Liver fibrosis and subsequent cirrhosis result from chronic damage to the liver that is caused by most types of chronic liver disease, including chronic hepatitis C virus infection and alcohol abuse.
In a recent study, researchers have uncovered the cause of suppression of immune function in patients with liver cirrhosis. Carl-Philipp Hackstein, from the University of Bonn, Germany, and colleagues published the results of their study in the journal Gut.
“In severe liver fibrosis and cirrhosis, failure to control bacterial infection is caused by augmented IFN [interferon] and IL-10 [interleukin-10] expression that incapacitates antibacterial immunity of myeloid cells,” the authors write.
Liver fibrosis and subsequent cirrhosis result from chronic damage to the liver that is caused by most types of chronic liver disease, including chronic hepatitis C virus infection and alcohol abuse. Cirrhosis is also associated with abnormalities in the function of the immune system that increase the patient’s susceptibility to bacterial infections—the most common cause of death in this patient population.
Indeed, studies have shown that bacterial translocation from the gut to the mesenteric lymph nodes, for example, is increased in individuals with cirrhosis. The cytokine IL-10 is also thought to play a key role in infection by limiting the response to bacteria in liver disease. However, the exact causes of impaired immunity in patients with cirrhosis that increase their susceptibility to pathogenic bacterial infections has been unclear. Hackstein and colleagues therefore conducted a study to investigate the mechanisms underlying this immune dysfunction.
The researchers induced experimental fibrosis in mice and then infected the animals with the pathogenic intestinal bacterium Listeria monocytogenes. In mice with fibrosis, type 1 IFN was produced on a continual basis by monocytes and macrophages—two types of immune cells—in the liver. Hackstein and colleagues also showed that translocated gut bacteria induced the release of IFN in these mice with cirrhosis. After the researchers infected the mice with L. monocytogenes, the mice were unable to control the bacterial infection and died within six days: bacterial infection markedly increased IFN production, which, in turn, caused monocytes and macrophages to release IL-10 which impaired bacterial immunity, thereby resulting in fatal bacterial infection.
In addition, the researchers examined monocytes from the blood of human patients with cirrhosis and also found markedly increased levels of IFN and IL-10 in these cells.
According to Hackstein and colleagues, the results of their study “provide evidence that translocation of gut microbiota or bacterial degradation products during liver fibrosis and their delivery via portal venous blood to the liver triggers tonic type I IFN expression and signalling that results in dysfunctional innate immunity in myeloid cells failing to control bacterial infection”.
“This identifies IFN and IL-10 receptor signalling as molecular targets for therapeutic intervention to control intractable bacterial infections during liver fibrosis and cirrhosis,” the authors conclude.
Dr. Parry graduated from the University of Liverpool, England in 1997 and is a board-certified veterinary pathologist. After 13 years working in academia, she founded Midwest Veterinary Pathology, LLC where she now works as a private consultant. She is passionate about veterinary education and serves on the Indiana Veterinary Medical Association’s Continuing Education Committee. She regularly writes continuing education articles for veterinary organizations and journals, and has also served on the American College of Veterinary Pathologists’ Examination Committee and Education Committee.