Week 1 - Immunology Flashcards
1
Q
What are the functions of the immune system?
A
- Protection from microbial pathogens
- Protection from “foreign” cells that may have malignant potential
- Detection of damaged tissue and facilitates regeneration of those tissues
- Permits microflora to aid in: protection and provision of nutrients
2
Q
Allergy and autoimmune disease are ____ diseases, whereas acute and chronic inflammatory states are ____ diseases
A
immune-mediated
outside of immune-mediated
3
Q
A “bystander” is damage that happens when attacking a ____
A
pathogen
4
Q
The components of the immune system contribute to 3 things:
A
1) Recognizing foreign molecules, microbes, or cells
2) Destroying foreign molecules, microbes, or cells (cell membrane disruption, cellular damage from free radicals, catalyzing degradation of cellular components)
3) Communicating between these two activities
5
Q
What are the 2 major functional divisions of the immune system?
A
- Innate immunity - “1st line of defense”
- Adaptive immunity - activated when innate
defenses are breached (delayed)
6
Q
What are the features of innate immunity?
A
less specific - each cell or molecule recognizes a range of targets
genetically “hard-wired” - cells and molecular effectors
don’t change during the lifespan of the organism
7
Q
What are the features of adaptive immunity?
A
highly specific - each cell or molecule recognizes a particular target
genetically “changeable” - cells and molecular effectors change their germline DNA to produce unique receptors/effectors during the lifespan of the organism
8
Q
When is adaptive immunity activated?
A
when innate defenses are breached (delayed)
9
Q
What is the response time for innate and adaptive immunity?
A
innate: hours to days
adaptive: days to 2 weeks
10
Q
The innate immune system has no ____
A
memory
- fixed responses with repeated exposures (to antigen)
11
Q
In adaptive immunity ____ is present and response can improve in specificity and rapidity of response with repeated exposures
A
memory
12
Q
The innate immune system often recognizes ____
A
patterns
13
Q
The adaptive immune system recognizes very ____
A
specific entities
14
Q
What is the difference in diversity between the innate and adaptive immune system?
A
Innate: limited (though large) repertoire of entities that can be recognized and neutralized/destroyed
Adaptive: Extremely large number of entities can be recognized and neutralized/destroyed
15
Q
Recognition of a foreign molecule by high-affinity binding to a receptor occurs in ____
A
adaptive immunity
16
Q
True or False: In adaptive immunity, the affinity can increase as the receptor is modified over time
A
True
17
Q
True or false: In adaptive immunity, receptors are generated by genetic recombination (gene shuffling)
A
True
18
Q
An ____ is a substance that can bind to a receptor of the adaptive immune system
A
antigen
19
Q
Receptors include:
A
B-cell and T-cell receptors
20
Q
____ receptors can be released from a ____ into the ECF forming an antibody
A
B-cell
B-cell
21
Q
An ____ is a substance that can generate an adaptive immune response
A
immunogen
22
Q
The molecular entity that binds to the receptor is called a:
A
epitope
23
Q
A substance that can bind to an antibody, but CANNOT generate an immune response is called a:
A
hapten
24
Q
True or false: no two naive T or B cells are activated by the same molecule
A
true
25
In adaptive immunity, diversity is accomplished by randomly “shuffling” portions of genes for lymphocyte receptors and selecting receptors that are___ and ______
functional
do not recognize self
26
The set of antigen (Ag) receptors in a given individual's immune system is known as:
lymphocyte receptor repertoire
27
True or false: Clonal Selection Theory is a part of innate immunity
False
Clonal Selection Theory is a part of adaptive immunity
28
In Clonal Selection Theory, each lymphocyte bears a single type of ____ with a ______
receptor
unique specificity
29
In Clonal Selection Theory, receptor binding is required for _____
cell activation
30
In Clonal Selection Theory, the differentiated effector cells derived from an _______ bear receptors of identical specificity as the ________
activated lymphocyte
parent cell
(they are clones of the parent cell - exact genetic copies with the same receptor)
31
In Clonal Selection Theory, lymphocytes bearing receptors for self molecules are ______ at an early stage
destroyed
- we select functional receptors that do not bind to self
32
Naive B cells express ____ on their surface, where they are called _____
antibodies
B-cell receptors
33
Once naive B cells are activated, they secrete _____ into the blood
antibodies
34
B cell receptors are made up of:
2 light chains and 2 heavy chains - each with variable and constant regions
35
The ____ regions of a B cell receptor are the portions that are "shuffled" and that can bind to an antigen
variable
36
True or false: some antigens can be bound by many different antibodies
true
- different epitopes on the same antigen
37
Most antibodies bind to ____ antigens
protein
- distinct sequences of amino acids
38
A recognized amino acid sequence can be either _____ or ______
Continuous (aka linear)
Discontinuous (aka conformational)
39
True or false: antibodies can also bind to lipid, nucleic acid, and carbohydrate moieties
true
- a wide range of molecules can be recognized
40
T cell receptors are composed of 2 chains, they are:
1 alpha, 1 beta - each with a variable region and a constant region
41
T cell receptors are best at recognizing _____
protein antigens
42
T cell receptors are never _____ , they always stay attached to the membrane
secreted
43
T cell receptors only recognize antigens by close communication with molecules on other cells, this is called _______
antigen presentation
44
Exposure of the adaptive immune system to an antigen _____ its ability to respond to the same or closely related antigen following ______
increases
re-exposure
45
Secondary immune responses are generally faster, larger, qualitatively different and often involve _______
high-affinity B-cell receptors
46
Control and down-regulation of the _______ is quite specific, as it activation
adaptive immune system
47
Immune responses to self can result in ______ , and immunological unresponsiveness to self can result in ______
autoimmunity
tolerance
48
A cell that has not reached a point where it can become activated –
usually refers to cells of the adaptive immune system, is called:
an immature cell
49
A mature cell that has not yet been activated – always refers to the adaptive
immune system, is called:
a naive cell
50
A cell (or group of cells) that is currently an active
participant in an immune response is called:
an activated or effector cell
51
A cell that responds to receptor binding by deactivation of the cell – it
“goes to sleep”, is called:
an anergic cell
52
A group of effector T/B cells that express the same antigen receptor and are
derived from the same parent cell, is called:
a clone
53
What are the 2 groups of hematopoietic stem cells?
