New research from the University of Geneva in Switzerland is inching in on the causes of multiple sclerosis.

In a multiple sclerosis, a cluster of lymphocytes T CD8+ (red) express TOX (green) within the nucleus (blue).
Image credits UNIGE.

Multiple sclerosis (MS) is a debilitating disease that affects roughly 3 in 10.000 people worldwide, and about 0.1% of the population (1 in 1,000 people) in the US. The disease is still as mysterious as ever: we know it involves the breakdown of the myelin sheaths around the tails of neurons in the brain, but not why. Symptoms range from physical or mental to psychiatric — vision problems, impairment of locomotor functions or speech difficulties among others — and they can come about in isolated attacks (relapsing forms) or set in over time (progressive forms). We can help patients manage the symptoms to some extent, but we don’t yet know how to cure the disease.

TOX and MS

Researchers at the University of Geneva (UNIGE), Switzerland, and Geneva University Hospitals (HUG) are investigating into one of the potential culprits behind MS. They have identified one DNA-binding factor named TOX which might play a role in triggering multiple sclerosis — the team reports that TOX enables cells to cause autoimmune damage to brain cells. The team’s findings could help us develop better treatments to both MS and autoimmune diseases in general.

We don’t know why some people develop MS while others don’t. We have observed, however, that the disease is linked with both genetic and environmental risk factors (among the latter being infection and even smoking). To get a better understanding of the processes that underpin MS’s onset, the team decided to look at the role infection factors play in its formation.

“We decided to analyse the infectious factors by studying the auto-immune reactions provoked by different pathogens,” explains Doron Merkler, a Professor at 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”.

The team used with two different pathogens — one viral, the other bacterial — that are known to elicit a response from the immune system. The research was performed using healthy mouse models. According to co-author Nicolas Page, a researcher in UNIGE’s Pathology and Immunology Department, both pathogens elicited a “quantitative identical immune reaction” from one particular type of white blood cells: lymphocytes CD8+ T.

“However, only the mouse infected with the viral pathogen developed an inflammatory brain disease reminiscent to Multiple Sclerosis,” he adds.

The team’s next step was to look at how gene expression levels in CD8+ T varied when different pathogens were used to activate them — which led to the discovery of TOX. This DNA-binding factor expressed only in cells activated by the viral pathogen, they explain. Later, the team confirmed the link between TOX and MS, using mice models in which they eliminating the expression of TOX in CD+ 8 lymphocytes. In this case, the mice didn’t develop the disease despite being infected with the viral pathogen.

However, for all the damage it can do, the team reports that TOX actually means well. Our brains can’t regenerate that well, and relying on tissue regrowth doesn’t guarantee the integrity of function or stored memories — so our body tries to prevent damage to neurons rather than make sure it can easily repair. Our brains are so fragile, however, that they also have to keep out our own immune system cells, which could damage the organ in their relentless fight against pathogens. So, the brain is insulated with barriers that prevent T lymphocytes from entering.

TOX, however, alters the expression of certain key receptors on the surface of CD+ T lymphocytes — the same receptors that receive the “stay away” signals from the brain’s barriers. The defending cells can thus bypass the filters, gain access to the brain, and inadvertently cause the outbreak of the disease, notes the team. Another damning piece of evidence, the team reports, is 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 researchers now plan to study if and how TOX is involved in other autoimmune diseases, as well as certain cancers.

The paper “Expression of the DNA-Binding Factor TOX Promotes the Encephalitogenic Potential of Microbe-Induced Autoreactive CD8+ T Cells” has been published in the journal Immunity.