Exam 1 Flashcards
1
Q
What is an innocuous antigen?
A
should not illicit an immune response
2
Q
What are atopic individuals?
A
predisposed to allergies (IgE)
3
Q
What is the Hygiene Hypothesis?
A
lack of early childhood exposure to innocuous, increases the susceptibility to allergic diseases
4
Q
What is responsible for allergies?
A
Type 1 HSR
5
Q
When is gut microbia established?
A
at birth
6
Q
Type 1 HSR is mediated by what isotype?
A
IgE
7
Q
What receptors recognize pathogens and communicate and provide signals to TH cells?
A
pattern recognition receptors
8
Q
What are the 3 steps to choosing a Th subset?
A
- APC binds to antigen + polarizing cytokines
- transcription factors induced
- production of effector cytokines
9
Q
Biased Th subsets are required to eliminate a pathogen/allergen. How are these subsets chosen?
A
pattern recognition receptors on APCs
10
Q
What are the polarizing cytokines for Tregs?
A
IL-2
TGF-B
11
Q
What are the polarizing cytokines for TH17?
A
IL-1
IL-6
IL-23
TGF-B
12
Q
What is the polarizing cytokine for TH2?
A
IL-4
13
Q
What are the polarizing cytokines for TFH?
A
IL-6
IL-21
14
Q
What are the polarizing cytokines for TH1?
A
IL-2
INF-g
IL-18
15
Q
What are the effector cytokines for Treg?
A
IL-10
TGF-B
16
Q
What are the effector cytokines for TH17?
A
IL-17A
IL-17F
IL-22
17
Q
What are the effector cytokines for TH2?
A
IL-4
IL-5
IL-13
18
Q
What are the effector cytokines for TFH?
A
IL-4
IL-21
19
Q
What are the effector cytokines for TH1?
A
INF-g
TNF
20
Q
What cytokine regulates immune supression?
A
TGF-B
21
Q
When in development (fetal–>adult) are Tregs and TGF-B the highest?
A
fetal stage
22
Q
When is immune tolerance the highest in development (fetal–>adult)?
A
fetal stage (lots of Tregs TGF-B present)
23
Q
When is protective immunity the highest in development (fetal–>adult)?
A
adult stage (low Tregs and TGF-B because immune system has developed)
24
Q
What is intrauterine IPEX?
A
inactivation of FOXP3 causing no Treg production = no tolerance developed
25
What is the fetal immune system controlled by?
Tregs
26
Atopic individuals have a ______ bias towards TH2 cells (overactivated)
skewed
27
What are some examples of factors that can cause immune skewing?
age
sex
obesity
pre-disposition
prior exposure
microbiome
28
What are the 5 mucosal surfaces the microbiome colonizes?
1. oral epithelium
2. airway epithelium
3. intestinal epithelium
4. reproductive epithelium
5. skin epithelium
29
What is the largest mucosal surface with the most microbiome?
intestinal epithelium
30
What 5 ways are intestinal microbiome help to the host?
1. enhances nutrion
2. provides competitive growth
3. produces metabolites
4. regulates local immune response
5. regulates immune homeostasis
31
What are 4 mucosal protection stratagies?
1. tightly packed epithelial cells
2. limited immune response to host bacteria
3. antimicrobial peptides
4. production of IgA
32
What is immune homeostasis?
balance between Tregs and Teffectors
33
What does immune imbalance look like =? (Tregs v. Teffectors)
More T effectors that T regs
34
What is tonic signaling?
immune system skewing above baseline set by barrier surfaces and other factors (like age or sex)
- more bad bacteria than good bacteria
35
What is an example of how pathology doesn't always describe the mechanism?
weak and excessive immune responses result in immunopathology (wrong response)
36
What does K means?
equilibrium constant
- strength of non-covalent interactions between 2 molecules
37
Are covalent or non-covalent interactions irreversible?
covalent
38
Are covalent or non-covalent interactions sharing of electrons with extensive orbital overlap?
covalent
39
What is an example of covalent interactions in immunology?
