A severe form of fatty liver disease, called non-alcoholic steatohepatitis (NASH), has become a growing problem in Western society due to rising obesity rates. When unaddressed, the inflammatory condition can cause organ scarring, failure and death.
Now, scientists have established a link between NASH and autoimmunity. The new study, published in Science Immunology, describes how fatty, sugary diets can stress immune cells and influence them to damage the liver.
Diet and Disease
It's no secret that a diet high in fat and sugar — such as the American diet — can cause obesity and increase the risk for diseases including type 2 diabetes and nonalcoholic fatty liver disease. NASH is an extreme version of the latter, when fat accumulation begins to cause inflammatory damage.
Because inflammation is an immune response, researchers have long suspected a relationship between the immune system and NASH. But they didn't know what exactly this relationship entailed and whether adaptive immunity — a branch of immunity to which T cells and B cells belong — was involved.
"For this condition, like with type 2 diabetes or chronic inflammation in general, there was this lingering question: how much is the immune system involved in the pathogenesis?" said Laura Santambrogio, the associate director for precision immunology at the Englander Institute for Precision Medicine at Weill Cornell Medicine and corresponding author of the study.
To find the answer to this question, first author of the study Cristina Clement, Santambrogio, and their colleagues fed mice a high-fat, high-sugar diet for three months. This caused the mice, who had a type 2 diabetes-like syndrome, to grow obese and gain NASH-like fat accumulation around their livers. The team then examined the mice's liver immune cells.
As they looked for changes in cell behavior, they noticed that a type of immune cell called a dendritic cell seemed stressed. Dendritic cells train T cells and B cells to attack threats by showing them antigens, or pieces of perceived pathogens. This process is called antigen presentation and it teaches the T cells and B cells "antigen specificity," meaning that the cells learn to target only certain antigens.
In this case, stressed dendritic cells in mice's livers had started presenting a helpful protein, called PDIA3, to other immune cells. This led T cells and B cells to mistakenly gain antigen specificity for PDIA3. They began creating autoantibodies that could cumulatively induce liver toxicity.
"Our work shows that the T cells and B cells [in this disease] are also pathogenic and do harm to the liver," said Santambrogio.
During this portion of the research in mice, the group also observed the presence of autoantibodies specific to other helpful proteins. These should be investigated in the future because they signal the presence of additional autoimmune mechanisms that could be contributing to NASH, said Clement.
From Mice to Humans
Once Clement and Santambrogio found this pathway in mice, they knew their next step was to see if these observations were also present in serum from blood samples from a diverse group of patients.
"First, we wanted to look at type 2 diabetes in people, because we were using animal models of type 2 diabetes. We found a statistically significant increase in autoantibodies, which made it look like this is a pathway also present in patients," said Santambrogio.
However, while type 2 diabetes has some characteristics of autoimmunity, it is not an autoimmune disease. Its autoimmune symptomology largely comes from associated inflammation. To truly establish a connection between anti-PDIA3 autoantibodies and autoimmunity, the collaborators examined serum from patients with autoimmune hepatitis.
"We were very excited to see that this protein is a target not only during chronic inflammation, but also in an autoimmune disease. It gives us the possibility in the future to study a real autoimmune disease which recognizes this target," said Santambrogio.
In addition to this possible opportunity for ongoing research, the team hopes to keep exploring adaptive immune cell responses during NASH, specifically focusing on the many subsets of T cells and the routes they take before becoming dysfunctional. For now, they stress that a key takeaway of their findings is the importance of a healthy diet.
"I think the easiest route for treatment is really the diet, because you take away the problem from the beginning," said Santambrogio.