Comparative Effectiveness of Rituximab Dosed Every 6 and 12 Months in Relapsing Multiple Sclerosis.

Trained immunity is the ability of the innate immune system to mount a heightened response to an environmental stimulus after a previous encounter with a noxious trigger. This effect is mediated by metabolic rewiring and epigenetic reprogramming in innate immune cells. In the context of neuroinflammation, trained immunity may represent a major contributor to the pathogenesis of neurological diseases, exerting both detrimental and potentially beneficial effects. While the general mechanisms and systemic implications of trained immunity are widely discussed, evidence in central nervous system (CNS) diseases remains fragmented and largely confined to individual pathological conditions. As a result, a comprehensive framework integrating these findings and identifying shared mechanisms across neurological disorders is still lacking. In this review, we explore the concept of trained immunity with a focus on neuroinflammatory and neurodegenerative diseases, synthetizing evidence from multiple CNS pathologies, including multiple sclerosis, Alzheimer's disease, Parkinson's disease, and cerebrovascular disorders. We first critically examine preclinical and experimental studies addressing innate immune memory in the CNS and subsequently integrate these findings with emerging clinical evidence, aiming to identify convergent mechanisms and disease-relevant immune memory signatures. Finally, we discuss potential therapeutic targets identified in preclinical settings and outline key unresolved issues, including the nature of triggering stimuli, thresholds, and temporal dynamics shaping innate immune memory in the CNS. By highlighting current limitations and defining critical questions for future research, this review presents a unifying perspective on trained immunity in neurological diseases and underscores the translational potential to modulate neuroinflammation and to influence disease progression.

Multiple sclerosis (MS) is a chronic progressive, demyelinating autoimmune CNS disease. Autoantibodies to the motif P-(SA)-x-(SGA)-R-(SN)-(LRKH) are a class of predictive markers specific to MS that could add to emerging diagnostic criteria for MS. In this study, we describe the discovery of an MS patient-derived monoclonal antibody (mAb) specific to this motif from memory B cells, and we develop a proof-of-principle autoantibody test to report the prevalence of seropositivity, predict MS early in disease, and identify underlying tolerance-breaking antigens in Epstein-Barr virus (EBV) and the CNS. Peptide tetramers containing the motif were used to screen activated memory B cells, collected from a patient with MS, on the Beacon Optofluidic system. A mAb to the motif and serum samples from clinically diagnosed patients with MS and healthy controls were used to qualify a Luminex xMAP autoantibody serologic test. Antigen discovery methods included phage-immunoprecipitation sequencing (PhIP-Seq), biolayer interferometry, human protein microarrays, isoelectric focusing gels and blots, and immunofluorescence staining of mouse brain cell cultures. A mAb cloned from an MS patient's memory B cells binds diverse peptides containing the MS signature motif with affinities ranging from 2 to 25 nM. Consensus peptides defined by alanine scanning PhIP-Seq were used to develop an autoimmune IgG test with a sensitivity equivalent to 0.5 ng/mL mAb, a precision of <11%, and a positivity rate of 11% among a cohort of 179 patients with MS (n = 91 healthy and n = 49 unrelated neurologic disease serum samples were negative). Utility of the assay for prodromal MS was demonstrated using retrospective, longitudinal samples from cases in the Department of Defense Serum Repository. The mAb identified EBV tegument protein BRRF2 as a tolerance-breaking antigen with nanomolar affinity, containing the motif with reactivity to oligoclonal bands in CSF from MS signature-positive patients. Immunocytochemical staining of mixed mouse neuronal cells showed the dominant cross-reactive human antigen to be vimentin. We describe a test for MS signature autoantibodies that could be used to support MS diagnosis, prodromal research, and early interventions. The integration of this assay with other emerging biomarkers will advance progress toward a combined predictive risk score for MS.

