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Multiple sclerosis is a severe demyelinating disease mediated by cells of the innate and adaptive immune system, especially pathogenic T lymphocytes that produce the pro-inflammatory cytokine granulocyte-macrophage colony stimulating factor (GM-CSF). Although the factors and molecules that drive the genesis of these cells are not completely known, some were discovered and shown to promote the development of such cells, such as dietary factors. In this regard, iron, the most abundant chemical element on Earth, has been implicated in the development of pathogenic T lymphocytes and in MS development via its effects on neurons and glia. Therefore, the aim of this paper is to revise the state-of-art regarding the role of iron metabolism in cells of key importance to MS pathophysiology, such as pathogenic CD4+ T cells and CNS resident cells. Harnessing the knowledge of iron metabolism may aid in the discovery of new molecular targets and in the development of new drugs that tackle MS and other diseases that share similar pathophysiology. [ABSTRACT FROM AUTHOR]

Introduction. PECAM-1 and NKRP1A are both involved in the vascular transmigration of T lymphocytes. Vascular transmigration is a crucial process in multiple sclerosis pathogenesis. Methods and aim. The current paper presents an analysis of PECAM-1 and NKRP1A expression on γδ T cells. Expression of PECAM-1 and NKRP1A on subsets of γδ T cells was performed with flow cytometry. Results. Based on the flow cytometry data, PECAM1 was slightly differentially modulated on γδ T cells—it was up-regulated during relapse, but down-regulated during remission. Moreover, a significant downregulation of CD3 expression was noted on γδ T cells from MS patients, most notably during relapse. Conclusions. This may be a sign of the overall activation of γδ T cells in the course of multiple sclerosis. [ABSTRACT FROM AUTHOR]

Neurodegeneration is a pathological condition that predominantly affects neurons. It represents a large spectrum of disorders with heterogeneous symptoms and distinct clinical features. In addition to the devastating effects it can have on the affected individual, it constitutes a heavy burden to the society in terms of health care costs. Although the exact cause of neurodegeneration is not known, there are plenty of evidences supporting the notion that the immune system is strongly associated with various forms of neurodegenerative diseases. Given the numerous functions of immune cells, a change in their expression can either be beneficial or deleterious to the host. A better understanding of the molecular and cellular processes in neurodegeneration is therefore needed. This could facilitate the development of new therapeutic targets and provide effective means to dampen the progression of neurodegenerative disorders. The overarching aim of this paper is to provide an overview of the roles that the innate and adaptive immune systems play in the central nervous system, and to discuss their beneficial or detrimental effects during neurodegeneration. This paper also critically examines the contribution of immune and inflammatory-mediated responses in the development of neurodegenerative diseases including Alzheimer's disease (AD), Parkinson's disease (PD), multiple sclerosis (MS), and amyloid lateral sclerosis by illustrating key findings from animal and human studies. [ABSTRACT FROM AUTHOR]

Background: Secondary progressive multiple sclerosis (SPMS) is defined by the irreversible accumulation of disability following a relapsing-remitting MS (RRMS) course. Despite treatments advances, a reliable tool able to capture the transition from RRMS to SPMS is lacking. A T cell chimeric MS model demonstrated that T cells derived from relapsing patients exacerbate excitatory transmission of central neurons, a synaptotoxic event absent during remitting stages. We hypothesized the re-emergence of T cell synaptotoxicity during SPMS and investigated the synaptoprotective effects of siponimod, a sphingosine 1-phosphate receptor (S1PR) modulator, known to reduce grey matter damage in SPMS patients. Methods: Data from healthy controls (HC), SPMS patients, and siponimod-treated SPMS patients were collected. Chimeric experiments were performed incubating human T cells on murine cortico-striatal slices, and recording spontaneous glutamatergic activity from striatal neurons. Homologous chimeric experiments were executed incubating EAE mice T cells with siponimod and specific S1PR agonists or antagonists to identify the receptor involved in siponimod-mediated synaptic recovery. Results: SPMS patient-derived T cells significantly increased the striatal excitatory synaptic transmission (n=40 synapses) compared to HC T cells (n=55 synapses), mimicking the glutamatergic alterations observed in active RRMS-T cells. Siponimod treatment rescued SPMS T cells synaptotoxicity (n=51 synapses). Homologous chimeric experiments highlighted S1P5R involvement in the siponimod’s protective effects. Conclusion: Transition from RRMS to SPMS involves the reappearance of T cell-mediated synaptotoxicity. Siponimod counteracts T cell-induced excitotoxicity, emphasizing the significance of inflammatory synaptopathy in progressive MS and its potential as a promising pharmacological target. [ABSTRACT FROM AUTHOR]

It is important to describe effective and non-toxic therapies for multiple sclerosis (MS), an autoimmune demyelinating disease. Experimental autoimmune encephalomyelitis (EAE) is an immune-mediated inflammatory disease that serves as a model for MS. Earlier we and others have shown that, gemfibrozil, a lipid-lowering drug, exhibits therapeutic efficacy in EAE. However, the underlying mechanism was poorly understood. Although gemfibrozil is a known ligand of peroxisome proliferator-activated receptor a (PPARa), here, we established that oral administration of gemfibrozil preserved the integrity of blood--brain barrier (BBB) and blood--spinal cord barrier (BSB), decreased the infiltration of mononuclear cells into the CNS and inhibited the disease process of EAE in both wild type and PPARα-/- mice. On the other hand, oral gemfibrozil was found ineffective in maintaining the integrity of BBB/BSB, suppressing inflammatory infiltration and reducing the disease process of EAE in mice lacking PPARb (formerly PPARd), indicating an important role of PPARβ/δ, but not PPARα, in gemfibrozil-mediated preservation of BBB/BSB and protection of EAE. Regulatory T cells (Tregs) play a critical role in the disease process of EAE/MS and we also demonstrated that oral gemfibrozil protected Tregs in WT and PPARα-/- EAE mice, but not PPARβ-/- EAE mice. Taken together, our findings suggest that gemfibrozil, a known ligand of PPARα, preserves the integrity of BBB/BSB, enriches Tregs, and inhibits the disease process of EAE via PPARβ, but not PPARα. [ABSTRACT FROM AUTHOR]

