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MICI3115 > Lecture 4: Innate Immunity Pt. 2 > Flashcards

Lecture 4: Innate Immunity Pt. 2 Flashcards

1
Q

Describe the process of opsonization of particulate antigens by C3b and phagocytosis

A
  • C3b component of complement attaches to an antigen (such as bacteria)
  • C3b binding allows the antigen to bind to a phagocytic receptor on a phagocyte, and the particle is internalized into a phagosome
  • The phagosome combinds with granules containing hydrolytic enzymes, making the phagolysosome.
  • Oxygen (in)dependent mechanisms kill the pathogen
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2
Q

What is the acute phase response responsible for?

A
  • The production of innate immune effector cells such as neutrophils
  • Production of soluble molecules such as cytokines and complement components
  • the fever response.
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3
Q

What initially causes the acute phase response? What does this lead to?

A
  • A local acute inflammatory response causes the acute phase response.
  • This causes the release of inflammatory cytokines and TNF, which act on the brain and bone marrow to produce immune cells and other responses.
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4
Q

Local acute inflammatory response -> brain ….

A

Hypothalamus-> prostaglandins -> fever

ACTH from pituitary -> adrenal cortex -> corticosteroids -> liver -> ACUTE PHASE PROTEINS: C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, mannose-binding protein, complement components

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5
Q

Acute phase proteins produced by the liver (5)

A

C-reactive protein (CRP), serum amyloid A (SAA), fibrinogen, mannose-binding protein, complement components

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6
Q

What inflammatory cytokines interact with cells in the hypothalamus during the acute phase response?

A

IL-1, TNF-alpha, IL-6

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7
Q

What inflammatory cytokines act on the liver during the acute phase response?

A

IL-1, TNF-alpha, IL-6, OSM

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8
Q

What inflammatory cytokines act on bone marrow during the acute phase response?

A

IL-6, TNF-alpha

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9
Q

The four innate immune effector cells

A
  • Neutrophils
  • Macrophages
  • Dendritic Cells
  • Natural Killer Cells
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10
Q

Functions of neutrophils (3)

A
  • Phagocytosis
  • Reactive oxygen and nitrogen species
  • Antimicrobial peptides
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11
Q

Functions of macrophages (6)

A
  • Phagocytosis
  • Inflammatory mediators
  • Antigen presentation
  • Reactive oxygen and nitrogen species
  • Cytokines
  • Complement proteins
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12
Q

Functions of dendritic cells (6)

A
  • Phagocytosis
  • Antigen presentation
  • Costimulatory signals
  • Reactive oxygen species
  • Interferon
  • Cytokines
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13
Q

Functions of NK cells (3)

A
  • Lysis of viral-infected cells
  • Interferon
  • Macrophage activation
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14
Q

Which innate immune effector cells present antigen?

A

Macrophages and dendritic cells

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15
Q

Which innate immune effector cells are able to phagocytose?

A

Neutrophils, macrophages, and dendritic cells

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16
Q

How do neutrophils, macrophages, and dendritic cells that bind microbes via pattern recognition receptors or opsonin receptors kill microbes after phagocytosis?

A

Phagocytosis activates these cells, which causes a respiratory burst that generates reactive oxygen and nitrogen intermediates that kill the microbe.

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17
Q

What enzyme is produced by activated neutrophils and macrophages, and what is produced with this enzyme?

A

Activated neutrophils and macrophages express inducible nitric oxide synthase that produces nitric oxide with potent antimicrobial activity

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18
Q

Which phagocytic cells can kill microbes by nonoxidative means?

A

Neutrophils and macrophages

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19
Q

What nonoxidative mechanisms can be used to kill microbes?

A

Hydrolytic enzymes and antimicrobial peptides

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20
Q

Human receptors that trigger phagocytosis

A
  • C-type lectin receptors (CLRs)
  • Scavenger receptors
  • Collagen-domain receptors
  • Complement receptors
  • Immunoglobulin Fc receptors
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21
Q

Pattern recognition receptors that trigger phagocytosis in humans (2)

A
  • C-type lectin receptors (CLRs)

- Scavenger receptors

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22
Q

Opsonin receptors that trigger phagocytosis in humans (3)

A
  • Collagen domain receptors
  • Complement receptors
  • Immunoglobulin Fc receptors
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23
Q

C-type lectin receptor examples (3)

A
  • Mannose receptor
  • Dectin 1
  • DC-SIGN
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24
Q

Scavenger receptor examples (2)

A
  • SR-A

- SR-B

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25
Q

Collagen-domain receptor example (1)

