Etiology Of Multiple Sclerosis Research Articles

Staphylococcus aureus is implicated in the etiology of multiple sclerosis

Staphylococcus aureus is implicated in the etiology of multiple sclerosis

Helicobacter pylori infection and disease severity in multiple sclerosis patients: Is there a link with HLA alleles?

Backgrounds: Environmental factors such as bacterial infections, as well as genetic factors—in particular the human leukocyte antigen (HLA) alleles—have been implicated in the etiology of multiple sclerosis (MS). This study aims to explore the relationship between Helicobacter pylori infection, HLA alleles, and disease severity in Iranian MS patients. Methods: The study population comprised 125 MS patients and 153 ethnically matched healthy controls. Stool antigen test was used to detect H. pylori, and the expanded disability status scale (EDSS) scores were assessed in the patients. HLA-DRB1 and DQB1 alleles and haplotypes were determined in both the patients and the controls. The relationships between H pylori infection, HLA alleles, and EDSS were also analyzed. Results: HLA-DRB1*15 and DQB1*06 alleles families and the DRB1*15~DQB1*06 haplotype were significantly more frequent in MS patients, whereas HLA-DRB1*14 and DRB1*14~DQB1*05 haplotype were less frequent. Of the 125 MS patients, 38 were diagnosed with active H. pylori infection. We found lower frequencies of HLA-DRB1*15 (P = .08) and DRB1*16 (P = .05) alleles and a higher frequency of DQB1*02 (P = .06) in the H. pylori-positive patients. HLA-DRB1*07 was more prevalent in patients with EDSS≤3.0 (P = .06). More severe MS cases (EDSS>3.0) were linked to H pylori positivity (P = .02), disease chronicity (P = .001), receiving non-steroidal anti-inflammatory drugs (P = .02), and female gender (P = .05). Conclusion: These preliminary findings suggest a link between H. pylori infection and the severity of MS H. pylori-positive patients regardless of the type of HLA carriage.

Macronutrients, vitamins and minerals in the diet of multiple sclerosis patients.

Multiple sclerosis (MS) is a chronic demyelinating disease of the central nervous system in which multifocal damage to the brain and spinal cord occurs. The etiology of MS remains unclear but it is often recognized by researchers as a multifactorial disease that involves autoimmune and genetic predisposition combined with environmental influences (e.g., low vitamin D levels, smoking, obesity). An adequate and balanced diet can be extremely helpful in improving the condition of MS patients, effectively supporting pharmacological therapy. The purpose of the study was to investigate whether, and if so, to what extent, the intake of macronutrients, vitamins, and microelements may affect the course of MS. The review presents data from studies published between 2017 and 2022. There are numerous studies on the role of specific dietary components in the treatment of MS, but the results are still limited. More work is needed to define the tools required for the assessment of patients' eating habits because dietary factors can affect the functioning and quality of life of MS patients and should therefore be evaluated to assist in comprehensive treatment and recovery.

Specific hypomethylation programs underpin B cell activation in early multiple sclerosis

Epigenetic changes have been consistently detected in different cell types in multiple sclerosis (MS). However, their contribution to MS pathogenesis remains poorly understood partly because of sample heterogeneity and limited coverage of array-based methods. To fill this gap, we conducted a comprehensive analysis of genome-wide DNA methylation patterns in four peripheral immune cell populations isolated from 29 MS patients at clinical disease onset and 24 healthy controls. We show that B cells from new-onset untreated MS cases display more significant methylation changes than other disease-implicated immune cell types, consisting of a global DNA hypomethylation signature. Importantly, 4,933 MS-associated differentially methylated regions in B cells were identified, and this epigenetic signature underlies specific genetic programs involved in B cell differentiation and activation. Integration of the methylome to changes in gene expression and susceptibility-associated regions further indicates that hypomethylated regions are significantly associated with the up-regulation of cell activation transcriptional programs. Altogether, these findings implicate aberrant B cell function in MS etiology.

Methyl Butyrate Alleviates Experimental Autoimmune Encephalomyelitis and Regulates the Balance of Effector T Cells and Regulatory T Cells.

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.

