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Dexamethasone-induced Ras-related protein 1 (RASD1) is a protein of the Ras family which probably has a regulatory function. We demonstrate that Rasd1 mRNA is expressed in mouse lymph node cells in response to inhibitory stimuli. Rasd1 mRNA is present at very low levels in freshly isolated cells, but it is rapidly up-regulated in culture and is expressed at elevated levels in cells whose proliferation is blocked by exposure to homogenized brain tissue. The cells expressing Rasd1 mRNA are positive for MHC class II and B220 and negative for Thy-1. Expression of Rasd1 mRNA is very low in B cell-deficient mice. We conclude that Rasd1 mRNA is expressed by B lymphocytes derived from lymph node cells in response to inactivating or inhibitory stimuli. It may play a role in regulating B lymphocyte activity and proliferation. [ABSTRACT FROM PUBLISHER]

Several investigators have reported experimental evidence of epitope spreading in experimental autoimmune encephalomyelitis (EAE). The role of epitope spreading in the pathogenesis of relapsing or chronic autoimmune disease is not established and the in vivo function of the T cells specific for new epitopes which appear during an autoimmune response is unclear. We recently demonstrated that mice which have recovered from an episode of EAE suffer a relapse shortly after reinjection with the original encephalitogen. The reinduced disease occurs in a reproducible fashion with an accelerated onset. This may be due to persistence of an expanded population of previously activated encephalitogenic cells which are rapidly reactivated when re-exposed to antigen. We reasoned that if epitope spread produces a significant number of encephalitogenic cells specific for a new epitope, then reinjection with that epitope should also cause the rapid onset of an episode of EAE. We tested this hypothesis using the known encephalitogenic epitopes in SJL mice. After recovery from EAE induced with the proteolipid protein peptide PLP139-151, five of 16 mice had an accelerated relapse of EAE when reinjected with a second encephalitogenic peptide, PLP178-191. All of the 10 mice reinjected with the original PLP139-151 peptide relapsed. We conclude that epitope spread may produce encephalitogenic cells specific for new epitopes, but that the response to new epitopes is minor compared to the response to the initial epitope [ABSTRACT FROM PUBLISHER]

Multiple sclerosis is a chronic inflammatory disease of the central nervous system and is associated with periods of disability (relapse) alternating with periods of recovery (remission) and often results in progressive neurologic disability. Scientists believe that multiple sclerosis may be a T cell-mediated autoimmune disease. Treatment with high-dose pulses of intravenous methyl-prednisolone is usually associated with a good outcome in the short term. A recent study suggests that interferon beta-1b may decrease the number of relapses in relapsing-remitting multiple sclerosis by 30 percent and also may decrease the development of new central nervous system lesions. Recently, another clinical trial of interferon beta-1a showed a 31 percent reduction in relapse rate and a significant reduction in the average number of active lesions. A third trial showed that 20 mg of copolymer-1, a random polymer of glutamic acid, lysine, alanine and tyrosine, reduced relapses by 21 percent without significant side effects. Further investigation is needed, but these new treatments show great promise in alleviating this difficult clinical problem. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) has not been well studied in racial and ethnic minorities, as these populations are typically underrepresented in clinical trials. Black or African Americans comprise ∼13 % of the US population, yet are represented by as little as 5 % in clinical trials. Differences in disease course and progression have been reported between races and ethnicities, so there is a need to understand the safety and efficacy of disease-modifying therapies (DMTs) in Black patients, to inform evidence-based approaches to treatment in this population., Methods: EVOLVE-MS-1 (NCT0234307) was an open-label, single-arm, phase 3 study assessing the long-term safety, tolerability, and efficacy of diroximel fumarate (DRF) over 96 weeks in adults with relapsing-remitting multiple sclerosis (RRMS). Patients were either newly initiated to DRF or rolled over from completing EVOLVE-MS-2 (NCT03093324). In this post-hoc analysis of the phase 3 EVOLVE-MS-1 study, we evaluate the safety and exploratory efficacy outcomes for DRF in Black and non-Black patient subgroups., Results: Of 1057 patients enrolled, 72 (6.8 %) were Black. In Black vs non-Black patients, mean age was 42 vs 43 years and 75 % vs 72 % were female, respectively. In both groups, median (range) duration of DRF exposure was 1.8 (0.0-2.0) years and mean Expanded Disability Status Scale (EDSS) was 2.7. The most common prior DMTs for both Black vs non-Black patients were interferons (47 % vs 37 %) and glatiramer acetate (36 % vs 24 %). DRF treatment was discontinued in 33 (46 %) Black and 224 (23 %) non-Black patients; most common reasons for discontinuation were withdrawal by patient (n = 11, 15.3 %), adverse events (AEs; n = 7, 9.7 %), and lost to follow-up (n = 7, 9.7 %) in Black patients; AEs (8.2 %) and withdrawal by patient (7.0 %) in non-Black patients. AEs were reported in 90 % Black and 89 % non-Black patients; most AEs were mild or moderate in both groups. Gastrointestinal (GI) AEs were reported in 36 % Black and 32 % non-Black patients; no Black patients discontinued due to GI AEs, vs 7 (0.7 %) non-Black patients. The most commonly reported AE was flushing (18 % Black and 28 % non-Black patients). No AEs of lymphopenia were reported in Black patients compared with 13 % of non-Black patients. Mean absolute lymphocyte count declined from baseline to week 48 by 15 % in Black patients and 29 % in non-Black patients, then plateaued and remained above the lower limit of normal (LLN; 0.91 × 10 9 /L). Adjusted annualized relapse rate (95 % confidence interval) was reduced by 78.2 % (54.6 - 89.5; p < 0.0001) in Black patients, from 12 months before to 96 weeks after DRF treatment; similar to 81.7 % (78.5 - 84.5 %; p < 0.0001) reduction in non-Black patients. Mean number of patients free from confirmed disability progression was 93.4 % by week 48, then 86.2 % vs 90.4 % by week 96 in Black vs non-Black patients, respectively., Conclusion: This study presents the first analysis of safety and efficacy of DRF in Black patients. Relapse rates remained low in Black patients on DRF, consistent with non-Black patients, and there were no new safety signals identified in the Black patient subgroup in EVOLVE-MS-1. Together, these outcomes support DRF as an effective treatment option in Black patients with RRMS., Competing Interests: Declaration of competing interest SFH has received consulting fees from Alexion, Biogen, BMS, Genentech, Horizon, Janssen, Sanofi, and Serono; contracted research at Anokion, Atara, Biogen, Genentech, Janssen, and Sanofi; and served on speaker bureaus for Biogen, BMS, EMD Serono, Horizon, and Janssen. JWL has received personal compensation for consulting from Biogen, Banner Life Sciences, Genentech, Horizon, and Mapi Pharmaceuticals; conducted clinical trials funded by Anokion, Atara, Biogen, EMD Serono, and Genentech; and received research funding from Genentech and the National MS Society. BO has contracted research at Biogen and served on speaker bureaus for Alexion, Biogen, BMS, Genentech, and Roche. SL, JBL, MS, and ZT are employees and stockholders of Biogen. FB was an employee and stockholder at Biogen at the time of analysis. BS and AA have nothing to disclose., (Copyright © 2024. Published by Elsevier B.V.)

