PCL469 > midterm > Flashcards

midterm Flashcards

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1
Q

Cytokines VS chemokines

A

Cyto: change cell types, modulating immune cell activation

Chemo: chemoattractant, attract immune cells

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2
Q

Why would leukocytes move to periphery blood vessels and extravasate to site of infection (leave blood vessels). (what mechanism allows it)

A

Adhesion molecules expressed by endothelium increase, which grab the circulating leukocytes

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3
Q

What is PAMPs? What about Antigen?

A

Conserved chemical elements of pathogen, low variation between subclass

Antigen = specific chemical matter processed by Immune cells, generating highly specific response

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4
Q

Which TLRs are extracellular/ intracellular? What do they recognize

A

Extra: TLR 1,2, 4, 5, 6. Recognize LPS/ flagellins (PAMPs)

Intra: 3, 7, 8, 9. Recognize dsRNA/ ssRNA/ DNA

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5
Q

What is required for a TLR to be signalling ( how to produce intense signalling)

A

Receptor clustering via PAMPs ligand

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6
Q

What is liberate by most TLR signalling, which enable rapid cytokine production? How to liberate it

A

TLR signalling destroy IkB inhibitor, release NFkB, which translocate to nucleus and activate cytokine transcription

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7
Q

What is the role of TNF-a and CXCL8 and IL6

A

TNF-a: bind TNF-aR, inflammatory, increase vascular permeability, increased IgG/ WBC to tissue –> fever, metabolite mobilization, shock

CXCL8: Chemokine, recruit neutrophils, basophils, T cell to site of infection

IL6: local effect in lymphocyte activation/ antibody production

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8
Q

How does neutrophil get instructed to enter site of infection? What does neutrophil do?

A

TNF-a and CXCL8 attract neutrophil, and promote extravasation

Produce NETS to trap pathogen
Engulf pathogen and fuse it with acidified granule (ROS) to destroy it

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9
Q

What is Sepsis

A

Acute innate inflammatory response that is due to systematic cytokine release, lethal

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10
Q

What is in charge of rapid contaminant VS recurring infection

A

Innate immunity
Adaptive immunity

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11
Q

What is the mechanism of dendritic cell in immunity

A
  1. At the site of infection, PAMPS bind to DC’s TLR, antigen uptake
  2. Antigen loaded PAMPs migrate to lymph node, mature into APC, present antigen to T cell
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12
Q

What is presented by MHC1 VS 2, and what cells present each? Present to what cell?

A

MHC1: intracellular antigen fragment (viral fragment), present by all cell types, to CD8+ cytotoxic T cell

MHC2: Internalized exogenous antigen fragment, present by APCs, to CD4+ helper T cell

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13
Q

What is antigen cross presentation? (exogenous antigen on MHC1/ intracellular antigen on MHC2)

A

To present exogenous antigen on MHC1, PAMPs TLR activation is required

To load intracell antigen on MHC2, no TLR activation is required

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14
Q

For a successful T cell stimulation, what are 2 things that must be able to recognized by TCR? What are the co-stimulations required for full activation?

A

Antigen loaded
specific MHC

CD28 con-stimulation: signal for survival
Cytokines for differentiation

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15
Q

What MHC does CD4+ and CD8+ T cell recognize

A

CD4+: helper, MHC2

CD8+: cytotoxic, MHC1

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16
Q

What’s a immunological synapses

A

APC-T cell binding interface

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17
Q

Name the T cell activation pathway (start from CD3 to differentiation)

A

CD3 contribution –> Ca2+ influx, activate calcineurin –> activate NFAT –> NFAT promote transcription of IL-2 –> IL-2 bind IL2R, activate mTOR –> T cell differentiation from naive to effector

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18
Q

Following DC mediated T cell activation, what stimulation is needed for T cell activity

A

TCR stimulation only

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19
Q

What determine the fate of TCR/CD28 stimulated naive T cell

A

Cytokines released by other immune cells, which activate STAT transcription factor pathway

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20
Q

What is the effect of cytokines produced by each Th cell on other Th phenotypes

A

It inhibit/ disfavour the differentiation of other phenotypes

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21
Q

Function of TH1, Th2, Th17

A

Th1: Release IFN-gama, macrophage activation, intracellular pathogen killing

Th2: Activation of granulocytes, kill parasitic worm (helminths)

Th17: combat extracellular fungi/ bacteria

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22
Q

What cytokines activate Tnaive to Treg? What is released by Treg? What is the function of Treg?