Multiple sclerosis (MS) susceptibility and severity are mediated by different genetic and environmental risk factors. Familial aggregation in MS is partially explained by susceptibility determinants, yet impact on early disease course after clinically isolated syndrome (CIS) is uncertain. We investigated associations of reported familial MS with genetic and environmental risk factors, and with clinical presentation and disease course after CIS. CIS participants were included in a prospective cohort within six months after symptom onset. Family history was assessed at baseline. We evaluated weighted genetic risk scores (wGRS) for MS susceptibility, 25-hydroxyvitamin D (25(OH)D) and body mass index (BMI), and determined HLA-DRB1*15:01 and MS severity SNP rs10191329 carriership. Anti-Epstein Barr virus Nuclear Antigen-1 (anti-EBNA1) IgG antibodies and 25(OH)D levels were measured. Disease course associations were estimated with Cox regression. Family members with MS were reported by 81/415 (19.5%) CIS participants. Familial MS was associated with higher MS susceptibility wGRS (7.54 (SD1.17) vs. 7.19 (SD1.22), p=0.04) and more frequent HLA-DRB1*15:01 carriership (first-degree 66.7%, other-degree 30.2%, no 38.4%, p=0.02). Anti-EBNA1 IgG and 25(OH)D levels did not differ, yet wGRS for lower 25(OH)D and higher adult BMI characterised MS participants with first-degree MS relatives. Baseline characteristics and disease severity measures were similar between participants with and without familial MS. Our results confirm that familial MS is associated with enrichment of genetic risk for MS susceptibility, low 25(OH)D and high BMI, but not with early disease course after CIS. These data support that MS susceptibility and disease course are driven by different pathophysiological processes.

This qualitative study explored the impact of comorbidities on multiple sclerosis (MS) management, integrating perspectives from individuals with lived MS experience and healthcare professionals who have direct experience in treating and managing MS. Semi-structured interviews were conducted with five individuals living with MS and five clinicians recruited through professional networks and advocacy groups. Interviews were conducted online between February 26th to March 15th, 2024. A thematic analysis was used to identify the main themes emerging from the interviews, focusing on the influence of comorbidities on MS progression, treatment decisions, and daily experiences. Comorbidities were found to significantly complicate MS management by exacerbating symptoms and influencing clinical decision-making. Individuals with lived MS experience and clinicians emphasized the need for enhanced coordination between healthcare providers and more comprehensive, interdisciplinary care models. Additionally, participants highlighted gaps in existing research on the relationship between comorbidities such as insomnia and substance use and their effects on MS outcomes. Comorbidities add a significant layer of complexity to MS management, both for individuals living with the disease and for clinicians providing care. Our findings suggest a need for integrated care models that address the unique needs of individuals with MS and comorbidities. Enhanced communication between specialists, comprehensive education for the individuals living with MS, and research that further explores the links between MS and comorbidities are critical steps toward improving outcomes. Not applicable.

Socioeconomic burden of multiple sclerosis: Insights from a cohort in Coimbra, Portugal.

Multiple sclerosis (MS) is a T helper (Th) cell-mediated disease that targets central nervous system (CNS) white matter. This disease affects three times more females than males. For many years, the etiology of MS was not well understood and the exact nature of the autoimmune reaction was speculative. It has now become clear that MS is a rare complication of Epstein-Barr Virus (EBV) infection and that the virus induces an EBV nuclear antigen (EBNA-1)-specific T and B cell response that is cross-reactive against a number of CNS antigens including Glial cell-associated membrane protein (GlialCAM), Anoctamin-2 (Ano-2), myelin basic protein (MBP), and alpha-B-crystallin (CRYAB). Recent studies have clarified the involvement of the major human leukocyte antigen (HLA) MS risk haplotype, HLA-DR15, in sustaining autoreactive T cell responses and its interaction with EBV. Here, we overview this literature through the lens that MS is a disease that affects females more than males. We describe how EBV seroprevalence and the incidence of infectious mononucleosis are greater in females during the early teen years, a period of increased MS susceptibility. We overview how females with MS develop greater levels of EBNA-1-cross-reactive autoantibodies and show greater myelin-specific T helper 1 (Th1) cells in peripheral blood. Finally, we provide evidence that EBV-infected B cells may achieve a greater state of latency in females and discuss how this may perpetuate CNS autoimmunity. At the same time, our literature search identified many missed opportunities to learn about sex differences in MS. Our hope is that this review will motivate researchers in the future to disaggregate data by sex to accelerate discoveries in this disease.

Cesarean section (CS) rates are increased in women with multiple sclerosis (MS). It is unknown whether CS in women with MS constitutes a risk of maternal postpartum infection compared to vaginal delivery. We used the Danish national health registers to establish a cohort of all live births by women with MS in Denmark from 1995 to 2023. We estimated the risk of maternal postpartum infections according to the mode of delivery in women with MS using logistic regression models adjusted for confounders such as age, body mass index, and comorbidity. Overall, 872 women with MS gave birth to their child by CS, and 2542 women with MS had a vaginal birth. Within the postpartum period of 42 days, 21.0% with CS and 14.1% with vaginal birth had an infectious complication. The overall risk of infections among women with MS giving birth by CS, relative to those with vaginal delivery, was an adjusted odds ratio (aOR) of 1.54, 95% confidence interval (95% CI 1.18-2.01). The risk of mild to moderate infections (prescriptions of antibiotics) was aOR 1.60 (95% CI 1.24-2.08), and the risk of severe infections (hospital-diagnosed) was aOR 1.55 (95% CI 0.82-2.94). Women with MS who give birth by CS have an increased risk of postpartum infection compared to women with MS who give birth vaginally. This is important to be aware of since infection can cause worsening of neurological symptoms or trigger a new relapse in patients with MS.

