Harbinger of hepatitis

11 May 2010

Flares of liver inflammation in hepatitis B patients are linked to an increase in the blood of two specific proteins

In healthy livers and chronic HBV patients, levels of the inflammatory molecules CXCL-9 and CXCL-10 do not increase.

In healthy livers and chronic HBV patients, levels of the inflammatory molecules CXCL-9 and CXCL-10 do not increase.

© iStockphoto/Eraxion

Damaging periods of inflammation in the liver—called hepatic flares—can be induced by the hepatitis B virus (HBV). Two proteins—specifically the chemokines CXCL-9 and CXCL-10, which are involved in controlling immune system activities—may regulate hepatic flares in human HBV patients, according to a study led by Antonio Bertoletti from A*STAR’s Singapore Institute for Clinical Sciences. 

In five HBV patients who interrupted their antiviral therapy due to toxicity concerns, the researchers tracked changes in a panel of blood cells and proteins that modulate inflammation. In a ‘longitudinal’ analysis where the patients’ blood was sampled every month for almost a year, Bertoletti and his team observed that therapy interruption led to an initial increase in HBV DNA in the blood, followed by a hepatic flare.

During this increase in HBV DNA, the researchers saw no changes in any types of inflammatory molecules in the blood, suggesting that HBV somehow escapes recognition by the immune system during the initial stages of viral replication.

In four of the five patients, however, they observed hepatic flares that occurred simultaneously with a substantial increase in CXCL-9 and CXCL-10. These molecules attract T cells—a type of white blood cell—to various organs, and may play a role in driving immune cell infiltration of the liver, leading to hepatitis.

In ‘cross-sectional’ studies that confirmed the longitudinal study, Bertoletti and his co-workers found high levels of CXCL-9 and CXCL-10 in other HBV patients with acute hepatitis, and in chronic HBV patients who spontaneously developed hepatic flares. However, they found no such increases in uninfected controls or in chronic HBV patients not experiencing hepatic flares.

Although CXCL-9 and CXCL-10 are involved in T cell recruitment, the researchers found no increase in HBV-specific T cells in the blood of the HBV patients during their hepatic flares. They therefore think that these T cells play a role in viral control, but not in liver inflammation.

“The demonstration that chemokines—able to recruit generic inflammatory cells—are increased during hepatic flares confirms the idea that liver damage is mainly mediated by the recruitment of inflammatory cells into the liver,” explains Bertoletti. “HBV-specific T cell responses are likely more important for protection.” Although observed previously in animal models, these are the first such observations in human HBV patients, he notes.

The team suggests that drugs that inhibit CXCL-9 and CXCL-10 may be efficacious in preventing hepatic flares—and therefore avert liver damage—in HBV-infected patients.

The A*STAR-affiliated authors in this highlight are from the Singapore Institute for Clinical Sciences.

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Tan, A.T., Koh, S., Goh, W., Zhe, H.Y., Gehring, A.J., Lim, S.G. & Bertoletti, A. A longitudinal analysis of innate and adaptive immune profile during hepatic flares in chronic hepatitis B. Journal of Hepatology 52, 330–339 (2010). | article

This article was made for A*STAR Research by Nature Research Custom Media, part of Springer Nature