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High-efficacy disease-modifying therapies have been proven to slow disability accrual in adults with relapsing–remitting multiple sclerosis. However, their impact on disability worsening in paediatric-onset multiple sclerosis, particularly during the early phases, is not well understood. We evaluated how high-efficacy therapies influence transitions across five disability states, ranging from minimal disability to gait impairment and secondary progressive multiple sclerosis, in people with paediatric-onset multiple sclerosis.

IMPORTANCE: Natalizumab cessation is associated with a risk of rebound disease activity. It is important to identify the optimal switch disease-modifying therapy strategy after natalizumab to limit the risk of severe relapses. OBJECTIVES: To compare the effectiveness and persistence of dimethyl fumarate, fingolimod, and ocrelizumab among patients with relapsing-remitting multiple sclerosis (RRMS) who discontinued natalizumab. DESIGN, SETTING, AND PARTICIPANTS: In this observational cohort study, patient data were collected from the MSBase registry between June 15, 2010, and July 6, 2021. The median follow-up was 2.7 years. This was a multicenter study that included patients with RRMS who had used natalizumab for 6 months or longer and then were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months after natalizumab discontinuation. Patients without baseline data were excluded from the analysis. Data were analyzed from May 24, 2022, to January 9, 2023. EXPOSURES: Dimethyl fumarate, fingolimod, and ocrelizumab. MAIN OUTCOMES AND MEASURES: Primary outcomes were annualized relapse rate (ARR) and time to first relapse. Secondary outcomes were confirmed disability accumulation, disability improvement, and subsequent treatment discontinuation, with the comparisons for the first 2 limited to fingolimod and ocrelizumab due to the small number of patients taking dimethyl fumarate. The associations were analyzed after balancing covariates using an inverse probability of treatment weighting method. RESULTS: Among 66 840 patients with RRMS, 1744 had used natalizumab for 6 months or longer and were switched to dimethyl fumarate, fingolimod, or ocrelizumab within 3 months of natalizumab discontinuation. After excluding 358 patients without baseline data, a total of 1386 patients (mean [SD] age, 41.3 [10.6] years; 990 female [71%]) switched to dimethyl fumarate (138 [9.9%]), fingolimod (823 [59.4%]), or ocrelizumab (425 [30.7%]) after natalizumab. The ARR for each medication was as follows: ocrelizumab, 0.06 (95% CI, 0.04-0.08); fingolimod, 0.26 (95% CI, 0.12-0.48); and dimethyl fumarate, 0.27 (95% CI, 0.12-0.56). The ARR ratio of fingolimod to ocrelizumab was 4.33 (95% CI, 3.12-6.01) and of dimethyl fumarate to ocrelizumab was 4.50 (95% CI, 2.89-7.03). Compared with ocrelizumab, the hazard ratio (HR) of time to first relapse was 4.02 (95% CI, 2.83-5.70) for fingolimod and 3.70 (95% CI, 2.35-5.84) for dimethyl fumarate. The HR of treatment discontinuation was 2.57 (95% CI, 1.74-3.80) for fingolimod and 4.26 (95% CI, 2.65-6.84) for dimethyl fumarate. Fingolimod use was associated with a 49% higher risk for disability accumulation compared with ocrelizumab. There was no significant difference in disability improvement rates between fingolimod and ocrelizumab. CONCLUSION AND RELEVANCE: Study results show that among patients with RRMS who switched from natalizumab to dimethyl fumarate, fingolimod, or ocrelizumab, ocrelizumab use was associated with the lowest ARR and discontinuation rates, and the longest time to first relapse.

IMPORTANCE: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS). OBJECTIVE: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials. DESIGN, SETTING, AND PARTICIPANTS: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics. EXPOSURE: AHSCT vs fingolimod, natalizumab, or ocrelizumab. MAIN OUTCOMES: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement. RESULTS: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%). CONCLUSION: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

