Exam 1 Flashcards
(597 cards)
1
Q
Which region on an antibody determines its class?
A
heavy chain constant region
2
Q
Clonal selection
A
when a B or T cell is activated, it proliferates and forms lots of “clones” to help fight off the antigen for which it is specific
3
Q
proliferation
A
When a B cell’s receptors bind to its cognate antigen, that B cell is triggered to double in size and divide into two daughter cells; both daughter cells then double in size and divide to produce a total of four cells, and so forth
4
Q
proliferation period
A
lasts about a week
5
Q
General characteristics of B cells
A
B cells use relatively few genes to create a huge diversity of antibodies
B cells are made on demand
Once selected, B cells proliferate rapidly to produce large #s of clones
Clones become antibody factories that can pump out large amounts of antibodies
When infection conquered, most B cells die
6
Q
antibody mechanism
A
tag invaders for destruction by other molecules (opsonization); can also form a bridge between invader and phagocyte
7
Q
neutralizing antibodies
A
can bind to a virus before it enters a cell and prevent it from either entering the cell or proliferating once it enters
8
Q
can antibodies get to a virus that has already entered a cell?
A
no – this is where killer T cells come in
9
Q
can you distinguish B and T cells under a microscope?
A
no
10
Q
where are B cells produced?
A
bone marrow
11
Q
where are T cells produced?
A
bone marrow
12
Q
where do B cells mature?
A
bone marrow
13
Q
where do T cells mature?
A
thymus
14
Q
B cell receptors
A
antibody-like molecules displayed on surface of B cell w/antigen-binding regions facing out; all BCRs on one B cell recognize the same antigen
15
Q
T cell receptors
A
antibody-like molecules displayed on surface of T cell
16
Q
what can B cell antibodies recognize?
A
any organic molecule
17
Q
what can T cell receptors recognize?
A
protein antigens (mostly inside cells)
18
Q
what is one major difference between B cell receptors and T cell receptors?
A
a B cell can export (secrete) its receptors in the form of antibodies, but a T cell’s receptors remain tightly glued to its surface
19
Q
how do B cells recognize antigens?
A
by themselves
20
Q
how do T cells recognize antigens?
A
must be presented by APCs
21
Q
4 types of T cells
A
cytotoxic
helper
regulatory
memory
22
Q
Killer T cells
A
destroy virus-infected cells – trigger apoptosis
23
Q
Helper T cells (Th)
A
cytokine factories that stimulate other immune cells (including B cells)
24
Q
Regulatory T cells
A
help keep the immune system from overreacting
25
MHC proteins
used by APCs to present antigens to T cells; also involved in compatibility of transplanted organs
26
Class I MHC function
function as “billboards” that inform killer T cells (CD8+) about what is going on *inside* the cells they are sitting on
27
Class II MHC function
expressed only by certain cells (APCs like macrophages); function as “billboards” that alert helper T cells (CD4) that something is going on *outside* the cell that needs attention (i.e. presents fragments of something the macrophage ate)
28
Class II MHC structure
two long chains (α and β); contains peptide binding region and invariant portion (β2) that binds CD4; open ends so can hold longer peptide
29
Class I MHC structure
one long chain (heavy chain) plus a short chain (β2-microglobulin); contains peptide binding region and invariant portion (α3) that binds CD8; closed ends so can only hold shorter peptides
30
Class I MHC protein holding
holds protein fragments that must be just the right size to fit (~9 AAs) b/c ends are closed (i.e. hotdog exactly the same length as bun)
31
Class II MHC protein holding
holds protein fragments that can be longer (~20 AAs) b/c the ends are open (i.e. hotdog longer than bun)
32
most important physiologic function of the immune system?
prevent infections and eradicate established infections
33
lymphocyte activation
requires 2 signals:
1. antigen recognition (on APC for T cells)
2. 2nd nonspecific signal (from costimulators, cytokines, or complement system)
34
why 2 signals required for lymphocyte activation?
helps prevent autoimmune responses
35
secondary/peripheral lymphoid organs
responsible for initiating adaptive immune response; organized in a manner that optimizes interactions btwn lymphocytes and antigens; includes lymph nodes, spleen, and mucosal and cutaneous lymphoid tissues
36
lymph node function in antigen recognition
“dating bars” – places where T cells, B cells, APCs, and antigens all gather for communication and activation; increases probability that all these molecules will interact to efficiently activate the adaptive immune system
37
memory cells
B and T cells that were activated in response to a particular antigen and that don't die off after infection is eradicated -- allow faster response to future infection by same microbe
38
innate immune system characteristics
fast
always ready
tuned to recognize common pathogens
39
adaptive immune system characteristics
slow
highly specific
highly diverse
40
innate immune system components
```
epithelial barriers
phagocytes
dendritic cells
complement
NK cells
```
41
adaptive immune system components
lymphocytes (B & T cells)
antibodies
effector T cells
42
TLRs
toll-like receptors; recognize endotoxins, viral RNA; activate inflammatory, antiviral genes, adaptive immunity (NF-kB, IRFs)
43
TLR1
surface; bacterial lipoproteins
44
TLR2
surface; bacterial lipoproteins
45
TLR3
endosome; viral NAs
46
TLR4
surface; bacterial LPS
47
TLR5
surface; bacterial flagellin
48
TLR6
surface; bacterial lipoproteins
49
TLR7
endosome; viral NAs
50
TLR8
endosome; viral NAs
51
TLR9
endosome; bacterial CpG DNA
52
NF-kB
stimulated by TLRs and NOD2; increases cytokines, adhesion, costimulators; mediates acute inflammation and adaptive immunity
53
IRFs
Interferon Regulatory Factors; stimulated by TLRs; increase Type I IFN (α/β) production; antiviral defense
54
Type I IFNs ( (α/β)
produced by macrophages (α), dendritic cells (α), fibroblasts (β); activated by TLRs; activate NK cells; antiviral functions
55
defensins
natural antibiotics; part of epithelial barrier
56
cathelicidings
natural antibiotics; part of epithelial barrier
57
γδ T cells
present in large #s at birth and help out until αβ T cells produced; hybrid B-T cell (TCR looks more like antibody); more flexible and recognize more presentation molecules than MHC; target microbial lipids; part of epithelial barrier
58
eosinophils
granulocytes that produce histamine and proteolytic enzymes
59
mast cells
granulocytes that mediate allergic rxns, parasite defense; activated by TLRs or antibody-dependent mechanisms
60
TLR downstream signaling mutations
can lead to bacterial pneumonia
61
NLRP3
NLR that activates inflammasome → IL-1β → inflammation/fever
62
NOD2
NLR that activates NF-kB (NOT inflammasome)
63
NLR-related diseases
autoinflammatory diseases; gout; atherosclerosis; obesity-associated type II diabetes
64
neutrophils
most abundant leukocyte; dominate during inflammation; short half-life (6-8hrs); also called PMNs; ingest & destroy microbes
65
monocytes
differentiate into macrophages when enter extravascular tissue
66
macrophages
resident in all body tissues; longer half-life; initiate & regulate inflammation & adaptive immunity; ingest & destroy microbes; clear dead tissue; initiate tissue repair
67
M1 macrophage
Classically Activated; stimulated by IFN-γ and TLRs; induces microbicidal activity and inflammation
68
M2 macrophage
Alternatively Activated; stimulated by IL-3 and IL-4; induces anti-inflammatory and wound repair functions
69
IFN-γ
produced by NK cells, T-cells; activates M1 macrophages; promotes inflammation
70
Produced by M1 macrophage to stimulate inflammation
IL-1
IL-12
IL-23
chemokines
71
Produced by M1 macrophage to stimulate microbicidal actions
ROS
NO
lysosomal enzymes
72
Produced by M2 macrophage to stimulate anti-inflammatory effects
IL-10
| TGF-β
73
Produced by M2 macrophage to stimulate wound repair
TGF-β
| proline pyramidines
74
NK Cells
```
recognize & kill infected cells
secrete IFN-γ to stimulate M1 macrophages
contain cytoplasmic granules
do NOT express Ig's
express unique surface proteins
have activating and inhibitory receptors
```
75
NK Cell activating receptors
NKG2D (ligand: Class I MHC-like proteins)
| CD16 (ligand: IgG)
76
NK Cell inhibitory receptors
Killer Cell Immunoglobulin-like Receptors (KIRs)
Receptors w/Protein CD94 + Lectin Subunit NKG2
(ligand for all: Self Class I MHC)
77
Macrophage-NK Cell interactions
Macrophages secrete cytokines that activate NK cells (IL-12, IL-15, Type I IFNs); some NK actions then improve macrophage effectiveness (IFN-γ release)
78
Factors that promote inflammation
```
C3a
C5a
Chemokines
Inflammasome
IFN-γ
IL-1(β)
IL-12
IL-23
NF-kB
NLRP3
TLRs
```
79
Anti-inflammatory factors
```
IL-3
IL-4
IL-10
TGF-β
Proline polyamines
```
80
Signal Phagocytosis
```
C3b
CRPs
IgG
Mannose-binding Lectin
Class I MHC-like proteins
```
81
C3a
complement protein that signals inflammation
82
C5a
complement protein that signals inflammation
83
C3b
complement protein that opsonizes
84
NK T-cells
located in epithelia & lymphoid organs; recognize CD1-bound microbial lipids
85
B-1 Cells
located in peritoneal cavity & mucosa; produce IgM; recognize bacterial cell wall carbs; produce antibodies against non-host blood types
86
Produce antibodies against non-host blood types
B-1 cells
87
marginal zone B-cells
