Immuno Exam 1 Flashcards
(555 cards)
1
Q
Immunology is the branch of biomedical science that studies…
A
resistance to infection and
mechanisms used by organisms to defend themselves against microorganisms or foreign particles
2
Q
Define immune system
A
mechanisms used by organisms to defend themselves against microorganisms or foreign particles
3
Q
Define immunity
A
state of being resistant to infection by a specific pathogen
4
Q
When was Thucydides’ eyewitness account of immunity to plague?
A
430 BCE
5
Q
When did Girolamo Fracastoro state that diseases were caused by seed-like entities transmitted by direct or indirect contact?
A
1546
6
Q
Whose belief contributed to the eventual germ theory of disease?
A
Girolamo Fracastoro
7
Q
What is the germ theory of disease?
A
diseases are caused by pathogens
8
Q
Define pathogens
A
microorganisms with the potential to cause disease
9
Q
Who are important figures related to the germ theory of disease?
A
Agostino Bassi
Ignaz Semmelweis
Louis Pasteur
Robert Koch
10
Q
What are examples of early forms of vaccination?
A
inhalation of crusts from smallpox lesions in 1000 AD
variolation against smallpox (16th century)
11
Q
Who developed the smallpox vaccine?
A
Edward Jenner
12
Q
What was hypothesized to provide protection against smallpox?
A
cowpox
13
Q
How did the developer of the smallpox vaccine provide an 8-year-old boy with smallpox immunity?
A
by inoculating him with cowpox pus
14
Q
What latin word is “vaccine” derived from, and what does it mean?
A
vaccinus - “of the cow”
15
Q
What did Paul Ehrlich discover?
A
granulocytes are part of the immune system
16
Q
What did Ilya Mechnikov discover?
A
white blood cells are capable of phagocytosis
cellular theory of immunology
17
Q
What did Emil von Behring and Shibasaburo Kitasato discover?
A
antitoxin to diptheria and tetanus in blood of infected individuals (antibody)
humoral theory of immunology
18
Q
How do opportunistic pathogens cause disease?
A
only when the immune system is not functioning properly or enters a site where it can grow uncontrollably
19
Q
What can be pathogenic organisms?
A
bacteria
viruses
fungi
protozoa
parasitic animals
20
Q
What are examples of pathogenic bacteria, and what diseases do they cause?
A
Staphylococcus aureus - skin infection, meningitis, toxic shock
Haemonophilus influenzae - pneumonia
Salmonella typhimurium - food poisoning
Vibrio cholera - cholera
21
Q
What are examples of pathogenic viruses, and what diseases do they cause?
A
Influenza A - influenza (flu)
Hepatitis B - hepatitis
Epstein–Barr - mononucleosis
Ebolavirus - hemorrhagic fever
22
Q
What are examples of pathogenic fungi, and what diseases do they cause?
A
Candida albicans - yeast infection
Cryptococcus neoformans - meningitis
Aspergillus flavus - aspergillosis
23
Q
What are examples of pathogenic parasites, and what diseases do they cause?
A
Plasmodium falciparum - malaria
Toxoplasma gondii - toxoplasmosis
Trypanosoma brucei - sleeping sickness
24
Q
What are examples of pathogenic protozoa, and what diseases do they cause?
A
Giardia intestinalis - giardiasis
Leishmania - leishmaniasis
25
Where do extracellular pathogens reside?
outside of the cells of organisms they infect
26
Where do intracellular pathogens reside?
mainly within the organism's cells
27
What are the lines of defense?
physical barriers
innate immunity
adaptive immunity
28
What are the physical barriers?
skin and mucosa
29
Define innate immunity
non-specific immunity present from birth
30
Define adaptive immunity
specific immunity learned after contact with a pathogen
protects upon subsequent exposure
identifies antigens
31
Define antigens
substances recognized as foreign
32
What type of cells are associated with humoral immunity?
B cells
33
Define B cells
immune cells that use cell-surface proteins to bind and recognize an antigen
34
What are the cell-surface proteins utilized by B cells called?
immunoglobulins
35
What happens after an immunoglobulin is used to bind and recognize an antigen?
activation and differentiation to produce an antibody
36
Define antibody
soluble form of immunoglobulin
37
What type of cells are associated with cell-mediated immunity?
T cells
38
Define T cells
immune cells that use T-cell receptor proteins to bind and recognize an antigen
39
What happens once an antigen is bound and recognized by T cells?
activation and differentiation to clear pathogens
support other immune cells to combat external pathogens or directly target and destroy pathogen-infected cells
40
What is another name for self-antigens?
autoantigens
41
Define self-antigens
components of normal tissue that stimulate an immune response
42
Does the immune system want to combat foreign antigens, self-antigens or both?
foreign antigens
43
Define tolerance
inactivation of immune response to self
44
When does tolerance occur?
during B and T cell development and in other ways throughout the body
45
What prevents entry of pathogens?
epithelium
46
What is produced by mucus membranes?
mucus
47
What is mucus?
destructive components that are constantly flushed and replenished
48
What do epithelial cells secrete?
antimicrobial substances
defensins
lysozyme
49
Define defensins
antimicrobial peptides that disrupt bacterial and viral membranes
50
What deters microorganisms?
low pH of skin, stomach and vagina
51
Define microbiota
collection of microorganisms that normally inhabit the body
52
What type of organisms make up the microbiota?
symbiotic
53
What are some characteristics of symbiotic organisms?
benefit from nutrient-rich environment
aid in digestion
compete with pathogens for nutrients and space
create environment inhibitory for pathogens
help develop immune system
54
What are the two main categories of leukocytes?
granulocytes and agranulocytes
55
What do granulocytes contain?
granules within cytoplasm
56
What are the granulocytes?
neutrophils
eosinophils
basophils
mast cells
57
What do neutrophils specialize in?
phagocytosis
58
What are the agranulocytes?
lymphocytes
monocytes
59
What are the lymphocytes?
B cells and T cells
60
What do monocytes differentiate into?
dendritic cells and macrophages
61
Define hematopoiesis
the process of formation of blood cells
62
What does hematopoiesis produce?
erythrocytes
megakaryocytes
leukocytes
63
What do hematopoietic stem cells differentiate into for a specific cell line?
progenitor cells
64
What do myeloid progenitor cells give rise to?
most cells involved in innate immunity and antigen presentation
65
What do antigen-presenting cells do?
process engulfed material into peptides
present peptides at surface for T cells
66
What cells are involved in innate immunity and antigen presentation?
antigen-presenting cells
granulocytes
monocytes
mast cells
67
What are macrophages?
long-lived cells that specialize in phagocytosis
inhabit specific organs in body areas
68
Macrophages are scavengers to eliminate what?
pathogens, dead cells or other debris from apoptosis
69
Define apoptosis
programmed cell death
70
What do macrophages secrete?
cytokines
71
What are dendritic cells important for?
phagocytosis and pathogen destruction
72
Dendritic cells link...
innate and adaptive immune response
73
What do dendritic cells play a major role in?
antigen uptake and presentation during innate immune response
74
What can dendritic cells process?
many different types of pathogens
75
Where do dendritic cells reside?
tissues of the body
76
Dendritic cells are able to leave the site of infection to...
display antigen
activate adaptive immunity
77
What do lymphoid progenitor (innate) cells give rise to?
innate lymphoid cells (ILCs)
natural killer (NK) cells
78
What do ILCs secrete, and what do they do?
cytokines - activate innate immune cells
79
What do NK cells do?
prevent viral infections
recognize and destroy viral-infected cells
secrete cytokines to minimize viral replication
80
What do lymphoid progenitor (adaptive) cells give rise to?
