Explore the vast range of titles available.

Some antimicrobial peptides (AMPs), microRNAs (miRs), and Toll-like receptor 4 (TLR-4) are involved in autoimmune diseases, which may be affected by exercise training. The purpose of this study was to investigate the effect of an eight-week combined exercise training (aerobic and resistance) on the expression of inflammatory factors, including, human beta-defensin-2 (hBD-2), cathelicidin (LL-37), TLR-4, miR-23b, miR-155, and miR-326 in women with relapsing and remitting multiple sclerosis (RRMS), which has not been investigated yet. Twenty-three women (20-40 years) with RRMS were randomized into the combined training (CT) and control (CON) groups. The CT group subjects completed eight weeks of supervised CT using a treadmill and stationary bicycle for aerobic exercise and weight machines for resistance exercise. The expression levels of hBD-2, LL-37, TLR-4, miR-23b, miR-155, and miR-326 were measured by real-time polymerase chain reaction (RT-PCR) at the baseline and end of the study. Although the expression of hBD-2 and miR-23b decreased in both CT and CON groups, the reduction was lower in the CT group than in the CON group (p=0.001). The expression of LL-37 in the CT group remained unchanged, but that of the CON group increased; thus, the between-group difference was significant. Although the TLR-4, miR-155, and miR-326 expression increased in both groups compared to the baseline, the increase in the CT group was lower than the CON group. Our results showed that the combined training might improve inflammatory symptoms by affecting the expression of some AMPs, miRs, and TLR-4 in patients with relapsing and remitting multiple sclerosis.

Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system, progressing from Relapsing–Remitting MS (RRMS) to Secondary Progressive MS (SPMS) in many cases. The transition involves complex biological changes. Our study aims to identify potential biomarkers for distinguishing SPMS by analyzing gene expression differences between normal-appearing and lesioned parietal grey matter, which may also contribute to understand the pathogenesis of SPMS. We utilized public datasets from the Gene Expression Omnibus (GEO), applying bioinformatics and machine learning techniques including Weighted Gene Co-expression Network Analysis (WGCNA), Kyoto Encyclopedia of Genes and Genomes (KEGG), Gene Ontology (GO) enrichment analysis, protein–protein interaction (PPI) networks, the Least Absolute Shrinkage and Selection Operator (LASSO), and Random Forest (RF) for predictive model construction. Our study also included analyses of immune cell infiltration. The study identified 359 DEGs, with 105 up-regulated and 254 down-regulated. WGCNA identified 264 common genes, which were subjected to KEGG and GO enrichment analyses, highlighting their role in immune response and viral infection pathways. Four genes (BCL3, GBP1, IFI16, and CCR1) were identified as key biomarkers for SPMS, supported by LASSO regression and RF analyses. These genes were further validated through receiver operating characteristic (ROC) curves, demonstrating significant predictive potential for SPMS. Our study provides a novel set of biomarkers for SPMS from lesioned grey matter of SPMS cases, offering potential for diagnosis and targeted therapeutic strategies. The identified biomarkers link closely with SPMS pathology, especially regarding immune system modulation.

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R , and confirmation of the previously reported association of AITD with TSHR and FCRL3 . These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

To understand the nature of genetic and environmental susceptibility to multiple sclerosis (MS) and, by extension, susceptibility to other complex genetic diseases. Certain basic epidemiological parameters of MS (e.g., population-prevalence of MS, recurrence-risks for MS in siblings and twins, proportion of women among MS patients, and the time-dependent changes in the sex-ratio) are well-established. In addition, more than 233 genetic-loci have now been identified as being unequivocally MS-associated, including 32 loci within the major histocompatibility complex (MHC), and one locus on the X chromosome. Despite this recent explosion in genetic associations, however, the association of MS with the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 (H+) haplotype has been known for decades. We define the \"genetically-susceptible\" subset (G) to include everyone with any non-zero life-time chance of developing MS. Individuals who have no chance of developing MS, regardless of their environmental experiences, belong to the mutually exclusive \"non-susceptible\" subset (G-). Using these well-established epidemiological parameters, we analyze, mathematically, the implications that these observations have regarding the genetic-susceptibility to MS. In addition, we use the sex-ratio change (observed over a 35-year interval in Canada), to derive the relationship between MS-probability and an increasing likelihood of a sufficient environmental exposure. We demonstrate that genetic-susceptibitly is confined to less than 7.3% of populations throughout Europe and North America. Consequently, more than 92.7% of individuals in these populations have no chance whatsoever of developing MS, regardless of their environmental experiences. Even among carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype, far fewer than 32% can possibly be members the (G) subset. Also, despite the current preponderance of women among MS patients, women are less likely to be in the susceptible (G) subset and have a higher environmental threshold for developing MS compared to men. Nevertheless, the penetrance of MS in susceptible women is considerably greater than it is in men. Moreover, the response-curves for MS-probability in susceptible individuals increases with an increasing likelihood of a sufficient environmental exposure, especially among women. However, these environmental response-curves plateau at under 50% for women and at a significantly lower level for men. The pathogenesis of MS requires both a genetic predisposition and a suitable environmental exposure. Nevertheless, genetic-susceptibility is rare in the population (< 7.3%) and requires specific combinations of non-additive genetic risk-factors. For example, only a minority of carriers of the HLA-DRB1*15:01~HLA-DQB1*06:02~a1 haplotype are even in the (G) subset and, thus, genetic-susceptibility to MS in these carriers must result from the combined effect this haplotype together with the effects of certain other (as yet, unidentified) genetic factors. By itself, this haplotype poses no MS-risk. By contrast, a sufficient environmental exposure (however many events are involved, whenever these events need to act, and whatever these events might be) is common, currently occurring in, at least, 76% of susceptible individuals. In addition, the fact that environmental response-curves plateau well below 50% (especially in men), indicates that disease pathogenesis is partly stochastic. By extension, other diseases, for which monozygotic-twin recurrence-risks greatly exceed the disease-prevalence (e.g., rheumatoid arthritis, diabetes, and celiac disease), must have a similar genetic basis.

