3. Innate Immune System Flashcards
What sort of pathogen is poorly affected by inflammation?
Intracellular pathogens
What is the downside to inflammation?
It can lead to substantial tissue damage and disease
What is a function of the innate immune system that has nothing to do with bacteria?
Initiation of the process of tissue repair
What might cause pain at the site of inflammation?
Inflammatory mediators released by immune cells stimulate the nerves.
What is the function of type 1 (non-immune) interferon?
Blocks viral replication within host cels
What do cells of the innate immune system chiefly recognize?
Pathogen associated molecular patterns
What are pathogen associated molecular patterns (PAMPs) unique to?
A given class of microbes
Innate immune cells recognize pathogens, so why is it we say they’re less specific than adaptive cells?
Since innate cells recognize PAMPs rather than unique antigens, so they are said to be less specific.
What are the four criteria for a pathogen associated molecular pattern to be recognized by our innate immune system?
- Effective indicator of pathogen
- Unique to a class of pathogen
- PAMP cannot be easily supressed or hidden by the pathogen (vital to life)
- No structural similarity to self antigens
What are the primary PAMPs for:
Gram Negative Bacteria
Lipopolysaccaride
Porin
Lipoproteins
What are the primary PAMPs for:
Gram Positive bacteria
Peptidoglycan
Lipoteichoic acid
Teichoic acid
What is the primary PAMP for:
Mycobacteria
Lipoarabinomannan
What is the primary PAMP for:
Fungi
Manno-proteins
What are two important locations for toll like receptors in the cell?
On the cell surface and on the inside of endosomes
What do endosomal TLRs respond to?
Nucleic acids only
Which four TLRs recognize intracellular pathogens?
TLR 3,
TLR 7,
TLR 8,
TLR 9
Why do mannose PRRs not respond to the mannose in our bodies?
Because they respond to glycans with terminal mannose only, which does not occur in humans.
For the TLR1:TLR2 heterodimer:
What ligands are recognized?
What cells carry the receptor?
Lipopeptides and GPI
Monocytes, dendritic cells, eosinophils, basophils, mast cells
For the TLR2:TLR6 heterodimer:
What ligands are recognized?
What cells carry the receptor?
Lipoteichoic acid and Zymosan
Monocytes, dendritic cells, eosinophils, basophils, mast cells
For TLR3
What ligands are recognized?
What cells carry the receptor?
Double stranded viral RNA
NK Cells
For the TLR4:TLR4 homodimer:
What ligands are recognized?
What cells carry the receptor?
Lipopolysaccaride
Macrophages, dendritic cells, mast cells, eosinophils
(not basophils)
For TLR5
What ligands are recognized?
What cells carry the receptor?
Flagellin
Intestinal epithelial cells
For TLR7
What ligands are recognized?
What cells carry the receptor?
Single stranded viral RNAs
Plasmacytoid dendritic cells, NK cells, eosinophils, B Cells
For TLR8
What ligands are recognized?
What cells carry the receptor?
Single stranded viral RNA
NK cells
For TLR 9
What ligands are recognized?
What cells carry the receptor?
Unmethylated CpG-rich DNA
Plasmacytoid dendritic cells, B cells, eosinophils, basophils
What dimers can TLR 10 form?
TLR10:TLR10 homodimer
TLR10:TLR1 heterodimer
TLR10:TLR2 heterodimer
Why is NF-κB so important in immunology?
It is a pan-inflammatory transcription factor
What adaptor protein does TLRs 1, 2, 5, 6, 7, 8, and 9 (not 3, 4, 10) use to activate NF-κB and IRF?
MyD88
What adaptor protein does TLR 3 use to activate NF-κB and IRF
TRIF
What adaptor protiens does TLR4 use to activate NF-κB and IRFs?
MyD88 and TRIF
What TLRs are used for fungi?
TLRs 2, 6
What TLRs are used against bacteria?
TLRs 1, 2, 4, 5, 9
What TLR’s are used against viruses?
TLRs 3, 7, 8, 9
(these are the endosomal TLRs)
What are the six steps from TLR 4 to NF-κB?
TLR4 binds MyD88
MyD88 activates IRAK
IRAK activates TRAF6
TRAF6 activates IKK
IKK activates IκB
IκB degrades, releasing NF-κB
What generates damage associated molecular patterns?
Necrosis
(Apoptosis does not)
What particular cells detect damage associated molecular patterns?
Dendritic cells
What is HMGB1
What is its receptor?
A DAMP released passively during necrosis
RAGE is the receptor
What are the three DAMPs discussed in class?
HMGB1 (High Mobility Group Box 1)
Uric Acid
HSPs (Heat Shock Protien)
What is the common transcription factor for DAMP and PAMP response?
NF-κB
What is the function of Nod Like Receptors (NLRs)?
They are a family of cytosolic receptors that sense PAMPs and DAMPs in the cytoplasm
What is the primary function of the inflammasome?
Activation of caspase 1
What is the main function of caspase 1?
Activation (via cleavage) of IL-1beta and IL-18 to drive inflammation and fever
What are the three members of the scavenger receptor family?
SR Class A Type I
SR Class A Type II
MARCO
What domain is missing from SR Class A type II, but is present in the other two types?
SR Cystine Rich domain (SRCR)
What domain is missing in MARCO scavenger receptors, but is present in the other two SRs?
Alpha Helical coiled coil domain
What domain is common among all three scavenger receptors?
Collagen like domain
How to scavenger receptors recognize bacteria to encourage phagocytosis?
