Multiple Sclerosis Susceptibility Research Articles

Genetics of immune response to Epstein-Barr virus: prospects for multiple sclerosis pathogenesis.

Epstein-Barr virus (EBV) infection has been advocated as a prerequisite for developing multiple sclerosis (MS) and possibly the propagation of the disease. However, the precise mechanisms for such influences are still unclear. A large-scale study investigating the host genetics of EBV serology and related clinical manifestations, such as infectious mononucleosis (IM), may help us better understand the role of EBV in MS pathogenesis. This study evaluates the host genetic factors that influence serological response against EBV and history of IM and cross-evaluates them with MS risk and genetic susceptibility in the Swedish population. Plasma IgG antibody levels against EBV nuclear antigen-1 (EBNA-1, truncated=aa[325-641], peptide=aa[385-420]) and viral capsid antigen p18 (VCAp18) were measured using bead-based multiplex serology for 8744 MS cases and 7229 population-matched controls. The MS risk association for high/low EBV antibody levels and history of IM was compared to relevant clinical measures along with sex, age at sampling, and associated HLA allele variants. Genome-wide and HLA allele association analyses were also performed to identify genetic risk factors for EBV antibody response and IM history. Higher antibody levels against VCAp18 (OR=1.74, 95% CI=1.60-1.88) and EBNA-1, particularly the peptide (OR=3.13, 95% CI=2.93-3.35), were associated with an increased risk for MS. The risk increased with higher anti-EBNA-1 IgG levels up to twelve times the reference risk. We also identified several independent HLA haplotypes associated with EBV serology overlapping with known MS risk alleles (e.g., DRB1*15:01). Although there were several candidates, no variants outside the HLA region reached genome-wide significance. Cumulative HLA risk for anti-EBNA-1 IgG levels, particularly the peptide fragment, was strongly associated with MS. In contrast, the genetic risk for high anti-VCAp18 IgG levels was not as strongly associated with MS risk. IM history was not associated with class II HLA genes but negatively associated with A*02:01, which is protective against MS. Our findings emphasize that the risk association between anti-EBNA-1 IgG levels and MS may be partly due to overlapping HLA associations. Additionally, the increasing MS risk with increasing anti-EBNA-1 levels would be consistent with a pathogenic role of the EBNA-1 immune response, perhaps through molecular mimicry. Given that high anti-EBNA-1 antibodies may reflect a poorly controlled T-cell defense against the virus, our findings would be consistent with DRB1*15:01 being a poor class II antigen in the immune defense against EBV. Lastly, the difference in genetic control of IM supports the independent roles of EBNA-1 and IM in MS susceptibility.

Relationship between vitamin D receptor genotypes (FOK1rs2228570) and IL18 gene expression in sample of multiple sclerosis Iraqi patients

BACKGROUND: Multiple Sclerosis known as MS, this chronic inflammatory demyelinating condition affects the nervous system. It is a heterogenic and multifactorial disease. The goal of the current study was to investigate the relationship between MS patients’ IL18 gene expression and the vitamin D receptor gene polymorphism (FOK1rs2228570). OBJECTIVE: The aim of the study to investigate the association of vitamin D receptor (FOK1rs2228570) gene polymorphism and pro inflammatory cytokine (IL18) gene expression among multiple sclerosis Iraqi patients. Detection VDR polymorphism and determine whether this SNP is involved in susceptibility to multiple sclerosis and estimation IL18 gene expression and explore its relation with multiple sclerosis susceptibility. METHODS: Blood samples were taken from 75 MS patients in Iraq (30 men and 45 women), as well as from 75 volunteers who seemed to be in a favorable state of health and fell within the age range of 20 to 50 years. Tetra-ARMS Polymerase Chain Reaction (Tetra-ARMS PCR) was used to find polymorphisms in the vitamin D receptor (VDR) gene, and Real-time Polymerase Chain Reaction (RT-PCR) was used to measure IL18 gene expression. RESULTS: The findings from the analysis of VDR gene polymorphism in patients with MS indicated that the wild-type genotype T/T was present in 8 individuals, accounting for 10.6%, the heterogeneous genotype TC was 36 (48%), and the homogeneous genotype CC was 31 (41.3%), whilst T allele frequency was 52(34.6%) and C allele was 98(65.3%) with (P⩽ 0.01) significant difference and even as in control T/T genotype was 49(65.3%), TC genotype was 21(28%), CC genotype was 5(6.66%), T allele frequency was 119(79.3%) and C allele was 31(20.6%) with significant difference (P⩽ 0.001). While estimation of IL18 expression showed high elevation in patients’ group (2.59 ± 0.51 fold) by significance difference (P⩽ 0.5) when compared to control group (1.35 ± 0.14 fold). The relationship between IL18 gene expression with VDR variant in MS patients demonstrated a significant rise (2.9 ± 0.51 fold) at CC genotype patients in IL18 folding gene expression, followed by (4.6 ± 0.17 fold) in TC genotype patients and finally (1.4 ± 0.08 fold) in TT genotype patients with highly significant (P⩽ 0.01). CONCLUSION: The VDR(FOK1rs2228570) genotype was significantly correlated with IL18 expression in MS patients from Iraq.

