Lecture 4: Innate Immunity Flashcards
1
Q
what are the key cells of the innate immune response?
A
neutrophils, eosinophils, basophils, mast cells
2
Q
what are the key cells involved in the early adaptive immune response?
A
NK, NKT, ILC, monocytes, macrophages, dendritic cells
3
Q
what are the keys cells involved in the primary adaptive response?
A
T and B cells
4
Q
what are the key cells in the secondary adaptive immune response?
A
T and B cells
5
Q
the innate and early adaptive immune responses are considered together as the ____ response
A
innate
6
Q
the primary and secondary adaptive immune responses are referred to as the ___ response
A
adaptive
7
Q
what are the 2 main roles of the innate immunity?
A
- first line of defence to slow infection until adaptive response can take over
- mechanism for directing the adaptive immune response (introduce inflammation, activate dendritic cells, produce cytokines that shape the adaptive immune response)
8
Q
what is the response time of the innate immune system?
A
minutes to hours
9
Q
what is the response time of the adaptive immune response?
A
days
10
Q
describe the level of specificty the innate immune response has
A
specific for molecules and molecular patterns that are typically found on pathogens and recognize the molecules typically produced by dead/damaged cells
11
Q
describe the level of diversity of the innate immune response
A
a limited number of cnserved, germ-line-encoded receptors
12
Q
describe the level of memory responses of the innate immune response
A
some (has been observed in invertebrate innate responses and mouse & human NK cells)
13
Q
describe how well the innate immune response can differentiate between self and nonself
A
perfectly bc they only recognize conserved features of pathogens
14
Q
what are the soluble compenents of blood from the innate immune response?
A
many antimicrobial peptides, proteins, and other mediators
15
Q
what are the major cell types of the innate immune response?
A
phagocytes (monocytes, macrophages, neutrophils), NK cells, leukocytes, epithelial and endothelial cellls
16
Q
describe the specificity of the adaptive immune response
A
highly specific, discriminates between tiny differences in molecular structure of microbial and non-microbial molecules
17
Q
describe the level of diversity of the adaptive immune resposne
A
highly diverse; very large number of receptors arising from genetic recombination or receptors genes in each person
18
Q
describe the memory responses of the adaptive immune responses
A
persistent memory with faster response of greater magnitude on subsequent exposure
19
Q
describe the level of self vs nonself discrimination in the adaptive immune response
A
very good, but there are occaisional failures which result in auti-immune diseases
20
Q
what are the soluble components of the blood of the adaptive immune response?
A
antibodies and cytokines
21
Q
what are the major cell types of the adaptive immune response?
A
T cells, B cells, and antigen presenting cells
22
Q
list 2 anatomic barriers to infection
A
- skin
2. mucus membranes
23
Q
t/f the skin (epidermis and dermis) is a mechanical barrier impermeable to most infectious agents
A
t
24
Q
what is the epidermis?
A
several layers of epithelial cells where the outermost layer contains dead cells filled with keratin (a waterproofing proetin)
25
what are mucus membranes?
epithelium lining the interior surfaces of the body that secrete mucus to trap foreign particles to prevent them from adhereing to epithelial cells
26
what happens to the foreign particles trapped in the mucus of mucus membranes?
expelled by the mechanical action of cilia or by sneezing, coughing, or swallowing
27
what is the function of commensal (good) gut bacteria?
inhibit the growth of pathogenic bacteria; produce protective peptides
28
what are the special feature of the mucus membranes in the GI tract that prevent infection?
enzymes and normal flora
29
what are the special features of the mucus membranes of the respiratory tract that help prevent infection?
mucus, mechanical action of cilia, macrophages in alveoli
30
what are the special features of the mucus membranes in the urogenital tract?
mucus, fluid flow, aggregation of urinary mucins, low pH, antimicrobial peptides, proteins in vaginal secretions
31
what are 3 physiologic and chemical barriers that the body's points of entry have to prevent infection?
