Liver inflammatory diseases I Flashcards
Lectures week 1 (76 cards)
1
Q
Liver lobes are made up of microscopic units called…?
A
Lobules
2
Q
Lobules comprise rows of…?
A
Hepatocytes
3
Q
Which structures encompass the portal triad? (3)
A
- Branches of hepatic artery
- Hepatic portal vein
- Bile duct
4
Q
Which structure are hepatocytes in close contact with?
A
Blood-filled sinusoids
5
Q
Which structure is present at the midpoint of the liver lobule?
A
Central vain
6
Q
How is blood transported out of the liver?
A
Blood flows out of sinusoids into the central vein
7
Q
What are the main functions of the liver? (8)
A
- Metabolism
- Detoxification
- Synthesis
- Blood regulation
- Immune system
- Digestion (bile)
- Removing bacteria from blood
- Storing of vitamins, minerals and sugars
8
Q
What encompasses the metabolism function of the liver?
A
Metabolizes or breaking down of nutrients from food to produce energy
9
Q
What encompasses the detoxification function of the liver?
A
Removing of potentially toxic byproducts of certain medications
10
Q
Which compounds are synthesized by the liver? (4)
A
- Bile
- Most proteins needed by the body
- Substances that regulate blood clotting
- Immunological factors
11
Q
Which immunological factors are produced by the liver?
A
- Complement
- SPRRs (CRP, LBP)
- APPs (fibrinogen)
12
Q
Which cytokine stimulates the production of acute phase proteins?
A
IL-6
13
Q
IL-6 is produced by?
A
Macrophages at the site
14
Q
Which acute phase proteins increase upon inflammation? (5)
A
- CRP
- SAA
- Fibrinogen
- C3
- Haptoglobin
15
Q
Which acute phase proteins decrease upon inflammation? (2)
A
- Albumin
- Transferrin
16
Q
What is meant with a tight balance in immune regulation by the liver?
A
Hepatic immunity vs. tolerance
17
Q
Liver immunity is needed against? (3)
A
- HAV
- HBV
- Many bacterial species
18
Q
Liver tolerance is needed for? (2)
A
- (Endo) toxins
- Food antigens
19
Q
The liver also exhibits unwanted tolerance. Against what is this unwanted tolerance response mounted? (4)
A
- HBV
- HCV
- Malaria
- Tumor metastases
20
Q
Which immune cells reside in the liver? (8)
A
- DCs
- NK
- Kuppfer cells
- Gamma-delta T cells
- B cells
- MAIT
- NKT
- LSEC
21
Q
What are Kuppfer cells?
A
Liver-resident macrophages
22
Q
What are the characteristics of Kuppfer cells? (5)
A
- Phagocytosis
- Direct contact with T cells entering the liver
- Modest stimulatory activity
- Secretion of IL-10
- Expression of scavenger receptors
23
Q
What is the function of liver sinusoidal cells (LSECs)?
A
Removal of waste products
24
Q
Via which ways do LSECs remove waste products? (2)
A
- Receptor-mediated endocytosis
- Lysosomal degradation
25
What facilitates the detection and capture of pathogens, proteins and toxins in the liver?
Slow blood flow in the sinusoids
26
Which types of receptors are used for receptor-mediated endocytosis in the liver? (2)
- Scavenger receptors
- Carbohydrate receptors
27
What are tolerogenic mechanisms in the liver? (4)
- MHC-I
- MHC-II
- Secretion of anti-inflammatory cytokines (IL-10, TGF-B)
- Expression of PDL-1
28
Which characteristic makes MHC-I tolerogenic in the liver?
Cross-presentation to CD8+ T cells -> non-productive activation
29
Which characteristic makes MHC-II tolerogenic in the liver?
Induction of T-reg
30
What is special about DCs in the liver?
Tolerize by default -> IL-10 and IDO secretion upon TLR stimulation
31
What is the main transmission route of HBV?
Blood-to-blood (mainly sexual, mother -> child)
32
What is the main transmission route of HCV?
Blood-to-blood (mainly needles, body piercings, tattoo's, IV drugs)
33
Is vaccination possible for HBV/HCV, yes/no?
HBV: Yes
HCV: No
34
What are the target cells of both HBV and HCV?
Hepatocytes
35
True or false: children are often symptomatic in HBV infection
False -> children are often asymptomatic
36
True or false: adults are often symptomatic in both HBV and HCV
True
37
What is the main disease pathogenesis in HBV/HCV infection?
Fibrosis -> cirrhosis -> liver failure -> HCC
38
How can you describe the viral load pattern in HBV?
Fluctuating
39
How can you describe the viral load pattern in HBV?
High at start -> not per se liver damage
40
How can you describe the immune response mounted during HBV infection?