Myeloid cells and lymphoid cells
54
What are the myeloid cells?
granulocytes
- neutrophils
- basophils
- eosinophils
- mast cells
monocytes
- macrophages
dendritic cells
55
What additional cells are derived from myeloid cells?
RBCs and platelets
56
What are the lymphoid cells?
T cells
B cells
NK cells
dendritic cells
57
What is the most abundant cell type?
neutrophils
58
What is the least abundant cell type?
basophils
59
Monocytes circulate in the blood & differentiate into _____ upon migration into tissue (long-lived)
macrophages
60
Macrophages are phagocytic, and are the mature form of a ______
monocyte
61
Macrophages often produce soluble ______ that help orchestrate
a wide range of adaptive and innate immune responses
messengers
62
What cells present antigens to T cells?
monocytes/macrophages
dendritic cells
63
True or false: dendritic cells are resident in the body's tissues
true
64
During infection _____ cells recognize infection and transports antigens to lymphoid organs
dendritic
65
Antigen presentation to T-cells is important in T-cell activation during ______ responses
adaptive immune
66
_______ are phagocytic and short-lived, enter sites of infection and die in infected tissues which forms pus
neutrophils
67
_____ defend against parasites and are involved in hypersensitivity responses
eosinophils
68
_____ along with mast cells, protect mucosal body surfaces & release histamine in hypersensitivity responses
basophils
69
______ reside in all connective tissues and orchestrate hypersensitivity responses (i.e., seasonal allergies), important in mucosal immune responses
mast cells
70
Mast cells participate in the expulsion of parasites from the body through the release of _____ containing histamine and other active agents
granules
71
Neutrophils kill microorganisms through _______
phagocytosis
72
Eosinophils kill antibody-coated parasites through the release of ______
granule contents
73
B-cells are derived from ______ , and upon activation differentiate into ______
bone marrow
antibody-secreting plasma cells
74
T-cells are derived from the _______ (though they originate in bone marrow)
thymus
75
What type of cells can T cells can become?
helper T cells (Th)
cytotoxic T lymphocytes (CTL)
76
What type of T cell activates other cells like macrophages and B cells?
helper T cells (Th)
77
What type of T cell kill cells that express foreign molecules?
cytotoxic T cells
78
True or false: T and B lymphocytes look alike, each having receptors for specific antigen
true
79
_________ are important in the innate immune system, lack antigen-specific receptors and kill infected/altered cells
Natural killer (NK) cells
80
What cells are absolutely key in presenting antigens to T-lymphocytes?
dendritic cells and macrophages
81
Many innate immune cells produce _____ that inform helper T-cells about how to help other immune cells
cytokines
82
True or false: certain subsets of helper T-cells are dedicated to ONLY aiding
innate immune responses
true
83
What cells are
important at helping to clear antigens that are bound by
antibody
Mast cells, neutrophils, eosinophils, and macrophages
84
Lymphoid tissues are organized tissues where lymphocytes interacts with ______ cells
non-lymphoid
85
true or false: lymphoid tissues are important in the initiation/maturation of adaptive immune
responses
true
86
What are the 2 types of lymphoid tissues?