located in edges of lymph follicles in spleen & elsewhere; recognize blood-borne polysaccharide-rich microbes
88
C-Reactive Protein (CRP)
binds microbial phosphorylcholine; targets for phagocytosis; marker for chronic inflammation in adults and acute inflammation in peds
89
TNF
secreted by macrophages & T cells; stimulates inflammation (neutrophil/monocyte recruitment); increased concentration can lead to septic shock
90
IL-1
secreted by macrophages, endothelial cells, some epithelial cells; stimulates inflammation (neutrophil/monocyte recruitment)
91
chemokines
secreted by macrophages, dendritic cells, endothelial cells, T-cells, fibroblasts, platelets; stimulate inflammation
92
IL-12
secreted by macrophages, dendritic cells; activates NK cells; stimulates CD4+ differentiation into Th1
93
Steps of inflammatory response
1. recruitment and leakage of cells & plasma proteins into extravascular tissue
2. phagocytosis of microbes
3. destruction of harmful substances
94
inflammation defends against
extracellular bacteria & fungi; intracellular bacteria
95
innate immunity primary functions
inflammation; antiviral activity
96
Inflammation - extracellular stimulus
recruit neutrophils, monocytes, complement; E & P selectins mediate initial weak adhesion; integrin activation allows firm adhesion; chemokines & chemoattractants allow transmigration into tissue
97
Inflammation - intracellular stimulus
recruit macrophages through cytokines, TLRs, other receptors
98
Leukocyte Adhesion Deficiency (LAD)
inherited; problems with selectin and integrin prevent recruitment of leukocytes
99
5 pillars of inflammation
heat, redness, swelling, pain, loss of function
100
phagocytosis pathway
ingest microbe → phagosome fuses w/lysosome → enzyme activation
101
phagocytic enzymes
Phagocyte Oxidase
Inducible Nitric Oxide Synthase (iNOS)
Lysosomal Proteases
102
Phagocyte Oxidase
phagocytic enzyme; converts O2 → ROS (toxic)
103
iNOS
phagocytic enzyme; converts Arg → NO (microbicidal)
104
Lysosomal Proteases
phagocytic enzyme; degrade proteins
105
Chronic Granulomatous Disease (CGD)
deficiency in phagocyte oxidase → can't destroy intracellular microbes → recruit more macrophages/lymphocytes → granulomas form
106
Neutrophil Extracellular Traps (NETs)
neutrophils commit suicide → extrude nuclear contents → histone networks trap microbes
*granular contents (ROS/NO) also released → can damage tissue
107
Innate Immunity Regulatory Mechanisms
IL-10
Il-1 Antagonists
Feedback Mechanisms
108
IL-10
anti-inflammatory cytokine produced by macrophages & dendritic cells; inhibits M1 activation; induces CD4 T-cells to become Regulatory T-cells (FoxP3+), which then inhibit T-cell responses
109
IL-1 Antagonists
block IL-1 → block inflammation
110
innate feedback mechanisms
inhibit cytokine signaling
111
innate stimulation of adaptive immunity
2 signals: one from microbe; second from molecule produced by innate system (costimulant, cytokine, complement) in response to microbes
112
IL-1, IL-6, IL-12
stimulate immature T-cells → effectors
113
C3d
made from C3b; B-cells bind microbe + C3d → differentiate into antibody-secreting cells
114
innate immunity
fast, always present, less specific, first responder
115
adaptive immunity
```
slow
huge diversity/specificity
can evolve
memory
clonal expansion
nonreactivity to self
```
116
humoral immunity
mediated by antibodies; extracellular; blocks infections and eliminates extracellular microbes
117
cell-mediated immunity
mediated by T cells; intracellular
118
APCs
present antigens to T-cells
| include dendritic cells, macrophages, B-cells
119
mucosal linings
constant interactions btwn innate & adaptive systems; lymphocytes in epithelium, lamina propria, MALT
120
Peyer's Patches
type of MALT/GALT; located in lamina propria; contain follicles for B-cell maturation and areas for T cells to be exposed to antigens
121
what happens if an antigen is encountered at one mucosal site?
you gain immunity at all other mucosal sites!
122
where do villi and Peyer's Patches drain?
lymphatic networks → mesenteric nodes
123
goblet cells
secrete mucin glycoproteins that increase thickness of mucosal layer → protective barrier that reduces bacterial adhesion to epithelium
124
Paneth (Crypt) Cells
sense microbes using TLRs 2, 4, 5, and 9 → secrete antimicrobial proteins & immunosuppressants into intestinal lumen that reduce bacterial adhesion to epithelium and prevent inflammatory response; regulated by NK T cells
125
M cells
primary fcn: antigen uptake; located above Peyer's Patches; have folded luminal surface and NO glycocalyx, which provides route for antigens to access lymph follicle underneath
126
which cells can pathogens use to access circulation?
M cells
127
commensal organisms
bacteria in gut that have symbiotic relationship with body; play a role in regulating intestinal epithelial cell function; provide various protections; 10x more of these than any other cell in body
128
benefits of commensal bacteria
occupy space to prevent pathogenic bacterial colonization
synthesize vit B12 and K
aid in calorie extraction
regulate composition of antimicrobial peptides secreted by Paneth cells
129
how is elimination of good bacteria from intestines prevented?
1. intestinal epithelial cells (IECs) express low levels of TLR4/MD2 → suppressed response to LPS (bacterial endotoxin)
2. IECs express low levels of TLR2 → normally responds to mRNA & proteins
3. IECs express high amt of TOLLIP inhibitory protein → poor response to Gram (+) and mycobacterial ligands.
4. commensals dampen inflammatory response (inhibit NF-kB)
5. polarized IECs allow differential responses
130
IEC recognition of bacteria
1. TLR & NOD1/NOD2 activation → cytokine/chemokine release
2 . Recruitment of neutrophils, macrophages, DCs
3. Commensal intervention → PPARγ activated, IkB degradation prevented
131
M cell - dendritic cell interaction
IECs secrete CCL9 & CCL20 to recruit DCs (CCR6/CCR1+) → DCs process antigens from M cells → DCs present antigens to T cells in Peyer's Patches and mesenteric lymph nodes
132
CCL9
secreted by IECs to recruit DCs to intestine
133
CCL20
secreted by IECs to recruit DCs to intestine
134
IEC activity in presence of commensal bacteria
produce TGF-β and prostaglandins (PGE2)→ maintain anti-inflammatory state w/i DCs → DCs travel to lymph nodes, secrete IL-10 and Retinoic Acid, which inhibit inflammatory response (activate reg T-cells)
135
what happens if pathogenic bacteria make it through the mucosal epithelium?
activated DC travels to mesenteric lymph node and stimulates CD4 T-cells → differentiate into Th1, Th2 and Th17
136
how could DCs "sample" intestinal contents w/o destroying barrier?
1. nonspecific transport across epithelium
2. FcRn-dependent transport
3. apoptosis-dependent transport
4. antigen capture (reach across lumen)
137
Salmonella infection
enters & kills M cell → infects neighboring epithelial cells & macrophages → macrophages secrete chemokines/cytokines to attract neutrophils & DCs → if this fails to destroy it, salmonella enters bloodstream and infection becomes systemic
138
lymphocyte locations in villi
1. epithelium - CD8
2. lamina propria - CD4
* important b/c allows body to respond immediately to any penetration of mucosa
139
integrin
cell-cell adhesion
140
CCR9
chemokine receptor used to attract lymphocytes from the bloodstream to the intestine
141
T-cell affinity for area
T-cell can express different receptors and adhesion molecules to increase the likelihood that it is in an area at any given time
142
L-selectin
expressed by naive T-cells; directs them to undergo extravasation from HEVs to Peyer’s Patches, where DCs present antigens to them
143
CCR7 in mucosa
expressed by naive T-cells; directs them to undergo extravasation from HEVs to Peyer’s Patches, where DCs present antigens to them
144
Priming
DCs present antigens to naive T-cells in T-cell regions of Peyer's Patches → T-cells activate, stop expressing L-selectin and begin expressing
145
unprimed (naive) T-cell expression
L-selectin, CCR7
146
regional dendritic cells
imprint homing on lymphocytes
147
IgA
associated w/mucosa; produced locally by plasma cells in lamina propria; about 5g secreted per day (more than all other Ig classes combined); Poor at C’ activation; Poor at opsonization
148
IgA1
monomer found mainly in blood; binds peptides
149
IgA2
dimer linked by J-chain; binds LPS and carbs
150
IgA binding
1. binds plgR on basal epithelial membrane → endocytosis/secretion into gut lumen
2. binds pathogenic & commensal bacteria in gut lumen to prevent adherence to epithelium
* does NOT activate classical complement pathway
* does NOT act as opsonin (no induction of inflammation)
151
Selective IgA Deficiency (SlgAD)
occurs in 1:50 celiac disease patients; IgM compensates
152
Intraepithelial Lymphocytes (IELs)
found in mucosa
153
IEL activation
stress activates via MIC-A/B and IL-15
154
TGF-β
anti-inflammatory cytokine; secreted by M2 macrophages and IECs
155
PGE2
anti-inflammatory cytokine (prostaglandin); secreted by IECs
156
regulation of tolerance and immunity in mucosa
GALT DCs
157
mesenteric lymph nodes
commensal-loaded DCs do not penetrate beyond here → prevents unwanted inflammatory response- oral tolerance induced exclusively here
158
oral tolerance
induced exclusively in mesenteric lymph nodes; mice fed ovalbumin had a lower systemic immune response when exposed to it again later
159
CDR diversity in B cells dramatically increased by?
somatic hypermutation
160
Ig function depends on...
