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B cells of people with multiple sclerosis (MS) are more responsive to IFN-γ, corresponding to their brain-homing potential. We studied how a coding single nucleotide polymorphism (SNP) in IFNGR2 (rs9808753) co-operates with Epstein-Barr virus (EBV) infection as MS risk factors to affect the IFN-γ signaling pathway in human B cells. In both cell lines and primary cells, EBV infection positively associated with IFN-γ receptor expression and STAT1 phosphorylation. The IFNGR2 risk SNP selectively promoted downstream signaling via STAT1, particularly in transitional B cells. Altogether, EBV and the IFNGR2 risk SNP independently amplify IFN-γ signaling, potentially driving B cells to enter the MS brain., Competing Interests: Declaration of competing interest Marvin M. van Luijn received research support from EMD Serono, Merck, Novartis, GSK and Idorsia Pharmaceutical Ltd. Joost Smolders received lecture and/or consultancy fees from Biogen, Merck, Novartis, Sanofi-Genzyme and Roche. The remaining authors declare no competing interests., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Control of microglia activity through CD200-CD200R and CD47-SIRPα interactions has been implicated in brain homeostasis. Here, we assessed CD200, CD47, CD200R and SIRPα expression with qPCR and immunohistochemistry in multiple sclerosis (MS) normal-appearing cortical grey matter (NAGM), normal-appearing white matter (NAWM), cortical grey matter (GM) lesions and perilesional GM, and compared this to control GM and white matter (WM), to investigate possible altered control of microglia in MS. In MS NAGM, CD200 expression is lower compared with control GM, specifically in cortical layers 1 and 2, and CD200 expression in NAGM negatively correlates with the cortical lesion rate. Interestingly, NAGM and NAWM CD200 expression is positively correlated, and NAGM CD200 expression negatively correlates with the proportion of active and mixed WM lesions. In GM lesions, CD200 and CD47 expressions are lower compared with NAGM and perilesional GM. CD200R expression is lower in MS NAGM, whereas SIRPα was increased in and around GM lesions. Taken together, our data indicate that CD200 and CD47 play a role in GM MS lesion formation and progression, respectively, and that targeting CD200 pathways may offer therapeutic avenues to mitigate MS pathology in both WM and GM., Competing Interests: The authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Uncertainty about disproportionate impact on health care budgets limits implementation of early highly effective treatment (EHT) in multiple sclerosis (MS)., Objective: To estimate cost-effectiveness of escalation versus EHT disease-modifying treatment (DMT) sequences., Methods: Using a health-economic approach, we analysed health benefits (relapse rate reduction, disability prevention), direct/indirect DMT and societal costs of escalation versus EHT DMT sequences. In scenario analyses, we allowed (1) earlier use of alemtuzumab (ALE) and (2) a single retreatment with cladribine (CLA)., Results: In our model, we showed that the ratio between costs and quality-adjusted life years (QALYs) for the most cost-effective EHT and escalation sequence results into a similar net health benefit with higher costs and also higher QALYs associated with an EHT versus escalation strategy. Earlier use of ALE is more cost-effective than in later lines, even when aggravating the impact of its side-effects tenfold. Retreatment with CLA was more cost-effective in both escalation and EHT sequences., Conclusions: Certain EHT sequences are equally cost-effective to escalation sequences and are likely to result in more health at uncertain additional costs. The favourable cost-benefit ratio of CLA and ALE suggests that a wider application of affordable highly effective therapies could promote the cost-effectiveness both EHT and escalation approaches., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship and/or publication of this article: B.H.A.W. declares no conflict of interest. S.A.H. and M.M.V. are shareholders of Huygens & Versteegh, which conducts research for government organizations and pharmaceutical companies, including research in MS. I.S. has received honoraria from Merck, Biogen Idec and Sanofi. J.S. received lecture and/or consultancy fee from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme.