Investigating the role of VDR gene variants in multiple sclerosis susceptibility: a case–control study in Egypt

BackgroundMultiple sclerosis (MS) is a chronic inflammatory disorder. Vitamin D has a major role in preventing inflammatory disorders as well as its role in the pathophysiology of MS. Vitamin D initiates its biological responses by binding to the nuclear vitamin D receptor (VDR). Several studies have been conducted over the last decade to investigate the relationship between VDR gene variants and the risk of MS, but the results have been inconsistent and inconclusive. The objective of this study is to investigate the association between the VDR gene variants (c.1025-49C>A) and (c.1056A>G) and MS susceptibility in a sample of the Egyptian population, and to shed light on its potential role in preventing inflammatory disorders and its impact on clinical outcomes and treatment using TaqMan Real-Time Polymerase Chain Reaction (PCR). This case-control study was conducted on 100 participants, categorized into two groups. The first group included 50 patients diagnosed with relapsing-remitting multiple sclerosis (RRMS) based on the Revised McDonald MS criteria, and the second group included 50 matched healthy participants. After collecting the blood samples, deoxyribonucleic acid (DNA) was extracted and detection of the VDR: c.1025-49C>A and VDR: c.1056A>G gene variants was done using TaqMan Real-Time PCR on all involved individuals.ResultsThe distribution of the genotypes and alleles of VDR gene variants (c.1025- 49C>A) and (c.1056A>G) did not differ significantly between MS patients and healthy participants (P>0.05 in both). ConclusionHere we show in this study that there was no association between the risk of MS and the VDR gene variants (c.1025-49C>A) and (c.1056A>G) in a group of the Egyptian population which may have impact on MS therapy and outcome.

HLA-DRB1*15:01 and the MERTK Gene Interact to Selectively Influence the Profile of MERTK-Expressing Monocytes in Both Health and MS.

HLA-DRB1*15:01 (DR15) and MERTK are 2 risk genes for multiple sclerosis (MS). The variant rs7422195 is an expression quantitative trait locus for MERTK in CD14+ monocytes; cells with phagocytic and immunomodulatory potential. We aimed to understand how drivers of disease risk and pathogenesis vary with HLA and MERTK genotype and disease activity. We investigated how proportions of monocytes vary with HLA and MERTK genotype and disease activity in MS. CD14+ monocytes were isolated from patients with MS at relapse (n = 40) and 3 months later (n = 23). Healthy controls (HCs) underwent 2 blood collections 3 months apart. Immunophenotypic profiling of monocytes was performed by flow cytometry. Methylation of 35 CpG sites within and near the MERTK gene was assessed in whole blood samples of individuals experiencing their first episode of clinical CNS demyelination (n = 204) and matched HCs (n = 345) using an Illumina EPIC array. DR15-positive patients had lower proportions of CD14+ MERTK+ monocytes than DR15-negative patients, independent of genotype at the MERTK SNP rs7422195. Proportions of CD14+ MERTK+ monocytes were further reduced during relapse in DR15-positive but not DR15-negative patients. Patients homozygous for the major G allele at rs7422195 exhibited higher proportions of CD14+ MERTK+ monocytes at both relapse and remission compared with controls. We observed that increased methylation of the MERTK gene was significantly associated with the presence of DR15. DR15 and MERTK genotype independently influence proportions of CD14+ MERTK+ monocytes in MS. We confirmed previous observations that the MERTK risk SNP rs7422195 is associated with altered MERTK expression in monocytes. We identified that expression of MERTK is stratified by disease in people homozygous for the major G allele of rs7422195. The finding that the proportion of CD14+ MERTK+ monocytes is reduced in DR15-positive individuals supports prior data identifying genetic links between these 2 loci in influencing MS risk. DR15 genotype-dependent alterations in methylation of the MERTK gene provides a molecular link between these loci and identifies a potential mechanism by which MERTK expression is influenced by DR15. This links DR15 haplotype to MS susceptibility beyond direct influence on antigen presentation and suggests the need for HLA-based stratification of approaches to MERTK as a therapeutic target.