C3b binding to pathogen surface
40
Are covalent or non-covalent interactions weaker?
non-covalent
41
What are 4 examples of non-covalent interactions?
1. hydrogen bonds
2. ionic bonds
3. hydrophobic interactions
4. van der Waal interactions
42
What does hydrogen bonding require?
donor
acceptor
hydrogen
43
What is a hydrogen bond?
2 electronegative atoms compete for the same hydrogen
44
What amino acids do hydrogen bonds occur between?
polar AA
45
What is an ionic bond?
bond between a cation and anion
46
What amino acids do ionic bonds occur between?
charged AA
47
What is a hydrophobic interaction?
hydrophobic molecules are attracted to one another
48
What amino acids do hydrophobic interaction occur between?
uncharged non-polar AA
49
What is a van der Waal interaction?
packing of atoms together
50
What amino acids do van der Waal interactions occur between?
all amino acids
51
What is Ka?
association constant
52
What is Kd?
disassociation constant
53
What is Ka measured in?
M-1
54
What is Kd measured in?
M
55
What is the equation for Ka?
[RL] / [R][L]
56
What is the equation for Kd?
[R][L] / [RL]
57
What is the relationship between Ka and Kd?
they are inverses of each other
Kd = 1/Ka
58
What does it mean for the [RL] formation if the Ka is large?
more RL formed
59
What does it mean for the [RL] formation if the Kd is small?
more RL formed
60
What is the equation for (f)?
f = Ka [L] / 1+Ka[L]
61
What does f tell us?
the fraction of RL complexes formed at a given [L]
62
Which axis is f and [L] on in a binding curve?
f = y axis
[L] = x axis
63
Using a binding curve, Kd = [L] when?
50% of RL complexes are formed
64
If 10% of RL is formed, ____x Kd
0.1 x Kd
65
If 50% of RL is formed, _____x Kd
1 x Kd
66
If 90% of RL is formed, ______ x Kd
10 x Kd
67
If 100% of RL is formed, _______ x Kd
100 x Kd
68
Kd or Ka is a constant?
Ka
69
If Ka is a constant, why does the binding increase with increasing concentrations?
there is a higher chance of R and L interacting if there is more ligand
70
How can you tell if a ligand has a stronger affinity than another?
If it can reach Kd (50% saturated) with less [L] then its stronger
* smaller Kd = stronger
71
If affinity or avidity stronger?
avidity
72
What is apparent Kd?
(avidity) when expected Kd is different from ther actual Kd
73
Why is avidity stronger?
grabbing 2 ligands at once is much stronger (multivalent/multiple binding interactions)
* like doing a pull up with both hands instead of 1
74
What 2 things are required for avidity?
1. R or L to be attached to a surface
2. other component has to have multiple binding sites
75
Does avidity or affinity have a smaller Kd if its the same interaction?
avidity (stronger)
76
What is responsible for the different affinities between molecules?
non-covalent interactions
77
What is the most important interaction for specificity?
van der Waal
78
How can antibodies disrupt non-covalent interactions to neutralize a microbe?
antibody will have higher affinity (lower Kd) for receptor where microbe wants to bind and blocks it
79
What is a hypersensitivity reaction?
when the immune system responds inappropriately to innocuous antigens
80
What does anaphylaxis stand for?
against protection
81
What is the recognition molecule for type 1 HSR?
IgE
82
What is the effector mechanism for type 1 HSR?
granulocytes degranulation
83
What are the 3 phases of type 1 HSR?
1. sensitization phase
2. early effector
3. late phase
84
What happens during the sensitization phase of type 1 HSR?
exposure to antigen
85
What happens during the early effector phase of type 1 HSR?
- mast cell degranulation mediated by IgE--FcERI
* release of primary and secondary mediators
86
What happens during the late phase of type 1 HSR?
- cytokine production
- granulocytes recruitment
87
What are the steps of the early effector phase of type 1 HSR?
1. IgE binds to FcERI
2. free antigen (multivalent) binds to IgE-FcERI
3. receptors cluster and induce degranulation signaling
4. mediators released
88
What T cells promote IgE class switching?