C segments, TCR/MHC contact (cell-to-cell)
161
what dictates isotype switch?
cytokine environment
162
immunity
resistance to disease
163
immune response
the coordinated reaction of immune system cells and molecules to microbes
164
functions of immune system
defense against wide variety of pathogens
waste management
wound healing
tumor defense
inflammatory diseases (allergies, autoimmune disorders)
165
what can impair immune function (particularly for med students?)
stress & lack of sleep
166
3 components of immune system
epithelial barrier
innate system
adaptive system
167
immunological triad
interactions btwn epithelial barriers, innate system, and adaptive system
168
epithelial barriers
first line of defense; block microbe entry; produce natural antibiotics; contain intraepithelial lymphocytes
169
innate immunity
defense mechanism that is always present in all organisms, ready & primed to eliminate microbes and dead cells immediately upon infection; usually responds the same way to each repeat encounter with a microbe; enhances adaptive immune response
170
adaptive immunity
the defense mechanism that requires expansion and differentiation of lymphocytes in response to microbes before it can provide effective defense
171
lymphocytes
B & T cells; originate from a common precursor in bone marrow; naïve lymphocytes will differentiate into effector cells and memory cells
172
B lymphocytes
can differentiate into plasma cells, which secrete antibodies
173
T lymphocytes
an differentiate into helper T cells, cytotoxic T cells, memory T cells, and regulatory T cells
174
phases of adaptive immune response
challenge, recognition, response, and outcome
175
what most effectively eliminates free extracellular antigens?
B lymphocytes
176
what most effectively eliminates phagocytosed extracellular antigens?
helper T lymphocytes
177
what most effectively eliminates intracellular microbes?
cytotoxic T lymphocytes
178
generative/central lymphoid organs
where T and B lymphocytes are produced and mature; bone marrow & thymus
179
B cell zone in lymph node
follicles within the cortex
180
T cell zone in lymph node
paracortex
181
CXCR5
directs B cell attraction to follicles in lymph node cortex by binding chemokines there
182
CCR7 in lymph node
directs T cell attraction to paracortex in lymph nodes by binding chemoattractants there
183
Dendritic cells
activated by phagocytosis of microbes; respond by producing cytokines that initiate inflammation and stimulate adaptive immunity; also can travel to lymph node, where interact w/other cells of adaptive immune system, causing them to differentiate into effectors
184
how are lymphocytes distinguishable?
by surface proteins (CD #) that can be ID'd using a panel of monoclonal antibodies
185
CD nomenclature
Cluster Differentiation numerical designation; assigned to surface proteins that can be used to differentiate lymphocytes
186
CD3
surface protein expressed by ALL T lymphocytes
187
CD4
surface protein expressed by helper T lymphocytes
188
CD8
surface protein expressed by cytotoxic T lymphocytes
189
Cytokines
a class of small molecules that promote cell signaling and cell communication; include chemokines, interleukins, tumor necrosis factor, interferons, and other molecules
190
Interleukins
molecules that induce growth and differentiation; named using the designation IL followed by a number (IL-#)
191
Chemokines
small molecules that function as chemoattractants -- guide migration of other cells; nomenclature is CC or CXC followed by L or R and then # ex: CCL25 or CXCR5.
(L=ligand; R=receptor)
192
2 ways the innate system recognizes common structures on foreigners and damaged cells via receptors
PAMPs and DAMPs
193
PAMP
Pathogen-Associated Molecular Pattern; innate system uses these to recognize structures shared by different microbes (lipopolysaccharides, mannose residues); encoded in germline
194
DAMP
Damage-Associated Molecular Patterns; innate system uses these to recognize molecules released from damaged or necrotic cells; encoded in germline
195
where/how are innate system receptors encoded?
germline
196
where/how are antibodies encoded?
somatic gene recombination
197
4 families of innate receptors
TLRs
NLRs
CLRs
RLRs
198
NLRs
NOD-like receptors; cytosolic receptors that respond to various stimuli (Bacterial products, Crystals, K+ efflux & ROS); form inflammasome → IL-1β → inflammation/fever
199
CLRs
C-Type Lectin Receptors; extracellular
200
RLRs
RIG-like receptors; cytosolic
201
5 types of cells that express innate system receptors
```
Phagocytes
Dendritic Cells
Lymphocytes
Epithelial cells
Endothelial cells
```
202
TLR recognition
Surface: extracellular microbes - bacteria - lipopeptides, LPS, flagellin
Endosomal: ingested microbes - viruses - DNA sequences
203
TLRs that recognize bacterial lipopeptides
TLR1
TLR2
TLR6
204
TLRs that recognize bacterial LPS
TLR4
205
TLRs that recognize bacterial flagellin
TLR5
206
TLRs that recognize viral RNA
TLR3
TLR7
TLR8
207
TLRs that recognize bacterial CpG DNA
TLR9
208
Transcription factors that can be activated by TLRs
NF-kB --> cytokine, adhesion, costimulator molecule expression
IRFs --> Type I IFN production
209
2 mechanisms for epithelial barrier protection
natural antibiotics
| intraepithelial lymphocytes
210
natural antibiotics produced by epithelial barriers
defensins and cathelicidings
211
intraepithelial lymphocytes
γδ T cells
212
most abundant leukocyte in blood?
neutrophils
213
GM-CSF
granulocyte/macrophage colony stimulating factor; stimulates neutrophil production in bone marrow
214
KIRs
receptors that recognize inhibitory signals (Self Class I MHC) for NK cells
215
Self Class I MHC
inhibitory ligand for NK cells
216
NKG2D
receptor that recognizes activating signals (Class I MHC-like proteins) for NK cells
217
CD16
receptor that recognizes activating signals (IgG) for NK cells
218
if a cell expresses Self MHC I complex, will NK cells be activated?
No. This is an inhibitory signal for NK cells.
219
what two things are required for NK cell activation?
lack of inhibitory signal (Self Class I MHC)
| presence of activating ligand
220
what does an NK cell do when activated?
empties contents of cytoplasmic granules extracellulary; granules enter cell and activate apoptotic proteins
221
IL-15
stimulates NK cell development & maturation
222
complement system
group of serum proteins that acts as an enzymatic cascade
223
3 main complement system functions
1. opsonize microbes w/C3b and CR1
2. recruit neutrophils for inflammation w/C3a and C5a
3. lyse microbes via MACs
224
MACs
membrane attack complexes; made up of complement proteins that lyse microbes
225
Lymphocytes w/somatically rearranged antigen receptors
γδ T cells
NK T cells
B-1 cells
Marginal zone B cells
226
antiviral defense
mediated by Type I IFNs and NK cells
227
what can serve as signal 2 for adaptive system activation?
1. costimulator (from dendritic cells): binds & activates T cells
2. cytokines IL-1, IL-6, IL 12 (from dendritic cells, macrophages): T cell differentiates into effector
3. complement protein C3d: B cell differentiates into antibody-secreting cells
228
alpha4:beta7
integrin on CD4 T cells that binds to MadCam in the lamina propria; secretes CCR9, which binds to CCL25
229
alphaE:beta7
integrin on CD8 T cells that binds to E-Cadherin on enterocytes; secretes CCR9, which binds to CCL25
230
unprimed T cells
express L-selectin and CCR7
231
primed T cells
express
232
what causes heat and redness in inflammation?
leaky vessels
233
intestinal epithelial cells express low levels of what to suppress immune response and keep commensal bacteria?
TLR2 and TLR4
234
what regulates paneth cells?
NK T cells
235
3 types of APCs
dendritic cells
macrophages
B cells
236
cell-mediated immunity - CD4
phagocytosed microbes activate and bind CD4 T cell, which works to eliminate the microbes
237
cell-mediated immunity - CD8
intracellular microbes (viruses) activate CD8 T cell, which binds and destroys infected cell
238
What are the origins of the antigens that are presented by MHC Class I molecules?
cytosol
239
most effective APC?
dendritic cells
240
what happens after recognition of antigen-peptide by APC?
antigen must be processed to a peptide and presented to receptors on lymphocytes that detect that specific antigen-peptide
241
2 things a dendritic cell can do
1. present antigens to naive T cells
| 2. express costimulators to fully activate T cells
242
2 types of dendritic cells
Conventional DCs
| Plasmacytoid DCs
243
Conventional DCs
induce T cell responses against most pathogens
244
Plasmacytoid DCs
antiviral innate immunity and induce T cell responses against viruses
245
site of antigen presentation to T cells?
lymph node and spleen
246
APC migration to lymph nodes once activated stimulated by
CCR7 expression in lymph tissues
247
APC maturation
occurs once the APCs reach the T-cell rich regions of the lymph node (or spleen).
248
TCRs
T cell receptors; recognize specific antigen-peptide presented by APC with MHC; this interaction directs the immune response
249
what interaction directs the immune response to a pathogen presented by APC?
MHC-TCR interaction
250
MHC-TCR interface
regions on the antigen-peptide bind to each molecule here: peptide anchor residue binds to MHC; T cell contact residue of peptide causes specificity of antigen and binds TCR
251
Cross Presentation
the presentation of extracellular antigens using the intracellular pathway
252
human leukocyte antigen (HLA) genes
code for MHCs; locus and subunits determine differences btwn Class I and Class II
253
Co-dominant expression of MHC molecules
both parental alleles of each MHC genes are expressed; allows for diversity among MHC molecules in an individual
254
Polymorphic genes of MHC molecules
provide diversity of MHC genes among the population
255
importance of many cell types expressing MHCs?
helping ensure a body-wide immune response.
