Therapeutic Target In Multiple Sclerosis Research Articles

InVitro and In Vivo Investigation of S1PR1 Expression in the Central Nervous System Using [3H]CS1P1 and [11C]CS1P1.

Sphingosine-1-phosphate receptor 1 (S1PR1) is ubiquitously expressed among all tissues and plays key roles in many physiological and cellular processes. In the central nervous system (CNS), S1PR1 is expressed in different types of cells including neurons, astrocytes, and oligodendrocyte precursor cells. S1PR1 has been recognized as a novel therapeutic target in multiple sclerosis and other diseases. We previously reported a promising S1PR1-specific radioligand, [11C]CS1P1 (previously named [11C]TZ3321), which is under clinical investigation for human use. In the current study, we performed a detailed characterization of [3H]CS1P1 for its binding specificity to S1PR1 in CNS using autoradiography and immunohistochemistry in human and rat CNS tissues. Our data indicate that [3H]CS1P1 binds to S1PR1 in human frontal cortex tissue with a Kd of 3.98 nM and a Bmax of 172.5 nM. The distribution of [3H]CS1P1 in human and rat CNS tissues is consistent with the distribution of S1PR1 detected by immunohistochemistry studies. Our microPET studies of [11C]CS1P1 in a nonhuman primate (NHP) show a standardized uptake value of 2.4 in the NHP brain, with test-retest variability of 0.23% among six different NHPs. Radiometabolite analysis in the plasma samples of NHP and rat, as well as in rat brain samples, showed that [11C]CS1P1 was stable in vivo. Kinetic modeling studies using a two-compartment tissue model showed that the positron emission tomography (PET) data fit the model well. Overall, our study provides a detailed characterization of [3H]CS1P1 binding to S1PR1 in the CNS. Combined with our microPET studies in the NHP brain, our data suggest that [11C]CS1P1 is a promising radioligand for PET imaging of S1PR1 in the CNS.

Reviewing the Significance of Blood-Brain Barrier Disruption in Multiple Sclerosis Pathology and Treatment.

The disruption of blood–brain barrier (BBB) for multiple sclerosis (MS) pathogenesis has a double effect: early on during the onset of the immune attack and later for the CNS self-sustained ‘inside-out’ demyelination and neurodegeneration processes. This review presents the characteristics of BBB malfunction in MS but mostly highlights current developments regarding the impairment of the neurovascular unit (NVU) and the metabolic and mitochondrial dysfunctions of the BBB’s endothelial cells. The hypoxic hypothesis is largely studied and agreed upon recently in the pathologic processes in MS. Hypoxia in MS might be produced per se by the NVU malfunction or secondary to mitochondria dysfunction. We present three different but related terms that denominate the ongoing neurodegenerative process in progressive forms of MS that are indirectly related to BBB disruption: progression independent of relapses, no evidence of disease activity and smoldering demyelination or silent progression. Dimethyl fumarate (DMF), modulators of S1P receptor, cladribine and laquinimode are DMTs that are able to cross the BBB and exhibit beneficial direct effects in the CNS with very different mechanisms of action, providing hope that a combined therapy might be effective in treating MS. Detailed mechanisms of action of these DMTs are described and also illustrated in dedicated images. With increasing knowledge about the involvement of BBB in MS pathology, BBB might become a therapeutic target in MS not only to make it impenetrable against activated immune cells but also to allow molecules that have a neuroprotective effect in reaching the cell target inside the CNS.

PD-1/PD-L1 Axis as a Potential Therapeutic Target for Multiple Sclerosis: A T Cell Perspective.

The programmed cell death protein-1/programmed death ligand-1 (PD-1/PD-L1) axis is a widely studied immune checkpoint that modulates signaling pathways related to T cell activation. The use of PD-1/PD-L1 inhibitors is a promising immune therapy strategy for cancer patients. However, individuals treated with PD-1/PD-L1 inhibitors may develop immune-related adverse events due to excessive immune reactions. Multiple sclerosis (MS) is a chronic demyelinating and neurodegenerative disease of the central nervous system. T cells and the PD-1/PD-L1 axis play vital roles in the pathogenesis of MS. A better understanding of the complex relationship between the PD-1/PD-L1 axis and T cells may extend our knowledge of the molecular mechanisms and therapeutic approaches for MS. In this review, we summarize the most recent findings regarding the role of the PD-1/PD-L1 axis in MS and discuss the potential therapeutic strategies to modulate the expression of PD-1/PD-L1 in MS.