1. acidic pH of lactic acid and fatty acids present in sweat and sebaceous secretions
2. acidic pH of the stomach
3. body temperatire and fever response
32
antimicrobial (host defence) peptides are short ____ (cationic or anionic) peptides that are usually ____ amino acids in length
cationic; 29-35
33
antimicrobial (host defence) peptides are ____ (hydrophillic or hydrophobic)
amphipathic (both hydrophillic and hydrophobic parts)
34
antimicrobial (host defence) peptides are ____ expressed
constitutively
35
antimicrobial host defence peptides are active against what types of pathogens?
bacteria, fungi, enveloped viruses
36
antimicrobial host defence peptides bind to ____ charged (positive or negative) microbial structures and membranes via what type of interactions?
negative; electrostatic
37
give an example of part of a pathogen that an antimicrobial host defence peptide might bind to
LPS
38
how do antimicrobial host defense peptides work to stop pathogens?
disrupt the microbial membrane integrity by introducing bulky hydrophobic amino acids & internalized peptides inhibit DNA/RNA/protein synthesis and activate antimicrobial enzymes
39
how long does it take antimicrobial host defence enzymes to kill pathogens?
rapidly (minutes to hours)
40
give an example of antimicrobial host defence peptides
defensins (alpha and beta)
41
defensins are secreted by ___ cells and other ___ cells and are stored in ___
intestinal epithelial Paneth cells and other epithelial cells; stored in netrophil granules
42
location of defensins can be found where?
skin, mucosal epithelia (mouth, intestine, nasal/respiratory tract, urogenital tract)
43
how do defensins have antimicrobial activity?
disrupt membranes of bacteria, fungi, protazoan parasite and viruses. Have additional toxic effects intracellularly
44
defensins are able to kill ___ and disable ___
bacteria; viruses
45
how does streptococcus pneumoniae get into the body?
airways
46
how does E.coli get into the body?
GI tract
47
how does HIV get into the body?
urogenital
48
how does staph. aureus get into teh body?
cuts in the skin
49
how does West Nile get into the body?
mosquito bites
50
after penetrating epithelial barriers, pathogens are detected by what 3 innate immune components?
1. soluble innate immune recognition elements
2. phagocytic and other cells
3. pattern recognition receptors like toll-like receptors
51
what are soluble innate immune recognition elements that recognize pathogens?
mannose-binding lectin, C-reactive proteins, complement, interferons
52
what are phagocytes and other cells that act as innate immune resposnes against pathogens?
neutrophils, macrophages, dendritic cells, NK cells
53
pattern recognition receptors (PRRs) like toll-like receptors (TLRs) can be found on what innate immune cells?
macrophages, mast cells, dendritic cells that function as sentinel cells
54
what is the acute phase response?
systemic, generic response to infection for containment and mobilization of immune cells and effector proteins
55
acute phase response creates a ____ response to slow pathogen growth and help immune reactions
fever
56
in the acute phase response, the local acute inflammation sends what cytokines to the hypothalamus?
IL-1, TNF-alpha, IL-6
57
in the acute phase response, the local acute inflammation sends what cytokines to the liver?
IL-1, TNF-a, IL-6, LIF, OSM
58
in the acute phase response, the local acute inflammation sends what cytokines to the bone marrow?
IL-6, TNF-a
59
what is the effect of cytokines being sent to teh hypothalamus in the acute phase response?
produce prostaglandins to create the fever; also sends ACTH via the pituitary to teh adrenal cortex which will send corticosteroids to the liver to release acute phase proteins
60
what is the effect of cytokines being sent to the liver in the acute phase response?
acute phase proteins are made; C-reactive protein (CRP), serum amyloid A (SAA), fibronogen, manose-binding protein, complement compoenents
61
what is the effect of cytokines being sent to the bone marrow in the acute phase response?
causes increased CSF by stromal cells and macrophages and induced leukocytosis (making more WBCs)
62
what are the 3 major pro-inflammatory cytokines that cause vascular permeability, systemic and local effects?
IL-1, IL-6, TNF-alpha
63
what is the anti-inflammatory cytokine?
IL-10
64
what cells produce IL-1?
monocytes, macrophages, dendritic cells, keratinocytes, epithelial cells, vascular endothelial cells
65
what cells does IL-1 act on?
lymphocytes, bone marrow, vascular endothelium, liver, hypothalamus
66
what is the immune response fo IL-1?
enhances inflammatory reponse, promotes neutrophil production, activates and increases vascular permeability, induces acute pahse response, fever
67
what is the immune response of IL-6?
regulates activity, promotes hematopeiesis (neutrophils), activates and increases vascular permiability, induces acute phase response, fever
68
what is the immune response of TNF-a?
activates inflammatatory response, activates and increases vascular permeability, fluid loss, local blood clotting, induces acute phase response, fever, cytotoxic for many tumor cells
69
what cells produce IL-6?
monocytes, macrophages, dendritic cells, NK cells, epithelial cells, vascular endothelial cells
70
what cells does IL-6 act on?
lymphocytes, bone marrow, vascular endothelium, liver, hypothalamus
71
what cells produce TNF-a?