256
MHC restriction
T lymphocyte clones can ONLY recognize peptides when they are displayed on the MHC molecules
257
Class I MHC Pathway
1. internal antigen (i.e. virus) ubiquitinated & degraded to peptide
2. peptide transported into ER by TAP and cleaved further
3. newly synthesized MHC I attached to TAP by tapasin
4. MHC I binds peptide and β2m
5. MHC I--peptide complex transported to cell surface for presentation to CD8+ T cells
258
TAP
transporter associated with antigen processing protein; transports intracellular antigens into ER and cleaves them in MHC I pathway
259
tapasin
attaches newly synthesized MHC I to TAP
260
Class II MHC Pathway
1. extracellular antigen ingested into endocytic vesicular compartments of cell
2. peptide processed in endosomal/lysosomal vesicles
3. MHC II synthesized and transported to endosome containing peptide
3a. MHC II binding site occupied by CLIP during synthesis for stabilization
3b. CLIP removed in endosome, facilitated by HLA-DM
4. HLA-DM helps load peptide into MHC II binding site
5. MHC II--peptide complex transported to cell surface for presentation to CD4+ T cells
261
CLIP
class II invariant chain peptide; occupies MHC II binding site during MHC II synthesis to stabilize the molecule
262
HLA-DM
removes CLIP from MHC II binding site in endosome and helps load peptide in
263
Differences btwn MHC I and MHC II pathways
MHC I: intracellular; ER; TAP and tapasin
| MHC II: extracellular; endosome; CLIP and HLA-DM
264
Cross-Presentation Pathway
1. dendritic cell recognizes virus-infected cell
2. APC ingests and processes infected CELL (not just antigen)
3. APC presents peptides to CD8+ T cell using MHC I molecules
265
genes that code for Class I MHC
HLA-A, HLA-B, HLA-C
266
genes that code for Class II MHC
HLA-DR, HLA-DP, HLA-DQ
267
how many peptides can MHC present at once?
MHC can bind many different peptides, but it is limited to presenting only ONE peptide at a given time
268
what property of MHCs ensures body-wide immune response?
many different cells can express MHCs
269
what property of MHCs ensures diversity within a population?
polymorphic genes - many alleles exist in the population
270
what property of MHCs ensures diversity within an individual?
co-dominant expression - both parental alleles expressed
271
how does peptide binding to MHC increase the chances for an immune response?
1. many different peptides can bind to an MHC
2. each T cell responds to a single MHC-peptide complex
3. MHC-restricted T cells respond only to protein antigens
4. Class I & II MHC display antigens from different cell compartments
5. stable surface expression of MHC requires bound peptide
6. MHC displays bound peptide long enough for T cell to recognize
272
which cells express Class I MHC?
all nucleated cells
273
which cells express Class II MHC?
```
APCs!
dendritic cells
mononuclear phagocytes
B cells
endothelial cells
thymic epithelium
```
274
β2m
β2 microglobulin; helps stabilize MHC I--peptide complex
275
segregation of antigen-processing pathways
ensures that different classes of T lymphocytes recognize antigens from different compartments
276
what accounts for the immunodominance of some peptides derived from complex protein antigens?
structural constraints on peptide binding to different MHC molecules
277
immunodominant peptides of antigen
When any protein is proteolytically degraded in APCs, many peptides may be generated, but only those able to bind to the MHC molecules can be presented for recognition by T cells -- these are the immunodominant peptides
278
what accounts for the inability of some individuals to respond to certain protein antigens?
some individuals may not express MHC molecules capable of binding any peptide derived from a particular antigen; these individuals would be nonresponders to that antigen
279
Bare Lymphocyte Syndrome
MHC molecules may not form stably due to mutations in Ii or TAP
280
how do B cells recognize native antigens?
using antibodies
281
what types of antigens do antibodies recognize?
specific peptides, polysaccharides, lipids and other small chemicals.
282
how are antigens presented to B cells?
Follicular Dendritic Cells or complement system
283
which TCR chains participate in specific recognition of MHC molecules and bound peptides?
Both the α chain and the β chain of the TCR participate in specific recognition of MHC molecules and bound peptides
284
What types of epitopes does TCR hold?
linear
285
which part of the TCR mediates antigen recognition?
variable (V) regions of the α and β chains
286
what mediates the signaling function of the TCR?
proteins in a complex associated with the TCR found in the cell membrane: CD3 and ζ
287
general pathway of TCR response to antigen
The TCR simply recognizes that an antigen is present and, through a signaling cascade, T cell response to the infection is mediated through other proteins.
288
TCR structure
has α chain and β chain w/2 domains on each chain: constant (C) region and variable (V; antigen-binding) region
also has CD3 complex and ζ chain needed for signal transduction
289
variable/antigen-binding region of TCR
α chain and β chain each contain 3 CDRs (complementarity determining regions); V regions constructed from unique splicing of several genetic elements to make large diversity of TCRs
290
constant region of TCR
does not change between TCRs; involved in anchoring the receptor to the membrane.
291
dual specificity
TCR must bind both the MHC and peptide in order to get a stable interaction between the T cell and the APC
292
does the affinity of antigen binding for the TCR change during times of immune response as opposed to times of rest?
no
293
what are the on and off rates for TCRs?
slow -- meaning the TCR slowly binds to antigens displayed on MHCs and slowly dissociates
294
General phases of B/T cell maturation and selection
```
commitment
proliferation
Pre-B/T antigen receptor expression
more proliferation
antigen receptor expression
positive and negative selection
```
295
C3bBb
C3 convertase enzyme generated in the alternative complement pathway and is responsible for splitting off the small peptide C3a, leaving C3b as a residue
296
interferons
Induce enzyme synthesis in the target cell (protein kinase and endonuclease)
297
Anaphylatoxins
fragments (C3a, C4a and C5a) produced as part of the activation of the complement system
298
Acute inflammation can be initiated by?
Activation of mast cells, which release chemotactic factors for neutrophils and also vasoactive mediators such as histamine
299
Tolerance
Immunological unresponsiveness to self antigens
300
the basic Ig unit is composed of...
2 identical heavy and 2 identical light chains
301
Fab fragment
fragment antigen binding -- binds antigen
302
The first immunoglobulin heavy chain class to be expressed on the surface of a newly produced B-cell
IgM, shortly followed by IgD
303
where are T cell progenitors produced?
bone marrow
304
where do T cell progenitors go from bone marrow?
enter thymus through HEVs, migrate to subcapsular region
305
what happens when T cell progenitors reach the subcapsular region of the thymus?
begin maturation by rearranging their receptor genes to generate a unique TCR through VDJ joining
306
what happens as T cell progenitors begin to express specific receptors?
they migrate further into the cortex
307
what happens if the pro-B/T cell fails to express pre-antigen receptor?
death
308
what happens if the pre-T cell fails to express 1 chain of antigen receptor?
death
309
General progression of B/T cell development and maturation
common lymphoid progenitor -->
Pro-B/T cells that express pre-antigen receptor (failure to express = death) -->
Pre-B/T cells that express 1 chain of antigen receptor (failure to express = death) -->
Immature B/T cells that express complete antigen receptor -->
--strong antigen recognition --> negative selection
--weak antigen recognition --> positive selection --> mature B/T cells
310
what happens if an immature B/T cell displays strong antigen recognition?
negative selection and death
311
what happens if an immature B/T cell displays weak antigen recognition?
positive selection and transformation into mature B/T cell
312
what receptor(s) does/do an immature T cell express?
CD4, CD8, unique αβ TCR
313
what happens after pre-T cells express 1 chain of antigen receptor?
pass through thymic epithelial cells that have lots of MHC I & II molecules on surface; T cells that can weakly bind MHC I gets survival signal + maturation signal that causes loss of CD4; T cells that can weakly bind MHC II get survival signal + maturation signal that causes loss of CD8 (positive selection!)
314
positive selection
thymocytes receive a "survival signal" to keep on living if they can appropriately bind MHC I or II
315
what happens to thymocytes that don't recognize MHC I or II?
no survival signal --> death
| *a large percentage are lost at this stage!
316
what happens to thymocytes that recognize MHC I or II too strongly?
death
317
at what stages of development/maturation can T cells undergo apoptosis?
Pro-T cells in thymus don't express complete β chain / pre-TCR complex
Pre-T cells in thymus don't express complete α chain / complete TCR
Immature T cells in thymic cortex express strong antigen recognition
Thymocytes in thymic epithelial cells don't recognize MHC I or II
Thymocytes in thymic epithelial cells recognize MHC I or II too strongly
Thymocytes near medulla bind too strongly to body antigens
318
negative selection
thymocytes that don't recognize MHC I or II or recognize MHC I or II too strongly die
319
central tolerance
through negative selection, T cells learn not to attack self
320
what happens after thymocytes recognize MHC I or II and begins to express exclusively CD4 or CD8?
continue moving toward thymic medulla, and medullary interdigitating cells present thymocytes with other antigens that belong to body
321
what is the progression of T cell types through maturation?
1. double-negative (CD4-, CD8-) pro-T cell that expresses complete β chain / pre-TCR complex
2. pre-T cell that expresses complete α chain / pre-TCR
3. double-positive (CD4+, CD8+) immature-T cell that expresses complete αβ TCR
4. mature single-positive (CD4+ or CD8+) cell OR death
322
what happens to a T cell near the medulla that reacts too strongly to body antigen?
death
323
what percentage of the original thymocytes survive the maturation process?