T cells
B cells
81
What do T cells differentiate into?
cytotoxic T cells
helper T cells
82
What do cytotoxic T cells do?
attack pathogen-infected cells
83
What do helper T cells do?
activate other cells
84
What do B cells differentiate into?
plasma cells
85
What do plasma cells do?
produce antibodies that bind and neutralize pathogens and toxins
86
What recognizes the pathogens that breach the skin and mucosal barrier?
proteins of the complement system
receptors of innate immune cells
87
What happens once pathogens are recognized after breaching the skin and mucosal barrier?
pathogens are removed or destroyed by membrane destabilization
pathogens are engulfed by phagocytosis and eliminated
induce inflammation
88
Define inflammation
increased fluid at the site of infection
can be acute or chronic
89
When does inflammation occur?
when innate immune cells recognize infection and release cytokines or inflammatory mediators
90
What occurs during inflammation?
vasodilation
secretion of complement proteins
recruit leukocytes to the site of infection
movement of dendritic cells and antigens to lymphoid tissue to activate adaptive immune response
91
What is a fever?
the byproduct of inflammation
rise in temperature caused by cytokines and inflammatory mediators
aids in immune system
92
How does fever aid the immune system?
lowers rate of replication of many pathogens
increases activity of the adaptive immune response
93
What immune response targets and destroys pathogens that evade the innate immune system?
adaptive
94
What receptors recognize a specific antigen in the adaptive immune response?
highly specific T cell and B cell receptors
95
What is the recognition process of highly specific T cell and B cell receptors of the adaptive immune response called?
clonal selection
96
What is clonal expansion?
cell proliferation and differentiation of the adaptive immune response
97
What is another name for daughter cells that recognize the same antigen as the highly specific T cell and B cell receptors?
effector cells
98
What is the key characteristic of adaptive immunity that allows for vaccines to work?
immunological memory
99
What is the primary immune response?
the first antigen encounter requires initial adaptive immune response after about 14 days
100
What do some of the effector cells produced in the primary immune response become?
memory cells
101
Define memory cells
long-lived cells capable of activation if exposed to the same pathogen
102
How long does the stronger, faster secondary immune response take?
2-3 days
103
What is primary lymphoid tissue?
sites where lymphocytes develop and mature
104
What takes place in bone marrow?
B cell and T cell production
B cell maturation
105
What are examples of primary lymphoid tissue?
bone marrow
thymus
106
What takes place in the thymus?
T cell development and maturation
107
What is secondary lymphoid tissue?
sites where antigen from pathogens is presented and lymphocytes are activated in response
108
What are examples of secondary lymphoid tissue?
lymph nodes
spleen
109
What are lymph nodes important in?
lymphocyte activation
110
Lymph nodes are the connection between...
circulatory and lymphatic systems
111
What is lymph?
extracellular fluid drained from tissues to blood by lymph nodes of the lymphatic system
112
What do lymph nodes facilitate?
antigen presentation and activation of the adaptive immune response
113
What is the name of the B-cell region contained by lymph nodes?
lymphoid follicles
114
What cells present T cells in T-cell area, also contained by lymph nodes, and what do they turn into?
dendritic cells, effector cells
115
Where do effector cells migrate, and what do they activate?
lymphoid follicles, B cells
116
What reside in the spleen?
macrophages and dendritic cells
117
What do the cells residing in the spleen do?
clear bloodborne pathogens
activate T cells and B cells circulating through the blood into the spleen
118
What are individuals without a spleen more prone to?
bloodborne bacterial infections
119
What occurs in the white pulp of the spleen?
antigen presentation
lymphocyte activation
120
What does MALT stand for?
mucosa-associated lymphoid tissue
121
Where is MALT found?
in the mucus membranes of the digestive, respiratory and urogenital tracts
122
What are the more-specific forms of MALT?
gut-associated lymphoid tissue (GALT)
bronchial-associated lymphoid tissue (BALT)
123
What is MALT structurally similar to but have different antigen delivery?
lymph nodes and spleen
124
How does MALT gain antigens for presentation to lymphocytes?
through M cells
125
What are the types of immune system malfunctions?
hypersensitivity reactions
autoimmune diseases
immunodeficiencies
cancer
126
What causes hypersensitivity reactions?
recognition of an allergen
127
Define allergen
a foreign but innocuous material
128
What are hypersensitivity reactions commonly known as?
allergies
129
What are severe and deadly hypersensitivity reactions called?
anaphylaxis
130
What do hypersensitivity reactions do?
activate granulocytes
induce localized symptoms to expel allergen
131
What are the localized symptoms induced by hypersensitivity reactions?
coughing
sneezing
vomiting
diarrhea
132
What happens when someone has an autoimmune disease?
B cells and T cells that recognize self-molecules enter circulatory and lymphatic systems, causing an adaptive immune response to tissues within the body
133
What is rheumatoid arthritis?
an autoimmune disease characterized by inflammation at recognition sites
134
What is type I diabetes?
an autoimmune disease characterized by destruction of the tissue at recognition sites
135
What causes immunodeficiencies?
lack of immune system function
can be inherited (genetic mutations) or acquired (environmental factors or infection)
136
What causes a higher likelihood of pathogen infection?
immune cells unable to mount proper response
137
What normally happens when individuals acquire random mutations in genes over a lifetime?
the immune system detects these changes as foreign and eliminates the cells that acquire them
138
What causes cancer?
the immune system fails to eliminate mutations occurring in genes controlling cell division, and cells begin to grow uncontrollably
139
What is the largest organ of the body?
skin
140
What else, besides skin, form a barrier?
cells that line the digestive tract and airways
141
What prevent entry by microbes between epithelial cells?
tight junctions
142
What continually removes microbes to prevent colonization?
secretion of fluids such as mucus and tears
143
What are chemical barriers?
acid pH
antimicrobial proteins
antimicrobial peptides
complement system
144
What is lysozyme?
an antimicrobial protein that digests bacterial cell walls
145
What are examples of phagocytes?
macrophages and neutrophils
146
What are recruited to the site of infection?
phagocytes
147
What do the cell surface receptors of phagocytes recognize?
opsonin or molecular pattern on pathogen surface
148
Clustering of receptors binding to pathogen induces ingestion of pathogen into membrane-enclosed...
phagosome
149
What is formed when a phagosome is fused with a lysosome?
phagolysosome
150
What does a phagolysosome have?
low pH and digestive enzymes for destruction and degradation of pathogen
151
What does PRR stand for?
pattern recognition receptor
152
What are PRRs?
receptors used by innate immune cells that recognize pathogen-associated molecular patterns (PAMPs)
153
What are PAMPs?
molecules that are characteristic of a broad range of microbes that are not normally present in the body
154
What are examples of PAMPs?
bacterial cell wall components, such as carbohydrates and lipids
viral or bacterial nucleic acids
155
What are the types of innate immune cell receptors?
toll-like receptors (TLRs)
lectin receptors
scavenger receptors
cytosolic innate receptors
opsonin receptors
156
What are TLRs, and where can they be found?
transmembrane proteins, cell surface and endosomes
157
What PAMPs do TLRs recognize?
lipopolysaccharide (gram-negative bacteria)
lipoteichoic acid (gram-positive bacteria)
single/double-stranded RNA (viruses)
some bacterial proteins
158
What do lectins do?
bind carbohydrates common to pathogen cell surfaces, which activates phagocytosis
159
What specific lectin recognizes sulfated sugars, polysaccharides with terminal mannose, fucose or N-acetylglucosamine?