monocytes, macrophages, dendritic cells, mast cells, NK cells, epithelial cells
72
what cells does TNF-a act on?
macrophages, vascular endothelium, liver, hypothalamus, tumors
73
most cytokines are controlled by ___
NF-kB
74
collection of cytokines enables comprhensive immune response form _____ to ___
anti-pathogen. to de novo differentiation of immune cells
75
giev 3 examples of soluble factors that contribute to immune response
1. various secretions contain substances with anti-bacterial activity
2. collectins
3. complement
76
what soluble factor is contained in gastric juice that has anti-bacterial activity?
acid
77
what soluble factor is contained in semen that has anti-bacterial activity?
spermine and zinc
78
what soluble factor is contained in breast milk that has anti-bacterial activity?
antimicrobial peptides; lactoperidase
79
what soluble factors are found in tears, saliva, and nasal secretions that have anti-bacterial activity?
lysozyme
80
what are collectins and their role in immunity?
small proteins tha are able to kill certain bacteria by disrupting their cell walls, causing bacteria to aggregate, which enhances their phagocytosis, and/or activates the complement by the lectin pathway
81
what is the complement and its contribution to immunity?
a feed-forward cascade that enables killing spontaneously or killing after antibodies or mannose-binding lectin binds to the target cells
82
what are the 2 key members of the type 1 (IFN) cytokines?
IFN-a and IFN-B
83
what is the function of type 1 IFNs (a and B)?
inhibit viral replication and genrate an antiviral state
84
type 1 IFN (a and B) are produced by what cells?
IFN-a is made by leukocytes, especially PDC
| IFN-B is made by fibrobalsts
85
what is the key type 2 IFN?
IFN-y
86
what is the function of IFN-y?
enhance killing of virus-infected cells, promote Th1 immunity
87
IFN-y is made by what 2 cell types?
NK cells and T cells
88
many cells make a small amount of type 1 IFN, but what typeof cells produce 100-1000x more type 1 IFN than any other cell type upon contact with viruses?
plasmacytoid dedritic cells
89
do plasmacytoid dendritic cells need a productive viral infection to upregulate genes coding for type 1 interferons?
no
90
the recognition mechanism for viral infection of plasmacytoid dendritic cells is via ___ that recogize ___
TLR7/8; ssRNA and TLR9 (CpG DNA)
91
t/f plasmacytoid dedritic cells are important in driving immune response against viral infections (ex: NK cell responses)
t
92
presence of viral ___ or ____ activates IFNa/B production by stimulating ____ receptors
DNA or RNA; pattern recognition receptors like toll-like receptors
93
interferons can induce antiviral responses in neighbouring cells by binding to ____ receptors, leading to ____
IFN-a/B; mRNA degradation and inhibition of protein synthesis
94
t/f virus infected cells produce type 1 interferons that act on neighbouring cells (i.e. paracrine signalling), making them refractory to viral groth
t
95
genes turned on by IFN are called ____
IFN stimulated genes (ISG)
96
the products of IFN stimulated genes typically inhibit ___ and ___ of ALL genes in the cell, which prevents viral genes from being used
transcription and translation
97
phagocytosis is initiated by binding to microbes via ____ or ____ receptor and is enhanced by pathogen binding to ____ receptors
bound antibodies (opsonization) or scavenger receptors, enhanced by pathogen binding to pattern recognition receptors
98
how does respiratory burst in phagocytosis kill pathogens?
generates reactive oxygen and nitrogen intermediates
99
how to activated neutrophils and macrophages kill phagocytosed pathogens?
express inducible nitric oxide synthase that produces nitric oxide to kill pathogens; can also kill by hydrolytic enzymes, or antimicrobial peptides
100
give 3 examples of C-type lectin receptors (CLRs) and their ligands
1. mannose receptor--> mannans (bacteria, fungi, parasites)
2. dectin-1 --> B-glucans (fungi, some bacteria)
3. DC-SIGN --> mannans (bacteria, fungi, parasites)
101
give 2 examples of scavenger receptors and their ligands
1. SR-A --> LPS, LTS (bacteria_
| 2. SR-B --> LTA, lipopeptides, diacylglycerides (bacteria), B-glucans (fungi)
102
what are the ligands to opsonin receptors?
microbe-binding opsonins (soluble, bind to micribes)
103
what are the ligands for pattern recognition receptors?
