Hepatitis B stimulates processes
that deprive the body's immune cells of key nutrients that they
need to function, according to new research led by scientists at
UCL (University College London).
The work helps to explain why the
immune system cannot control hepatitis B virus infection once it
becomes established in the liver, and offers a target for potential
curative treatments down the line. The research also offers
insights into controlling the immune system, which could be useful
for organ transplantation and treating auto-immune diseases.
Worldwide 240 million people have
chronic hepatitis B and 780,000 people die each year from the liver
cirrhosis and cancer that it causes; existing treatments can rarely
cure this infection. A preventative vaccination against the virus
is available, however it is not routinely given in the UK and is of
no use once you have the infection. Liver disease is the only major
cause of premature death currently increasing in the UK, and
hepatitis B and C are the second commonest underlying causes after
alcohol.
Most adults' immune systems can
control hepatitis B virus within a year (acute infection), but
chronic infection is common in children, particularly in newborns
whose mothers carry the virus, and lasts a lifetime. The new study
suggests that hepatitis B can persist by taking advantage of
suppressor cells in the liver that starve immune responses to
silence them.
"Hepatitis B patients usually don't
have symptoms for decades, so can carry the virus unknowingly and
can spread it through childbirth, sexual contact or contaminated
needles" said Professor Mala Maini of UCL. "Our work has shown that
during this 'silent phase' of infection, specialised suppressor
cells switch off the immune response by cutting off its food
supply. This is one of the many ways the liver protects itself from
inflammation and immune damage but at the same time, prevents
elimination of pathogens like hepatitis B.
"If we could boost the immune
system and counteract the liver's suppressive effect, then the
infection could potentially be cleared after a large 'burst' of
immune activity. This might cause short-term damage to the liver,
but would prevent the long-term damage from scarring and liver
cancers that we see in chronic patients."
The team compared blood samples
from 138 chronic hepatitis B patients and 99 healthy controls, and
examined liver tissue samples from 42 patients. They found that
patients in the silent phases of infection had high levels of cells
called granulocytic myeloid-derived suppressor cells (gMDSCs).
These gMDSCs, which suppress T cells (immune cells) by cutting off
their food supply, were found to accumulate in the liver.
"The gMDSCs suppressed both the T
cells that fight hepatitis B virus and those that cause
inflammation in the liver," explained Dr Laura Pallett, also of
UCL. "So patients with more gMDSC tended to have less liver damage
but were unable to control hepatitis B virus. Women had higher
levels of gMDSC than men, which fits with their threefold lower
risk of developing liver inflammation from hepatitis B."
These findings emphasise how
nutrient supplies can regulate the immune system. They also suggest
that suppressor cells such as gMSDC might have clinical uses in
cases where the immune system attacks healthy tissue, such as
autoimmune diseases or immune rejection of donated organs.
"If these cells can prevent immune
cells from damaging the liver in hepatitis B patients, perhaps they
could+ help to prevent immune rejection of transplanted livers,"
said Professor Maini. "Similarly, such suppressor cells could
potentially be harnessed to protect specific organs from damage in
patients with autoimmune diseases."
The paper, Metabolic regulation of hepatitis B immunopathology by
myeloid-derived suppressor cells, is
published in Nature Medicine.