No lack of regulatory B cells in patients with Multiple Sclerosis

International audienc

αβ T-cell receptors from multiple sclerosis brain lesions show MAIT cell–related features

Objectives: To characterize phenotypes of T cells that accumulated in multiple sclerosis (MS) lesions, to compare the lesional T-cell receptor (TCR) repertoire of T-cell subsets to peripheral blood, and to identify paired α and β chains from single CD8+ T cells from an index patient who we followed for 18 years. Methods: We combined immunohistochemistry, laser microdissection, and single-cell multiplex PCR to characterize T-cell subtypes and identify paired TCRα and TCRβ chains from individual brain-infiltrating T cells in frozen brain sections. The lesional and peripheral TCR repertoires were analyzed by pyrosequencing. Results: We found that a TCR Vβ1+ T-cell population that was strikingly expanded in active brain lesions at clinical onset comprises several subclones expressing distinct yet closely related Vα7.2+ α chains, including a canonical Vα7.2-Jα33 chain of mucosal-associated invariant T (MAIT) cells. Three other α chains bear striking similarities in their antigen-recognizing, hypervariable complementarity determining region 3. Longitudinal repertoire studies revealed that the TCR chains that were massively expanded in brain at onset persisted for several years in blood or CSF but subsequently disappeared except for the canonical Vα7.2+ MAIT cell and a few other TCR sequences that were still detectable in blood after 18 years. Conclusions: Our observation that a massively expanded TCR Vβ1-Jβ2.3 chain paired with distinct yet closely related canonical or atypical MAIT cell–related α chains strongly points to an antigen-driven process in early active MS brain lesions

MD1003 (high-dose biotin) for the treatment of progressive multiple sclerosis: A randomised, double-blind, placebo-controlled study.

BACKGROUND: Treatment with MD1003 (high-dose biotin) showed promising results in progressive multiple sclerosis (MS) in a pilot open-label study. OBJECTIVE: To confirm the efficacy and safety of MD1003 in progressive MS in a double-blind, placebo-controlled study. METHODS: Patients (n = 154) with a baseline Expanded Disability Status Scale (EDSS) score of 4.5-7 and evidence of disease worsening within the previous 2 years were randomised to 12-month MD1003 (100 mg biotin) or placebo thrice daily, followed by 12-month MD1003 for all patients. The primary endpoint was the proportion of patients with disability reversal at month 9, confirmed at month 12, defined as an EDSS decrease of ⩾1 point (⩾0.5 for EDSS 6-7) or a ⩾20% decrease in timed 25-foot walk time compared with the best baseline among screening or randomisation visits. RESULTS: A total of 13 (12.6%) MD1003-treated patients achieved the primary endpoint versus none of the placebo-treated patients (p = 0.005). MD1003 treatment also reduced EDSS progression and improved clinical impression of change compared with placebo. Efficacy was maintained over follow-up, and the safety profile of MD1003 was similar to that of placebo. CONCLUSION: MD1003 achieves sustained reversal of MS-related disability in a subset of patients with progressive MS and is well tolerated.journal article2016 Nov2016 09 01importe

JAMA Neurol

Importance: Moderately effective therapies (METs) have been the main treatment in pediatric-onset multiple sclerosis (POMS) for years. Despite the expanding use of highly effective therapies (HETs), treatment strategies for POMS still lack consensus.Objective: To assess the real-world association of HET as an index treatment compared with MET with disease activity.Design, setting, and participants: This was a retrospective cohort study conducted from January 1, 2010, to December 8, 2022, until the last recorded visit. The median follow-up was 5.8 years. A total of 36 French MS centers participated in the Observatoire Français de la Sclérose en Plaques (OFSEP) cohort. Of the total participants in OFSEP, only treatment-naive children with relapsing-remitting POMS who received a first HET or MET before adulthood and at least 1 follow-up clinical visit were included in the study. All eligible participants were included in the study, and none declined to participate.Exposure: HET or MET at treatment initiation.Main outcomes and measures: The primary outcome was the time to first relapse after treatment. Secondary outcomes were annualized relapse rate (ARR), magnetic resonance imaging (MRI) activity, time to Expanded Disability Status Scale (EDSS) progression, tertiary education attainment, and treatment safety/tolerability. An adapted statistical method was used to model the logarithm of event rate by penalized splines of time, allowing adjustment for effects of covariates that is sensitive to nonlinearity and interactions.Results: Of the 3841 children (5.2% of 74 367 total participants in OFSEP), 530 patients (mean [SD] age, 16.0 [1.8] years; 364 female [68.7%]) were included in the study. In study patients, both treatment strategies were associated with a reduced risk of first relapse within the first 2 years. HET dampened disease activity with a 54% reduction in first relapse risk (adjusted hazard ratio [HR], 0.46; 95% CI, 0.31-0.67; P < .001) sustained over 5 years, confirmed on MRI activity (adjusted odds ratio [OR], 0.34; 95% CI, 0.18-0.66; P = .001), and with a better tolerability pattern than MET. The risk of discontinuation at 2 years was 6 times higher with MET (HR, 5.97; 95% CI, 2.92-12.20). The primary reasons for treatment discontinuation were lack of efficacy and intolerance. Index treatment was not associated with EDSS progression or tertiary education attainment (adjusted OR, 0.51; 95% CI, 0.24-1.10; P = .09).Conclusions and relevance: Results of this cohort study suggest that compared with MET, initial HET in POMS was associated with a reduction in the risk of first relapse with an optimal outcome within the first 2 years and was associated with a lower rate of treatment switching and a better midterm tolerance in children. These findings suggest prioritizing initial HET in POMS, although long-term safety studies are needed.Observatoire Français de la Sclérose en Plaque