1-4%
324
what happens to mature CD4+ and CD8+ T cells?
leave the thymus through bloodstream or lymphatics; travel to secondary lymphatic organs; wait there until stimulated by antigen (APCs)
325
what type of peptides are used for T cell positive and negative selection and why?
self-peptides
T cells need to be able to bind antigens well enough, but not so well that they will bind body cells and cause an autoimmune reaction
326
how many times does negative selection take place?
twice:
MHC I or II recognition in thymic epithelial cells
T cell exposure to body antigens in thymic medulla
327
interdigitating cells
bone marrow-derived cells, including medullary epithelial cells, dendritic cells, and
macrophages, that bring body antigens to developing T cells in the thymic medulla
328
what happens to the peptides from the T cells that die during maturation?
used by cortical epithelial cells or interdigitating cells in the medulla to further educate surviving T cells
329
why do T cells proliferate at various stages of maturation?
increases the chances that one of the copies will survive
330
which type of selection (pos/neg) is stronger?
positive - must be stronger otherwise would end up with no T cells
331
can T cells move backward in the development process?
No. After a T cell has progressed through a given stage, the enzyme that was required for that step is shut off, and it can only move in the direction the next enzyme wants it to go. (signaling dependent on APCs)
332
Allelic exclusion
only one version of a T cell is kept after each stage of maturation (b/c enzymes are shut off after each step)
333
one reason for sibling transplant incompatibility?
allelic exclusion
334
what happens if you have no thymus?
can't produce T cells
335
what happens if you have a defect in an enzyme necessary for producing lymphocytes in circulation?
can't produce T cells
336
what happens if you transplant a thymus into an animal without a thymus, but with a normal ability to produce lymphocytes into circulation?
can produce T cells!
337
what happens if you transplant bone marrow stem cells into an animal without lymphocytes but with a normal thymus?
can produce T cells!
338
what happens when the thymus degenerates in adulthood?
we retain T cell function b/c those suckers live for a long time once they've made it through the gauntlet!
339
alloreactivity
your T cells will respond to someone else’s T cells if they have a different set of MHC and TCRs than you -- important for transplants
340
VDJ Joining
method of alternative splicing that creates diversity in TCRs/BCRs; cell randomly selects one piece from V, D, and J regions and combines them to form unique TCR; imperfections in this process add to diversity
341
combinatorial diversity
VDJ joining
342
junctional diversity
2 ways:
1. imprecise cutting of segments at D and J regions
2. TdT enzyme randomly adds in additional nucleotides
343
4 ways diversity is generated in TCR
1. baseline variability in V segments
2. combinatorial diversity (VDJ joining)
3. junctional diversity (imprecise cutting, TdT additions)
4. secondary combinatorial diversity (random assortment of heavy/light chains)
344
secondary combinatorial diversity
random assortment of heavy/light chains in TCR assembly
345
which method of generating TCR diversity leads to permanent changes?
VDJ joining - this is DNA splicing so diversity generated here becomes a permanent part of that clone
346
Erk
protein involved in γδ T cell development
- -strong Erk --> γδ TCR
- -weak Erk --> αβ TCR
347
what directs the development of secondary lymphoid tissues?
the TNF family -- trimeric cytokine molecules that are very stable and can be manipulated by small alterations in specific regions
348
in what gene region is the TNF family located?
in the middle of the MHC gene region (so if you alter the MHC, you also alter the TNF)
349
what is the result of the large variation within the TNF family?
TNF family members can cross-react with each other
350
how does immunodeficiency relate to vaccination?
people with these conditions cannot be given normal vaccines -- they will die
351
what stimulates pro-T cell (double negative) proliferation?
IL-7 from thymus
352
what must happen for a pro-T cell to become a pre-T cell?
a complete TCR β chain must be produced and expressed on the surface in association with invariant protein pre-Tα to form the pre-TCR complex
353
pre-TCR complex
a complete TCR β chain + invariant protein pre-Tα expressed on surface of developing T cell; allows pro-T cell to become pre-T cell
354
Different clones of double-positive T cells express what?
different αβ TCRs
355
cytotoxic T cells
```
express CD8
respond to MHC I
respond to cytosolic antigens
cell-mediated immunity
secrete cytotoxins that induce apoptosis in infected cells
```
356
helper T cells
```
express CD4
respond to MHC II
respond to endosomal antigens
cell-mediated immunity
secrete cytokines that induce activation of specific immune responses
```
357
αβ T cells
pretty much all T cells!
358
CDRs (T cells)
complementarity-determining regions; hypervariable; produced by VDJ recombination; located on α and β chains; bind antigen and MHC to provide signal 1 for T cell activation
359
B7 proteins
expressed on APCs; upregulated by microbes; binds to CD28 on T cell to provide signal 2 for T cell activation (costimulators)
360
General steps of initial T cell activation
1. T cell αβ TCR binds APC MHC/antigen peptide (signal 1)
1a. T cell CD4/CD8 binds APC MHC I/II (right class)
2. T cell CD28 binds APC B7 (signal 2)
3. T cell LFA-1 binds APC ICAM-1 for adhesion
4. T cell CD3 proteins (γ, δ, ε) and zeta chain (ζ) mediate intracellular signaling and allow ZAP70 docking
4a. T cell CD45 mediates intracellular signaling and phosphatase
5. T cell CTLA-4 can bind B7 to INHIBIT immune response
361
CD28
expressed on T cells; binds to B7 on APCs to provide signal 2 for T cell activation
362
CD3
T cell proteins (γ, δ, ε) that contain cytosolic domains that can be phosphorylated and mediate intracellular signaling by serving as docking stations (ZAP70)
363
ζ chains
T cell proteins that contain cytosolic domains that can be phosphorylated and mediate intracellular signaling by serving as docking stations (ZAP70)
364
T cell proteins that mediate intracellular signaling by serving as docking stations
CD3
| ζ chains
365
CD45
T cell protein that mediates intracellular signaling and phosphatase
366
CTLA-4
T cell protein that can bind B7 to INHIBIT immune response; role in autoimmunity
367
LFA-1
T cell integrin that binds ICAM-1 on APC to ensure the two stick together; affinity increased when T cell activated
368
ICAM-1
APC ligand that binds LFA-1 on T cell to ensure the two stick together
369
how are all of the molecules involved in T cell activation co-localized within the membranes of the T cell and APC?
lipid rafts allow them to stay close together -- optimizes T cell ability to respond quickly and effectively
370
general sequence of T cell response to antigen
1. T cells activated by APC/antigen in lymph node
2. T cells expand and differentiate
3. differentiated T cells enter circulation
4. effector T cells & other leukocytes migrate to site of infection
5. effector T cells are activated by antigens and carry out their function
6. some T cell clones become memory cells
371
what specifically provides signal 1 for T cell activation?
αβ TCR binds MHC/antigen peptide on APC
AND
T cell CD4/CD8 coreceptor binds MHC I/II on APC
372
what specifically provides signal 2 for T cell activation?
CD28 on T cell binds B7 on APC
373
what happens when a T cell is activated?
a signaling cascade is initiated that results in alteration of gene transcription
374
major T cell integrin involved in binding to APCs?
LFA-1
375
costimulators for T cell activation?
B7 proteins, which bind to CD28 on T cell
376
CD40
expressed on APCs; binds T cell CD40L, which activates APCs to express more B7 costimulators and secrete cytokines (IL-12) that enhance T cell differentiation; also expressed on B cells and is important mediator of B cell isotype switching
377
CD40L
expressed on T cells (particularly CD4+); binds CD40 on APC, which activates APCs to express more B7 costimulators and secrete cytokines (IL-12) that enhance T cell differentiation; also important mediator of B cell isotype switching with Th cell assistance
378
CD40-CD40L interaction
promotes T cell activation by making APCs better at stimulating T cells
379
adjuvants
substances that enhance T/B cell activation mainly by promoting accumulation & activation of APCs at site of antigen exposure; stimulate expression of T cell-activating costimulators and cytokines by APCs, and may also prolong expression of peptide-MHC complexes on APC surface; used in vaccines to provide signal 2
380
Agents that block B7:CD28 are used in the treatment of?
rheumatoid arthritis, other inflammatory diseases, and graft rejection
381
antibodies to block CD40:CD40L interactions could be used for?
treating inflammatory diseases; preventing graft rejection
382
what would happen if you blocked CTLA-4?
immune response would be enhanced; potential for treating tumors/cancer
383
HIV kills what kind of cells?