Background: Nasopharyngeal Bordetella pertussis (BP) colonization is common, with about 5% of individuals having PCR evidence of subclinical BP infection on nasal swab, even in countries with high vaccination rates. BP secretes pertussis toxin (PTx). PTx is an adjuvant commonly used to induce autoimmunity in multiple animal models of human disease. Colocalization of PTx and myelin from myelinated nerves in the nasopharynx may lead to host sensitization to myelin with subsequent autoimmune pathology., Methods: C57BL/6J female adult mice were given varied doses and schedules of intranasal PTx, MOG 35-55 antigen, or controls to test whether intranasal administration of PTx and myelin oligodendrocyte peptide (MOG 35-55 ) could induce experimental autoimmune encephalomyelitis (EAE) in mice. While we observed systemic cell-mediated immunity against MOG 35-55 , we did not observe EAE. Unexpectedly, many mice developed alopecia. We systematically investigated this finding., Results: Patchy alopecia developed in 36.4% of mice with the optimized protocol. Pathology consistent with alopecia areata was confirmed histologically by documenting concomitant reduced anagen phase and increased telogen phase hair follicles (HFs) in biopsies from patches of hair loss in mice with alopecia. We also found reduced CD200 staining and increased CD3 + T cells surrounding the HFs of mice with alopecia compared to the mice without alopecia, indicating HF Immune Privilege (HFIP) collapse. Systemic immune responses were also found, with increased proportions of activated T cells and B cells, as well as MHCII + dendritic cells in peripheral blood and/or splenocytes. Finally, in mice initially exposed to intranasal MOG 35-55 and PTx in combination, but not to either agent alone, splenocytes were shown to proliferate after in vitro stimulation by MOG 35-55. Consistent with prior investigations, PTx exhibited a dose-response effect on immune cell induction and phenotype, with the lowest PTx dose failing to induce autoimmunity, the highest PTx dose suppressing autoimmunity, and intermediate doses optimizing autoimmunity., Conclusions: We propose that this is the first report of an autoimmune disease in an animal model triggered by colocalization of intranasal PTx and autoantigen. This model parallels a natural exposure and potential intranasal sensitization-to-pathology paradigm and supports the plausibility that nasopharyngeal subclinical BP colonization is a cause of alopecia areata., Competing Interests: KR and SG are employed by ILiAD Biotechnologies LLC, which is developing a vaccine for the prevention of Bordetella pertussis infection. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Author YL declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. The authors declare that this study received funding from ILiAD Biotechnologies LLC (P00427002 to JR). The funder had the following involvement in the study: the study design and the writing of this article (review and edit)., (Copyright © 2024 Liu, Freeborn, Okeugo, Armbrister, Saleh, Fadhel Alvarez, Hoang, Park, Lindsey, Rapini, Glazer, Rubin and Rhoads.)

In a variety of species and behavioral contexts, learning and memory formation recruits two neural systems, with initial plasticity in one system being consolidated into the other over time. Moreover, consolidation is known to be selective; that is, some experiences are more likely to be consolidated into long-term memory than others. Here, we propose and analyze a model that captures common computational principles underlying such phenomena. The key component of this model is a mechanism by which a long-term learning and memory system prioritizes the storage of synaptic changes that are consistent with prior updates to the short-term system. This mechanism, which we refer to as recall-gated consolidation, has the effect of shielding long-term memory from spurious synaptic changes, enabling it to focus on reliable signals in the environment. We describe neural circuit implementations of this model for different types of learning problems, including supervised learning, reinforcement learning, and autoassociative memory storage. These implementations involve synaptic plasticity rules modulated by factors such as prediction accuracy, decision confidence, or familiarity. We then develop an analytical theory of the learning and memory performance of the model, in comparison to alternatives relying only on synapse-local consolidation mechanisms. We find that recall-gated consolidation provides significant advantages, substantially amplifying the signal-to-noise ratio with which memories can be stored in noisy environments. We show that recall-gated consolidation gives rise to a number of phenomena that are present in behavioral learning paradigms, including spaced learning effects, task-dependent rates of consolidation, and differing neural representations in short- and long-term pathways., Competing Interests: JL, AL No competing interests declared, (© 2023, Lindsey and Litwin-Kumar.)