1) primary (central) lymphoid organs
2) secondary (peripheral) lymphoid organs
87
Primary lymphoid organs where lymphocytes are generated and mature include:
bone marrow and thymus
88
Both B and T cells are generated in the bone marrow, however B cells mature in the ____ and T cells mature in the ____
bone marrow
thymus
89
For B cells, additional maturation steps can occur in the ____
spleen
90
Once lymphocytes mature, they leave primary lymphoid organs and are capable of responding to an ____
antigen
91
Secondary lymphoid organs are where adaptive immune responses are _____
initiated
- antigens and B/T Cell receptors encounter each other
92
Secondary lymphoid organs exist to bring antigen and lymphocytes together and include:
lymph nodes, spleen and MALT
93
Lymph nodes lie at junctions of ______ , collect _____ and return it to the blood via lymphatics
lymphatic vessels
ECF/lymph
94
Afferent lymphatics drain _____ and _____ from tissues, carrying it to the nodes where antigen is _____
lymph
antigens
trapped
95
The ____ filters for blood, collects blood-borne antigens and destroys aged RBCs
spleen
96
B-cells in the ____ produce large quantities of ____ and secrete them into the bloodstream
spleen
antibodies
97
The spleen organ is divided into _____ and _____
red pulp
white pulp
98
What division of the spleen does the destruction of RBCs take place?
red pulp
99
What division of the spleen is where lymphocytes surround arterioles entering the organ?
white pulp
100
White pulp can be further subdivided into _____ and _______
corona
periarteriolar lymphoid sheath (PALS)
101
Mucosa-associated lymphoid tissues (MALT) includes:
gut associated lymphoid tissues (GALT) and bronchial- associated lymphoid tissues
BALT
102
The purpose of MALT is to collect _____ from mucosal surfaces
antigens
103
______ is a specialized lymphoid tissue at the body’s “wet” surfaces required due to large surface area, and is rich with potential pathogens
MALT
104
______ includes tonsils, adenoids, appendix and Peyer’s Patches (PP)
GALT
105
______ collect antigens from epithelial surfaces of the GI tract via M cells
peyer's patches
106
_______ are composed of distinct T and B cell areas
peyer's patches
107
True or false: only when innate defenses are overwhelmed/bypassed/evaded is an adaptive immune response required
true
108
What are the 3 barriers of the immune system?
1) mechanical
2) chemical
3) microbiological
109
What are the mechanical, chemical and microbiological barriers of the skin?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, perspiration, sloughing off of skin
chemical
- antimicrobial peptides (defensins)
- sebum (fatty acids, lactic acid, lysozyme)
microbiological
- normal flora of the skin
110
What are the mechanical, chemical and microbiological barriers of the GI tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, mucus, food, and saliva
chemical
- antimicrobial peptides (defensins)
- acidity, enzymes (proteases)
microbiological
- normal flora of the GI tract
111
What are the mechanical, chemical and microbiological barriers of the respiratory tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid and mucus e.g., by cilia, air flow
chemical
- antimicrobial peptides (defensins)
- lysozyme in nasal secretions
microbiological
- normal flora of the respiratory tract
112
What are the mechanical, chemical and microbiological barriers of the urogenital tract?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, urine, mucus, sperm
chemical
- antimicrobial peptides (defensins)
- acidity in vaginal secretions, spermine and zinc in semen
microbiological
- normal flora of the urogenital tract
113
What are the mechanical, chemical and microbiological barriers of the eyes?
mechanical
- epithelial cells joined by tight junctions
- flow of fluid, tears
chemical
- antimicrobial peptides (defensins)
- lysozyme in tears
microbiological
- normal flora of the eyes
114
Chemical barriers include _____ and ______
lysozymes
antimicrobial peptides - defensins
115
Lysozymes present in secretions and uses _____ to break apart the peptidoglycan wall, causing lysis of the bacterial cell wall
hydrolysis
116
Antimicrobial peptides/defensins are small, heterogenous, cationic peptides that kill _____ and _____ bacteria, some enveloped viruses and fungi
Gram-negative
Gram-positive
117
What are the antimicrobial effects of antimicrobial peptides/defensins?
- Destabilize membranes and Pore formation in bacterial cell walls
- Proteolytic degradation of bacterial proteins
- Inhibit viral binding and entry
- Inhibit virus particle assembly
118
Defensins are prototypical AMPs that can act as a chemical barrier when they are secreted by _______ in a variety of mucosal surfaces
epithelial cells
119
Defensins and other AMPs (i.e. cathelicidins) are also stored
in _______ and can be released within tissues in
response to inflammation
neutrophil granules
120
Defensins and other AMPs (i.e., cathelicidins) can kill microbes _____ when neutrophils die during inflammation, and _____ after a cell phagocytoses a pathogen
extracellularly
intracellularly
121
Phagocytes are a _____ of defense as they can recognize, ingest and destroy many pathogens without the aid of an adaptive immune response
first line
122
True or false: Phagocytosis can also occur after an antibody (signal) has bound to an antigen and triggers phagocytosis
true
123
What are the 2 major phagocytes in the body?