Distinct microstructural white matter alterations in demyelinating diseases: Insights from myelin- and axon-sensitive MRI.

Facial emotion recognition (FER) is affected in multiple sclerosis (MS), impacting interpersonal functioning. Standard FER tests utilize static/posed stimuli, lacking in ecological validity. In this pilot study, we used the Emotion Authenticity Recognition (EAR) test, featuring both genuine/posed dynamic expressions, to assess FER in an MS sample, also investigating behavioral/neuroimaging correlates. A group of 54 MS patients (36 F; age = 41.4 ± 11.0, education = 14.7 ± 2.8) and a matched age/sex/education sample of 54 healthy controls (HCs) completed the EAR test, which provides two indices: Emotion Recognition (ER) and Emotion Authenticity (EA). Associations were explored with clinical/neuropsychological/self-report/MRI data. Structural 3T-MRI was analyzed using Voxel-Based Morphometry (VBM) for regional gray matter volumes. No significant differences were found with standard t-tests for ER and EA between MS and HCs. Bayesian independent t-tests revealed moderate evidence for no group difference in ER (BF10 = 0.210, % error = 0.029) and anecdotal evidence in favor of the null hypothesis for EA (BF10 = 0.658, % error = 0.017). In MS, ER correlated with age (r = -0.50, p < 0.001), disease duration (R = -0.30, p = 0.030), education (R = 0.34, p = 0.012), and with domain-specific/global cognitive functioning (all r indexes among 0.3 - 0.5). EA was lower in patients with severe cognitive impairment (r = 0.47, p < 0.001) and associated with empathy (R = 0.29, p = 0.037). ER was associated with bilateral widespread cortical regions and cerebellum, while EA with fronto-temporal cortices and amygdala. Despite no statistically significant differences observed compared to HCs, EAR in MS reflected age, cognition, and brain damage: this test captures subtle alterations, underscoring the value of dynamic and genuineness-based measures in MS assessment. These preliminary findings warrant further investigation into emotion-cognition interactions in MS.

Multiple sclerosis in the All of Us Research Program: Prevalence and associated demographic and geographic characteristics.

Targeting Epstein-Barr virus (EBV) for treatment of multiple sclerosis.

Multiple sclerosis (MS) is characterized by peripheral immune cell infiltration into the central nervous system (CNS) and associated reactive gliosis, demyelination, and neuroaxonal degeneration. Existing therapies broadly target adaptive immune cells and treat acute inflammation but are not effective in halting chronic neurodegeneration that occurs in progressive MS. High-efficacy precision therapies that target pathways in the CNS known to contribute to MS pathophysiology are lacking. Several MS studies have identified prominent dysregulation of macrophage migration inhibitory factor (MIF), a multifunctional protein with both cytokine and enzyme activity, in inflammatory diseases. MIF is elevated in the CSF of people with MS and MIF gene variants have been linked with progressive MS, but its precise contributions to the pathophysiologic underpinnings of MS remain unclear. MIF has extracellular signaling capacity through CD74. MIF also has 2 discrete and endogenous enzymatic functions as a tautomerase and nuclease. We used a MIF transgenic mouse line with a point mutation in the tautomerase domain (MIF-P2G) to dissect MIF's non-nuclease function during inflammation. We also utilized flow cytometry and immunohistochemistry to characterize the cellular and molecular mechanisms by which MIF tautomerase contributes to pathophysiology in the experimental autoimmune encephalomyelitis (EAE) mouse model of MS. We show that MIF tautomerase contributes to immune cell infiltration, glial cell proliferation, and neuroaxonal degeneration in EAE. MIF tautomerase-deficient EAE mice have reduced paralysis scores and less neuroaxonal pathology throughout the optic nerve and lumbar spinal cord. Furthermore, we show that MIF-P2G mutated mice have less peripheral immune cell trafficking and downstream reactive gliosis, neuroinflammation, and neurodegeneration during EAE. Together, this work elucidates the role of MIF's tautomerase domain in contributing to peripheral immune-mediated neurodegeneration in the context of neuroinflammatory diseases such as MS.

High burden of poor prognostic factors at first presentation in treatment-naïve relapsing multiple sclerosis: Real-world evidence from a large Egyptian cohort.