Object classification has been proposed as a principal objective of the primate ventral visual stream and has been used as an optimization target for deep neural network models (DNNs) of the visual system. However, visual brain areas represent many different types of information, and optimizing for classification of object identity alone does not constrain how other information may be encoded in visual representations. Information about different scene parameters may be discarded altogether ('invariance'), represented in non-interfering subspaces of population activity ('factorization') or encoded in an entangled fashion. In this work, we provide evidence that factorization is a normative principle of biological visual representations. In the monkey ventral visual hierarchy, we found that factorization of object pose and background information from object identity increased in higher-level regions and strongly contributed to improving object identity decoding performance. We then conducted a large-scale analysis of factorization of individual scene parameters - lighting, background, camera viewpoint, and object pose - in a diverse library of DNN models of the visual system. Models which best matched neural, fMRI, and behavioral data from both monkeys and humans across 12 datasets tended to be those which factorized scene parameters most strongly. Notably, invariance to these parameters was not as consistently associated with matches to neural and behavioral data, suggesting that maintaining non-class information in factorized activity subspaces is often preferred to dropping it altogether. Thus, we propose that factorization of visual scene information is a widely used strategy in brains and DNN models thereof., Competing Interests: JL, EI No competing interests declared, (© 2024, Lindsey and Issa.)

Competing Interests: The authors report no conflicts of interest.

Trigeminal neuralgia is a heterogeneous disorder with likely multifactorial and complex etiology; however, trigeminal nerve demyelination and injury are observed in almost all patients with trigeminal neuralgia. The current management strategies for trigeminal neuralgia primarily involve anticonvulsants and surgical interventions, neither of which directly address demyelination, the pathological hallmark of trigeminal neuralgia, and treatments targeting demyelination are not available. Demyelination of the trigeminal nerve has been historically considered a secondary effect of vascular compression, and as a result, trigeminal neuralgia is not recognized nor treated as a primary demyelinating disorder. In this article, we review the evolution of our understanding of trigeminal neuralgia and provide evidence to propose its potential categorization, at least in some cases, as a primary demyelinating disease by discussing its course and similarities to multiple sclerosis, the most prevalent central nervous system demyelinating disorder. This proposed categorization may provide a basis in investigating novel treatment modalities beyond the current medical and surgical interventions, emphasizing the need for further research into demyelination of the trigeminal sensory pathway in trigeminal neuralgia. PERSPECTIVE: This article proposes trigeminal neuralgia as a demyelinating disease, supported by histological, clinical, and radiological evidence. Such categorization offers a plausible explanation for controversies surrounding trigeminal neuralgia. This perspective holds potential for future research and developing therapeutics targeting demyelination in the condition., (Copyright © 2024 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the RNA for T cell receptors (TCR) from CSF, unselected blood cells, and the antigen-specific cells. We used the TCR Vβ CDR3 sequences from the antigen-specific cells to assign antigen specificity to the sequences from the CSF and blood. LCL-specific cells comprised 13.0 ± 4.3% (mean ± SD) of the total reads present in CSF and 13.3 ± 7.5% of the reads present in blood. The next most abundant antigen specificity was flu, which was 4.7 ± 1.7% of the reads in the CSF and 9.3 ± 6.6% in the blood. The prominence of LCL-specific reads was even more marked in the top 1% most abundant CSF clones with statistically significant 47% mean overlap with LCL. We conclude that LCL-specific sequences form a major portion of the TCR repertoire in both CSF and blood and that expanded clones specific for LCL are present in MS CSF. This has important implications for the pathogenesis of MS., Competing Interests: Competing interests statement:The authors declare no competing interest.

Background: Trigeminal neuralgia (TN) is a well-recognized symptom of multiple sclerosis (MS), yet its clinical characteristics related to MS subtype is poorly studied. Our aim was to evaluate whether development and clinical outcome of TN are influenced by MS phenotype., Methods: In this retrospective cohort study, our database from 2007 to 2022 was reviewed to identify patients who had both the diagnosis of MS and TN, whether TN was an initial symptom of MS or developed later in diagnosis. A detailed medical history and treatment outcome was obtained. Pain status was assessed retrospectively using the Barrow Neurological Institute Pain Scale (BNI-PS), with BNI-PS I-III considered as good pain control and BNI-PS IV-V as poor pain control., Results: 58 patients had MS-related TN. 44 patients had relapsing remitting multiple sclerosis (RRMS) at the time of TN diagnosis, 11 had secondary progressive multiple sclerosis (SPMS) at the time of TN diagnosis, and type of MS was not clear in 3 patients at the time of TN diagnosis (either RRMS or SPMS). Over a mean follow up of 18.8 (SD=10.9) years, 30 transitioned to SPMS. TN was refractory to medical management in 9 RRMS and 22 SPMS patients (p = 0.001). TN patients with RRMS required lower median number of pain medications compared to SPMS (p = 0.014). Brain MRI was available in 41 of the entire cohort. Of these, 27 patients had demyelinating lesions in the trigeminal sensory pathway and 14 did not. Patients with existing lesions had a higher chance of failure of medical management (74% versus 36%, p = 0.017) and required surgical intervention (55% versus 7%, p = 0.003)., Discussion: TN was not seen in primary progressive multiple sclerosis (PPMS). In patients who transitioned to SPMS, TN was more likely to be refractory to medical management. TN was more refractory in the presence of demyelinating plaque involving trigeminal sensory pathway., Competing Interests: Declaration of Competing Interest Seyed H. Mousavi, MD, Declarations of interest none, John W. Lindsey, MD, Declarations of interest none, Rajesh K. Gupta, MD, Declarations of interest none, Jerry S. Wolinsky, MD, Declarations of interest none, John A. Lincoln, MD, PhD, (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Epstein-Barr Virus (EBV) is strongly associated with multiple sclerosis (MS). After initial infection, EBV maintains a life-long latent infection in B lymphocytes. Depletion of B lymphocytes from the blood with the anti-CD20 antibody ocrelizumab (OCR) markedly reduces disease activity in MS. Our objective was to measure the effect of OCR treatment on the antibody response to EBV and human antigens that are cross-reactive with EBV., Methods: Blood was collected from MS patients before and during OCR treatment. Antibodies to three EBV antigens (EBNA-1, BFRF3, and gp350) and three human proteins that are cross-reactive with EBV (septin-9, DLST, and HNRNPL) were quantified with Western blots. Antibodies to EBNA-1 and BFRF3 were also quantified with ELISA., Results: Antibodies to the EBV proteins BFRF3 and EBNA-1 measured on Western blot were significantly decreased after 12 months on OCR. Subsequent testing with ELISA confirmed the decrease for both BFRF3 and EBNA-1. With Western blots, there was a trend to decreased antibody response to septin-9 and DLST, but not HNRNPL. Total IgG concentration did not change., Conclusion: The antibody response to some EBV antigens decreases in OCR treated patients. The benefit of OCR for MS may be through removal of EBV antigenic stimulus., Competing Interests: Disclosure/Conflict of interest J.W. Lindsey has received personal compensation for speaking or consulting for EMD Serono, Celgene, Mapi Pharmaceuticals, Banner Life Sciences, TG Therapeutics, Genentech, and Genzyme; is participating in clinical trials funded by Genentech, Biogen, Atara, EMD Serono, and AbbVie; and has received research funding from the National MS Society and Genentech. Ms. Pham and Dr. Saroukhani have no conflicts to report., (Copyright © 2023. Published by Elsevier B.V.)