macrophages and neutrophils
124
Pro-monocytes are found in the ____, monocytes are found in the ____ and macrophage/macrophage-like cells are found in the ____
bone marrow
blood
tissues
125
_____ are a non-dividing short-lived cell type in the blood (dominant WBC), and are derived from hematopoietic precursors in the bone marrow
neutrophils
126
Review the stages of phagocytosis:
1 - bacterium binds to pattern recognition receptors on membrane evaginations called pseudopodia
2 - bacterium is ingested, forming phagosome
3 - phagosome fuses with lysozyme
4 - bacterium is killed and then digested by low pH activated lysosomal enzymes
5 - digestion products are released from cell
127
Evolutionarily conserved mechanism for
recognizing common, conserved ‘signs’ of microbial
infection, physiological stress, or other damage is known as:
pattern recognition
128
True or false: Pattern recognition is immediate, does not require prior
recognition, and activates several arms of the
innate (and adaptive) immune response
true
129
Responses are elicited via the engagement of
Pattern Recognition Receptors (PRRs) found on
phagocytes, in response to:
- Pathogen Associated Molecular Patterns (PAMPs)
- Danger Associated Molecular Patterns (DAMPs)
130
Pattern recognition receptors include:
- Toll-like receptors
- Nod-like receptors
- Lectins
131
Pattern recognition receptors illicit responses such as:
phagocytosis and cytokine secretion
132
In step 1 of the phagocytosis process, a pattern-recognition-receptor (PRR) binds to a microbe or bit of
debris, OR an ____ created by
another cell binds to the microbe
opsonin
133
An opsonin is a
soluble, secreted PRR
that enhances the
effectiveness of
_____
phagocytosis
134
An opsonin coats a
microbe, the ____
has receptors for parts of
that opsonin
phagocyte
135
Lectin receptors (i.e., mannose receptor) recognize _____
carbohydrate patterns
136
Scavenger receptor examples are:
SR-A and SR-B
137
Complement receptors (i.e., CR3) binds to _____
complement opsonins
138
Fc receptors are receptors for the _____ region of an antibody
constant
139
In step 2 of the phagocytosis process (microbe engulfment), the PRR receptors signal the
________ to
approach, coat and
surround the sites where
the receptor is bound.
cell membrane
140
In step 2 of the phagocytosis process, we form a ____ , mediated by intracellular signaling events and actin polymerization
phagosome
141
PI3 kinase is important in which step of phagocytosis?
the 2nd step
142
In step 3 of the phagocytosis process (microbe killing), phagosomes fuse with _____ as well as primary and secondary ______
lysosomes
granules
143
Phagosomes have many molecules that are effective at cellular killing. Major groups include:
* Reactive oxygen species
* “pore”-forming proteins or peptides
* Hydrolytic enzymes
* pH changes – i.e. acidic
environment of the
lysozyme
144
In step 3 of the phagocytosis process (microbe killing), the microbe remnants are either _______ or can be excreted from the phagocyte
digested and used
145
After the microbe has been phagocytosed, the phagosome will
dock with a ____ and/or neutrophil granules
lysozyme
146
What are the characteristics of lysozymes?
- they can pretty much break down anything (acid hydrolases)
- they have a low pH of a lysozyme which is unpleasant for many bacteria
147
The NADPH oxidase complex becomes associated with the membrane of the ____ and uses a large amount of ____
phagolysosome
oxygen
148
True or false: If a particle is too large to phagocytose, macrophages will surround
it and “place” their NADPH oxidases close to it to try to kill it
true
149
Macrophages are also capable of killing cells by inducing the synthesis of ______ at high concentrations
nitric oxide
150
Neutrophils have a multitude of pore-forming molecules within their _____ , that will fuse with the phagosome
granules
151
Neutrophil granules include:
defensins
cathepsin
cathelicidins
lysozyme
lactoferrin
152
Defensins causes lysis and are very rich in ____
cysteine
153
Defensins form voltage-dependent pores in ____ that are permeable to water
bacteria
154
Cathepsin is a type of ___
protease
155
Cathelicidans are pore-forming molecules that causes ____
lysis
156
Lysozome is a glycoside hydrolase that doesn't require an ____, is found in a variety of glandular secretions, and is great at killing gram ____
acidic pH
positive bacteria
157
Lactoferrin is an iron-binding protein that interferes with _____ in microbes
iron metabolism
158
When neutrophils are in an environment with many bacteria, they can lyse and release their ____ into the ___
DNA
ECF
159
NETs are neutrophil extracellular traps that are sticky and contain ____ where most bacteria are trapped
chromatin
160
True or false: histones are toxic to many bacteria
true
161
True or false: the granule contents will remain close to the NETs and
help with killing bacteria, even after the neutrophil itself is dead
true
162
LPS, dsRNA, ssRNA, DNA, and Flagellin are all examples of ____
toll-like receptor ligands
163
Cytokines secreted in response to TLR's include:
inflammatory cytokines (IL-1b, IL-6, CXCL8, IL-12, TNFa) and interferons
164
What are the functions of inflammatory cytokines?
small protein messenger secreted by many cells that can:
- Influence the differentiation of a wide variety of cells,
including leukocytes
- Mediate – activate or inactivate – the activity of many cells, including leukocytes
- Increase or decrease the production of a wide variety of stem/hematopoietic cells
165
What are the types of interferons (IFN)?
alpha, beta, and lambda (IFNa, IFNb, IFNl)
166
Interferons are autocrine and paracrine signaling molecules that are effective in activating _____ and ____ cells, and inducing an _____ state
macrophages
NK
antiviral
167
MyD88 is an essential adaptor in ___ signaling
TLR
168
People with MyD88 deficiency suffer frequent and severe _____ infections, while antiviral responses are generally unaffected
bacterial
169
People with constitutively active MyD88 are prone to developing ____ and ____
blood disorders
blood cancers
- overproduction or dysregulated production of igM
- B cell lymphoma, marginal cell lymphoma
170
Nod-like receptors are a family of intracellular receptors found in the ____ that detect products derived from the intracellular degradation of phagocytosed pathogens
cytoplasm
171
True or false: Nod-like receptors can recognize DAMPs associated with cellular stress
true
172
Nod-like receptors activate expression of _______
inflammatory cytokines
173
What are the 3 steps of acute inflammation?