A

CD91/calreticulin

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26
Q

Complement receptor examples (5)

A
  • CR1
  • CR3
  • CR4
  • CRIg
  • C1qRp
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27
Q

Immunoglobulin Fc receptor examples (2)

A
  • FcαR

- FcγRs

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28
Q

The C-type lectin mannose receptors binds:

A

Mannans (bacteria,fungi, parasites)

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29
Q

The C-type lectin receptor Dectin-1 binds

A

beta-glucans (fungi, some bacteria

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30
Q

The C-type lectin receptor DC-SIGN binds

A

Mannans (bacteria, fungi, parasites

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31
Q

SR-A binds

A

LPS, LTA (bacteria)

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32
Q

SR-B binds

A

LTA, lipoproteins, diacylglycerides (bacteria), B-glucans (fungi)

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33
Q

The collagen domain receptor CD91/calreticulin binds

A

Collectins SP-A, SP-D, MBL; L-ficolin; C1q

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34
Q

Complement receptors CR1, CR3, CR4, CRIg, and C1qRp bind

A

Complement components and fragments

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35
Q

Immunoglobulin Fc receptor FcαR binds

A

Specific IgA antibodies bound to antigen

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36
Q

Immunoglobulin Fc receptor FcγRs binds

A

Specific IgG antibodies bound to antigen, C-reactive protein

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37
Q

The 5 steps of phagocytosis

A
  1. Bacterium becomes attached to membrane evaginations called pseudopodia
  2. Bacterium is ingested, forming phagosome
  3. Phagosome + lysosome= phagolysosome
  4. Bacterium is killed and digested by lysosomal enzymes
  5. Digestion products are released from the cell
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38
Q

Four major reactive oxygen species

A
  • Superoxide anion (O2-)
  • Hydroxyl radical ( •OH)
  • Hydrogen peroxide (H2O2)
  • Hypochlorous acid (HClO)
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39
Q

How does regular O2 get converted to the four ROS?

A

Oxygen + NADPH phagosome oxidase enzyme -> Superoxide anion
Superoxide anion + Superoxide dismutase -> H2O2 -> Hydroxyl radicals
H2O2 + Cl- + Myeloperoxidase -> Hypochlorous acid

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40
Q

Oxygen + ________ -> Superoxide anion

A

NADPH phagosome oxidase enzyme

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41
Q

Superoxide anion + ________ -> H2O2

A

Superoxide dismutase

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42
Q

H2O2 + Cl- + _________ -> Hypochlorous acid

A

Myeloperoxidase

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43
Q

Reactive Nitrogen Species (3)

A
  • Nitric oxide (NO)
  • Nitrogen dioxide (NO2)
  • Peroxynitrite (ONOO-)
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44
Q

What amino acid is converted to an RNS?

A

L-arginine

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45
Q

L-arginine + ______ -> Nitric oxide

A

Inducible nitric oxide synthase

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46
Q

Nitric oxide + superoxide anion –>

A

ONOO- (peroxynitrite)

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47
Q

Nitric oxide can be converted to 2 things (with 1 byproduct):

A 
Peroxynitrite
Nitrogen dioxide (S-nitrosothiols byproduct)
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48
Q

ROS and RNS are expressed after interaction with

A

Pattern Recognition Receptors (PRRs)

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49
Q

T/F: ROS and RNS can only kill internalized pathogens

A

False. ROS and RNS are also released from activated neutrophils and macrophages to kill extracellular pathogens

50
Q

NK cells are (specific/nonspecific) cytotoxic effector cells that provide early defence against ___ (2 things)

A
  • Nonspecific

- Viruses and cancer

51
Q

What is similar and different between NK cells and T cells?

A
  • NK cells and T cells aris from the same progenitor cells but do not develop exclusively in the thymus
  • NK cells do not express TCR, CD3, or CD8 like T cells do
52
Q

What do NK cells expres that is also expressed in T cells?

A

IL-2 receptor beta chains, Fc receptor for IgG, CD2, and CD16

53
Q

Unlike T cells, NK cells do not recognize foreign antigens via:

A

MHC

54
Q

IFN-γ is produced by NK cells. What function does it have?

A

INF-γ increases the microbial activity of macrophages and impacts adaptive immunity by promoting Th1 differentiation, inhibiting Th2 development, and driving CTL development

55
Q

How does IFN-γ impact adaptive immunity?