Multiple sclerosis (MS) is a heterogeneous neurological disorder with regards to clinical presentation and pathophysiology. Here, we investigated the heterogeneity of MS by performing an exploratory factor analysis on quantitative and qualitative neuropathology data collected for 226 MS donors in the Netherlands Brain Bank autopsy cohort. Three promising dimensions were identified and subsequently validated with clinical, neuropathological, and genetic data. Dimension 1 ranged from a predominance of remyelinated and inactive lesions to extensive pathological changes, higher proportions of active and mixed lesions, and foamy microglia morphology. This pattern was positively correlated with more severe disease, the presence of B and T cells, and neuroaxonal damage. Scoring high on dimension 2 was associated with active lesions, reactive sites, and the presence of nodules. These donors had less severe disease, a specific pattern of cortical lesions, and MS risk variants in the human leukocyte antigen region, the latter indicating a connection between disease onset and this neuropathological dimension. Donors scoring high on dimension 3 showed increased lesional pathology with relatively more mixed and inactive lesions and ramified microglia morphology. This pattern was associated with longer disease duration, subpial cortical lesions, less involvement of the adaptive immune system, and less axonal damage. Taken together, the three dimensions may represent (1) demyelination and immune cell activity associated with pathological and clinical progression, (2) microglia (re)activity and possibly lesion initiation, and (3) loss of lesion activity and scar formation. Our findings highlight that a thorough understanding of the interplay between multiple pathological characteristics is crucial to understand the heterogeneity of MS pathology, as well as its association with genetic predictors and disease outcomes. The scores of donors on the dimensions can serve as an important starting point for further disentanglement of MS heterogeneity and translation into observations and interventions in living cohorts with MS., (© 2024. The Author(s).)

Background: In multiple sclerosis (MS), B cells are considered main triggers of the disease, likely as the result of complex interaction between genetic and environmental risk factors. Studies on monozygotic twins discordant for MS offer a unique way to reduce this complexity and reveal discrepant subsets., Methods: In this study, we analyzed B cell subsets in blood samples of monozygotic twins with and without MS using publicly available data. We verified functional characteristics by exploring the role of therapy and performed separate analyses in unrelated individuals., Findings: The frequencies of CXCR3 + memory B cells were reduced in the blood of genetically identical twins with MS compared to their unaffected twin siblings. Natalizumab (anti-VLA-4 antibody) was the only treatment regimen under which these frequencies were reversed. The CNS-homing features of CXCR3 + memory B cells were supported by elevated CXCL10 levels in MS cerebrospinal fluid and their in vitro propensity to develop into antibody-secreting cells., Conclusions: Circulating CXCR3 + memory B cells are affected by non-heritable cues in people who develop MS. This underlines the requirement of environmental risk factors such as Epstein-Barr virus in triggering these B cells. We propose that after CXCL10-mediated entry into the CNS, CXCR3 + memory B cells mature into antibody-secreting cells to drive MS., Funding: This work was supported by Nationaal MS Fonds (OZ2021-016), Stichting MS Research (19-1057 MS, 20-490f MS, and 21-1142 MS), the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program grant agreement no. 882424, and the Swiss National Science Foundation (733 310030_170320, 310030_188450, and CRSII5_183478)., Competing Interests: Declaration of interests J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis, and Sanofi Genzyme. M.M.v.L. received research support from EMD Serono, Merck, GSK, Novartis, and Idorsia Pharmaceuticals, Ltd. L.A.G. has received speaker honoraria, personal fees for advisory boards, or research funding from Roche Pharma, Teva, Biogen, and Merck Healthcare GmbH., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Microglia nodules (HLA-DR + cell clusters) are associated with brain pathology. In this post-mortem study, we investigated whether they represent the first stage of multiple sclerosis (MS) lesion formation. We show that microglia nodules are associated with more severe MS pathology. Compared to microglia nodules in stroke, those in MS show enhanced expression of genes previously found upregulated in MS lesions. Furthermore, genes associated with lipid metabolism, presence of T and B cells, production of immunoglobulins and cytokines, activation of the complement cascade, and metabolic stress are upregulated in microglia nodules in MS. Compared to stroke, they more frequently phagocytose oxidized phospholipids and possess a more tubular mitochondrial network. Strikingly, in MS, some microglia nodules encapsulate partially demyelinated axons. Taken together, we propose that activation of microglia nodules in MS by cytokines and immunoglobulins, together with phagocytosis of oxidized phospholipids, may lead to a microglia phenotype prone to MS lesion formation., (© 2024. The Author(s).)

