Tyzzerella nexilis strains enriched in mobile genetic elements are involved in progressive multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune-demyelinating disease with an inflammatory pathology formed by self-reactive lymphocytes with activated glial cells. Progressive MS, characterized by resistance to medications, significantly differs from the non-progressive form in gut microbiome profiles. After confirming an increased abundance of "Tyzzerella nexilis" in various cohorts of progressive MS, we identified a distinct cluster of T. nexilis strains enriched in progressive MS based on long-read metagenomics. The distinct T. nexilis cluster is characterized by a large number of mobile genetic elements (MGEs) and a lack of defense systems against MGEs. Microbial genes for sulfate reduction and flagella formation with pathogenic implications are specific to this cluster. Moreover, these flagellar genes are encoded on MGEs. Mono-colonization with MGE-enriched T. nexilis made germ-free mice more susceptible to experimental autoimmune encephalomyelitis. These results indicate that the progression of MS may be promoted by MGE-enriched T. nexilis with potentially pathogenic properties.

Multimodal imaging analyses in neuromyelitis optica spectrum disorder with or without visual disturbance.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder is a demyelinating and inflammatory affliction that often leads to visual disturbance. Various imaging techniques, including free-water imaging, have been used to determine neuroinflammation and degeneration. Therefore, this study aimed at determining multimodal imaging differences between patients with neuromyelitis optica spectrum disorder, especially those with visual disturbance, and healthy controls. MATERIALS AND METHODS: Eighty-five neuromyelitis optica spectrum disorder patients and 89 age- and sex-matched healthy controls underwent 3-T magnetic resonance imaging (MRI). We analyzed adjusted brain-predicted age difference, voxel-based morphometry, and free-water-corrected diffusion tensor imaging (DTI) by tract-based spatial statistics in each patient group (MRI-positive/negative neuromyelitis optica spectrum disorder patients with or without a history of visual disturbance) compared with the healthy control group. RESULTS: MRI-positive neuromyelitis optica spectrum disorder patients exhibited reduced volumes of the bilateral thalamus. Tract-based spatial statistics showed diffuse white matter abnormalities in all DTI metrics in MRI-positive neuromyelitis optica spectrum disorder patients with a history of visual disturbance. In MRI-negative neuromyelitis optica spectrum disorder patients with a history of visual disturbance, voxel-based morphometry showed volume reduction of bilateral thalami and optic radiations, and tract-based spatial statistics revealed significantly lower free-water-corrected fractional anisotropy and higher mean diffusivity in the posterior dominant distributions, including the optic nerve radiation. CONCLUSION: Free-water-corrected DTI and voxel-based morphometry analyses may reflect symptoms of visual disturbance in neuromyelitis optica spectrum disorder.

'Grasshopper sign': the novel imaging of post-COVID-19 myelopathy with delayed longitudinal white matter abnormalities.

Introduction: Recently, there have been a few reports of atypical post-coronavirus disease 2019 (COVID-19) myelopathy manifesting tract-specific lesions similar to those due to vitamin B12 deficiency. However, the precise characteristics of imaging or clinical course remain not well understood. Methods: A retrospective analysis of the clinical and imaging characteristics of four patients who were referred to our hospital with a unique post-COVID-19 myelopathy was performed. Results: Four-to-six weeks following COVID-19 infection in the summer of 2023, four middle-aged men developed paraparesis, hypo/dysesthesia and bladder/bowel disturbance, suggesting myelopathy. Although spinal MRI showed no abnormalities in the early stages, tract-specific longitudinal lesions along the dorsal and lateral columns became apparent as the symptoms progressed. Owing to the lack of MRI findings at the early stage, all cases were challenging to diagnose. However, the patients remained partially responsive to aggressive immunosuppressive therapies, even in the advanced stage. Discussion: We termed these tract-specific longitudinal lesions in the presented case series 'Grasshopper sign' because brain coronal and spine axial MRI findings looked like a grasshopper's antennae and face. Early identification of the characteristic MRI abnormality could allow for early intervention using intensive immunosuppressive therapy, which could improve patient outcomes.

Pathogenic Potential of Eomesodermin-Expressing T-Helper Cells in Neurodegenerative Diseases.