Exploring the association between weight loss-inducing medications and multiple sclerosis: insights from the FDA adverse event reporting system database.

Several studies have demonstrated that early childhood and adolescent obesity are risk factors for multiple sclerosis (MS) susceptibility. Obesity is thought to share inflammatory components with MS through overproduction of pro-inflammatory adipokines (e.g., leptin) and reduction of anti-inflammatory adipokines (e.g, adiponectin). Recently, drug repurposing (i.e. identifying new indications for existing drugs) has garnered significant attention. The US Food and Drug Administration Adverse Event Reporting System (FAERS) database serves not only as a resource for mining adverse drug reactions and safety signals but also for identifying inverse associations and potential medication repurposing opportunities. We aimed to explore the association between weight-loss-inducing drugs and MS using real-world reports from the FAERS database. Secondary analysis of existing data from the FAERS database. We conducted a disproportionality analysis using the FAERS database between the fourth quarter of 2003 and the second quarter of 2023 to explore associations between MS and weight loss-inducing drugs. Disproportionality was quantified using the reporting odds ratio (ROR). An inverse association was defined when the upper limit of the 95% confidence interval for ROR was <1. We found an inverse association between MS and anti-diabetic weight loss-inducing drugs including semaglutide (ROR: 0.238; 95% CI: 0.132-0.429), dulaglutide (ROR: 0.165; 95% CI: 0.109-0.248), liraglutide (ROR: 0.161; 95% CI: 0.091-0.284), empagliflozin (ROR: 0.234; 95% CI: 0.146-0.377), and metformin (ROR: 0.387; 95% CI: 0.340-0.440). No inverse associations were found for other weight loss-inducing drugs such as phentermine, bupropion, topiramate, zonisamide, and amphetamine. An exception was naltrexone (ROR: 0.556; 95% CI: 0.384-0.806). Our findings suggest a potential consideration for repurposing anti-diabetic weight loss-inducing drugs including semaglutide, dulaglutide, and liraglutide (glucagon-like peptide-1 receptor agonists), empagliflozin (sodium-glucose cotransporter-2 inhibitor), and metformin (biguanide), for MS. This warrants validation through rigorous methodologies and prospective studies.

Multiple sclerosis susceptibility may be associated with the coding rs20541 (R130Q) IL-13 gene polymorphism in the Polish population

Some of the multiple autoimmune diseases have been already associated with IL-13 single-nucleotide polymorphisms (SNPs). However, there are only few studies regarding multiple sclerosis (MS) risk and IL-13 rs20541 (R130Q) polymorphism, and their results are conflicting. Therefore, the aim of our study was to investigate the frequency of the IL-13 gene rs20541 (R130Q) polymorphism in MS participants and its association with MS clinical subsets in the Polish population. We conducted a case‒control study including 94 relapsing remitting MS patients and 160 healthy volunteers. We genotyped the rs20541 polymorphism in the IL-13 gene and analysed the genotype frequency, age of MS onset and clinical condition (EDSS values) of the MS participants. Fisher’s exact test was used for statistical analysis, and the log-linear model was applied to test for associations. Allele A, as well as the AA and AG genotypes, was observed to be significantly more common in the MS subjects. The OR (odds ratio) for the A compared to the G allele was 1.71 (1.14–2.56), whereas OR 2.33 (0.86–6.26) and OR 1.92 (1.11–3.30) were obtained for the AA and AG genotypes, respectively. We did not identify any significant associations of the studied IL-13 SNP with the investigated clinical parameters of the MS participants. Our results suggest that the rs20541 polymorphism in the IL-13 gene may play an important role in MS predisposition but not in investigated clinical parameters in MS subjects of the Polish population.

