(L20) Innate Immunity Flashcards by Priyanka Barad

What are some of the major barriers created by the innate immunity?

L20 S3-5

skin
acidic pH
mucous epithelium
ciliated epithelium

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What are the hallmark characteristics of inflammation (5)?

L20 S8

heat
redness
swelling
pain
loss of function

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Why does the body induce inflammation during an infection?

L20 S11

Bloody supply to a region is increased during inflammation, aiding in bringing immune cells to the site. (Redness and warmth)

Vessels become more permeable allowing immune cells and immune plasma proteins to enter the site. (Swelling)

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What causes fever?
Is it helpful or harmful to the host?

L20 S12

Fever is induced by the host immune system, not the pathogen!!!

Pyrogenic cytokines (TNF, IL-1, and IL-6) are responsible.

The body does this as pathogens replicate less effectively outside of normal physiologic body temperature.

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How do innate immune cells differentiate between self and non-self?

L20 S14

PAMPs (pathogen-associated molecular patterns)

They are factors that are unique to pathogens and not found on host cells.

Typically they are common, constitutively express cell surface molecules that are required for the pathogens

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What are examples of PAMPs?

L20 S15

porin
certain lipoproteins*
certain lipopolysaccharides*
lipoteichoic acid*
teichoic acid
mannoprotein*
β-glycine
lipoarabinomannan

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What are TLRs?
What TLRs are extracellular and which are intracellular and what do they detect?

L20 S17-18

Toll-like receptor, form of PRR (pattern recognition receptor) that detects PAMPs.

Extracellular: (bacterial cell membrane components)

TLR-1:2 (lipopeptides & GPI (parasites))
TLR-2:6 (lipoteichoic acid (gram+) and zymosan (fungi))
TLR-4:4 (LPS (gram-)
TLR-5 (flagellin)

Intracellular: (bacterial DNA/RNA products)

TLR-3 (dsRNA
TLR-7 (ssRNA)
TLR-8 (ssRNA)
TLR-9 (CpG DNA)

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What signaling pathways do TLRs activate and which TLRs activate each?

L20 S22

MyD88:

all TLR except TLR3
TLR4 activates both

TRIF:

only TLR3 and TLR4
TLR4 activates both

MyD88 and TRIF are adaptor protein which activate transcription factors NFκB and IRF

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What are the results of MyD88 and IRAK-4 deficiencies?

L20 S27

Susceptibility to bacterial and viral infections.

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What are NLRs and what is their function?

L20 S28-29

NOD-like receptors

Detect intracellular PAMPs and activate inflammasomes.

Inflammasomes activate caspase-1 which activates precursors of IL-1β and IL-18, pro-inflammatory

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What are DAMPs and how are they different from DAMPs?
What are examples?

L20 S32

Damage-associated molecular patterns

Molecules that are released from damaged/dying host cells and activate PRRs on innate immune cells inducing inflammatory response.

Examples (all normally located in the cell hidden from immune cells):

phosphotidylserine
HMGB1
uric acid
HSP

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What autoimmune disease are related to DAMPs?

L20 S37

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What is fMet and how is it used by the innate immune system?

L20 S40

Constituent of prokaryotes (PAMP) which is recognized by formal peptide receptor.

Used as a chemotatic factor by phagocytes

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What are the functions of macrophages?

L20 S41

Detect PAMPs and DAMPs

Mediate extravasation/chemotaxis of other immune cells (inflammation)

Phagocytosis and tissue repair

Release of effector substances (cyto/chemokines, ROS, NO, prostaglandins, and defensins)

Ag presentation to T cells (APC)

Immunomodulation of other immune cells via cytokines

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What are the functions of mast cells?

L20 S43-44

Mast cells can be proinflammtory or anti-inflammatory.

Primarily control blood vessel permeability (granule histamine), controlling extravasation of other immune cells.

Frequently primary and rapid response to innate immune triggers in tissues.

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Differentiate between cytokines and chemokines.

What is the function of each?

L20 S50

Cytokines:

long range signaling peptides
extremely wide range of functions with frequent redundancies

Chemokines:
-chemoattractants that guide immune cells to areas of inflammation

What are the main categories of innate immune cytokines and what are the key examples of each?

L20 S51-52

Pro-inflammatory:

TNF
IL-1
IL-6
all the ones above induce FEVER

Anti-inflammatory:

TGF-β
IL-10

What is the most important regulator of macrophage function and where does it come form?

L20 S51

IFN-γ which is secreted by T cells

What is the major attractant of neutrophils?

L20 S52

IL-8

What are the different pathways of compliment activation and what is activating factor of each pathway?

