First clues to the causes of multiple sclerosis

Multiple sclerosis, which affects 1 in 1,000 people, is frequently characterised by relapses associated with variable functional impairments including among others vision problems, impairment of locomotor functions or difficulties with speech. There is still no cure for multiple sclerosis, with current treatments largely based on managing symptoms, especially accelerating recovery phases following a relapse and reducing the number and severity of relapses. Researchers at the University of Geneva (UNIGE), Switzerland, and Geneva University Hospitals (HUG) have identified a DNA-binding factor called TOX that might play a role in triggering multiple sclerosis. They found that TOX license immune cells to cause autoimmune tissue destruction in the brain. The results of the research, published in the journal Immunity, deliver important insights into our understanding and treatment of auto-immune diseases.

Multiple sclerosis is as much of a mystery today as it has always been. We know that genetic risk factors but also environmental ones such as infection or even smoking are known to play a role in the development of the disease. However, it is still not known why it is triggered in some cases and not in others. "We decided to analyse the infectious factors by studying the auto-immune reactions provoked by different pathogens," explains Doron Merkler, Professor in the Pathology and Immunology Department in UNIGE's Faculty of Medicine and in the HUG Clinical Pathology Department. "This was to try to pinpoint an element that might influence the development of multiple sclerosis where there has been an infection".

Viral pathogen versus bacterial pathogen

The UNIGE researchers 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. "We found that the inflammation environment influences the expression of TOX in T lymphocytes, and that it could play a role in triggering the illness," continues Page.

Nothing stops TOX

The immunologists validated the link between TOX and multiple sclerosis in the experimental model by eliminating the expression of this DNA-binding factor in the CD8+ T lymphocytes of healthy mice. "And, although they received the viral pathogen, the mice did not develop the disease," mentioned Merkler.

What, then, is the role of TOX in setting off multiple sclerosis? "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.

A step towards a better understanding of multiple sclerosis

Following these analyses, the UNIGE researchers noted that TOX was also expressed in T cells present in multiple sclerosis lesions. "This is an encouraging result for understanding the causes of the disease but there is still lots of work to be done to ascertain what really causes multiple sclerosis in humans," admits Page. The UNIGE researchers will now target the functioning of TOX and its involvement in other auto-immune diseases as well as in some types of cancer.

Nicolas Page, Bogna Klimek, Mathias De Roo, Karin Steinbach, Hadrien Soldati, Sylvain Lemeille, Ingrid Wagner, Mario Kreutzfeldt, Giovanni Di Liberto, Ilena Vincenti, Thomas Lingner, Gabriela Salinas, Wolfgang Brück, Mikael Simons, Rabih Murr, Jonathan Kaye, Dietmar Zehn, Daniel D. Pinschewer, Doron Merkler.
Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells.
Immunity, Volume 48, Issue 5, p937-950.e8. doi: 10.1016/j.immuni.2018.04.005.

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