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I&I WC2 > Liver inflammatory diseases I > Flashcards

Liver inflammatory diseases I Flashcards

Lectures week 1

1
Q

Liver lobes are made up of microscopic units called…?

A

Lobules

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2
Q

Lobules comprise rows of…?

A

Hepatocytes

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3
Q

Which structures encompass the portal triad? (3)

A
  • Branches of hepatic artery
  • Hepatic portal vein
  • Bile duct
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4
Q

Which structure are hepatocytes in close contact with?

A

Blood-filled sinusoids

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5
Q

Which structure is present at the midpoint of the liver lobule?

A

Central vain

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6
Q

How is blood transported out of the liver?

A

Blood flows out of sinusoids into the central vein

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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
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8
Q

What encompasses the metabolism function of the liver?

A

Metabolizes or breaking down of nutrients from food to produce energy

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9
Q

What encompasses the detoxification function of the liver?

A

Removing of potentially toxic byproducts of certain medications

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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
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11
Q

Which immunological factors are produced by the liver?

A
  • Complement
  • SPRRs (CRP, LBP)
  • APPs (fibrinogen)
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12
Q

Which cytokine stimulates the production of acute phase proteins?

A

IL-6

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13
Q

IL-6 is produced by?

A

Macrophages at the site

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14
Q

Which acute phase proteins increase upon inflammation? (5)

A
  • CRP
  • SAA
  • Fibrinogen
  • C3
  • Haptoglobin
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15
Q

Which acute phase proteins decrease upon inflammation? (2)

A
  • Albumin
  • Transferrin
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16
Q

What is meant with a tight balance in immune regulation by the liver?

A

Hepatic immunity vs. tolerance

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17
Q

Liver immunity is needed against? (3)

A
  • HAV
  • HBV
  • Many bacterial species
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18
Q

Liver tolerance is needed for? (2)

A
  • (Endo) toxins
  • Food antigens
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19
Q

The liver also exhibits unwanted tolerance. Against what is this unwanted tolerance response mounted? (4)

A
  • HBV
  • HCV
  • Malaria
  • Tumor metastases
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20
Q

Which immune cells reside in the liver? (8)

A
  • DCs
  • NK
  • Kuppfer cells
  • Gamma-delta T cells
  • B cells
  • MAIT
  • NKT
  • LSEC
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21
Q

What are Kuppfer cells?

A

Liver-resident macrophages

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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
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23
Q

What is the function of liver sinusoidal cells (LSECs)?

A

Removal of waste products

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24
Q

Via which ways do LSECs remove waste products? (2)

A
  • Receptor-mediated endocytosis
  • Lysosomal degradation
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25
Q

What facilitates the detection and capture of pathogens, proteins and toxins in the liver?

A

Slow blood flow in the sinusoids

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26
Q

Which types of receptors are used for receptor-mediated endocytosis in the liver? (2)

A
  • Scavenger receptors
  • Carbohydrate receptors
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27
Q

What are tolerogenic mechanisms in the liver? (4)

A
  • MHC-I
  • MHC-II
  • Secretion of anti-inflammatory cytokines (IL-10, TGF-B)
  • Expression of PDL-1
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28
Q

Which characteristic makes MHC-I tolerogenic in the liver?

A

Cross-presentation to CD8+ T cells -> non-productive activation

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29
Q

Which characteristic makes MHC-II tolerogenic in the liver?

A

Induction of T-reg

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30
Q

What is special about DCs in the liver?

A

Tolerize by default -> IL-10 and IDO secretion upon TLR stimulation

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31
Q

What is the main transmission route of HBV?

A

Blood-to-blood (mainly sexual, mother -> child)

32
Q

What is the main transmission route of HCV?

A

Blood-to-blood (mainly needles, body piercings, tattoo’s, IV drugs)

33
Q

Is vaccination possible for HBV/HCV, yes/no?

A

HBV: Yes
HCV: No

34
Q

What are the target cells of both HBV and HCV?

A

Hepatocytes

35
Q

True or false: children are often symptomatic in HBV infection

A

False -> children are often asymptomatic

36
Q

True or false: adults are often symptomatic in both HBV and HCV

37
Q

What is the main disease pathogenesis in HBV/HCV infection?

A

Fibrosis -> cirrhosis -> liver failure -> HCC

38
Q

How can you describe the viral load pattern in HBV?

A

Fluctuating

39
Q

How can you describe the viral load pattern in HBV?

A

High at start -> not per se liver damage

40
Q

How can you describe the immune response mounted during HBV infection?

A

T cell abundance correlates with viral clearance -> exhaustion

41
Q

How can you describe the immune response mounted during HCV infection?

