When fat accumulates within the liver, the immune system may assault the organ. A latest study from Weill Cornell Medicine researchers identifies the molecule that trips these defenses, a discovery that helps to clarify the dynamics underlying liver damage that may accompany type 2 diabetes and obesity.

In a study published Aug. 19 in Science Immunology, researchers mimicked these human metabolic diseases by genetically altering mice or feeding them a high-fat, high-sugar weight loss plan. They then examined changes throughout the arm of the rodent’s immune system that mounts defenses tailored to specific threats. When misdirected back on the body, this immune response, which involves B and T cells, damages the organs and tissues it is supposed to guard.

For the longest time, people have been wondering how T and B cells learn to attack liver cells, that are under increased metabolic stress resulting from a high fat high sugar weight loss plan. We’ve identified one protein -; probably the primary of many -; that’s produced by stressed liver cells after which recognized by each B and T cells as a goal.”

Dr. Laura Santambrogio, lead investigator, professor of radiation oncology and of physiology and biophysics, and associate director for precision immunology, Englander Institute for Precision Medicine, Weill Cornell Medicine

The activation of the immune system further aggravates the damage already occurring inside this organ in individuals who have these metabolic conditions, she said.

In type 2 diabetes or obesity, the liver stores an excessive amount of fat, which may stress cells, resulting in a condition referred to as nonalcoholic steatohepatitis, commonly called fatty liver disease. The stress results in inflammation, a nonspecific immune response that, while meant to guard, can harm tissue over time. Researchers now even have evidence that B and T cells activity contributes, too.

B cells produce proteins called antibodies that neutralize an invader by latching onto a particular a part of it. Likewise, T cells destroy infected cells after recognizing partial sequences of a goal protein. Sometimes, as happens in autoimmune diseases, these cells activate the body by recognizing “self” proteins.

Dr. Santambrogio and her colleagues, including Dr. Lorenzo Galluzzi, assistant professor of cell biology in radiation oncology at Weill Cornell Medicine and Dr. Marcus Goncalves, assistant professor of drugs at Weill Cornell Medicine and an endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center, in addition to researchers from Dr. Lawrence Stern’s group on the University of Massachusetts Medical School, desired to know what molecule inside liver cells became their goal.

Examining the activity of one other kind of immune cell, called dendritic cells, led them to a protein, called PDIA3, that they found prompts each B and T cells. When under stress, cells make more PDIA3, which travels to their surfaces, where it becomes easier for the immune system to attack.

While these experiments were done in mice, an analogous dynamic appears to be at play in humans. The researchers found elevated levels of antibodies for PDIA3 antibodies in blood samples from individuals with type 2 diabetes, in addition to in autoimmune conditions affecting the liver and its bile ducts.

Unlike in autoimmune conditions, nevertheless, improving one’s weight loss plan and losing a few pounds can reverse this liver condition. The reference to weight loss plan and a decrease in fatty liver disease was already well established, Dr. Santambrogio said.

“We’ve added a latest piece to the puzzle,” she said, “by showing how the immune system starts to attack the liver.”

Source:

Journal reference:

Clement, C.C., et al. (2022) PDIA3 epitope-driven immune autoreactivity contributes to hepatic damage in type 2 diabetes. Science Immunology. doi.org/10.1126/sciimmunol.abl3795.