Autoaggressive T cells aggravate the progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC). The gut-liver axis contributes to NASH, however, the mechanisms behind NASH-induced fibrosis and liver cancer remain unknown. German Cancer Research Center (DKFZ) scientists investigated the role of gastrointestinal B cells in the development of NASH, fibrosis, and NASH-induced HCC. They found B cells promote the development of liver cancer with a dual strategy: via direct cell-cell contact, they activate autoaggressive T cells. In addition, the B cells produce IgA class antibodies that activate specific immune cells, thereby driving liver fibrosis.

The findings are published in the Journal of Hepatology in an article titled, “Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signaling.”

“Worldwide, fatty liver and NASH are assuming pandemic proportions,” said Mathias Heikenwälder, PhD, a group leader at the German Cancer Research Center.

The B cells exert their disastrous influence on the liver in two ways: In the small intestine, they instigate T cells to behave autoaggressively via direct cell-cell contacts. The researchers were also able to reproduce this in the culture dish when they brought B cells from NASH mice together with CD8 T cells from a healthy animal, which were thereby activated to autoaggressive behavior.

In addition, the immunoglobulin A (IgA) produced by the B cells activates another group of immune cells, macrophages, which carry special IgA receptors on their surface. The activated macrophages aggravate fibrotic changes in the liver. If the B cells are switched off with a specific antibody in the NASH-afflicted animals, both the inflammation driven by the autoreactive T cells and the fibrosis regress.

Heikenwälder’s team also examined tissue samples from people who had undergone bariatric surgery. The findings strongly resembled those of mice suffering from NASH: Compared with healthy individuals, the tissue from NASH patients contained significantly more B cells, higher IgA levels, and a higher number of activated macrophages.

“The results clearly show us that B cells, as well as IgA, are required to drive the pathological cascade in the development of liver cancer,” Heikenwälder summarized. “The good thing is that these results show us new ways to preventively interrupt this cancer-driving cascade: If we switch off the B cells with antibodies, the NASH symptoms regress and the animals develop fewer and smaller cancer foci. Fortunately, approved drugs already exist that suppress B-cell activation and that could possibly also stop NASH in humans and thus perhaps also liver cancer. However, there are no results from human studies on this yet.”

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