Background: Glatiramer acetate (GA) is US-approved for relapsing multiple sclerosis., Objectives: To describe GA long-term clinical profile. To compare effectiveness of early start (ES) versus delayed start (DS; up to 3 years) with GA., Methods: Phase 3 trial participants entered a randomized placebo-controlled period then an open-label extension (OLE) with GA., Results: Overall, 208 out of 251 (82.9%) randomized participants entered the OLE; 24 out of 101 (23.8%, ES) and 28 out of 107 (26.2%, DS) participants completed the OLE. Median GA treatment was 9.8 (0.1-26.3) years. Annualized change in Expanded Disability Status Scale (EDSS) score was lower with ES versus DS ( p  = 0.0858: full study; p  = 0.002; Year 5). Participants with improved/stable EDSS was consistently higher with ES versus DS: 40.3% versus 31.6% ( p  = 0.1590; full study); 70.8% versus 55.6% ( p  = 0.015; Year 5). ES prolonged time-to-6-month confirmed disease worsening (CDW) versus DS (9.8 vs 6.7 years), time-to-12-month CDW (18.9 vs 11.6 years), and significantly reduced time-to-second-6-month CDW ( p  = 0.0441). No new safety concerns arose., Conclusion: GA long-term treatment maintained clinical benefit with a similar safety profile to phase 3 results; a key limitation was that only 25% of participants completed the OLE. Early initiation of GA had sustained benefits versus delayed treatment.

A method to stimulate T lymphocytes with a broad range of brain antigens would facilitate identification of the autoantigens for multiple sclerosis and enable definition of the pathogenic mechanisms important for multiple sclerosis. In a previous work, we found that the obvious approach of culturing leukocytes with homogenized brain tissue does not work because the brain homogenate suppresses antigen-specific lymphocyte proliferation. We now report a method that substantially reduces the suppressive activity. We used this non-suppressive brain homogenate to stimulate leukocytes from multiple sclerosis patients and controls. We also stimulated with common viruses for comparison. We measured proliferation, selected the responding CD3+ cells with flow cytometry, and sequenced their transcriptomes for mRNA and T-cell receptor sequences. The mRNA expression suggested that the brain-responding cells from MS patients are potentially pathogenic. The T-cell receptor repertoire of the brain-responding cells was clonal with minimal overlap with virus antigens., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gottlieb, Pham and Lindsey.)

Background: Epstein-Barr Virus (EBV) is strongly associated with multiple sclerosis (MS). After initial infection, EBV maintains a life-long latent infection in B lymphocytes. Depletion of B lymphocytes from the blood with the anti-CD20 antibody ocrelizumab markedly reduces disease activity in MS. Our objective was to measure the effect of ocrelizumab treatment on the cellular immune response to EBV., Methods: Blood was collected from MS patients before and during ocrelizumab treatment. Peripheral blood mononuclear cells were stimulated with various antigens, and the response was measured using tritiated thymidine for proliferation and ELIspot for number of interferon-γ producing cells., Results: The proliferation to autologous EBV-infected cells (LCL) was decreased after both 6 and 12 months of treatment. The number of interferon-γ producing cells on ELIspot in response to stimulation with either LCL or EBV also decreased. Responses to varicella zoster virus, influenza virus, and a mitogen did not change significantly., Conclusion: The cellular immune response to EBV and LCL decreases during treatment with ocrelizumab. The benefit of ocrelizumab for MS may be through removal of EBV antigenic stimulus., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Background: Risk factors associated with coronavirus disease 2019 (COVID-19) severity in patients with multiple sclerosis (MS) have been described. Recent improvements in supportive care measures and increased testing capacity may modify the risk of severe COVID-19 outcome in MS patients. This retrospective study evaluates the severity and outcome of COVID-19 in MS and characterizes temporal trends over the course of the pandemic in the United States., Methods: We conducted a comparative cohort study using de-identified electronic health record (EHR) claims-based data. MS patients diagnosed with COVID-19 between February 2, 2020 and October 13, 2020 were matched (1:2) to a control group using propensity score analysis. The primary outcome was a composite of intensive care unit (ICU) admission, mechanical ventilation, and/or death., Results: A total of 2,529 patients (843 MS and 1,686 matched controls) were included. Non-ambulatory and pre-existing comorbidities were independent risk factors for COVID-19 severity. The risk for the severe composite outcome was lower in the late cohorts compared with the early cohorts., Conclusions: The majority of MS patients actively treated with a disease-modifying therapy (DMT) had mild disease. The observed trend toward a reduction in severity risk in recent months suggests an improvement in COVID-19 outcome., (Copyright © 2021 Elsevier B.V. All rights reserved.)