1) alteration of vascular caliber - vasodilation
2) enhancement of vascular permeability
3) emigration and activation of leukocytes
174
Vasodilation leads to increases in blood flow at the capillary bed due to _____ dilation, dilation of precapillary sphincters
arteriolar
175
What components contribute to vasodilation in acute inflammation?
* Nitric oxide and histamine
* Prostaglandins (PGI2, PGE2, PGD2)
* Platelet activating factor (at low concentrations – higher
concentrations cause vasoconstriction)
* Complement (C5a and C3a stimulate histamine release)
176
At low concentrations _____ is a potent vasodilator
nitric oxide
177
At high concentrations ____ is capable of destroying both microbes and host cells since it's a _____
nitric oxide
free radical
178
In macrophages, higher concentrations of nitric oxide are produced by an inducible _____
nitric oxide synthase
179
Vasodilation and fluid loss due to increase permeability lead to slower blood flow known as ______ , which helps with margination of leukocytes
vascular congestion
180
Prostaglandins and leukotrienes are produced when PLA2
generates ______ from membrane phospholipids
arachidonic acid
181
Different types of cyclooxygenases produce different types
of prostaglandins from ______
arachidonic acid
182
What prostaglandins cause vasodilation and increase vascular permeability?
PGE2, PGD2, and PGI2
183
Different types of 5-lipoxygenase produce different types of leukotrienes from _____ that are
important in lung tissue
arachidonic acid
184
LTB4 is a leukotriene that is an important _____
chemotactic agent
185
Many leukotrienes increase vascular permeability and _______
smooth muscle constriction
186
Lipoxins are generated from arachidonic acid by 12-lipoxygenase and they decrease ____
inflammation
187
Capillaries and venules become more "leaky" with the release of numerous mediators:
* Histamine and serotonin (released by activated
platelets)
* Prostaglandins (PGD2 and PGE2)
* Leukotrienes (LTC4, LTD4, LTE4)
* Platelet activating factor
* C3a and C5a
* Bradykinin
188
Increased vascular permeability is due to contraction of
_______ , which is often short-lived and occurs mainly in the ____
endothelial cells
venules
189
Vascular permeability can also occur through ______ caused by trauma, burns and microbial damage, or leukocyte-mediated damage to the _____ , which is longer-lived
endothelial damage
endothelium
190
Increased transcytosis can result in ____ of plasma components into the _____
leakage
interstitial space
191
Active, vesicle-mediated transport across the capillary endothelial cell is known as:
transcytosis
192
In transcytosis, larger molecules can move across the endothelium via _____ and _____
* Pinocytosis (caveolin
pathway)
* Receptor-mediated
endocytosis
193
Mechanisms of increased vascular permeability:
Retraction of endothelial cells --> endothelial injury --> leukocyte-mediated vascular injury --> increased transcytosis
194
A interstitial fluid accumulates during inflammation, pressure increases in the interstitial space and _____ increases
lymphatic drainage
195
Excess fluid, microbes, debris, and leukocytes all migrate into the ____ during inflammation
lymph
196
When lymphatic vessels themselves become inflamed this is called:
lymphangitis
197
During emigration and activation of leukocytes, neutrophils, monocytes, eosinophils, and basophils will all migrate from the circulation into _____
inflamed tissue
198
What are the 5 steps of leukocyte migration?
1) Margination
2) Rolling (Mediated by binding of selectins and
cellular adhesion molecules to their respective ligands on leukocytes)
3) Adhesion (Mediated by binding of selectins and
cellular adhesion molecules to their respective ligands on leukocytes)
4) Diapedesis
5) Chemotaxis of leukocytes to sites of injury or infection
199
What are the functions of cytokines?
1) Influence the differentiation of a wide variety of cells, including leukocytes
2) Mediate – activate or inactivate – the activity of many cells,
including leukocytes
3) Increase or decrease the production of a wide variety of stem/hematopoietic cells
200
What are the functions of chemokines?
1) Bind to cell-surface receptors (usually leukocytes)
2) Induce movement of leukocytes along the chemokine concentration
gradient
3) Mediate adhesion of leukocytes for the purposes of:
* Differentiation
* Inflammation/migration
201
What are the 2 major chemokine families?
