Home Immunity identify the target of immune attacks on liver cells in metabolic disorders | Writing

identify the target of immune attacks on liver cells in metabolic disorders | Writing


When fat builds up in the liver, the immune system can attack the organ. A new study from Weill Cornell Medicine researchers identifies the molecule that triggers these defenses, a finding that helps explain the underlying dynamics of liver damage that can accompany type 2 diabetes and obesity.

In a study published Aug. 19 in Science Immunology, researchers mimicked these human metabolic diseases by genetically modifying mice or feeding them a diet high in fat and sugar. They then looked at changes in the arm of the rodent’s immune system that mounts defenses tailored to specific threats. When misdirected at the body, this immune response, which involves B and T cells, damages the organs and tissues it is meant to protect.

“For a very long time, people have wondered how T and B cells learn to attack liver cells, which are under increased metabolic stress due to a high-fat, high-sugar diet,” said lead researcher Dr. Dr. Laura Santambrogio, who is Professor of Radiation Oncology and Physiology and Biophysics, and Associate Director of Precision Immunology at Weill Cornell Medicine’s England Institute for Precision Medicine. “We have identified a protein – probably the first of a long series – that is produced by stressed liver cells and then recognized by B and T cells as a target.”

Back row left to right: Madhur Shetty; Marcus DaSilva Goncalves; Laura Santambrogio; Lorenzo Galluzzi; Aitziber Buque. Front row left to right: Jaspreet Osan; Shakti Ramsamooj; Cristina Clement; Takahiro Yamazaki

Activating the immune system further compounds the damage that already occurs in this organ in people with these metabolic conditions, she said.

In type 2 diabetes or obesity, the liver stores excess fat, which can stress the cells, leading to a condition known as non-alcoholic steatohepatitis, commonly known as fatty liver disease. Stress leads to inflammation, a nonspecific immune response that, although intended to protect, can damage tissue over time. Researchers now also have evidence that B and T cell activity also contributes.

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

Dr. Santambrogio and his colleagues, including Dr. Lorenzo Galluzzi, assistant professor of cell biology in radiation oncology at Weill Cornell Medicine and Dr. Marcus Goncalves, assistant professor of medicine at Weill Cornell Medicine and endocrinologist at NewYork-Presbyterian/Weill Cornell Medical Center, along with researchers from Dr. Lawrence Stern’s group at the University of Massachusetts Medical School, wanted to know which molecule in liver cells became their target.

Examining the activity of another type of immune cell, called dendritic cells, led them to a protein, called PDIA3, which they believe activates both B and T cells. , cells make more PDIA3, which travels to their surfaces, where it becomes easier for the immune system to attack.

While these experiments were performed on mice, a similar dynamic appears to be at play in humans. Researchers have found elevated antibody levels for PDIA3 antibodies in blood samples from people with type 2 diabetes, as well as autoimmune conditions affecting the liver and its bile ducts.

Unlike autoimmune diseases, however, improving your diet and losing weight can reverse this liver disease. The link to diet and a decrease in fatty liver was already well established, Dr. Santambrogio said.

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

Many physicians and scientists at Weill Cornell Medicine maintain relationships and collaborate with outside organizations to foster scientific innovation and provide expert advice. The institution makes this information public for the sake of transparency. For this information, see the profiles for Dr. Lorenzo Galluzzi and Dr Marcus Goncalves.