We have previously performed preclinical studies with the oxidized mannan-conjugated peptide MOG35–55 (OM-MOG35–55) in vivo (EAE mouse model) and in vitro (human peripheral blood) and demonstrated that OM-MOG35–55 suppresses antigen-specific T cell responses associated with autoimmune demyelination. Based on these results, we developed different types of dendritic cells (DCs) from the peripheral blood monocytes of patients with multiple sclerosis (MS) or healthy controls presenting OM-MOG35–55 or MOG-35–55 to autologous T cells to investigate the tolerogenic potential of OM-MOG35–55 for its possible use in MS therapy. To this end, monocytes were differentiated into different DC types in the presence of IL-4+GM-CSF ± dexamethasone (DEXA) ± vitamin D3 (VITD3). At the end of their differentiation, the DCs were loaded with peptides and co-cultured with T cells +IL-2 for 4 antigen presentation cycles. The phenotypes of the DC and T cell populations were analyzed using flow cytometry and the secreted cytokines using flow cytometry or ELISA. On day 8, the monocytes had converted into DCs expressing the typical markers of mature or immature phenotypes. Co-culture of T cells with all DC types for 4 antigen presentation cycles resulted in an increase in memory CD4+ T cells compared to memory CD8+ T cells and a suppressive shift in secreted cytokines, mainly due to increased TGF-β1 levels. The best tolerogenic effect was obtained when patient CD4+ T cells were co-cultured with VITD3-DCs presenting OM-MOG35–55, resulting in the highest levels of CD4+PD-1+ T cells and CD4+CD25+Foxp3+ Τ cells. In conclusion, the tolerance induction protocols presented in this work demonstrate that OM-MOG35–55 could form the basis for the development of personalized therapeutic vaccines or immunomodulatory treatments for MS. [ABSTRACT FROM AUTHOR]

Objective: Soluble CD27 is a promising cerebrospinal fluid inflammatory biomarker in multiple sclerosis. In this study, we investigate relevant immune and neuro-pathological features of soluble CD27 in multiple sclerosis. Methods: Protein levels of soluble CD27 were correlated to inflammatory cell subpopulations and inflammatory cytokines and chemokines detected in cerebrospinal fluid of 137 patients with multiple sclerosis and 47 patients with inflammatory and non-inflammatory neurological disease from three independent cohorts. Production of soluble CD27 was investigated in cell cultures of activated T and B cells and CD27-knockout T cells. In a study including matched cerebrospinal fluid and post-mortem brain tissues of patients with multiple sclerosis and control cases, levels of soluble CD27 were correlated with perivascular and meningeal infiltrates and with neuropathological features. Results: We demonstrate that soluble CD27 favours the differentiation of interferon-γ-producing T cells and is released through a secretory mechanism activated by TCR engagement and regulated by neutral sphingomyelinase. We also show that the levels of soluble CD27 correlate with the representation of inflammatory T cell subsets in the CSF of patients with relapsing-remitting multiple sclerosis and with the magnitude of perivascular and meningeal CD27 + CD4 + and CD8 + T cell infiltrates in post-mortem central nervous system tissue, defining a subgroup of patients with extensive active inflammatory lesions. Interpretation: Our results demonstrate that soluble CD27 is a biomarker of disease activity, potentially informative for personalized treatment and monitoring of treatment outcomes. [ABSTRACT FROM AUTHOR]

Choroid plexus (CP) can be seen as a watchtower of the central nervous system (CNS) that actively regulates CNS homeostasis. A growing body of literature suggests that CP alterations are involved in the pathogenesis of multiple sclerosis (MS) but the underlying mechanisms remain elusive. CPs are enlarged and inflamed in relapsing-remitting (RRMS) but also in clinically isolated syndrome (CIS) and radiologically isolated syndrome (RIS) stages, far beyond MS diagnosis. Increases in the choroid plexus/total intracranial volume (CP/TIV) ratio have been robustly associated with increased lesion load, higher translocator protein (TSPO) uptake in normal-appearing white matter (NAWM) and thalami, as well as with higher annual relapse rate and disability progression in highly active RRMS individuals, but not in progressive MS. The CP/TIV ratio has only slightly been correlated with magnetic resonance imaging (MRI) findings (cortical or whole brain atrophy) and clinical outcomes (EDSS score) in progressive MS. Therefore, we suggest that plexus volumetric assessments should be mainly applied to the early disease stages of MS, whereas it should be taken into consideration with caution in progressive MS. In this review, we attempt to clarify the pathological significance of the temporal CP volume (CPV) changes in MS and highlight the pitfalls and limitations of CP volumetric analysis. [ABSTRACT FROM AUTHOR]

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. Microglia nodules are associated with brain pathology. Here, the authors show demyelination in microglia nodules in multiple sclerosis (MS), likely due to oxidized phospholipid phagocytosis and immune activation, suggesting that nodules could be involved in MS lesion formation. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, and CD4+ T cells formthe core immunopathogenic cascade leading to chronic inflammation. Traditionally, Th1 cells (interferon-γ-producing CD4+ T cells) driven by interleukin 12 (IL12) were considered to be the encephalitogenic T cells in MS and experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Currently, Th17 cells (Il17-producing CD4+ T cells) are considered to play a fundamental role in the immunopathogenesis of EAE. This paper highlights the growing evidence that Th17 cells play the core role in the complex adaptive immunity of EAE/MS and discusses the roles of the associated immune cells and cytokines. These constitute the modern immunological basis for the development of novel clinical and preclinical immunomodulatory therapies for MS discussed in this paper. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) infection has long been associated with multiple sclerosis (MS), but the role of EBV in the pathogenesis of MS is not clear. Our hypothesis is that a major fraction of the expanded clones of T lymphocytes in the cerebrospinal fluid (CSF) are specific for autologous EBV-infected B cells. We obtained blood and CSF samples from eight relapsing-remitting patients in the process of diagnosis. We stimulated cells from the blood with autologous EBV-infected lymphoblastoid cell lines (LCL), EBV, varicella zoster virus, influenza, and candida and sorted the responding cells with flow cytometry after 6 d. We sequenced the RNA for T cell receptors (TCR) from CSF, unselected blood cells, and the antigen-specific cells. We used the TCR Vβ CDR3 sequences from the antigen-specific cells to assign antigen specificity to the sequences from the CSF and blood. LCL-specific cells comprised 13.0 ± 4.3% (mean ± SD) of the total reads present in CSF and 13.3 ± 7.5% of the reads present in blood. The next most abundant antigen specificity was flu, which was 4.7 ± 1.7% of the reads in the CSF and 9.3 ± 6.6% in the blood. The prominence of LCL-specific reads was even more marked in the top 1% most abundant CSF clones with statistically significant 47% mean overlap with LCL. We conclude that LCL-specific sequences form a major portion of the TCR repertoire in both CSF and blood and that expanded clones specific for LCL are present in MS CSF. This has important implications for the pathogenesis of MS. [ABSTRACT FROM AUTHOR]