Eomesodermin-expressing (Eomes+) T-helper (Th) cells show cytotoxic characteristics in secondary progressive multiple sclerosis. We found that Eomes+ Th cell frequency was increased in the peripheral blood of amyotrophic lateral sclerosis and Alzheimer's disease patients. Furthermore, granzyme B production by Th cells from such patients was high compared with controls. A high frequency of Eomes+ Th cells was observed in the initial (acutely progressive) stage of amyotrophic lateral sclerosis, and a positive correlation between Eomes+ Th cell frequency and cognitive decline was observed in Alzheimer's disease patients. Therefore, Eomes+ Th cells may be involved in the pathology of amyotrophic lateral sclerosis and Alzheimer's disease. ANN NEUROL 2024;95:1093-1098.

High frequency of circulating non-classical monocytes is associated with stable remission in relapsing-remitting multiple sclerosis.

'No evidence of disease activity (NEDA)', judged by clinical and radiological findings, is a therapeutic goal in patients with multiple sclerosis (MS). It is, however, unclear if distinct biological mechanisms contribute to the maintenance of NEDA. To clarify the immunological background of long-term disease stability defined by NEDA, circulating immune cell subsets in patients with relapsing-remitting MS (RRMS) were analyzed using flow cytometry. Patients showing long-term NEDA (n = 31) had significantly higher frequencies of non-classical monocytes (NCMs) (6.1% vs 1.4%) and activated regulatory T cells (Tregs; 2.1% vs 1.6%) than those with evidence of disease activity (n = 8). The NCM frequency and NCMs to classical monocytes ratio (NCM/CM) positively correlated with activated Treg frequency and duration of NEDA. Co-culture assays demonstrated that NCMs could increase the frequency of activated Tregs and the expression of PD-L1, contributing to development of Tregs, was particularly high in NCMs from patients with NEDA. Collectively, NCMs contribute to stable remission in patients with RRMS, possibly by increasing activated Treg frequency. In addition, the NCM frequency and NCM/CM ratio had high predictive values for disease stability (AUC = 0.97 and 0.94, respectively), suggesting these markers are potential predictors of a long-term NEDA status in RRMS.

CD11chigh B Cell Expansion Is Associated With Severity and Brain Atrophy in Neuromyelitis Optica.

BACKGROUND AND OBJECTIVES: Neuromyelitis optica (NMO) is an autoimmune astrocytopathy mediated by anti-AQP4 antibody-producing B cells. Recently, a B-cell subset highly expressing CD11c and T-bet, originally identified as age-associated B cells, has been shown to be involved in the pathogenesis of various autoimmune diseases. The objective of this study was to determine the relationship between the frequency of CD11chigh B cells per CD19+ B cells in the peripheral blood of patients with NMO and the clinical profiles including the brain volume. METHODS: In this observational study, 45 patients with anti-AQP4 antibody-positive NMO in remission and 30 healthy control subjects (HCs) were enrolled. Freshly isolated peripheral blood mononuclear cells were analyzed for immune cell phenotypes. The frequency of CD11chigh B cells per CD19+ B cells was assessed by flow cytometry and was evaluated in association with the clinical profiles of patients. Brain MRI data from 26 patients were included in the study for the analysis on the correlation between CD11chigh B-cell frequency and brain atrophy. RESULTS: We found that the frequency of CD11chigh B cells in CD19+ B cells was significantly increased in patients with NMO compared with HCs. The expansion of CD11chigh B cells significantly correlated with EDSS, past relapse numbers, and disease duration. In addition, a higher frequency of CD11chigh B cells negatively correlated with total brain, white matter, and gray matter volumes and positively correlated with T2/FLAIR high lesion volumes. When the past clinical relapse episodes of patients with or without the expansion of CD11chigh B cells were compared, relapses in the brain occurred more frequently in patients with CD11chigh B-cell expansion. CD11chigh B cells had distinct features including expression of chemokine receptors associated with migration into peripheral inflammatory tissues and antigen presentation. CD11chigh B-cell frequency was positively correlated with T peripheral helper-1 (Tph-1) cell frequency. DISCUSSION: Even during the relapse-free period, CD11chigh B cells could expand in the long disease context, possibly through the interaction with Tph-1 cells. The increased frequency of CD11chigh B cells associated with brain atrophy and disease severity, indicating that this cell population could be involved in chronic neuroinflammation in NMO.