CD206
160
What are examples of scavenger receptors?
SR-A and SR-B on macrophages
161
What do scavenger receptors do?
bind negatively charged ligands, such as sulfated sugars, lipoteichoic acid and lipopolysaccharide, which activates phagocytosis
162
What do cytosolic innate receptors recognize?
intracellular cytosolic PAMPs, such as viral nucleic acids and bacterial signaling molecules
163
What specific cytosolic innate receptor recognized viral RNA?
RIG-1
164
What type of cytosolic innate receptor recognizes bacterial cell wall components in the cytosol?
NOD-like receptors (NLRs)
165
What do cytosolic innate receptors do?
activate cell responses that inhibit growth of intracellular pathogens and recruit white blood cells to destroy infected host cells
166
What are two related examples of opsonin receptors, and what do they bind?
complement receptors CR3 and CR4, complement proteins bound to microbial cell surfaces
167
What is a single example of an opsonin receptor, and what does it bind?
Fc receptors, immunoglobulins bound to microbial cell surfaces or to soluble foreign molecules
168
What does binding of opsonin receptors trigger?
phagocytosis
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What triggers intracellular signaling pathways?
receptor clustering
170
What leads to the production and secretion of cytokines?
changes in gene expression
171
What are cytokines?
secreted proteins that have signaling roles in the immune response
172
What are two inflammatory cytokines?
TNF-α and IL-1
173
What do inflammatory cytokines cause?
swelling and fluid accumulation
dilation of blood vessels
increased vascular permeability
induced local blood vessels to express cell surface proteins that bind and recruit immune cells
174
What are chemokines?
a type of cytokine that act as chemoattractants for immune cells, attract immune cells to site of infection, and lead to inflammation to better fight infections
175
What are antiviral cytokines?
a family of secreted proteins that includes IL-12, interferon-α and interferon-β
176
What do antiviral cytokines do?
activate NK cells to find and destroy virus-infected cells
177
Where are TLRs that recognize extracellular ligands located?
plasma membrane
178
Where are TLRs that recognize nucleic acids located?
endosomal membranes
179
How is the pathogen recognition domain of TLRs shaped?
has an overall C-shape and consists of repeating segments of the leucine-rich repeat (LRR) motif
180
What are required by TLRs to bind some ligands?
cofactors
181
What does ligand binding by TLRs activate via signaling pathways?
transcription factors
182
What is the cytosolic signaling domain of TLRs called?
toll-interleukin receptor (TIR) domain
183
What transcription factor is activated by TLRs that recognize bacterial PAMPs, and what does the signaling pathway start with?
NFκB, MyD88
184
What transcription factors are activated by TLRs that recognize nucleic acids, and what are involved in the signaling pathway?
IRF3 and IRF7
TRIF (toll-receptor-associated activator or interferon) and TRAM (toll-receptor-associated molecule)
185
What happens when TLRs that bind extracellular bacterial PAMPs activate the transcription factor?
ligand binding causes MyD88 to bind to the TIR domain
MyD88 brings the protein kinase IRAK4
IRAK4 phosphorylates and activates IRAK1
IRAK1 phosphorylates and activates TRAF6
TRAF6 modifies and causes destruction of NEMO and TAB to free and activate TAK1
TAK1 phosphorylates and activates IKK
IKK phosphorylates IκB and causes destruction of IκB to free NFκB to enter the nucleus and transcribe genes for cytokines IL-1 and TNF-α
186
What happens when TLRs that bind viral nucleic acids activate their transcription factors?
ligand binding causes TRIF and TRAM to bind to the TIR domain
TRIF and TRAM activate TRAF3
TRAF3 phosphorylates and activates IRF3 and IRF7
phosphorylated IRF3 and IRF7 enter nucleus to transcribe interferons and other genes that promote defense against viral infection
187
What are the functions of macrophages?
phagocytosis
inflammation
188
What is phagocytosis by macrophages facilitated by?
opsonin receptors
189
What causes inflammation due to macrophages?
TLR signaling activates transcription factor NFκB
NFκB induces production of inflammatory cytokines
190
What are key inflammatory cytokines produced by macrophages?
IL-1 and TNF-α
IL-6
CXCL8
IL-12
191
What do IL-1 and TNF-α do?
induce fever and increase vasculature permeability
192
What does IL-6 do?
induces fever and activates liver cells to produce acute phase response proteins
193
What does the CXCL8 chemokine do?
attracts neutrophils and basophils
194
What does IL-12 do?
recruits and activates NK cells
195
What is the inflammasome?
a complex of innate cytosolic receptors of NOD-like receptor proteins (NLRPs) and apoptosis-associated speck-like protein containing a CARD domain (ASC)
196
How is IL-1 activated?
NLRPs responding to viral infection as a part of the inflammasome activate Caspase 1 to cleave pro-IL-1 and generate active IL-1
197
Which of the following are more mobile: neutrophils or macrophages?
neutrophils
198
What percentage of circulating white blood cells do neutrophils comprise?
50%
199
How quickly do neutrophils die?
within hours of phagocytosing pathogens
200
What is extravasation?
neutrophil migration
neutrophils exit blood circulation via extravasation to sites of infection and inflammation
201
What does extravasation require?
cell adhesion molecule interactions
202
What are examples of cell adhesion molecule interactions?
glycoproteins on neutrophil surface binding to selectins on vascular endothelial cell surface
integrin on neutrophil surface binding to ICAM on vascular endothelial cell surface
203
What is the first step of extravasation?
rolling adhesion via weak interaction between neutrophil glycoproteins and selectins on endothelial cells
204
What is the second step of extravasation?
tight binding of neutrophil integrin LFA-1 to ICAM-1 in response to chemokine CXCL8
205
What is the third step of extravasation?
neutrophils cross the endothelial cell layer (diapedesis)
206
What is the fourth and final step of extravasation?
chemotaxis of neutrophils towards source of CXCL8 (migration)
207
What are effector (bacteriocidal) mechanisms?
fusion of phagosome with granules containing proteases and antimicrobial proteins and peptides
respiratory burst
neutrophil extracellular traps (NETs)
208
What does respiratory burst entail?
activation of NADPH oxidase in phagosomes consumes oxygen and generates superoxide radicals
superoxide dismutase and catalase convert superoxide radicals to water and oxygen gas
209
What are NETs?
extracellular fibers of DNA and granule contents
210
What are type-1 interferons?