CD4+ T cells
384
immunologic synapse
region of contact between the APC and T cell
385
NFAT (Nuclear factor of activated T cells)
Transcription factor required for the expression of IL-2, IL-4, TNF, and other cytokine genes; the 4 different NFATs are each encoded by separate genes
386
NFAT activation and nuclear translocation depends on?
concentration of Ca2+ ions in the cell
387
intracellular signaling pathway following T cell activation
1. CD4/CD8 binding to MHC causes co-localization of these molecules
(1a. CD28-B7 costimulation)
2. CD45 phosphatase activated, removes P from/activates Lck
3. Lck adds P to/activates ITAMs located in CD3 and zeta chain cytosol
4. CD3 and zeta chains can now serve as docking stations for ZAP70
5. ZAP70 docks on ITAMs
6. Lck adds P to/activates ZAP70
388
3 cascades initiated by active ZAP70
1. phospholipase C (PLC) cascade
2. MAP kinase cascade
3. PI-3 kinase/Akt & mTOR cascades
389
PLC cascade
Active PLC → DAG and IP3
a. IP3 → Ca2+ release from ER → Ca2+--calmodulin complex → calcineurin activation → removes P from/activates NFAT → NFAT enters nucleus & regulates transcription
b. DAG → PKC activation → adds P to IKB → IKB releases NF-kB → NF-kB enters nucleus & regulates transcription
390
MAP Kinase cascade
ZAP70 recruits Rac and Ras (G proteins) → MAP Kinase cascades → AP-1 activated → AP-1 enters nucleus & regulates transcription
391
PI-3 kinase/Akt & mTOR cascades
ZAP70 + costimulation recruit PI-3 kinase → adds P to/activates PIP3 → PIP3 activates PKB & mTOR pathways → increased transcription of AP-1 or NF-kB
392
IL-2
causes T cells to differentiate into effector T cells and undergo clonal expansion;
IL-2 receptors are upregulated on activated T cells and can be involved in autocrine signaling
393
what kinds of effects do cytokines have in general?
wide variety of effects on a wide variety of cell types; effects of different cytokines also overlap
394
2 types of T cell migration
1. naive T cell: blood → lymph tissue → blood (until encounter APC)
2. activated T cell: blood/lymph → site of infection
395
Which protein chains of the IL-2 receptor is/are expressed on the surface of activated T cells to form the high-affinity IL-2 receptor?
α, β, and γ
396
Which protein chains of the IL-2 receptor is/are expressed on the surface of T cells to form the low-affinity IL-2 receptor?
β and γ
397
cells that express CD40
dendritic cells
B lymphocytes
macrophages
398
dendritic cell CD40 activation by CD40L causes?
increase in co-stimulation and cytokine production
399
B lymphocyte CD40 activation by CD40L causes?
secretion of antibodies with high affinity for the antigen
400
Macrophage CD40 activation by CD40L causes?
upregulation of lysosomal proteases and enzymes that stimulate synthesis of ROS
401
3 major subsets of CD4+ effector cells
1. Th1
2. Th2
3. Th17
402
What drives CD4+ differentiation to Th1?
IFN-γ and IL-12
through
STAT1, STAT4, and T-bet transcription factors
403
What drives CD4+ differentiation to Th2?
IL-4
through
STAT6 and GATA3 transcription factors
404
What drives CD4+ differentiation to Th17?
TGF-β, IL-6, and IL-22
through
STAT3 and RORgT transcription factors
405
Can Th1 cells re-differentiate into Th2 or Th17?
No
406
Can Th2 cells re-differentiate into Th1?
Yes
407
Can Th17 cells re-differentiate into Th1?
Yes
408
What is notable about the cytokines that induce differentiation of each CD4+ cell?
they are also the cytokines produced by those Th subsets
| ex: IFN-γ stimulates Th1 differentiation, and then Th1 cells produce IFN-γ
409
How do Th1 cells activate macrophages?
CD40-CD40L interaction + IFN-γ → classical macrophage (M1) activation
* macrophage response enhanced by Th1
* macrophages also secrete IL-12, which stimulates further CD4+ diff into Th1 cells
410
Th1 cell effects
1. enhance macrophage killing function through IFN-γ
| 2. enhance macrophage recognition of antigens through stimulation of B cell secretion of IgG, an opsonizer
411
Th2 cell effects
1. mast cell & eosinophil activation through IL-4 stimulation of IgE for parasite defense, allergic rxns
2. alt macrophage (M2) activation through IL-4 for tissue repair
3. sometimes suppress Th1-mediated immunity by inhibiting macrophage microbicidal activity
412
Match the CD4+ subset with its general function(s) and cytokine(s)
Th1: macrophage enhancement; IFN-γ
Th2: parasite defense, tissue repair; IL-4
Th17: inflammation, bacterial/fungal defense; IL-17 / IL-22
413
Th17 cell effects
1. attract neutrophils through stimulation of chemokine production by IL-17
2. increase barrier functions of epithelial cells and stimulate defensin production through IL-22
414
IL-4
stimulates and produced by Th2 cells; activates mast cell, eosinophils, and M2 macrophages and sometimes suppresses Th1 responses
415
IL-17
stimulates and produced by Th17 cells; induces inflammation by stimulating production of chemokines that attract neutrophils
416
IL-22
stimulates and produced by Th17 cells; increases barrier functions of epithelial cells and stimulates defensin production
417
what cytokine acts on naive T cells to stimulate differentiation into effectors and clonal expansion?
IL-2
418
3 mechanisms for CD8+ cell effector functions
1. Perforin & Granzymes (main mechanism)
2. FasL-Fas
3. TNF-α & IFN-γ Cytokines
419
Perforin & Granzymes
main effector mechanism for CD8+; perforin perforates cell membrane, allowing granzymes to enter cell and induce apoptosis
420
FasL-Fas
CD8+ effector mechanism; induces apoptosis via a similar pathway to perforin-granzyme
421
TNF-α & IFN-γ
CD8+ effector mechanism; induces apoptosis via NF-κB/Stat-1 pathway
422
3 ways CD4+ cells interact with CD8+ cells
1. cytokine production (IL-2)
2. CD40-CD40L
3. CD4-CD8 cooperation
423
What signaling molecule is inhibited by Cyclosporin?
Calcineurin
424
What is highly expressed on High Endothelial Venules (HEVs) that allows for T-cell adhesion that is NOT expressed on regular venules?
Sialomucins
425
factors expressed for T cell migration from Blood → Lymph Node (via HEVs)
1. Naive T-cells express L-Selectin (CD62L), CCR7, & LFA-1 Integrins
2. L-Selectin Ligands on HEVs bind L-Selectin
3. CCL19/21 from HEVs bind CCR7
4. ICAM-1 on HEVs bind LFA-1
426
factors expressed for T cell migration from Lymph Node → site of infection
1. activated T cells downregulate L-selectin & CCR7, begin expressing CXCR3, S1PR1, ligands for E-selectin or P-selectin, LFA-1, and VLA-4
2. S1Ps bind S1PRs
3. CXCL10 from endothelium of site of infection binds CCR3
4. ICAM-1 or VCAM-1 on endothelium of SoI bind LFA-1 or VLA-4, respectively
427
HEVs
located in Peyer’s Patches & peripheral Lymph Nodes; special characteristics facilitate T-cell adhesion, including:
a. high levels of ICAM-1
b. high levels of Sialomucin
c. chemokines (CCL19/21, CXCL12/13)
d. Prominent Perivascular Sheaths
428
S1P gradient
guides T-cell migration; levels higher in blood/lymph than inside lymph nodes
429
FTY720
interferes w/T cell S1PR → T cell can't bind & follow the S1P gradient → T cell sequestration
*basis of MS drug Gilenya
430
Gilenya
Drug based on FTY720 that decreases relapses in relapsing-remitting MS
431
3 stages of adaptive immune response
1. Initial Response
2. Protective Immunity
3. Memory
* each stage begins with expansion and ends with contraction
432
L-selectin
expressed by naive T cells; mediates selective migration into lymph nodes through HEVs, specifically through rolling interactions that allow chemokines to bind to T cell CCR7
433
CCR7
expressed by naive T cells; mediates selective migration into lymph nodes (parafollicular regions) through HEVs
434
why are effector T cells not drawn toward lymph nodes?
they don't express CCR7 or L-selectin
435
why are naive T cells not drawn toward sites of infection?
they don't express ligands for E-selectin or P-selectin, and they don't express receptors for chemokines produced at inflammatory sites
436
what determines effector T cell homing to site of infection?
adhesion molecules and chemokines; any T cell can go there but the ones that recognize the antigens are preferentially retained
437
expansion
antigen exposure + costimulation induce T & B cell expansion to fight off the antigen
438
contraction
after defeating antigen, T & B cells die (leaving memory cells behind)
439
memory
how the immune system reactivates an expansion of effector cells after a contraction has occurred; also how vaccines work!
440
Central Memory
in lymphoid organs → undergo rapid clonal expansion following antigen re-exposure
441
Effector Memory
in peripheral tissues → rapid effector functions upon antigen re-exposure
442
CD8+ lymphocytes are used primarily to combat what kind of infections?
viral infections, plus some intracellular bacterial infections
443
Mycobacteria
inhibits phagolysosomes
444
Herpes Simplex Virus
inhibits TAP transporter (MHC Class I assembly!)
445
Cytomegalovirus
Inhibits Proteasome & MHC I removal from ER
446
Epstein-Barr Virus
Inhibits Proteasome & M2 activation via IL-10
447
Pox Virus
Induces production of soluble cytokine receptors (IL-1 or IFN-γ) which act as decoys so cytokines can’t act on effector cells
448
how are NK cells' responses tempered?
by the balance of activating & inhibitory receptors expressed on their surface
449
Which T-cell subset contributes the most to an allergic response?
Th2 (mast cells!)
450
Cytotoxic T-Lymphocytes use which mechanisms to lyse target cells?
Perforin/Granzymes, Fas/Fas Ligand, & TNF-α
451
Which adhesion molecules facilitate naïve T-cell entry into the lymph node?
L-selectin & CCR7
452
immunoglobulin
BCR / antibody
453
what is the difference between BCR and antibody?
BCR is membrane-bound; antibody is soluble
454
BCR
membrane-bound receptor that recognizes antigens and uses Igα and Igβ for signaling functions
455
what determines B or T cell lineage?
changes in common progenitors in bone marrow
456
what kinds of molecules can Ig recognize?
peptides, lipids, polysaccharides, and nucleic acids; can recognize entire molecules (as opposed to only fragments)
457
antibody structure
heavy chain w/several constant regions and 1 variable region; light chain w/1 constant and 1 variable region; Fab region; Fc region
* heavy chain determines class
* each V region made up of 3 CDRs
458
Fab region
antigen binding occurs here
459
Fc region
where BCR attaches to B cell membrane
OR
where antibody can bind to phagocyte Fc receptors
460
how many antigen binding sites per antibody?