Efficacy and Safety of the Natural Killer T Cell-Stimulatory Glycolipid OCH-NCNP1 for Patients With Relapsing Multiple Sclerosis: Protocol for a Randomized Placebo-Controlled Clinical Trial.

BACKGROUND: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes myelin sheath damage and axonal degeneration. The glycolipid (2S, 3S, 4R)-1-O-(α-d-galactosyl)-2-tetracosanoylamino-1,3,4-nonaetriol (OCH-NCNP1 or OCH) exerts an immunoregulatory action that suppresses T helper (Th)1 cell-mediated immune responses through natural killer T cell activation, selective interleukin-4 production, and Th2 bias induction in human CD4-positive natural killer T cells. OBJECTIVE: This trial aims to investigate the efficacy and safety of the immunomodulator OCH in patients with relapsing MS through 24-week repeated administration. METHODS: This protocol describes a double-blind, multicenter, placebo-controlled, randomized phase II clinical trial that was initiated in September 2019. The participants were randomly assigned to either a placebo control group or an OCH-NCNP1 group and the investigational drug (3.0 mg) was orally administered once weekly for the 24-week duration. Major inclusion criteria are as follows: patients had been diagnosed with relapsing MS (relapsing-remitting and/or secondary progressive MS) based on the revised McDonald criteria or were diagnosed with MS by an attending physician as noted in their medical records; patients with at least two medically confirmed clinical exacerbations within 24 months prior to consent or one exacerbation within 12 months prior to consent; patients with at least one lesion suspected to be MS on screening magnetic resonance imaging (MRI); and patients with 7 points or less in the Expanded Disability Status Scale during screening. Major exclusion criteria are as follows: diagnosis of neuromyelitis optica and one of optic neuritis, acute myelitis, and satisfying at least two of the following three items: (1) spinal cord MRI lesion extending across at least three vertebral bodies, (2) no brain MRI lesions during onset (at least four cerebral white matter lesions or three lesions, one of which is around the lateral ventricle), and (3) neuromyelitis optica-immunoglobulin G or antiaquaporin-4 antibody-positive. Outcome measures include the primary outcome of MRI changes (the percentage of subjects with new or newly expanded lesions at 24 weeks on T2-weighted MRI) and the secondary outcomes annual relapse rate (number of recurrences per year), relapse-free period (time to recurrence), sustained reduction in disability (SRD) occurrence rate, period until SRD (time to SRD occurrence), no evidence of disease activity, and exploratory biomarkers from phase I trials (such as gene expression, cell frequency, and intestinal and oral microbiome). RESULTS: We plan to enroll 30 patients in the full analysis set. Enrollment was closed in June 2021 and the study analysis was completed in March 2023. CONCLUSIONS: This randomized controlled trial will determine whether OCH-NCNP1 is effective and safe in patients with MS as well as provide evidence for the potential of OCH-NCNP1 as a therapeutic agent for MS. TRIAL REGISTRATION: ClinicalTrials.gov NCT04211740; https://clinicaltrials.gov/study/NCT04211740. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46709.

Exploring the Potential of the Corpus Callosum Area as a Predictive Marker for Impaired Information Processing in Multiple Sclerosis.

Early cognitive impairment (CI) detection is crucial in multiple sclerosis (MS). However, it can progress silently regardless of relapse activity and reach an advanced stage. We aimed to determine whether the corpus callosum area (CCA) is a sensitive and feasible marker for CI in MS compared to other neuroimaging markers. We assessed cognitive function in 77 MS patients using the Symbol Digit Modalities Test, Paced Auditory Serial Additions Task, Wechsler Adult Intelligence Scale-IV, and Wechsler Memory Scale-Revised. The neuroimaging markers included manually measured CCA, two diffusion tensor imaging markers, and nine volumetric measurements. Apart from volumes of the hippocampus and cerebellum, ten markers showed a significant correlation with all neuropsychological tests and significant differences between the groups. The normalized CCA demonstrated a moderate-to-strong correlation with all neuropsychological tests and successfully differentiated between the CI and cognitively normal groups with 80% sensitivity and 83% specificity. The marker had a large area under the curve and a high Youden index (0.82 and 0.63, respectively) and comparability with established cognitive markers. Therefore, the normalized CCA may serve as a reliable marker for CI in MS and can be easily implemented in clinical practice, providing a supportive diagnostic tool for CI in MS.