Molecular characterization of the gut microbiome in egyptian patients with remitting relapsing multiple sclerosis

BackgroundMultiple Sclerosis is the most common chronic demyelinating disease of the central nervous system, representing the main cause of non-traumatic disabling disorders in young adults. The etiology of Multiple Sclerosis is not fully appreciated, although strong evidence points to genetic and environmental factors. The role of the gut microbiome in Multiple Sclerosis pathogenesis is a rapidly emerging area of study in that field. AimThe aim of the present study is to identify the gut microbiome that are likely related to Multiple Sclerosis as well as their possible role in the susceptibility and the course of the disease. MethodsThirty Egyptian patients with relapsing remitting multiple sclerosis, who presented to the Multiple Sclerosis Clinic of Alexandria University Hospital were enrolled in the study. These were diagnosed according to the McDonald 2017 criteria. A cross matching control group of 20 healthy subjects of similar age and sex was included. Stool specimens were taken from each for detection of gut microbiome profile by quantitative SYBR Green Real Time PCR assay. ResultsThe present study demonstrate that RRMS patients have a distinct gut microbiome compared to healthy controls, with certain gut microbes showing decreased or increased abundance in Multiple Sclerosis patients compared to controls. Multiple Sclerosis patients have significantly higher B. fragilis than the normal control. Although the level of Prevotella, and Lactobacilli appear much less in MS patients than the control, the difference was not statistically significant. The same for C. perfringes which was higher in Multiple Sclerosis patients. ConclusionThe overall results of the study agree with previous studies reporting that patients with Multiple Sclerosis in Egypt exhibit microbial gut dysbiosis. However, the results of individual bacteria may differ, according to the age, treatment, level of physcial exercise and type of therapy at the time of enrollment.

Analysis of Micro-RNA-144 Expression Profile in Patients with Multiple Sclerosis in Comparison with Healthy Individuals.

Etiology of multiple sclerosis is non-clarified. It seems that environmental factors impact epigenetic in this disease. Micro-RNAs (MIR) as epigenetic factors are one of the most important factors in non-genetically neurodegenerative diseases. It has been found MIR-144 plays a main role in the regulation of many processes in the central nervous system. Here, we aimed to investigation of MIR-144 expression alteration in Multiple sclerosis (MS) patients. In this study 32 healthy and 32 MS patient's blood sample were analyzed by quantitative Real-Time PCR method and obtained data analyzed by REST 2009 software. Analysis of Real-Time PCR data revealed that miR-144 Increase significantly in MS patients compared to healthy controls. The increase of MIR-144 expression in MS patients is obvious. MIR-144 can be used as a biomarker of MS and help to early diagnosis and treatment of this disease.

Adipokines as Immune Cell Modulators in Multiple Sclerosis

Multiple sclerosis (MS), a chronic inflammatory and demyelinating disease of the central nervous system (CNS), is a major clinical and societal problem, which has a tremendous impact on the life of patients and their proxies. Current immunomodulatory and anti-inflammatory therapies prove to be relatively effective; however, they fail to concomitantly stop ongoing neurological deterioration and do not reverse acquired disability. The proportion to which genetic and environmental factors contribute to the etiology of MS is still incompletely understood; however, a recent association between MS etiology and obesity was shown, with obesity greatly increasing the risk of developing MS. An altered balance of adipokines, which are white adipose tissue (WAT) hormones, plays an important role in the low-grade chronic inflammation during obesity by their pervasive modification of local and systemic inflammation. Vice versa, inflammatory factors secreted by immune cells affect adipokine function. To explore the role of adipokines in MS pathology, we will here review the reciprocal effects of adipokines and immune cells and summarize alterations in adipokine levels in MS patient cohorts. Finally, we will discuss proof-of-concept studies demonstrating the therapeutic potential of adipokines to target both neuroinflammation and neurodegeneration processes in MS.