TH2
89
Where does somatic hypermutation occur on an antibody?
Fab region
90
Where does isotype switching occur on an antibody?
Fc region
91
What is unique about IgE?
3 domain Fc structure
binds high affinity to FcERI
low in blood
92
What Ig is similar to IgE's Fc region?
IgM (pentameric)
93
Will IgE bind to FcERI even with no antigen present?
yes, no signaling will occur though
94
What isotype is low in the serum?
IgE
95
Where are mast cells located?
tissue (final epithelial layer)
96
Where are basophils found?
blood
97
Where are eosinophils found?
blood (migrate to tissue)
98
Where are neutrophils found?
blood
99
What granulocyte is critical for the late phase response of type 1 HSR?
eosinophils
100
What type of antigens/molecules can bind to IgE's Fab region?
proteins and glycoproteins
101
What does it mean when an allergen has proteolytic activity?
can cut through the epithelial cell barrier
102
What are the steps of the IgE SIGNALING cascade?
1. allergen binds to IgE--FcERI
2. FcERI clusters = activated Lyn
3. Lyn phosphorylates ITAMs
4. Syk recruits SH2 domain to ITAMs
5. Syk autophosphorylates
6. PLC-g is activated
7. degranulation, PLA activation, cytokine production
103
What is the difference between primary and secondary mediators?
primary: already stored in granules
secondary: must be synthesized
104
What are 2 examples of primary mediators?
histamine
heparin
105
What are primary mediators derived from?
decarboxylated histidine
106
How many histamine receptors do humans have?
4
107
Which histamine receptor do anti-histamines target?
H1
108
What are 3 examples of secondary mediators?
Leukotrienes
Prostaglandins
IL-1/TNF-a
109
Degranulation activates PLA which will generate ____________ to produce leukotrienes and prostaglandins
Arachidonic acid (AA)
110
What enzyme pathway synthesizes leukotrienes?
lipoxygenase
111
What enzyme pathway synthesizes prostaglandins?
COX2
112
What are the steps of leukotriene synthesis?
1. PLA + phospholipids
2. AA
3. LOX
4. cys-LTR1 (receptor)
113
What are the steps of prostaglandin synthesis?
1. PLA + phospholipids
2. AA
3. COX 1&2
4. DP1 & CRTH2 (receptors)
114
How does Montelukast (Singulair) prevent asthma symptoms?
prevents leukotrienes from binding to their cys-LTR
115
What is TNF-a?
inflammatory cytokine
116
Where is TNF-a stored?
mast cell granules
117
What increases in expression when TNF-a is expressed?
selectin and integrins
118
What ROS do eosinophils produce?
major basic protein (MBP)
119
What ROS do neutrophils produce?
myeloperoxidase (MPO)
120
What enzyme turns hydrogen peroxide into hypochlorous acid in ROS?
myeloperoxidase (MPO)
121
What enzyme turns L-arginine into nitric oxide in (RNS)?
iNOS
122
What happens to nitric oxide if its high in concentration?
combines with superoxide anion and become peroxinitrite
123
What happens to nitric oxide if its low in concentration?
its a signaling molecule
124
What induces iNOS?
epithelial cell damage
TH2 inflammatory cytokines
125
What are the 3 effects of peroxinitrite
1. inactivates mitochondria (apoptosis)
2. oxidizes proteins (inactivates enzymes)
3. DNA damage (necrosis)
126
What is a systematic reaction of type 1 HSR?
anaphylaxis
127
What is a localized reaction of type 1 HSR?
hives, asthma, eczema
128
What 4 things affect the severity of clinical symptoms of type 1 HSR?
1. route of allergen
2. concentration of allergen
3. prior exposure
4. host pre-disposition
129
How does epinephrine prevent anaphylaxis?
binds to beta adrenergic receptors which will counteract mediators by relaxing smooth muscles and reducing vascular permeability
andis vasoconstrictive
130
What receptor does epinephrine bind to inhibit the allergic response?
GCRP alpha & beta adrenergic receptors
131
Besides opening the airways what does epinephrine do for the heart?
increases cardiac output (increased BP)
132
What drug is a leukotriene antagonist?
