Viral Hepatitis Flashcards
Describe the blood supply of the liver
- hepatic artery = normal blood flow
- hepatic portal vein = collects blood from the stomach, pancrease, gallbladder, small and large intestine, and spleen and deliverys in to the liver
Due to the unique blood supply to the liver, what is the liver constantly exposed to?
- food Ags
- bacterial products (e.g. LPS)
- nutrients
- toxins
What is the function of hepatocytes?
generate bile and secrete bile to the gallbladder, sites for viral replicaton
What are the two major functions of bile?
- digestive - emulsify fats and aid uptake of fat and cholesterol
- waste elimination - bilirubin = waste from catabolism of heme from RBCs; liver disease - excess bilirubin –> jaundice
How does blood enter the sinusoids of the liver?
via leaky endothelial cells - LSECs
What are the various cell types present in the liver?
- hepatocytes
- bilirary cells
- CD4/8 T cells
- gd T cells
- NK cells
- B cells
- LSECs
- Kupffer cells - phagocytes
- stellate cells - healthy liver –> quiscent; liver damge –> secrete collagen –> fibrosis
What is a result of LSECs lacking a basement memb?
T cells can get in easily to the sunusoids and see lots of Ags –> bad (can cause uneccessary inflammation) –> solution: the liver is immunoprivileged
Describe the liver under non-inflammatory vs inflammatory conditions
non-inflam:
- Ag presentation by LSECs –> tolerance of T cells
- CD4 T cells secrete IL-4 and 10 (become Tregs)
- CD 8 T cells undergo apoptosis
inflam:
- LSECs down-regulate their MHC expression –> allowing for T cell activation
Describe Kupffer cells (KCs) origin and where they are located
origin: derived from YSP
location: exclusively located to the hepatic sinusoids, do not migrate
Describe the activating and inhibiting Rs on NK cells and what their ligans are, what pathway is stronger?
- KIR (inhibting) binds to MHC-I (stronger)
- KAR (activating )binds to KARL
Describe three different stages of liver injury
- fibrotic liver: from chronic viral infection, alcohol/drug abuse, high fat diet –> NASH (fatty liver disease)
- cirrhotic liver: lots of fibrosis, impaired function
- liver cancer: liver failure/death
Describe how we monitor liver injury
healthy liver:
- hepatocyte intracellular proteins are low in blood (e.g. ALT and ALP)
- hepatocyte secreted proteins are high in blood (e.g. albumin)
fibrotic liver:
- hepatocyte intracellular proteins are high in blood (e.g. ALT and ALP)
- hepatocyte secreted proteins are low in blood (e.g. albumin)
HBV - describe the virus mutation rate, and chronic infection frequencies
mut rate = low (easier to make vaccine)
chronic infection = 90% (vertical), 10% (horizontal)
Describe modes of horizontal and vertical transmission of HBV, and which transmissions are most common where
horizontal:
- blood and blood products
- IV drug use
- sexual tranmission
- mostly in non-endmeic regions
vertical:
- mother to infant at the time of birth
- most common in endemic regions
What HBV Ag does the HBV vaccine target?
targets HBsAg
What HBV molecules are used for diagnosis?
- HBV DNA and HBsAg and HBeAg are elevated in blood
- host Abs against HBcAG, HBeAg, and HBsAg (though not applicable if vaccinated)
Describe HBV’s lifecycle
- entry via NTCP
- generation of cccDNA
- ts and tl
- RT by HBV pol.
- assembly
- release
What HBV viral products are generated during infection?
- infectious virions
- circulating RNAs (present in sub-viral particles)
- HBsAg
- HBcAg
- HBeAg
many different particles –> exasterbate the problem by constantly activating the IS
What factors are monitored to determine what stage of chronic HBV infection your in, are these stages sequential?
factors = cccDNA, HbeAg, ALT
not sequential - can bounce back and forth between stages
Why is it difficult to make a vaccine for HCV?
7 major genotypes + high mutation rate –> increase variability between genotypes
How is HCV transmitted?
- needle - highly efficient, any contamination of drug paraphernalia
- sexual transmission - low efficiency, but common route because a) sex is common behaviour and b) large chronic reservoir in population –> increase change of having an infected partner(s)
What tests do we use for HCV?
- NAAT - detects HCV RNA
- EIA - detects host Abs to HCV
Describe the strucuture of HCV virion
- ss(+)RNA genome
- VLDL coat –> hides virion
- capsid
- env
- E1 and E2 glycoproteins
Describe the HCV life cycle
- entry via Rs (utilizes recognition by lipoprotein)
- uncoating and tl of proteins
- assmebly
- release
What factors do we look at to monitor HCV infection, how do the levels of these factors change over time?
- RNA remains steady
- ALT peaks in the acute phase
- Anti-HCV abs rise over time (but are most often ineffective)
What key thing do we think is necessary to clear an HCV infection?
early induction of HCV nAbs
What do PRR signals increase the production of?
IFNa/B
What do IFNs stimulate?
ISGs –> dampen ability of virus to spread
What signaling pathways do HBV and HCV interfere with?
- infected hepatocyte: RIG-I/TLR3 signaling –> decrease IFNa/B production
- IFN stimulated cells: JAK/STAT –> weaked response of ISGs
Why is HBV considered a stealth virus?
ISG responses are typically quite weak
Describe 6 Bcell/Ab reposnses to HBV
- Ab sequesteratio by sub viral HBsAg particles
- virus neutralization (only anti-HBsAg Abs; if lacking –> chronicity)
- ADCP via KCs
- ADCC via NK cells
- Ag uptake and presentation
- HBV-specific B cells generate antiviral cytokines that: a) supress cccDNA replication, b) downregulated NTCP, c) impair virion assmebly/release
Describe HBV-specific CD8 T cell non cytolytic antiviral activities
- release IFNg and TNFa + express lymphotixin aB on their surface –> mediate antiviral responses in hepatocytes
- APOBEC3 deaminates cytosine residues in cccDNA –> stop codons –> degradation of cccDNA
Describe HBV-specific CD8 T cell cytolytic anti viral activity
release granzyme B and perforin to induce apoptsis of infected hepatocytes
What factors cause HCV to progress to chronic infection?
- ISG responses typically greater than HBV, but weaken over time
- HCV-specific Abs are typically delayed –> failure to neutralize and clear the virus
- chronic type 1 IFN state: induces environent of IL-10 and TGFB = Treg and T cell exhaustion