A

TGF-B

Release TGF-B and IL10
Antigen-specific immunosuppression, shut off other T cell activity

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23
Q

What is the relationship between B and T cell

A

B cell present internalized antigen via MHC class 2 to CD4+ Th

Th release cytokine to promote B cell differentiation into plasma cell, release antibody

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24
Q

What are the 2 portions of antibody? Which is the more variable? How are they linked? How many antigen can be recognized by 1 antibody

A

Fab region: antigen binding, most variable
Fc
Link by disulfide bond
Grab 2 antigen at once

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25
What are the main roles of antibody
Bind and neutralize toxins via macrophage ingestion Bind and block virus from fusing into cell (eg bind spike protein, block its access to host receptor) Bind and opsonize extracellular bacteria, promote phagocytosis
26
What is ADCC (antibody dependent cellular cytotoxicity) , use NK cell as example
Antibody Fab bind target cell CD16 of NK recognize and bind Fc of cell bound antibody, release cytotoxicity Antibody = adapter, cross link target and NK
27
What r the 5 main antibody subtypes
IgG, E, M, D, A
28
What is IgG1 and 4 good at?
IgG1= neutralization+opsonization+NK cells, promote inflammation IgG4= neutralization + some opsonization, no NK, promote neutralization without cell disruption
29
Why is IgG1 a concern for pregnant woman?
It has high placental transfer, which can be used for fetal therapy, or a problem
30
What are three common cases when corticosteroid (dexamethasone) is prescribed
1. Acute inflammation 2. Organ transplant recipient 3. Rheumatoid arthritis
31
What is IL10 for
Anti-inflammatory cytokines
32
What is monoclonal VS polyclonal antibody? Which is more preferred as therapeutics
Mono: single clone of antibody produced by same B cell, recognize same antigen same epitope Poly: Mix of multiple antibody recognize different epitope of same antigen Mono is preferred, more homogenous& reproducible PKs/ PDs
33
What is -omab, -ximab, -zumab, -umab?
omab: fully mouse antibody ximab: chimeric, mous Fab human Fc zumab: hummanized umab: fully human
34
What is the problem of animal derived antibody
Unwanted antibody rejection/ immune response
35
What is TMDD/ ATA? What is their imapct on antibody PK profile(serum concentration)
TMDD: target mediated drug distribution. Antibody have high affinity, quickly deposited to target, rapid decrease in serum conc'n ATA: Anti therapeutic antibody. Rapid decrease in serum concentration, as antibody are cleared by immune system
36
What are 2 common strategy to decrease inflammatory T cell activity using antibody
1: Antibody bind and destroy T cell via NK with FcR 2: Bind and block IL2 receptor
37
What is the cause of Rheumatoid Arthritis? What are the cytokines involved
Autoreactive T cell activate macrophage, which produce inflammatory cytokines, which cause cartilage destruction by osteoclast IL1B, IL6, TNF-a
38
What is insufficient immune response against malignant cells a hallmark/ indicator of
Cancer
39
Compare immunotherapy for Cancer VS autoimmune disease (transplant rejection, etc), what do they do to the immune system
Cancer: immunostimulatory Autoimmune: immunosuppressive
40
What are 2 main strategies of cancer immunotherapy
1. Direct immune cell to kill cancer cell (ADCC) 2. Deliver toxin/ radioactive material to cancer cell (antibody conjugates)
41
What is immunological cold tumours
Very few immune cell infiltrating tumor, making it hard to be killed by immune cells
42
What would tumor do to T cells? What can immunotherapy do about it?
Tumor will up-regulate inhibitory receptor/ ligand to inactivate T cell (T cell anergy) Antibody can block these inhibitory interactions, restore T cell activation (disinhibition)
43
What is special about linker used in antibody-drug conjugate
They can be metabolized by enzyme in target cell once internalized, so toxin is only released in target cell, increasing drug safety
44