BackgroundEarly recognition of markers of faster disability worsening in paediatric-onset multiple sclerosis (MS) is a key requisite of personalised therapy for children with MS at the earliest possible time.ObjectiveTo identify early predictors of rapid disability accrual in patients with paediatric-onset MS.MethodsUsing the global MSBase registry, we identified patients who were <18 years old at the onset of MS symptoms. The clinico-demographic characteristics examined as predictors of future MS Severity Score (MSSS) included sex, age at symptom onset, absence of disability at the initial assessment, maximum Expanded Disability Status Scale (EDSS) score, relapse frequency and presence of brainstem, pyramidal, visual or cerebellar symptoms in the first year. A Bayesian log-normal generalised linear mixed model adjusted for cumulative proportion of time on higher-efficacy disease-modifying therapies (DMTs) was used to analyse the data.Results672 patients (70% female) contributing 9357 visits were included. The median age at symptom onset was 16 (quartiles 15–17) years. Older age at symptom onset (exp(β)=1.10 (95% CI 1.04 to 1.17)), higher EDSS score (1.22 (1.12 to 1.34)) and pyramidal (1.31 (1.11 to 1.55)), visual (1.25 (1.10 to 1.44)) or cerebellar (1.18 (1.01 to 1.38)) symptoms in the first year were associated with higher MSSS. MSSS was reduced by 4% for every 24% increase in the proportion of time on higher-efficacy DMTs (0.96 (0.93 to 0.99)).ConclusionsA relatively later onset of MS in childhood, higher disability and pyramidal, visual or cerebellar symptoms during the first year predicted significant worsening in disability in patients with paediatric-onset MS. Persistent treatment with higher-efficacy DMTs was associated with a reduced rate of disability worsening.

Multiple sclerosis (MS) is an autoimmune demyelinating disease that involves the central nervous system (CNS). Individuals with Multiple Sclerosis (MS) may experience difficulty adapting to their diagnosis as the unpredictable nature of the disease can be challenging to cope with.

ABSTRACTWe recently showed that Tiam1 expression is induced in pro-inflammatory T helper 17 (Th17) cells differentiated with interleukin (IL)-6 and TGF-β1, and together with Rac1 promote Th17 cell development and autoimmunity in a mouse model of multiple sclerosis. Here we found that STAT3 and Smad3, downstream transcription factors of IL-6 and TGF-β1, respectively, play opposing roles in regulating Tiam1 transcription in CD4+T-cells. While IL-6-STAT3 signaling promotes Tiam1 expression, TGF-β1-Smad3 induces the opposite outcome. At the Tiam1 promoter, both STAT3 and Smad3 bind to the Tiam1 promoter in Th17 cells. However, STAT3 induces Tiam1 promoter activity whereas Smad3 competes with STAT3 and inhibits its activity. Our findings uncover the complexity of STAT3/Smad3 signaling in regulating Tiam1 expression and Th17 cells.

Although mental disorders are a leading cause of disability in the Arab region, which includes 5·54% of the global population, Arab countries produce only 1·0% of the global output of peer-reviewed publications in mental health research. Various stakeholders, including Arab mental health researchers, institutional and funding agency officials, and international research collaborators, convened to identify challenges faced by Arab mental health researchers and propose an evidence-informed call for action. Challenges identified include prevalent stigma and low awareness, conflict and war, scarce institutional and funding resources, inadequate publishing opportunities, insufficient training in mental health research, and shortage of reliable and valid assessment tools. The proposed action plan includes ways of addressing stigma and spreading awareness, increasing collaborative efforts, building research infrastructure, strengthening the mental health workforce, and translating research findings into a call to action on societal and governmental levels. The proposed action plan could provide a roadmap for Arab mental health researchers and research institutions, which might ultimately increase research productivity in the Arab region and close the gap between Arab countries and the rest of the world.

•The Health-Related Quality of Life (HRQoL) of Lebanese Multiple Sclerosis (MS) patients deteriorates significantly and gradually as MS progresses. This deterioration leads to lower HRQoL (utility scores) for patients with higher Expanded Disability Status Scale (EDSS) levels and lower neurological functioning.•A higher educational level, longer disease duration, employment, lower EDSS scores, and a decrease in cognitive difficulties were found to be significantly associated with higher HRQoL utilities in Lebanese patients with MS. These utilities were generated from the EuroQoL (EQ-5D-5L) and the Multiple Sclerosis International Quality of Life (MusiQoL) instruments.•Our results revealed the need to develop a local index for the EuroQoL (EQ-5D-5L) value set in Lebanon, ensuring an accurate approach for conducting future economic burden studies. Nevertheless, this study is part of a broader research on the economic burden of MS in Lebanon, where we developed a protocol that serves as a guide for assessing societal cost-of-illness and HRQoL burden in Lebanon and other low- and middle-income countries. The questionnaire included in the study protocol is adaptable for similar studies in these countries.