IFN-α and IFN-β
211
Where and how are type-1 interferons induced?
in virus infected cells, by activation of endosomal TLRs and cytosolic innate receptors
212
What do type-1 interferons induce?
NK cell proliferation
RNAse L
p53 to trigger apoptosis of infected cells
expression of cell surface proteins that signal viral infection of NK cells
213
What do type-1 interferons activate?
protein kinase R to inhibit protein synthesis
214
How do inhibitory receptors recognize infected host cells?
bind cell surface proteins present on all healthy cells, which present peptide fragments from inside the cell
215
What do virus infections do regarding cell surface presentation of protein fragments?
they reduce cell surface presentation of protein fragments
216
How do activating receptors recognize infected host cells?
NKG2D binds MIC-A and MIC-B, which are expressed by target cells in response to cellular stress
217
What type of receptors may inhibitory and activating receptors be?
killer-cell immunoglobulin-like receptors (KIR)
lectin-like receptors
218
What activates NK cells?
signaling from activating receptors in absence of signaling from inhibitory receptors
219
What do NK cells have to create holes in cell membranes and initiate apoptosis?
granules with perforin and granzymes
220
Where do NK cells release granule contents?
toward the surface of stressed and altered target cells
221
What do dendritic cells do to pathogens?
phagocytose and transport pathogens to lymph nodes
process and present pathogen protein fragments to T cells
222
What do pattern recognition receptors do?
elicit production of cytokines to direct appropriate adaptive immune response
223
What do activated NK cells secrete?
IFN-γ, which recruits cytotoxic T cells
224
What is a systemic infection?
infection that spreads through bloodstream
225
During a systemic infection, what causes vasodilation throughout the body?
TNF-α
226
What does rapid loss of blood pressure lead to?
septic shock
227
What does septic shock cause?
organ failure of kidneys, liver, heart and lungs
228
What does failure of TLR signaling cause?
lack of cytokine production
229
What does inadequate innate immune response lead to?
greater susceptibility to infection
230
What can defective macrophage function lead to?
persistence of infection
231
What leads to granulomas?
defective neutrophil function
neutrophils phagocytose bacteria but fail to destroy them
macrophages attempt to clear infected neutrophils, fuse and form granulomas
232
What causes chronic and recurrent viral infections?
defective NK cells
233
Over how many different proteins related to the complement system are in blood plasma?
30
234
A cascade of what type of reactions make up the complement system?
proteolytic cleavage reactions
235
What does the complement system do?
tag proteins for phagocytosis and directly kill pathogens by creating holes in their membranes
236
What tags proteins for phagocytosis?
opsonin
237
What directly kills pathogens by creating holes in their membranes?
membrane attack complex (MAC)
238
All pathways of complement activation converge at the point of creating which enzyme?
C3
239
What is C3 cleaved to form?
C3a and C3b
240
What is the smaller C3 fragment?
C3a
241
What does C3a do?
acts as an anaphylatoxin to induce inflammation
recruit phagocytes and induce their degranulation
242
What does C3b do?
covalently attaches to pathogen surface to induce phagocytosis, via a newly exposed reactive thioester group
243
What are the three pathways of complement activation, from first to act to last?
alternative pathway
lectin pathway
classical pathway
244
What do the three pathways of complement activation all form?
C3 convertase
245
What pathway is spontaneous, already initiated and ready to go whenever pathogen enters the body?
alternative pathway
246
What pathway is activated by recognition of bacterial oligosaccharides ending in mannose and fucose?
lectin pathway
247
What pathway is best activated by antibodies bound to pathogen surface?
classical pathway
248
Where is C3 always present?
plasma
249
What is "tickover" in regards to the spontaneous reaction undergone by C3 in the alternative pathway?
reaction of its internal thioester bond with water to form iC3
250
What are the steps of "tickover"?
iC3 binds factor B
factor B bound to iC3 is cleaved by factor D to form Ba and Bb fragments
Bb fragments remain bound to iC3 to form iC3Bb, a soluble C3 convertase
iC3Bb cleaves C3 to form C3a, a small soluble peptide, and C3b, which attaches to the surface of a pathogen
251
How is alternative pathway C3 convertase (C3bBb) formed?
C3b bound to pathogen surface binds factor B
factor B bound to C3b is cleaved by factor D, and the larger Bb fragment remains bound to C3b
252
How does alternative C3 convertase form more alternative C3 convertase?
alternative C3 convertase cleaves more C3 to form C3b that covalently attaches to pathogen surface to react with factor B and factor D
253
How is the alternative pathway regulated?
alternative C3 convertase (C3bBb) forms more C3 convertase in positive feedback loop
accelerators stabilize C3bBb on pathogen surfaces
brakes destabilize C3 convertase on host cell surfaces
254
Is attachment of C3b to cell surface specific or non-specific?
non-specific
255
What are plasma protein regulators?
properdin (factor P)
factor H
256
What is the accelerator plasma protein regulator?
factor P
257
What is the brake plasma protein regulator?
factor H
258
What does factor P do?
stabilizes C3bBb on pathogen cell surfaces
259
What does factor H do?
binds to C3b and promotes cleavage of C3b by factor I to form inactive iC3b
binds preferentially to host cell membranes via interaction with sialic acid
260
What are the host cell surface regulators?
decay accelerating factor (DAF)
membrane cofactor protein (MCP)
261
What does DAF do?
inactivates C3bBb by promoting dissociation of Bb from C3b
262
What does MCP do?
binds to C3bBb and promotes both dissociation of Bb and cleavage of remaining C3b by factor I to form inactive iC3b
263
What does C3b bind to on macrophages to stimulate phagocytosis?
complement receptor CR1
264
What do iC3b bind to on macrophages to stimulate phagocytosis?
complement receptors CR3 and CR4
265
How is the membrane attack complex formed?
C3bBb recruits another molecule of C3b to form C3b2Bb (alternative C5 convertase)
alternative C5 convertase cleaves C5 to C5a, an anaphylatoxin, and C5b
C5b associates with C6 and C7
exposed hydrophobic region of C7 allows association of C5b67 with pathogen membrane
addition of C8 nucleates polymerization of C9 molecules in the target cell membrane to form a pore
266
How are host cells protected from the membrane attack complex?
soluble plasma proteins inhibit recruitment of C6 and C7 to C5b
membrane proteins on host cells inhibit C9 polymerization
267
What soluble plasma proteins inhibit recruitment of C6 and C7 to C5b?
S protein
clusterin
factor J
268
What membrane proteins on host cells inhibit C9 polymerization?
protectin (CD59)
homologous restriction factor (HRF)
269
What do C3a and C5a have in common?
they are both anaphylatoxins
270
What does C3 convertase cleave, and what is released?
C3, small diffusible peptide C3a
271
What does C5 convertase cleave, and what is released?