Neurology

The question of the long-term safety of pregnancy is a major concern in patients with multiple sclerosis (MS), but its study is biased by reverse causation (women with higher disability are less likely to experience pregnancy). Using a causal inference approach, we aimed to estimate the unbiased long-term effects of pregnancy on disability and relapse risk in patients with MS and secondarily the short-term effects (during the perpartum and postpartum years) and delayed effects (occurring beyond 1 year after delivery). We conducted an observational cohort study with data from patients with MS followed in the Observatoire Français de la Sclérose en Plaques registry between 1990 and 2020. We included female patients with MS aged 18-45 years at MS onset, clinically followed up for more than 2 years, and with ≥3 Expanded Disease Status Scale (EDSS) measurements. Outcomes were the mean EDSS score at the end of follow-up and the annual probability of relapse during follow-up. Counterfactual outcomes were predicted using the longitudinal targeted maximum likelihood estimator in the entire study population. The patients exposed to at least 1 pregnancy during their follow-up were compared with the counterfactual situation in which, contrary to what was observed, they would not have been exposed to any pregnancy. Short-term and delayed effects were analyzed from the first pregnancy of early-exposed patients (who experienced it during their first 3 years of follow-up). We included 9,100 patients, with a median follow-up duration of 7.8 years, of whom 2,125 (23.4%) patients were exposed to at least 1 pregnancy. Pregnancy had no significant long-term causal effect on the mean EDSS score at 9 years (causal mean difference [95% CI] = 0.00 [-0.16 to 0.15]) or on the annual probability of relapse (causal risk ratio [95% CI] = 0.95 [0.93-1.38]). For the 1,253 early-exposed patients, pregnancy significantly decreased the probability of relapse during the perpartum year and significantly increased it during the postpartum year, but no significant delayed effect was found on the EDSS and relapse rate. Using a causal inference approach, we found no evidence of significantly deleterious or beneficial long-term effects of pregnancy on disability. The beneficial effects found in other studies were probably related to a reverse causation bias.Observatoire Français de la Sclérose en Plaque

Multiple sclerosis: From new concepts to updates on management

International audienceno abstrac

Étude du retentissement des stimulations ovariennes réalisées dans le cadre de fécondations in vitro chez 28 patientes atteintes de sclérose en plaques

La sclérose en plaques (SEP) est une maladie inflammatoire chronique démyélinisante du système nerveux central, qui touche de manière majoritaire les femmes avec un sex ratio de 3/1. Les hormones sexuelles, par le biais essentiellement des estrogènes, sont probablement impliquées dans la physiopathologie de la maladie. Dans le cadre d'une étude multicentrique rétrospective sur 12 CHU, nous avons évalué le retentissement des stimulations ovariennes réalisées dans le cadre de fécondations in vitro sur la sclérose en plaques. 28 patientes ont pu être retrouvées en croisant les bases de données du PMSI et par appel aux neurologues traitants. Les stimulations ovariennes sont à l'origine d'une augmentation significative du nombre de poussées au moins à court terme. Cette augmentation est liée de manière significative au type de molécule utilisé (agoniste ou antagoniste de la GnRH), mais également au résultat de la FIV. Cette étude, tout en renforçant le rôle des hormones sexuelles dans la physiopathologie de la SEP, peut permettre de mieux orienter les patientes ayant un désir de grossesse et devant utiliser des techniques d'assistance médicale à la procréation.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Retentissement des stimulations ovariennes sur le taux de poussée au cours de la Sclérose en plaques