Multiple sclerosis (MS) is a common and devastating chronic inflammatory disease of the CNS. CD4 + T cells are assumed to be the first to cross the blood-central nervous system (CNS) barrier and trigger local inflammation. Here, we explored how pathogenicity-associated effector programs define CD4 + T cell subsets with brain-homing ability in MS. Runx3- and Eomes-, but not T-bet-expressing CD4 + memory cells were diminished in the blood of MS patients. This decline reversed following natalizumab treatment and was supported by a Runx3 + Eomes + T-bet - enrichment in cerebrospinal fluid samples of treatment-naïve MS patients. This transcription factor profile was associated with high granzyme K (GZMK) and CCR5 levels and was most prominent in Th17.1 cells (CCR6 + CXCR3 + CCR4 -/dim ). Previously published CD28 - CD4 T cells were characterized by a Runx3 + Eomes - T-bet + phenotype that coincided with intermediate CCR5 and a higher granzyme B (GZMB) and perforin expression, indicating the presence of two separate subsets. Under steady-state conditions, granzyme K high Th17.1 cells spontaneously passed the blood-brain barrier in vitro. This was only found for other subsets including CD28 - cells when using inflamed barriers. Altogether, CD4 + T cells contain small fractions with separate pathogenic features, of which Th17.1 seems to breach the blood-brain barrier as a possible early event in MS., (© 2023 The Authors. European Journal of Immunology published by Wiley-VCH GmbH.)

The anti-CD20 monoclonal antibody ocrelizumab reduces disability progression in primary progressive multiple sclerosis. CD20 is a prototypical B-cell marker; however, subpopulations of CD4 + and CD8 + T cells in peripheral blood and cerebrospinal fluid also express low levels of CD20 (CD20 dim ). Therefore, direct targeting and depletion of these CD20 dim T-cell subpopulations may contribute to the therapeutic effect of ocrelizumab. The aim of this observational cohort study was to compare CD20 + B-cell and CD20 dim T-cell distributions between peripheral blood and cerebrospinal fluid of ocrelizumab-treated or ocrelizumab-untreated people with primary progressive multiple sclerosis. Ocrelizumab treatment was associated with depletion of circulating B cells and CD20 dim CD4 + and CD20 dim CD8 + T cells ( P < 0.0001, P = 0.0016 and P = 0.0008, respectively) but, in cerebrospinal fluid, only with lower proportions of B cells and CD20 dim memory CD4 + T cells ( P < 0.0001 and P = 0.0043, respectively). The proportional prevalence of cerebrospinal fluid CD20 dim memory CD8 + T cells was not significantly reduced ( P = 0.1333). Only in cerebrospinal fluid, the proportions of CD20 dim cells within CD4 + and not CD8 + T cells positive for CCR5, CCR6 and CXCR3 were reduced in ocrelizumab-treated participants. The proportion of CD20 dim CD4 + T cells and abundance of CD4 + relative to CD8 + T cells in cerebrospinal fluid correlated positively with age ( R = 0.6799, P = 0.0150) and Age-Related Multiple Sclerosis Severity score ( R = 0.8087, P = 0.0014), respectively. We conclude that, in contrast to cerebrospinal fluid CD20 dim CD8 + T cells, B cells and CD20 dim CD4 + T cells are reduced in cerebrospinal fluid of people with primary progressive multiple sclerosis with an ocrelizumab-associated depletion of circulating B cells and CD20 dim T cells. Therefore, these cells are likely to contribute to the therapeutic effects of ocrelizumab in people with primary progressive multiple sclerosis., Competing Interests: M.M.v.L. received research support from EMD Serono, Merck, GSK and Idorsia Pharmaceuticals Ltd. J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis, Roche and Sanofi-Genzyme. 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., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS), which can clinically manifest as attacks of neurologic disability and new lesion formation, and a progression of sustained neurologic disability over time. In MS, activated B and T cells are recruited from outside the CNS, and contribute to inflammation, demyelination, and tissue damage inside the brain parenchyma. In the last decades, the treatment of MS has improved by the introduction of several disease-modifying therapies (DMTs). These drugs target generic mechanisms of lymphocyte activation and recruitment or deplete lymphocyte fractions from the circulation. This contributes to a suppression of relapses and new MS lesion formation on MRI. However, the impact on disability progression without relapses is much more variable. In addition, risk mitigation strategies are warranted to control for unwanted side effects of the attenuated immune competence induced by DMTs. In this chapter, we argue that an understanding of the impact of these DMTs on B and T cells both outside and inside the CNS can help to understand the benefits of these therapies