Autoreactive T lymphocytes crossing the blood-brain barrier (BBB) into the central nervous system (CNS) play a crucial role in the initiation of demyelination and neurodegeneration in multiple sclerosis (MS). Recently, extracellular vesicles (EV) secreted by BBB endothelial cells (BBB-EC) have emerged as a unique form of cell-to-cell communication that contributes to cerebrovascular dysfunction. However, the precise impact of different size-based subpopulations of BBB-EC-derived EV (BBB-EV) on the early stages of MS remains unclear. Therefore, our objective was to investigate the content and function of distinct BBB-EV subpopulations in regulating BBB integrity and their role in T cell transendothelial migration, both in vitro and in vivo. Our study reveals that BBB-ECs release two distinct size based EV populations, namely small EV (sEV; 30-150 nm) and large EV (lEV; 150-300 nm), with a significantly higher secretion of sEV during inflammation. Notably, the expression patterns of cytokines and adhesion markers differ significantly between these BBB-EV subsets, indicating specific functional differences in the regulation of T cell migration. Through in vitro experiments, we demonstrate that lEV, which predominantly reflect their cellular source, play a major role in BBB integrity loss and the enhanced migration of pro-inflammatory Th1 and Th17.1 cells. Conversely, sEV appear to protect BBB function by inducing an anti-inflammatory phenotype in BBB-EC. These findings align with our in vivo data, where the administration of sEV to mice with experimental autoimmune encephalomyelitis (EAE) results in lower disease severity compared to the administration of lEV, which exacerbates disease symptoms. In conclusion, our study highlights the distinct and opposing effects of BBB-EV subpopulations on the BBB, both in vitro and in vivo. These findings underscore the need for further investigation into the diagnostic and therapeutic potential of BBB-EV in the context of MS. [ABSTRACT FROM AUTHOR]

Background: In multiple sclerosis (MS), disturbed T-cell homeostasis affects both conventional CD4+ T cells (Tcon) and regulatory T cells (Treg). Functionally, this is linked to a loss of Treg-suppressive properties. Concerns exist as to whether fingolimod might further aggravate Treg dysfunction by inhibiting thymic egress and, thus, promoting premature immunosenescence. Objective: The objective of this paper is to investigate whether fingolimod, by sequestration of developing cells in the thymus, might deteriorate numeric and/or functional disequilibrium of T-cell subtypes. Methods: We assessed numbers and phenotypes of blood Tcon and Treg in 74 MS patients treated with fingolimod and in 37 healthy donors. Treg and Tcon were also analyzed for immunoreactivity, suppressive function, sphingosine-1-phosphate-triggered (S1P) trafficking, and S1P-receptor expression. This was complemented by assessing surrogate markers of thymic T-cell development, including frequencies of cells expressing T-cell receptors (TCR) of dual specificity, and TCR diversity in Treg. Results: Fingolimod did not negatively affect naive T-cell phenotypes or markers of thymic T-cell development. By reducing CCR7-expressing Tcon, fingolimod increased relative proportions of Treg. As a result of this shift, fewer proliferative CCR7− Tcon became enriched and Treg-dysfunction was indirectly reversed. Conclusion: These observations argue against harmful interference of fingolimod with thymic T-cell output that, particularly in pediatric MS, might possibly counteract its beneficial effects. [ABSTRACT FROM AUTHOR]

[CD8.sup.+] T cells outnumber CD4* cells in multiple sclerosis (MS) lesions associated with disease progression, but the pathogenic role and antigenic targets of these clonally expanded effectors are unknown. Based on evidence that demyelination is necessary but not sufficient for disease progression in MS, we previously hypothesized that CNS-infiltrating [CD8.sup.+] T cells specific for neuronal antigens directly drive the axonal and neuronal injury that leads to cumulative neurologic disability in patients with MS. We now show that demyelination induced expression of MHC class I on neurons and axons and resulted in presentation of a neuron-specific neoantigen (synapsin promoter-driven chicken ovalbumin) to antigen-specific [CD8.sup.+] T cells (anti-ovalbumin OT-I TCR-transgenic T cells). These neuroantigen-specific effectors surveilled the CNS in the absence of demyelination but were not retained. However, upon induction of demyelination via cuprizone intoxication, neuroantigen-specific [CD8.sup.+] T cells proliferated, accumulated in the CNS, and damaged neoantigen-expressing neurons and axons. We further report elevated neuronal expression of MHC class I and [beta]2-microglobulin transcripts and protein in gray matter and white matter tracts in tissue from patients with MS. These findings support a pathogenic role for autoreactive anti-axonal and anti-neuronal [CD8.sup.+] T cells in MS progression., Introduction Multiple sclerosis (MS) (1, 2) affects nearly 3 million people worldwide, with an estimated annual economic burden in excess of $100B USD. Progressive disease accounts for the bulk of [...]

Uncontrolled activity of T cells mediates autoimmune and inflammatory diseases such as multiple sclerosis, inflammatory bowel diseases, rheumatoid arthritis, type 1 diabetes, and atherosclerosis. Recent findings suggest that enhanced activity of interleukin-17 (IL-17) producing T helper 17 cells (Th17 cells) plays an important role in autoimmune diseases and inflammatory diseases. Previous papers have revealed that a lipid-lowering synthetic ligand of peroxisome proliferator-activated receptor α (PPARα), fenofibrate, alleviates both atherosclerosis and a few nonlipid-associated autoimmune diseases such as autoimmune colitis and multiple sclerosis. However, the link between fenofibrate and Th17 cells is lacking. In the present study, we hypothesized that fenofibrate inhibited the differentiation of Th17 cells. Our results showed that fenofibrate inhibited transforming growth factor-β (TGF-β) and IL-6-induced differentiation of Th17 cells in vitro. However, other PPARα ligands such as WY14643, GW7647 and bezafibrate did not show any effect on Th17 differentiation, indicating that this effect of fenofibrate might be PPARα independent. Furthermore, our data showed that fenofibrate reduced IL-21 production and STAT3 activation, a critical signal in the Th17 differentiation. Thus, by ameliorating the differentiation of Th17 cells, fenofibrate might be beneficial for autoimmunity and inflammatory diseases. [ABSTRACT FROM AUTHOR]