Brain-regional characteristics and neuroinflammation in ME/CFS patients from neuroimaging: A systematic review and meta-analysis.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by an elusive etiology and pathophysiology. This study aims to evaluate the pathological role of neuroinflammation in ME/CFS by conducting an exhaustive analysis of 65 observational studies. Four neuroimaging techniques, including magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS), electroencephalography (EEG), and positron emission tomography (PET), were employed to comparatively assess brain regional structure, metabolite profiles, electrical activity, and glial activity in 1529 ME/CFS patients (277 males, 1252 females) and 1715 controls (469 males, 1246 females). Clinical characteristics, including sex, age, and fatigue severity, were consistent with established epidemiological patterns. Regional alterations were most frequently identified in the cerebral cortex, with a notable focus on the frontal cortex. However, our meta-analysis data revealed a significant hypoactivity in the insular and thalamic regions, contrary to observed frequencies. These abnormalities, occurring in pivotal network hubs bridging reason and emotion, disrupt connections with the limbic system, contributing to the hallmark symptoms of ME/CFS. Furthermore, we discuss the regions where neuroinflammatory features are frequently observed and address critical neuroimaging limitations, including issues related to inter-rater reliability. This systematic review serves as a valuable guide for defining regions of interest (ROI) in future neuroimaging investigations of ME/CFS.

Free-water-corrected diffusion and adrenergic/muscarinic antibodies in myalgic encephalomyelitis/chronic fatigue syndrome.

BACKGROUND AND PURPOSE: Free-water-corrected diffusion tensor imaging (FW-DTI), a new analysis method for diffusion MRI, can indicate neuroinflammation and degeneration. There is increasing evidence of autoimmune etiology in myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS). We used FW-DTI and conventional DTI to investigate microstructural brain changes related to autoantibody titers in patients with ME/CFS. METHODS: We prospectively examined 58 consecutive right-handed ME/CFS patients who underwent both brain MRI including FW-DTI and a blood analysis of autoantibody titers against ß1 adrenergic receptor (ß1 AdR-Ab), ß2 AdR-Ab, M3 acetylcholine receptor (M3 AchR-Ab), and M4 AchR-Ab. We investigated the correlations between these four autoantibody titers and three FW-DTI indices-free water (FW), FW-corrected fractional anisotropy (FAt), and FW-corrected mean diffusivity-as well as two conventional DTI indices-fractional anisotropy (FA) and mean diffusivity. The patients' age and gender were considered as nuisance covariates. We also evaluated the correlations between the FW-DTI indices and the performance status and disease duration. RESULTS: Significant negative correlations between the serum levels of several autoantibody titers and DTI indices were identified, mainly in the right frontal operculum. The disease duration showed significant negative correlations with both FAt and FA in the right frontal operculum. The changes in the FW-corrected DTI indices were observed over a wider extent compared to the conventional DTI indices. CONCLUSIONS: These results demonstrate the value of using DTI to assess the microstructure of ME/CFS. The abnormalities of right frontal operculum may be a diagnostic marker for ME/CFS.

First-in-human clinical trial of the NKT cell-stimulatory glycolipid OCH in multiple sclerosis.