Immunosuppressive Amino-Acid Catabolizing Enzymes in Multiple Sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease that affects the central nervous system. Although the pathogenesis of MS is not yet fully elucidated, several evidences suggest that autoimmune processes mediated by Th1, Th17, and B cells play an important role in the development of the disease. Similar to other cells, immune cells need continuous access to amino acids (AA) in order to maintain basal metabolism and maintain vitality. When immune cells are activated by inflammation or antigenic signals, their demand for AA increases rapidly. Although AA deprivation itself may weaken the immune response under certain conditions, cells also have AA sensitive pathways that can activate intense alterations in cell metabolism based on changes in AA levels. Several data indicate that cells expressing enzymes that can degrade AA can regulate the functions of antigen-presenting cells and lymphocytes, revealing that the AA pathways are essential for controlling the function, and survival of immune cells, as well as immune cell gene expression. Basal AA catabolism may contribute to immune homeostasis and prevent autoimmunity, while increased AA catalytic activity may enhance immune suppression. In addition, there is increasing evidence that some downstream AA metabolites are important biological mediators of autoimmune response regulation. Two of the most important AA that modulate the immune response are L-Tryptophan (Trp) and L-Arginine (Arg). Tryptophan is catabolized through 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO) 1 and IDO2 enzymes, while three other enzymes catabolize Arg: inducible nitric oxide synthetase (iNOS), and two arginase isoforms (ARG1, ARG2). Genes encoding IDO, iNOS and ARG are induced by inflammatory cues such as cytokines, a key feature that distinguishes them from enzymes that catabolize other AA. Evidence suggests that AA catabolism is decreased in MS patients and that this decrease has functional consequences, increasing pro-inflammatory cytokines and decreasing Treg cell numbers. These effects are mediated by at least two distinct pathways involving serine/threonine kinases: the general control nonderepressible 2 kinase (GCN2K) pathway; and the mammalian target of rapamycin (mTOR) pathway. Similarly, IDO1-deficient mice showed exacerbation of experimental autoimmune encephalomyelitis (EAE), increased Th1 and Th17 cells, and decreased Treg cells. On the contrary, the administration of downstream Trp metabolite 3-HAA, inhibits Th1/Th17 effector cells and promotes Treg response by up-regulating TGF-β production by dendritic cells, thereby improving EAE. Collectively, these observations stand out the significance of AA catabolism in the regulation of the immune responses in MS patients. The molecules related to these pathways deserve further exploration as potential new therapeutic targets in MS

Cell type-specific transcriptomics identifies neddylation as a novel therapeutic target in multiple sclerosis.

Multiple sclerosis is an autoimmune disease of the CNS in which both genetic and environmental factors are involved. Genome-wide association studies revealed more than 200 risk loci, most of which harbour genes primarily expressed in immune cells. However, whether genetic differences are translated into cell-specific gene expression profiles and to what extent these are altered in patients with multiple sclerosis are still open questions in the field. To assess cell type-specific gene expression in a large cohort of patients with multiple sclerosis, we sequenced the whole transcriptome of fluorescence-activated cell sorted T cells (CD4+ and CD8+) and CD14+ monocytes from treatment-naive patients with multiple sclerosis (n = 106) and healthy subjects (n = 22). We identified 479 differentially expressed genes in CD4+ T cells, 435 in monocytes, and 54 in CD8+ T cells. Importantly, in CD4+ T cells, we discovered upregulated transcripts from the NAE1 gene, a critical subunit of the NEDD8 activating enzyme, which activates the neddylation pathway, a post-translational modification analogous to ubiquitination. Finally, we demonstrated that inhibition of NEDD8 activating enzyme using the specific inhibitor pevonedistat (MLN4924) significantly ameliorated disease severity in murine experimental autoimmune encephalomyelitis. Our findings provide novel insights into multiple sclerosis-associated gene regulation unravelling neddylation as a crucial pathway in multiple sclerosis pathogenesis with implications for the development of tailored disease-modifying agents.

The Microbiome as a Therapeutic Target for Multiple Sclerosis: Can Genetically Engineered Probiotics Treat the Disease?