In multiple sclerosis (MS), compromised blood-brain barrier (BBB) integrity contributes to inflammatory T cell migration into the central nervous system. Matrix metalloproteinase-9 (MMP-9) is associated with BBB disruption and subsequent T cell migration into the CNS. The aim of this paper was to evaluate the effects of omega-3 fatty acids on MMP-9 levels and T cell migration. Peripheral blood mononuclear cells (PBMC) from healthy controls were pretreated with two types of omega-3 fatty acids, eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA). Cell supernatants were used to determine MMP-9 protein and activity levels. Jurkat cells were pretreated with EPA and DHA and were added to fibronectin-coated transwells to measure T cell migration. EPA and DHA significantly decreased MMP-9 protein levels, MMP-9 activity, and significantly inhibited human T cell migration. The data suggest that omega-3 fatty acids may benefit patients with multiple sclerosis by modulating immune cell production of MMP-9. [ABSTRACT FROM AUTHOR]

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Multiple sclerosis (MS) is thought to be an autoimmune disease in which activated T-cells initiate a macrophage mediated destruction of CNS myelin. Bone marrow transplantation (BMT) is currently being evaluated in the treatment of MS in patients with aggressive disease activity. Autologous BMT could potentially reset the immune response to myelin antigens leading to immune tolerance and decreased disease activity. Allogeneic transplantation could reconstitute the immune system potentially arresting the progression of autoimmune disease. The purpose of this paper is to report a patient with MS who underwent allogeneic BMT for chronic myelogenous leukemia (CML) and showed continued evidence of active demyelinating disease by clinical and radiologic criteria over a period of two years. While this is only a single case report with inherent limitations, it suggests that the immune mediated destruction of CNS myelin in MS may not be prevented or aborted by immune system reconstitution, and is consistent with the idea that immune mediated tissue destruction in MS could be targeted against an abnormal antigen. [ABSTRACT FROM AUTHOR]

Methylprednisolone plays an important role in the current treatment of multiple sclerosis (MS), particularly in the acute phase of relapse. It acts in various ways to decrease the inflammatory cycle including: dampening the inflammatory cytokine cascade, inhibiting the activation of T cells, decreasing the extravasation of immune cells into the central nervous system, facilitating the apoptosis of activated immune cells, and indirectly decreasing the cytotoxic effects of nitric oxide and tumor necrosis factor alpha. This paper reviews the most recent observations on these mechanisms both to understand the disease mechanism and its treatment. As more becomes known about these mechanisms, it may become possible to design treatment regimes that are more specific towards both the individual and the disease state. [ABSTRACT FROM AUTHOR]

Cognate interactions between immune effector cells and antigen-presenting cells (APCs) govern immune responses. Specific signals occur between the T-cell receptor peptide and APCs and nonspecific signals between pairs of costimulatory molecules. Costimulation signals are required for full T-cell activation and are assumed to regulate T-cell responses as well as other aspects of the immune system. As new discoveries are made, it is becoming clear how important these costimulation interactions are for immune responses. Costimulation requirements for T-cell regulation have been extensively studied as a way to control many autoimmune diseases and downregulate inflammatory reactions. The CD28:B7 and the CD40:CD40L families of molecules are considered to be critical costimulatory molecules and have been studied extensively. Blocking the interaction between these molecules results in a state of immune unresponsiveness termed‘anergy’. Several different strategies for blockade of these interactions are explored including monoclonal antibodies (mAbs), Fab fragments, chimeric, and/or fusion proteins. We developed novel, immune-specific approaches that interfere with these interactions. Using experimental autoimmune encephalomyelitis (EAE), an animal model for multiple sclerosis mediated by central nervous system (CNS)-specific T-cells, we developed a multi-targeted approach that utilizes peptides for blockade of costimulatory molecules. We designed blocking peptide mimics that retain the functional binding area of the parent protein while reducing the overall size and are thus capable of blocking signal transduction. In this paper, we review the role of costimulatory molecules in autoimmune diseases, two of the most well-studied costimulatory pathways (CD28/CTLA-4:B7 and CD40:CD40L), and the advantages of peptidomimetic approaches. We present data showing the ability of peptide mimics of costimulatory molecules to suppress autoimmune disease and propose a mechanism for disease suppression. [ABSTRACT FROM AUTHOR]

Beta-interferon (beta-IFN) has a proven treatment effect on relapsing–remitting multiple sclerosis (MS), presumably through its regulatory properties on T-cell activation and cytokine production. This paper examines whether combination therapy of beta-IFN with prednisone would enhance immunoregulatory effects of beta-IFN by measuring serum levels of selected proinflammatory cytokines and soluble T-cell activation markers associated with MS. The selected markers were analyzed in MS patients treated with beta-IFN alone (n = 22) and beta-IFN combined with a low daily dose of prednisone (n =33), as compared with those in 27 healthy controls at baseline and at a three-month interval for one year. The study confirmed that beta-IFN treatment inhibited serum levels of tumor necrosis factor-alpha (TNFα) and intracellular adhesion molecule-1 (IC AM-1) in patients with MS. However, combination therapy did not significantly enhance the inhibitory effect of beta-IFN treatment on the production of TNFα, interleukin (IL)-12, IL-2R, and ICAM-1, while the addition of prednisone antagonized the effect of beta-IFN on up-regulation of IL-10 and soluble CD95. No difference in the occurrence of binding antibodies to beta-IFN was found between the two treatment groups. The findings are important for the understanding of the role of combination therapy in the treatment of MS. [ABSTRACT FROM AUTHOR]

The occurrence of B cell aggregates within the central nervous system (CNS) has prompted the investigation of the potential sources of pathogenic B cell and T cell responses in a subgroup of secondary progressive multiple sclerosis (MS) patients. Nevertheless, the expression profile of molecules associated with these aggregates and their role in aggregate development and persistence is poorly described. Here, we focused on the expression pattern of osteopontin (OPN), which is a well-described cytokine, in MS brain tissue. Autopsied brain sections from MS cases with and without B cell pathology were screened for the presence of CD20+ B cell aggregates and co-expression of OPN. To demonstrate the effect of OPN on B cells, flow cytometry, ELISA and in vitro aggregation assays were conducted using the peripheral blood of healthy volunteers. Although OPN was expressed in MS brain tissue independent of B cell pathology, it was also highly expressed within B cell aggregates. In vitro studies demonstrated that OPN downregulated the co-stimulatory molecules CD80 and CD86 on B cells. OPN-treated B cells produced significantly lower amounts of IL-6. However, OPN-treated B cells also exhibited a higher tendency to form homotypic cell aggregates in vitro. Taken together, our data indicate a conflicting role of OPN in modulating B cell responses. [ABSTRACT FROM AUTHOR]

