Multiple sclerosis is an autoimmune disease of the central nervous system. It affects some 140,000 people in France and is the leading cause of severe non- traumatic disability in young adults. Gut microbiota, hormones, artificial intelligence… Researchers at Université Paris- Saclay are exploring new avenues to better understand and treat the disease. (This article was originally published in L'Édition n°30)
Motor disorders, balance and coordination problems, visual and cognitive impairments… The symptoms of multiple sclerosis (MS) are as unpredictable as the disease itself, which affects 140,000 people in France. MS is a disease of young adults, often diagnosed between the ages of 25 and 35. Although not hereditary, it is multifactorial. It is triggered by a combination of genetic predispositions and environmental factors. The Epstein-Barr virus, which causes mononucleosis, is one of the most significant environmental factors. “We can now define MS as a late complication of this infection,” explains Vito Ricigliano, a neurologist specialising in inflammatory diseases of the central nervous system at Paris- Saclay Hospital and a researcher at the Clinical and Translational Neuroimaging Research Unit (UNIACT – Univ. Paris-Saclay/CEA) at the NeuroSpin centre. Other factors contribute to the development of MS alongside infection with this virus, such as vitamin D deficiency – MS being much more common in northern countries with less sunshine – obesity, smoking and intestinal inflammation.
Multiple sclerosis is an autoimmune disease that affects the central nervous system and causes damage to the brain, spinal cord and optic nerve. In healthy individuals, the axon – which conducts nerve impulses from the neuron to target cells – is surrounded by myelin, a membrane that acts as a protective sheath, much like the insulation around an electrical wire. Myelin thus serves to insulate the axons, accelerate the speed of action potential conduction and support neuronal metabolism. In MS, this sheath becomes the target of the immune system: the body no longer recognises it as its own and attacks it.
This condition has three distinct courses. In 80 to 85% of cases, it presents as the so-called relapsing-remitting form, characterised by alternating phases of inflammatory flare-ups — during which neurological symptoms appear or pre-existing symptoms worsen — and phases of more or less complete remission. During flare-ups,“the immune system becomes dysregulated. Pathogenic T and B lymphocytes are produced and infiltrate the central nervous system,” explains Elisabeth Traiffort, research director and head of the Myelinopathies team at the Neuro-Bicêtre laboratory (Univ. Paris-Saclay/Inserm).The blood-brain barrier, which normally protects the central nervous system from the rest of the body, becomes permeable. Immune cells rush in, triggering inflammation and producing antibodies that attack the myelin. This is demyelination.
Over time, these repeated attacks trigger a secondary reaction. “In the relapsing-remitting form of MS, there is inflammation originating in the periphery that is responsible for the development of lesions. But this also triggers an inflammatory environment within the central nervous system, linked to microglia,” adds Vito Ricigliano. Microglia are the immune cells specific to the central nervous system, the equivalent of macrophages in the rest of the body. They serve to maintain the balance of the cerebral environment. “But when they are activated by peripheral inflammation, they shift into a pro-inflammatory state from which they struggle to emerge.” It is the development of this persistent inflammation that compromises myelin regeneration and prevents complete remission during remitting phases.
Under these inflammatory conditions, oligodendrocytes – cells of the central nervous system responsible for producing myelin – are no longer able to complete their maturation. “Myelin-producing oligodendrocytes represent the final stage of a complex process of differentiation and maturation, initiated at the level of what is known as the oligodendrocyte progenitor,” explains Elisabeth Traiffort. “Central inflammation therefore contributes to the failure of remyelination, leading to the progressive form of the disease.” This form, which is called secondary progressive, is characterised by a worsening of symptoms. However, there are patients (10–15%) in whom the course of MS is progressive from the outset, without a prior relapsing-remitting phase. This is referred to as the primary progressive form.
Given these mechanisms, the treatments available today act solely upstream, by preventing the deregulation of the immune system. “We won’t cure the disease, but we are able to stabilise it using immuno-suppressants and immunomodulators that prevent the immune system from attacking the brain or spinal cord,” explains Vito Ricigliano. These treatment methods have, in fact, come a long way. “When I first became interested in multiple sclerosis in 2012, there were five treatments available. Today, we have twenty.” But the limitation of these treatments is clear: “The drugs do not affect recovery from the after-effects of a relapse; they work by preventing the onset of the next one.” Furthermore, there is currently no approved treatment targeting the mechanisms underlying the progressive forms of MS.
Therefore, it is crucial to study the factors that promote the remyelination of neurons and influence inflammation in the central nervous system, in order to develop new treatments.