There is an increasing interest in the intestinal microbiota as a critical regulator of the development and function of the immune, nervous, and endocrine systems. Experimental work in animal models has provided the foundation for clinical studies to investigate associations between microbiota composition and function and human disease, including multiple sclerosis (MS). Initial work done using an animal model of brain inflammation, experimental autoimmune encephalomyelitis (EAE), suggests the existence of a microbiota–gut–brain axis connection in the context of MS, and microbiome sequence analyses reveal increases and decreases of microbial taxa in MS intestines. In this review, we discuss the impact of the intestinal microbiota on the immune system and the role of the microbiome–gut–brain axis in the neuroinflammatory disease MS. We also discuss experimental evidence supporting the hypothesis that modulating the intestinal microbiota through genetically modified probiotics may provide immunomodulatory and protective effects as a novel therapeutic approach to treat this devastating disease.

Microglial Phagocytosis-Rational but Challenging Therapeutic Target in Multiple Sclerosis.

Multiple sclerosis (MS) is the most common autoimmune and demyelinating disease of the central nervous system (CNS), characterized, in the majority of cases, by initial relapses that later evolve into progressive neurodegeneration, severely impacting patients’ motor and cognitive functions. Despite the availability of immunomodulatory therapies effective to reduce relapse rate and slow disease progression, they all failed to restore CNS myelin that is necessary for MS full recovery. Microglia are the primary inflammatory cells present in MS lesions, therefore strongly contributing to demyelination and lesion extension. Thus, many microglial-based therapeutic strategies have been focused on the suppression of microglial pro-inflammatory phenotype and neurodegenerative state to reduce disease severity. On the other hand, the contribution of myelin phagocytosis advocating the neuroprotective role of microglia in MS has been less explored. Indeed, despite the presence of functional oligodendrocyte precursor cells (OPCs), within lesioned areas, MS plaques fail to remyelinate as a result of the over-accumulation of myelin-toxic debris that must be cleared away by microglia. Dysregulation of this process has been associated with the impaired neuronal recovery and deficient remyelination. In line with this, here we provide a comprehensive review of microglial myelin phagocytosis and its involvement in MS development and repair. Alongside, we discuss the potential of phagocytic-mediated therapeutic approaches and encourage their modulation as a novel and rational approach to ameliorate MS-associated pathology.

The Role of MicroRNAs in Repair Processes in Multiple Sclerosis.

Multiple sclerosis (MS) is an autoimmune disorder characterised by demyelination of central nervous system neurons with subsequent damage, cell death and disability. While mechanisms exist in the CNS to repair this damage, they are disrupted in MS and currently there are no treatments to address this deficit. In recent years, increasing attention has been paid to the influence of the small, non-coding RNA molecules, microRNAs (miRNAs), in autoimmune disorders, including MS. In this review, we examine the role of miRNAs in remyelination in the different cell types that contribute to MS. We focus on key miRNAs that have a central role in mediating the repair process, along with several more that play either secondary or inhibitory roles in one or more aspects. Finally, we consider the current state of miRNAs as therapeutic targets in MS, acknowledging current challenges and potential strategies to overcome them in developing effective novel therapeutics to enhance repair mechanisms in MS.

Interleukin‑1β attenuates the proliferation and differentiation of oligodendrocyte precursor cells through regulation of the microRNA‑202‑3p/β‑catenin/Gli1 axis.

The inflammatory cytokine interleukin (IL)‑1β has been implicated in demyelinating diseases, such as multiple sclerosis and experimental autoimmune encephalomyelitis, and brain degenerative diseases, such as Alzheimer's disease. However, the cellular and molecular mechanisms underlying the damaging effects of IL‑1β on myelination are poorly understood. Therefore, the present study was designed to investigate whether IL‑1β modifies the proliferation and differentiation of oligodendrocyte precursor cells (OPCs) through regulating the miR‑202‑3p/β‑catenin/glioma‑associated oncogene homolog 1 (Gli1) axis. It was observed that IL‑1β significantly attenuated the proliferation and differentiation of OPCs, as evidenced by a decrease in bromodeoxyuridine incorporation and reduced percentage of myelin basic protein‑positive cells among the total number of oligodendrocyte transcription factor 2‑positive cells. In addition, IL‑1β markedly decreased the expression of miR‑202‑3p and increased the protein expression of β‑catenin and Gli1, all of which were reversed by the IL‑1β inhibitor, IL‑1Ra. Treatment with the β‑catenin inhibitor XAV939, Gli1 siRNA, or miR‑202‑3p mimic transfection, attenuated the IL‑1β‑induced suppression of OPC proliferation and differentiation. Treatment with XAV939 decreased the expression of Gli1. Transfection of miR‑202‑3p mimic attenuated the expression of β‑catenin and Gli1. As demonstrated by the findings of the present study, IL‑1β suppressed the proliferation and differentiation of OPCs through regulation of the miR‑202‑3p/β‑catenin/Gli1 axis. Therefore, the miR‑202‑3p/β‑catenin/Gli1 axis may be of value as a therapeutic target in multiple sclerosis.