The CHORDS trial evaluated ocrelizumab (OCR) in patients with relapsing-remitting multiple sclerosis who had a suboptimal response to previous disease-modifying treatment. The objective of the present study was to assess the safety of shorter OCR infusions in a substudy of CHORDS. After completing four doses of OCR per initial US prescribing recommendations in the main study, participants in the substudy (N = 129) received a fifth dose over a 2-h duration (vs. 3.5 h). Infusion-related reactions occurred in 12.4% of patients. None were severe, life-threatening or led to treatment discontinuation. Shorter infusion time did not change the safety profile of OCR. Clinicaltrials.gov (NCT0237856)., (© 2021 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Autoimmune conditions affect 23 million Americans or 7% of the US population. There are more than 100 autoimmune disorders, affecting every major organ system in humans. This chapter aims to further explain Treg dysfunction autoimmune disorders, including monogenic primary immune deficiency such as immune dysregulation polyendocrinopathy, enteropathy, X-linked inheritance (IPEX) syndrome, and polygenic autoimmune diseases with Treg dysfunction such as multiple sclerosis (MS), inflammatory bowel disease (IBD), and food allergy. These conditions are associated with an abnormal small intestinal and colonic microbiome. Some disorders clearly improve with therapies aimed at microbial modification, including probiotics and fecal microbiota transplantation (FMT). Approaches to prevent and treat these disorders will need to focus on the acquisition and maintenance of a healthy colonic microbiota, in addition to more focused approaches at immune suppression during acute disease exacerbations.

Making inferences about the computations performed by neuronal circuits from synapse-level connectivity maps is an emerging opportunity in neuroscience. The mushroom body (MB) is well positioned for developing and testing such an approach due to its conserved neuronal architecture, recently completed dense connectome, and extensive prior experimental studies of its roles in learning, memory, and activity regulation. Here, we identify new components of the MB circuit in Drosophila , including extensive visual input and MB output neurons (MBONs) with direct connections to descending neurons. We find unexpected structure in sensory inputs, in the transfer of information about different sensory modalities to MBONs, and in the modulation of that transfer by dopaminergic neurons (DANs). We provide insights into the circuitry used to integrate MB outputs, connectivity between the MB and the central complex and inputs to DANs, including feedback from MBONs. Our results provide a foundation for further theoretical and experimental work., Competing Interests: FL, JL, EM, NO, MD, GD, IS, AB, MP, PS, AN, ST, NE, TY, AF, AB, RP, MC, LS, YA, GJ, LA, AL, SW, GR No competing interests declared, (© 2020, Li et al.)

Objective: Large demyelinating lesions with possible mass effect (tumefactive multiple sclerosis or tumefactive demyelination) can be mistaken for tumour-like space-occupying lesions suggesting a malignant outcome., Methods: We reviewed our own experience of multiple sclerosis subjects ( n  = 28) with tumefactive demyelination to determine the relationship between clinical outcomes and lesion evolution, clinical outcomes and their relationship to different therapies. Patients with central nervous system demyelinating disease were identified from our database over the last 10 years., Results: No patient increased in extended disability status scale (EDSS). Overall, lesion regression was associated with improved EDSS. Lesion regression was also associated with therapy versus no therapy. No specific therapy or corticosteroid infusions improved EDSS over the long term. The absence of enhancement on follow up on magnetic resonance imaging portended lesion regression., Conclusion: Tumefactive demyelination may predict a more benign overall course and is susceptible to traditional immunomodulatory treatments.

The gut microbiome plays an important role in immune function and has been implicated in multiple sclerosis (MS). However, how and if the modulation of microbiota can prevent or treat MS remain largely unknown. In this study, we showed that probiotic Lactobacillus reuteri DSM 17938 ( L. reuteri ) ameliorated the development of murine experimental autoimmune encephalomyelitis (EAE), a widely used animal model of MS, a model which is primarily mediated by T H 17 and T H 1 cells. We discovered that L. reuteri treatment reduced T H 1/T H 17 cells and their associated cytokines IFN-γ/IL-17 in EAE mice. We also showed that the loss of diversity of gut microbiota induced by EAE was largely restored by L. reuteri treatment. Taxonomy-based analysis of gut microbiota showed that three "beneficial" genera Bifidobacterium, Prevotella , and Lactobacillus were negatively correlated with EAE clinical severity, whereas the genera Anaeroplasma, Rikenellaceae , and Clostridium were positively correlated with disease severity. Notably, L. reuteri treatment coordinately altered the relative abundance of these EAE-associated taxa. In conclusion, probiotic L. reuteri changed gut microbiota to modulate immune responses in EAE, making it a novel candidate in future studies to modify the severity of MS.

Background: Identifying pathways linking neuroinflammation and neurodegeneration is essential to help prevent disability progression in people with multiple sclerosis (MS). Endothelin-1 (ET-1) is a potent vasoconstrictor thought to contribute to cerebral hypoperfusion and tissue damage in MS. Its link with the neuroinflammatory process remains poorly investigated., Objectives: To determine plasma ET-1 levels in treatment-naïve people with MS and controls, and the relationship between ET-1 and other peripheral immune mediator levels as potential markers of the disease process., Methods: This is a retrospective study that included specimens previously collected from 35 treatment-naïve patients with clinically isolated syndrome highly suggestive of MS or definite MS and 35 sex- and age-matched controls. ET-1 plasma levels were measured by enzyme-linked immunosorbent assay (ELISA), and plasma cytokine levels [interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-10, IL-12(p70), IL-13, interferon (IFN)-γ and tumor necrosis factor (TNF)-α] were simultaneously measured by Multiplex assay., Results: ET-1 levels were significantly increased in MS patients compared to controls. No significant difference in cytokine levels between the groups were found. However, a significant increase in IFN-γ/IL-4 ratio was observed in patients with MS in comparison with controls, suggestive of Th1 skewed response. Binary logistic regression was performed to ascertain the effects of age, sex, ET-1 and cytokine levels on the likelihood of MS diagnosis. In the final model, ET-1, IL-4 and IFN-γ levels remained as predictors of MS. There was no significant correlation between ET-1 and cytokine levels., Conclusions: Patients with MS presented increased levels of ET-1 and an immune response biased towards a Th1 profile. Although both ET-1 and Th1 cytokine profile were predictors of MS diagnosis, ET-1 levels were not associated with peripheral immune markers, suggesting that these changes may occur independently., (Copyright © 2018 Elsevier B.V. All rights reserved.)

