Novel insights from basic and translational studies are reshaping concepts of the immunopathogenesis of multiple sclerosis and understanding of the different inflammatory responses throughout the ...disease course. Previously, the cellular immunology of relapsing multiple sclerosis was considered to be principally T-cell driven; however, this process is now understood to involve multiple cell types and their functionally distinct subsets. Particularly, relapsing multiple sclerosis appears to involve imbalanced interactions between T cells, myeloid cells, B cells, and their effector and regulatory subpopulations. The major contributors to such imbalances differ across patients. Several emerging techniques enable comprehensive immune cell profiling at the single-cell level, revealing substantial functional heterogeneity and plasticity that could influence disease state and response to treatment. Findings from clinical trials with agents that successfully limit new multiple sclerosis disease activity and trials of agents that inadvertently exacerbate CNS inflammation have helped to elucidate disease mechanisms, better define the relevant modes of action of current immune therapies, and pave the way for new therapeutic strategies.
The success of clinical trials of selective B‐cell depletion in patients with relapsing multiple sclerosis (MS) and primary progressive MS has led to a conceptual shift in the understanding of MS ...pathogenesis, away from the classical model in which T cells were the sole central actors and toward a more complex paradigm with B cells having an essential role in both the inflammatory and neurodegenerative components of the disease process. The role of B cells in MS was selected as the topic of the 27th Annual Meeting of the European Charcot Foundation. Results of the meeting are presented in this concise review, which recaps current concepts underlying the biology and therapeutic rationale behind B‐cell–directed therapeutics in MS, and proposes strategies to optimize the use of existing anti–B‐cell treatments and provide future directions for research in this area. ANN NEUROL 2021;89:13–23
Leptomeningeal and perivenular infiltrates are important contributors to cortical grey matter damage and disease progression in multiple sclerosis (MS). Whereas perivenular inflammation induces ...vasculocentric lesions, leptomeningeal involvement follows a subpial “surface‐in” gradient. To determine whether similar gradient of damage occurs in deep grey matter nuclei, we examined the dorsomedial thalamic nuclei and cerebrospinal fluid (CSF) samples from 41 postmortem secondary progressive MS cases compared with 5 non‐neurological controls and 12 controls with other neurological diseases. CSF/ependyma‐oriented gradient of reduction in NeuN+ neuron density was present in MS thalamic lesions compared to controls, greatest (26%) in subventricular locations at the ependyma/CSF boundary and least with increasing distance (12% at 10 mm). Concomitant graded reduction in SMI31+ axon density was observed, greatest (38%) at 2 mm from the ependyma/CSF boundary and least at 10 mm (13%). Conversely, gradient of major histocompatibility complex (MHC)‐II+ microglia density increased by over 50% at 2 mm at the ependyma/CSF boundary and only by 15% at 10 mm and this gradient inversely correlated with the neuronal (R = −0.91, p < 0.0001) and axonal (R = −0.79, p < 0.0001) thalamic changes. Observed gradients were also detected in normal‐appearing thalamus and were associated with rapid/severe disease progression; presence of leptomeningeal tertiary lymphoid‐like structures; large subependymal infiltrates, enriched in CD20+ B cells and occasionally containing CXCL13+ CD35+ follicular dendritic cells; and high CSF protein expression of a complex pattern of soluble inflammatory/neurodegeneration factors, including chitinase‐3‐like‐1, TNFR1, parvalbumin, neurofilament‐light‐chains and TNF. Substantial “ependymal‐in” gradient of pathological cell alterations, accompanied by presence of intrathecal inflammation, compartmentalized either in subependymal lymphoid perivascular infiltrates or in CSF, may play a key role in MS progression.
Summary for Social Media
Imaging and neuropathological evidences demonstrated the unique feature of “surface‐in” gradient of damage in multiple sclerosis (MS) since early pediatric stages, often associated with more severe brain atrophy and disease progression. In particular, increased inflammation in the cerebral meninges has been shown to be strictly associated with an MS‐specific gradient of neuronal, astrocyte, and oligodendrocyte loss accompanied by microglial activation in subpial cortical layers, which is not directly related to demyelination.
To determine whether a similar gradient of damage occurs in deep grey matter nuclei, we examined the potential neuronal and microglia alterations in the dorsomedial thalamic nuclei from postmortem secondary progressive MS cases in combination with detailed neuropathological characterization of the inflammatory features and protein profiling of paired CSF samples.