What happen to efficacy of antibody-drug conjugate, when the DAR (amount of conjugate on antibody) increase to very high
The efficacy drop, since antibody will be cleared quicker by ATA
45
What is bystander effect in antibody drug conjugate therapy
Cells nearby the cell killed by internalized drug will also be impacted by the leaked drug, killing neighbouring cancer cells
46
What does CTLA-4 do? What is its therapeutic application?
It compete CD28 for binding CD80/86. It can be used to treat rheumatoid arthritis, decrease T cell activity by inhibiting CD28 T cell activation signal (2nd signal)
47
What is cytokine release syndrome
Too man/ untrolled release of inflammatory cytokines, causing global inflammation
48
What is adjuvant
Innate immune signal in vaccines, which trigger innate immune response (eg TLR agonist) to initiate antigen presenting
49
What is phospholipase A2 (PLA2) upregulated by? What does it do? What is the effect of membrane damage on it? How can it be a therapeutic target
Activate by inflammatory cytokines &receptor binding Cleaves phospholipid into arachidonic acid (make inflammatory signals PG/LT) Membrane damage increase free phospholipid conc'n, providing more substrate of PLA2 It can be inhibited by glucocorticoids, which decrease arachidonic acid production
50
name the pathway from arachidonic acid to PGD/PGE/PGF/PGI
Arachidonic acid --(COX1/2)--> PGG2--(COX1/2)--> PGH2 --(PGD/E/F/I synthase)--> PGD/E/F/I
51
What is effect of structure change on PGs?
Significantly change PG half life and function
52
Compare structure of PGG/PGH/PGD/PGE/PGF/PGI
PGG: has a peroxyl bridge on its cyclopentane ring, has a unstable peroxide group (-OOH) PGH: Same as PGG, but -OOH cleaved to -OH PGD: -OH on top of ring (C9), -O below the ring (C11) PGE: Opposite -OH(C11) / -O(C9) to PGE PGF: -OH on both site of ring (C9/11) PGI: Second fused ring on top of cyclopentane (C9/8)
53
What does the 2 mean in PGD2
2 unsaturated/ double bond on the chain (not part of the ring)
54
What is the result of chronic PG production What is the action of PG (global/local?) and duration of action
Unwanted chronic inflammatory disease Act locally, degraded rapidly with short half life
55
What does HPGD and CBR1 do?
HPGD: deactivate PGs by oxidizng -OH on C15 to ketone -O CBR1: deactivate PGs by reducing C9 ketone to -OH
56
What makes the action of PG specific/ regulated PG activity? 2 things
Different PG bind to specific receptor expressed in specific tissue Biosynthesis of specific PG is restricted to certain tissue/ cell types
57
What is specific action of PGF2a and PGE2? (hint: lung/ stomach)
PGF2a: bronchoconstriction PGFE2: Inhibit gastric acid secretion, prevent low pH/ ulcer
58
What type of receptor are all PG receptors
GPCR
59
What are the 2 PGs predominantly associated with inflammation? What benefits (non-inflammatory) are provided by them
PGE2 and PGI2 GI protection, CV protection, inhibition of T and B cell prevent overreactive
60
What's difference between COX1 and COX2? Which one do we want to target for anti-inflammatory property
COX1: expressed in tissue that need it for homeostatic effect, such as GI COX2: induced/ expressed when there's acute/ chronic inflammation COX2
61
What is the function of IgE
Sensitization of mast cell, for inflammation/allergy
62
What is mast cell? How is it activated for function? What is the main agent produced?
Cells contain packages of granules (cytotoxic/ inflammatory materials) IgE Fc region bind to the FcRI of mast cell, cause receptor clustering via multivalent antigen ligation(crosslink of bound IgE via antigen), instructing degranulation Histamine
63
What does histamine do
Toxic to some microenvironment Increase vascular permeability Indirect promote leukocytes recruitment
64
What are hallmarks of allergic
Swelling, fluid/mucus production
65
What type of receptor is histamine receptor? What is H1 and H2 mainly for?
GPCR H1: allergic reaction H2: GI pathologies
66
What are two way to counter histamine mediated allergy? What does most 1st line treatment do
1. Decrease degranulation/ histamine release 2. Inhibit downstream effect of histamine Target histamine receptor