High-resolution DNA methylation screening of the major histocompatibility complex in multiple sclerosis.

The HLA-DRB1 gene in the major histocompatibility complex (MHC) region in chromosome 6p21 is the strongest genetic factor identified as influencing multiple sclerosis (MS) susceptibility. DNA methylation changes associated with MS have been consistently detected at the MHC region. However, understanding the full scope of epigenetic regulations of the MHC remains incomplete, due in part to the limited coverage of this region by standard whole genome bisulfite sequencing or array-based methods. We developed and validated an MHC capture protocol coupled with bisulfite sequencing and conducted a comprehensive analysis of the MHC methylation landscape in blood samples from 147 treatment naïve MS study participants and 129 healthy controls. We identified 132 differentially methylated region (DMRs) within MHC region associated with disease status. The DMRs overlapped with established MS risk loci. Integration of the MHC methylome with human leukocyte antigen (HLA) genetic data indicate that the methylation changes are significantly associated with HLA genotypes. Using DNA methylation quantitative trait loci (mQTL) mapping and the causal inference test (CIT), we identified 643 cis-mQTL-DMRs paired associations, including 71 DMRs possibly mediating causal relationships between 55 single nucleotide polymorphisms (SNPs) and MS risk. The results describe MS-associated methylation changes in MHC region and highlight the association between HLA genotypes and methylation changes. Results from the mQTL and CIT analyses provide evidence linking MHC region variations, methylation changes, and disease risk for MS.

Expression profiling of cerebrospinal fluid identifies dysregulated antiviral mechanisms in multiple sclerosis.

Despite the overwhelming evidence that multiple sclerosis is an autoimmune disease, relatively little is known about the precise nature of the immune dysregulation underlying the development of the disease. Reasoning that the CSF from patients might be enriched for cells relevant in pathogenesis, we have completed a high-resolution single-cell analysis of 96 732 CSF cells collected from 33 patients with multiple sclerosis (n = 48 675) and 48 patients with other neurological diseases (n = 48 057). Completing comprehensive cell type annotation, we identified a rare population of CD8+ T cells, characterized by the upregulation of inhibitory receptors, increased in patients with multiple sclerosis. Applying a Multi-Omics Factor Analysis to these single-cell data further revealed that activity in pathways responsible for controlling inflammatory and type 1 interferon responses are altered in multiple sclerosis in both T cells and myeloid cells. We also undertook a systematic search for expression quantitative trait loci in the CSF cells. Of particular interest were two expression quantitative trait loci in CD8+ T cells that were fine mapped to multiple sclerosis susceptibility variants in the viral control genes ZC3HAV1 (rs10271373) and IFITM2 (rs1059091). Further analysis suggests that these associations likely reflect genetic effects on RNA splicing and cell-type specific gene expression respectively. Collectively, our study suggests that alterations in viral control mechanisms might be important in the development of multiple sclerosis.

Causal Relationships between Immune-Mediated Inflammatory Diseases and Hodgkin's Lymphoma: A Mendelian Randomization Study