Background: Multiple sclerosis (MS) is an autoimmune inflammatory disease of the central nervous system that causes the damage to the myelin sheath as well as axonal degeneration. Individuals with MS appear to have changes in the numbers and functions of T-cell subsets, leading to an immunological imbalance accompanied by enhanced autoreactivity. In previous preclinical studies, (2 S,3 S,4R)-1-O-(α-D-Galactopyranosyl)-N-tetracosanoyl-2-amino-1,3,4-nonanetriol (OCH), a synthetic analog of α-galactosylceramide stimulatory for invariant NKT (iNKT) cells, has shown therapeutic or disease-preventive immunoregulatory effects in autoimmune disease models such as experimental autoimmune encephalomyelitis (EAE). Objectives: This study is the first-in-human study of oral OCH to evaluate the pharmacokinetics and to examine the effects on immune cells as well as related gene expression profiles. Methods: Fifteen healthy volunteers and 13 MS patients who met the study criteria were enrolled. They were divided into five cohorts and received oral administration of various doses of granulated powder of OCH (0.3-30 mg), once per week for 4 or 13 weeks. Plasma OCH concentrations were measured by high-performance liquid chromatography. Frequencies of lymphocyte subsets in peripheral blood were evaluated by flow cytometry, and microarray analysis was performed to determine OCH-induced changes in gene expression. Results: Oral OCH was well tolerated, and its bioavailability was found to be sufficient. Six hours after a single dose of OCH, increased frequencies of Foxp3+ regulatory T-cells were observed in some cohorts of healthy subjects and MS patients. Furthermore, gene expression analysis demonstrated an upregulation of several immunoregulatory genes and downregulation of pro-inflammatory genes following OCH administration. Conclusion: This study has demonstrated immunomodulatory effects of the iNKT cell-stimulatory drug OCH in human. Safety profiles together with the presumed anti-inflammatory effects of oral OCH encouraged us to conduct a phase II trial.

[Myalgic Encephalitis/Chronic Fatigue Syndrome: Diagnostic and Therapeutic Approach and Biological Research].

Myalgic encephalitis/chronic fatigue syndrome, an intractable disease characterized by profound fatigue, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features, often occurs after infectious episodes. Patients experience various types of chronic pain; however, post-exertional malaise is the most significant feature, which requires pacing. In this article, I summarize the current diagnostic and therapeutic approaches and describe recent biological research in this domain.

Ratio of lymphocyte to monocyte area under the curve as a novel predictive factor for severe infection in multiple sclerosis.

Background: Individuals with multiple sclerosis (MS) are vulnerable to all types of infection, because MS itself involves immunodeficiency, in addition to involving treatment with immunosuppressants. Simple predictive variables for infection that are easily assessed in daily examinations are warranted. Lymphocyte area under the curve (L_AUC), defined as the sum of serial absolute lymphocyte counts under the lymphocyte count-time curve, has been established as a predictive factor for several infections after allogenic hematopoietic stem cell transplantation. We assessed whether L_AUC could also be a useful factor for predicting severe infection in MS patients. Methods: From October 2010 to January 2022, MS patients, diagnosed based on the 2017 McDonald criteria, were retrospectively reviewed. We extracted patients with infection requiring hospitalization (IRH) from medical records and matched with controls in a 1:2 ratio. Variables including clinical severity and laboratory data were compared between the infection group and controls. L_AUC was calculated along with the AUC of total white blood cells (W_AUC), neutrophils (N_AUC), lymphocytes (L_AUC), and monocytes (M_AUC). To correct for different times of blood examination and extract mean values of AUC per time point, we divided the AUC by follow-up duration. For example, in evaluating lymphocyte counts, we defined the ratio of [L_AUC] to [follow-up duration] as [L_AUC/t]. Multivariate regression analysis was conducted to extract predictive factors associated with IRH. Also, discriminative analysis was conducted using candidate variables from multivariate analysis. Results: The total case-control sample included 177 patients of MS with IRH (n=59) and non-IRH (controls) (n=118). Adjusted odds ratios (OR) for the risk of serious infection in patients with MS with higher baseline expanded disability status scale (EDSS) (OR 1.340, 95% confidence interval [CI] 1.070-1.670, p = 0.010) and lower ratio of L_AUC/t to M_AUC/t (OR 0.766, 95%CI 0.591-0.993, p = 0.046) were significant. Notably, the kind of treatment, including glucocorticoids (GCs), disease-modifying drugs (DMDs) and other immunosuppressants agents, and dose of GCs were not significantly associated with serious infection after correlated with EDSS and ratio of L_AUC/t to M_AUC/t. In discriminative analysis, sensitivity was 88.1% (95%CI 76.5-94.7%) and specificity was 35.6% (95%CI 27.1-45.0%), using EDSS ≥ 6.0 or ratio of L_AUC/t to M_AUC/t ≤ 3.699, while sensitivity was 55.9% (95%CI 42.5-68.6%) and specificity was 83.9% (95%CI 75.7-89.8%), using both EDSS ≥ 6.0 and ratio of L_AUC/t to M_AUC/t ≤ 3.699. Conclusion: Our study revealed the impact of the ratio L_AUC/t to M_AUC/t as a novel prognostic factor for IRH. Clinicians should pay more attention to laboratory data such as lymphocyte or monocyte counts itself, directly presenting individual immunodeficiency, rather than the kind of drug to prevent infection as a clinical manifestation.