BackgroundThe pathogenesis of multiple sclerosis (MS) requires both genetic factors and environmental events. The question remains, however, whether these factors and events completely describe the MS disease process. This question was addressed using the Canadian MS data, which includes 29 478 individuals, estimated to represent 65–83% of all Canadian patients with MS.MethodThe ‘genetically-susceptible’ subset of the population, (G), includes everyone who has any non-zero life-time chance of developing MS, under some environmental conditions. A ‘sufficient’ environmental exposure, for any genetically-susceptible individual, includes every set of environmental conditions, each of which is ‘sufficient’, by itself, to cause MS in that person. This analysis incorporates many epidemiological parameters, involved in MS pathogenesis, only some of which are directly observable, and establishes ‘plausible’ value ranges for each parameter. Those parameter value combinations (ie, solutions) that fall within these plausible ranges are then determined.ResultsOnly a small proportion of the population (≤52%) has any possibility of developing MS, regardless of any environmental conditions that they could experience. Moreover, some of these genetically-susceptible individuals, despite their experiencing a ‘sufficient’ environmental exposure, will still not develop disease.ConclusionsThis analysis explicitly includes all of those genetic factors and environmental events (including their interactions), which are necessary for MS pathogenesis, regardless of whether these factors, events and interactions are known, suspected or as yet unrecognised. Nevertheless, in addition, a ‘truly’ random mechanism also seems to play a critical role in disease pathogenesis. This observation provides empirical evidence, which undermines the widely-held deterministic view of nature. Moreover, both sexes seem to share a similar genetic and environmental disease basis. If so, then it is this random mechanism, which is primarily responsible for the currently-observed differences in MS disease expression between susceptible women and susceptible men.

Deimination (or citrullination) is a post-translational modification catalyzed by a calcium-dependent enzyme family of five peptidylarginine deiminases (PADs). Deimination is involved in physiological processes (cell differentiation, embryogenesis, innate and adaptive immunity, etc.) and in autoimmune diseases (rheumatoid arthritis, multiple sclerosis and lupus), cancers and neurodegenerative diseases. Intermediate filaments (IF) and associated proteins (IFAP) are major substrates of PADs. Here, we focus on the effects of deimination on the polymerization and solubility properties of IF proteins and on the proteolysis and cross-linking of IFAP, to finally expose some features of interest and some limitations of citrullinomes.

ObjectiveMany genomic loci have been identified for multiple sclerosis (MS) by genome-wide association studies (GWAS). Discrimination of the most functionally relevant genes in these loci remains challenging. The aim of this study was to highlight potential causal genes for MS.MethodsWe detected potential causal DNA methylations and gene expressions for MS by integrating data from large scale GWAS and quantitative trait locus (QTL) studies using the summary data-based Mendelian randomization method. Potential functional SNPs in the identified genes were searched.ResultsWe found 178 DNA methylation sites and mRNA expressions of 29 genes that were causally associated with MS. The identified genes enriched in 21 specific KEGG pathways and 80 GO terms (e.g., antigen processing and presentation, interferon gamma mediated signaling pathway). Among the identified non-MHC genes, METTL21B, METTL1 and TSFM were strongly connected. MS-associated SNPs in DDR1 were strongly associated with plasma MHC class I polypeptide-related sequence B (MICB) and Granzyme A levels. And plasma MICB and Granzyme A levels were causally associated with MS. Many SNPs in the causal genes showed QTL effects. The association between m6A-SNPs rs923829 and METTL21B expression level was validated in 40 unrelated Chinese Han individuals.ConclusionsThis study identified many DNA methylations and genes as important risk factors for MS and provided novel evidence on the association between circulating MICB and Granzyme A and MS. We also showed that the interaction among DDR1, MICB and GZMA and interaction among METTL21B, METTL1 and TSFM may participate in the pathogenesis of MS.