Singulair
133
What 4 things do corticosteroid do to inhibit immune response?
1. anti-inflammatory (block mediators)
2. immunosuppressant (suppress T cells)
3. anti-proliferative (inhibit epidermal cell turnover)
4. vasoconstrictive (inhibit histamine)
134
What does glucocorticosteroids inhibit to stop inflammation?
NfkB nuclear factor
135
All pattern recognition receptors activate _________
NfkB
136
SCITs are a type of _____sensitization therapy
hyposensitization
137
What are SCITs?
atopic patients are slowly exposed to more and more allergen
138
What is the overall goal of SCITs?
divert the TH2 response from pathogenic to tolerant
139
What are the steps of SCITs mechanism?
1. TH2 diverts to Treg via IL-10
2. IgE is not made and now IgG is
3. IgG binds to FcGRIIB receptor
4. SHIP phosphatase is recruited by ITIMS and FcGRIIB and removes the phosphate group from ITAMs
5. signal cascade is blocked
140
What is the inhibitory version of FcERI?
FcGRIIB
141
Which cytokine induces IgE class switching?
IL-4
142
Which cytokine induces IgG class switching?
IL-10
143
What does SHIP phosphatase inhibit?
Lyn phosphorylating ITAMS
144
Beta-2 agonists use the same receptor as?
epinephrine
145
What does FEV stand for?
force expiratory volume
146
What does PEF?
peak expiratory force
147
What type of TH cells may promote tolerance?
Tregs
148
What immune homeostasis?
balance between activation and suppression on barrier surfaces
149
How do you find Kd on a binding curve?
go to 50% on y axis and and move down to [L] on x axis
150
The relationship between _____ and RL formation is the same for all interactions
Kd
151
Why are molecules repulsed from one another in van der Waal interactions?
steric repulsion
152
What cytokine initiates the transition to the late phase response?
TNF-a
153
What is the mechanism of anti-IL5Ra therapy?
blocks IL-5 receptor and induces AMCT
154
What is the mechanism of anti-TSLP therapy?
prevent CD4 cells from commiting to the Th2 lineage
155
What is the mechanism of anti-IL4 AMG317 therapy?
blocks IL-4Ra receptor because IL-13 or IL-4 both use it
- doesn’t work well because its outcompeted
- TYPE2 IL-4R
156
What is the mechanism of IL-4Ra therapy?
blocks IL-4Ra receptor because IL-13 or IL-4 both use it
- worked
157
What is the mechanism of anti-IL13 therapy?
blocks IL-13 or its receptor
- doesnt work very well because IL-4 picks up the pace
158
What is the mechanism of anti-IgE therapy?
bind to IgE Fc region and prevents it from binding to FcERI
159
What does SHIP phosphatase do for FcGRIIB?
removes phosphate from ITAMs to inactivate them
160
Does FcGRIIB use ITAMs or ITIMS?
ITIMs
161
What is unique about IgE?
low in serum
binds high affinity to FcERI
162
Why did anti-IL5 therapy initially not work?
Patients with asthma were chosen not eosinphil asthma
163
How do you choose what therapy is right for a certain diseae?
target the most important cytokine or its receptor
164
What are 3 examples of biomarkers?
blood eosinophil levels
FeNO
serum IgE
165
What increases the level of FeNO in the breath?
inflammation that causes epithelial cell damage
166
What does IgE bind to with high affinity?
FcERI
167
When does atopic dermatitis onset usually?
early in life
168
What makes AD atopic?
elevated IgE
family history (genetics)
169
What 4 things affect AD?
1. environment (pollution or diet)
2. skin microbes
3. epithelial barrier dysfunction (FLG mutation)
4. immune response (core Th2 response)
170
What is the mutation in AD patient?
FLG gene
171
What cytokine is AD most reliant on?
IL-13
172
What cytokine is asthma most reliant on?