Correlation between vitamin D and lipid profile in multiple sclerosis patients

Abstract Background Studies have suggested that vitamin D and lipid profile have been linked to the etiology of multiple sclerosis and have an impact on the activity and progression of the disease. Objectives The aim of the present study was to determine correlation between vitamin D level and lipid profile in multiple sclerosis (MS) patients and their effect on disease activity and progression for better management and control of risk factors. Patients and Methods It is a cross-sectional hospital based study carried on clinically definite 111 Relapsing Remitting MS (RRMS) patients according to McDonald criteria 2010 recruited from Multiple sclerosis unit at Ain Shams University Hospitals, both genders included and aged from 18 to 50 years old. All subjects were assessed regarding their basic demographic data, serum vitamin D level and lipid profile and correlated these data with their state of disease activity and degree of disability. Results The mean level of serum vitamin D was 18.93 ± 9.85 ng/mL. Serum vitamin D level was insufficient (< 30 ng/mL) in 81.08% of patients and sufficient (≥ 30 ng/mL) in 18.92% of patients. The mean level of total cholesterol (TC) was 204.9 ± 50.9 mg/dL, of tri-glycerides (TG) was 105.4 ± 44.6 mg/dL, of low density lipoprotein (LDL) was 122.2 ± 38.8 mg/dL and of high density lipoprotein (HDL) level was 56.2 ± 16.6 mg/dL. High relapse frequency was found to be significantly related to low serum vitamin D level with P-value 0.005. Near all lipid related variables were positively correlated to disease duration. TC and TG were positively related to EDSS while HDL was negatively related with it. Number of brain T2 lesions was significantly correlated with TC and TG levels with P-value 0.001 and 0.002 respectively. Fingolimod was found to be associated with dyslipidemia. We found that each 1 ng/mL increase in vitamin D was associated with decrease in TC of 1.48 mg/dL (95% CI: -2.42 to -0.54, P-value 0.002) and increase in HDL of 0.35 mg/dL (95% CI: 0.04 to -0.66, P-value 0.028). Conclusion Vitamin D deficiency is predominant among Egyptian MS patients. Patients with insufficient vitamin D were found to have higher annualized relapse rate (ARR). Patients with dyslipidemia found to have longer duration, more disability and higher brain T2 lesion load. Vitamin D was correlated positively with HDL and negatively with TC.

Platelet Inhibition by Low-Dose Acetylsalicylic Acid Reduces Neuroinflammation in an Animal Model of Multiple Sclerosis.

Aside from the established immune-mediated etiology of multiple sclerosis (MS), compelling evidence implicates platelets as important players in disease pathogenesis. Specifically, numerous studies have highlighted that activated platelets promote the central nervous system (CNS)-directed adaptive immune response early in the disease course. Platelets, therefore, present a novel opportunity for modulating the neuroinflammatory process that characterizes MS. We hypothesized that the well-known antiplatelet agent acetylsalicylic acid (ASA) could inhibit neuroinflammation by affecting platelets if applied at low-dose and investigated its effect during experimental autoimmune encephalomyelitis (EAE) as a model to study MS. We found that oral administration of low-dose ASA alleviates symptoms of EAE accompanied by reduced inflammatory infiltrates and less extensive demyelination. Remarkably, the percentage of CNS-infiltrated CD4+ T cells, the major drivers of neuroinflammation, was decreased to 40.98 ± 3.28% in ASA-treated mice compared to 56.11 ± 1.46% in control animals at the disease maximum as revealed by flow cytometry. More interestingly, plasma levels of thromboxane A2 were decreased, while concentrations of platelet factor 4 and glycoprotein VI were not affected by low-dose ASA treatment. Overall, we demonstrate that low-dose ASA could ameliorate the platelet-dependent neuroinflammatory response in vivo, thus indicating a potential treatment approach for MS.

Low sun exposure acts synergistically with high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels in multiple sclerosis etiology.

Among multiple sclerosis (MS) patients, an association has been observed between low levels of vitamin D and high Epstein-Barr nuclear antigen 1 (EBNA-1) antibody levels. However, whether sun exposure/vitamin D moderates the role of Epstein-Barr virus (EBV) infection in MS etiology is unclear. We aimed to investigate potential synergistic effects between low sun exposure and elevated EBNA-1 antibody levels regarding MS risk. We used a population-based case-control study involving 2017 incident cases of MS and 2443 matched controls. We used logistic regression models to calculate the odds ratios of MS with 95% confidence intervals (CIs) in subjects with different sun exposure habits and EBNA-1 status. Potential interaction on the additive scale was evaluated by calculating the attributable proportion due to interaction (AP). Low sun exposure acted synergistically with high EBNA-1 antibody levels (AP 0.2, 95% CI 0.03-0.3) in its association to increased MS risk. The interaction was present regardless of HLA-DRB1*15:01status. Low sun exposure may either directly, or indirectly by affecting vitamin D levels, synergistically reinforce pathogenic mechanisms, such as aspects of the adaptive immune response, related to MS risk conveyed by EBV infection.

Widespread Disruptions of White Matter in Familial Multiple Sclerosis: DTI and NODDI Study.