C5, small diffusible peptide C5a
272
How do both C3a and C5a provoke inflammation?
bind to endothelial cells to increase vascular permeability
induce degranulation of mast cells and basophils
act as chemoattractants for phagocytes
increase expression of complement receptors on phagocytes
273
What does C3a produced by alternative C3 convertase recruit and activate?
innate immune cells
274
What does C3b act as?
an opsonin
275
What are lectin and classical pathway initiator proteins secreted by in response to inflammatory cytokines?
liver cells
276
What does MBL bind to?
mannose on pathogen cell surfaces
277
What does the MBL hexamer complex with?
proteases MASP-1 and MASP-2
278
What are the lectin and classical pathway initiator proteins?
mannose binding lectin (MBL)
C-reactive protein
279
What does C-reactive protein bind to?
phosphocholine on pathogen cell surfaces
280
What does C-reactive protein on pathogen cell surfaces bind?
C1q hexamer complexed with proteases C1r and C1s
281
What do MBL and C-reactive protein both act as?
opsonins
282
What have receptors for MBL and C-reactive protein?
monocytes and macrophages
283
The initiation of parallel and homologous pathways by MBL and C-reactive protein form what?
classical C3 convertase
284
What does MBL binding activate?
associated MASP-1 and MASP-2
285
What does C1q binding to C-reactive protein or immunoglobulin complexes activate?
associated C1r and C1s
286
Activated proteases in both parallel and homologous MBL and C-reactive protein pathways cleave what to make what?
C4 to C4a and C4b
C2 to C2a and C2b
287
How is C4b similar to C3b?
C4b attaches to cell surface by thioester bond
288
What does C2b associate with, and what is the name of that complex?
C4b, C4bC2b
289
What is C4bC2b also known as?
the classical C3 convertase
290
What homologs were identified in echinoderms?
C3 and factor B
291
Homologs of C3 were also identified in...
fruit flies
292
Homologs identified in echinoderms and fruit flies enhance...
phagocytosis
293
Homologs identified in echinoderms and fruit flies are upregulated by...
bacterial infection
294
What are components of lectin and classical pathways found in?
urochordates, close relatives of vertebrates
295
What does the blood coagulation system do?
minimizes blood loss
hinders entry of pathogens into blood circulation
296
Why do platelets release prostaglandin and other factors?
to boost innate immune response
297
What does bradykinin do?
cause vasodilation
attract innate immune cells
298
Why do many pathogens release proteases?
to aid in tissue breakdown and invasion
299
What percentage of plasma proteins are protease inhibitors?
10%
300
What does α2 macroglobulin do?
undergoes shape change to enclose protease and prevent access to other substrates
301
What does protease attack do to α2 macroglobulin?
expose their internal thioester that then bonds with protease
302
What are defensins?
small amphipathic peptides
303
How small are defensins?
35-40 amino acids
304
What are α-defensins made by?
neutrophils, Paneth cells of small intestine
305
What are β-defensins made by?
various types of epithelial cells
306
What are among the evolutionarily oldest of immune defense mechanisms?
defensins
307
What happens when there is a deficiency in complement?
abnormal clearance of gram-positive bacteria
difficulty removing immune complexes
recurring bacterial infections
308
What happens when there is abnormal clearance of gram-positive bacteria?
PAMPs are masked from PRRs of innate immune cells
opsonization by complement facilitates clearance by phagocytes
309
What happens when there is difficulty removing immune complexes?
classical pathway tags immune complexes
accumulation of soluble immune complexes can lead to hypersensitive reactions, autoimmunity
310
What cells are a part of the innate immune system?
phagocytes
granulocytes
311
What cells are a part of the adaptive immune system?
B cells
T cells
312
What type of immunity is unable to recognize novel pathogens?
innate immunity
313
What type of immunity is capable of recognizing novel foreign molecules?
adaptive immunity
314
How does innate immunity function?
by using PRRs that recognize common pathogen-associated molecular patterns (PAMPs)
315
How does adaptive immunity function?
through the use of diverse receptors specific for particular molecules on particular pathogens
316
What cells have immune memory?
subset of B cells and T cells whose receptors recognize the pathogen
317
How does immune memory work?
increasing numbers of daughter B cells and T cells with the same specificity serve to combat future infections by the same pathogen more quickly and effectively
318
What are T-cell receptors?
transmembrane proteins with very short cytoplasmic tails
heterodimers
319
What is the most common type of T-cell receptor?
alpha-chain and beta-chain
320
What is not the most common type of T-cell receptor?
gamma-chain and delta-chain
321
What does each chain of a T-cell receptor have?
N-terminal variable region
constant region closer to the membrane
322
What do the variable regions of the two chains of a T-cell receptor form?
antigen binding site
323
What does each T cell start with?
its own unique T-cell receptor
324
What kind of peptide do most T-cell receptors bind?
short peptides
325
What must the peptides bound to T-cell receptors be "presented" by?
MHC molecule
326
What are most T cells able to recognize?
a particular peptide from a specific pathogen
327
What do MHC molecules bind?
peptide, T-cell receptor and a coreceptor
328
What does a class I MHC present?
peptides from degradation of proteins in cytosol
329
What does a class I MHC bind to?
CD8 coreceptor on CD8+ T cells
330
What does a class II MHC present?
peptides from externally acquired proteins degraded in lysosomes
331
What does a class II MHC bind to?
CD4 coreceptor on CD4+ T cells
332
What is the MHC genetic locus called in humans?
human leukocyte antigen (HLA) locus
333
How can an MHC protein differ in different people?
differing amino acid sequence and peptide binding specificities
334
What are immunoglobulins also known as?
antibodies
335
What serve as B-cell receptors when expressed as a cell surface protein with a transmembrane domain?
immunoglobulins
336
What do immunoglobulins serve as when secreted by activated and differentiated B cell progeny?
soluble effector molecule
337
What are differentiated B cell progeny called?
plasma cells
338
What is the basic structure of an immunoglobulin?
four polypeptide chains with two identical heavy chains plus two identical light chains held together by disulfide linkages
339
What do both heavy and light chains of immunoglobulins have?
variable and constant regions
340
What forms a single antigen-binding site?
a heavy chain variable region and a light chain variable region
341
How many identical antigen-binding sites does each immunoglobulin have?
two
342
How many different secreted soluble immunoglobulin isotypes are there?
five
343
What are the effector functions of secreted soluble immunoglobulins?
neutralization of foreign particle or pathogen
opsonization
complement activation
activation of innate immune cells
protection of internal mucosal surfaces
344
What type of cells express multiple PRRs encoded in their genome?
innate immune cells
345
What express just one antigen receptor from genes that undergo recombination to generate diversity?
lymphocytes
346
What cells have receptors for constant regions of immunoglobulins?
innate immune cells
347
What can activate the classical pathway of complement activation?
immunoglobulins
348
What cells present peptide antigens to T cells?
dendritic cells
349
What immune system can clear most common pathogens?
innate
350
What immune system can target novel pathogens or pathogens expressing new antigens?
adaptive
351
How long does the adaptive immune system require to respond to a new pathogen?