microbial ligands (found on microbes)
104
give an example of a collagen domain receptor and its ligand
CD91/calrectculin --> collectins SPA, SPD, MBL; L-ficolin, C1q
105
give 5 examples of complement receptors and their ligands
CR1, CR3, CR4, CRIg, C1qRp --> complement components and fragments
106
give 2 examples of Ig Fc receptors and their ligands
FcaR --> specific IgA antibodies bound to antigen
| FcyRs --> specific IgG antibodies bound to antigen, & c-reactive protein
107
what are pattern racognition receptors
molecular sensors that recognize structural motifs (pathogen-associated molecular patterns; PAMPs) in microbes that are highly conserved and usually needed for their survival AND innate inlammatory reponses
108
what are DAMPs? What is their function?
damage-associated molecular patterns like heat shock proteins. Not expressed on healthy cells, so they trigger TLRs and NLRs to cause clearance of dead, dying, and aging cells by macrophage-mediated phagocytosis
109
on what cells are pattern recognition receptors found?
myeloid cells, lymphoid subsets, and other cells that are commonly exposed to pathogens such as skin and mucosal epithelial cells, endothelial cells and fibroblasts
110
what are the 3 main classes of pattern recognition receptors?
1. toll-like receptors (TLRs)
2. Nod-like receptors (NLRs)
3. C-type lectin receptors (CLRs)
111
what is detected by TLRs?
a variety of PAMPs and DAMPs
112
how do TLRs detect PAMPs and DAMPs?
bind to their leucine-rich repeat (LRR) domains that make up the extracellular ligand binding structure. Lingand binding caused dimerization of the TLR and signal trnasduction
113
can TLRs promote phagocytosis?
no
114
what are Nod-like receptors (NDLs)?
intracellular PRRs that are activated by PAMPs and DAMPs
115
how do C-type lectin receptors (CLRs) work?
bind to carbohydrates on the surface of pathogens and promote phagocytosis
116
______ receptors bind vrial RNAs and are additional important PRRs
retinoic acid inducible gene-I-like receptors (RLRs)
117
the u-shaped domain of TLRs is made of ___ rich repeats
leucine
118
describe the structure of the TLRs
u-shaped, leucine rich extracellular domain and endosomal TIR domain
119
when ligands bind to TLRs, they can dimerize in what 2 ways?
1. homodimerize (TLR3/3) or heterodimerize (TLR2/1)
120
what is the function of the Toll/IL-1 receptor (TIR) domain of the TLR?
interacts with adaptor molecules that function as sorting receptors for other adaptor molecules and can initiate early specialization (polarization) of immune responses tailored to pathogens
121
t/f some TLR are found in the cell surface and some are found in the endosomes
t
122
which 3 TLR are found in the endosomes?
TLR-3, TLR-7 and TLR-9
123
which 6 TLR are found in the plasma membrane?
TLR-1, TLR-2, TLR-4, TLR-5, TLR-6
124
TLR-5 in the plasma membrane binds to ____
flagellin
125
the combo TLR-2/TLR-1 in the plasma membrane binds to __
triacycle lipopeptides
126
the combo TLR-2/TLR-6 in the plasma membrane binds to ___
diacyle lipopeptides
127
the TLR-4 in plasma membranes binds to ____
LPS (and MD-2?)
128
TLR-3 in the endosome binds to ___
dsRNA
129
TLR-7 in the endosome binds to
ssRNA
130
TLR-9 in the endosome binds to ___
CpG DNA
131
TLR signalling from the plasma membrane relies on the ___ adaptor
MyD88
132
what are the 3 major steps in the MyD88-dependent TLR signalling pathway?
1. mitogen-activated protein kinase (MAPK) pathways leading to AP-1 translocation
2. NK-kB activation and translocation
3. IFN response factors (IRFs) are activated downstream of endosomal MyD88 activation
133
inflammation-promoting genes regulated by NF-kB include what 5 main categories?
1. inflammatory cytokines
2. chemokines
3. adhesions molecules on endothelial cells
4. immune effector molecules
5. costimulatory molecules
134
what are the inflammatory cytokines regulated by NF-kB?
TNF-a, IL-1, IL-6, IL-12, GM-CSF, IFN-a/B
135
what are the chemokines regulated by NF-kB?
IL-8, MCP, RANTES, eotaxin
136
what are the adhesion molecules on endothelial cells that are regulated by NF-kB?
ICAM -1, VCAM-1, E-selectin, P-selectin
137
what are the immune effector molecules that are regulated by NF-kB?
inducible nitric oxide synthase (iNOS), defensins
138
what are the costimulatory molecules that are rugulated by NF-kB?
CD40 and CD80/CD86 on dendritic cells
139
MyD88 can additionally activate ____
IRFs
140
TRIF-dependent signalling activates what 3 things?