2 (except IgA and IgM)
461
isotype switching
Ig molecules can change their class of antibody through heavy-chain switching; antibody specificity (V region) does not change; mediated by interaction btwn B cell CD40 receptor and Th cell CD40L
462
specifically which part of an antibody does antigen bind to?
CDRs in V regions of heavy & light chains
463
BCR vs TCR affinity
affinity of a BCR is 1,000 to 10,000x higher than that of a TCR, and it changes
and increases with repeated exposure to an antigen
464
BCR on/off rate
rapid on rate, variable off rate -- grab on quickly, then decide what to do
465
antibody isotypes
IgM, IgG, IgA, IgE, IgD
466
how many antigen binding sites does IgA have?
4 - it is a dimer, so has 2x that normal amount
467
how many antigen binding sites does IgM have?
10 - it is a pentamer, so has 5x the normal amount
468
which antibody isotypes are expressed on the surface of naive B cells?
IgM & IgD
469
which antibody isotype has no secreted form?
IgD
470
which antibody isotype is most prevalent in circulation?
IgG - longest half-life
471
which antibody isotype is most prevalent in mucosa?
IgA
472
B cell maturation steps
1. pro-B cell rearranges V regions through VDJ recombination
2. success in making heavy chain → pre-B cell w/Igμ protein
3. μ chain associates w/Igα and Igβ signaling molecules to form pre-BCR complex
4. pre-BCR complex sends cell survival signals, among others
5. light chain associates w/μ chain to form complete IgM receptor → immature B cell
6. IgM receptor sends out survival signals, among others
7. coexpression of IgM & IgD → mature B cell
473
first checkpoint in B cell development?
correctly assembled pre-BCR complex sends signals to cell to continue development
474
what happens to pro-B cells that don't succeed in rearranging heavy chain?
death
475
what happens to developing B cells that don't express pre-BCR complex?
death
476
signals sent out by pre-BCR complex?
1. signals to cell to continue development
2. allelic exclusion: signals to shut off recombination of Ig heavy chain genes on 2nd chromosome
3. triggers recombination at κ light-chain locus
477
second checkpoint in B cell development?
fully-expressed IgM receptor sends out survival signals
478
what molecules do B cells express during each phase of development?
pro-B cell: CD10, CD19
pre-B cell: Igμ; recombined H chain
immature B cell: IgM; recombined H chain; κ or λ light chain
mature B cell: IgM & IgD
479
B cell negative selection
if an immature B cell binds an antigen in bone marrow with high affinity, the VDJ recombinase may be reactivated to change the antigen receptor specificity (receptor editing); may also involve deletion of self-reactive B cells
480
receptor editing
if an immature B cell binds an antigen in bone marrow with high affinity, the VDJ recombinase may be reactivated to change the antigen receptor specificity
481
what role do bone marrow stromal cells play in B cell development?
presents antigens to developing B cells (similar to thymic epithelial cells in T cell development)
482
IL-7
necessary for lymphocyte growth
483
SCF
helps early B cells develop by stimulating proliferation
484
Kit
helps early B cells develop by stimulating proliferation
485
what happens if SCF and/or Kit don't function?
you won't get B cells! (not enough clones will be made to ensure some make it through selection)
486
SLC / CCL21
attracts dendritic cells to lymph nodes; secreted by stromal cells and dendritic cells in node
487
affinity maturation
affinity of antibodies produced in response to an antigen increases with prolonged/repeated exposure to antigen
488
what do dendrites in lymph nodes secrete to attract B & T cells?
SLC / CCL21 and MIP3β
489
follicular dendritic cells
establish B cell areas in lymph node by secreting BLC / CXCL13
490
BLC / CXCL13
secreted by follicular dendritic cells to attract B cells to particular areas in lymph nodes
491
C regions
constant region genes that can form the different heavy chains
492
heavy chain segments in VDJ recombination
mix and match with V, D, and J segments
493
light chain segments in VDJ recombination
only V and J segments
494
RSS motifs
specific signal sequences expressed by genes that can be recombined; randomly bind to complexes containing RAG1 & RAG2; eventually, cleaved at these motifs and ends are joined to form a closed loop of DNA that is no longer used
495
RAG1 / RAG2
recombination activator genes; randomly bind to RSS motifs
496
RAG protein complex
brings together the gene segments to be recombined and cleave the DNA exactly at the junction of the gene segment at the RSS motif
497
proteins involved in recombining cleaved DNA / gene segments
DNA-PK, Ku, Artemis, and DNA ligase/XRCC4
498
5 ways diversity is generated in BCR
1. baseline variability in V segments
2. combinatorial diversity (VDJ joining)
3. junctional diversity (imprecise cutting, TdT additions)
4. secondary combinatorial diversity (random assortment of heavy/light chains)
5. somatic hypermutation (cell mutations during germinal center rxn)
499
2 ways to activate B cell
1. clustering of IgG receptors bound to antigens → receptor cross-linking → activation signal through Igαβ receptors to ITAMS → phosphorylation → recruitment of Syk kinase → signal propagation
2. complement-coated microbes attach to BCR & C3d binds CD21 (CR2) receptor → activate CD19 and Igαβ phosphorylation → recruitment of Syk kinase → signal propagation
500
what happens after B cell activation?
B cells interact w/CD4+ T cells outside of B cell follicles in lymph node → present antigen to T cells → T cell CD40 binds B cell CD40LR → T cells secrete cytokines → some B cells proliferate/differentiate into antibodies immediately; other B cells migrate back into follicles to undergo germinal center rxn
501
germinal center reaction
when somatic hypermutation and potentially isotype switching occur
502
why do B cells undergo somatic hypermutation and isotype switching?
help make the antibody affinity for the antigen much greater and help the body mount a more effective defense
503
T-FH cells
T follicular helper cells: some T cells migrate into B cell follicles and develop into these
504
somatic hypermutation
occurs in germinal center; introduces many mutations in V region of BCR genome to generate BCRs that have a higher affinity for the antigen being presented
505
molecules involved in somatic hypermutation
- AID promotes mutations by changing cytosine → uridine
| - UNG corrects these mutations using BER → other mutations
506
what happens to B cells after somatic hypermutation?
mutated BCRs compete to bind to antigens displayed by follicular dendritic cells in B cell follicle; those that bind strongly are given a survival signal, and the many that are non-functional or weakly-binding die
507
enzymes involved in isotype switching
AID, UNG, and APE1
508
APE1
induces double stranded breaks that allows the initial C region to be swapped out for a different C region denoting a different heavy chain
509
AID
promotes mutations by changing cytosine → uridine
510
UNG
corrects mutations induced by AID using BER → other mutations
511
what determines isotype switching?
cytokine environment secreted by surrounding helper T cells
512
IgM principal effector function
complement activation
513
IgG3 principal effector function
complement activation
514
IgG1 principal effector function
complement activation; can cross placental barrier
515
IgE principal effector function
high-affinity binding to mast cells and basophils to defend against helminths
516
IgA principal effector function
mucosal immunity
517
what will a lab report show on first exposure to antigen?
lots of IgM (naive B cells)
518
what will a lab report show on subsequent exposure to antigen?
lots of IgG (longest lasting; form memory cells)
519
thymus-dependent reaction
any reaction that involves T cells / antigens with protein component
520
thymus-independent reaction
any reaction to a lipid, polysaccharide, or nucleic acid antigen (i.e. lacking peptide component)
521
Termination of BCR signaling
as the antibodies bind antigens, they also tend to conglomerate with other antibodies binding antigens, and these large complexes bind the surface of B cells, activating ITIMS, which are inhibitory and terminate the signals.
522
antibody feedback
complexes of antibodies responding to antigens bind the surface of B cells and activate inhibitory ITIMS
523
Omenn syndrome
no RAG → no B cells
524
IR/RS SCID
lack of Artemis → defects in DNA repair & low Ig and TCR diversity b/c lack ability to do VDJ recombination properly
525
Ataxia Telangiectasia
ATMmut → low B/T cells, low Ab switch
526
AID deficiency
low Ab diversity, high IgM due to lack in class switching and hypermutation
527
X-linked hyper IgM
defect in CD40L → No class switching, most antibodies will be IgM
528
IgG functions
- microbe/toxin neutralization
- antigen opsonization
- classical pathway complement activation
- antibody-dependent cellular cytotoxicity (NK cells)
- neonatal immunity
- feedback inhibition of B cell activation
529
IgM functions
classical pathway complement activation
530
IgA functions
- mucosal immunity
| - IgA secretion into GI & respiratory tracts
531
IgE functions
parasite defense and hypersensitivity (allergic) reactions
532
FcRn
Neonatal Fc Receptor; found on placental tissue, endothelium, phagocytes and a few other cell types; contributes to long half-life of IgG (increases by 3 weeks)
533
how does FcRn contribute to long half-life of IgG?
