Rheumatoid arthritis finding may lead to new inflammation blockers

Dec. 27, 2021

Mayo Clinic researchers have linked the T cell dysfunction seen in rheumatoid arthritis with a metabolic deficiency.

They reported their results in Nature Immunology.

In "helper" T cells from patients with rheumatoid arthritis, low levels of a specific amino acid led to cellular miscommunication, but supplying it may provide a new therapeutic strategy for autoimmune disease. Rheumatoid arthritis is an autoimmune disorder characterized by chronic inflammation, including high levels of a cytokine called tumor necrosis factor, or TNF. This protein is used to recruit immune system resources and can cause cell death (necrosis).

"For the last 25 years, tumor necrosis factor has been an important therapeutic target to treat autoimmune disease and tissue inflammation," says Cornelia Weyand, MD, PhD, Mayo Clinic Immunologist and Rheumatologist. "The introduction of tumor necrosis factor-inhibitors was a paradigm shift for the management of inflammatory disease. But while they block the action of TNF in the inflamed tissue site, they cannot prevent the production of the cytokine. Therefore, they cannot treat the root cause of TNF-induced disease.”

In collaboration with Mayo Clinic patients, as well as their rheumatologists and surgical teams, researchers found that T cells are a significant source of tumor necrosis factor. They turned to cell and mouse models to determine why and eventually discovered that the T cells had a defect in their mitochondria.

Through a series of experiments, the researchers discovered that aspartate acts as a messenger between the mitochondria and the endoplasmic reticulum. When mitochondria decrease aspartate communication with the endoplasmic reticulum, that organelle assumes the mitochondria are under stress. The endoplasmic reticulum begins to expand and overproduce proteins in response, one of which is tumor necrosis factor.

"In essence, TNF hyperproduction is a result of a metabolic defect," explains Dr. Weyand. "Misnourished T cells dedicate themselves to TNF production and become highly efficient pro-inflammatory effector cells."

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