Multiple sclerosis and autoimmunity: learnings from post-streptococcal autoimmunity.

Immune dysfunction contributes to comorbid depression in patients with multiple sclerosis.

Patient profiles and disease characteristics of the IMSRN cohort: a multicentre study (2021-2025).

Multiple sclerosis (MS) is an autoimmune chronic inflammatory disease of the central nervous system characterized by oxidative stress, demyelination, and neuronal damage. Current MS therapies are unsatisfactory and new therapies are encouraged. Adenosine is highly implicated in MS as it regulates, via activation of its A2A receptor (A2AR), the inflammatory and immune response. The aim of this study is to investigate the therapeutic potential of new selective A2AR antagonists, P400 and P625, in the experimental autoimmune encephalomyelitis (EAE), the principal animal model of MS. P400 and P625 administration (10 μg/mouse intranasal) for 14 days reduced motor disability (clinical score, rotarod) and thermal (hot plate) and mechanical (von Frey) hypernociceptive symptoms associated with a chronic MS model. Quantitative analysis of lymphocytes infiltration in the spinal cord sections stained with hematoxylin and eosin (H&E) showed a larger number of inflammatory cells in EAE sections that were markedly reduced by P400 and P625. P400 also reduced the immunostaining of Iba1, marker of microglia. Luxol Fast Blue (LFB) staining and myelin basic protein (MBP) immunostaining of spinal cord sections showed a robust loss of myelin that was partially restored by P400 and P625. Both treatments increased spinal neurofilament H (NfH) and GAP43 protein expression compared to untreated immunize mice. These data illustrate the efficacy of the new selective A2AR antagonists in ameliorating EAE symptoms by attenuating neuroinflammation and demyelination. These findings further highlight A2AR blocking as a promising perspective to control neurological disturbances in MS patients.

Multiple Sclerosis (MS) is a chronic neurological condition that frequently compromises upper limb (UL) function. Despite its functional relevance, few instruments validated in Brazilian Portuguese are specific to this population. The Arm Function in Multiple Sclerosis Questionnaire (AMSQ) was originally developed in Dutch to measure this function in individuals with MS. To translate, cross-culturally adapt, and validate the AMSQ for Brazilian Portuguese. The study was approved by the HCPA Research Ethics Committee (CAAE: 82069424.0.0000.5327) and followed international guidelines, including translation, synthesis, back-translation, content validation and reliability. The Content Validity Index (CVI) was calculated. In the reliability stage, 50 individuals with MS answered the AMSQ at two time points, with an interval of 3-5 days. Internal consistency was assessed using Cronbach's alpha, and test-retest reproducibility was evaluated by the Intraclass Correlation Coefficient (ICC 2,1). The questionnaire was well understood by the participants, confirming its cultural appropriateness. The AMSQ-BR showed a CVI above 90% for all items and presented excellent reproducibility (ICC = 0.932) and internal consistency (α = 0.984). The Brazilian version of the AMSQ-BR is valid and reliable for the assessment of upper limb function in individuals with multiple sclerosis. It presents content validity, test-retest reproducibility, and internal consistency, making it a relevant tool for clinical and research use in the Brazilian context.

Depressive, anxiety, and fatigue symptoms are highly prevalent in people with multiple sclerosis (pwMS) and have been found to co-occur. Together, these symptoms result in poorer outcomes for pwMS. However, the network topology of comorbid depression, anxiety, and fatigue in pwMS has been to be investigated. We estimated depressive, anxiety, and fatigue symptom networks using data from the same people with multiple sclerosis at two time points: at baseline (N = 272) and at 6-months follow-up (N = 141). Expected influence (EI) centrality analyses were performed to estimate the relative influence of each symptom within the two networks. Bridge EI and community analyses were performed to identify potential bridge symptoms and densely connected symptom groups. 'Worthlessness' and 'anhedonia' emerged with the highest EI at baseline and follow-up, respectively. In terms of bridging symptoms, 'worthlessness', 'afraid something awful would happen', and 'fatigue severity' emerged as potential bridging symptoms that clustered depressive, anxiety, and fatigue symptoms in pwMS. This changed to 'restlessness', 'uncontrollable worry', and 'suicidal ideation' at follow-up. Further analyses indicated that the two networks remained similar with respect to global strength (p = .97) CONCLUSIONS: Our findings demonstrate that depressive, anxiety, and fatigue symptoms are highly interconnected in MS. Identifying bridging symptoms may allow for a renewed therapeutic focus and avenue for symptomatic improvement across board areas of psychopathology in MS.