La Sclérose en Plaques est une maladie inflammatoire et démyélinisante du système nerveux central, probablement d'origine auto-immune, et atteignant préférentiellement la femme en âge de procréer. Il existe d'étroites relations entre les hormones sexuelles et le système immunitaire. La variation du taux de ces hormones peut avoir des conséquences sur l'activité clinique de la maladie, comme, par exemple, au cours de la grossesse. Nous avons donc étudié l'impact sur la maladie des traitements de stimulations ovariennes et des différents protocoles utilisés dans le cadre des fécondations in-vitro. Cinq patientes ont pu être retrouvées et, chez quatre d'entre elles, le taux de poussée de SEP semblait plus élevé au cours des trois mois suivants la FIV par rapport aux 3 mois la précédant et à deux périodes contrôle de 3 mois. Les patientes concernées avaient bénéficié d'un traitement par agoniste du GnRH, hormone ayant une activité potentiellement stimulante du système immunitaire. D'autres études, portant sur des nombres plus importants de malades seront nécessaires pour conclure plus aisément sur le retentissement des ces traitements sur l'activité de la sclérose en plaques.NANTES-BU Médecine pharmacie (441092101) / SudocPARIS-BIUM (751062103) / SudocSudocFranceF

Analyse de la régulation lymphocytaire dans la sclérose en plaques

La Sclérose En Plaques (SEP) est considérée comme une maladie auto-immune démyélinisante du Système Nerveux Central (SNC), dépendante des LT CD4+ auto-réactifs. La fréquence de ces cellules a été abondamment étudiée dans la littérature mais leur augmentation par rapport aux individus sains reste controversée. Cependant, que leur fréquence soit ou non augmentée, une question reste en suspens : Comment ces cellules auto-réactives s activent-elles et échappent-elles aux mécanismes de tolérance périphérique dans la SEP ? Un des mécanismes proposés serait un défaut de régulation en périphérie. Plusieurs études ont ainsi impliqué les LT et B régulateurs dans le développement et la rémission de l Encéphalite Auto-immune Expérimentale (EAE). Chez l homme, la fréquence et la fonction de ces cellules restent cependant controversées. Nous avons choisi, dans ce travail, d explorer la fréquence et la fonction des LT régulateurs naturels Foxp3+ (Tregs), et des LB régulateurs (Bregs) chez des patients atteints de SEP non traités. Nous n avons pas mis en évidence de défaut de fréquence ou de fonction de ces deux sous populations dans notre cohorte de patients. L implication des populations régulatrices T et B ne peut cependant pas être exclue dans la physiopathologie de la maladie, en raison de la connaissance encore limitée des Bregs chez l homme, mais aussi en raison de la description récente de nouvelles sous populations de Tregs. Ces cellules peuvent par ailleurs représenter des cibles thérapeutiques intéressantes en rétablissant une homéostasie immunitaire déficiente.Multiple Sclerosis (MS) is considered as an autoimmune demyelinating disease of the Central Nervous System (CNS), mediated by autoreactive CD4+ T cells. The frequency of these cells has been extensively studied in the literature but their increase compared to healthy individuals remains controversial. However, whether their frequency is increased or not, a question remains: How are these autoreactive cells activated and how do they escape peripheral tolerance in MS? One mechanism proposed could be a lack of regulation in periphery. Several studies have implicated T and B regulatory cells in the development and remission of Experimental Autoimmune Encephalomyelitis (EAE), the animal model of MS. However, in human, the frequency and function of these cells remain controversial. We decided, in this work, to explore the frequency and function of Foxp3+ natural regulatory T cells (Tregs) and regulatory B cells (Bregs) in untreated MS patients. We did not reveal any defect in frequency or function of these two subpopulations within our cohort. Nonetheless, the involvement of regulatory T and B populations cannot be excluded in the pathophysiology of the disease, due to the still limited knowledge of Bregs in humans, but also because of the recent description of new subsets of Tregs. These cells may also represent interesting therapeutic targets by restoring a deficient immune homeostasis.NANTES-BU Médecine pharmacie (441092101) / SudocSudocFranceF

Single-Cell Analysis to Better Understand the Mechanisms Involved in MS

International audienceMultiple sclerosis is a chronic and inflammatory disease of the central nervous system. Although this disease is widely studied, many of the precise mechanisms involved are still not well known. Numerous studies currently focusing on multiple sclerosis highlight the involvement of many major immune cell subsets, such as CD4+ T cells, CD8+ T cells and more recently B cells. However, our vision of its pathology has remained too broad to allow the proper use of targeted therapeutics. This past decade, new technologies have emerged, enabling deeper research into the different cell subsets at the single-cell level both in the periphery and in the central nervous system. These technologies could allow us to identify new cell populations involved in the disease process and new therapeutic targets. In this review, we briefly introduce the major single-cell technologies currently used in studies before diving into the major findings from the multiple sclerosis research from the past 5 years. We focus on results that were obtained using single-cell technologies to study immune cells and cells from the central nervous system