The trafficking of autoreactive leukocytes across the blood-brain barrier (BBB) endothelium is a hallmark of multiple sclerosis (MS) pathogenesis. Although the BBB endothelium represents one of the main central nervous system (CNS) borders to interact with the infiltrating leukocytes, its exact contribution to neuroinflammation remains understudied. Here, we show that Mcam identifies inflammatory brain endothelial cells (ECs) with pro-migratory transcriptomic signature during experimental autoimmune encephalomyelitis (EAE). In addition, MCAM was preferentially upregulated on BBB ECs in MS lesions in situ and at EAE disease onset by molecular magnetic resonance imaging. In vitro and in vivo, we demonstrate that MCAM on BBB ECs contributes to EAE development by promoting the cellular trafficking of TH1 and TH17 lymphocytes across the BBB. Lastly, we showcase ST14 as an immune ligand to brain endothelial MCAM, enriched on CD4+ T lymphocytes that cross the BBB in vitro, in vivo and in MS lesions as detected by flow cytometry on rapid autopsy derived brain tissue from MS patients. Collectively, our findings reveal that MCAM is at the center of a pathological pathway used by brain ECs to recruit pathogenic CD4+ T lymphocyte from circulation early during neuroinflammation. The therapeutic targeting of this mechanism is a promising avenue to treat MS. [ABSTRACT FROM AUTHOR]

Autoantibodies against myelin oligodendrocyte glycoprotein (MOG) have recently been established to define a new disease entity, MOG-antibody-associated disease (MOGAD), which is clinically overlapping with multiple sclerosis. MOG-specific antibodies (Abs) from patients are pathogenic, but the precise effector mechanisms are currently still unknown and no therapy is approved for MOGAD. Here, we determined the contributions of complement and Fc-receptor (FcR)-mediated effects in the pathogenicity of MOG-Abs. Starting from a recombinant anti-MOG (mAb) with human IgG1 Fc, we established MOG-specific mutant mAbs with differential FcR and C1q binding. We then applied selected mutants of this MOG-mAb in two animal models of experimental autoimmune encephalomyelitis. First, we found MOG-mAbinduced demyelination was mediated by both complement and FcRs about equally. Second, we found that MOG-Abs enhanced activation of cognate MOG-specific T cells in the central nervous system (CNS), which was dependent on FcR-, but not C1q-binding. The identification of complement-dependent and -independent pathomechanisms of MOG-Abs has implications for therapeutic strategies in MOGAD. [ABSTRACT FROM AUTHOR]

Objective: To report for the first time an Italian epidemiological analysis of the prevalence of multiple sclerosis (MS) in patients with endometriosis (EMS), through the study of the endometriosis population of our referral center; to analyze the clinical profile and perform a laboratory analysis to examine the immune profile and the possible correlation to other autoimmune diseases of the enrolled patients. Methods: We evaluated 1652 women registered with EMS in the University of Naples Federico II and retrospectively searched patients with a co-diagnosis of MS. Clinical features of both conditions were recorded. Serum autoantibody and immune profiles were analyzed. Results: 9 out of 1652 patients presented a co-diagnosis of EMS and MS (9/1652 = 0.005%). Clinically, EMS and MS presented in mild forms. Hashimoto's thyroiditis was found in two patients (2/9). Even if not statistically significant, a trend of variation in CD4- CD8 T lymphocytes and of B cells were found. Conclusion: Our findings suggest an increased risk of MS in women with EMS. However, large-scale prospective studies are needed. [ABSTRACT FROM AUTHOR]

Background and objectives: alemtuzumab is a monoclonal anti-CD52 antibody acting on B and T cells in highly active multiple sclerosis (MS). We analyzed changes in lymphocyte subsets after alemtuzumab administration in relation to disease activity and autoimmune adverse events. Methods: lymphocyte subset counts were assessed longitudinally using linear mixed models. Subset counts at baseline and during follow-up were correlated with relapse rate, adverse events, or magnetic resonance (MRI) activity. Results: we recruited 150 patients followed for a median of 2.7 years (IQR: 1.9–3.7). Total lymphocytes, CD4, CD8, and CD20 significantly decreased in all patients over 2 years (p < 0.001). Previous treatment with fingolimod increased the risk of disease activity and adverse events (p = 0.029). We found a higher probability of disease reactivation in males and in patients with over three active lesions at baseline. Higher EDSS scores at baseline and longer disease duration predicted the switch to other treatments after alemtuzumab. Discussion and conclusions: Our real-world study supports data from clinical trials in which lymphocyte subsets were not useful for predicting disease activity or autoimmune disease during treatment. The early use of an induction therapy such as alemtuzumab in patients with a lower EDSS score and short history of disease could mitigate the risk of treatment failure. [ABSTRACT FROM AUTHOR]

The aim of the retrospective study was to compare the immunophenotyping of T-lymphocytes, B-lymphocytes, and natural killer cells before the administration of the first and the second dose of ocrelizumab in 22 patients with multiple sclerosis in a three-year period (2019–2021) at the Department of Neurology of the University Hospital of Split. The values of cell immunophenotyping and protein electrophoresis, as well as laboratory parameters, were investigated. There was no significant decrease in serum albumin and globulins before the second dose of ocrelizumab (p > 0,05). A decrease in the number of T-lymphocytes before administration of the second dose of ocrelizumab was observed, but without statistical significance (p = 0.274). Significant depletion occurred in median CD19+ B-lymphocytes (p < 0.001) before the intake of the second dose of ocrelizumab confirming the primary action of ocrelizumab on the B cell lineage. [ABSTRACT FROM AUTHOR]

Glucocorticoids (GCs) are used to treat inflammatory disorders such as multiple sclerosis (MS) by exerting prominent activities in T cells including apoptosis induction and suppression of cytokine production. However, little is known about their impact on energy metabolism, although it is widely accepted that this process is a critical rheostat of T cell activity. We thus tested the hypothesis that GCs control genes and processes involved in nutrient transport and glycolysis. Our experiments revealed that escalating doses of dexamethasone (Dex) repressed energy metabolism in murine and human primary T cells. This effect was mediated by the GC receptor and unrelated to both apoptosis induction and Stat1 activity. In contrast, treatment of human T cells with rapamycin abolished the repression of metabolic gene expression by Dex, unveiling mTOR as a critical target of GC action. A similar phenomenon was observed in MS patients after intravenous methylprednisolon (IVMP) pulse therapy. The expression of metabolic genes was reduced in the peripheral blood T cells of most patients 24 h after GC treatment, an effect that correlated with disease activity. Collectively, our results establish the regulation of T cell energy metabolism by GCs as a new immunomodulatory principle. [ABSTRACT FROM AUTHOR]