T cell abundance correlates with viral clearance -> exhaustion
41
How can you describe the immune response mounted during HCV infection?
Lack of innate response -> exhaustion
42
Which therapy is given for chronic hepatitis?
PEG-IFNa + antiviral
43
How does HBV inhibit innate type1 IFN responses?
Active suppression of signals downstream of PRRs (JAK/STAT)
44
How does HCV trigger an IFN response, but inhibits their effects?
Cleavage of IPS-1 and TRIF in the downstream pathway -> inhibits sensing dsRNA structures ands reduction of antiviral state
45
Describe the T cell dynamics in chronic hepatitis patients
T cells initially rise -> magnitude/breath of the response correlates with viral clearance -> T cell responses disappear/exhaustion
46
Which process induces T cell exhaustion?
Prolonged exposure to antigens
47
Which cytokines/processes increase/decrease in T cell exhaustion?
Decrease: IFN-y, TNF, CTL, IL-2 and proliferative potential
Increase: apoptosis
48
How can you tackle cell exhaustion?
Checkpoint inhibition
49
How do both HBV and HCV lead to HCC? (4)
- Integration (HBV)
- Inflammation and fibrosis
- Cell stress
- ROS
50
What are the side effects of PEG-IFN? (5)
- Mild sickness
- Headache
- Fatigue
- Heart- and kidney failure
- Depression
51
HCV has three main genotypes, which genotype accounts for ~72% of the cases?
Genotype 1
52
IFNaR/IFNyR is present on almost every cell type in the body
IFNaR
53
True or false: downstream signaling overlaps between IFNa and IFNy
True
54
How can you use JFH-1 cells to study infectious HCV?
Electroporasis
55
Which particles made by HCV (and host) and necessary for viral replication are used as therapy targets nowadays? (4)
- NS3
- NS5A
- NS5B
- Cycophilin A (host)
56
What is NS3?
Serine protease
57
What is NS5A?
Multifunctional phosphoprotein -> component of the HCV-RNA replication complex
58
What is NS5B?
RNA-dependent RNA polymerase
59
What is cyclophilin A?
Host protein interacting with NS5A and NS5B
60
HCV: What are disadvantages of direct acting antivirals? (4)
- Expensive
- Limited access to treatment in RLS
- Drug-drug interactions
- Screening/prevention programs
61
What are the steps of the HBV lifecycle? (7)
1. HBV Virton binds to cell surface via NTCP
2. Core particle migrates to nucleus
3. Genome repaired to form cccDNA
4. Transcription to form viral mRNA
5. Translation of viral mRNA in cytoplasm to form surface core and polymerase proteins
6. Core particle assembly
7. Recycling genome/export from cell
62
HBV: What are the HBsAg and HBcAg proteins?
HBsAg = surface core
HBcAg = polymerase proteins
63
What are the three HBV particle types? Indicate infectious/non-infectious
- HBV filament -> non-infectious
- HBV sphere -> non-infectious
- HBV virion -> infectious
64
Which proteins are part of the HBV filament, HBV sphere, and HBV virion?
Filament: HBsAg (small and large)
Sphere: HBsAg (small)
Virion: HBsAg, HBcAg, polymerase and HBV DNA
65
What are the treatment options for HBV? (2)
- PEG-IFN
- Nucleos(t)ide analoges (NUC)
66
What is the mechanism of action of nucleus(tide) analogues?
Cause chain termination in step from pregenomic RNA to DNA (eliminate AND suppress viral replication)
67
What is the most targeted step in the viral life cycle of HBV? Why?
Reverse transcriptase step -> not present in humans
68
What are the effects on immune parameters of prolonged NUC treatment? (6)
- CD8+ impaired viral response
- CD4+ reduced proliferative capacity and low frequency
- Decrease in Treg relative frequency
- NK cell impaired IFNy production
- HBsAg, ALT and HBV DNA decrease
- Clearance of HBsAg is rare
69
What is the correlation relationship between Treg and HBV DNA?
Inverse
70
What are immune stimulatory approaches to boost HBV immunity? (3)
- Innate immunomodulators
- Antigen reduction
- Vaccine and checkpoint inhibitors
71
What are the main limitations of HBV treatments? (3)
- Virus not completely eliminated (cccDNA)
- Not all patients are treated
- Access to care
72
What are solutions to combat limitations in HBV treatment? (4)
- Eliminate cccDNA
- Cripple the virus
- Inhibit translation of viral proteins
- Boost immune system
73
HBV: How can you cripple the virus?
Capsid inhibitors
74
HBV: How can you inhibit the translation of viral proteins? (2)
siRNA, anti-sense oligo
75
Why is it hard to design a clinical trial for HBV?
Lots of variation between patients
76
QUANTIFICATION OF B- AND T CELLS