but can also help to identify the challenges and opportunities that lie ahead for future MS therapies., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background: Three sphingosine-1-phosphate receptor (S1PR) modulators are currently available as disease-modifying therapies (DMTs) for relapsing MS in the Netherlands (i.e. fingolimod, ozanimod and ponesimod). We aimed to identify which S1PR modulator yields the highest benefit from a health-economic and societal perspective during a patient's lifespan., Methods: Incorporating Dutch DMT list prices, we used the ErasmusMC/iMTA MS model to compare DMT sequences, including S1PR modulators and eight other DMT classes, for treatment-naïve patients with relapsing MS in terms of health outcomes (number of lifetime relapses, time to Expanded Disability Status Scale (EDSS) 6, lifetime quality-adjusted life years (QALYs)) and cost-effectiveness (net health benefit (NHB)). We estimated the influence of list price and EDSS progression on cost-effectiveness outcomes., Results: In deterministic and probabilistic analysis, DMT sequences with ponesimod have lower lifetime costs and higher QALYs resulting in a higher average NHB compared to sequences with other S1PR modulators. Ponesimod remains the most cost-effective S1PR modulator when EDSS progression is class-averaged. Given the variable effects on disability progression, list price reductions could make fingolimod but not ozanimod more cost-effective than ponesimod., Conclusion: Our model favours ponesimod among the S1PR modulators for the treatment of relapsing MS. This implies that prioritizing ponesimod over other S1PR modulators translates into a more efficacious spending of national healthcare budget without reducing benefit for people with MS. Prioritizing cost-effective choices when counselling patients contributes to affordable and accessible MS care., Competing Interests: Declaration of Competing Interest Cato E.A. Corsten and Beatrijs H.A. Wokke declare no conflicts of interest. Simone A. Huygens and Matthijs M. Versteegh are shareholders of Huygens & Versteegh which conducts research for government organizations and pharmaceutical companies, including research in MS. Ide Smets has received honoraria from Merck and Biogen Idec. Joost Smolders received lecture and/or consultancy fee from Biogen, Merck, Novartis, and Sanofi Genzyme., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Despite the 2017 revisions to the McDonald criteria, diagnosing primary progressive multiple sclerosis (PPMS) remains challenging. To improve clinical practice, the aim was to identify frequent diagnostic challenges in a real-world setting and associate these with the performance of the 2010 and 2017 PPMS diagnostic McDonald criteria., Methods: Clinical, radiological and laboratory characteristics at the time of diagnosis were retrospectively recorded from designated PPMS patient files. Possible complicating factors were recorded such as confounding comorbidity, signs indicative of alternative diagnoses, possible earlier relapses and/or incomplete diagnostic work-up (no cerebrospinal fluid examination and/or magnetic resonance imaging brain and spinal cord). The percentages of patients fulfilling the 2010 and 2017 McDonald criteria were calculated after censoring patients with these complicating factors., Results: A total of 322 designated PPMS patients were included. Of all participants, it was found that n = 28/322 had confounding comorbidity and/or signs indicative of alternative diagnoses, n = 103/294 had possible initial relapsing and/or uncertainly progressive phenotypes and n = 73/191 received an incomplete diagnostic work-up. When applying the 2010 and 2017 diagnostic PPMS McDonald criteria on n = 118 cases with a full diagnostic work-up and a primary progressive disease course without a better alternative explanation, these were met by 104/118 (88.1%) and 98/118 remaining patients (83.1%), respectively (p = 0.15)., Conclusion: Accurate interpretation of the initial clinical course, consideration of alternative diagnoses and a full diagnostic work-up are the cornerstones of a PPMS diagnosis. When these conditions are met, the 2010 and 2017 McDonald criteria for PPMS perform similarly, emphasizing the importance of their appropriate application in clinical practice., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