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20dimCD8+ T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20dimCD8+ T cells had a greater contribution to treatment-associated changes in the CD8+ T cell pool than was the case for CD4+ T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20dimCD8+ T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19+CD24highCD38high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20dimCD8+ T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8+ T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development. [ABSTRACT FROM AUTHOR]

Although cladribine induces sustained reductions in peripheral T and B lymphocytes, little is known about its effect on axonal damage reduction in multiple sclerosis (MS), which could be demonstrated by assessing the serum neurofilament light chain (sNfL) levels. We investigated the reduction/reconstitution of different lymphocyte subsets (LS) by verifying the correlation with no evidence of disease activity (NEDA) and the variation in sNfL levels during cladribine treatment. We analysed 33 highly active relapsing MS patients and followed them up for 12 ± 3.3 months; blood samples were collected at treatment start (W0) and after 8, 24 and 48 weeks. Seventeen patients (60.7%) showed NEDA during the first treatment. At week 8, we observed a significant decrease in B memory cells, B regulatory 1 CD19+/CD38+ and B regulatory 2 CD19+/CD25+, a significant increase in T regulatory CD4+/CD25+, a slight increase in T cytotoxic CD3+/CD8+ and a non-significant decrease in T helper CD3+/CD4+. Starting from week 24, the B subsets recovered; however, at week 48, CD19+/CD38+ and CD19+/CD25+ reached values near the baseline, while the Bmem were significantly lower. The T cell subsets remained unchanged except for CD4+/CD25+, which increased compared to W0. The LS changes were not predictive of NEDA achievement. The sNfL levels were significantly lower at week 24 (p = 0.046) vs. baseline. These results could demonstrate how cladribine, by inflammatory activity depletion, can also reduce axonal damage, according to the sNfL levels. [ABSTRACT FROM AUTHOR]

Background: Immunosuppressive properties grant mesenchymal stromal cells (MSCs) promising potential for treating autoimmune diseases. As autologous MSCs suffer from limited availability, the readily available allogeneic MSCs isolated from menstrual blood (MB-MSCs) donated by young, healthy individuals offer great potential. Here, we evaluate the therapeutic potential of MB-MSCs as ready-to-use allo-MSCs in multiple sclerosis, an autoimmune disease developed by the activation of myelin sheath-reactive Th1 and Th17 cells, by application in its animal model experimental autoimmune encephalomyelitis (EAE). Methods: We assessed the therapeutic effect of MB-MSCs transplanted via either intravenous (i.v.) or intraperitoneal (i.p.) route in EAE in comparison with umbilical cord-derived MSCs (UC-MSCs). We used histology to assess myelin sheath integrity and infiltrated immune cells in CNS and flow cytometry to evaluate EAE-associated inflammatory T cells and antigen-presenting cells in lymphoid organs. Results: We observed disease-ameliorating effects of MB-MSCs when transplanted at various stages of EAE (day − 1, 6, 10, and 19), via either i.v. or i.p. route, with a potency comparable to UC-MSCs. We observed reduced Th1 and Th17 cell responses in mice that had received MB-MSCs via either i.v. or i.p. injection. The repressed Th1 and Th17 cell responses were associated with a reduced frequency of plasmacytoid dendritic cells (pDCs) and a suppressed co-stimulatory capacity of pDCs, cDCs, and B cells. Conclusions: Our data demonstrate that the readily available MB-MSCs significantly reduced the disease severity of EAE upon transplantation. Thus, they have the potential to be developed as ready-to-use allo-MSCs in MS-related inflammation. [ABSTRACT FROM AUTHOR]

In recent years, several disease-modifying therapies have been developed for the treatment of multiple sclerosis (MS). Cladribine transiently depletes B and T lymphocytes, with subsequent gradual cell recovery. No cases are reported in literature describing Cladribine drug-induced liver injury (DILI). We describe the case of a 19-year-old woman who developed acute idiosyncratic liver injury 12 days after treatment with Cladribine. Post-marketing adverse event reporting is of paramount importance to allow an early recognition and treatment. Moreover, evaluation of the physiopathological mechanism underlying drug-induced hepatic toxicity can provide clinicians with valuable instruments for prevention and treatment. [ABSTRACT FROM AUTHOR]

Autologous hematopoietic stem cell transplantation (aHSCT) is a highly effective treatment of multiple sclerosis (MS). It depletes autoreactive cells and subsequently renews adaptive immune cells. The possible proinflammatory potential of surviving T cells early after aHSCT has not been studied. Here, we examined the dynamics of new and surviving T cells in 27 patients after aHSCT by multidimensional flow cytometry, T cell receptor (TCR) sequencing, specificity testing, telomere length profiling, and HLA genotyping. Early after aHSCT, naïve T cells are barely detectable, whereas effector memory (EM) T cells quickly reconstitute to pre-aHSCT values. EM CD4+ T cells early after aHSCT have shorter telomeres, have higher expression of senescence and exhaustion markers, and proliferate less than those before aHSCT. We find a median TCR repertoire overlap of 26% between the early post-aHSCT EM CD4+ T cells and pre-aHSCT, indicating persistence of EM CD4+ T cells early after transplantation. The EM CD4+ TCR repertoire overlap declines to 15% at 12 months after aHSCT, whereas the naïve TCR repertoire entirely renews. HLA-DR–associated EM CD4+ T cell reactivity toward MS-related antigens decreased after aHSCT, whereas reactivity toward EBV increased. Our data show substantial survival of pre-aHSCT EM CD4+ T cells early after transplantation but complete renewal of the T cell repertoire by nascent T cells later. Time for T cell renewal: Autologous hematopoietic stem cell transplantation (aHSCT) has shown great potential in subjects with multiple sclerosis (MS). Previous work showed a slow return of naïve T cells after aHSCT. However, the dynamics of new and surviving T cells after aHSCT remain to be elucidated. Here, Ruder et al. analyzed samples from patients with MS after aHSCT and showed that whereas effector memory T cells quickly reconstitute, naïve T cells show a slower complete renewal. In addition, the authors performed a complete characterization of the renewed T cell population. The results will provide a valuable resource for understanding the mechanisms mediating the efficacy of aHSCT in patients with MS. [ABSTRACT FROM AUTHOR]