We observed a substantial “subependymal‐in” gradient of neuro‐axonal loss and microglia activation in active thalamic lesions of progressive MS cases, in particular in the presence of increased leptomeningeal and cerebrospinal fluid (CSF) inflammation. This altered graded pathology was found associated with more severe and rapid progressive MS and increased inflammatory degree either in large perivascular subependymal infiltrates, enriched in B cells, or within the paired CSF, in particular with elevated levels of a complex pattern of soluble inflammatory and neurodegeneration factors, including chitinase 3‐like‐1, TNFR1, parvalbumin, neurofilament light‐chains and TNF.
These data support a key role for chronic, intrathecally compartmentalized inflammation in specific disease endophenotypes. CSF biomarkers, together with advance imaging tools, may therefore help to improve not only the disease diagnosis but also the early identification of specific MS subgroups that would benefit of more personalized treatments. ANN NEUROL 2022;92:670–685
Anti‐myelin oligodendrocyte glycoprotein immunoglobulin G (MOG‐IgG) antibodies are associated clinically with either a monophasic or relapsing disease course. We investigated the frequency and ...clinical importance of acquired asymptomatic brain magnetic resonance imaging (MRI) lesions in a prospective incident cohort of 74 MOG‐IgG positive children with serial MRI scans over a median of 5 years from presentation. Silent new lesions were detected in 14% of MOG‐IgG positive participants, most commonly within the first months post‐onset, with a positive predictive value for clinically relapsing disease of only 20%. Detection of asymptomatic lesions alone need not prompt initiation of chronic immunotherapy. ANN NEUROL 2021;89:408–413
To determine early magnetic resonance imaging (MRI) features of new multiple sclerosis (MS) lesions that will develop into paramagnetic rim lesions (PRLs), which have been associated with progressive ...tissue injury in MS.
New contrast-enhancing lesions observed on routine clinical MRI were imaged at 7 T within 4 weeks of observation, and 3 and 6 months later. The 6-month MRI was used to classify PRL status (PRL or non-PRL). The relationship between early lesion characteristics and subsequent PRL status was assessed using generalized linear mixed effects models. Random forest classification was performed to classify early predictors of subsequent PRL status.
From 93 contrast-enhancing lesions in 23 MS patients, 37 lesions developed into a PRL. In lesions that developed into PRLs compared with those that did not, the average lesion T
on the initial 7 T MRI was 1994 ms compared with 1,670 ms (p-value <0.001), and the average volume was 168.7 mL compared with 44 mL (p-value <0.001) in lesions that did not. These volume differences were also found on 3 T scans (p-value <0.001), and for intensity-normalized T
-w (p-value = 0.011) and fluid-attenuated inversion recovery (p-value = 0.005). The area under the receiver operating characteristic curve for the random forest classification with leave-one-out cross-validation was found to be 0.86 using initial 7 T features.
New MS lesions that evolve into PRLs can be identified early in lesion evolution. These findings suggest that biological mechanisms underlying PRL development begin early, which has important implications for clinical trials targeting PRLs development and subsequent therapeutics. ANN NEUROL 2023.
Reported rates of Epstein–Barr virus (EBV) seropositivity in children meeting multiple sclerosis (MS) diagnostic criteria are considerably lower than those reported in adult‐onset MS, putting in ...question a requisite role for EBV in MS development. As prior work preceded recognition of myelin oligodendrocyte glycoprotein‐associated disease (MOGAD), we assessed viral serologies in 251 children with incident demyelination and prospectively ascertained diagnoses. When MOGAD was serologically accounted for, the prevalence of EBV infection among MS children exceeded 90%, whereas remote EBV infection was not associated with MOGAD risk. Together, these findings substantiate EBV's role across the MS spectrum, and support distinct pathobiological mechanisms in MS versus MOGAD. ANN NEUROL 2024;95:700–705
Objective
To define the functional significance of increased miR‐155 expression in myeloid cells in multiple sclerosis (MS).
