Lecture 14 (8B) - Chronic Viral Hepatitis Flashcards Preview

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Flashcards in Lecture 14 (8B) - Chronic Viral Hepatitis Deck (30):
1

Hepatitis B

300 million
sex
drug injection
50% of UK drug users

2

Hepatitis c

220 million
drugs - blood to blood
50% of drug users
40% in cairo from british injecting everyone in attempt to eradicate bilharzia

3

HBV replication

3 kilobases (when average gene 4-5 kilobases)
• 4 proteins
• DNA virus - can integrate into own chromosomes, use our body enzymes to replicate
• makes pieces of RNA to make DNA again
= REVERSE TRANSCRIPTASE STEP

4

HepB prevalence

• highest - africa, E and SE asia, N canada and greenlad
• intermediate - russia, india, medierranea, brazil, japan
• low - UK, w Europe, USA, australia, new zealand, scandanavia

5

HCV

• RNA virus so makes mistakes (1 mutation per 10,000 bases)
• is 10,000 bases long --> 1 mutation every new strand
• so many changes that T and B cells can't get it because it's changed by the time they're made

6

Symptoms

liver fibrosis --> cirrhosis
ascites - fluid filled abdomen that can burst
multi-focal HCC - liver carcinoma

7

HBV has 2 forms

• acute - fightable
• chronic - worrying one

HepB makes you live long enough to pass it on (mom to kid)

8

Individuals most at risk of developing chronic hepatitis B infection

• neonatal vertical transmission
• infants less than 3 years old
• immunocompromised individuals
- receiving chemotherapy
- haemodialysis patiens
- transplant recipients

9

Outcome of HBV infection according to age at time of infection

chronic from mom, change during puberty
• HepB smart enough to cause pandemic
• 11 years to form adult response to it

10

Hepatitis B natural history

• mother tolerizes, so no liver inflammation because no cells against
• teenage = switches on immune, antigens

alanine transaminase - enzyme commonly assocciated with liver - measures liver health

1. immunotolerant phase
- HBsAg+
- HBeAg+

2. Immunoactive phase
- HBsAg +
- HBeAg+

3. Immunosurveillance phase
- HBsAg+
- HBeAg-

4. Immunoescape phase
- HBsAg+
- HBsAg-

11

HBV therapy

either:
• lamivudine + tenofovir - indefinite therapy of tablets
• pegasys - pegylate interferon - 48 weeks of injections

12

constant battle between immunology and hepatitis B

• low liver inflammation = no T cells from hep B
• passed from mother
• first 20 years of life - 100million per ml of blood
- phase 1
• virus changes in teen year - immune system starts trying to kill it - causes body damage
• disease reactivation in 50s
- phases 2 and 4

13

Hepatitis C

• transmitted by blood-blood contact
• causes slowly progressive liver fibrosis
• cirrhosis and cancer are common
• in the UK drug users are at greatest risk
• junkies virus
• not just a problem in drug users
• common in immigrant communities
• therapy is very effective
• prominent in 3rd world from poor medical practice
• viral disease - transient, self limiting

14

Chronic viral hepatitis

• HBV infects 400 million people worldwide
• HCV infects 180 million people worldwide

15

Viral defences

1. INNATE IMMUNITY - type 1 interferons
2. antibody response (slow)
3. cytotoxic T cells (slow)

16

Interferon and the immune system

IFN-α
• very potent virus killer
• never found a person lacking it
• biggest reason for virus elimination
• induced by viral TLRs in infection
• activates DC - kickstarting active immune response
• good immune booster
• successful virus must switch off IFN
- Hep B and Hep C very good at this
- 1 in 4 Hep B proteins devoted to killing IFN system

17

The interferons - production

• HBV polymerase inhibits the production of interferon
• HCV protease inhibits the production of IFN - chewed up by rigI

18

The interferons - effects

• HBV polymerase inhibits the actions of interferon
• HCV NS5a and E1 inhibit the effects of IFN
• both viruses encode proteins that inhibit production and effects of type I IFN
- virus ttries to make protein to kill IFN and cell tries to make IFN - race, block, rate of production

19

NK cells

not clear how HCV and HBV avoid NK cellls
- host genetic factors?
- right NK --> less likely to get chronic

20

Once a virus has avoided the innate immune response it needs to avoid the

acquired immune response (T and B cells)
• little is known how it avoids
• variable regions mutate so quickly immune system can't get it

21

HBV uses different strategies to avoid the immune response at different stages of its life
• phase 1 immunotolerant

• phase 1 immunotolerant - virus not seen by immune system because it induces tolerance
- the main immune target against HBV is the HBV core protein
- E antigen induces tolerance --> no reaction

1st ATG codes precore/core, into ER --> hijacked, excretory program to excrete E that's like core but small enough to cross placenta (E antigen)

- induced by HBeAg - crossing placcenta
- ATG starts coding for core
- other ATG begins coding for "pre-core" core
- virus hijacks protein excretory system so produces E antigen by hep

• phase 2 immunoactive
- tries to kill virus - damages liver cells
T cell or antibody kill infected cell and virus
- leads to inflammation

22

HBeAg

• HBV core protein is the major target for immune attack
• if HBV is acquired perinatally the disease is always chronic
• HBeAg crosses the placenta and induces tolerance

- hepB tolerizes, introduces to hepB then gets chronic infection

23

HBV uses different strategies to avoid the immune response at different stages of its life
• phase 2 immunoactive

• phase 2 immunoactive
- tries to kill virus - damages liver cells
T cell or antibody kill infected cell and virus
- leads to inflammation
- break tolerance --> get chronic
- the host immune response kills both the virus and the infected cells
- this leads to liver inflammation

24

Immune attack on HBV

phase 2 immunoactive
• T cells kill the infected cell
• antibodies kill the infected cell

25

How does HBV avoid antibodies

• block production
tolerance
• mutate viral proteins

26

Forming HBeAg

pre-core/core with a portion before ATG - ATG
E antigen dependent
clip portion of both
enters ER clipped
get HBeAg
• non needed for replication, affects that region
• gene to stop making target for immune system that will stop it

27

HBeAg
HBV can mutate the

pre-core gene to stop E antigen being made

28

How does HBV get around the cellular immune system?

• indcue tolerance
• block immune priming - infect dendritic cells
• mutate antiviral epitopes
• block IFN production and thereby stop HLA expression on the surface of the cell
• kills cells against itself, mutates itself

29

Viral hepatitis and the immune system

• HBV and HCV both cause chronic disease
• to achieve this they overcome the host defense network
• multiple defense mechanisms operate and most are improperly understood

30

HBV avoids cytotoxic response

• mutate pre-core to stop E antigen being made
• induce tolerance
• block immune priming - infect DC
• mutate anti-viral epitopes
• block INF-production and thereby stop HLA expression on the surface of the cell