Infection 6: Pathogenesis of viral hepatitis Flashcards
Acute hepatitis
More florid the attack, chronic sequelae less likely
Chronic hepatitis
Abnormal LFTs and positive serological markers > 6 months
Histological stage 1
Fibrous expansion of some portal areas
Histological stage 3
Fibrous expansion of most portal areas with occasional portal to portal bridging
Histological stage 4
Fibrous expansion of portal areas with marked bridging
Histological stage 5,6
Cirrhosis probable or defined
Nodular fibrous scarring of the liver
HBV replication
Replication of DNA genome by reverse transcription of RNA intermediate
Commonest causes of liver damage and cirrhosis
Hepatitis
Structure of virus
Viral DNA inside protein envelope
Lipid bilayer around it
Viral life cycle
Viral particle infects liver cells
Binds to receptor
Goes into nucleus where DNA is linear
Repaired to become readable circular DNA
Remains in nucleus to be transcribed
Virus is assembled
New particle exocytosed
Neighbouring cells infected
Damage
PAMP recognised by TLR3 leading to RIG-1 signalling
Interferon regulatory factors and NF-kB leads to interferon stimulating genes
This activates INF a/B
- down regulates viral protein synthesis
- inhibit viral replication
- promote adaptive immunity via MHC class 1 expression on APC
- activates NK, CD8 and dendritic cells
- activate cell death trough secretions of perforins
Lack of HBV clearance
Evades detection of innate system
- ? cccDNA
Not recognised by hbost immune system
Interferes with expression of TLR
HBsAb
Development of HBsAb provides life long immunity
Neutralising antibody forms complex with HBSAg and prevents uptake by uninfected hepatocytes
FAS ligand/ perforin
LATE: CD8 attaches to receptor on hepatitis cell
Leads to apoptosis so is cytopathic
EARLY: CD8 with IFN y/a doesn’t bind
Non-cytopathic
Resolved infection
96% immunocompetent adults
Life long immunity
Polyclonal and multispecific intrahepatic CD8+ cells response
Early CD4+ primary contribute to synchronised influx HBV specific CD8+ cells resulting in viral clearance
Persistent infection: age
HBeAg only antigen that crosses the placenta
- induces tolerance to HhcAg (most immunogenic)
- suppress immune mediated elimination of infected cells
- switches immune response to Th2
Persistent infection: immunosuppresion- inadequate CMI
Weak/ narrow intrahepatic CD4+/CD8+ cell response
- high viral load: anergy, exhaustion of T and B cells
- antiviral therapy: recovery of HBV specific CD4+/CD8+ cells
Persistent infection
HBV X protein interferes with antigen processing and presentation- protects cccDNA
Foxp3 expressed on Tregs: suppress HBV specific T cell responses
Programmed death 1 receptor (CD28) upregulated- promote apoptosis thereby down regulate virus specific T cell
Cytotoxic T lymphocyte antigen 4: immune off switch when bound to CD80 or CD86 on the surface of antigen presenting cells
Persistent infection: IL10
Down regulates antiviral immune responses
- CD4+ and CD8+ suppression with inhibition of IFN-y/a production
Attenuates inflammatory response but at cost of efficient antiviral immune responses
Chronic HBV treatment
Pegylated interferon
Tenofovir/ tenefovir alafenamide
Entecavir
Cure defined by loss of HBsAg- happens only rarely
Course of hepatitis B infection
Age at infection
Immunosuppression
Host immune response
HBV genotype and mutations
Coexisting risk factor: alcohol, HCV, HIV
HBV key points
HBV evades innate immune responses
Early priming of CD4 cells –> CD8 cells activation
Humoral response late: no contribution to viral clearance by reduce viral spread
- HBsAb prevents reinfection
95% of immunocompetent adults clear the infection
90% neonates develop chronic infection
Hepatitis C infection
RNA virus
Rapid rate of replication
80% develop chronic infection
No vaccine
HCV high replication rate of viral antigen load
CD8+/CD4+ anergic/ exhausted: unable to proliferate/ secrete cytokines
Display normal immune responses to other viruses
HCV high error rate of RNA dependent polymerase
Leading to mutations (quasispecies)
Escape neutralizing antibodies and cellular immune responses
HCV proteins interfere with immune response
NS proteins inhibit innate immune reponses (recognition of TLR) through disruption of RIG-I signalling
Core protein down regulates IL-12 production
HCV neutralizing AB
Core, envelope, NS3, NS4
Develops too slowly, too late, short lived inducing HCV escape mutations
HCV key points
Not directly cytopathic
Up to 80% can develop chronic disease
Defects in both humoral and especially cellular immunity
Neutralising antibody does not prevent reinfection
High replicative rate and generation of escape mutants
Direct acting antiviral resulted in paradigm shift in HCV management