Previous research have implicated critical roles of systemic inflammation in the development of Multiple Sclerosis (MS). But the causal relationship between interleukins (ILs) and MS has not been fully elucidated. In this study, we applied Mendelian randomization (MR) approaches to address the causal associations between genetically determined circulating levels of ILs and the risk of MS. Genetic instruments for circulating IL-1 receptor antagonist (IL-1Ra), IL-2 receptor α subunit (IL-2Rα), IL-6, IL-16, IL-17, and IL-18 were obtained from recently published genome-wide association studies (GWAS). Summary-level data for MS were obtained from the International Multiple Sclerosis Genetics Consortium. MR analyses were performed using the R software (version 3.6.1, The R Foundation) and the TwoSampleMR package. Genetic predisposition to higher circulating levels of IL-2Rα were significantly associated with MS risk. The odds ratio (OR) was 1.22 (95% confidence interval [CI], 1.12-1.32; < 0.001) per one standard deviation increase in circulating IL-2Rα levels. There was a suggestive association of circulating IL-1Ra with MS risk (OR, 0.94; 95% CI, 0.88-0.99; = 0.027). The other ILs were not associated with the outcome. Our results indicated that circulating IL-2Rα was causally associated with risk of MS.

Background Striking changes in the demographic pattern of multiple sclerosis (MS) strongly indicate an influence of modifiable exposures, which lend themselves well to intervention. It is important to pinpoint which of the many environmental, lifestyle, and sociodemographic changes that have occurred over the past decades, such as higher smoking and obesity rates, are responsible. Mendelian randomization (MR) is an elegant tool to overcome limitations inherent to observational studies and leverage human genetics to inform prevention strategies in MS. Methods We use genetic variants from the largest genome-wide association study for smoking phenotypes (initiation: N  = 378, heaviness: N  = 55, lifetime smoking: N  = 126) and body mass index (BMI, N  = 656) and apply these as instrumental variables in a two-sample MR analysis to the most recent meta-analysis for MS. We adjust for the genetic correlation between smoking and BMI in a multivariable MR. Results In univariable and multivariable MR, smoking does not have an effect on MS risk nor explains part of the association between BMI and MS risk. In contrast, in both analyses each standard deviation increase in BMI, corresponding to roughly 5 kg/m 2 units, confers a 30% increase in MS risk. Conclusion Despite observational studies repeatedly reporting an association between smoking and increased risk for MS, MR analyses on smoking phenotypes and MS risk could not confirm a causal relationship. This is in contrast with BMI, where observational studies and MR agree on a causal contribution. The reasons for the discrepancy between observational studies and our MR study concerning smoking and MS require further investigation.

To explore and describe the basis and implications of genetic and environmental susceptibility to multiple sclerosis (MS) using the Canadian population-based data. Certain parameters of MS-epidemiology are directly observable (e.g., the recurrence-risk of MS in siblings and twins, the proportion of women among MS patients, the population-prevalence of MS, and the time-dependent changes in the sex-ratio). By contrast, other parameters can only be inferred from the observed parameters (e.g., the proportion of the population that is \"genetically susceptible\", the proportion of women among susceptible individuals, the probability that a susceptible individual will experience an environment \"sufficient\" to cause MS, and if they do, the probability that they will develop the disease). The \"genetically susceptible\" subset (G) of the population (Z) is defined to include everyone with any non-zero life-time chance of developing MS under some environmental conditions. The value for each observed and non-observed epidemiological parameter is assigned a \"plausible\" range. Using both a Cross-sectional Model and a Longitudinal Model, together with established parameter relationships, we explore, iteratively, trillions of potential parameter combinations and determine those combinations (i.e., solutions) that fall within the acceptable range for both the observed and non-observed parameters. Both Models and all analyses intersect and converge to demonstrate that probability of genetic-susceptibitly, P(G), is limited to only a fraction of the population {i.e., P(G) ≤ 0.52)} and an even smaller fraction of women {i.e., P(G│F) < 0.32)}. Consequently, most individuals (particularly women) have no chance whatsoever of developing MS, regardless of their environmental exposure. However, for any susceptible individual to develop MS, requires that they also experience a \"sufficient\" environment. We use the Canadian data to derive, separately, the exponential response-curves for men and women that relate the increasing likelihood of developing MS to an increasing probability that a susceptible individual experiences an environment \"sufficient\" to cause MS. As the probability of a \"sufficient\" exposure increases, we define, separately, the limiting probability of developing MS in men (c) and women (d). These Canadian data strongly suggest that: (c < d ≤ 1). If so, this observation establishes both that there must be a \"truly\" random factor involved in MS pathogenesis and that it is this difference, rather than any difference in genetic or environmental factors, which primarily accounts for the penetrance difference between women and men. The development of MS (in an individual) requires both that they have an appropriate genotype (which is uncommon in the population) and that they have an environmental exposure \"sufficient\" to cause MS given their genotype. Nevertheless, the two principal findings of this study are that: P(G) ≤ 0.52)} and: (c < d ≤ 1). Threfore, even when the necessary genetic and environmental factors, \"sufficient\" for MS pathogenesis, co-occur for an individual, they still may or may not develop MS. Consequently, disease pathogenesis, even in this circumstance, seems to involve an important element of chance. Moreover, the conclusion that the macroscopic process of disease development for MS includes a \"truly\" random element, if replicated (either for MS or for other complex diseases), provides empiric evidence that our universe is non-deterministic.