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
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.
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.
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
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
6
Q
What inflammatory cytokines interact with cells in the hypothalamus during the acute phase response?
A
IL-1, TNF-alpha, IL-6
7
Q
What inflammatory cytokines act on the liver during the acute phase response?
A
IL-1, TNF-alpha, IL-6, OSM
8
Q
What inflammatory cytokines act on bone marrow during the acute phase response?
A
IL-6, TNF-alpha
9
Q
The four innate immune effector cells
A
- Neutrophils
- Macrophages
- Dendritic Cells
- Natural Killer Cells
10
Q
Functions of neutrophils (3)
A
- Phagocytosis
- Reactive oxygen and nitrogen species
- Antimicrobial peptides
11
Q
Functions of macrophages (6)
A
- Phagocytosis
- Inflammatory mediators
- Antigen presentation
- Reactive oxygen and nitrogen species
- Cytokines
- Complement proteins
12
Q
Functions of dendritic cells (6)
A
- Phagocytosis
- Antigen presentation
- Costimulatory signals
- Reactive oxygen species
- Interferon
- Cytokines
13
Q
Functions of NK cells (3)
A
- Lysis of viral-infected cells
- Interferon
- Macrophage activation
14
Q
Which innate immune effector cells present antigen?
A
Macrophages and dendritic cells
15
Q
Which innate immune effector cells are able to phagocytose?
A
Neutrophils, macrophages, and dendritic cells
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.
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
18
Q
Which phagocytic cells can kill microbes by nonoxidative means?
A
Neutrophils and macrophages
19
Q
What nonoxidative mechanisms can be used to kill microbes?
A
Hydrolytic enzymes and antimicrobial peptides
20
Q
Human receptors that trigger phagocytosis
A
- C-type lectin receptors (CLRs)
- Scavenger receptors
- Collagen-domain receptors
- Complement receptors
- Immunoglobulin Fc receptors
21
Q
Pattern recognition receptors that trigger phagocytosis in humans (2)
A
- C-type lectin receptors (CLRs)
- Scavenger receptors
22
Q
Opsonin receptors that trigger phagocytosis in humans (3)
A
- Collagen domain receptors
- Complement receptors
- Immunoglobulin Fc receptors
23
Q
C-type lectin receptor examples (3)
A
- Mannose receptor
- Dectin 1
- DC-SIGN
24
Q
Scavenger receptor examples (2)
A
- SR-A
- SR-B
25
Collagen-domain receptor example (1)
CD91/calreticulin
26
Complement receptor examples (5)
- CR1
- CR3
- CR4
- CRIg
- C1qRp
27
Immunoglobulin Fc receptor examples (2)
- FcαR
| - FcγRs
28
The C-type lectin mannose receptors binds:
Mannans (bacteria,fungi, parasites)
29
The C-type lectin receptor Dectin-1 binds
beta-glucans (fungi, some bacteria
30
The C-type lectin receptor DC-SIGN binds
Mannans (bacteria, fungi, parasites
31
SR-A binds
LPS, LTA (bacteria)
32
SR-B binds
LTA, lipoproteins, diacylglycerides (bacteria), B-glucans (fungi)
33
The collagen domain receptor CD91/calreticulin binds
Collectins SP-A, SP-D, MBL; L-ficolin; C1q
34
Complement receptors CR1, CR3, CR4, CRIg, and C1qRp bind
Complement components and fragments
35
Immunoglobulin Fc receptor FcαR binds
Specific IgA antibodies bound to antigen
36
Immunoglobulin Fc receptor FcγRs binds
Specific IgG antibodies bound to antigen, C-reactive protein
37
The 5 steps of phagocytosis
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
38
Four major reactive oxygen species
- Superoxide anion (O2-)
- Hydroxyl radical ( •OH)
- Hydrogen peroxide (H2O2)
- Hypochlorous acid (HClO)
39
How does regular O2 get converted to the four ROS?
Oxygen + NADPH phagosome oxidase enzyme -> Superoxide anion
Superoxide anion + Superoxide dismutase -> H2O2 -> Hydroxyl radicals
H2O2 + Cl- + Myeloperoxidase -> Hypochlorous acid
40
Oxygen + ________ -> Superoxide anion
NADPH phagosome oxidase enzyme
41
Superoxide anion + ________ -> H2O2
Superoxide dismutase
42
H2O2 + Cl- + _________ -> Hypochlorous acid
Myeloperoxidase
43
Reactive Nitrogen Species (3)
- Nitric oxide (NO)
- Nitrogen dioxide (NO2)
- Peroxynitrite (ONOO-)
44
What amino acid is converted to an RNS?