CXC and CC
202
CXC chemokines attract ____ and are ____
neutrophils
angiogenic
203
In CXC chemokines, the "X" indicates the location of a _____ bond
disulphide
204
CC chemokines act on/attract a wide variety of _____
leukocytes
205
Review the steps for emigration and activation of leukocytes:
a) Margination – leukocytes migrate towards vessel wall
b) Rolling – formation & dissociation of adhesion bonds between
leukocytes and endothelial cells
c) Stable/Tight Adhesion – Formation of tight/stable
adhesion bonds between leukocytes and endothelial cells
d) Diapedesis/Transmigration – leukocyte migrates through
endothelium
e) Chemotaxis of
leukocytes to sites of injury or infection
206
Activation by chemokines presented on endothelial cells is required before the leukocyte can form ______
stable adhesion
207
When an endothelial cell presents a chemokine that stimulates the activation of leukocytes, this increases the affinity of leukocyte integrin for it's ____ , allowing _____ to form
ligand
stable/tight adhesion bonds
208
What are the 3 families of endothelial and leukocyte adhesion molecules?
selectin, integrin and Ig
209
How does histamine and thrombin increase the ability of leukocytes to migrate to a target?
rolling and selectin expression by endothelial cells
210
How does TNF and IL1 increase the ability of leukocytes to migrate to a target?
ICAM expression by endothelial cells
211
How do chemokines increase the ability of leukocytes to migrate to a target?
increased integrin affinity
212
Chemotactic agents are produced in higher concentrations at sites of _____
cellular damage/pathogen invasion
- i.e., leukotriene B4, bacterial products containing N-formyl-methionine, activated complement (C5a), chemokines (IL-8, RANTES, eotaxin)
213
Leukocytes can "follow the breadcrumbs" to the site of pathology via the _______
chemotactic agent concentration gradient
214
What is the complement system?
A blood-borne molecular defense system that "complements" the immunity provided by antibodies
215
What 3 functions does the complement system aid in?
1) phagocytosis - some complement components are opsonins
2) destruction of microorganisms - the end result of complement activation is formation of a large, antimicrobial protein complex
3) inflammation - some complement components are potent inflammatory mediators
216
How is the complement system activated?
Through a tightly-controlled enzyme-triggered cascade
- cascade = enzymatic reactions that activate protein effectors in a sequence
217
What are the 3 pathways of complement activation?
1) Alternative pathway
- complement component 3 (C3) acts as a PRR binding to the surface of a pathogen
2) Mannose-binding-lectin (MBL)
- triggered by binding of MBL, a PRR, to mannose-containing CHO on bacteria/viruses
3) Classical pathway
- when antibodies bind to a pathogen, C1q binds to the Fc portion of those antibodies
218
The _____ pathway and ______ pathway have a similar activation mechanism
mannose-binding-lectin
classical
219
C3 convertase cleaves C3 into ___ and ___
C3b
C3a
220
C3b is an important ____ , forms part of the _____ convertase, and causes progression through the rest of the complement cascade
opsonin
C5
221
C5 convertase cleaves C5 into ___ and ___
C5a
C5b
222
C5b becomes associated with the cell wall/membrane of the microbe and causes ____ as it activates other components of the complement system
lysis
223
What complement molecules all associate to form a large pore in the microbial membrane and cause lysis
C5b, C6, C7, C8, C9
224
True or false: C3a and C5a are incorporated into the microbes membrane and also mediate inflammation
true
225
The classical and lectin pathways have the same ___ and ___ convertases, and C1q and MBL look very similar
C3
C5
226
C3 forms C3a and C3b spontaneously in the bloodstream, but is ____ quickly under normal conditions
degraded
227
Factor B, a circulating proteins is spontaneously ____ to a protein known as ____
cleaved
Bb (complexes with C3b to form C3bBb)
228
C3bBb is a C3 convertase and can convert C3 into ___ and ___
C3a
C3b
229
C3bBb is rapidly inactivated in the ____. If an bacterium is present, then it will bind to the _____
uninfected host
bacterial membrane
230
C3Bb bound to the bacterial membrane is a stable _____
C3 convertase
231
As more C3b is generated, more ___ is formed
C3Bb
232
The circulating protein, properdin helps stabilize the alternative pathway complex to form the stable ___ and ___ convertases
C3 and C5
233
C3bBbC3b and properdin are components of the C5 convertase of the _____ pathway. They need to bind to the bacterial membrane to stay stable and keep converting C5 into ___ and ___
alternative
C5a
C5b
234
When C1q detects a bound antibody or MBL detects mannose on a membrane, they bind ______ proteins, and these proteins cleave ___ and ___
complement-activating
C2
C4
235
C4b2a is formed from the cleavage of ___ and ___ upon C1q or MBL activation
C4
C2
236
The membrane attack complex (MAC) generates a ___ in lipid bilayer membranes
pore
237
What is the sequence of events for cell lysis in the MAC?