We hypothesize that the immune response to Epstein-Barr virus (EBV) drives the autoimmune damage in multiple sclerosis (MS). We investigated whether antibodies to two EBV proteins targeted by MS patients cross-react with self proteins. Using affinity columns, immunoprecipitation, and mass spectrometry, we found that antibodies to the EBV protein BFRF3 cross-react with the cytoplasmic protein septin-9, and antibodies to BRRF2 also bind mitochondrial proteins. Using Western blots and ELISA, we demonstrated that MS patients were more likely to have high levels of antibodies to one or another of these self antigens., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, and the antibody response to EBV is reported to be increased in MS. EBV contains multiple antigens, and only a few have been investigated. Our hypothesis is that MS patients will have an increased antibody response to only selected EBV antigens. We used immunoprecipitation and quantitative mass spectrometry to identify candidate EBV antigens. We then measured the antibody response to 10 individual EBV proteins with quantitative ELISA. We found that the antibody response was increased in MS to three of the EBV proteins, but not to the other seven., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Objective: The objective of this study was to determine whether reactivation of Epstein-Barr (EBV) or activation of the anti-EBV immune response correlates with MS disease activity on MR imaging., Methods: Subjects with early, active relapsing-remitting MS were studied for 16 weeks with blood and saliva samples collected every 2 weeks and brain MRI performed every 4 weeks. We isolated peripheral blood mononuclear cells from each blood sample and tested the immune response to EBV, autologous EBV-infected lymphoblastoid cell lines (LCL), human herpesvirus 6 (HHV6), varicella zoster virus (VZV), tetanus, and mitogens. We measured the proliferative response and the number of interferon-γ secreting cells with ELISPOT. We measured the amounts of EBV, HHV6, and VZV DNA in blood and saliva with quantitative PCR. On MRI, we measured number and volume of contrast enhancing and T2 lesions. We tested for correlation between the immunologic assays and the MRI results, assessing different time intervals between the MRI and immunologic assays., Results: We studied 20 subjects. Ten had enhancing lesions on one or more MRI scans and one had new T2 lesions without enhancement. The most significant correlation was between proliferation to autologous LCL and the number of combined unique active lesions on MRI 4 weeks later. Both proliferation and number of cells secreting interferon-γ in response to LCL correlated with the number of enhancing lesions 8 weeks later., Conclusions: We find evidence for correlation of antiviral immune responses in the blood with subsequent disease activity on MRI scans., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and antibodies to the EBV nuclear antigen-1 (EBNA-1) are consistently increased in MS patients. The hypothesis of this study is that anti-EBNA-1 antibodies cross-react with a self antigen in MS patients. We affinity purified anti-EBNA-1 antibodies from human plasma, used the anti-EBNA-1 to immunoprecipitate antigens from human brain, and identified bound antigens with mass spectrometry. Anti-EBNA-1 consistently bound heterogeneous nuclear ribonucleoprotein L (HNRNPL). We expressed both the long and short isoforms of this protein, and verified with Western blots and ELISA that the long isoform cross-reacts with EBNA-1. Immunohistochemistry demonstrated that anti-EBNA-1 bound to an antigen in the nucleus of cultured rat central nervous system cells. ELISA demonstrated the presence of antibodies to HNRNPL in the plasma of both healthy controls and MS patients, but anti-HNRNPL was not increased in MS patients. We conclude that HNRNPL is an autoantigen which cross-reacts with EBNA-1. The relevance of this autoantigen to MS and other autoimmune diseases remains to be investigated., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Development of an immune or autoimmune response involves T-cell activation in lymphoid organs and subsequent migration to peripheral tissues. Here we show that T-cell-specific ablation of the kinase TBK1 promotes T-cell activation but causes retention of effector T cells in the draining lymph node in a neuroinflammatory autoimmunity model, experimental autoimmune encephalomyelitis (EAE). At older ages, the T-cell-conditional TBK1-knockout mice also spontaneously accumulate T cells with activated phenotype. TBK1 controls the activation of AKT and its downstream kinase mTORC1 by a mechanism involving TBK1-stimulated AKT ubiquitination and degradation. The deregulated AKT-mTORC1 signalling in turn contributes to enhanced T-cell activation and impaired effector T-cell egress from draining lymph nodes. Treatment of mice with a small-molecule inhibitor of TBK1 inhibits EAE induction. These results suggest a role for TBK1 in regulating T-cell migration and establish TBK1 as a regulator of the AKT-mTORC1 signalling axis.

Background: Chronic cerebrospinal venous insufficiency (CCSVI) was implicated in the pathophysiology of multiple sclerosis (MS)., Objective: We evaluated neurosonography (NS), magnetic resonance venography (MRV), and transluminal venography (TLV) in subsets of MS patients drawn from a single-center, prospective, case-control study of 206 MS and 70 non-MS volunteers., Methods: As previously reported, findings on high-resolution B-mode NS imaging with color and spectral Doppler of the extracranial and intracranial venous drainage consistent with CCSVI were similar among MS and non-MS volunteers (3.88% vs 7.14%; p = 0.266). Ninety-nine MS participants consented to intravascular contrast-enhanced 3D MRV to assess their major systemic and intracranial venous circulation, and 40 advanced to TLV that included pressure measurements of the superior vena cava, internal jugular, brachiocephalic, and azygous veins., Results: NS findings and MRV patterns were discrepant for 26/98 evaluable subjects, including four with abnormal findings on NS that had normal venous anatomy by MRV. In no instance were TLV pressure gradients indicative of clinically significant functional stenosis encountered. The three imaging approaches provided generally consistent data with discrepancies referable to inherent technique properties., Conclusions: Our findings lend no support for altered venous outflow dynamics as common among MS patients, nor do they likely contribute to the disease process.