A
  • Promotes Th1 differentiation
  • Inhibits Th2 development
  • Drives cytotoxic T lymphocyte (CTL) development
56
Q

What rapidly activates NK cells when there is viral infection? (3)

A

IL-12 produced by dendritic cells, IFN-alpha, and IFN-beta

57
Q

IFN-γ produced by NK cells induces the production of

A

Virus-specific cytotoxic T lymphocytes (CTLs)

58
Q

What effect to IFN-alpha and IFN-beta have on NK cells?

A

They activate NK cells and increase their lytic activity against virus-infected cells

59
Q

NK cells use a ________ to discriminate between healthy and infected cells

A

dual receptor system

60
Q

What induces NK cell mediated cytotoxicity, cytokine synthesis, and proliferation?

A

A loss of the inhibitory signal coupled with an activating signal, or a very strong activating signal that overrides the inhibitory signal.

61
Q

An important category of activating receptor is _____. What do they recognize?

A

C-type lectins. They recognize altered carbohydrate structures on virus infected cells or cancer cells

62
Q

Inhibitory receptors consist of 2 types:

A
  • Lectin-like inhibitory receptors

- Killer cell inhibitory receptors

63
Q

How do lectin-like and killer cell inhibitory receptors act?

A

They deliver an inhibitory signal following interaction with class I MHC molecules

64
Q

Viruses (up/down)-regulate class I MHC molecules

A

Downregulate

65
Q

Target cells that express low levels of class I MHC are (detected/undetected) by NK cells

A

Detected by NK cells because there is no interaction of class I MHC with the inhibitory receptor on the NK cell

66
Q

NKG2D; structure, ligands, inhibiting/activating

A

Lectin-like
Binds MHC class I
Mostly activating

67
Q

Natural cytotoxicity receptors (NCRs) ; structure, ligands, inhibiting/activating

A

Immunoglobulin family
Binds heparin sulfate on tumor cells
Most (all?) activating

68
Q

KIR receptors; structure, ligands, activating/inhibiting

A

Immunoglobulin family
Binds MHC class I; HLA-B and HLA-C
Mostly inhibiting

69
Q

Ly49; structure, ligands, activating/inhibiting

A

Lectin-like
Binds MHC class 1 and homologs
Mostly inhibiting

70
Q

Lectin-like NK cell receptors (2)

A

NKG2D and Ly49

71
Q

Immunoglobulin family NK cell receptors (2)

A

Natural cytotoxicity receptors (NCRs) and KIR

72
Q

Granule dependent killing by NK cells

A

Cytotoxic granules are polarized toward the site of contact with the target cell after the activating receptor C16 (IgG FcR) is triggered. This causes the exocytosis of granzyme B and perforin, causes death via apoptosis

73
Q

Death ligand killing by NK cells

A

Fas ligand or TRAIL on the NK cell triggers apoptosis when they interact with target cell death receptors. NK cells secrete TNF-alpha, which can kill virus infected cells that have upregulated their TNF receptor

74
Q

Two types of PRRs of innate immunity and what they recognize

A

Toll-like receptors (TLRs) and Nod-like receptors (NLRs). Recognize structural motifs (PAMPs) in microbes that are highly conserved and usually necessary for their survival

75
Q

What do PRRs activate?

A

Innate and inflammatory responses

76
Q

What do TLRs and NLRs recognize on dead, dying, and aging cells? What does this recognition lead to?

A

Damage-associated molecular patterns (DAMPs), such as heat shock proteins, which are not expressed on healthy cells. Recognition causes the clearance of these cells by macrophage-mediated phagocytosis.

77
Q

How do TLRs bind to PAMPs and DAMPs?

A

Via their leucine-rich repeat (LRR) domains that make up the extracellular ligand-binding structure

78
Q

Ligand binding to the TLR induces 2 things:

A

TLR dimerization and signal transduction

79
Q

T/F: TLRs promote phagocytosis

A

False

80
Q

What activates NLRs?

A

extracellular PAMPs and DAMPs

81
Q

Two additional important PRRs are:

A

C-type lectin receptors (CLRs) and retinoic acid-inducible gene-I-like receptors (RLRs)

82
Q

C-type lectin receptor function

A

Bind carbohydrates on the surface of pathogens and promote phagocytosis

83
Q

RLR function

A

Bind viral RNAs

84
Q

PRRs are found on:

A
  • Myeloid cells
  • Lymphocyte subsets
  • Cells commonly exposed to pathogens (skin, mucosal epithelial cells, endothelial cells, and fibroblasts)
85
Q

TLRs have two main structural features:

A

Leucine-rich repeats (LRRs) and the Toll/IL-1 receptor (TIR) domain

86
Q

Function of LRRs on TLR

A

Horse shoe shaped extracellular and endosomal binding domain for TLR ligands

87
Q

Function of the toll/IL-1 receptor (TIR) domain

A

Interacts with adaptor molecules that function as sorting receptors for other adaptor molecules

88
Q

TLRs that recognize cell surface structures on pathogens are located:

A

On the cell surface

89
Q

TLRs that recognize nucleic acids are located:

A

Inside cells

90
Q

TLR 4 on the plasma membrane recognizes:

A

LPS on gram-negative bacteria

91
Q

TLR4 on endosome/lysosome membranes recognizes:

A

Viral proteins

92
Q

TLR5 on the plasma membrane interacts with:

A

Flagellated bacteria

93
Q

TLR 3 on endosomes/lysosome membranes recognizes

A

viral dsRNA

94
Q

TLR9 on endosome/lysosome membranes recognizes

A

CPG motifs on bacterial and viral DNA

95
Q

TLR2 and TL6 on the plasma membrane recognize

A

Peptidoglycan and zymosan of gram-positive bacteria and fungi

96
Q

TLR7 and TLR8 on endosome/lysosome membranes recognize

A

viral ssRNA

97
Q

TLR11 on the plasma membrane recognizes

A

Uropathogenic bacteria

98
Q

Signalling through TLRs can be dependent on one of two things:

A

MyD88 or TRIF

99
Q

4 adaptor proteins involved with TLR signalling

A

MyD88, TRIF, TIRAP, TRAM

100
Q

TIRAP function

A

Promotes MyD88 recruitment to cell-surface TLRs 2/1, 2/6, and 4.

101
Q

TRAM function

A

promotes TRIF recruitment to endosomal TLR3 and TLR4

102
Q

MyD88-dependent TLR signaling activates 3 things:

A
  • MAPK pathways
  • Interferon regulatory factors (IRF)
  • NF-κB
103
Q

TRIF-dependent pathways activate 2 things, which induces the expression of _______

A

Activation of MAPKs and IRFs to induce IFN-alpha/beta expression

104
Q

Most TLRs are expressed by

A

Immature dendritic cells

105
Q

TLRs are direct inducers of

A

dendritic cell maturation

106
Q

What does a maturing dendritic cell express (2), upregulate and produce?

A

Expresion of CD80/CD86 and CD40
Upregulation of MHC II
Production of IL-12

107
Q

What indirectly induces dendritic cells to mature?

A

Response to TNF and IL-1

108
Q

Mature dendritic cells are no longer phagocytic; instead, they:

A

present antigen

109
Q

Mature dendritic cells upregulate ______ and migrate to ______

A

CCR7 (chemokine receptor); lymph nodes

110
Q

Monocytes, macrophages, dendritic cells, neutrophils, and T and B cell subsets express:

A

At least 15 human C-type lectin receptors (CLRs)

111
Q

Upon binding to _____ of microbes, some CLRs trigger ______ while all trigger _______

A

Carbohydrate components (e.g. glucans); phagocytosis; signalling pathways

112
Q

CLR signalling is similar to the distal events of MyD88-dependent TLR signaling because ___ and ___ are activated

A

NF-κB and AP-1

113
Q

When CLR and TLR signaling occur in the same cell:

A

They combine to enhance the production of inflammation-promoting cytokines

114
Q

retinoic acid-inducible gene-I-like receptors (RLR) stimulation by viral dsRNA induces:

A

IFN-alpha/beta via IRF7/3

115
Q

NF-κB regulates inflammation-promoting genes in 5 categories:

A
  • Inflammatory cytokines
  • Chemokines
  • Adhesion molecules on endothelial cells
  • Immune effector molecules
  • Costimulatory molecules
116
Q

Inflammatory cytokines upregulated by NF-κB (6)

A

TNF-alpha, IL-1, IL-6, IL-12, GM-CSF, IFN-alpha/beta

117
Q

Chemokines upregulated by NF-κB (4)

A

IL-8, MCP, RANTES, eoxtaxin

118
Q

Adhesion molecules on endothelial cells upregulated by NF-κB (4)

A

ICAM-1, VCAM-1, E-selectin, P-selectin

119
Q

Immune effector molecules upregulated by NF-κB (2)

A

Inducible nitric oxide synthase (iNOS, involved in making RNS), defensins

120
Q

Costimulatory molecules upregulated by NF-κB (2)

A

CD40 and CD80/CD86 on dendritic cells

MICI3115 (3 decks)

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