•In our study, the relapse rate during pregnancy in MS patients was assessed.•The relapse rate in fingolimod and natalizumab treated patients was high.•Longer washout period of therapies was associated with higher relapse risk.•Patients on high efficacy therapies should be counseled on the updated relapse risk.

•BREMSO is associated with cognitive and physical disability in early MS patients.•BREMSO identifies low risk patients at disease onset who will benefit from safer DMTs•SDMT associated to BREMSO better categorize intermediate BREMSO risk scores patients.

•Extending the dosing interval of NTZ might decrease the risk of PML.•We assessed the effect of extended interval dosing (EID) ranging from 5–8 weeks on the efficacy of NTZ.•We reviewed 85 patients treated with NTZ at two MS centers in the Middle East.•Shifting to EID has no negative effect on relapse rate, EDSS and MRI activity.

CD47 is known to play an important role in CD4+T cell homeostasis. We recently reported a reduction in mice deficient in the Cd47gene (Cd47-/-) CD4+T cell adhesion and transendothelial migration (TEM) in vivo and in vitro as a result of impaired expression of high-affinity forms of LFA-1 and VLA-4 integrins. A prior study concluded that Cd47-/-mice were resistant to experimental autoimmune encephalomyelitis (EAE) as a result of complete failure in CD4+T cell activation after myelin oligodendrocyte glycoprotein peptide 35–55 aa (MOG35–55) immunization. As the prior EAE study was published before our report, authors could not have accounted for defects in T cell integrin function as a mechanism to protect Cd47-/-in EAE. Thus, we hypothesized that failure of T cell activation involved defects in LFA-1 and VLA-4 integrins. We confirmed that Cd47-/-mice were resistant to MOG35–55-induced EAE. Our data, however, supported a different mechanism that was not a result of failure of CD4+T cell activation. Instead, we found that CD4+T cells in MOG35–55-immunized Cd47-/-mice were activated, but clonal expansion contracted within 72 h after immunization. We used TCR crosslinking and mitogen activation in vitro to investigate the underlying mechanism. We found that naïve Cd47-/-CD4+T cells exhibited a premature block in proliferation and survival because of impaired activation of LFA-1, despite effective TCR-induced activation. These results identify CD47 as an important regulator of LFA-1 and VLA-4 integrin-adhesive functions in T cell proliferation, as well as recruitment, and clarify the roles played by CD47 in MOG35–55-induced EAE.

•OCT can differentiate definite NMOSD from patients suspected of NMOSD but not fulfilling the diagnostic criteria.•Retinal layer measures by OCT in patients with possible NMOSD are similar to those in definite NMOSD.•Retinal layer measures by OCT in possible NMOSD are lower than in MS and healthy controls.•OCT could be a valuable addition to the current consensus diagnostic criteria of NMOSD.

We set out to characterize the clinical impact and functional consequences of rs1800693G, the multiple sclerosis (MS) susceptibility allele found in the TNFRSF1Alocus.

BACKGROUND Interleukin 12 (IL-12), a cytokine that promotes generation of helper T cells subtype 1, is increased in multiple sclerosis. Albuterol sulfate, a β2-adrenergic agonist, reduces IL-12 expression, so we tested the effect of albuterol as an add-on treatment to glatiramer acetate therapy. OBJECTIVES To investigate the clinical and immunologic effects of albuterol treatment as an add-on therapy in patients starting glatiramer acetate treatment. DESIGN Single-center double-masked clinical trial. SETTING Academic research. PATIENTS Subjects with relapsing-remitting multiple sclerosis. MAIN OUTCOME MEASURES In this single-center double-masked clinical trial, subjects with relapsing-remitting multiple sclerosis were randomized to receive a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of placebo daily for 2 years or a subcutaneous injection of glatiramer acetate (20 mg) plus an oral dose of albuterol daily for 2 years. The primary clinical efficacy measurement was the change in Multiple Sclerosis Functional Composite at 2 years, and the primary immunologic end point was the change in expression of IL-13 and interferon γ at each study time point. The classification level of evidence from this trial is C for each question, as this is the first class II clinical trial addressing the efficacy of glatiramer acetate plus albuterol. RESULTS Forty-four subjects were randomized to receive glatiramer acetate plus albuterol or glatiramer acetate plus placebo, and 39 subjects contributed to the analysis. Improvement in the Multiple Sclerosis Functional Composite was observed in the glatiramer acetate plus albuterol group at the 6-month (P = .005) and 12-month (P = .04) time points but not at the 24-month time point. A delay in the time to first relapse was also observed in the glatiramer acetate plus albuterol group (P = .03). Immunologically, IL-13 and interferon-γ production decreased in both treatment groups, and a treatment effect on IL-13 production was observed at the 12-month time point (P &lt; .05). Adverse events were generally mild, and only 3 moderate or severe events were considered related to the treatment. CONCLUSION Treatment with glatiramer acetate plus albuterol is well tolerated and improves clinical outcomes in patients with multiple sclerosis. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00039988Arch Neurol. 2010;67(9):1055-1061--