B cells expressing the transcription factor T-bet are found to have a protective role in viral infections, but are also considered major players in the onset of different types of autoimmune diseases. Currently, the exact mechanisms driving such 'atypical' memory B cells to contribute to protective immunity or autoimmunity are unclear. In addition to general autoimmune-related factors including sex and age, the ways T-bet + B cells instigate autoimmune diseases may be determined by the close interplay between genetic risk variants and Epstein-Barr virus (EBV). The impact of EBV on T-bet + B cells likely relies on the type of risk variants associated with each autoimmune disease, which may affect their differentiation, migratory routes and effector function. In this hypothesis-driven review, we discuss the lines of evidence pointing to such genetic and/or EBV-mediated influence on T-bet + B cells in a range of autoimmune diseases, including systemic lupus erythematosus (SLE) and multiple sclerosis (MS). We provide examples of how genetic risk variants can be linked to certain signaling pathways and are differentially affected by EBV to shape T-bet + B-cells. Finally, we propose options to improve current treatment of B cell-related autoimmune diseases by more selective targeting of pathways that are critical for pathogenic T-bet + B-cell formation., Competing Interests: Declaration of Competing Interest M.M.v.L. received research support from EMD Serono, Merck, GSK and Idorsia Pharmaceutical Ltd. J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis and Sanofi-Genzyme. The remaining authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: In high-income countries, four anti-CD20 monoclonal antibodies (mAbs) are used or in the pipeline for relapsing MS: ocrelizumab, ofatumumab (both registered), ublituximab (awaiting registration) and rituximab (off-label). List prices differ significantly between registered and off-label drugs., Objective: Comparing differences in benefits between anti-CD20 mAbs from a health-economic and societal perspective., Methods: To reflect lifetime use of DMTs, we used a treatment-sequence model to compare ocrelizumab/ofatumumab and eight other drug classes in terms of health (lifetime relapses, time to Expanded Disability Status Scale [EDSS] 6, lifetime quality-adjusted life years) and cost-effectiveness (net health benefit). To become cost-effective compared to ocrelizumab, we modelled the list price of ublituximab and desired effect on EDSS progression of rituximab., Results: Although drug sequences with ocrelizumab in first- and second-line were more cost-effective than ofatumumab, our probabilistic analysis suggests this outcome was very uncertain. To be more cost-effective than ocrelizumab, ublituximab needs to be about 25% cheaper whilst rituximab needs to equal the effect on disability progression seen with first-line treatments., Conclusions: Our model showed no clear difference in cost-effectiveness between ocrelizumab and ofatumumab. Hence, prescribing the least costly anti-CD20 mAb can democratise MS care without a loss in health benefits., (© The Author(s), 2023.)

Objective: Changes in the normal-appearing white matter (NAWM) in multiple sclerosis (MS) may contribute to disease progression. Here, we systematically quantified ultrastructural and subcellular characteristics of the axon-myelin unit in MS NAWM and determined how this correlates with low-grade inflammation., Methods: Human brain tissue obtained with short postmortem delay and fixation at autopsy enables systematic quantification of ultrastructural characteristics. In this study, we performed high-resolution immunohis tochemistry and quantitative transmission electron microscopy to study inflammation and ultrastructural characteristics of the axon-myelin unit in MS NAWM (n = 8) and control white matter (WM) in the optic nerve., Results: In the MS NAWM, there were more activated and phagocytic microglia cells (HLA + P2RY12 - and Iba1 + CD68 + ) and more T cells (CD3 + ) compared to control WM, mainly located in the perivascular space. In MS NAWM compared to control WM, there were, as expected, longer paranodes and juxtaparanodes and larger overlap between paranodes and juxtaparanodes. There was less compact myelin wrapping, a lower g-ratio, and a higher frequency of axonal mitochondria. Changes in myelin and axonal mitochondrial frequency correlated positively with the number of active and phagocytic microglia and lymphocytes in the optic nerve., Interpretation: These data suggest that in MS NAWM myelin detachment and uncompact myelin wrapping occurs, potassium channels are unmasked at the nodes of Ranvier, and axonal energy demand is increased, or mitochondrial transport is stagnated, accompanied by increased presence of activated and phagocytic microglia and T cells. These subclinical alterations to the axon-myelin unit in MS NAWM may contribute to disease progression. ANN NEUROL 2023;93:856-870., (© 2022 The Authors. Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Although distinct brain-homing B cells have been identified in multiple sclerosis (MS), it is unknown how these further evolve to contribute to local pathology. We explored B-cell maturation in the central nervous system (CNS) of MS patients and determined their association with immunoglobulin (Ig) production, T-cell presence, and lesion formation., Methods: Ex vivo flow cytometry was performed on post-mortem blood, cerebrospinal fluid (CSF), meninges and white matter from 28 MS and 10 control brain donors to characterize B cells and antibody-secreting cells (ASCs). MS brain tissue sections were analysed with immunostainings and microarrays. IgG index and CSF oligoclonal bands were measured with nephelometry, isoelectric focusing, and immunoblotting. Blood-derived B cells were cocultured under T follicular helper-like conditions to evaluate their ASC-differentiating capacity in vitro., Findings: ASC versus B-cell ratios were increased in post-mortem CNS compartments of MS but not control donors. Local presence of ASCs associated with a mature CD45 low phenotype, focal MS lesional activity, lesional Ig gene expression, and CSF IgG levels as well as clonality. In vitro B-cell maturation into ASCs did not differ between MS and control donors. Notably, lesional CD4 + memory T cells positively correlated with ASC presence, reflected by local interplay with T cells., Interpretation: These findings provide evidence that local B cells at least in late-stage MS preferentially mature into ASCs, which are largely responsible for intrathecal and local Ig production. This is especially seen in active MS white matter lesions and likely depends on the interaction with CD4 + memory T cells., Funding: Stichting MS Research (19-1057 MS; 20-490f MS), National MS Fonds (OZ2018-003)., Competing Interests: Declaration of interests M.M.v.L. received research support from EMD Serono, Merck, GSK and Idorsia Pharmaceutical Ltd. J.S. received lecture and/or consultancy fees from Biogen, Merck, Novartis and Sanofi-Genzyme. The remaining authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Multiple sclerosis (MS) is associated with abnormal B-cell function, and MS genetic risk alleles affect multiple genes that are expressed in B cells. However, how these genetic variants impact the B-cell compartment in early childhood is unclear. In the current study, we aim to assess whether polygenic risk scores (PRSs) for MS are associated with changes in the blood B-cell compartment in children from the general population., Methods: Six-year-old children from the population-based Generation R Study were included. Genotype data were used to calculate MS-PRSs and B-cell subset-enriched MS-PRSs, established by designating risk loci based on expression and function. Analyses of variance were performed to examine the effect of MS-PRSs on total B-cell numbers (n = 1261) as well as naive and memory subsets (n = 675)., Results: After correction for multiple testing, no significant associations were observed between MS-PRSs and total B-cell numbers and frequencies of subsets therein. A naive B-cell-MS-PRS (n = 26 variants) was significantly associated with lower relative, but not absolute, naive B-cell numbers (p = 1.03 × 10 -4 and p = 0.82, respectively), and higher frequencies and absolute numbers of CD27 + memory B cells (p = 8.83 × 10 -4 and p = 4.89 × 10 -3 , respectively). These associations remained significant after adjustment for Epstein-Barr virus seropositivity and the HLA-DRB1*15:01 genotype., Conclusions: The composition of the blood B-cell compartment is associated with specific naive B-cell-associated MS risk variants during childhood, possibly contributing to MS pathophysiology later in life. Cell subset-specific PRSs may offer a more sensitive tool to define the impact of genetic risk on the immune system in diseases such as MS., (© 2022 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

The human brain is populated by perivascular T cells with a tissue-resident memory T (T RM )-cell phenotype, which in multiple sclerosis (MS) associate with lesions. We investigated the transcriptional and functional profile of freshly isolated T cells from white and gray matter. RNA sequencing of CD8 + and CD4 + CD69 + T cells revealed T RM -cell signatures. Notably, gene expression hardly differed between lesional and normal-appearing white matter T cells in MS brains. Genes up-regulated in brain T RM cells were MS4A1 (CD20) and SPP1 (osteopontin, OPN). OPN is also abundantly expressed by microglia and has been shown to inhibit T cell activity. In line with their parenchymal localization and the increased presence of OPN in active MS lesions, we noticed a reduced production of inflammatory cytokines IL-2, TNF, and IFNγ by lesion-derived CD8 + and CD4 + T cells ex vivo . Our study reports traits of brain T RM cells and reveals their tight control in MS lesions., Competing Interests: C.C.H., J.H.E., A.J., and P.D.M. declare that they have no competing interests. I.H., J.S., and J.H. obtained financial support from Biogen for conducting this study. J.Z., B.Z., and M.M. are employees of Biogen and hold stocks from the company., (© 2022 The Author(s).)