Background: Multiple sclerosis (MS) is a chronic, debilitating condition characterized by CNS autoimmunity stemming from a complex etiology involving both environmental and genetic factors. Our current understanding of MS points to dysregulation of the immune system as the pathogenic culprit, however, it remains unknown as to how the many genes associated with increased susceptibility to MS are involved. One such gene linked to MS susceptibility and known to regulate immune function is the self-ligand immune cell receptor SLAMF7.Methods: We subjected WT and SLAMF7-/- mice to multiple EAE models, compared disease severity, and comprehensively profiled the CNS immune landscape of these mice. We identified all SLAMF7-expressing CNS immune cells and compared the entire CNS immune niche between genotypes. We performed deep phenotyping and in vitro functional studies of B and T cells via spectral cytometry and BioPlex assays. Adoptive transfer studies involving the transfer of WT and SLAMF7-/- B cells into B cell-deficient mice (μMT) were also performed. Finally, B-T cell co-culture studies were performed, and a comparative cell-cell interaction network derived from scRNA-seq data of SLAMF7+ vs. SLAMF7- human CSF immune cells was constructed.Results: We found SLAMF7-/- mice to be more susceptible to EAE compared to WT mice and found SLAMF7 to be expressed on numerous CNS immune cell subsets. Absence of SLAMF7 did not grossly alter the CNS immune landscape, but allowed for altered immune cell subset infiltration during EAE in a model-dependent manner. Global lack of SLAMF7 expression increased myeloid cell activation states along with augmented T cell anti-MOG immunity. B cell profiling studies revealed increased activation states of specific plasma and B cell subsets in SLAMF7-/- mice during EAE, and functional co-culture studies determined that SLAMF7-/- B cells induce exaggerated T cell activation. Adoptive transfer studies revealed that the increased susceptibility of SLAMF7-/- mice to EAE is partly B cell dependent and reconstruction of the human CSF SLAMF7-interactome found B cells to be critical to cell-cell communication between SLAMF7-expressing cells.Conclusions: Our studies have identified novel roles for SLAMF7 in CNS immune regulation and B cell function, and illuminate underpinnings of the genetic association between SLAMF7 and MS. [ABSTRACT FROM AUTHOR]

Serotonin (5-HT) is known as a potent immune cell modulator in autoimmune diseases and should be protective in the pathogenesis of multiple sclerosis (MS). Nevertheless, there is limited knowledge about receptors involved in 5-HT effects as well as induced mechanisms. Among 5-HT receptors, the 5-HT7 receptor is able to activate naïve T cells and influence the inflammatory response; however, its involvement in the disease has never been studied so far. In this study, we collected blood sample from three groups: acute relapsing MS patients (ARMS), natalizumab-treated MS patients (NTZ), and control subjects. We investigated the 5-HT7 expression on circulating lymphocytes and evaluated the effects of its activation on cytokine production with peripheral blood mononuclear cell (PBMC) cultures. We found a significant increase in the 5-HT7 surface expression on T lymphocytes and on the different CD4+ T cell subsets exclusively in NTZ-treated patients. We also showed that the selective agonist 5-carboxamidotryptamine (5-CT)-induced 5-HT7R activation significantly promotes the production of IL-10, a potent immunosuppressive cytokine in PBMCs. This study provides for the first time a dysregulation of 5-HT7 expression in NTZ-MS patients and its ability to promote IL-10 release, suggesting its protective role. These findings strengthen the evidence that 5-HT7 may play a role in the immuno-protective mechanisms of NTZ in MS disease and could be considered as an interesting therapeutic target in MS. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a highly prevalent demyelinating autoimmune condition; the mechanisms regulating its severity and progression are unclear. The IL-17-producing Th17 subset of T cells has been widely implicated in MS and in the mouse model, experimental autoimmune encephalomyelitis (EAE). However, the differentiation and regulation of Th17 cells during EAE remain incompletely understood. Although evidence is mounting that the antimicrobial peptide cathelicidin profoundly affects early T cell differentiation, no studies have looked at its role in longer-term T cell responses. Now, we report that cathelicidin drives severe EAE disease. It is released from neutrophils, microglia, and endothelial cells throughout disease; its interaction with T cells potentiates Th17 differentiation in lymph nodes and Th17 to exTh17 plasticity and IFN-γ production in the spinal cord. As a consequence, mice lacking cathelicidin are protected from severe EAE. In addition, we show that cathelicidin is produced by the same cell types in the active brain lesions in human MS disease. We propose that cathelicidin exposure results in highly activated, cytokine-producing T cells, which drive autoimmunity; this is a mechanism through which neutrophils amplify inflammation in the central nervous system. A study of role of the antimicrobial peptide cathelicidin in autoimmunity shows that it is expressed in lesions of patients with multiple sclerosis and in the spinal cords of mice with experimental autoimmune encephalomyelitis; cathelicidin exposure promotes T cell activation and differentiation, and strongly induces interferon-gamma production in the inflamed nervous system. [ABSTRACT FROM AUTHOR]

The composition of the intestinal microbiota plays a critical role in shaping the immune system. Modern lifestyle, the inappropriate use of antibiotics, and exposure to pollution have significantly affected the composition of commensal microorganisms. The intestinal microbiota has been shown to sustain inappropriate autoimmune responses at distant sites in animal models of disease, and may also have a role in immune-mediated central nervous system (CNS) diseases such as multiple sclerosis (MS). We studied the composition of the gut mycobiota in fecal samples from 27 persons with MS (pwMS) and in 18 healthy donors (HD), including 5 pairs of homozygous twins discordant for MS. We found a tendency towards higher fungal abundance and richness in the MS group, and we observed that MS twins showed a higher rate of food-associated strains, such as Saccharomyces cerevisiae. We then found that in pwMS, a distinct population of cells with antibacterial and antifungal activity is expanded during the remitting phase and markedly decreases during clinically and/or radiologically active disease. These cells, named MAIT (mucosal-associated invariant T cells) lymphocytes, were significantly more activated in pwMS compared to HD in response to S. cerevisiae and Candida albicans strains isolated from fecal samples. This activation was also mediated by fungal-induced IL-23 secretion by innate immune cells. Finally, immunofluorescent stainings of MS post-mortem brain tissues from persons with the secondary progressive form of the disease showed that MAIT cells cross the blood–brain barrier (BBB) and produce pro-inflammatory cytokines in the brain. These results were in agreement with the hypothesis that dysbiosis of the gut microbiota might determine the inappropriate response of a subset of pathogenic mucosal T cells and favor the development of systemic inflammatory and autoimmune diseases. [ABSTRACT FROM AUTHOR]

