Multiple sclerosis (MS) is an inflammatory and neurodegenerative autoimmune disease that is potentially disabling on motor, sensory and cognitive levels. Its exact cause remains poorly understood, but it is probably multifactorial, involving genetic or environmental factors. Among the latter, the Epstein-Barr virus (EBV), which is very widespread and particularly responsible for infectious mononucleosis, is a recognized risk factor. The dominant hypothesis on this subject suggests that a protein of the virus, EBNA1, has similarities with proteins of our central nervous system. Consequence: in certain individuals, the immune system mistakenly recognizes EBNA1 in the latter and triggers autoreactivity, leading to an inflammatory cascade and tissue damage at the origin of the clinical manifestations of multiple sclerosis. These reactions which “mistakenly” target our own tissues are called “crossed”.
This mechanism would concern several proteins of our central nervous system, with varied implications in the course of the disease. Some have already been identified, but others are the subject of suspicion without the link having yet been formally established. This is the case of the ANO2 molecule that Olivia Thomas, from the neuroscience department at the Karolinska Institute in Stockholm, and her colleagues studied.
To begin their study, the researchers first confirmed that immune cells from MS patients can accidentally recognize ANO2. They put this protein in contact with T lymphocytes from patients or healthy individuals – a class of immune cells that detect molecules foreign to the body. They then found that in more than 50% of MS patients, T lymphocytes were activated in the presence of ANO2, unlike those of healthy individuals.
This result raised the question: were these ANO2-reactive lymphocytes initially directed against the EBNA1 protein of EBV? The scientists then injected mice with this protein and waited around ten days for the immune system to react specifically to it. They then took the T lymphocytes from these animals and put them in the presence of ANO2 in vitro. These T lymphocytes, manufactured by the immune system to specifically recognize EBNA1, then activated against ANO2, proving the existence of a cross-reaction.
It remained to understand the consequences of this new mechanism on the development of the disease. With this objective, Olivia Thomas’ team directly injected these ANO2-specific lymphocytes into healthy mice and then regularly assessed their state of health. The researchers then found that the injection alone was not enough to cause the disease. In contrast, in mice treated to trigger experimental encephalomyelitis (an animal model of MS), injection of ANO2-specific T cells worsened symptoms.
If this study contributes to the understanding of MS by questioning the contribution of ANO2-specific lymphocytes, many questions remain unresolved, such as the reason for their harmless nature when they are injected alone into healthy animals. Olivia Thomas and her team suspect that these lymphocytes are not capable, on their own, of penetrating the central nervous system and therefore triggering the disease. But pathology, natural or experimentally reproduced, alters the barriers that isolate the nervous system from the immune system. According to the researchers, this alteration could allow the passage of lymphocytes and accentuate inflammation, as well as the intensity of clinical signs. The cross-reaction with ANO2 is therefore an aggravating factor, but is not one of the triggering elements.
The T lymphocytes studied in this work are called CD4 and essentially play a role as coordinators in the reactions of the immune system. A second, even more recent study has in turn linked another large family of T lymphocytes to EBV in multiple sclerosis: killer CD8 T lymphocytes. This confirms that the mechanism linking EBV and MS has not yet revealed its full complexity.
From a broader perspective, although numerous studies implicate EBV in MS, this virus has also been associated with other diseases such as lupus, rheumatoid arthritis and certain cancers. By working on therapies that would make it possible to specifically target it, researchers and clinicians therefore harbor the hope of not only reducing MS, but of improving the prognoses of many other pathologies.
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