receptor family.
SR class A type I
SR class A type II
MARCO (Macrophage Receptor with Collagenous Structure)
How exactly to SRs bind to bacterial constituents?
they bind based on the negative charges on the bacterial constituents
(LPS, Lipoteichoic acid, nucleic acids, beta-glucan, and proteins are all examples of these negatively charged constituents)
Compare SR-A and CD36
Both are scavenger receptors AND both are expressed on resident tissue macrophages in order to mediate recognition/phagocytosis of microorganisms
CD36, however, also functions as a coreceptor in TLR2/6 recognition
CD36 also mediates responses to bacterially derived lipoteichoic acid and diacylated lipopeptides
Name the receptor domain that all C-type lectin family cells have and the 3 specific carbohydrates that it can use this domain to detect
All lectin family cells have a carbohydrate recognition domain
They can detect
Microbial mannose
N-acetylglucosamine
Beta-glucans
Compare lectins that are soluble proteins to lectins that are integral membrane proteins in terms of the location that these lectin receptors can be found.
Soluble proteins lectins are found in the blood and extracellular fluids
Integral membrane proteins are found on the surfaces of resident tissue macrophages, DCs, and some tissue cells
Explain how Lectin receptors can activate the complement system in response to a pathogen
Soluble Mannose-binding lectin (MBL ; OR mannan-binding proteins MBP) is a protein that is involved in complement activation via the lectin pathway
State 2 functions of Lectin receptors
facilitate the phagocytosis of microbes
triggers the secretion of cytokines that promote adaptive immune response