Neuropilin-1 (NRP1) expression distinguishes self-reactive helper T cells in systemic autoimmune disease.

Pathogenic T helper cells (Th cells) that respond to self-antigen cannot be easily distinguished from beneficial Th cells. These cells can generate systemic autoimmune disease in response to widely expressed self-antigens. In this study, we have identified neuropilin-1 (NRP1) as a cell surface marker of self-reactive Th cells. NRP1+ Th cells, absent in non-regulatory T cell subsets in normal mice, appeared in models of systemic autoimmune disease and strongly correlated with disease symptoms. NRP1+ Th cells were greatly reduced in Nr4a2 cKO mice, which have reduced self-reactive responses but showed normal responses against exogenous antigens. Transfer of NRP1+ Th cells was sufficient to initiate or accelerate systemic autoimmune disease, and targeting NRP1-expressing Th cells therapeutically ameliorated SLE-like autoimmune symptoms in BXSB-Yaa mice. Peripheral NRP1+ Th cells were significantly increased in human SLE patients. Our data suggest that self-reactive Th cells can be phenotypically distinguished within the Th cell pool. These findings offer a novel approach to identify self-reactive Th cells and target them to treat systemic autoimmune disease.

Pathogenic neuropsychiatric effect of stress-induced microglial interleukin 12/23 axis in systemic lupus erythematosus.

OBJECTIVES: The central nervous system disorder in systemic lupus erythematosus (SLE), called neuropsychiatric lupus (NPSLE), is one of the most severe phenotypes with various clinical symptoms, including mood disorder, psychosis and delirium as diffuse neuropsychological manifestations (dNPSLE). Although stress is one of the aggravating factors for neuropsychiatric symptoms, its role in the pathogenesis of dNPSLE remains to be elucidated. We aimed to investigate stress effects on the neuropsychiatric pathophysiology in SLE using lupus-prone mice and patients' data. METHODS: Sleep disturbance stress (SDS) for 2 weeks was placed on 6-8-week-old female MRL/lpr and control mice. Behavioural phenotyping, histopathological analyses and gene and protein expression analyses were performed to assess SDS-induced neuroimmunological alterations. We also evaluated cytokines of the cerebrospinal fluid and brain regional volumes in patients with dNPSLE and patients with non-dNPSLE. RESULTS: SDS-subjected MRL/lpr mice exhibited less anxiety-like behaviour, whereas stressed control mice showed increased anxiety. Furthermore, stress strongly activated the medial prefrontal cortex (mPFC) in SDS-subjected MRL/lpr. A transcriptome analysis of the PFC revealed the upregulation of microglial activation-related genes, including Il12b. We confirmed that stress-induced microglial activation and the upregulation of interleukin (IL) 12/23p40 proteins and increased dendritic spines in the mPFC of stressed MRL/lpr mice. IL-12/23p40 neutralisation and tyrosine kinase 2 inhibition mitigated the stress-induced neuropsychiatric phenotypes of MRL/lpr mice. We also found a higher level of cerebrospinal fluid IL-12/23p40 and more atrophy in the mPFC of patients with dNPSLE than those with non-dNPSLE. CONCLUSIONS: The microglial IL-12/23 axis in the mPFC might be associated with the pathogenesis and a promising therapeutic target for dNPSLE.

[Patients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) Who Have Already Visited Some Medical Institutions: Diagnosis, Treatment and Research].