1. MAPKs and IRFs to induce IFN a/B expression
2. NF-kB
3. IRFs
141
Dendritic cells must do what in order to be able to present antigens?
must mature from their immature (tissue-resident) form to mature cels
142
what are the hallmarks of dendritic cell maturation?
expression of CD80/CD86 and CD40, upregulation of class 2 MHC and production of IL-12 and CCR7 to migrate to lymph nodes
143
what 2 things induce maturation of dendritic cells?
1. TLR binding (most iDCs express most TLRs)
| 2. acute phase cytokines, TNF and IL-1B
144
what are NOd-like receptors?
intracellular complexes that bind to conserved microbial features like flagellin and non-microbial substances like DAMPs
145
some nod-like receptors assemble into ____, which contain proteases to form a complex that converts prescursor forms of ___ and ___ into active inflammation-promoting cytokines via ____
inflammasomes; IL-1B and IL-8; caspase-mediated cleavage (acute phase)
146
inflammasomes act in tandem with other ___ in response to ___ or ___ to prime the inflammatory reposne
PRRs; PAMPs and DAMps
147
give 3 examples of self-derived sterile activators of inflammasomes
1. atp
2. glucose
3. cholesterol crystals
148
give 3 examples of environmentally derived sterile activators of inflammasomes
1. UV radiation
2. asbestos
3. skin irritants
149
give 3 examples of bacteria derived pathogen activators of inflammasomes?
1. flagelling
2. RNA
3. DNA
150
give 2 examples of virus derived pathogen activators of inflammasomes
1. RNA
| 2. influenza M2 protein
151
give 3 examples of fungi derived pathogen activators of inflammasomes
1. B glucans
2. mannan
3. hyphae
152
give an example of protozoa derived pathogen activators of inflammasomes
hemozoin
153
the NLRP3 inflammasome is expressed by what 6 cell types?
1. monocytes
2. macrophages
3. neutrophils
4. dendritic cells
5. some lymphocytes
6. epithelial cells
154
In addition to signalling from PAMPs and DAMPs, inflammasomes need a second signal for activation; what are the 3 proposed models?
1. ATP influx secondary to pore formation
2. crystalline/particulate substances secondary to lysosomal rupture
3. reactive oxygen species
155
there are at least ___ human c-type lectin receptors (CLRs)
15
156
c-type lectin receptors (CLRs) are expressed on what cell types? (6)
1. monocytes
2. macrophages
3. dendritic cells
4. neutrophils
5. T cells
6. B cells
157
C-type lectin receptors are responsible for detecting what?
carbohydrate components (like glucans) of microbes
158
binding to c-type lectin receptors triggers ___ and sometimes ____
intracellular signalling; phagocytsosis
159
____ (distal or proximal) CLR signalling differs from MyD88-dependent TLR signalling, but, ____ (distal or proximal) events are similar
proximal; distal
160
what makes distal CLR signalling similar to MyD88 TLR signalling?
NK-kB and AP-1 are activated
161
CLR and TLR signalling can occur in the same cell and combine to enhance the production of _____
inflammation-promoting cytokines
162
what are the functions of neutrophils?
phagocytosis, reactive oxygen & nitrogen species, antimicrobial peptides
163
what are the functions of macrophages?
phagocytosis, inflammatory mediators, antigen presentation, reactive oxygen and nitrogen species, cytokines, and complement proteins
164
what are the functions of dedritic cells?
Antigen presentation, costimulatory signals, reactive oxygen species, IFN, cytokines
165
what are the functions of NK cells?
lysis of viral infected cells, IFN, macrophage activation
166
why are NK cells the first line of defence against viral infections?
they have rapid activation by IFN-a and IFN-B and by IL-12 produced by dendritic cells
167
NK cells are important for virus-specific ____ induction
CTL
168
why are NK cells important to CTL induction?
because of their production og source of CTL-promoting IFN-y
169
what are NK cells?
non-specific cytotoxic effector cells that provide early defence against viruses and cancer
170
NK cells make up ___% of peripheral blood lymphocytes
5-10%
171
Natural killer cells arise from what pathway?
T/NK progenitor downstream from the common lymphocyte progenitor (most closely related to T cells)
172
List 4 functions of NK cells
1. produce IFN-y & respond to type 1 IFN
2. induce target cell death through receptor-ligand signalling and release of toxic products (ex: perforin and granzyme)
3. respond to antibodies bound to target cells by inducing antibody-dependent cellular toxicity (ADCC)
4. NK cell function is regulated by MHC receptors
173
NK function os regulated by ___ receptors
MHC