When Vito Ricigliano is not with his patients in the hospital, he conducts research into the gut-brain axis, which is one of the avenues for understanding the factors and mechanisms that influence successful remyelination of neurons and the reduction of chronic central inflammation. “My research is based on the observation, established some fifteen years ago, that the composition of the microbiota – the collection of bacteria that colonise human gut – differs between a healthy individual and someone with MS,” explains the neurologist. “In the latter group, we observe a reduction in bacteria that produce short-chain fatty acids. This results in a decrease in certain metabolites — molecules produced by bacteria and released into the bloodstream — which are thought to have a beneficial effect indiseases such as MS." In particular, the reduction in certain of these molecules, such as butyrate or propionate, creates a pro-inflammatory environment. Other molecules, conversely, are produced in greater quantities and also contribute to this imbalance. “The gut influences both central microglial inflammation — which is sensitive to these molecules — and peripheral inflammation.”
“There is also a link between the gut and the brain in terms of lesion repair, and therefore the remyelination of neurons, but this remains poorly characterised,” the researcher emphasises. It has been shown in an animal model of MS that an imbalance in certain metabolites plays a role in the maturation of oligodendrocytes. "If we can show in humans what has been shown in mice, this would pave the way for therapeutic applications.” It should be noted that remyelination does occur in MS, but it remains partial and inadequate, as it affects only about 20% of lesions. What intrigues Vito Ricigliano is the disparity between patients: why do some people repair theirmyelin better than others? “What is interesting is to identify the profiles of good and poor remyelinators to try to understand what makes the difference.”
This is precisely the aim of his ongoing study. “I am going to study around sixty patients with MS,” he explains. At the first visit, each subject undergoes three types of sampling: a stool sample, to determine the composition of their microbiota; a blood sample, to identify the metabolites produced by gut bacteria; and an MRI scan, to measure myelin levels in the brain. All this data is used to build a comprehensive profile of each subject. They will then be classified as good, moderate or poor remyelinators based on their progress as seen on a repeat MRI scan six months later. The profiles will then be cross-referenced with microbiota data: if good remyelinators show higher levels of certain molecules from the outset, and poor remyelinators lower levels, this would constitute a first direct link between the microbiota and the ability to repair myelin in humans. This would confirm what has already been observed in mice.
Finally, by studying the role of the microbiota in the permeability of the blood-brain barrier, Vito Ricigliano hopes to shed light on indirect effects on remyelination. Certain molecules produced by gut bacteria are capable of influencing thispermeability and the circadian rhythm. This, however, affects the waste drainage system, where “toxic elements, reactive oxygen species and pro-inflammatory molecules accumulate when they should be eliminated.” If the microbiota turns out to be involved in remyelination, either directly or indirectly, the therapeutic implications could be highly promising. By modifying one’s diet or lifestyle, it would be possible to promote certain beneficial bacteria and provide a therapeutic approach that could be combined with disease-modifying treatments, which remain central to the management of MS.
The role of the microbiota is not the only avenue being explored at Université Paris-Saclay. The issue of biological sex also reveals fundamental mechanisms in MS – a disease that affects three women for every man in its relapsing-remitting form. “Very early on, the sex dimorphism of MS – that is, the fact that the disease manifests differently in men and women – was highlighted clinically,” explains Elisabeth Traiffort. “Autoimmune diseases are generally much more common in women than in men.”
The role of biological sex has long been studied in the context of this disease: “The involvement of male sex hormones in male MS patients and female sex hormones in female patients with the disease has been the subject of extensive research.” Nevertheless, whilst the hormonal environment of men and women is very different, it should not be reduced to high levels of androgens in men and fluctuating levels of oestrogen and progesterone in women. In fact, men also produce oestrogen, whilst women produce small amounts of androgens. It is precisely this latter point that Elisabeth Traiffort has focused on in a recent study examining the role of the small amounts of androgens present in the central nervous system of women with MS.
To figure this out, she looked at the AR receptor (androgen receptor) – the protein that allows androgens to transmit their signal inside cells. In collaboration with British histopathologists, the team analysed the expression of this receptor in the brain tissue of women and men with MS. Theresult was unexpected: “We found that in demyelinated regions, this receptor was expressed much more strongly in women than in men,” explains the research director. Using mouse models, the team has confirmed this observation: they showed that when the androgenic signal is completely suppressed in female mice, myelin regeneration is significantly reduced. This experiment demonstrates that these hormones, even in small quantities, are essential for optimal myelin regeneration.
The team’s research also showed that androgens influence inflammation in the central nervous system of females. In the demyelinated areas of the female nervous system, it is the microglial cells that predominantly express the AR receptor. By binding to their receptor, androgens “exert a very powerful local anti-inflammatory effect”, which is not observed in males. Yet chronic inflammation in nerve tissue is precisely one of the drivers of the disease’s progression to its most severe forms. Androgens therefore appear to play a dual role in females: directly promoting myelin regeneration and helping to reduce the inflammatory environment that prevents this regeneration.
In order to find treatments for progressive forms of MS, we need “molecules that act both on the inflammation present in the central nervous system and on remyelina-tion. And androgens possess both these properties in females,” explains Elisabeth Traiffort. But there is still a long way togo. “Administering male hormones to women is a very delicate matter.” This requires the development of drug formulations capable of releasing infinitesimal doses of male hormones, primarily into the central nervous system, in order to "normalise" the low levels present in women.
