How viruses can overwhelm the liver's defences

by Toni Stevens
Liver section from a mouse treated with recombinant adeno-associated viral vectors (rAAV) to force the main liver cell type (hepatocytes) to express Green Fluorescent Protein (GFP).These vectors are the same as those used in gene therapy to correct a gene defect in humans. In this study, these vectors were however used as tools to express both GFP and a model antigen and investigate how immune cells recognise this antigen. The actin (a protein mostly localised under the cell membrane that allows the cell to maintain its shape) is in red while the blue stain reveals the cell nuclei. Credit: David McDonald, Centenary Institute

(Medical Xpress)—The liver is the only organ in the body that can modify our immune response. This, paradoxically, leaves it open to violent immune attack.

Researchers at Sydney's Centenary Institute and the University of Sydney have now discovered the means by which this happens. In the process they may have opened a pathway towards improving treatment of .

The key is in the way the 's T cells operate in the liver.

The researchers found that when the liver T cells encounter a small number of cells making a foreign protein, they function in the normal way—stimulating the production of cells to kill off the source of the protein.

But when they encounter large amounts of foreign protein beyond a certain threshold, the T cells are overwhelmed and fail. This weakening of the defence system is the Achilles heel of the liver, making it more susceptible to invasion by viruses that replicate rapidly and produce large amounts of protein.

"That's what we think happens when a virus such as hepatitis B or C invades the liver," says Dr Patrick Bertolino, co-head with Dr David Bowen of Centenary's Liver Immunology Research Group. "The viruses multiply very fast, spreading to many , and in doing so they force a high proportion of them to make huge amounts of protein."

If this process could be slowed or delayed on initial infection, the researchers believe that the immune system would have a much better chance of clearing the virus – as it already does in about 30 per cent of cases of hepatitis C.

Their work, which was undertaken in collaboration with the Children's Medical Research Institute at the Westmead Hospital, has just been published online in the Proceedings of the National Academy of Sciences.

In earlier studies, the Centenary research team found that the liver is the only place in the body outside of the lymph nodes with the capacity to activate T cells. But, in contrast to the lymph nodes, the T cells activated by the liver do not function efficiently and most of them are eliminated. By this means, the liver can damp down immune system activity.

Bertolino says the next step in this work is to see if T cells, exhausted by high concentrations of viral protein, can be rescued in some way. The group has already shown in mice that it is possible to revive such overwhelmed within the first week after they have encountered a high amount of protein in the .

In 2011 about 209,000 people were living with Hepatitis B infection in Australia resulting in about 382 deaths, according to a 2012 report from the Kirby Institute at the University of New South Wales. The equivalent figures for Hepatitis C are 304,000 resulting in about 380 deaths.

More information: Szun Szun Tay, Yik Chun Wong, David M. McDonald, Nicole A. W. Wood, Ben Roediger, Frederic Sierro, Claire Mcguffog, Ian E. Alexander, G. Alex Bishop, Jennifer R. Gamble, Wolfgang Weninger, Geoffrey W. McCaughan, Patrick Bertolino, and David G. Bowen. "Antigen expression level threshold tunes the fate of CD8 T cells during primary hepatic immune responses." PNAS 2014 ; published ahead of print June 10, 2014, DOI: 10.1073/pnas.1406674111

add to favorites email to friend print save as pdf

Related Stories

How liver kills 'killer cells'

Sep 19, 2011

Our livers can fight back against the immune system -- reducing organ rejection but also making us more susceptible to liver disease.

Liver cancer vaccine effective in mice

Jun 03, 2014

Tweaking a protein expressed by most liver cancer cells has enabled scientists to make a vaccine that is exceedingly effective at preventing the disease in mice.

Hepatitis C virus: How viral proteins interact in human cells

May 08, 2014

Scientists at the Helmholtz Zentrum München have for the first time decrypted the interaction network of hepatitis C virus proteins in living human cells. Their findings will contribute to a better understanding of the mechanisms ...

Recommended for you

Study unlocks basis of key immune protein's two-faced role

Nov 26, 2014

A Brigham and Women's Hospital-led team has identified a long sought-after partner for a key immune protein, called TIM-3, that helps explain its two-faced role in the immune system—sometimes dampening it, other times stimulating ...

Profilin can induce severe food-allergic reactions

Nov 25, 2014

(HealthDay)—Profilins are complete food allergens in food-allergic patient populations that are exposed to high levels of grass pollen, according to a study published in the December issue of Allergy.

Structured education program beneficial for anaphylaxis

Nov 21, 2014

(HealthDay)—A structured education intervention improves knowledge and emergency management for patients at risk for anaphylaxis and their caregivers, according to a study published online Nov. 19 in Allergy.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.