Lecture 2: Innate Immunity

Question 1

PAMPs

Answer 1

Pathogen Associated Molecular Patterns e.g. LPS, viral dsRNA, unmethylated CpG nucleic acids

Question 2

DAMPs

Answer 2

Damage Associated Molecular Patterns e.g. necrotic myocardial cells post-MI

Question 3

PRRs

Answer 3

Pattern Recognition Receptors; cellular receptors that bind to PAMPs/DAMPs

Question 4

PRR types

Answer 4

Endosome (nucleic acids):
- TLR3 (dsRNA)
- TLR7/8 (ssRNA)
- TLR9 (CpG DNA)
Extracellular:
- TLR1/2/6 (G+ bacteria)
- TLR4 (LPS, G-)
- TLR5 (flagellated bacteria)
Cytosol:
- Rig-Like Receptor (RLRs)
- Cytosolic DNA Receptors (CDRs)
- NOD-Like Receptors (NLRs)

Question 5

TLR signaling process

Answer 5

1. PAMP/DAMP binds receptor
2. TF activated -> nuclear translocation
3. Upregulation of cytokines, adhesion molecules, costimulators, Type I IFNs (α, β)

Question 6

NLRP3 inflammasome pathway

Answer 6

E.g. uric acid crystals in gout
1. Crystals, bacterial products, K+ efflux, ROS etc. stimulate NLRP3 sensor
2. Inflammasome complex assembly
3. Caspase-1 activtaion
4. IL-1β secretion, acute inflammatory activity

Question 7

MAVS pathway

Answer 7

Mitochondrial AntiViral Signaling:
1. RIG-1, MDA5 sense cytosolic viral RNA
2. MAVS -> kinase activation
3. TF nuclear translocation
4. Expression of Type 1 IFNs (α, β) and other antiviral genes

Question 8

STING pathway

Answer 8

STimulator of INterferon Genes:
1. Cytosolic DNA recognized by cGAS
2. STING complex activation
3. Upregulation of Type I IFNs
Can be antiviral, antibacterial, or autoreactive

Question 9

Innate immune cells

Answer 9

• Macrophages
• Neutrophils
• DCs
• Mast cells
• NK lymphocytes

Question 10

Complement activation pathways

Answer 10

1. Classical (Ab)
2. Alternative (PAMPs)
3. Lectin (Mannose-Binding Lectin)

Question 11

Cytokines

Answer 11

Fever: IL-1, IL-6, TNF-α
Chemokines/chemotaxis: IL-8
NK cell activation: IL-12, IL-15, IL-18
Macrophage activation: IFN-γ
Antiviral: IFN-α, -β
Anti-inflammatory: IL-10, TGF-β

Question 12

Innate immunity of the epithelium

Answer 12

1. Physical barrier (keratinocytes)
2. Locally produced antimicrobial peptides
3. Intraepithelial lymphocytes
4. DCs

Question 13

Antiviral actions of Type I IFNs

Answer 13

1. Inhibit ALL protein synthesis
2. Degrade viral RNA
3. Inhibit viral gene expression and virion assembly

Question 14

Activation pathways of macrophages and resulting actions

Answer 14

1. TLRs
2. Cytokine Rs
3. Complement Rs
4. IgG Fc Rs

Inflammation/adaptive immune enhancement (TNF, IL-1, IL-6, IL-12 cytokine secretion)
Phagocytosis/microbicide (phagocyte oxidase -> ROS, iNOS -> NO, phagosomes)

Question 15

NK cell functions

Answer 15

1. Kill infected cells (MHC I inhibitory absence)
2. Secrete IFN-γ to stimulate macrophage killing

Question 16

Arthritis pathway

Answer 16

1. Increased inflammation, MMP, PG expression via cytokines to synovial cells
2. Increased immune cell recruitment via cytokines to endothelial cells

Question 17

PMN recruitment pathway

Answer 17

1. Rolling adhesion to selectins
2. Integrin activation by chemokines
3. Stable adhesion to integrins
4. Migration through endothelium

Question 18

Functions of leukocyte adhesion molecules

Answer 18

1. Recruit PMNs quickly to sites of inflammation
2. Slowly drive migration of T/B cells in lymph node for adaptive response

Question 19

Phagocyte killing of microbes pathway

Answer 19

1. Phagocyte receptors bind microbe and envelope
2. Microbe ingested in phagosome
3. Formation of phagolysosome through lysosome fusion
4. Killing of microbe with ROS, NO, lysosomal enzymes

Question 20

Immune evasion mechanisms and examples

Answer 20

1. Inhibit phagocytosis
2. Inhibit ROS
3. Resistance to complement