Natalizumab was the first FDA-approved monoclonal antibody for the treatment of multiple sclerosis (MS). We report on 3 natalizumab-treated patients who developed herpes zoster infections. In addition to progressive multifocal leukoencephelopathy, other opportunistic infections have been rarely reported during Natalizumab treatment. We believe that clinicians need heightened awareness of these infections in view of the risks of serious complications.

BACKGROUND Benign multiple sclerosis (MS) is defined by minimal or no disability after many years of observation, therefore a less degenerative disease process is suspected to be present in this subset of patients. OBJECTIVE To compare brain atrophy rates in patients with long-standing benign MS vs typical early MS. DESIGN A longitudinal prospective cohort study and a retrospective database review. SETTING An academic MS center. PATIENTS Thirty-nine patients with clinically defined benign MS and an age-matched group of 40 patients with early relapsing-remitting MS. MAIN OUTCOME MEASURES Baseline demographic, treatment, brain magnetic resonance imaging measures, and annualized atrophy rates, derived from serial brain parenchymal fraction measurements across 2 years, were compared. RESULTS In the baseline analysis, patients with benign MS were matched to the early MS group on age, sex, treatment with immunomodulatory therapy, T2 lesion volume, and brain parenchymal fraction. The mean (SD) annualized brain atrophy rate in patients with benign MS (−0.16% [0.51%]) was lower than that in patients with early MS (−0.46% [0.72%]) (P = .02). The difference remained significant after controlling for age, sex, and treatment (P = .04). CONCLUSIONS Serial magnetic resonance imaging revealed a low 2-year rate of brain atrophy in patients with clinically benign MS, suggesting a less prominent degenerative component in its pathogenesis than in patients with typical early MS. Identification of patients with a low rate of brain atrophy may indicate a benign course.Arch Neurol. 2009;66(2):234-237--

BACKGROUND Individual magnetic resonance imaging (MRI) disease severity measures, such as atrophy or lesions, show weak relationships to clinical status in patients with multiple sclerosis (MS). OBJECTIVE To combine MS-MRI measures of disease severity into a composite score. DESIGN Retrospective analysis of prospectively collected data. SETTING Community-based and referral subspecialty clinic in an academic hospital. PATIENTS A total of 103 patients with MS, with a mean (SD) Expanded Disability Status Scale (EDSS) score of 3.3 (2.2), of whom 62 (60.2%) had the relapsing-remitting, 33 (32.0%) the secondary progressive, and 8 (7.8%) the primary progressive form. MAIN OUTCOME MEASURES Brain MRI measures included baseline T2 hyperintense (T2LV) and T1 hypointense (T1LV) lesion volume and brain parenchymal fraction (BPF), a marker of global atrophy. The ratio of T1LV to T2LV (T1:T2) assessed lesion severity. A Magnetic Resonance Disease Severity Scale (MRDSS) score, on a continuous scale from 0 to 10, was derived for each patient using T2LV, BPF, and T1:T2. RESULTS The MRDSS score averaged 5.1 (SD, 2.6). Baseline MRI and EDSS correlations were moderate for BPF, T1:T2, and MRDSS and weak for T2LV. The MRDSS showed a larger effect size than the individual MRI components in distinguishing patients with the relapsing-remitting form from those with the secondary progressive form. Models containing either T2LV or MRDSS were significantly associated with disability progression during the mean (SD) 3.2 (0.3)–year observation period, when adjusting for baseline EDSS score. CONCLUSION Combining brain MRI lesion and atrophy measures can predict MS clinical progression and provides the basis for developing an MRI-based continuous scale as a marker of MS disease severity.Arch Neurol. 2008;65(11):1449-1453--