Through the negative charges present on bacterial lipopolysaccharide, lipoteichoic acid, nucleic acids, beta-glucan, and protiens.
Generally speaking, what are bound by the lectin family of Pattern Recognition Receptors?
Carbohydrates
What important immune function is associated with soluable Mannose Binding Lectin (MBP)?
Compliment activation
What lectin receptor subset is present on macrophages and, in soluable form, in blood?
Mannose receptors
What are cathelicidins?
Antimicrobial peptides produced by neutrophils and the epithelial cells in the skin, GI and respiratory tract.
What three mechanisms would an activated neutrophil undergo to control bacterial growth?
Respiratory Burst
Release of Granules
Phagocytosis
What can macrophages do that neutrophils don’t usually do?
Release inflammatory mediators and present antigens
What is the special function of eosinophils?
Combat helminthes and multicellular parasites through the use of cationic granules
What do natural killer cells use to kill infected host cells?
The cytolytic mediator perforin and granzymes
How do granzymes kill a cell?
They force the cell into apoptosis
Why is N-Formylmethionyl peptide important to macrophages?
It exists in prokaryotes, but not in eukaryotes. Macrophages use it to help determine self vs non-self.
What reaction is incited by a TLR in a phagocyte?
Production of cytokines and reactive oxygen intermediates (ROIs) which leads to phagocytosis of the offending organism
What mechanism to dendritic cells use to acquire antigens for presentation?
Receptor mediated endocytosis and pinocytosis
Not phagocytosis
Where do classical (myeloid) dendritic cells reside?
Skin, mucosa, and organ parenchyma
To what cells are antigens displayed by dendritic cells?
T Cells
What is the primary function of plasmacytoid dendritic cells?
Antiviral functions relating to the production of interferon 1
Where will you not be able to find mature mast cells?
In the blood. Mature mast cells are only found in the tissues
Why are natural killer cells less likely to kill a cell that is producing lots of MHC 1?
MHC 1 inhibits NK activity
What are NK cell’s activating receptors called?
Killer cell immunoglobulin like receptors (KIRs)
What is activated by NK cell activating receptors (killer cell immunoglobulin like receptors, KIR’s)?
Protein Tyrosine Kinase
What do natural killer cells produce to signal macrophages that a potentially infected cell is about to apoptose?
Interferon gamma
What are the three paths to activate compliment?
Alternative pathway
Classical Pathway
Lectin Pathway
What is the intersection point for the three pathways of compliment activation?
Production of C3b
What initiates the classical pathway?
Binding of IgM or two IgG’s on the microbial surface.
What are the unique steps of the classical pathway of compliment activation?
(Starts with C1 and goes to C3b)
C1 is activated by IgM or 2x IgG
C1 cleaves C2 and C4 into a and b domains
C4b binds to the bacterial surface and C2a binds to C4b.
C2a:C4b functions as a C3 convertase, cleaving C3 and forming C3b
In the classical pathway, what forms the C5 convertase?
C2a, C4b, C3b
What are the functions of the products of the C5 convertase?
C5a (anaphylatoxin): potent mediator of inflammation
C5b: initiates MAC attack
What are the four functions of the compliment system?
Lysis of foreign cells and bacteria (MAC)
Opsonization (C3b, C3bi)
Vasodilation (C3a, C4a, C5a)
Clearance of immune complexes (C3a, C3b - absence leads to autoimmune disease)
What is the function of acute phase protiens?
Initiation of systemic inflammation
What organ produces acute phase proteins, and what signaling molecule regulates their production?
Liver hepatocytes produce acute phase protiens in response to IL-6 mostly, and to a lesser extent, TNF and IL-1)
What is the function of the acute phase protiens:
granulocyte colony stimulating factor, serum amyloid A, and secreted phospholipase A2?
Inflammatory response
What is the function of the acute phase proteins:
Finbrinogen, plasminogen, tissue plasminogen factor?
Coagulation
What acute phase proteins are also able to kill pathogens directly?
Compliment proteins
What specific interleukin is an important chemoattractant for neutrophils?
IL-8
What is the function of macrophage inflammatory protein?
Chemoattractant for monocytes
Which cytokine is the ONLY cytokine of innate immunity to not be produced by macrophages?
Interferon gamma
Which two cytokines of the innate immune system are anti-inflammatory?
Interleukin-10
TGF-beta
How does inflammation increase vascular permiability to neutrophils?
Endothelial cells start to produce E-Selectin (ES) and P-Selectin (PS)
(Neutrophils have ligands for E-Selectin and P-Selectin on hand at all times)
Which cytokine is most important in very early activation of endothelial cells during infection?
TNF-alpha
What adhesion molecules are found on leukocytes in an unactivated state until they meet chemokines on the endothelial wall?
Integrins (such as ICAM-1 and VCAM-1)
What four conditions in a phagolysosome make a toxic environment for microbes?
Low pH
Presence of ROS (Reactive Oxygen Species)
Presence of NO (Nitric Oxide)
Presence of Lysosomal Proteases
Which type of interferons are useful to inhibit viral replication?
Type 1 interferons
What cell is a major source for Type 1 interferons?
Plasmacytoid dendritic cells
What three things do Type 1 interferons do to create an antiviral environment?
Induces Protein Kinase RNA-activated (PKR) to prevent guanidine diphosphate recycling which prevents viral RNA translation
Activates RNaseL (a latent nuclease) to mediate RNA degradation
Activates NK cells to eliminate infected cells
What two signals are required for lymphocyte activation?
Recognition of antigen
Costimulators (substances produced during innate immune response)