several days to two weeks
352
Why do relatively few T cells and B cells recognize a new pathogen?
adaptive immune system receptor diversity
353
What must antigens from a pathogen go through in order to be presented to T cells?
they have to be processed and delivered to secondary lymphoid organs such as lymph nodes
354
What must antigen-specific B cells and T cells go through before their progeny migrate to sites of infection?
they must be activated, proliferate and differentiate in secondary lymph nodes
355
Where to T cells mature?
thymus
356
Where do B cells develop?
bone marrow
357
What do both T cells and B cells undergo?
somatic recombination of their receptor genes
selection for functional receptors that don't recognize self-antigens
358
What do dendritic cells do at the site of infection in regards to antigen processing and presentation?
phagocytose pathogens and migrate to lymph nodes
359
What do dendritic cells do in lymph nodes?
present peptide fragments to circulating T cells that interact via cell-adhesion molecules
360
Where are cytosolic pathogen proteins processed, and where are their peptide fragments presented?
cytosol, on class I MHC molecules
361
Where are extracellular pathogen proteins processed, and where are their peptide fragments presented?
phagolysosomes, class II MHC molecules
362
What results in the signaling and activation of the T cell?
T-cell receptor and co-receptor engagement with MHC and peptide
363
What happens once the T cell is activated?
CD8 T cells engaged with a class I MHC differentiate into cytotoxic T cells
CD4 T cells engaged with a class II MHC differentiate into various types of helper T cells
364
Where do some helper T cells migrate to, and what do they interact with?
part of a lymph node, circulating B cells
365
What happens to B cells that recognize the same pathogen as a T cell?
they become activated, divide and differentiate
366
What determines what B cells differentiate into?
cytokine signals from helper T cells
367
What do some B cells differentiate into?
antibody-secreting plasma cells
368
What do some progeny B cells become?
memory B cells
369
What are some refinements undergone by the B-cell receptors of some B cells?
higher affinity for the antigen
different heavy chain type
370
What generates B cells with higher affinity for the antigen, and what is this process called?
somatic hypermutation and selection
affinity maturation
371
What results in a different heavy chain type of a B cell, and what is this process called?
recombination of heavy chain constant region genes
isotype switching
372
What are the genetic mechanisms for T-cell and B-cell receptor diversity?
recombination of different randomly selected variable gene segments
addition or removal of random nucleotides at junctions of recombined variable gene segments
combination of different subunits
373
What are the different subunits that can be combined for T-cell receptors?
alpha-chain and beta-chain
374
What are the different subunits that can be combined for B-cell receptors?
heavy chain and light chain
375
What process splices DNA segments?
somatic recombination
376
What segments for T-cell receptor alpha-chain and immunoglobulin light chain undergo somatic recombination?
V and J segments
377
What segments for T-cell receptor beta-chain and immunoglobulin heavy chain undergo somatic recombination?
V, D and J segments
378
In what type of cells does antigen receptor gene rearrangement (somatic recombination) occur?
developing T cells and B cells
379
What are expressed as a result of antigen receptor gene rearrangement?
spliced gene segments
380
How does alpha-chain T-cell receptor gene rearrangement occur?
alpha-chain joins a single randomly selected Vα to a single randomly selected Jα segment
many different combinations
381
How does beta-chain T-cell receptor gene rearrangement occur?
beta-chain first joins Dβ to Jβ segment
then join a Vβ segment
many different combinations
382
What happens to the possible number of unique T-cell receptors as a result of alpha-chain and beta-chain combination?
multiplied
383
What type of rearrangement is heavy chain immunoglobulin gene rearrangement similar to?
T-cell receptor beta-chain rearrangement
384
How does heavy chain immunoglobulin rearrangement take place?
a VH segment combines with a DH and a JH to form many possible VHDHJH segments
385
What types of immunoglobulin light chains are there?
κ and λ
386
Each immunoglobulin light chain recombines to form multiple of what combinations?
VκJκ or VλJλ
387
Each B cell expresses how many unique heavy and light chains?
a single unique heavy chain with a single unique light chain, either a κ or λ
388
What further immunoglobulin gene changes do activated B cells undergo?
somatic hypermutation (affinity maturation)
isotype switching
389
What does B cell somatic hypermutation do?
improves receptor binding to the same antigen
390
What does B cell isotype switching do?
changes only the constant region of the heavy chain and affects function but not antigen binding
391
What are the key proteins of V(D)J recombinase?
RAG1 (recombination activating gene 1) and RAG2
392
What enzymes are involved with V(D)J recombinase?
enzymes in the non-homologous end joining (NHEJ) DNA repair pathway
393
What do RAG1/RAG2 bind and recognize?
recombination signal sequences (RSSs) that border V, D and J DNA segments
394
What do RSSs contain?
heptamer sequence
nonomer sequence
either a 12-bp or 23-bp spacer between
395
What does RAG1/RAG2 recombinase cutting at the RSSs create?
hairpins
396
What does nicking by Artemis create?
single-strand palindromic overhangs that create P-nucleotides
397
What do exonucleases and terminal deoxynucleotidyl transferase do?
delete and add random nucleotides, respectively, called N-nucleotides
398
What amplifies receptor diversity?
junctional sequence diversity
399
How do jawed fish and all higher vertebrates use V(D)J recombinase with RAG1/RAG2?
to diversify lymphocyte receptors
400
What have recombinases that cut and join DNA segments with specific border sequences, similar to V(D)J recombination at RSSs?
DNA transposons
401
What do DNA transposons produce?
changes in sequence at sites of insertion
402
What are self-tolerance mechanisms?
processes that generate receptor diversity that create receptors that recognize self-molecules
403
What does positive selection select?
cells with functional receptors
404
What does negative selection select against?
cells with self-reactive receptors
405
How do T-cell receptor and immunoglobulin gene rearrangements proceed?
in defined sequence
406
What happens after each T-cell receptor and immunoglobulin recombination event during positive selection?
the protein product is tested for functionality
407
What does failure to produce functional protein product cause during positive selection?
apoptosis of developing T cell or B cell
408
What does successful production of functional protein allow during positive selection?
cell to proceed to next step of development
409
What is tested during negative selection, and what are they tested for?
lymphocytes with functional antigen receptors
reactivity to self molecules
410
What do cells in thymus express?
many self peptides on MHC molecules to test developing T cells
411
During negative selection, T cells that recognize self-peptide:MHC complexes too well are...
induced to undergo apoptosis
412
During negative selection, T cells that recognize self-peptide:MHC complexes only moderately...
survive
413
What do positive and negative selection test developing lymphocytes for?
functional receptors that do not react with self-molecules
414
What do lymphocytes do once they pass positive and negative selection?
mature and enter circulation
415
Why do MHC molecules present peptides on the surface of a cell?
for inspection by T cells
416
What are removed by negative selection in the thymus?
self-reactive T cells
417
What are most of the peptides presented by MHC molecules derived from?
normal cell proteins that are not recognized by T cells
418
During an infection, what do some MHC molecules present that can be recognized by some T cells?
peptides from pathogens
419
What do class I MHC molecules present?