Diffusion tensor imaging (DTI) is a noninvasive, quantitative MRI technique that measures white matter (WM) integrity. Many brain dimensions are heritable, including white matter integrity measured with DTI. Family studies are valuable to provide insights into the interactive effects of non-environmental factors on multiple sclerosis (MS). To examine the contribution of familial factors to the diffusion signals across WM microstructure, we performed DTI and calculated neurite orientation dispersion plus density imaging (NODDI) diffusion parameters in two patient groups comprising familial and sporadic forms of multiple sclerosis and their unaffected relatives. We divided 111 subjects (49 men and 62 women: age range 19–60) into three groups conforming to their MS history. The familial MS group included 30 participants (patients; n = 16, healthy relatives; n = 14). The sporadic group included 41 participants (patients; n = 10, healthy relatives; n = 31). Forty age-matched subjects with no history of MS in their families were defined as the control group. To study white matter integrity, two methods were employed: one for calculating the mean of DTI, FA, and MD parameters on 18 tracts using Tracts Constrained by Underlying Anatomy (TRACULA) and the other for whole brain voxel-based analysis using tract-based spatial statistics (TBSS) on NDI and ODI parameters derived from NODDI and DTI parameters. Voxel-based analysis showed considerable changes in FA, MD, NDI, and ODI in the familial group when compared with the control group, reflecting widespread impairment of white matter in this group. The analysis of 18 tracts with TRACULA revealed increased MD and FA reduction in more tracts (left and right ILF, UNC, and SLFT, forceps major and minor) in familial MS patients vs. the control group. There were no significant differences between the patient groups. We found no consequential changes in healthy relatives of both patient groups in voxel-based and tract analyses. Considering the multifactorial etiology of MS, familial studies are of great importance to clarify the effects of certain predisposing factors on demyelinating brain pathology.

K etiology of multiple sclerosis

There is currently no serious objection that multiple sclerosis is caused by an infection. According to Kuhn'y and Steiner'y, its causative agent is Spirochaeta argentinensis.

An integrative study of genetic variants with brain tissue expression identifies viral etiology and potential drug targets of multiple sclerosis

Multiple sclerosis (MS) is a neuroinflammatory disorder leading to chronic disability. Brain lesions in MS commonly arise in normal-appearing white matter (NAWM). Genome-wide association studies (GWAS) have identified genetic variants associated with MS. Transcriptome alterations have been observed in case-control studies of NAWM. We developed a Cross-Dataset Evaluation (CDE) function for our network-based tool, Edge-Weighted Dense Module Search of GWAS (EW_dmGWAS). We applied CDE to integrate publicly available MS GWAS summary statistics of 41,505 cases and controls with collectively 38 NAWM expression samples, using the human protein interactome as the reference network, to investigate biological underpinnings of MS etiology. We validated the resulting modules with colocalization of GWAS and expression quantitative trait loci (eQTL) signals, using GTEx Consortium expression data for MS-relevant tissues: 14 brain tissues and 4 immune-related tissues. Other network assessments included a drug target query and functional gene set enrichment analysis. CDE prioritized a MS NAWM network containing 55 unique genes. The gene list was enriched (p-value = 2.34 × 10−7) with GWAS-eQTL colocalized genes: CDK4, IFITM3, MAPK1, MAPK3, METTL12B and PIK3R2. The resultant network also included drug signatures of FDA-approved medications. Gene set enrichment analysis revealed the top functional term “intracellular transport of virus”, among other viral pathways. We prioritize critical genes from the resultant network: CDK4, IFITM3, MAPK1, MAPK3, METTL12B and PIK3R2. Enriched drug signatures suggest potential drug targets and drug repositioning strategies for MS. Finally, we propose mechanisms of potential MS viral onset, based on prioritized gene set and functional enrichment analysis.

Cytomegalovirus seropositivity is associated with reduced risk of multiple sclerosis-a presymptomatic case-control study.

Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) are associated with increased risk of multiple sclerosis (MS). Conversely, infection with cytomegalovirus (CMV) has been suggested to reduce the risk of MS but supporting data from presymptomatic studies are lacking. Here, it was sought to increase the understanding of CMV in MS aetiology. A nested case-control study was performed with presymptomatically collected blood samples identified through crosslinkage of MS registries and Swedish biobanks. Serological antibody response against CMV, EBV and HHV-6A was determined using a bead-based multiplex assay. Odds ratio (OR) with 95% confidence interval (CI) for CMV seropositivity as a risk factor for MS was calculated by conditional logistic regression and adjusted for EBV and HHV-6A seropositivity. Potential interactions on the additive scale were analysed by calculating the attributable proportion due to interaction (AP). Serum samples from 670 pairs of matched cases and controls were included. CMV seropositivity was associated with a reduced risk for MS (OR=0.70, 95% CI 0.56-0.88, p=0.003). Statistical interactions on the additive scale were observed between seronegativity for CMV and seropositivity against HHV-6A (AP 0.34, 95% CI 0.06-0.61) and EBV antigen EBNA-1 (amino acid 385-420) at age 20-39years (AP 0.37, 95% CI 0.09-0.65). Cytomegalovirus seropositivity is associated with a decreased risk for MS. The protective role for CMV infection in MS aetiology is further supported by the interactions between CMV seronegativity and EBV and HHV-6A seropositivity.

Association of miRNA and mRNA Levels of the Clinical Onset of Multiple Sclerosis Patients.

Simple SummaryIn this study, we investigated the effect of microRNAs on the expression level of neuroprotective proteins, heat shock proteins, and sirtuin in peripheral blood mononuclear cells in the development of multiple sclerosis. Our results show that the gene expression of neurotrophins, heat shock proteins, SIRT1, and miRNAs by the immune cells of MS is d changed. A decrease in the expression of the BDNF and SIRT1 genes and an increase in the expression of miR-132-3p, miR-34a, and miR-132 in PBMCs may indicate an inhibition of the neuroprotective function of these cells, which may be associated with the transition of the immune system towards inflammation in the development of multiple sclerosis.Multiple sclerosis (MS) is a demyelinating disease characterized by chronic inflammation of the central nervous system, in which many factors can act together to influence disease susceptibility and progression. To date, the exact cause of MS is still unclear, but it is believed to result from an abnormal response of the immune system to one or more myelin antigens that develops in genetically susceptible individuals after their exposure to a, as yet undefined, causal agent. In our study, we assessed the effect of microRNAs on the expression level of neuroprotective proteins, including neurotrophins (BDNF and NT4/5), heat shock proteins (HSP70 and HSP27), and sirtuin (SIRT1) in peripheral blood mononuclear cells in the development of multiple sclerosis. The analysis of dysregulation of miRNA levels and the resulting changes in target mRNA/protein expression levels could contribute to a better understanding of the etiology of multiple sclerosis, as well as new alternative methods of diagnosis and treatment of this disease. The aim of this study was to find a link between neurotrophins (BDNF and NT4), SIRT1, heat shock proteins (HSP27 and HSP27), and miRNAs that are involved in the development of multiple sclerosis. The analysis of the selected miRNAs showed a negative correlation of SIRT1 with miR-132 and miR-34a and of BDNF with 132-3p in PBMCs, which suggests that the miRNAs we selected may regulate the expression level of the studied genes.

Antipsychotic drugs counteract autophagy and mitophagy in multiple sclerosis

Multiple sclerosis (MS) is a neuroinflammatory and neurodegenerative disease characterized by myelin damage followed by axonal and ultimately neuronal loss. The etiology and physiopathology of MS are still elusive, and no fully effective therapy is yet available. We investigated the role in MS of autophagy (physiologically, a controlled intracellular pathway regulating the degradation of cellular components) and of mitophagy (a specific form of autophagy that removes dysfunctional mitochondria). We found that the levels of autophagy and mitophagy markers are significantly increased in the biofluids of MS patients during the active phase of the disease, indicating activation of these processes. In keeping with this idea, in vitro and in vivo MS models (induced by proinflammatory cytokines, lysolecithin, and cuprizone) are associated with strongly impaired mitochondrial activity, inducing a lactic acid metabolism and prompting an increase in the autophagic flux and in mitophagy. Multiple structurally and mechanistically unrelated inhibitors of autophagy improved myelin production and normalized axonal myelination, and two such inhibitors, the widely used antipsychotic drugs haloperidol and clozapine, also significantly improved cuprizone-induced motor impairment. These data suggest that autophagy has a causal role in MS; its inhibition strongly attenuates behavioral signs in an experimental model of the disease. Therefore, haloperidol and clozapine may represent additional therapeutic tools against MS.

Hormones in experimental autoimmune encephalomyelitis (EAE) animal models.