The persistence of human autoimmune diseases is thought to be mediated predominantly by memory T cells. We investigated the phenotype and migration of memory versus effector T cells in vivoin experimental autoimmune encephalomyelitis (EAE). We found that memory CD4+T cells up-regulated the activation marker CD44 as well as CXCR3 and ICOS, proliferated more and produced more interferon-γ and less interleukin-17 compared to effector T cells. Moreover, adoptive transfer of memory T cells into T cell receptor (TCR)αβ−/−recipients induced more severe disease than did effector CD4+T cells with marked central nervous system inflammation and axonal damage. The uniqueness of disease mediated by memory T cells was confirmed by the differential susceptibility to immunomodulatory therapies in vivo. CD28-B7 T cell costimulatory signal blockade by CTLA4Ig suppressed effector cell-mediated EAE but had minimal effects on disease induced by memory cells. In contrast, ICOS-B7h blockade exacerbated effector T cell-induced EAE but protected from disease induced by memory T cells. However, blockade of the OX40 (CD134) costimulatory pathway ameliorated disease mediated by both memory and effector T cells. Our data extend the understanding of the pathogenicity of autoreactive memory T cells and have important implications for the development of novel therapies for human autoimmune diseases.

Axonal damage secondary to inflammation is likely the substrate of chronic disability in multiple sclerosis and is found in the animal model of experimental autoimmune encephalomyelitis (EAE). Wldsmice have a triplication of the fusion gene Ube4b/Nmnatand a phenotype of axon protection. Wldsmice develop an attenuated disease course of EAE, with decreased demyelination, reduced axonal pathology, and decreased central nervous system (CNS) macrophage and microglial accumulation. We show that attenuated disease in Wldsmice was associated with robust constitutive expression of the nonsignaling CD200 molecule on neurons in the CNS compared with control mice. CD200 interacts with its signaling receptor CD200R, which we found to be expressed on microglia, astrocytes, and oligodendrocytes at similar levels in control and Wldsmice. Administration of blocking anti-CD200 antibody to Wldsmice abrogated disease attenuation and was associated with increased CNS inflammation and neurodegeneration. In vitro, Wldsneuronal cultures were protected from microglial-induced neurotoxicity compared with control cultures, but protection was abrogated by anti-CD200 antibody. The CD200-CD200R pathway plays a critical role in attenuating EAE and reducing inflammation-mediated damage in the CNS. Strategies that up-regulate the expression of CD200 in the CNS or molecules that ligate the CD200R may be relevant as neuroprotective strategies in multiple sclerosis.

Despite recent advances in the diagnosis and treatment of multiple sclerosis, we still lack a consensus regarding the causes, pathogenesis, and mechanisms of disease progression. Current evidence indicates that multiple sclerosis is an inflammatory neurodegenerative disorder in which both adaptive and innate immunity play important roles in initiation and maintenance of the disease. Recent evidence supports the notion of molecular pathologic abnormalities beyond the plaques and dysfunction of neurons in normal appearing areas, in addition to the multifocal demyelination and axonal loss, as important features that may underlie early reversible changes in the disease. Chronic failure of remyelination, axonal regeneration, and neuronal dysfunction may contribute to disease progression. This article discusses the emerging molecular evidence for the progression of multiple sclerosis with particular focus on alterations in the local central nervous system microenvironment of neural and glial cells. The molecular pathways leading to structural and functional neurodegeneration and those that prevent regeneration need to be identified in order to design new therapeutic strategies that can halt or even reverse disease progression.Arch Neurol. 2006;63:25-33 --