[Display omitted] In this paper, a series of artemisinin derivatives were synthesized and evaluated. Studies have shown that IFN-γ produced by Th1 CD4+ T cells and IL-17A secreted by Th17 CD4+ T cells played critical roles in the treatment of multiple sclerosis. We used different concentrations of artemisinin derivatives to inhibit Th1 / Th17 differentiation in naive CD4+ T cells and to characterize IFN-γ / IL-17A in in vitro experiments. The preliminary screening results showed that ester compound 5 exhibited obvious inhibitory activities on Th1 and Th17 (IFN-γ decreased from 41% to 3% and IL-17A decreased from 24% to 8% at the concentration of 10 nM to 10 μM), and carbamate compounds also had obvious inhibitory activities against Th17 at high concentration. Moreover, we investigated the effect of compound 5 on myelin oligodendrocyte glycoprotein (MOG)-induced mice experimental autoimmune encephalomyelitis (EAE) model in vivo. 100 mg/kg compound 5 effectively reduced the disease severity of EAE compared with the vehicle group. This research revealed that compound 5 could be a promising avenue as potential MS inhibitor. [ABSTRACT FROM AUTHOR]

Epstein-Barr virus (EBV) has been identified as a putative trigger of multiple sclerosis (MS). Previously, we reported that mice latently infected with murine gammaherpesvirus 68 (gHV-68), the murine homolog to EBV, and induced for experimental autoimmune encephalomyelitis (EAE), developed an enhanced disease more reminiscent of MS. These prior results showed that expression of CD40 on CD11b+CD11c+ cells in latently infected mice was required to prime the strong Th1 response driving disease as well as decreasing Treg frequencies in the periphery and CNS. Subsequent work demonstrated that transfer of B cells from latently infected mice was sufficient to enhance disease. Herein, we show that B cells from infected mice do not need type I IFN signaling to drive a strong Th1 response, yet are important in driving infiltration of the CNS by CD8+ T cells. Given the importance of type I IFNs in MS, we used IFNARko mice in order to determine if type I IFN signaling was important in the enhancement of EAE in latently infected mice. We found that while type I IFNs are important for the control of gHV-68 infection and maintenance of latency, they do not have a direct effect in the development of enhanced EAE. [ABSTRACT FROM AUTHOR]

Caspase-8 functions at the crossroad of programmed cell death and inflammation. Here, using genetic approaches and the experimental autoimmune encephalomyelitis model of inflammatory demyelination, we identified a negative regulatory pathway for caspase-8 in infiltrated macrophages whereby it functions to restrain interleukin (IL)-1β-driven autoimmune inflammation. Caspase-8 is partially activated in macrophages/microglia in active lesions of multiple sclerosis. Selective ablation of Casp8 in myeloid cells, but not microglia, exacerbated autoimmune demyelination. Heightened IL-1β production by caspase-8-deficient macrophages underlies exacerbated activation of encephalitogenic T cells and production of GM-CSF and interferon-γ. Mechanistically, IL-1β overproduction by primed caspase-8-deficient macrophages was mediated by RIPK1/RIPK3 through the engagement of NLRP3 inflammasome and was independent of cell death. When instructed by autoreactive CD4 T cells in the presence of antigen, caspase-8-deficient macrophages, but not their wild-type counterparts, released significant amount of IL-1β that in turn acted through IL-1R to amplify T cell activation. Moreover, the worsened experimental autoimmune encephalomyelitis progression in myeloid Casp8 mutant mice was completely reversed when Ripk3 was simultaneously deleted. Together, these data reveal a functional link between T cell-driven autoimmunity and inflammatory IL-1β that is negatively regulated by caspase-8, and suggest that dysregulation of the pathway may contribute to inflammatory autoimmune diseases, such as multiple sclerosis. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS), characterized by demyelinating neuropathy. The etiology of MS is not yet clear and its treatment remains a major medical challenge. While we search for drugs that can effectively treat experimental autoimmune encephalomyelitis (EAE), the animal model of MS, we also hope to further explore its possible pathogenesis. In the present study, we investigated whether methyl butyrate (MB) could alleviate EAE and its potential mechanisms. In EAE mice, we found that administration of MB was effective in alleviating their clinical signs and improving histopathological manifestations of the CNS. In the CNS and intestinal lamina propria, we observed fewer effector T cells, including Th1 and Th17, in the MB-treated group. MB also increased the proportion of regulatory T cells and the secretion of IL-10 in peripheral immune organs. In vitro, MB led to suppression of Th1 cells and promotion of regulatory T cells in their differentiation. Given that MB had no direct effect on Th17 cell differentiation in vitro, we hypothesized that MB suppressed Th17 cells indirectly by inhibiting the secretion of IL-6, which was later confirmed both in vitro and in vivo. In addition, we found that MB treatment upregulated Maf gene expression in mice, which explained its promotion of IL-10 secretion. The above findings suggest that MB may provide new ideas for the study of the mechanism of MS and have positive implications for new drug development. [ABSTRACT FROM AUTHOR]

In recent years, different studies have highlighted the importance of B cells in the pathophysiology of multiple sclerosis (MS): they secrete cytokines to modulate the inflammatory environment, present antigens for the activation of T lymphocytes, and they secrete antibodies contributing to the destruction of the myelin sheath. Combined, these findings have lead to new possible means for treating MS. In this review, we provide an up-to-date overview of the characteristics of ofatumumab (aka Kesimpta), and the differences between this drug and the other anti-CD20 monoclonal antibodies used to treat MS. The evolution of disease-modifying treatment algorithms in MS underlines the importance of starting treatment as soon as the diagnosis is defined, and with adequate 'treatment intensity.' Monoclonal antibodies and other aggressive treatments are now considered as an option at the clinical presentation of the disease, based to the prognostic profile emerging through clinical and paraclinical investigations. The recent adoption of new diagnostic criteria allows for the early diagnosis of MS. This, together with the availability of disease-modifying therapies (DMTs), such as ofatumumab, with a good efficacy/safety profile and which are easy to administer, could contribute to significant improvements in the long-term prognosis of MS. [ABSTRACT FROM AUTHOR]