Introduction: Immune-mediated inflammatory diseases (IMIDs) constitute a clinically heterogeneous group with a disruption of the immune system that provokes inflammation of any organ system on a chronic basis. Previous observational investigations have demonstrated an association between a person's or their family's medical background of IMIDs and a higher likelihood of developing Hodgkin's lymphoma (HL). Nevertheless, the exact causal connection between specific IMIDs and HL remains ambiguous. Therefore, the investigation aims to explore the causal effects between IMIDs and HL. Methods: A two-sample Mendelian randomization (TSMR) approach was employed in this study, using publicly available genome-wide association study summary statistics. The inverse variance weighted (IVW) method was the primary approach used for the Mendelian randomization (MR) analysis. Furthermore, supplementary statistical approaches such as MR-Egger, simple mode, weighted median, and MR-PRESSO were employed. In order to identify potential heterogeneity and pleiotropy, several tests were conducted, including Cochran's Q test, the MR-Egger regression test, and the MR-PRESSO test. Moreover, the leave-one-out method was implemented to examine the reliability of the MR results. Results: Based on the IVW analysis the findings revealed a positive causal link at risk for multiple sclerosis (MS) and HL [odds ratio (OR) = 1.281; 95% CI = 1.087-1.510, p = 0. 003] and a negative causal link at risk for type 1 diabetes (T1D) and HL (OR = 0.853; 95% CI = 0.776-0.937, p = 0.001). However, no significant causal relationship was found between the risk of HL and the other eight IMIDs, including inflammatory bowel diseases (OR = 1.034; 95%CI = 0.910-1.176, p = 0.606), systemic lupus erythematosus (OR = 1.041; 95%CI = 0.944-1.149, p = 0.422), Crohn's disease (OR = 0.952; 95%CI = 1.840-1.078, p = 0.436), ulcerative colitis (OR = 1.042; 95%CI = 0.874-1.242, p = 0.644), primary sclerosing cholangitis (OR = 1.061; 95%CI = 0.937-1.202, p = 0.349), primary biliary cirrhosis (OR = 1.046; 95%CI = 0.918-1.192, p = 0.495), psoriasis (OR = 0.989; 95%CI = 0.954-1.026, p = 0.565), celiac disease (OR = 1.198; 95%CI = 0.911-1.574, p = 0.195). Figure 1 displayed a detailed visual representation of the findings obtained in the study. No indication was made of any potential heterogeneity or horizontal pleiotropy. Besides, no outliers were discovered in the MR using MR-PRESSO. In addition, the leave-one-out analysis indicates that the MR estimates are not driven by any single SNP, suggesting that the observed associations are robust and reliable. Conclusions: The present investigation emphasizes an increased susceptibility of MS to the risk of HL and a potential protective effect of T1D against the risk of HL. In light of these findings, patients with MS receiving immunosuppressive therapy are highly suggested to undergo periodic physical evaluations and lymphoma surveillance. Further investigations are warranted to explore the potential mechanisms of MS and T1D on the development of HL.

Smoking affects epigenetic ageing of lung bronchoalveolar lavage cells in Multiple Sclerosis.

A compelling body of evidence implicates cigarette smoking and lung inflammation in Multiple Sclerosis (MS) susceptibility and progression. Previous studies have reported epigenetic age (DNAm age) acceleration in blood immune cells and in glial cells of people with MS (pwMS) compared to healthy controls (HC). We aimed to examine biological ageing in lung immune cells in the context of MS and smoking. We analyzed age acceleration residuals in lung bronchoalveolar lavage (BAL) cells, constituted of mainly alveolar macrophages, from 17 pwMS and 22 HC in relation to smoking using eight DNA methylation-based clocks, namely AltumAge, Horvath, GrimAge, PhenoAge, Zhang, SkinBlood, Hannum, Monocyte clock as well as two RNA-based clocks, which capture different aspects of biological ageing. After adjustment for covariates, five epigenetic clocks showed significant differences between the groups. Four of them, Horvath (Padj=0.028), GrimAge (Padj=4.28×10-7), SkinBlood (Padj=0.001) and Zhang (Padj=0.02), uncovered the sole effect of smoking on ageing estimates, irrespective of the clinical group. The Horvath, SkinBlood and Zhang clocks showed a negative impact of smoking while GrimAge detected smoking-associated age acceleration in BAL cells. On the contrary, the AltumAge clock revealed differences between pwMS and HC and indicated that, in the absence of smoking, BAL cells of pwMS were epigenetically 5.4 years older compared to HC (Padj=0.028). Smoking further affected epigenetic ageing in BAL cells of pwMS specifically as non-smoking pwMS exhibited a 10.2-year AltumAge acceleration compared to pwMS smokers (Padj=0.0049). Of note, blood-derived monocytes did not show any MS-specific or smoking-related AltumAge differences. The difference between BAL cells of pwMS smokers and non-smokers was attributable to the differential methylation of 114 AltumAge-CpGs (Padj<0.05) affecting genes involved in innate immune processes such as cytokine production, defense response and cell motility. These changes functionally translated into transcriptional differences in BAL cells between pwMS smokers and non-smokers. BAL cells of pwMS display inflammation-related and smoking-dependent changes associated to epigenetic ageing captured by the AltumAge clock. Future studies examining potential confounders, such as the distribution of distinct BAL myeloid cell types in pwMS compared to control individuals in relation to smoking may clarify the varying performance and DNAm age estimations among epigenetic clocks.