The thesis advanced in this essay is that stem cells—particularly those in the nervous system—are components in a series of inborn ‘programs’ that not only ensure normal development, but persist throughout life so as to maintain homeostasis in the face of perturbations—both small and great. These programs encode what has come to be called ‘plasticity’. The stem cell is one of the repositories of this plasticity. This review examines the evidence that interaction between the neural stem cell (as a prototypical somatic stem cell) and the developing or injured brain is a dynamic, complex, ongoing reciprocal set of interactions where both entities are constantly in flux. We suggest that this interaction can be viewed almost from a ‘systems biology’ vantage point. We further advance the notion that clones of exogenous stem cells in transplantation paradigms may not only be viewed for their therapeutic potential, but also as biological tools for ‘interrogating’ the normal or abnormal central nervous system environment, indicating what salient cues (among the many present) are actually guiding the expression of these ‘programs’; in other words, using the stem cell as a ‘reporter cell’. Based on this type of analysis, we suggest some of the relevant molecular pathways responsible for this ‘cross–talk’ which, in turn, lead to proliferation, migration, cell genesis, trophic support, protection, guidance, detoxification, rescue, etc. This type of developmental insight, we propose, is required for the development of therapeutic strategies for neurodegenerative disease and other nervous system afflictions in humans. Understanding the relevant molecular pathways of stem cell repair phenotype should be a priority, in our view, for the entire stem cell field.

Increased expression of the costimulatory molecule CD80 (B7–1) was noted in the subventricular zone of the brain during the course of experimental autoimmune encephalomyelitis (EAE). This area of the brain is a neural stem cell (NSC) niche in the adult. We show that isolated NSCs from adult brain express CD80 and CD86 (B7–2) and this expression is increased after exposure to IFN-γ or TNF-α, the prototypical Th1 cytokines expressed during EAE. CD80 and CD86 expressed by NSCs are functional and can costimulate allogeneic cells in a mixed lymphocyte reaction. Furthermore, cross-linking of CD80 on the surface of NSCs results in apoptosis of NSCs. In vitro, we show that T cells can interact with NSCs and form conjugates with redistribution of CD3 on the surface of T cells to the area of contact. These data raise the possibility that during CNS inflammatory diseases such as EAE, NSCs may express immune molecules and interact with the inflammatory environment potentially resulting in injury to the NSCs, which may have implications for repair mechanisms in the central nervous system.

In recent years, it has become evident that the adult mammalian CNS contains a population of neural stem cells (NSCs) described as immature, undifferentiated, multipotent cells, that may be called upon for repair in neurodegenerative and demyelinating diseases. NSCs may give rise to oligodendrocyte progenitor cells (OPCs) and other myelinating cells. This article reviews recent progress in elucidating the genetic programs and dynamics of NSC and OPC proliferation, differentiation, and apoptosis, including the response to demyelination. Emerging knowledge of the molecules that may be involved in such responses may help in the design of future stem cell-based treatment of demyelinating diseases such as multiple sclerosis.

Programmed death-1 (PD-1) receptor, an inhibitory costimulatory molecule found on activated T cells, has been demonstrated to play a role in the regulation of immune responses and peripheral tolerance. We investigated the role of this pathway in the development of autoimmune diabetes. PD-1 or PD-L1 but not PD-L2 blockade rapidly precipitated diabetes in prediabetic female nonobese diabetic (NOD) mice regardless of age (from 1 to 10-wk-old), although it was most pronounced in the older mice. By contrast, cytotoxic T lymphocyte–associated antigen 4 (CTLA-4) blockade induced disease only in neonates. Male NOD mice also developed diabetes after PD-1–PD-L1 pathway blockade, but NOR mice, congenic to NOD but resistant to the development of diabetes, did not. Insulitis scores were significantly higher and frequency of interferon γ–producing GAD-reactive splenocytes was increased after PD-1–PD-L1 pathway blockade compared with controls. Interestingly, PD-L1 but not PD-L2 was found to be expressed on inflamed islets of NOD mice. These data demonstrate a central role for PD-1–PD-L1 interaction in the regulation of induction and progression of autoimmune diabetes in the NOD mouse and provide the rationale to develop new therapies to target this costimulatory pathway in this disease.

Experimental autoimmune encephalomyelitis (EAE) is mediated by autoantigen-specific T cells dependent on critical costimulatory signals for their full activation and regulation. We report that the programmed death-1 (PD-1) costimulatory pathway plays a critical role in regulating peripheral tolerance in murine EAE and appears to be a major contributor to the resistance of disease induction in CD28-deficient mice. After immunization with myelin oligodendrocyte glycoprotein (MOG) there was a progressive increase in expression of PD-1 and its ligand PD-L1 but not PD-L2 within the central nervous system (CNS) of mice with EAE, peaking after 3 wk. In both wild-type (WT) and CD28-deficient mice, PD-1 blockade resulted in accelerated and more severe disease with increased CNS lymphocyte infiltration. Worsening of disease after PD-1 blockade was associated with a heightened autoimmune response to MOG, manifested by increased frequency of interferon γ–producing T cells, increased delayed-type hypersensitivity responses, and higher serum levels of anti-MOG antibody. In vivo blockade of PD-1 resulted in increased antigen-specific T cell expansion, activation, and cytokine production. Interestingly, PD-L2 but not PD-L1 blockade in WT animals also resulted in disease augmentation. Our data are the first demonstration that the PD-1 pathway plays a critical role in regulating EAE.