Objective: Chronic cerebrospinal venous insufficiency (CCSVI) has been implicated in the pathophysiology of multiple sclerosis (MS). We sought to determine whether neurosonography (NS) provides reliable information on cerebral venous outflow patterns specific to MS., Methods: This was a single-center, prospective case-control study of volunteer MS and non-MS participants. A neurosonologist, blind to the subjects' diagnosis, used high-resolution B-mode imaging with color and spectral Doppler to systematically investigate, capture, and record extracranial and intracranial venous drainage. These neuroimaging results were evaluated and scored by an expert blinded to subjects' information and with no interactions with the participants., Results: Altogether, 276 subjects were studied: 206 with MS and 70 non-MS. MS patients were older than non-MS subjects (48.3±9.9 vs 44.3±11.8 years, p<0.007), with durations from first symptoms and diagnosis of 13.7±10 and 9.9±7.8 years, and Expanded Disability Status Scale of 2.6±2.0. Overall, 82 subjects (29.7%) fulfilled 1 of 5 NS criteria proposed for CCSVI; 13 (4.7%) fulfilled 2 criteria required for diagnosis, and none fulfilled >2 criteria. The distribution of subjects with 0, 1, or 2 criteria did not differ significantly across all diagnostic groupings, between MS and non-MS subjects, or within MS subgroups. CCSVI was present in 7.14% of non-MS and 3.88% of MS patients (p=0.266). No significant differences emerged between MS and non-MS subjects for extracranial or intracranial venous flow rates., Interpretation: NS findings described as CCSVI are much less prevalent than initially reported, and do not distinguish MS from other subjects. Our findings do not support the hypothesis that CCSVI is causally associated with MS., (© 2013 American Neurological Association.)

Infection with Epstein-Barr virus (EBV) is associated with multiple sclerosis (MS), and patients with MS have an increased antibody response to some EBV antigens. The major antigens of EBV are only partly defined. Our hypothesis is that the antibody response to EBV is altered in MS. With ELISA, we found that antibodies to EB virions were increased in both serum and CSF of MS patients. Western blots demonstrated that there are multiple different antigens recognized. The antibody response was generally higher in MS to all EBV antigens, with particularly significant increases for certain antigens. We conclude that the antibody response to EBV in MS is generally increased with altered specificity., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Our objective was to assess the efficacy of rituximab (RTX) in neuromyelitis optica (NMO). We conducted a retrospective review of cases personally treated by the authors. We identified nine subjects meeting criteria for either NMO or recurrent longitudinally extensive transverse myelitis (LETM) who were treated with RTX and documented their clinical course. Six of the nine subjects continued to have relapses after RTX treatment. RTX was the first immunosuppressive treatment used after diagnosis in five subjects, and four of these continued to have relapses. We conclude that outcomes after RTX treatment of NMO are inconsistent. The observed variability may reflect differences in disease activity between individuals, differences in disease activity over time, or differences in the underlying immunopathogenesis of NMO. More effective treatments are needed., (Copyright © 2012 Elsevier B.V. All rights reserved.)

Background: Interferon-β1a (IFNB) and glatiramer acetate (GA) are distinct therapies which are both partially effective for relapsing MS. It is not known if combining the two treatments would be more effective., Objective: To review the rationale, design, and baseline characteristics of the CombiRx study of combined treatment with IFNB and GA., Methods: The key inclusion criteria included a diagnosis of relapsing MS, at least 2 episodes of MS activity in the previous 3 years, expanded disability status scale of 0-5.5, and no prior treatment with either IFNB or GA. Subjects were randomized to IFNB+GA, IFNB monotherapy, or GA monotherapy in a 2:1:1 ratio., Results: From 2005 to 2009, we enrolled 1008 subjects. The participants were 72.4% female and 87.6% Caucasian with a mean age of 37.7 years. The median duration of symptoms was 2 years at entry into the study, and the mean EDSS was 2.1. On the baseline MRI, the mean total lesion load was 12.2ml, and 40% of the participants had enhancing lesions., Conclusion: We have recruited a population of patients with clinical and MRI characteristics typical for early MS. The study results will aid in deciding on the optimum early treatment. This trial should serve as a model for future studies of combination therapy., (Copyright © 2012 Elsevier B.V. All rights reserved.)

A defining feature of multiple sclerosis (MS) is the occurrence of clinical relapses separated by periods of clinical stability. Better understanding of the events underlying clinical relapse might suggest new approaches to treatment. The objective of this study was to measure changes in the expression of RNA in the blood during relapse. We used microarrays to measure mRNA expression in paired samples from 14 MS patients during clinical relapse and while stable. Seventy-one transcripts changed expression at the P < 0.001 significance level. The most notable finding was decreased expression of transcripts with regulatory function, expressed primarily in non-T cells. These decreased transcripts included the interleukin-1 receptor antagonist, which had a corresponding decrease in the protein concentration in serum. Transcripts with increased expression were expressed primarily in T cells. Pathways analysis suggested involvement of the cytokine network, coagulation and complement cascades, IL-10 signaling and NF-κB signaling. We conclude that there are alterations of mRNA expression in both T cells and non-T cells during MS relapse.

We investigated T cell immunity to Epstein-Barr virus (EBV) in multiple sclerosis (MS) and assessed cross-reactivity of the anti-EBV cellular response with brain antigens. We measured the proliferation, cytotoxicity, and number of interferon-γ secreting cells following stimulation with autologous EBV-infected lymphoblastoid cell lines (LCL) in MS patients and matched controls. There were no statistically significant differences for any of the measured responses, but there was a trend towards decreased proliferative responses in MS patients. There was no measured cross-reactivity between LCL and brain antigens. We conclude that the cellular immune response against EBV-infected cells is neither increased nor decreased in MS., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Background: Our objective was to determine whether antibodies against the Epstein-Barr virus (EBV) nuclear antigen-1 (EBNA-1), early antigen (EA), and EBV neutralizing antibodies (NeutAb) are altered in multiple sclerosis (MS)., Methods: We measured EBNA-1 IgG, EA IgG, and EA IgA using quantitative ELISA. We measured NeutAb using a quantitative competitive ELISA. We studied 80 patients with MS, 80 matched controls, and 19 patients with MS with samples collected both whilst stable and in relapse., Results: Epstein-Barr virus nuclear antigen-1 IgG and EA IgA were increased in MS compared to controls. The EBNA-1 index value was 23.3 ± 18.3 in the patients with MS (mean ± SD) and 16.3 ± 17.4 in the controls (P = 0.007, paired t-test). EA IgA had a median value of 1.964 in the patients with MS and 1.248 in the controls (P = 0.029, Wilcoxon signed rank test). EA IgG and NeutAb were not significantly different. None of the antibody levels were altered in relapse. The correlation between concentrations of different antibodies was minimal., Conclusions: IgG antibodies to EBNA-1 are significantly increased in MS. IgA antibodies against EBV EA are also increased. The EBV neutralizing antibody response is similar in MS and controls., (© 2010 The Author(s). European Journal of Neurology © 2010 EFNS.)