Could NCOA5 a novel candidate gene for multiple sclerosis susceptibility?

Multiple sclerosis (MS) is an inflammatory immune-mediated demyelinating disease that causes a challenging and disabling condition. Environmental and genetic factors play a role in appearing the state of the disease. Recent studies have shown that nuclear cofactor genes may play a role in the pathogenesis of MS. NCOA5 is a nuclear receptor coactivator independent of AF2 that modulates ERa-mediated transcription. This gene is involved in the pathogenesis of diseases such as psoriasis, Behcet's disease, and cancer. We investigated the relationship between the rs2903908 polymorphism of the NCOA5 gene and MS among 157 unrelated MS patients and 160 healthy controls by RT-PCR. The frequencies of the CC, CT, and TT genotypes were 19.87%, 37.82%, and 42.31%, respectively, for the MS group and 5.63%, 43.75%, and 50.62%, respectively, for the control group. The CC genotype and the C allele were found to be significantly higher in the patient group (the p values were 0.0002 and 0.003, respectively). The fact that the CC genotype was found to be significantly higher in the patient group compared to the control group (p = 0.0002) and that it had a statistically significantly higher OR value (OR, 95% CI = 4.16, 1.91-9.05) suggests that the C allele may recessively predispose to MS for this polymorphism. These results suggest for the first time that the NCOA5 gene may have an effect on the occurrence of MS through different molecular pathways, which are discussed in the manuscript.

Linking Mechanisms of Vitamin D Signaling with Multiple Sclerosis.

Environmental triggers often work via signal transduction cascades that modulate the epigenome and transcriptome of cell types involved in the disease process. Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system being characterized by a combination of recurring inflammation, demyelination and progressive loss of axons. The mechanisms of MS onset are not fully understood and genetic variants may explain only some 20% of the disease susceptibility. From the environmental factors being involved in disease development low vitamin D levels have been shown to significantly contribute to MS susceptibility. The pro-hormone vitamin D3 acts via its metabolite 1α,25-dihydroxyvitamin D3 (1,25(OH)2D3) as a high affinity ligand to the transcription factor VDR (vitamin D receptor) and is a potent modulator of the epigenome at thousands of genomic regions and the transcriptome of hundreds of genes. A major target tissue of the effects of 1,25(OH)2D3 and VDR are cells of innate and adaptive immunity, such as monocytes, dendritic cells as well as B and T cells. Vitamin D induces immunological tolerance in T cells and reduces inflammatory reactions of various types of immune cells, all of which are implicated in MS pathogenesis. The immunomodulatory effects of 1,25(OH)2D3 contribute to the prevention of MS. However, the strength of the responses to vitamin D3 supplementation is highly variegated between individuals. This review will relate mechanisms of individual's vitamin D responsiveness to MS susceptibility and discuss the prospect of vitamin D3 supplementation as a way to extinguish the autoimmunity in MS.

A Case of Coexistent Spinocerebellar Ataxia Type 2 and Primary Progressive Multiple Sclerosis-Coincidental or Associated?

Spinocerebellar ataxia type 2 (SCA2) is a dominantly inherited ataxia primarily characterised by progressive cerebellar syndrome, which is developed due to the expansion of the CAG trinucleotide repeat within the first exon of the ATXN2 gene. We report a rare case of a 41-year-old woman with coexistent genetically verified SCA2 and primary progressive multiple sclerosis (MS). Considering our case and a few others reported in the literature, as well as a possible genetic association between ATXN2 and MS susceptibility, we suggest that the coexistence of SCA and MS may not be coincidental, especially in patients with a progressive MS course.

A Comprehensive Review on Neuroimmunology: Insights from Multiple Sclerosis to Future Therapeutic Developments.