- circulating IgG ingested by endothelial cells & bind Fc-region of FcRn
- FcRn sequesters IgG in endosomal vesicles (pH 4)
- FcRn-IgG complexes recycled back to surface
- IgG released back into blood
534
neutralization
antibodies inhibit the infectivity of a pathogen or the toxicity of a toxin; foundation for vaccines (stimulate neutralizing antibodies)
535
neutralizing antibodies are like goalies
they're always blocking stuff
536
types of antibody neutralization
1. block microbe penetration through epithelial barrier
2. block microbe from binding to and infecting cells by binding to the microbe
3. block infection of adjacent cells
4. block toxin binding to cellular receptor by binding to toxin
537
major defense mechanism against encapsulated bacteria?
opsonization by antibody → phagocytosis by macrophages/neutrophils
538
phagocyte Fc receptors
recognize opsonization signals
539
FcγRI
recognizes IgG
540
FcγRIIA
recognizes IgG (lower affinity)
541
FcγRIIB
feedback inhibition of B cells (reduces inflammation)
542
FcγRIIIA/CD16
mediates NK-IgG binding in antibody-dependent cellular cytotoxicity (ADCC)
543
FcεRI
recognizes/activates mast cells and basophils for allergic reactions by binding IgE
544
ADCC
Antibody-dependent cellular cytotoxicity; process by which NK cells target and kill IgG-coated cells; NK-IgG binding mediated by FcγRIIIA/CD16; important anti-viral and anti-tumor process
545
antibody-mediated eosinophil/mast cell activation
IgE opsonizes parasite/allergen; pathogen recognized by FcεRI receptors on eosinophil, aided by IL-5 (made by Th2 cells); activated eosinophil kills parasite/neutralizes allergen
546
neonatal immunity
maternal antibodies, such as IgG, are actively transported across the placenta via the FcRN receptor to the fetus, across the gut epithelium, entering neonatal circulation and protecting newborn from infections
547
IgA and neonatal immunity
After birth, neonates ingest maternal IgA antibodies through colostrum and milk (mucosal immunity). Neonate’s intestinal epithelial cells also express FcRn receptors, which bind ingested IgG antibodies and carry them across the epithelium
548
only example of naturally occurring passive immunity?
mother passing antibodies to newborn
549
poly-Ig receptor
can bind IgA and IgM; transports IgA across the epithelium/mucosal barrier
550
IgA/poly-Ig receptor complex
When it crosses the mucosal barrier, this complex is endocytosed and released into lumen of GI or respiratory tract, after proteolytic cleavage, where the Ab can bind microbes. IgA remains attached to poly-Ig receptor, which helps protect antibody from degradation when it reaches lumen, where it may experience harsh environment (i.e. GI tract)
551
3 pathways to activate complement system
1) Classical pathway
2) Lectin pathway
3) Alternate pathway
552
C3 convertase
protease generated by all 3 complement pathways; recruits inflammatory mediators and phagocytes, opsonizes pathogens for phagocytosis, and kills pathogens
553
can the Lectin and Alternative complement pathways be activated in the absence of antibodies?
Yes!
554
which antibody isotypes can activate classical complement pathway?
IgM, IgG1, IgG2, and IgG3
* role in innate and adaptive immunity
* GM makes classic cars
555
relative strength of potency of complement inflammatory chemoattractants?
C5a > C3a > C4a
556
Classical Complement Pathway
1. activation of protein C1 complex
2. cleavage of C4 to C4a & C4b
3. C4b binds pathogen, where it can now bind C2
4. C4b recruits C1 to cleave C2 to C2a & C2b
5. C4bC2a complex created (aka classical C3 convertase)
6. C3 convertase continuously cleaves C3 to C3a & C3b
7. C3b opsonizes pathogen
8. C3b covalently binds C3 convertase, forming C4bC2aC3b protease (aka C3/C5 convertase)
9. C3/C5 convertase cleaves C5 to C5a & C5b
(1, 4, 2, 3, 5)
557
anaphylatoxin
small fragment that can be recognized by receptors to recruit fluids and inflammatory cells
558
Alternate Complement Pathway
1. plasma C3 spontaneously undergoes cleavage to C3a & C3b
2. C3b opsonizes pathogen, then binds Factor B
3. C3b/FactorB complex allows factor D to cleave factor B to Ba & Bb
4. Bb binds C3b, becoming C3bBb (aka alternate C3 convertase)
5. C3 convertase continuously cleaves C3 to C3a & C3b
6. C3b covalently binds C3 convertase, forming C3bBbC3b convertase (aka alternate C3/C5 convertase)
7. alternate C3/C5 convertase promotes terminal steps of pathway cascade
559
Lectin Complement Pathway
1. initiated by Mannose- Binding Lectin (MBL) protein, which binds mannose sugar residues present on many pathogen surfaces
2. follows same steps as classical pathway
560
Terminal Steps of complement pathway
1. C5b binds C6 and C7, forming C5b67 complex
2. C5b67 complex binds to microbe membrane using C7
3. C8 recruited to membrane
4. C8 induces polymerization of C9, forming pore known as MAC
5. MAC disrupts lipid bilayer, letting all kinds of characters in and out
561
Complement regulators
slow down the system!
562
down-regulation of alternate C3 convertase
use membrane proteins CR1, MCP, and DAF:
1. DAF or CR1 displaces Bb in C3bBb convertase
2. MCP or CR1 serves as cofactor for Factor I, which cleaves C3b to inactive form
563
classical and MBL pathway regulation
primarily by C1-INH, which prevents appropriate assembly of the C1 complex so that it cannot become proteolytically active
564
C4 binding protein
can also cause the dissociation of the classical complement pathway; acts as a cofactor for factor-I mediated cleavage of C4b
565
CD59
inhibits C9 binding, preventing MAC formation
566
Paroxysmal nocturnal hemoglobinuria (PNH)
very rare disorder; RBCs lack DAF / CD59; causes complement pathways to attack RBCs; Currently treated with Eculizumab (anti-C5 antibody)
567
Hereditary angioedema (HAE)
lack C1-INH regulator; probably NOT a complement-mediated disease; Treated with C1-INH concentrates
568
Atypical hemolytic uremic syndrome (aHUS)
genetic disease that can damage vital organs; occurs in heterozygous individuals with mutations in MCP, Factor H, or Factor I; pts have blood clots form in small vessels (systemic thrombotic microangiopathy)
569
Which immunoglobulin has the highest level in a normal 1-day-old infant?
IgG (from mother placental transfer)
570
Which complement component is most closely related to anaphylatoxin?
C5b
571
C1 complex
classical pathway initiator protein; can bind antibodies such as IgM and IgG subtypes
572
2 sites of tolerance development
central (bone marrow/thymus) or peripheral
573
Central tolerance
main site for elimination of autoreactive lymphocytes
574
partial defect in central tolerance is associated with...?
onset of autoimmunity
575
loss of peripheral tolerance mechanisms leads to...?
increased risk of autoimmune disorders
576
2 principal mechanisms of central tolerance in T cells
1. cell death
| 2. generation of CD4+ regulatory T cells
577
mutations in AIRE gene
associated w/autoimmune polyendocrine disorder (APECED)
578
regulatory T cell development
express slightly stronger reaction to antigens presented during development, but not strong enough to warrant death
579
regulatory T cell surface markers
CD3
CD4+
CD25+ (chain of IL-2 receptor)
FoxP3 TF
580
can regulatory T cells survive w/o CD25?
No.
581
peripheral tolerance induction
T cell recognizes self-antigen in periphery, leading to:
1. apoptosis
2. anergy (functional inactivation)
3. suppression by reg T cells
582
what happens when a T cell recognizes a self-Antigen?
may preferentially bind CTLA-4 (inhibitory) to B7 to prevent autoimmune response
583
Genetic polymorphisms in CTLA4 gene
associated with autoimmunity
584
regulatory T cell function
block activation of harmful lymphocytes specific for the self-antigens; suppress CD4 and CD8 effector functions
585
regulatory T cell mechanisms
1. expression of CTLA-4, which downregulates B7 costimulator
2. secretions of inhibitory/anti-inflammatory cytokines like TGF-B and IL-10
3. "soak up" excess IL-2 to prevent expansion of other T cells
586
Immune Dysregulation Polyendocrinopathy Enteropathy (IPEX)
X-linked disease caused by mutation in FoxP3
587
FoxP3 mutation
causes IPEX
588
what usually causes inappropriate activation of T cells?
lack of signal 2 (costimulation) leads T cells down 1 of 2 pathways:
1. intrinsic: expression of pro-apoptotic pathways
2. Coexpression of death receptors and ligands – Both cells express Fas (CD95) and the Fas Ligand (FasL). Binding of these on both cells together induces apoptosis.
589
how does CD4 help regulate B cell development in regard to autoimmunity?
Naive B cells can only mature in the presence of proper CD4 T cell signaling. CD4 T cells will not provide these signals to a B cell that is binding self-antigen
590
main cause of autoimmune disorders?
chance
| some genetic defects may lead to increased risk (mainly defects in peripheral tolerance)
591
how could one self-reactive molecule slipping through the cracks cause a big problem?
if self-reactive lymphocyte happens to recognize a self-Ag being presented by an infected APC, which will be expressing high levels of the costimulator B7; now you've activated a lymphocyte the recognizes self-antigens and created an autoimmune disorder
592
mutation in AIRE
causes autoimmune polyendocrine disorder (APS-1)
593
mutation in Fas
causes autoimmune lymphoproliferative syndrome (ALPS)
594
what kinds of defects lead to an increased risk of acquiring an autoimmune disorder?
costimulation
antigen presentation or removal
signaling molecules
effector cell clearance
595
HLA phenotype (MHC)
has one of the clearest associations with relative risk of autoimmunity
596
TH1 cells express abundant functional ligands for?
E-selectin and P-selectin and the chemokine receptors CXCR3 and CCR5, which bind to various chemokines found at sites of active innate immune responses
597
invariant chain
ensures peptide gets matched up with correct MHC class