Circulating and tissue-resident T cells collaborate in the protection of tissues against harmful infections and malignant transformation but also can instigate autoimmune reactions. Similar roles for T cells in the brain have been less evident due to the compartmentized organization of the central nervous system (CNS). In recent years, beneficial as well as occasional, detrimental effects of T-cell-targeting drugs in people with early multiple sclerosis (MS) have increased interest in T cells patrolling the CNS. Next to studies focusing on T cells in the cerebrospinal fluid, phenotypic characteristics of T cells located in the perivascular space and the meninges as well as in the parenchyma in MS lesions have been reported. We here summarize the current knowledge about T cells infiltrating the healthy and MS brain and argue that understanding the dynamics of physiological CNS surveillance by T cells is likely to improve the understanding of pathological conditions, such as MS., (© 2022. The Author(s).)

Background: Inertial sensors hold the promise to objectively measure functional recovery after total knee (TKA) and hip arthroplasty (THA), but their value in addition to patient-reported outcome measures (PROMs) has yet to be demonstrated. This study investigated recovery of gait after TKA and THA using inertial sensors, and compared results to recovery of self-reported scores of pain and function., Methods: PROMs and gait parameters were assessed before and at two and fifteen months after TKA ( n  = 24) and THA ( n  = 24). Gait parameters were compared with healthy individuals ( n  = 27) of similar age. Gait data were collected using inertial sensors on the feet, lower back, and trunk. Participants walked for two minutes back and forth over a 6m walkway with 180° turns. PROMs were obtained using the Knee Injury and Osteoarthritis Outcome Scores and Hip Disability and Osteoarthritis Outcome Score., Results: Gait parameters recovered to the level of healthy controls after both TKA and THA. Early improvements were found in gait-related trunk kinematics, while spatiotemporal gait parameters mainly improved between two and fifteen months after TKA and THA. Compared to the large and early improvements found in of PROMs, these gait parameters showed a different trajectory, with a marked discordance between the outcome of both methods at two months post-operatively., Conclusion: Sensor-derived gait parameters were responsive to TKA and THA, showing different recovery trajectories for spatiotemporal gait parameters and gait-related trunk kinematics. Fifteen months after TKA and THA, there were no remaining gait differences with respect to healthy controls. Given the discordance in recovery trajectories between gait parameters and PROMs, sensor-derived gait parameters seem to carry relevant information for evaluation of physical function that is not captured by self-reported scores., Competing Interests: The authors declare there are no competing interests., (©2022 Boekesteijn et al.)

Recent clinical trials have shown promising results for the next-generation Bruton's tyrosine kinase (BTK) inhibitor evobrutinib in the treatment of multiple sclerosis (MS). BTK has a central role in signaling pathways that govern the development of B cells. Whether and how BTK activity shapes B cells as key drivers of MS is currently unclear. Compared with levels of BTK protein, we found higher levels of phospho-BTK in ex vivo blood memory B cells from patients with relapsing-remitting MS and secondary progressive MS compared with controls. In these MS groups, BTK activity was induced to a lesser extent after anti-IgM stimulation. BTK positively correlated with CXCR3 expression, both of which were increased in blood B cells from clinical responders to natalizumab (anti-VLA-4 antibody) treatment. Under in vitro T follicular helper-like conditions, BTK phosphorylation was enhanced by T-bet-inducing stimuli, IFN-γ and CpG-ODN, while the expression of T-bet and T-bet-associated molecules CXCR3, CD21, and CD11c was affected by evobrutinib. Furthermore, evobrutinib interfered with in vitro class switching, as well as memory recall responses, and disturbed CXCL10-mediated migration of CXCR3+ switched B cells through human brain endothelial monolayers. These findings demonstrate a functional link between BTK activity and disease-relevant B cells and offer valuable insights into how next-generation BTK inhibitors could modulate the clinical course of patients with MS.