L-arginine
45
L-arginine + ______ -> Nitric oxide
Inducible nitric oxide synthase
46
Nitric oxide + superoxide anion -->
ONOO- (peroxynitrite)
47
Nitric oxide can be converted to 2 things (with 1 byproduct):
```
Peroxynitrite
Nitrogen dioxide (S-nitrosothiols byproduct)
```
48
ROS and RNS are expressed after interaction with
Pattern Recognition Receptors (PRRs)
49
T/F: ROS and RNS can only kill internalized pathogens
False. ROS and RNS are also released from activated neutrophils and macrophages to kill extracellular pathogens
50
NK cells are (specific/nonspecific) cytotoxic effector cells that provide early defence against ___ (2 things)
- Nonspecific
| - Viruses and cancer
51
What is similar and different between NK cells and T cells?
- 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
What do NK cells expres that is also expressed in T cells?
IL-2 receptor beta chains, Fc receptor for IgG, CD2, and CD16
53
Unlike T cells, NK cells do not recognize foreign antigens via:
MHC
54
IFN-γ is produced by NK cells. What function does it have?
INF-γ increases the microbial activity of macrophages and impacts adaptive immunity by promoting Th1 differentiation, inhibiting Th2 development, and driving CTL development
55
How does IFN-γ impact adaptive immunity?
- Promotes Th1 differentiation
- Inhibits Th2 development
- Drives cytotoxic T lymphocyte (CTL) development
56
What rapidly activates NK cells when there is viral infection? (3)
IL-12 produced by dendritic cells, IFN-alpha, and IFN-beta
57
IFN-γ produced by NK cells induces the production of
Virus-specific cytotoxic T lymphocytes (CTLs)
58
What effect to IFN-alpha and IFN-beta have on NK cells?
They activate NK cells and increase their lytic activity against virus-infected cells
59
NK cells use a ________ to discriminate between healthy and infected cells
dual receptor system
60
What induces NK cell mediated cytotoxicity, cytokine synthesis, and proliferation?
A loss of the inhibitory signal coupled with an activating signal, or a very strong activating signal that overrides the inhibitory signal.
61
An important category of activating receptor is _____. What do they recognize?
C-type lectins. They recognize altered carbohydrate structures on virus infected cells or cancer cells
62
Inhibitory receptors consist of 2 types:
- Lectin-like inhibitory receptors
| - Killer cell inhibitory receptors
63
How do lectin-like and killer cell inhibitory receptors act?
They deliver an inhibitory signal following interaction with class I MHC molecules
64
Viruses (up/down)-regulate class I MHC molecules
Downregulate
65
Target cells that express low levels of class I MHC are (detected/undetected) by NK cells
Detected by NK cells because there is no interaction of class I MHC with the inhibitory receptor on the NK cell
66
NKG2D; structure, ligands, inhibiting/activating
Lectin-like
Binds MHC class I
Mostly activating
67
Natural cytotoxicity receptors (NCRs) ; structure, ligands, inhibiting/activating
Immunoglobulin family
Binds heparin sulfate on tumor cells
Most (all?) activating
68
KIR receptors; structure, ligands, activating/inhibiting
Immunoglobulin family
Binds MHC class I; HLA-B and HLA-C
Mostly inhibiting
69
Ly49; structure, ligands, activating/inhibiting
Lectin-like
Binds MHC class 1 and homologs
Mostly inhibiting
70
Lectin-like NK cell receptors (2)
NKG2D and Ly49
71
Immunoglobulin family NK cell receptors (2)
Natural cytotoxicity receptors (NCRs) and KIR
72
Granule dependent killing by NK cells
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
Death ligand killing by NK cells
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
Two types of PRRs of innate immunity and what they recognize
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
What do PRRs activate?
Innate and inflammatory responses
76
What do TLRs and NLRs recognize on dead, dying, and aging cells? What does this recognition lead to?
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
How do TLRs bind to PAMPs and DAMPs?