L20 S55

Classical pathway:
-Ab binds pathogen and C1 recognizes Ab activating C2 and C4

Lectin pathway:
-MBL binds pathogen mannose and MBL activates C2 and C4

Alternative pathway:
C3 spontaneously degrades and C3b binds pathogen

What are the effector mechanisms of complement?

L20 S54

MAC (membrane attack complex) leading to cell lysis

Opsonization with C3b leading to phagocytosis

Production of anaphylatoxins (C3a, C4a, C5a) leading to vasodilation and degranulation

Clearance of Ab immune complexes

Enhancement of immune response (C3d binding CR2 of B cells)

What is the first step of complement cascade and what does this look like in each pathway?

L20 S56

Classical and lectin:
-C1 (classical) or MBL (lectin) convert C2 and C4 into C2a and C4b which binds pathogen and form C3 convertase (C4bC2a)

Alternative:
-C3 spontaneously cleaves (tickover) into C3b which bind pathogen. C3b converts factor B into Bb forming alternative C3 convertase (C3bBb)

What is the second step of complement cascade and what does this look like in each pathway?

L20 S57

Classical and lectin:
-C3 convertase (C4bC2a) converts C3 into C3b. C3b binds C3 convertase forming C5 convertase (C4BC2aC3B)

Alternative:
-alternative C3 convertase (C3bBb) converts C3 to C3b. C3b binds C3 convertase forming C5 convertase (C3bBbC3b)

What is the final step of complement cascade and what does this look like in each pathway?

L20 S58

Shared by all pathways:

C5 convertase converts C5 to C5b
C5b inserts into membrane
C5b mediates insertion of C6, C7, and C8 into memabrane
C5-8 insert numerous C9 forming a pore in membrane called the MAC (membrane attack complex)

What are APPs? What are the most common examples? L20 S60-61

Acute phase proteins Elevated levels indicate inflammation (they molecules themselves don’t necessarily directly induce inflammation) Examples: - CRP (C-reactive protein) - MBL/MBP (mannose binding lectin/protein) - SAA (serum amyloid A)

What are the steps of neutrophil recruitment? L20 S65-67

Tethering (rolling): - activated endothelium expressed P and E selectin which bind their constitutively expressed ligands on neutrophils - neutrophils stop Tight binding: - selectin bind stimulates expression of integrins (LFA-1 and VLA-4) on neutrophils which bind ligands on endothelium (ICAM-1 and VCAM-1) - neutrophils stop Diapedesis: -neutrophils transmigrate across endothelium Chemotaxis: -IL-8 gradient directs neutrophil to site of inflammation

How does monocyte recruitment differ from neutrophil recruitment? L20 S70

Tethering, tight binding, and diapedesis are the same Chemotaxis is instead mediated by MCP-1 (monocyte chemoattractant protein-1) Monocytes mature into Mφ once in tissue

What are the different pathways of Mφ activation and what is the function of Mφs of each pathway? L20 S71

Classically activated (M1): - activated by TLR and IFN-γ - microbical effectors (phagocytosis, ROS, and NO) - pro-inflammatory response (IL-1, IL-12, IL-23, and chemokines) Alternatively activated (M2): - activated by IL-13 and IL-4 - tissue repair and fibrosis - anti-inflammatory (IL-10 and TGF-β)

How are pathogens recognized for phagocytosis and how are they killed once phagocytosed? L20 S73-75

PRRs bind PAMPs stimulating phagocytosis forming phagosome Phagosome fuses with lysosome forming phagolysosome Bacteria killed via exposure to ROS and NO of lysosome (hydrogen peroxide,hydroxyl radicals, and hypochlorite)

How are viral cells recognized and killed? L20 S77-80

Viral infected cells produce type I interferons (IFN-α/β) IFN-α/β: - blocks viral RNA translation (blocks GDP -> GTP) - degrades viral RNA (ribonuclease L) - activates NK cells NK cells: - kill virus infected cells releasing viruses - produce type II interferon (IFN-γ) which stimulates phagocytes to uptake and destroy released viruses

How is NK activity regulated? L20 S81-82

Activation: - KAR (killer activating receptors) bind MICA and MICB which are expressed on stressed host cells - KAR activate PTKs which generate activating signal Inhibiting: - KIR (killer cell IG like receptors) recognize constitutive class I MHC of healthy cells - KIR activates PTPs which generate inhibitory signals - class I MHC expression is inhibited in unhealthy cells

What is the mechanism of NK mediated cell killing? L20 S83

NK cells release perforins which form pores in target cell Granzymes are released next which enter targeted cell via pores and induces apoptosis

How does the innate immune system link to the adaptive immune system? L20 S86-87

Innate APCs (antigen presenting cells) present processed antigens to lymphocytes stimulating development and maturation. Innate cells also release cytokines that guide lymphocyte development and maturation.