B Cell Maturation Antigen deficiency increases inflammatory B-cell functions in multiple sclerosis

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. Here, we identified that the expression of BCMA is dysregulated in B cells from MS patients and is important in inhibiting inflammatory B cell responses in EAE. We discovered that BCMA expression is decreased on transitional B cells in MS. In mice we found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+. The increased disease was associated with increased CNS inflammation, significantly reduced transitional B cells and a skewing of B-cells toward a mature/inflammatory phenotype. Bone marrow chimeric and in vitro experiments demonstrated that BCMA directly inhibits memory B cell expansion and anti-inflammatory cytokine production by B cells. Strikingly, BCMA impacts the efficacy of B cell depleting therapies, as anti-CD20 antibody treatment attenuated EAE in BCMA-deficient mice but not BCMA-sufficient mice. These data provide novel insights into B-cell dysregulation in MS.

MAFG-driven astrocytes promote CNS inflammation.

Multiple sclerosis is a chronic inflammatory disease of the CNS1. Astrocytes contribute to the pathogenesis of multiple sclerosis2, but little is known about the heterogeneity of astrocytes and its regulation. Here we report the analysis of astrocytes in multiple sclerosis and its preclinical model experimental autoimmune encephalomyelitis (EAE) by single-cell RNA sequencing in combination with cell-specific Ribotag RNA profiling, assay for transposase-accessible chromatin with sequencing (ATAC-seq), chromatin immunoprecipitation with sequencing (ChIP-seq), genome-wide analysis of DNA methylation and in vivo CRISPR-Cas9-based genetic perturbations. We identified astrocytes in EAE and multiple sclerosis that were characterized by decreased expression of NRF2 and increased expression of MAFG, which cooperates with MAT2α to promote DNA methylation and represses antioxidant and anti-inflammatory transcriptional programs. Granulocyte-macrophage colony-stimulating factor (GM-CSF) signalling in astrocytes drives the expression of MAFG and MAT2α and pro-inflammatory transcriptional modules, contributing to CNS pathology in EAE and, potentially, multiple sclerosis. Our results identify candidate therapeutic targets in multiple sclerosis.

Should mast cells be considered therapeutic targets in multiple sclerosis?

Mast cells are immune cells of the myeloid lineage that are found throughout the body, including the central nervous system. They perform many functions associated with innate and specific immunity, angiogenesis, and vascular homeostasis. Moreover, they have been implicated in a series of pathologies (e.g., hypersensitivity reactions, tumors, and inflammatory disorders). In this review, we propose that this cell could be a relevant therapeutic target in multiple sclerosis, which is a central nervous system degenerative disease. To support this proposition, we describe the general biological properties of mast cells, their contribution to innate and specific immunity, and the participation of mast cells in the various stages of multiple sclerosis and experimental autoimmune encephalomyelitis development. The final part of this review is dedicated to an overview of the available mast cells immunomodulatory drugs and their activity on multiple sclerosis and experimental autoimmune encephalomyelitis, including our own experience related to the effect of ketotifen fumarate on experimental autoimmune encephalomyelitis evolution.

Metabolic checkpoints in neurodegenerative T helper 17 (TH17) and neuroregenerative regulatory T (Treg) cells as new therapeutic targets for multiple sclerosis.

Metabolic checkpoints in neurodegenerative T helper 17 (TH17) and neuroregenerative regulatory T (Treg) cells as new therapeutic targets for multiple sclerosis.