Via their leucine-rich repeat (LRR) domains that make up the extracellular ligand-binding structure
78
Ligand binding to the TLR induces 2 things:
TLR dimerization and signal transduction
79
T/F: TLRs promote phagocytosis
False
80
What activates NLRs?
extracellular PAMPs and DAMPs
81
Two additional important PRRs are:
C-type lectin receptors (CLRs) and retinoic acid-inducible gene-I-like receptors (RLRs)
82
C-type lectin receptor function
Bind carbohydrates on the surface of pathogens and promote phagocytosis
83
RLR function
Bind viral RNAs
84
PRRs are found on:
- Myeloid cells
- Lymphocyte subsets
- Cells commonly exposed to pathogens (skin, mucosal epithelial cells, endothelial cells, and fibroblasts)
85
TLRs have two main structural features:
Leucine-rich repeats (LRRs) and the Toll/IL-1 receptor (TIR) domain
86
Function of LRRs on TLR
Horse shoe shaped extracellular and endosomal binding domain for TLR ligands
87
Function of the toll/IL-1 receptor (TIR) domain
Interacts with adaptor molecules that function as sorting receptors for other adaptor molecules
88
TLRs that recognize cell surface structures on pathogens are located:
On the cell surface
89
TLRs that recognize nucleic acids are located:
Inside cells
90
TLR 4 on the plasma membrane recognizes:
LPS on gram-negative bacteria
91
TLR4 on endosome/lysosome membranes recognizes:
Viral proteins
92
TLR5 on the plasma membrane interacts with:
Flagellated bacteria
93
TLR 3 on endosomes/lysosome membranes recognizes
viral dsRNA
94
TLR9 on endosome/lysosome membranes recognizes
CPG motifs on bacterial and viral DNA
95
TLR2 and TL6 on the plasma membrane recognize
Peptidoglycan and zymosan of gram-positive bacteria and fungi
96
TLR7 and TLR8 on endosome/lysosome membranes recognize
viral ssRNA
97
TLR11 on the plasma membrane recognizes
Uropathogenic bacteria
98
Signalling through TLRs can be dependent on one of two things:
MyD88 or TRIF
99
4 adaptor proteins involved with TLR signalling
MyD88, TRIF, TIRAP, TRAM
100
TIRAP function
Promotes MyD88 recruitment to cell-surface TLRs 2/1, 2/6, and 4.
101
TRAM function
promotes TRIF recruitment to endosomal TLR3 and TLR4
102
MyD88-dependent TLR signaling activates 3 things:
- MAPK pathways
- Interferon regulatory factors (IRF)
- NF-κB
103
TRIF-dependent pathways activate 2 things, which induces the expression of _______
Activation of MAPKs and IRFs to induce IFN-alpha/beta expression
104
Most TLRs are expressed by
Immature dendritic cells
105
TLRs are direct inducers of
dendritic cell maturation
106
What does a maturing dendritic cell express (2), upregulate and produce?
Expresion of CD80/CD86 and CD40
Upregulation of MHC II
Production of IL-12
107
What indirectly induces dendritic cells to mature?
Response to TNF and IL-1
108
Mature dendritic cells are no longer phagocytic; instead, they:
present antigen
109
Mature dendritic cells upregulate ______ and migrate to ______
CCR7 (chemokine receptor); lymph nodes
110
Monocytes, macrophages, dendritic cells, neutrophils, and T and B cell subsets express:
At least 15 human C-type lectin receptors (CLRs)
111
Upon binding to _____ of microbes, some CLRs trigger ______ while all trigger _______
Carbohydrate components (e.g. glucans); phagocytosis; signalling pathways
112
CLR signalling is similar to the distal events of MyD88-dependent TLR signaling because ___ and ___ are activated
NF-κB and AP-1
113
When CLR and TLR signaling occur in the same cell:
They combine to enhance the production of inflammation-promoting cytokines
114
retinoic acid-inducible gene-I-like receptors (RLR) stimulation by viral dsRNA induces:
IFN-alpha/beta via IRF7/3
115
NF-κB regulates inflammation-promoting genes in 5 categories:
- Inflammatory cytokines
- Chemokines
- Adhesion molecules on endothelial cells
- Immune effector molecules
- Costimulatory molecules
116
Inflammatory cytokines upregulated by NF-κB (6)
TNF-alpha, IL-1, IL-6, IL-12, GM-CSF, IFN-alpha/beta
117
Chemokines upregulated by NF-κB (4)
IL-8, MCP, RANTES, eoxtaxin
118
Adhesion molecules on endothelial cells upregulated by NF-κB (4)
ICAM-1, VCAM-1, E-selectin, P-selectin
119
Immune effector molecules upregulated by NF-κB (2)
Inducible nitric oxide synthase (iNOS, involved in making RNS), defensins
120
Costimulatory molecules upregulated by NF-κB (2)
CD40 and CD80/CD86 on dendritic cells