1. C5b triggers the assembly of complexes C5b, C6, C7 and C8
2. Upon binding to C7, C8 inserts into the membrane
3. Polymerization of C9, forming a pore in the membrane
238
True or false: The MAC and the pro-inflammatory effects of C5a and C3a can be extremely damaging to cells if they are not tightly regulated
true
239
___ and ___ both cause vasodilation, increased vascular permeability, smooth muscle contraction (i.e., bronchoconstriction) and histamine release from mast cells
C3a
C5a
240
____ is a chemotactic agent for a wide variety of cells (neutrophils & macrophages)
C5a
241
Inadequate complement proteins C2, C3, C4, C5, MBL, and MAC complex tend to make patients vulnerable to _____ infection
bacterial
242
Deficiencies in ___ highly predispose patients to systemic lupus erythematosus
C1q
243
C1q helps macrophages to clear _____ bodies and initiate the ____ pathway, as it recognizes phosphatidylserine
apoptotic
classical
244
The alternative pathway is the first responder, while the lectin/classical pathways are more effective later because ___ is always present in the bloodstream and is constantly being produced by the liver, cleaved and degraded
C3
245
Mannose-binding lectin does not circulate in high ____ unless it is secreted by the liver in response to pro-inflammatory signals
concentrations
246
What do toll-like receptors 1-4 detect?
TLR1 - can detect mycobacteria (like Tb) and gram-negative bacteria
TLR2 - can detect peptidoglycans (major component of cell wall of gram-positive bacteria)
TLR3 - can detect double stranded RNA (only found in viruses)
TLR4 - can detect lipopolysaccharide (LPS) (major component of gram-negative bacteria)
247
TLRs tend to recognize PAMPs in the ____ or in ___
ECF
endosomes
247
C-type lectin receptors detect ____ components of many microbes, and are found on the cell membrane of a wide variety of _____ cells
carbohydrate
immune
248
True or false: C-type lectin receptors are found on the cell membrane and detect pathogens in the cytosol
false
- they do NOT detect pathogens in the cytosol
249
NOD-like receptors (NLRs) are present in the ____ of a wide range of immune cells and non-immune cells (i.e., epithelial cells)
cytosol
250
Most NLRs detect ____ or parasite cell walls and some can also detect ____
bacteria
viruses
251
Activation of ____ leads to activation of NF-KB and AP-1
NLRs
252
RIG-like receptors (RLRs) are present in the ___ of many immune cells and non-immune cells. They detect viral ___ and activate NF-KB and transcriptions factors which leads to the production of antiviral ____
cytosol
RNA
cytokines (interferons)
253
DAMPs are molecular signals that are present when a cell is damaged but they can also present as crystals including:
cholesterol crystals (cellular damage or oxidized LDL)
uric acid crystal (gout)
254
When a DAMP activates NLRP3, it associated with caspase 1 and activates it by forming a large molecular complex known as an ____
inflammasome
255
What are the 2 major effects of caspase 1 activation?
1) activation of pro-IL-1-beta to IL-1-beta
2) insertion of a cell membrane pore - gasdermin - into the cell membrane
256
If enough gasdermin is produced, the cell will ____ , and release more ____
lyse/die (pyroptosis)
DAMPs
256
Inflammasomes are a molecular assembly that activates _____
caspase 1
256
IL-1 leaves the cell via ____
gasdermin pores
257
True or false: The release of DAMPs can lead to activation of neighboring cells
true
258
Review the 2-step process of IL-1 generation/release:
1) Priming - detection of PAMPs or DAMPs leading to synthesis and storage of pro-IL-1
2) release - continued or larger DAMP or PAMP stimuli, causing NLRP3 activation leading to caspase 1 activation and the conversion of pro-IL-1 to IL-1, releasing IL-1
258
What cells are cellular sentinels/important DAMP and PAMP detectors?
Resident macrophages, endothelial cells, epithelial cells
258
Il-1-beta is one of the most important _____, and is released in large quantities by macrophages in response to _____ or _____
pro-inflammatory cytokines
significant infection
tissue damage
259
What cells express most PAMP and DAMP receptors and can secrete large quantities of pro-inflammatory cytokines?
Langerhans cells - dermis and epidermis
Kupffer cell - liver
Alveolar macrophages - lung
Microglia - brain
Resident macrophages also found in connective tissue
Spleen (and other secondary lymphoid organs)
260
Endothelial cells in the blood and lymph vessels express TLRs and RLRs, and when they detect a PAMP they do 2 things:
1) increase the expression of ICAMs and selectins
2) increase the production of pro-inflammatory cytokines and chemokines
261
The PRRs in epithelial cells (found in skin and mucosal surfaces) tend to result in increased production of local ______ peptides
antimicrobial
262
Chemokines and cytokines in epithelial cells can be produced if more ____ need to be recruited from circulation
leukocytes
263
What are the major pro-inflammatory cytokines?
IL-1-beta, IL-6, IL-12, CXCL8, and TNF-alpha
263
What are the important cellular sources for IL-6?
Macrophages/monocytes, dendritic cells, NK cells, epithelial cells, endothelial cells
263
What are the important cellular sources for IL-1?
Macrophages/monocytes, dendritic cells, keratinocytes, epithelial cells, endothelial cells
264
What are the important cellular sources for TNF-alpha?
Macrophages/monocytes, dendritic cells, mast cells, NK cells, epithelial cells
264
Which 3 cytokines have redundant and pleiotropic effects?
IL-1, IL-6, TNF-alpha
265
IL-1-beta, IL-6 and TNF-alpha all act on the ____ to cause fever, participate in the synthesis and release of acute-phase proteins by the ____, and increase vascular permeability
hypothalamus
liver
266
IL-1-beta and TNF-alpha both increase ____ molecules on vascular endothelium, produce the chemokine ____, and IL-6
adhesion
CXCL8
267
What are the mechanisms of higher body temperature?
