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Immunology (Parham) > Chapter 3 > Flashcards

Chapter 3 Flashcards

Innate immunity: the induced response to infection

1
Q

What are Toll-like receptors?

A
  • signalling receptors in innate immunity
  • ex: TLR4 binds LPS (on Gram-negative bacteria)
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2
Q

What are the properties of Toll-like receptor 4 (TLR4)

A
  • homodimer
  • binds to LPS on bacteria
  • has a TIR domain
    • signalling domain (intracellular)
    • receptor for IL-1B (inflammatory cytokine) also has TIR domain
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3
Q

What are the properties shared by Toll-like receptors?

A
  • TLR can have different ligand specificity based on differences in motifs
  • 2 polypeptides -> homo or heterodimer
  • horseshoe-shaped pathogen-recognition domains
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4
Q

What happens in macrophage when a Gram-negative bacterium is engulfed?

A
  • LPS released -> binds to LPS-binding protein
  • LBP with LPS delivered to CD14
    • into exocytic vesicle
  • TLR4, MD2, LPS with CD14 complex forms on cell surface
  • signalling cascade: TIR-> MyD88-> IRAK4 ->…-> activation of NFkB (by removing its inhibitor IkB)
  • transcription of inflammatory cytokine genes
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5
Q

What are the different types of Toll-like receptors?

A
  • on membrane
    • recognise extracellular pathogens
  • in cytoplasm
    • recognise non-self genetic material
  • there are four main groups recognising different pathogens
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6
Q

What are NOD1 and NOD2?

A
  • cytoplasmic receptors
  • detect products from degradation of bacteria in cell
  • form a dimer
    • when a bacterial peptide is bound -> cascade starts
    • NFkB activation
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7
Q

What happens when virus invades a cell?

A
  • cytoplasmic proteins recognise viral genetic material or proteins
    • signalling cascade activates transcription factors for interferon genes
  • type I interferon is produced
    • interferes with viral replication
    • warns cells around
    • signal for NK cells
  • interferon receptors on cell surface -> bind interferon
    • start a response
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8
Q

What are the autocrine and paracrine actions of IFN-B?

A
  • cytokine IFN-B secreted when virus infects a cell
  • bound by type I interferon receptors
    • on the cell itself
      • stimulates autocrine IFN-a response
    • on other cells
      • paracrine IFN-B response
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9
Q

What is the function of plasmacytoid dendritic cells?

A
  • secretion of interferon
  • has TLR (7,9)
    • detect viral material -> start signalling cascade -> activation of NFkB and IRFs (transcription factors for interferon genes)
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10
Q

What is the role of IL-1B?

A
  • inflammatory cytokine: drives inflammation
  • made by macrophages
    • pre-made in the cell, waiting to be activated and released by macrophaeg
    • converstion of pro-IL-1B to IL-1B by inflammasome
      • contains NOD-like receptor to detect infection
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11
Q

What are neutrophils?

A
  • granulocytes
  • short-lived
    • travel in blood to site of infection
    • recruited by macrophages
  • polymorphonuclear leukocytes = irregular nuclei shapes
  • TNF-a, IL-6, CXCL8, CCL2, IL-12 released by macrophages
    • CCL2, CXCL8 => chemokines attracting effector cells (neutrophils)
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11
Q

What are the roles of different cytokines at the site of infection?

A
  • TNF-a: permeability of blood vessels
    • cells, fluid, soluble effectors enter infected tissue
  • IL-6: fat and muscle cells metabolise, generation of heat, raise in temp
  • CXCL8: recruits neutrophils
  • CCL2: recruits monocytes
    • differentiate into macrophages at the site of infection
  • IL-12: recruits and activates NK cells to strengthen macrophage reaction
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12
Q

What is the role of adhesion molecules in recruiting neutrophils?

A
  • allow them to move from blood to tissue
  • on neutrophils
    • L-selectin or LFA-1
  • on endothelium
    • CD34 or ICAM-1
  • inflammatory cytokines induce expression of adhesion molecules -> binding is possible
  • TNF-a induces production of adhesion mol
    • strengthened by CXCL8
  • gradient of CXCL8 guides neutrophils
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13
Q

Why is pus and other physical effects of inflammtion formed?

A
  • damaged tissues are usually anaerobic environment
    • neutrophils die and accumulate
  • increased passage of fluid and cells from blood -> swelling, reddening, pain
    • IL-6 causes cells to adjust metabolism -> heat produced
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14
Q

What is the mode of action of neutrophil?

A
  • binds bacteria through LPS receptor (CD14), CR4
    • engulfs (phagocytosis) and eliminates in cell
  • different types of granules -> release contents -> digestion of microbes
    • ingested bacteria in a vesicle -> fuse with granules
    • NADPH oxidase can be found in granules
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15
Q

How is release of granules controlled in neutrophils?

A
  • by calcium concentrations
  • in blood: calcium concentrations low
    • signal from CXCL8 from macrophage activates release of granules
      • after release, membrane of vesicles fuses with plasma membrane -> increase of surface area for adhesion molecules and more CXCL8 signalling
  • high calcium in tissue -> degranulation
    • pores between granules and cell membrane formed -> release easy
    • in epicenter of infection calcium levels even higher = more release
16
Q

What is respiratory burst?