67
What is parietal cell for? How is it activated under inflammation? Mechanism of action?
Produce gastric acid It is in close proximity to leukocytes/ histamine release. Histamine bind H2 on parietal, H2 clustering, stimulate cAMP production, PKA increase H+ export via H+/K+ ATPase.
68
What are causes of peptic ulcers?
Excessive acid production (parietal cell) Chronic NSAID use (COX1) H. pylori infection
69
How does H.pylori survive low pH in stomach What are ways to test for H.Pylori How to treat infection
H.Pylori urease enzyme turn urea to NH3+, to buffer acidic environment 12C assay test(breath test), PCR test on stool PPI + cocktail of antibiotics
70
What is crohn disease VS ulcerative colitis What is the mechanism of IBD
Both are IBD Crohn: both large and small intestine ulcerative colitis: only large intestine Loss of intestinal mucus layer, gut microbiome extravasate and interact with leukocyte, induce inflammatory cytokines production
71
What is a key material released under asthma
Leukotrienes
72
What is the mechanism of action of asthma
Allergen recruit inflammatory leukocytes to airway, degranulation, release cytokines,etc, and cause bronchoconstriction, plasma leakage, vasodilation, mucus production
73
What happen to the FEV and FVC if you have asthma? What is normal range? What about restrictive lung
Decrease FEV, normal FVC Decrease FEV/FVC ratio Normal ratio: 0.7-0.8 Decrease in both
74
What is the long term consequence of asthma
Long term airway remodelling, bronchial wall thicken, making breathing harder
75
How is LTs synthesized? Where is the enzyme involved located
From arachidonic acid, via 5-LOX, which make LTA4 (unstable) 5-LOX expressed in leukocytes (mast cell, neutrophils, basophils)
76
What are the 3 cysteinyl leukotrienes? How are the derived?
LTC4, D4, E4 Derived from LTA4 by adding glutathione, producing LTC4 LTC4 glutathione further reduced to make D4/E4
77
What are the 2 potent bronchoconstrictors (LTs) secreted in asthma? How do they act(what receptors? What action)
LTC4, LTD4 Agonize receptor CysLT1/ CysLT2 (GPCR), which inhibit adenyl cyclase, decrease cAMP-->bronchoconstriction
78
What is chronic bronchitis and emphysema? How to treat?
Both are COPD bronchitis: inflammation of bronchioles, increase mucous Emphysema: destruction of walls between alveoli, increased dead volume, decreased lung elasticity, less surface area for gas exchange Quit smoking, vaccination against infectious disease, oxygen supplementation, medication
79
Where is insulin released from What is the general action of insulin
Pancreatic Beta cell Promote glucose uptake, glycogen formation
80
What is released in hypoglycemic situation
Glucagon Induce glycogen breakdown into glucose
81
What is the mechanism of insulin secretion What is the mechanism of action of insulin
GLUT2 transfer glucose into beta cell Glucose breakdown into ATP ATP inhibit K+ channel Depolarization, Ca2+ influx promote insulin exocytosis, secretion to blood stream Insulin bind receptor, receptor clustering, GLUT4 translocate to cell surface for glucose uptake
82
What causes type 1 diabete
Autoreactive CD8+ CTLs destroy pancreatic Beta cell Autoreactive CD4+ cell instruct B cell to make autoantibody causing insufficient/ no insulin secretion
83
What is the problem/ result of hyperglycaemia
Promote ROS production in mitochondria, which cause DNA damage PARP for DNA damage response will inhibit GADPH, which decrease glycolysis, build up og glycolytic intermediate Glycation of protein
84
What is the level of fasting plasma glucose, plasma glucose level, and glycated hemoglobin level of. a diabetic patient
fasting: 126 plasma: 200 glycated: 6.5%
85
Until which stage of type 1 diabete will be symptomatic
stage 3
86
What are the 2 HLA that makes it more susceptible to be type 1 diabetic
DQ2 DQ8
87
What happen to insulin in the presence of Zn2+
It will hexamerizes
88
What are incretins
GLP1 Bind GLP1R, promote insulins secretion, satiation, slow down gastric emptying
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