1. peripheral vasoconstriction (blood flows away from the periphery to the core)
2. shivering
3. increased metabolic rate
267
What is the benefit to fever?
adaptive immune mechanisms in general are more effective at higher temperatures
267
The hypothalamic set-point is altered by increased levels of _____
pro-inflammatory cytokines
268
IL-1-beta and TNF-alpha can induce fever at low ____ , and IL-6 induces fever at higher (10X) ____
serum concentrations
concentrations
269
Pro-inflammatory cytokines cause elevation of ____ E2 production by cells in the 3rd ventricle, which leads to signaling that changes the _____ setpoint
Prostaglandin
hypothalamic
270
What are the 5 major acute phase proteins?
1. C-reactive protein (CRP)
2. Ferritin
3. Hepcidin
4. Mannose-binding lectin (MBL)
5. Serum amyloid protein A (SAA)
271
Blockers of cyclooxygenase activity (i.e., tylenol) are effective _____
anti-pyretics
272
Elevated levels of inflammatory cytokines cause the ____ to increase the secretion of useful ___ into the bloodstream, known as acute _____
liver
proteins
phase proteins
273
C-reactive protein (CRP) includes ___ which binds to phosphorylcholine. CRP can activate ____ to trigger the classical complement cascade.
opsonin
C1q
273
True or false: CRP is a common lab measurement ordered to diagnose inflammatory disease
true
273
Ferritin binds to ____ with high affinity, and many microbes depend on ____ for their metabolism
serum iron
iron
274
Mannose-binding lectin is the PRR that initiates the ______ cascade
lectin complement
274
Hepcidin interferes with intestinal transport of ___ into the bloodstream
iron
274
Serum amyloid protein A modulates/increases the activation of the ____ and ____, and also opsonizes ____ bacteria
inflammasome
TLRs
gram-negative
275
IFN-alpha and IFN-beta are secreted by:
macrophages, dendritic cells and cells that have detected viruses via PRRs
275
What are the 2 major groups of interferons?
1) Group 1 - interferon-alpha (IFN-alpha) and interferon-beta (IFN-beta)
2) Group 2 - interferon-gamma (IFN-gamma)
276
The role of IFN-alpha and IFN-beta is to:
interfere with viral replication
277
IFN-gamma is secreted by ___ cells and ___ cells, and it activates ____to push the adaptive immune system to a cell-mediated response
Th
NK
macrophages
278
Type 1 interferons act in an ___ and ___ fashion to provide a rapid, innate protection to viral infection
autocrine
paracrine
279
If type-1 IFNs and the NK response is inadequate, then we rely on the ______
adaptive immune response
280
What are the 3 ways type 1 interferons protect against viral infection?
1) induce resistance to viral replication in all cells
2) increase MHC class I expression and antigen presentation in all cells
3) activate NK cells to kill virus-infected cells
281
How do interferons interfere with viral replication inside cells?
- they inhibit protein translation in the presence of viral RNA
- they degrade viral mRNA
- they inhibit viral protein assembly
282
Natural killer cells are specialized cells derived from the ____ lineage, and has a non-specific way of detecting cancer cells or virally-infected cells
lymphoid
283
Large lymphocytes that are activated by Type 1 IFNs and IL-12 do 2 things:
1) kill cells that are infected by viruses
2) secrete cytokines that predispose the adaptive immune system to adopt a response that relies on cellular effectors rather than antibodies
284
NK cells survey the body for ___ or ____ abnormal cells
infected
stressed
285
What are the two types of NK cell receptors?
1) NK activating receptors (NKARs)
2) NK inhibitory receptors (NKIRs)
286
_____ detect molecules expressed on the membrane of cells that are infected by viruses or have developed into cells that may be malignant, while ____ detect molecules that are typically expressed by normal cells
NKARs
NKIRs
286
NKG2D is an NKAR that detects _____ molecules on cells
strange MHC-I
286
KIR is an NKIR that detects -_____ molecules on a cell membrane
normal MHC-I
287
While normal MHC-I proteins can present intracellular ____, abnormal MHC-I proteins cannot and are typically expressed by virally-infected cells or cells with damaged genomes.
antigens
288
Before NK cells can be activated, they need to be licensed to make sure their ____ are functional. This is done by _____
NKIRs
dendritic cells (protect body from indiscriminate NK-killing and tissue damage)
288
Once NK cells are activated an licensed, they travel to areas of ____ and ___ the cells
damage/inflammation
survey
289
If a cell expresses mostly normal MHC-I proteins, ____ over-rule ____ and vice versa for abnormal MHC-I proteins
NKIRs
NKARs
290
When NKARs are activated, it kills the cell by:
1) receptor-mediated apoptosis via Fas-Fas ligand interaction
2) secretion of the proteins perforin and granzyme
- perforin pokes holes in membrane
- granzyme activated BH3-only apoptotic protein Bid and executioner caspase 3
