The role of B cells and immunoglobulins in ALD

Unhealthy nutrition and alcohol abuse causes fat accumulation in the liver (steatosis), which may progress to fibrosis and end-stage organ disease (cirrhosis), the 12th leading cause of mortality worldwide. In fact, approximately half of all cirrhotic deaths are alcohol-related. Currently, the underlying mechanisms by which alcohol contributes to liver injury are largely unknown. Hence, therapeutic options are poor with liver transplantation the only cure for end-stage liver disease. An important role has been proposed for intestinal bacteria in developing alcohol-associated liver disease (ALD). Due to increased alcohol-induced damage in the gut, bacteria and their products leak into circulation and travel to the liver where they are able to induce inflammation and injury. In order to protect against invading pathogens, our body produces antibodies or immunoglobulins that exist in various types and forms that can recognize, bind and clear foreign material. Interestingly, ALD patients have been shown to display increased antibody titers in their blood compared to healthy individuals, indicating altered immune response towards specific substances. Yet, the exact role of different antibodies and their contribution to alcohol-related liver disease is not entirely known. We hypothesize that increased antibody levels in circulation during ALD reflect altered immunity against gut-derived molecules that propagate liver injury. Hence, we aim to characterize antibodies, their targets and the cells that produce them (B cells) in blood and liver of ALD patients. Moreover, we will test their functional role during alcohol-related liver disease in genetically modified mice and appropriate mouse models for ALD. Taken together, these studies will result in novel insights in the disease mechanisms by which alcohol usage results in liver disease and identify novel targets for therapy.