The activation of T lymphocytes is thought to require at least two signals, one delivered by the T cell receptor (TCR) complex after antigen recognition, and one provided on engagement of costimulatory receptors. The B7-1/B7-2–CD28/cytotoxic T lymphocyte antigen-4 (CTLA-4) and CD154–CD40 pathways have been shown to be crucial in regulating T cell activation and tolerance. Novel members of the B7–CD28 superfamily have recently been discovered and they seem to be particularly important for regulating the responses of previously activated T cells. Superimposition of inhibitory signals like those delivered by CTLA-4 and programmed death (PD)-1–PD-1-ligand (PD-L1) pathway leads to a complex network of positive and negative costimulatory signals, the integration of which modulates immune responses. Furthermore, expression of several B7 homologues on cells other than professional antigen-presenting cells (APCs), indicate new mechanisms for regulating T cell responses in peripheral tissues. This review focuses on our current understanding of the members of the B7–CD28 superfamily and discusses their therapeutic potential.

Immune-mediated disorders of each of the structural subdivisions of the nervous and neuromuscular system have been described. Despite the immune privilege of the central nervous system, and to a lesser extent the peripheral nervous system, immune dysregulation is not uncommon. Environmental, genetic, and immunologic factors have been postulated to be involved in the development of these disorders. Major immune-mediated neurologic diseases of the central nervous system include multiple sclerosis and acute disseminated encephalomyelitis. Immune-mediated diseases of the peripheral nervous system include myasthenia gravis, Guillain-Barré syndrome, chronic inflammatory demyelinating polyneuropathy, idiopathic polymyositis, dermatomyositis, and inclusion body myositis. Some of these disorders, such as myasthenia gravis and certain forms of acute inflammatory demyelinating polyneuropathy, are clearly autoimmune in nature, whereas the immune system plays an important role in pathogenesis in others. Understanding the immune mechanisms of disease and uncovering potential therapeutic targets are essential for the design of new treatments. The epidemiology, pathogenesis, diagnostic criteria, and current therapeutic approaches to the major neuroimmunologic diseases are reviewed. (J Allergy Clin Immunol 2003;111:S659-68.)

•Fingolimod has a potential role in reducing retinal neurodegeneration in RRMS.•Interferons have a small but potential effect on cognitive function over time.•Longitudinal OCT measures appear to be sensitive to changes in cognitive function.•Longitudinal OCT measures may be useful for monitoring neuroprotective therapies.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. There is increased interferon (IFN)‐γ secretion in MS patients in vitro, and IFN‐γ administration induces exacerbations of disease suggesting a link between IFN‐γ and disease activity. We observed significantly increased IFN‐γ production in the autumn and winter months compared with the spring and summer months in chronic progressive MS, and this increase was linked to endogenous interleukin (IL)‐12 production. Increased seasonal IFN‐γ was not observed in normal control subjects, and there were no seasonal changes in IL‐10 in progressive MS. These results suggest a potential environmental link between dysregulated IFN‐γ production and MS disease progression and pathogenesis.