Interferon-beta, but not Glatiramer Acetate treatment induces gender-specific increase in BDNF serum levels in relapsing-remitting multiple sclerosis female patients

Neuroprotection is considered a major therapeutic target in Multiple Sclerosis (MS), a chronic inflammatory demyelinating disease of the central nervous system (CNS). Accordingly, current disease modifying drugs (DMDs) for MS have been revaluated for their ability to stimulate production of neurotrophic factors that may provide support to neural cells against neurodegeneration. Brain-derived neurotrophic factor (BDNF) is considered the best candidate for such neuroprotective effects in MS. In the present study, we explored a potential effects of Glatiramer Acetate (GA), and Interferon-beta (IFN-b), the first two available treatments of MS, on circulating levels of BDNF considering the different BDNF forms. Using ELISA assays, we quantified mature and total BDNF in the serum of 20 relapsing-remitting MS (RR-MS) patients treated with GA and 31 with INF-beta compared with 20 age-matched RR-MS patients without any DMD. Mature BDNF but not total BDNF was significantly increased by treatment with IFN-b in female patients only, while GA had no effect. These results support a gender-specific role of BDNF in the treatment of RR-MS with INF-b. Of note, the present study was carried out with standardized ELISA assays which are commercially available and, prospectively, might be routinely used in the common clinical practice to monitor the individual response to the therapy with IFN-b.

Exogenous activation of tumor necrosis factor receptor 2 promotes recovery from sensory and motor disease in a model of multiple sclerosis

Tumor necrosis factor receptor 2 (TNFR2) is a transmembrane receptor that promotes immune modulation and tissue regeneration and is recognized as a potential therapeutic target for multiple sclerosis (MS). However, TNFR2 also contributes to T effector cell function and macrophage-TNFR2 recently was shown to promote disease development in the experimental autoimmune encephalomyelitis (EAE) model of MS. We here demonstrate that systemic administration of a TNFR2 agonist alleviates peripheral and central inflammation, and reduces demyelination and neurodegeneration, indicating that protective signals induced by TNFR2 exceed potential pathogenic TNFR2-dependent responses. Our behavioral data show that systemic treatment of female EAE mice with a TNFR2 agonist is therapeutic on motor symptoms and promotes long-term recovery from neuropathic pain. Mechanistically, our data indicate that TNFR2 agonist treatment follows a dual mode of action and promotes both suppression of CNS autoimmunity and remyelination. Strategies based on the concept of exogenous activation of TNFR2 therefore hold great promise as a new therapeutic approach to treat motor and sensory disease in MS as well as other inflammatory diseases or neuropathic pain conditions.

RGC-32 and diseases: the first 20years.

The response gene to complement (RGC)-32 acts as a cell cycle regulator and mediator of TGF-β effects. However, recent studies have revealed other functions for RGC-32 in diverse processes such as cellular migration, differentiation, and fibrosis. In addition to its induction by complement activation and the C5b-9 terminal complement complex, RGC-32 expression is also stimulated by growth factors, hormones, and cytokines. RGC-32 is induced by TGF-β through Smad3 and RhoA signaling and plays an important role in cell differentiation. In particular, RGC-32 is essential for the differentiation of Th17 cells. RGC-32-/- mice display an attenuated experimental autoimmune encephalomyelitis phenotype that is accompanied by decreased central nervous system inflammation and reductions in IL-17- and GM-CSF-producing CD4+ T cells. Accumulating evidence has drawn attention to the deregulated expression of RGC-32 in human cancers, atherogenesis, metabolic disorders, and autoimmune disease. Furthermore, RGC-32 is a potential therapeutic target in multiple sclerosis and other Th17-mediated autoimmune diseases. A better understanding of the mechanism(s) by which RGC-32 contributes to the pathogenesis of all these diseases will provide new insights into its therapeutic potential.

Efficacies of anti-CD20 antibody and Atacicept are differentially impacted by B Cell Maturation Antigen in neuro-autoimmunity

Abstract B cells have emerged as a therapeutic target for multiple sclerosis (MS). Depleting B cells with anti-CD20 antibodies are effective in treating MS. Yet, TACI-Ig treatment, which blocks BAFF and APRIL (two cytokines important for B cell development and function), paradoxically increased disease activity in MS patients. The stark differences in clinical outcomes with these therapies demonstrate that B cells have both inflammatory and regulatory effects in MS. B cell Maturation Antigen (BCMA), a receptor that binds BAFF and APRIL, plays a prominent role in B cell function. The role BCMA plays in MS remains enigmatic and therefore we explored the impact BCMA deficiency has on the development and progression of the experimental autoimmune encephalomyelitis (EAE), a rodent model of MS. We found that EAE induced with MOG35–55 was severe in BCMA−/− mice compared to BCMA+/+ mice. The increased disease was associated with increased CNS inflammation and a skewing of B-cells toward a mature/inflammatory phenotype. Also, for the first time, we observed that BCMA deficiency directly affects the infiltration of inflammatory myeloid cells during EAE. We found that anti-CD20 treatment significantly reduced EAE in BCMA−/− mice but had no effect on BCMA+/+ mice. Conversely, we found that TACI-Ig treatment had no effect on BCMA−/− mice but did reduce EAE in BCMA+/+ mice. Our study demonstrates that BAFF and APRIL constrain the development and function of inflammatory B-cells through BCMA. We further demonstrate that BCMA inhibits inflammatory B cell responses, yet promotes inflammatory responses in macrophages. Finally, our data provide clues into the paradoxical results of clinical trials with anti-CD20 and TACI-Ig in MS patients.

Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis

Regional differences in neurons, astrocytes, oligodendrocytes, and microglia exist in the brain during health, and regional differences in the transcriptome may occur for each cell type during neurodegeneration. Multiple sclerosis (MS) is multifocal, and regional differences in the astrocyte transcriptome occur in experimental autoimmune encephalomyelitis (EAE), an MS model. MS and EAE are characterized by inflammation, demyelination, and axonal damage, with minimal remyelination. Here, RNA-sequencing analysis of MS tissues from six brain regions suggested a focus on oligodendrocyte lineage cells (OLCs) in corpus callosum. Olig1-RiboTag mice were used to determine the translatome of OLCs in vivo in corpus callosum during the remyelination phase of a chronic cuprizone model with axonal damage. Cholesterol-synthesis gene pathways dominated as the top up-regulated pathways in OLCs during remyelination. In EAE, remyelination was induced with estrogen receptor-β (ERβ) ligand treatment, and up-regulation of cholesterol-synthesis gene expression was again observed in OLCs. ERβ-ligand treatment in the cuprizone model further increased cholesterol synthesis gene expression and enhanced remyelination. Conditional KOs of ERβ in OLCs demonstrated that increased cholesterol-synthesis gene expression in OLCs was mediated by direct effects in both models. To address this direct effect, ChIP assays showed binding of ERβ to the putative estrogen-response element of a key cholesterol-synthesis gene (Fdps). As fetal OLCs are exposed in utero to high levels of estrogens in maternal blood, we discuss how remyelinating properties of estrogen treatment in adults during injury may recapitulate normal developmental myelination through targeting cholesterol homeostasis in OLCs.

Integrative analysis of OIP5-AS1/HUR1 to discover new potential biomarkers and therapeutic targets in multiple sclerosis.

Multiple sclerosis (MS) is a devastating autoimmune disease of the central nervous system associated with demyelination and axonal injury. This study was designed to find potential lncRNAs and their targets that are associated with the molecular basis of MS pathogenesis. In this study, peripheral blood samples were obtained from 50 relapsing-remitting MS (RR-MS) patients and 50 healthy controls. lncRNAs and their target were selected for validation using TaqMan Real-Time PCR. Interactions were studied based on approaches that used to investigation biological functions and signaling pathways affected by differentially expressed messenger RNAs (mRNAs). The results of this study indicate an increase in the expression of HUR1 (p = 0.0001), CPSF7 (p = 0.02), and reduction of CSTF2 expression (p = 0.04). Also, an increase in the expression of OIP5-AS1 (p = 0.01) was observed in men less than 30 years old. We performed a comparative analysis of the long noncoding RNAs (lncRNAs), and then we ranked them as candidate biomarkers according to a decreasing area under the receiver operating characteristic (ROC) curve (AUC) and plotted the results. Dysregulation of lncRNA expression has been linked to diseases. Further studies on the HUR1 gene can be used as diagnostic tools for the identification of high-risk individuals in families with a history of disease before, during, and even after treatment. Our data uncovered the expression profiles of lncRNAs and mRNAs in MS patients, which will help delineate the molecular mechanisms in MS pathogenesis. However, further studies need to determine the precise role of these genes in the pathological process in MS.

Serotonergic system as a therapeutic target in multiple sclerosis

The article presents the current literature on the role of serotonin in immunomodulation in multiple sclerosis, in particular, on the effect of serotonin on Th17-immune response and function of dendritic cells. The role of serotonin in the regulation of the gut-brain axis and the prospects for serotoninergic drugs as pathogenetic therapy in multiple sclerosis are discussed.