A
  • intiation of neutrophil attack -> increase in oxygen consumption
  • NADPH oxidase catalyses oxidation of NADPH -> produces superoxide radicals -> converted to hydrogen peroxide by superoxide dimutase
    • reactions need H+ = raising pH
    • antimicrobial peptides activated in high pH
    • toxic oxygen species => damage to nearby cells (this has to be limited, thus hydrogen peroxide is coverted by catalase to H2O and O2)
17
Q

How do neutrophils die?

A
  • apoptosis
  • phagocytosed by macrophage
  • NETosis
    • swelling and bursting
    • chromatin extruded in a network of decondensed DNA and trapped pathogens
18
Q

What are pyrogens and why are they needed?

A
  • substances inducing fever (including cytokines)
  • energy mobilisation in fat and muscle tissues
  • fever needed: raise in temp
    • disfavours growth of pathofens
    • tissue cells more resistant to effects of TFN-a
19
Q

How does IL-6 affect liver?

A
  • induces acute-phase response
    • liver shifts its production of common plasma proteins (incl. albumin) to production of proteins for innate immunity
    • C-reactive protein (CRP), serum amyloid A, MBL
20
Q

What is the role of CRP?

A
  • binds C-polysaccharides on pathogens -> osponisation
    • activates classical pathway
    • if no antibodies, binds to phagocytes to then bind to pathogens -> phagocytosis
21
Q

What is the role of serum amyloid A protein?

A
  • cell-surface receptors on macrophages -> activates production of inflammatory cytokines
22
Q

What is the role of mannose-binding lectin (MBL) and what happens during the pathway it contributes to?

A
  • MBL = C-type lectin binding mannose-containing carbs on pathogens
  • triggers lectin pathway of complement activation -> opsonin
    • taken up by monocytes (have receptors for MBL)
  • associated with MBL are two proteins MASP-1 and MASP-2
    • when pathogen is bound -> MASP-2 active -> cuts itself and the other MASP-2
    • substrates for activated MASP-2 proteases are C4 and C2
  • C4 similar to C3, C2 similar to factor B
    • C4 cleaved into C4b and C4a -> C4b covalently bound to cell surface
      • C4a recruits leukocytes (weaker than C3a or C5a)
    • C2 -> C2a (larger) and C2b
    • together they form C4bC2a = C3 convertase
      • cleaves C3 -> C3b attaches to surface -> activate factor B -> C3bBb assembled -> alternative pathway
23
Q

What are the steps of classical pathway activation?

A
  • CRP binds to bacteria -> interacts with C1
    • C1 similar structure to MBL with MASPs (here, C1r and C1s polypeptides)
  • CRP binds C1 stalk and C1r -> activated cuts itself, second C1r polypeptide, 2 C1s
  • C1s cleaves C4 -> C4b on pathogen surface
    • cleaves C2 as well -> C4bC2a assembled
24
Q

What are receptors on macrophages and what is their role?

A
  • receptor-mediated endocytosis -> pathogens degraded inside the cell
  • pattern-recognition receptors (PRRs) recognise common feautures on microbe (pathogen-associated molecular pattern = PAMP)
    • for human cells that are damaged damaeg-associated molecular patterns (DAMPs) are recognised
  • pattern recognition receptors can be scavenger receptors
    • cell adhesion, phagocytosis, intracellular signalling
    • removing dead cells
    • some scavenger receptors are lectins have C-type lectin domain
      • calcium ion responsible for interaction of carb ligand with protein receptor
        - scavenger receptors have collagen-like triple helix feature (ex: MARCO) -> binding to LPS (Gram-negative bacteria)
        - SR-A1 binds Gram-positive
25
Q

What are the two main functions of NK cells?

A
  • kill infected tissue cells
  • secrete cytokines acting on resident macrophages -> increase inflammation
26
Q
A
27
Q

What are the two subpopulations of NK cells and their role?

A
  • CD56-dim NK cells have less CD56 than CD56-bright NK cells
  • dim: cytotoxic effector cells
    • mainly in blood
  • bright: make cytokines
    • mainly in tissues
28
Q

What are the steps of NK-cell cytotoxicity?

A
  • IFN-a and -B (type I interferon) activate CD56-bright NK cell -> differentiation into dim
    • binds to cells in infected tissue -> if altered-self, kills
  • CR3 and LFA-1 adhesion molecules for binding to target
    • localised region of action => forms NK-cell synapse
    • into the synapse granules are released containing enzymes, glycoproteins, proteoglycans
  • NK cells have Toll-like receptora recognising viral DNA -> secretion of interferon -> activation of NK-cell cytotoxicity
29
Q

How do NK cells cooperate with macrophages?

A
  • macrophages secrete IL-12 -> activates NK cells
    • best contact through synapse
    • NK cells differentiate into effector cells secreting interferon-y
  • IFN-y (type II interferon) binds receptors on macrophages -> pahgocytosis and cytokine production
30
Q

What are the interactions between DCs and NK cells?

A
  • NK controlls DC actvity
    • if DC infected, cell surface altered -> detected by NK cell -> synapse formed
    • DCs produce IL-15 upon interaction
      • for NK proliferation and growth
  • if signal from DC strong enough -> many NK cells emerge -> kill infected cells (including DC)
  • if signal is too weak, DCs will outnumber NK
    • NK secretes cytokines -> DC goes to secondary lymphoid tissue
    • innate immunity failed -> adaptive immune response needed

Immunology (Parham) (13 decks)

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