peptides from proteins made inside the cell
420
What do class II MHC molecules present?
peptides from extracellular proteins taken into phagolysosomes
421
What transmembrane chains act when class I MHC molecules present peptides, and what do they do?
transmembrane alpha chain forms peptide binding pocket plus β2-microglobulin
422
What transmembrane chains act when class II MHC molecules present peptides, and what do they do?
transmembrane alpha and beta chains together form peptide binding pocket
423
What do class III genes include?
immune regulatory proteins
some complement proteins
424
What is step one of MHC class I peptide presentation in most cells?
proteins in the cytoplasm are digested to peptide fragments by the proteasome
425
What is step two of MHC class I peptide presentation in most cells?
peptide fragments transported into ER and loaded onto class I MHC molecules
426
What is step three of MHC class I peptide presentation in most cells?
class I MHC:peptide complexes exit ER, travel to plasma membrane via secretory pathway
427
What is step four of MHC class I peptide presentation in most cells?
a CD8 T cell that recognizes the class I MHC:peptide complex can be activated
428
What is step one of MHC class II peptide presentation in professional antigen-presenting cells?
proteases in phagolysosomes degrade endocytosed or phagocytosed proteins into peptide fragments
429
What is step two of MHC class II peptide presentation in professional antigen-presenting cells?
phagolysosomes then fuse with secretory vesicles that contain MHC class II proteins
430
What is step three of MHC class II peptide presentation in professional antigen-presenting cells?
class II MHC:peptide complexes travel to plasma membrane
431
What is step four of MHC class II peptide presentation in professional antigen-presenting cells?
a CD4 T cell that recognizes the class II MHC:peptide complex can then be activated
432
What type of cytoplasmic tails do the T-cell receptor α and β (or γ and δ) chains have?
short cytoplasmic tails
433
What do T-cell receptors associate with?
other transmembrane proteins that form the CD3 complex
434
What type of cytoplasmic tails do proteins of the CD3 complex have?
cytoplasmic tails with signaling motifs
435
What coreceptors have important signaling roles?
coreceptors of CD4 or CD8
436
What activates T cells?
T-cell receptor signaling
437
What are effector T cells?
cytotoxic T cells (CTLs) from CD8 T cells
438
What does the effector T cell TH1 do?
activates macrophages
439
What does the effector T cell TH2 do?
helps activate B cells
440
What does the effector T cell TH17 do?
activates neutrophils
441
What do natural killer (NK) T cells act like?
CTLs
442
What do regulatory T cells do?
induce tolerance
443
What can form memory T cells?
all activated T cells
444
What do naive B cells have?
cell surface IgM and IgD, with transmembrane forms of µ and δ heavy chains, that act as the B-cell receptor
445
What do B-cell receptors associate with?
two proteins Igα and Igβ that have cytoplasmic domains with signaling motifs
446
What does signaling from a B-cell receptor complex activate?
B cells to differentiate into antibody-secreting cells
447
What do naive B cells initially secrete?
IgM
448
What can IgM undergo to produce IgG, IgA or IgE?
class switching
449
When does the primary immune response take place?
the first exposure to an antigen
450
What contributes to the time required by the primary immune response?
antigen processing
migration of dendritic cells to lymph nodes
presentation to T cells
activation and differentiation of T cells and B cells
451
What may happen when antigen-specific T cells and B cells proliferate?
some of their progeny turn into memory T cells and memory B cells
452
What do memory cells do?
increase the number of antigen-specific T cells and B cells
primed to respond faster if/when the same antigen re-enters the body
453
Because of the great diversity of receptors, how many T cells and B cells may exist in the body when a pathogen infects?
relatively few
454
What can encounter each other in lymph nodes?
dendritic cells presenting antigen
circulating T cells
circulating B cells
455
What facilitate and speed up activation of T cells and B cells?
lymph nodes
456
What happens during the secondary immune response?
memory cells encounter antigen faster, respond more quickly and more strongly
457
What do memory B cells produce?
antibodies with better affinity
458
How long may the primary response take to clear an infection?
weeks
459
How long does the secondary response take to clear an infection?
within a few days
460
What is the basis for vaccines and immunity after recovery from an infection?
immune memory
461
What is the primary lymphoid organ responsible for T-cell development and maturation?
thymus
462
What migrate from the bone marrow and blood to the thymus?
undifferentiated lymphocyte precursor cells
463
How many lobes does the thymus have?
two
464
What does each lobe of the thymus contain?
outer cortex
inner medulla
465
What are immature T cells called?
thymocytes
466
What happens to immature T cells?
they undergo key developmental steps to ensure proper TCR expression in the cortex
467
What takes place in the medulla
mature thymocytes undergo negative selection and finish their development into naive T cells
468
What do resident cells of the thymus do?
drive the development of thymocytes into naive T cells
469
What are resident cells of the thymus?
thymic epithelial cells (TECs)
macrophages
dendritic cells
Hassall's corpuscles
470
What are characterized by cell-surface markers present on the stem cell precursors, along with the absence of lineage-specific markers?
hematopoietic stem cells
471
What are expressed on both human and mouse T cells?
CD34 and CD38
472
What are precursors to several cell types, and what must they receive to commit to a differentiate cell type?
lymphoid progenitors
appropriate signal
473
What regulates cell proliferation and differentiation?
the Notch signaling pathway
474
What is Notch?
a cell-surface receptor protein that interacts with transmembrane ligands on adjacent cells
475
What does not express either coreceptor (CD4 or CD8)?
double-negative thymocyte
476
Where are double-negative thymocytes found?
thymic cortex during initial development
477
What do double-negative thymocytes begin?
somatic recombination at the TCR loci
478
What do double-negative thymocytes continue until?
both subunits of the receptor have properly rearranged, and both coreceptors are expressed
479
What expresses a fully rearranged TCR, and both CD4 and CD8?
double-positive thymocytes
480
What are the possible fates of double-positive thymocytes?
develop into regulatory T cells
develop into NK T cells
begin the process of positive and negative selection to test the TCR and select for a single coreceptor
481
What thymocytes have a single coreceptor?
single-positive thymocyte
482
How does the initial development of the double-negative thymocyte in humans differ from in mice?
in regard to the cell-surface molecules present during the developmental process
483
What is the first stage of double-negative thymocyte initial development?
human lymphoid progenitor cells in the thymus shut down expression of the step cell marker CD34 and begin expressing the adhesion and signaling molecules CD2, CD5 and CD7
484
As double-negative thymocytes continue to develop, they begin to express...
CD1 at their cell surface
485
What are the critical checkpoints that a thymocyte must pass to continue development and become a functional naive T cell?
checkpoint of the γδ subunit of the T-cell receptor
checkpoint of the beta subunit of the T-cell receptor
checkpoint of the alpha subunit of the T-cell receptor
486
What percentage of T cells in mice do γδ T cells represent?
0.5%
487
What percentage of T cells in humans do γδ T cells represent?