Methods
miR‐155 expression levels were measured in CD14+ monocytes from ...untreated relapsing–remitting MS patients and compared to healthy controls. Similar microRNA (miRNA) analyses were performed in laser‐captured CD68+ cells from perivascular (blood‐derived macrophages) and parenchymal (microglia) brain regions in both active MS lesions and noninflammatory cases. Using human adult blood‐derived macrophages and brain‐derived microglia, in vitro experiments were performed to demonstrate how miR‐155 influences the polarization state, phenotype, and functional properties of myeloid cells, in addition to their ability to subsequently impact adaptive T‐cell responses.
Results
In MS, miR‐155 expression was significantly increased in both peripheral circulating CD14+ monocytes and active lesions (CD68+ cells) compared to control donor monocytes and parenchymal microglia, respectively. In vitro, miR‐155 was significantly increased in both M1‐polarized primary human macrophages and microglia. Transfection of an miR‐155 mimic increased proinflammatory cytokine secretion and costimulatory surface marker expression in both cell types; an miR‐155 inhibitor decreased proinflammatory cytokine expression. Coculture experiments demonstrated that allogeneic T‐cell responses were significantly enhanced in the presence of miR‐155–transfected myeloid cells compared to controls.
Interpretation
Our results demonstrate that miR‐155 regulates proinflammatory responses in both blood‐derived and central nervous system (CNS)‐resident myeloid cells, in addition to impacting subsequent adaptive immune responses. Differential miRNA expression may therefore provide insight into mechanisms responsible for distinct phenotypic and functional properties of myeloid cells, thus impacting their ability to influence CNS injury and repair. Ann Neurol 2013;74:709–720
Summary The clinical features, diagnostic challenges, neuroimaging appearance, therapeutic options, and pathobiological research progress in childhood—and adolescent—onset multiple sclerosis have ...been informed by many new insights in the past 7 years. National programmes in several countries, collaborative research efforts, and an established international paediatric multiple sclerosis study group have contributed to revised clinical diagnostic definitions, identified clinical features of multiple sclerosis that differ by age of onset, and made recommendations regarding the treatment of paediatric multiple sclerosis. The relative risks conveyed by genetic and environmental factors to paediatric multiple sclerosis have been the subject of several large cohort studies. MRI features have been characterised in terms of qualitative descriptions of lesion distribution and applicability of MRI aspects to multiple sclerosis diagnostic criteria, and quantitative studies have assessed total lesion burden and the effect of the disease on global and regional brain volume. Humoral-based and cell-based assays have identified antibodies against myelin, potassium-channel proteins, and T-cell profiles that support an adult-like T-cell repertoire and cellular reactivity against myelin in paediatric patients with multiple sclerosis. Finally, the safety and efficacy of standard first-line therapies in paediatric multiple sclerosis populations are now appreciated in more detail, and consensus views on the future conduct and feasibility of phase 3 trials for new drugs have been proposed.
Objective
Central nervous system pathology in multiple sclerosis includes both focal inflammatory perivascular injury and injury to superficial structures, including the subpial region of the cortex, ...which reportedly exhibits a gradient of damage from the surface inward. We assessed how early in the multiple sclerosis course a "surface‐in" process of injury suggesting progressive biology may begin.
Methods
We focused on the thalamus, which notably has both a cerebrospinal fluid (CSF) interface and a white matter interface. Thalamic volume trajectories were assessed in a prospectively followed cohort of children from initial presentation with either multiple sclerosis or monophasic acquired demyelination, and healthy controls. Voxelwise volume changes were calculated using deformation‐based morphometry, and analyzed in relation to distance from the CSF interface by mixed effects modeling and semiparametric smoothing methods.
Results
Twenty‐seven children with multiple sclerosis and 73 children with monophasic demyelination were prospectively followed with yearly brain scans (mean follow‐up = 4.6 years, standard deviation = 1.9). A total of 282 healthy children with serial scans were included as controls. Relative to healthy controls, children with multiple sclerosis and children with monophasic demyelination demonstrated volume loss in thalamic regions adjacent to the white matter. However, only children with multiple sclerosis exhibited an additional surface‐in gradient of thalamic injury on the ventricular side, which was already notable in the first year of clinical disease (asymptote estimate = 3.01, 95% confidence interval CI = 1.44–4.58, p = 0.0002) and worsened over time (asymptote:time estimate = 0.33, 95% CI = 0.12–0.54, p = 0.0021).
Interpretation
Our results suggest that a multiple sclerosis disease‐specific surface‐in process of damage can manifest at the earliest stages of the disease. ANN NEUROL 2019;85:340–351.
PDF