This review delves into neuroimmunology, focusing on its relevance to multiple sclerosis (MS) and potential treatment advancements. Neuroimmunology explores the intricate relationship between the immune system and the central nervous system (CNS). Understanding these mechanisms is vital for grasping the pathophysiology of diseases like MS and for devising innovative treatments. This review introduces foundational neuroimmunology concepts, emphasizing the role of immune cells, cytokines, and blood-brain barrier in CNS stability. It highlights how their dysregulation can contribute to MS and discusses genetic and environmental factors influencing MS susceptibility. Cutting-edge research methods, from omics techniques to advanced imaging, have revolutionized our understanding of MS, offering valuable diagnostic and prognostic tools. This review also touches on the intriguing gut-brain axis, examining how gut microbiota impacts neuroimmunological processes and its potential therapeutic implications. Current MS treatments, from immunomodulatory drugs to disease-modifying therapies, are discussed alongside promising experimental approaches. The potential of personalized medicine, cell-based treatments, and gene therapy in MS management is also explored. In conclusion, this review underscores neuroimmunology's significance in MS research, suggesting that a deeper understanding could pave the way for more tailored and effective treatments for MS and similar conditions. Continued research and collaboration in neuroimmunology are essential for enhancing patient outcomes.

Under the influence: environmental factors as modulators of neuroinflammation through the IL-10/IL-10R axis.

The IL-10/IL-10 receptor (IL-10R) axis plays an important role in attenuating neuroinflammation in animal models of Multiple Sclerosis (MS) and increased IL-10 has been associated with a positive response to MS disease modifying therapy. Because environmental factors play an important role in MS susceptibility and disease course, identification of environmental factors that impact the IL-10/IL-10R axis has therapeutic potential. In this review, we provide historical and updated perspectives of how IL-10R signaling impacts neuroinflammation, discuss environmental factors and intestinal microbes with known impacts on the IL-10/IL-10R axis, and provide a hypothetical model for how B cells, via their production of IL-10, may be important in conveying environmental "information" to the inflamed central nervous system.

The RNA helicase DDX39B activates FOXP3 RNA splicing to control T regulatory cell fate.

Genes associated with increased susceptibility to multiple sclerosis (MS) have been identified, but their functions are incompletely understood. One of these genes codes for the RNA helicase DExD/H-Box Polypeptide 39B (DDX39B), which shows genetic and functional epistasis with interleukin-7 receptor-α gene (IL7R) in MS-risk. Based on evolutionary and functional arguments, we postulated that DDX39B enhances immune tolerance thereby decreasing MS risk. Consistent with such a role we show that DDX39B controls the expression of many MS susceptibility genes and important immune-related genes. Among these we identified Forkhead Box P3 (FOXP3), which codes for the master transcriptional factor in CD4+/CD25+ T regulatory cells. DDX39B knockdown led to loss of immune-regulatory and gain of immune-effector expression signatures. Splicing of FOXP3 introns, which belong to a previously unrecognized type of introns with C-rich polypyrimidine tracts, was exquisitely sensitive to DDX39B levels. Given the importance of FOXP3 in autoimmunity, this work cements DDX39B as an important guardian of immune tolerance.

The CYP24A1 gene variant rs2762943 is associated with low serum 1,25-dihydroxyvitamin D levels in multiple sclerosis patients.

Vitamin D is considered to play a role in multiple sclerosis (MS) etiopathogenesis. A polymorphism in the CYP24A1 gene, rs2762943, was recently identified that was associated with an increased MS risk. CYP24A1 encodes a protein involved in the catabolism of the active form of vitamin D. The immunological effects of carrying the rs2762943 risk allele were investigated, as well as its role as genetic modifier. Serum levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D (1,25(OH)2 D) were measured in a cohort of 167 MS patients. In a subgroup of patients, expression levels of major histocompatibility complex class II and co-stimulatory molecules were determined by flow cytometry, and serum levels of pro-inflammatory (interferon gamma, granulocyte macrophage colony-stimulating factor, C-X-C motif chemokine ligand 13) and anti-inflammatory (interleukin 10) cytokines and neurofilament light chain were measured by single-molecule array assays. The effect of the rs2762943 polymorphism on disease activity and disability measures was evaluated in 340 MS patients. Compared to non-carriers, carriers of the rs2762943 risk allele were characterized by reduced levels of 1,25(OH)2 D (p = 0.0001) and elevated levels of interferon gamma (p = 0.03) and granulocyte macrophage colony-stimulating factor (p = 0.008), whereas no significant differences were observed for the other markers. The presence of the rs2762943 risk allele had no significant impact on disease activity and disability outcomes during follow-up. However, risk allele carriers were younger at disease onset (p = 0.04). These findings suggest that the CYP24A1 rs2762943 polymorphism plays a more important role in MS susceptibility than in disease prognosis and is associated with lower 1,25(OH)2 D levels and a heightened pro-inflammatory environment in MS patients.