3.5%
488
Why are γδ T cells important?
they protect the fetus during development
in adults, they play an important role in protecting mucosal surfaces
489
What produces all cell types of the circulatory system from a common stem cell?
hematopoiesis
490
Where do T cells begin their life as a lymphoid progenitor?
bone marrow
491
What commit the common lymphoid progenitors to the T-cell lineage?
migration of common lymphoid progenitors to the thymus
signals given by cells
492
What is somatic recombination activated through?
the expression of the RAG1 and RAG2 proteins
493
Where do recombination events begin?
at the β, γ and δ loci of the TCR
494
What happens if productive rearrangements occur at the γ and δ loci?
thymocyte becomes a γδ T cell
495
How many possible productive beta-chain rearrangements are there?
four
496
Most T cells will express which chain?
beta-chain
497
What must the developing thymocyte assemble to test for a productive arrangement of the beta chain?
a surrogate T-cell receptor complex
498
What occurs once the beta-chain checkpoint has been passed?
recombination of the alpha-chain locus
499
What is the name of a surrogate alpha chain?
pre-T alpha chain (pTα)
500
What is the pTα?
it assembles with the rearranged beta chain and the CD3 complex to form the pre-TCR
501
What does the pre-T cell receptor complex do?
ensures that a functioning T-cell receptor can signal via the same transduction pathways used to activate T cells
502
Once through the beta-chain checkpoint, what does the cell do?
proliferates
expresses RAG1 and RAG2 again
begins recombination at the other T-cell receptor loci (α, γ and δ)
undergoes allelic exclusion
503
What must be tested to ensure TCR function?
rearrangement of the alpha chain
504
Where is the alpha chain tested?
ER membrane
505
If the expressed alpha chain does not function properly, what happens to the alpha-chain locus?
it is further rearranged
506
If a functional alpha chain is produced, what happens to the developing thymocyte?
it continues development into a naive T cell
507
What are the later stages of development in which thymocytes continue through after successfully passing through both checkpoints?
positive selection
negative selection
508
What does positive selection do?
promotes the selection of thymocytes that can bind to self-MHC molecules (MHC restriction)
509
What does negative selection do?
prevents the release of thymocytes that can recognize MHC-self-peptide complexes with high-affinity (self-tolerance)
510
What does development of T cells in the thymus involve?
somatic recombination of T-cell receptor loci
511
What receptor loci can thymocytes rearrange?
α and β
γ and δ
512
What do double-positive thymocytes interact with to test the affinity of the TCR with MHC-peptide complexes at the cell surface?
cortical thymic epithelial cells (cTECs)
513
What can cTECs express?
both MHC class I and class II molecules
514
Why can cTECs present a variety of self-peptides?
to promote positive selection of double-positive thymocytes based on the affinity of the T-cell receptor for the MHC-peptide complexes
515
What does positive selection of double-positive thymocytes positively select?
those with the ability of the TCR to interact with MHC
516
What are the three possible outcomes of selection within the thymic cortex?
death by neglect
negative selection
positive selection
517
What is death by neglect?
double-positive (DP) thymocytes cannot interact with any MHC-peptide complexes
518
What is negative selection within the thymic cortex?
DP thymocytes bind too tightly with an MHC-peptide complex
519
What is positive selection within the thymic cortex?
DP thymocytes with TCRs that can interact with an MHC-peptide complex with a low or intermediate affinity survive and proliferate
520
What happens during selection within the thymic cortex?
DP thymocytes further develop and express only a single coreceptor (either CD4 or CD8)
521
What is lineage commitment?
commitment of a thymocyte to express a single coreceptor
522
What play roles in lineage commitment?
transcriptional control
epigenetics
523
What are the two proposed models of lineage commitment?
instructive and kinetic signaling
524
What type of selection is the instructive model?
interaction-driven selection
525
What happens if a TCR engages an MHC class I molecule presenting a peptide in the instructive model?
the interaction will also promote CD8 interaction with the complex and shut down CD4 expression
526
What happens if a TCR engages an MHC class II molecule presenting a peptide in the instructive model?
the CD4 coreceptor will engage in the interaction, and the thymocyte will receive a signal to prevent CD8 expression
527
What type of selection is the kinetic signaling model?
signal strength-driven selection
528
What will positively selected thymocytes become if the T-cell receptor/coreceptor signal is continuous in the kinetic signaling model?
CD4+
529
What will positively selected thymocytes become if the T-cell receptor/coreceptor signal is interrupted in the kinetic signaling model?
CD8+
530
When can negative selection occur within the thymic medulla?
if the T-cell receptor:MHC-peptide complex has too high an affinity
531
What is central tolerance?
negative selection processes that occur in primary lymphoid tissues that are responsible for the removal of self-reactive lymphocytes
532
What is AIRE?
a transcriptional activator (autoimmune regulator) which allows cells to express genes not normally expressed by epithelial cells of the thymus (promiscuous gene expression)
533
What domains does AIRE contain?
CARD domain (caspase recruitment)
SAND domain (SP100, AIRE1, NucP41/PP75 and DEAF1)
two PHD domains (plant homeodomain)
534
What acts as a "gas pedal" for RNA polymerase II?
AIRE
535
What does the "gas pedal" for RNA polymerase II cause?
transcription of tissue-restricted genes and presentation of tissue-specific antigens on MHC I within mTECs
536
What can engulf mTECs and present tissue-specific antigens via MHC class II?
medullary thymic dendritic cells
537
What does the engulfing of mTECs allow for?
negative selection of CD4+ thymocytes that bear a TCR that interacts too strongly with an MHC class II–tissue-specific antigen peptide
538
What does negative selection drive and limit, respectively?
central tolerance
the circulation of self-restrictive T cells
539
What will a subset of CD4 T cells that express a self-reactive TCR begin to express?
the transcription factor FOXP3
540
What cells continue development to become natural regulatory T cells (nTregs)
CD4+ and FOXP3+
541
When nTregs are released into circulation, what do they promote?
peripheral tolerance
542
Where to T cells undergo both positive and negative selection after rearranging their T-cell receptor loci?
thymus
543
Why do T cells undergo positive selection?
to ensure that they have a functional receptor
544
Why do T cells undergo negative selection?
to ensure that they are not self-reactive
545
What provides further means of tolerance?
the action of regulatory T cells
546
What can regulatory T cells inactivate?
self-reactive T cells in the periphery
547
How to T cells target pathogens for destruction?
directly or by activating other immune system components
548
What receptor do the majority of circulating T cells express?
αβ T-cell receptor
549
What can αβ T-cells do when activated?
differentiate into effector cells that activate a range of innate or adaptive immune responses
directly destroy an infected cell
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What may αβ T-cells be a target for?
infection and destruction by SARS-CoV-2, the virus responsible for COVID-19
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What receptor do a small subset of T cells in the body express?
γδ T-cell receptor
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Where do γδ T-cell receptors mainly reside?
within the gut mucosa as intraepithelial lymphocytes
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What do expressed γδ T-cell receptors behave like?
pattern recognition receptors of the innate immune system
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What is T-cell diversity driven in part by?
the number of V, D and J subunits present for all chains associated with the receptor
junctional diversity
random association of subunits
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What is junctional diversity?
adding or removing P and N nucleotides during recombination