IL-4
173
What is the FLG gene important for?
cross linking epithelial layer making it strong
174
What does the mutation in the FLE gene cause?
disruption of skin layers causing microbiome to get where it shouldn't
175
The FLE mutation is most common in what race and less common in what race?
common: white/asian
less common: african american
176
In asian people, AD is more mediated IL-__/TH___
IL-17
TH17
177
What does it mean that asian people's AD is more reliant on TH17/IL-17?
AD is not just TH2 mediated but also POLARIZING TH17 mediated activation depending on race
178
African americans are higher in TH___ response
TH2/IgE
179
What is the atopic march?
If you have AD as an infant you will likely have food allergies --> asthma --> rhinitis
180
How do anticholingerics work?
reduce swelling by binding acetylcholine to the M2 receptor which block ACs function
181
What happens when AC is in the airways?
induces bronchial spasms and hyper-reactivity
182
What happens to the M2 receptor when eosinophils in the airway degranulate?
the major basic protein released in the granules binds to the inhibitory receptor M2 and now acetylcholine is not inhibited = bronchial spasms and hyper-reactivity
183
Where are type 1 IL-4R found?
lymphocytes
184
Where are type 2 IL-4R found?
epithelial cells, goblet cells, smooth muscles
185
Type 1 and Type 2 IL-4R share ___________ but have different _________
share: IL-4Ra
different: 2nd chains
186
What do all of the Ig isotypes do?
neutralize
187
What is IgM responsible for? (chart)
complement activation
188
What are all the IgGs responsible for? (chart)
opsonization
189
What is IgG1 responsible for? (chart)
everything
190
What is IgG2 responsible for? (chart)
neutralization
opsonization
complement activation
191
What is IgG4 responsible for? (chart)
neutralization
opsonization
192
What is IgE responible for? (chart)
mast cell and basophil sensitization
193
What region of IgE binds to FcERI?
Fc region
194
What cells make IgE?
plasma cells
195
What is special about TSLP?
epitheial derived cytokine showing that there are different mechanisms of activation
196
How is IL-4 receptor polymorphic?
people have differences in the genes encoding IL-4Ra
197
Atopic Dermatitis is an IL-___ dominant disease
IL-13
198
Psoriasis is an IL-____ /Th___dominant disease
IL-23/Th17
199
What cytokines are elevated in AD?
IL-36
IL-13
IL-20
200
What cytokines are elevated in psoriasis?
IL-17
IL-36
IFN
IL-20
201
What cytokine was surprisingly low in AD?
IL-4
202
What cytokines were used to differentiate psoriasis skin from AD skin?
IL-17
IL-4
IL-13
203
What was the overall goal of the AD paper?
comparing AD and psoriasis using RNAseq
204
What are the 3 AD-specific molecular findings reported by this paper?
1. IL-13 as a predominate cytokine and IL-4 as a less significant
2. more dysregulated long noncoding RNA
3. heterogeneity
205
What three distinct features are associated with AD?
1. issues involving the integrity of the epidermal
2. other IgE-mediated immune problems like asthma
3. increased vulnerability for infection.
206
How strong is the comorbid relationship between AD and Asthma? and why?
Very strong, 60%
IL-13 and IL-4 share a receptor
207
The AD paper suggests that chronic AD shares a molecular component with Psoriasis. What is that component?
Chronic AD and psoriasis both have over activation of TH1 which secretes INF-g causing the inflammatory response.
208
What is the current optimal therapeutic for AD and Asthma?
combo anti-IL4/IL-13 therapies
209
IL-____ and IL-___ encourage the production of IgE
IL-4 and IL-13
210
What therapy causes apoptosis of eosinophils?
Anti-IL5Ra
211
What drug does not work for asthma therapy?
Anti-IL13s
212
List 3 granulocytes and their locations?
1. mast cells - tissue
2. eosinophils - blood
3. basophils - blood
213
What is a major primary mediator stored in granules?
histamine
214
What drug binds to B adrenergic receptors?
epinepherine
215
What are 2 mechanisms of SCITs?
1. Th2 ---> Tregs (IL-10)
2. IgE ---> IgG
216
What is a major transcription factors inhibited by corticosteroids?
NfKB
217
What race had the highest IgE serum levels in AD?
african american