ADAMS project: a genetic Association study in individuals from Diverse Ancestral backgrounds with Multiple Sclerosis based in the UK

PurposeGenetic studies of multiple sclerosis (MS) susceptibility and severity have focused on populations of European ancestry. Studying MS genetics in other ancestral groups is necessary to determine the generalisability of...

Epstein-Barr Virus and Multiple Sclerosis: A Convoluted Interaction and the Opportunity to Unravel Predictive Biomarkers.

Since the early 1980s, Epstein-Barr virus (EBV) infection has been described as one of the main risk factors for developing multiple sclerosis (MS), and recently, new epidemiological evidence has reinforced this premise. EBV seroconversion precedes almost 99% of the new cases of MS and likely predates the first clinical symptoms. The molecular mechanisms of this association are complex and may involve different immunological routes, perhaps all running in parallel (i.e., molecular mimicry, the bystander damage theory, abnormal cytokine networks, and coinfection of EBV with retroviruses, among others). However, despite the large amount of evidence available on these topics, the ultimate role of EBV in the pathogenesis of MS is not fully understood. For instance, it is unclear why after EBV infection some individuals develop MS while others evolve to lymphoproliferative disorders or systemic autoimmune diseases. In this regard, recent studies suggest that the virus may exert epigenetic control over MS susceptibility genes by means of specific virulence factors. Such genetic manipulation has been described in virally-infected memory B cells from patients with MS and are thought to be the main source of autoreactive immune responses. Yet, the role of EBV infection in the natural history of MS and in the initiation of neurodegeneration is even less clear. In this narrative review, we will discuss the available evidence on these topics and the possibility of harnessing such immunological alterations to uncover predictive biomarkers for the onset of MS and perhaps facilitate prognostication of the clinical course.

The serum kynurenine pathway metabolic profile is associated with overweight and obesity in multiple sclerosis.

Overweight and obesity increase multiple sclerosis (MS) susceptibility, disease severity, and disability progression. Kynurenine pathway (KP) dysregulation is present in overweight and obesity, and in MS. Since the effect of overweight and obesity on KP dysregulation in persons with MS (pwMS) remains to be established, this study primarily aims to explore the effect of overweight and obesity on the serum KP metabolic profile in pwMS. This cross-sectional study represents a secondary analysis of a randomized clinical trial at Valens rehabilitation clinic, Switzerland. Registration was performed on 22 April 2020 at clinicaltrials.gov (NCT04356248, https://clinicaltrials.gov/ct2/show/NCT04356248). The first participant was enrolled on 13 July 2020. Based on body mass index (BMI), 106 MS inpatients (Expanded Disability Status Scale (EDSS) score ≤ 6.5) were dichotomised to a lean group (LG, BMI < 25kg/m2), and an overweight/obese group (OG, BMI ≥ 25kg/m2). Targeted metabolomics (LC-MS/MS) was performed to determine serum concentrations of tryptophan (TRP), KP downstream metabolites, and neopterin (Neopt). Correlations between BMI, kynurenine-to-TRP ratio (KTR), and serum concentrations of TRP, KP downstream metabolites, and Neopt were calculated. ANCOVA was used to determine differences in KTR, and serum concentrations of TRP, KP downstream metabolites and Neopt between OG and LG, and across MS phenotypes. Higher BMI correlated with higher KTR (r=0.425, p <0.001) and serum concentrations of most KP downstream metabolites, but not with EDSS score. Higher KTR (r=0.470, p < .001) and serum concentrations of most KP downstream metabolites correlated with a higher serum concentration of Neopt. The OG (n=44, 59% female, 51.68 (9.98) years, EDSS: 4.71 (1.37)) revealed higher KTR (0.026 (0.007) vs. 0.022 (0.006), p=.001) and serum concentrations of most KP downstream metabolites than the LG (n=62, 71% female, 48.37 (9.63) years, EDSS: 4.60 (1.29)). KP metabolic profiles did not differ between MS phenotypes. Overweight and obesity are associated with a systemic elevation of KP metabolic flux and an accumulation of most KP downstream metabolites in pwMS. Further research is needed to clarify if KP involvement serves as a mechanism linking overweight and obesity with symptom expression, disease severity, and disability progression in pwMS.