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS) in which activated immune cells attack the CNS and cause inflammation and demyelination. While the etiology of MS is still largely unknown, the interaction between hormones and the immune system plays a role in disease progression, but the mechanisms by which this occurs are incompletely understood. Several in vitro and in vivo experimental, but also clinical studies, have addressed the possible role of the endocrine system in susceptibility and severity of autoimmune diseases. Although there are several demyelinating models, experimental autoimmune encephalomyelitis (EAE) is the oldest and most commonly used model for MS in laboratory animals which enables researchers to translate their findings from EAE into human. Evidences imply that there is great heterogeneity in the susceptibility to the induction, the method of induction, and the response to various immunological or pharmacological interventions, which led to conflicting results on the role of specific hormones in the EAE model. In this review, we address the role of endocrine system in EAE model to provide a comprehensive view and a better understanding of the interactions between the endocrine and the immune systems in various models of EAE, to open up a ground for further detailed studies in this field by considering and comparing the results and models used in previous studies.

An Overview of Venous Abnormalities Related to the Development of Lesions in Multiple Sclerosis.

The etiology of multiple sclerosis (MS) is currently understood to be autoimmune. However, there is a long history and growing evidence for disrupted vasculature and flow within the disease pathology. A broad review of the literature related to vascular effects in MS revealed a suggestive role for abnormal flow in the medullary vein system. Evidence for venous involvement in multiple sclerosis dates back to the early pathological work by Charcot and Bourneville, in the mid-nineteenth century. Pioneering work by Adams in the 1980s demonstrated vasculitis within the walls of veins and venules proximal to active MS lesions. And more recently, magnetic resonance imaging (MRI) has been used to show manifestations of the central vein as a precursor to the development of new MS lesions, and high-resolution MRI using Ferumoxytol has been used to reveal the microvasculature that has previously only been demonstrated in cadaver brains. Both approaches may shed new light into the structural changes occurring in MS lesions. The material covered in this review shows that multiple pathophysiological events may occur sequentially, in parallel, or in a vicious circle which include: endothelial damage, venous collagenosis and fibrin deposition, loss of vessel compliance, venous hypertension, perfusion reduction followed by ischemia, medullary vein dilation and local vascular remodeling. We come to the conclusion that a potential source of MS lesions is due to locally disrupted flow which in turn leads to remodeling of the medullary veins followed by endothelial damage with the subsequent escape of glial cells, cytokines, etc. These ultimately lead to the cascade of inflammatory and demyelinating events which ensue in the course of the disease.

Illumination of Molecular Pathways in Multiple Sclerosis Lesions and the Immune Mechanism of Matrine Treatment in EAE, a Mouse Model of MS.

The etiology of multiple sclerosis (MS) is not clear, and the treatment of MS presents a great challenge. This study aimed to investigate the pathogenesis and potential therapeutic targets of MS and to define target genes of matrine, a quinolizidine alkaloid component derived from the root of Sophorae flavescens that effectively suppressed experimental autoimmune encephalomyelitis (EAE), an animal model of MS. To this end, the GSE108000 gene data set in the Gene Expression Omnibus Database, which included 7 chronic active MS lesions and 10 control samples of white matter, was analyzed for differentially expressed genes (DEGs). X cell was used to analyze the microenvironmental differences in brain tissue samples of MS patients, including 64 types of immune cells and stromal cells. The biological functions and enriched signaling pathways of DEGs were analyzed by multiple approaches, including GO, KEGG, GSEA, and GSVA. The results by X cell showed significantly increased numbers of immune cell populations in the MS lesions, with decreased erythrocytes, megakaryocytes, adipocytes, keratinocytes, endothelial cells, Th1 cells and Tregs. In GSE108000, there were 637 DEGs, including 428 up-regulated and 209 down-regulated genes. Potential target genes of matrine were then predicted by the network pharmacology method of Traditional Chinese medicine, and 12 key genes were obtained by cross analysis of the target genes of matrine and DEGs in MS lesions. Finally, we confirmed by RT-PCR the predicted expression of these genes in brain tissues of matrine-treated EAE mice. Among these genes, 2 were significantly downregulated and 6 upregulated by matrine treatment, and the significance of this gene regulation was further investigated. In conclusion, our study defined several possible matrine target genes, which can be further elucidated as mechanism(s) of matrine action, and novel targets in the treatment of MS.