OBJECTIVE: To assess the correlation between cognitive dysfunction and disease burden in multiple sclerosis (MS) during a 1-year period. DESIGN: The Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis was performed at entrance and 1 year. Patients underwent at least 20 proton density (range, 20-24) and T2-weighted axial magnetic resonance imaging (MRI) brain scans except for stable patients who were scanned monthly. Magnetic resonance imaging was evaluated using computer-automated, 3-dimensional volumetric analysis. SETTING: A research clinic of a university hospital. Patients: Forty-four patients with MS of the following disease categories: relapsing-remitting (14), relapsingremitting progressive (12), chronic progressive (13), and stable (5). MAIN OUTCOME MEASURES: The relationships between scores on the Brief, Repeatable Battery of Neuropsychological Tests in Multiple Sclerosis and 2 MRI measures (total lesion volume and brain to intracranial cavity volume ratio) were assessed using linear regression. These MRI measures were also compared with cognitive status at 1 year using analysis of variance. RESULTS: Overall, there was no decline in mean cognitive test performance during 1 year. Significant correlations were found between baseline neuropsychological test scores of nonverbal memory, informationprocessing speed, and attention and both MRI measures. Patients with chronic progressive MS demonstrated the strongest correlations. At 1 year, change in information-processing speed and attention correlated with change in total lesion volume. The mean increase in total lesion volume was 5.7 mL for 4 patients whose cognitive status worsened compared with 0.4 mL for 19 patients who improved and 0.5 mL for 21 patients who remained stable. CONCLUSIONS: During a 1-year period mean cognitive performance did not worsen. Automated volumetric MRI measures of total lesion volume and brain to intracranial cavity volume ratio correlated with neuropsychological performance, especially in patients with chronic progressive MS. Worsening MRI lesion burden correlated with cognitive decline.

Injection of antigen into the thymus of adult animals induces specific systemic tolerance, but the mechanisms of acquired thymic tolerance are not well understood. To investigate these mechanisms we used a model of intrathymic injection of ovalbumin (OVA) in BALB/c mice. We show an antigen-specific decrease in proliferative responses to OVA, as well as a significant decrease in antigen-specific IL-2 secretion and IFN-γ production by splenocytes and lymph node cells of tolerant mice. Addition of recombinant IL-2in vitroreversed the defect in IFN-γ production by cells from OVA-tolerized animals, but did not reverse the proliferation or IL-2 production defects. By using an adoptive transfer system, where a small population of OVA peptide-specific CD4+TCR transgenic T cells are transferred into syngeneic normal recipients, we show an absence of peripheral antigen-dependent clonal expansion of transferred CD4+TCR transgenic cells in tolerant micein vivo.There was an increase in clonotype-positive T cells in the thymus after immunization, confirming that activated T cells circulate through the thymus. Furthermore, thymectomy after intrathymic injection abrogates the effect of acquired thymic tolerance and restores antigen-dependent clonal expansionin vivo.We conclude that intrathymic injection of antigen induces Th1 cell unresponsiveness and prevents the peripheral expansion of antigen-specific CD4+T cellsin vivo.This is the first demonstration that in acquired thymic tolerance antigen-specific T cells circulate to the thymus where they may be anergized or ultimately deleted.

Recent evidence indicates that T cells primed via the indirect pathway of allorecognition play an important role in allograft rejection, although the effector mechanisms remain unknown. The purpose of this study was to characterize and study the in vivo function of self-restricted MHC allopeptide-specific T-cell clones generated from animals undergoing allograft rejection.

Multiple sclerosis (MS) is postulated to be a Th1‐type cell‐mediateds autiommune disease. Thus therapies that decrease T cell interferon (IFN)‐γ production or increase interleukin (IL)‐4 production would be expected to have an ameliorating effect on MS. Some progressive MS patients receiving pulse cyclophosphamide therapy developed periheral blood eosinophilia. We investigated whether cyclophosphamide‐treated patients had immune deviation toward Th2 responses. We measured cytokine production in patients receiving either monthly intravenous methylprednisolone (MP), intravenous cyclophosphamide plus methylprednisolone (CY/MP), methotrexate, IFN‐β1b, in untreated MS patients, and in healthy controls. Minimal IL‐4 was secreted in untreated patients (129 · 62 pg/ml), methotrexate‐treated patients (99 · 79 pg/ml), and healthy controls (50 · 13 pg/ml). A marked increase in IL‐4 was observed in CY/MP patients (1,503 · 291 pg/ml). Patients treated with MP (418 · 160 pg/ml) or IFN‐β1b (425 · 167 pg/ml) showed small increases. Eosinophilia in CY/MP‐treated patients (6.0 · 0.7%) correlated with increased IL‐4. IL‐10 production was also increased in CY/MP‐treated patients. Both CY/MP‐ and MP‐treated groups had decreased production of IFN‐γ compared with untreated MS. These findings demonstrate pronounced immune deviation favoring Th2‐type responses after pulse cyclophosphamide therapy.