A

Lack of innate response -> exhaustion

42
Q

Which therapy is given for chronic hepatitis?

A

PEG-IFNa + antiviral

43
Q

How does HBV inhibit innate type1 IFN responses?

A

Active suppression of signals downstream of PRRs (JAK/STAT)

44
Q

How does HCV trigger an IFN response, but inhibits their effects?

A

Cleavage of IPS-1 and TRIF in the downstream pathway -> inhibits sensing dsRNA structures ands reduction of antiviral state

45
Q

Describe the T cell dynamics in chronic hepatitis patients

A

T cells initially rise -> magnitude/breath of the response correlates with viral clearance -> T cell responses disappear/exhaustion

46
Q

Which process induces T cell exhaustion?

A

Prolonged exposure to antigens

47
Q

Which cytokines/processes increase/decrease in T cell exhaustion?

A

Decrease: IFN-y, TNF, CTL, IL-2 and proliferative potential

Increase: apoptosis

48
Q

How can you tackle cell exhaustion?

A

Checkpoint inhibition

49
Q

How do both HBV and HCV lead to HCC? (4)

A
  • Integration (HBV)
  • Inflammation and fibrosis
  • Cell stress
  • ROS
50
Q

What are the side effects of PEG-IFN? (5)

A
  • Mild sickness
  • Headache
  • Fatigue
  • Heart- and kidney failure
  • Depression
51
Q

HCV has three main genotypes, which genotype accounts for ~72% of the cases?

A

Genotype 1

52
Q

IFNaR/IFNyR is present on almost every cell type in the body

53
Q

True or false: downstream signaling overlaps between IFNa and IFNy

54
Q

How can you use JFH-1 cells to study infectious HCV?

A

Electroporasis

55
Q

Which particles made by HCV (and host) and necessary for viral replication are used as therapy targets nowadays? (4)

A
  • NS3
  • NS5A
  • NS5B
  • Cycophilin A (host)
56
Q

What is NS3?

A

Serine protease

57
Q

What is NS5A?

A

Multifunctional phosphoprotein -> component of the HCV-RNA replication complex

58
Q

What is NS5B?

A

RNA-dependent RNA polymerase

59
Q

What is cyclophilin A?

A

Host protein interacting with NS5A and NS5B

60
Q

HCV: What are disadvantages of direct acting antivirals? (4)

A
  • Expensive
  • Limited access to treatment in RLS
  • Drug-drug interactions
  • Screening/prevention programs
61
Q

What are the steps of the HBV lifecycle? (7)

A
  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
Q

HBV: What are the HBsAg and HBcAg proteins?

A

HBsAg = surface core
HBcAg = polymerase proteins

63
Q

What are the three HBV particle types? Indicate infectious/non-infectious

A
  • HBV filament -> non-infectious
  • HBV sphere -> non-infectious
  • HBV virion -> infectious
64
Q

Which proteins are part of the HBV filament, HBV sphere, and HBV virion?

A

Filament: HBsAg (small and large)
Sphere: HBsAg (small)
Virion: HBsAg, HBcAg, polymerase and HBV DNA

65
Q

What are the treatment options for HBV? (2)

A
  • PEG-IFN
  • Nucleos(t)ide analoges (NUC)
66
Q

What is the mechanism of action of nucleus(tide) analogues?

A

Cause chain termination in step from pregenomic RNA to DNA (eliminate AND suppress viral replication)

67
Q

What is the most targeted step in the viral life cycle of HBV? Why?

A

Reverse transcriptase step -> not present in humans

68
Q

What are the effects on immune parameters of prolonged NUC treatment? (6)

A
  • 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
Q

What is the correlation relationship between Treg and HBV DNA?

70
Q

What are immune stimulatory approaches to boost HBV immunity? (3)

A
  • Innate immunomodulators
  • Antigen reduction
  • Vaccine and checkpoint inhibitors
71
Q

What are the main limitations of HBV treatments? (3)

A
  • Virus not completely eliminated (cccDNA)
  • Not all patients are treated
  • Access to care
72
Q

What are solutions to combat limitations in HBV treatment? (4)

A
  • Eliminate cccDNA
  • Cripple the virus
  • Inhibit translation of viral proteins
  • Boost immune system
73
Q

HBV: How can you cripple the virus?

A

Capsid inhibitors

74
Q

HBV: How can you inhibit the translation of viral proteins? (2)

A

siRNA, anti-sense oligo

75
Q

Why is it hard to design a clinical trial for HBV?

A

Lots of variation between patients

76
Q

QUANTIFICATION OF B- AND T CELLS

I&I WC2 (22 decks)

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