Myalgic encephalitis/chronic fatigue syndrome (ME/CFS) is an acquired intractable disease characterized by profound fatigue, post-exertional malaise, sleep disturbance, cognitive impairment, and orthostatic intolerance, among other features. The onset often follows an infectious episode. Importantly, the various types of autonomic dysfunctions, pain, and intolerance to various stimuli in ME/CFS patients are intrinsically different from the "fatigue" of healthy individuals. In this short essay, I summarize the current diagnostic and therapeutic strategies for ME/CFS, as well as the progress in the immunological and imaging research on this intractable disease.

Th1 - CD11c+ B Cell Axis Associated with Response to Plasmapheresis in Multiple Sclerosis.

OBJECTIVE: Although plasmapheresis is a treatment option for patients with autoimmune neurological diseases, treatment response varies greatly among patients. The main objective of this study was to find out if biological/immune traits correlate with a beneficial response. METHODS: We thoroughly analyzed immune phenotypes in paired blood samples from a cohort of 31 patients with multiple sclerosis before and after plasmapheresis, in parallel with clinical evaluation of treatment response. RESULTS: The frequency of IFN-γ+ Th1 cells was persistently higher in those who obtained benefit from plasmapheresis (responders) than nonresponders. The Th1 cell frequency before plasmapheresis provided a high predictive value for beneficial response, achieving area under the curve (AUC) of 0.902. Plasmapheresis treatment decreased inflammation-related gene expressions in Th1 cells. Meanwhile, IFNG expression in Th1 cells positively correlated with the frequency of CD11c+ B cells, of which a pathogenic role has been suggested in several autoimmune diseases. In line with this, in vitro experiments showed that CD11c+ B cells would increase in response to exogenous IFN-γ compared to IL-4, and secrete high amounts of IgG. B cell receptor analysis indicated that clonal expansion of CD11c+ B cells takes place in patients with multiple sclerosis. Interestingly, CD11c+ B cells, which showed unique gene expression profile, decreased after plasmapheresis treatment along with all the immunoglobulin subsets in the circulation. INTERPRETATION: Taken together, we postulate that Th1 cell - CD11c+ B cell axis is involved in treatment response to plasmapheresis, giving us clues to better understanding of complicated pathogenesis of autoimmune diseases, and getting closer to a personalized therapy. ANN NEUROL 2021;90:595-611.

Skewing of the B cell receptor repertoire in myalgic encephalomyelitis/chronic fatigue syndrome.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

Involvement of cytotoxic Eomes-expressing CD4+ T cells in secondary progressive multiple sclerosis.

Multiple sclerosis (MS), a putative autoimmune disease of the central nervous system (CNS), commonly presents as relapsing-remitting MS (RRMS), characterized by recurrent episodes of peripheral disabling symptoms resulting from inflammatory CNS damage. Many RRMS patients transition to a chronic disease course with progressive neurological dysfunctions (secondary progressive MS, SPMS), with the progression rate varying between patients and over time. SPMS pathogenesis is now linked to immune-cell-mediated processes, although the mechanisms driving SPMS transition and progression remain elusive, and SPMS lacks biomarkers and effective treatments. We report the crucial involvement of cytotoxic CD4+ T cells expressing Eomes (Eomes+ Th cells) in SPMS pathogenesis-a Th cell subset previously identified in a mouse model of late/chronic autoimmune CNS inflammation. Few Eomes+ Th cells circulate in RRMS patient peripheral blood (n = 44), primary progressive MS (PPMS) patients (n = 25), or healthy controls (n = 42), but Eomes+ Th cells were significantly increased in SPMS (n = 105, P < 0.0001). Strikingly, lymphocytes isolated from SPMS autopsy brain samples revealed CD4+ T cells infiltrating CNS that coexpressed Eomes and the cytotoxic molecule granzyme B. In particular, the Eomes+ Th cell levels were increased in SPMS patients in progressive disease phases versus SPMS patients without current disability increases (P < 0.0001). Moreover, Eomes level acted as a biomarker to predict SPMS patients at risk of disease worsening with over 80% accuracy (ROC-AUC = 0.8276). Overall, our results indicate that granzyme B-expressing Eomes+ T helper cells are involved in the pathogenesis of SPMS, with significant implications for SPMS biomarkers and therapeutic targets.