Furthermore, the discovery of this sexual dimorphism, observed at the cellular and molecular levels, has other implications. On the one hand, it raises questions regarding the prognosis of the disease, which is known to be poorer in men than in women. Could this be, at least in part, linked to the absence of the anti-inflammatory effect of androgens in the demyelinated central nervous system of men? On the other hand, the team’s new data highlight a largely underestimated concept, namely the need to take the sex of people with MS into account in the therapeutic management of the disease.
Research on multiple sclerosis also focuses on imaging tools. When it comes to monitoring and diagnosis, MRI has established itself as the gold standard. Its role is to detect and locate the characteristic lesions of the disease, which appear as demyelinating plaques scattered through-out the central nervous system. While visually detecting a lesion is a challenge in itself, quantifying its progression is a major clinical challenge. In patients with a high lesion burden, identifying a new small plaque amidst many others is like “looking for a needle in a haystack”, explains Myriam Edjlali-Goujon, a neuroradiologist and deputy director of the Laboratory of Multimodal Biomedical Imaging at Paris-Saclay (BioMaps - Univ. Paris-Saclay/CEA/CNRS/Inserm).
MRI is not a one-size-fits-all tool: it actually encompasses a wide variety of technologies “that acquire images in very specific ways”, explains Myriam Edjlali-Goujon. The strength of the magnetic field – measured in tesla (T) – varies considerably from one machine to another. “Here, on the Paris-Saclay plateau, we have everything from very low-field machines (64 milliteslas) to standard clinical devices ranging from 1.5 to 3 T, and research equipment used in clinical settings, from 7 T up to 11.7 T.” In addition, there is a wide variety of coils used to capture the signal, which influence the nature of the information gathered. Once the image has been acquired, it is time for analysis. This is what specialists call post-processing, which encompasses all the techniques used to extract quantitative information from the raw data. It is in this field that artificial intelligence (AI) is used as a “statistical data processing tool”, although it is also “already present in image acquisition”.
AI has been used in medical imaging for over ten years now. But what is its added value in the caseof MS? This is the question that Myriam Edjlali-Goujon and her PhD student Milica Mastilovic Jovanovic aim to answer in a study focusing on a population that is particularly complex to monitor: patients with a high lesion burden. Two MRIs taken at different times are available for each subject – allowing researchers to track the progression of the disease – along with the radiological reports. These same images are then reviewed retrospectively, but this time they are accompanied by a report generated by Pixyl, an AI system specifically designed for MS. “The study demonstrates that by combining human interpretation and AI on this cohort, we can better diagnose the progression of the disease,” summarises the professor and neuroradiologist. With this study, “another question then arises: would treatment differ? The answer is yes, in aquarter of cases within a specific sub-population with a high lesion burden.” By improving the detection of new lesions and the accuracy with which disease activity is assessed, the tool leads to a review of certain therapeutic decisions and contributes to more appropriate patient management.
On this basis, a new project has been launched in partnership with Pixyl. It tackles two major obstacles that are hindering the practical deployment of AI in the monitoringof MS. The first is organisational. A patient is often monitored by the same neurologist, but has their successive MRI scans carried out at different centres – using machines of varying power and from different manufacturers. However, an algorithm trained on 3T images will not produce reliable results on data acquired at 1.5T. The project therefore aims to create a centralised server capable of collecting successive MRI scans from the same patient, regardless of the centre, and automatically assessing the degree of compatibility with the AI – indicating whether the conditions are met for the AI to operate within its optimal range.
The second challenge is clinical: measurement of brain atrophy. Over time, advanced MS causes the brain to gradually shrink, as seen in neurodegenerative diseases. Although this marker is linked to disability, it remains impossible for a radiologist to quantify it visually. To validate the brain atrophy quantification algorithm, researchers at BioMaps are drawing on a rare asset: one of the few machines combining PET (positron emission tomography) and MRI available in France. PET provides the gold standard – it reveals metabolic abnormalities even before atrophy is visible on MRI – whilst MRI allows the affected areas to be precisely located. By combining these two sources, the aim is to validate a tool capable of “predicting the formation of new lesions, an increase in the volume of existing ones, and the onset of atrophy. Thanks to these technological advances, we are getting to the heart of the disease,” emphasises Myriam Edjlali-Goujon. “These new data offer the possibility of tailoring treatments much more precisely and at an earlier stage.”
Researchers at Université Paris-Saclay are tackling the mysteries of multiple sclerosis on all fronts. They understand that behind every aspect of this multifactorial disease lie potential therapeutic avenues that have yet to be explored. Although no treatment for the progressive form of MS is yet on the horizon, this remains an ambition which, as research and tools are refined, seems less and lessout of reach.
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This article was originally published in L'Édition n°30.
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