The ongoing US Glatiramer Acetate (GA) Trial is the longest evaluation of continuous immunomodulatory therapy in relapsing-remitting multiple sclerosis (RRMS). The objective of this study was to evaluate up to 15 years of GA as a sole disease-modifying therapy. Two hundred and thirty-two patients received at least one GA dose since study initiation in 1991 (mITT cohort), and 100 (43%, Ongoing cohort) continued as of February 2008. Patients were evaluated every 6 months using the Expanded Disability Status Scale (EDSS). Mean GA exposures were 8.6 +/- 5.2, 4.81 +/- 3.69, and 13.6 +/- 1.3 years and mean disease durations were 17, 13, and 22 years for mITT, Withdrawn and Ongoing cohorts, respectively. For Ongoing patients, annual relapse rates (ARRs) maintained a decline from 1.12 +/- 0.82 at baseline to 0.25 +/- 0.34 per year; 57% had stable/improved EDSS scores (change < or = 0.5 points); 65% had not transitioned to secondary progressive multiple sclerosis (SPMS); 38%, 18%, and 3% reached EDSS 4, 6, and 8. For all patients on GA therapy (the mITT cohort), ARRs declined from 1.18 +/- 0.82 to 0.43 +/- 0.58 per year; 54% had stable/improved EDSS scores; 75% had not transitioned to SPMS; 39%, 23%, and 5% reached EDSS 4, 6, and 8. In conclusion, multiple sclerosis patients with mean disease duration of 22 years administering GA for up to 15 years had reduced relapse rates, and decreased disability progression and transition to SPMS. There were no long-term safety issues.

Background: Epstein-Barr virus (EBV) is associated with MS, but it is not clear whether EBV plays a role in the pathogenesis of MS., Hypothesis: We hypothesized that the immune control of EBV might be defective in MS, and that reactivation of EBV might drive the immune response in MS., Methods: We collected blood from controls and patients with MS, and measured the amounts of EBV DNA and RNA using quantitative PCR., Results: We found that EBV DNA and RNA were frequently detectable in peripheral blood leukocytes from both patients with MS and normal controls. There was no significant difference between patients with MS or controls. Paired samples from a small number of subjects suggest that EBV DNA may increase before and during clinical relapse., Conclusions: We conclude that the immune control of EBV infection is similar in MS and controls, and that reactivation of EBV may correlate with MS disease activity.

Objective: To determine whether the presence of Nogo-A protein in CSF is a useful biomarker for multiple sclerosis (MS)., Methods: We performed Western blots on CSF from patients with MS and controls with the commercially available Nogo-A antibody and secondary antibody used in a prior report. We used densitometry to measure band density on Western blot. Controls included blots without primary antibody, samples without dithiothreitol (DTT), CSF passed through a protein G column, and Western blots with anti-Ig-light chain antibody. IgG concentration in CSF was measured by ELISA., Results: A band at about 25 kD band was detectable in almost all CSF specimens, but was darker in samples from patients with MS. The density relative to a reference sample (mean +/- SD) was 0.84 +/- 0.67 for relapsing MS (n = 17), 1.16 +/- 0.74 for primary progressive MS (n = 11), and 0.49 +/- 0.22 in controls (n = 12). This band was still present when the primary antibody was omitted, but was absent if the sample buffer did not include DTT or if the CSF was first adsorbed with protein G. IgG concentration was higher in MS CSF and correlated closely with the 25 kD band density (r = 0.78)., Conclusions: A 25 kD band is detectable on Western blots stained with Nogo-A antibody in almost all CSF specimens, but is darker in MS specimens. Our results suggest this band is immunoglobulin light chains rather than Nogo-A. It is not likely to be a useful biomarker for multiple sclerosis.

The cause of multiple sclerosis (MS) is currently unknown. The hypothesis of this study is that MS is caused by a chronic bacterial infection of the central nervous system (CNS) and the ensuing immune response. We developed a sensitive two-stage polymerase chain reaction method using nested or semi-nested primers specific for the bacterial 16S ribosomal DNA to test for the presence of bacterial DNA in cerebrospinal fluid. We designed seven sets of primers to amplify DNA from spirochetes , Campylobacter, Mycoplasma, Chlamydia, Bartonella, Mycobacteria and Streptococcus and tested cerebrospinal fluid from patients with relapsing-remitting MS, primary progressive MS, transverse myelitis and controls. We did not detect DNA from any of the groups of bacteria in patients or controls. We conclude that we were unable to find evidence for CNS infection with any of these seven groups of bacteria in MS.

Background: Multiple sclerosis (MS) is associated with Epstein-Barr virus (EBV) infection, but the relationship between the virus and the disease is not clear. As many different types of EBV exist, it is possible that MS is caused by one particular type of EBV. Objectives - The aim of this study was to determine whether MS is associated with a particular genotype of EBV., Materials and Methods: We collected blood from MS patients and controls, amplified and sequenced the latent membrane protein-1 (LMP-1) gene, and compared the groups., Results: We found a variety of LMP-1 sequences in both MS and controls, with no significant differences between the groups. Conclusion - We conclude that MS is not associated with a particular genotype of EBV.