DNA binding factor gives clues to the causes of MS

Researchers have identified a DNA-binding factor that might play a role in triggering multiple sclerosis.

There is still no cure for multiple sclerosis, with current treatments largely based on managing symptoms.

Doron Merkler, Professor in the Pathology and Immunology Department the University of Geneva’s Faculty of Medicine said: “We decided to analyse the infectious factors by studying the auto-immune reactions provoked by different pathogens. This was to try to pinpoint an element that might influence the development of multiple sclerosis where there has been an infection.”

Merkler’s team found that the DNA binding factor ‘TOX’ can trigger immune cells to cause autoimmune tissue destruction in the brain. The team say the results of the research, published in the journal Immunity, deliver important insights into our understanding and treatment of autoimmune diseases.

They selected two distinct pathogens that elicit a response from the immune system – one viral and one bacterial – which were then injected into healthy mice. “We saw a quantitatively identical immune reaction from the lymphocytes called CD8+ T,” says Nicolas Page, a researcher in UNIGE’s Pathology and Immunology Department. “However, only the mouse infected with the viral pathogen developed an inflammatory brain disease reminiscent to Multiple Sclerosis.”

Based on these outcomes, the scientists analysed how the expression of the genes in the CD8+ T cells varied according to the pathogen used to activate them. This helped them identify TOX, a DNA-binding factor expressed only in the cells activated by the viral pathogen. They found that the inflammation environment influences the expression of TOX in T lymphocytes, and this, they think, could play a role in triggering the illness.

By developing a TOX-knockout mouse model the immunologists validated the link between TOX and multiple sclerosis. When given the viral pathogen the mice did not develop the disease. “Our brains have a limited regenerative capacity,” says Merkler, “which is why they have to protect themselves against the body’s immune reactions, which can destroy its cells by wanting to fight the virus, creating irreversible damage. The brain then sets up barriers that block the passage of T lymphocytes.” However, by altering the expression of some of the receptors on the surface of the CD8+ T lymphocytes responsible for receiving the blocking signals sent by the brain, TOX enables the cells to cross the safeguards and attack the brain cells, causing the outbreak of the disease.