Etiology Of Multiple Sclerosis Research Articles

Choroid plexus volume changes in multiple sclerosis: insights from a systematic review and meta-analysis of magnetic resonance imaging studies.

Multiple sclerosis (MS) is a chronic autoimmune disease characterized by the destruction of the myelin sheath within the central nervous system. The etiology of MS involves a complex interplay of genetic, environmental, and immunological factors. Recent studies indicated the potential role of the choroid plexus (CP) in the pathogenesis and progression of MS. This systematic review aims to assess existing research on the volume alterations of the CP in MS patients compared to the normal population. A comprehensive search was conducted across databases including PubMed, Embase, Scopus, and Web of Science up to June 2024. Data from the included studies were synthesized using a meta-analytical approach with a random-effects model, assessing heterogeneity with the I2 and Tau-squared indices. We included 17 studies in this systematic review. The meta-analysis, which included data from eight studies reporting CP volume relative to TIV, found a statistically significant increase in CP volume in MS patients compared to healthy controls (HCs). The SMD was 0.77 (95% CI: 0.61 to 0.93), indicating a large effect size. This analysis showed no heterogeneity (I² = 0%). A separate meta-analysis was conducted using five studies that reported CP volume as normalized volume, resulting in an SMD of 0.63 (95% CI: 0.2-1.06). This study demonstrates an increase in CP volume among MS patients compared to HCs, implying the potential involvement of CP in MS pathogenesis and/or progression. These results show that CP might serve as a radiological indicator in the diagnosis and prognosis of MS.

Rubella virus seropositivity after infection or vaccination as a risk factor for multiple sclerosis.

Multiple sclerosis (MS) is a demyelinating disease affecting millions of people worldwide. Hereditary susceptibility and environmental factors contribute to disease risk. Infection with Epstein-Barr virus (EBV) and human herpesvirus 6A (HHV-6A) have previously been associated with MS risk. Other neurotropic viruses, such as rubella virus (RV), are possible candidates in MS aetiopathogenesis, but previous results are limited and conflicting. In this nested case-control study of biobank samples in a Swedish cohort, we analysed the serological response towards RV before the clinical onset of MS with a bead-based multiplex assay in subjects vaccinated and unvaccinated towards RV. The association between RV seropositivity and MS risk was analysed with conditional logistic regression. Seropositivity towards RV was associated with an increased risk of MS for unvaccinated subjects, even when adjusting for plausible confounders including EBV, HHV-6A, cytomegalovirus and vitamin D (adjusted odds ratio [AOR] = 4.0, 95% confidence interval [CI] 1.8-8.8). Cases also had stronger antibody reactivity towards rubella than controls, which was not seen for other neurotropic viruses such as herpes simplex or varicella zoster. Furthermore, we observed an association between RV seropositivity and MS in vaccinated subjects. However, this association was not significant when adjusting for the aforementioned confounders (AOR = 1.7, 95% CI 1.0-2.9). To our knowledge, these are the first reported associations between early RV seropositivity and later MS development. This suggests a broadening of the virus hypothesis in MS aetiology, where molecular mimicry between rubella epitopes and human central nervous system molecules could be an attractive possible mechanism.

Altered gene expression of miR-155 in peripheral blood mononuclear cells of Multiple sclerosis patients: Correlation with TH17 frequency, inflammatory cytokine profile and autoimmunity

In the chronic, organ-specific autoimmune disorder known as multiple sclerosis (MS), the myelin sheath is attacked by immune cells, leading to damage to the central nervous system (CNS). It has been discovered that miRNAs are important in the etiology of MS, since deregulation of miRNAs can lead to defects in immune tolerance. In this study, we sought to investigate the involvement of miR-155 in MS disorder through examination of its altered expression in peripheral blood mononuclear cells (PBMCs) of patients with MS in compare with healthy controls. Furthermore, we investigated the frequency of T helper 17 cells (Th17) in MS patients and analyzed not only the expression of inflammatory cytokines including IL-6, IL-17 and IL-21 in patients’ PBMCs, but also their secreted levels in serum of patients suffering from MS. Subsequently, we assessed the correlation between miR-155 expression with Th17 frequency and levels of released cytokines in serum. Upregulated expression of miR-155 was detected in PBMCs of MS patients and the positive correlation between its expression with increased frequency of Th17 cells and their related inflammatory cytokine profile augmented secretion in serum were identified. In conclusion, our study revealed the significant association between Th17 frequency, increased level of cytokines related to Th17 differentiation and function with miR-155 augmented expression in PBMCs. So, our findings suggested that miR-155 and especially its expression in immune cells including effector T cells can be the target of future therapeutic strategies for the management and prevention of MS progression, however, further research is requisite before this approach can be utilized in clinical practice.

Ultrastructural Characterization of PBMCs and Extracellular Vesicles in Multiple Sclerosis: A Pilot Study.

Growing evidence identifies extracellular vesicles (EVs) as important cell-to-cell signal transducers in autoimmune disorders, including multiple sclerosis (MS). If the etiology of MS still remains unknown, its molecular physiology has been well studied, indicating peripheral blood mononuclear cells (PBMCs) as the main pathologically relevant contributors to the disease and to neuroinflammation. Recently, several studies have suggested the involvement of EVs as key mediators of neuroimmune crosstalk in central nervous system (CNS) autoimmunity. To assess the role of EVs in MS, we applied electron microscopy (EM) techniques and Western blot analysis to study the morphology and content of plasma-derived EVs as well as the ultrastructure of PBMCs, considering four MS patients and four healthy controls. Through its exploratory nature, our study was able to detect significant differences between groups. Pseudopods and large vesicles were more numerous at the plasmalemma interface of cases, as were endoplasmic vesicles, resulting in an activated aspect of the PBMCs. Moreover, PBMCs from MS patients also showed an increased number of multivesicular bodies within the cytoplasm and amorphous material around the vesicles. In addition, we observed a high number of plasma-membrane-covered extensions, with multiple associated large vesicles and numerous autophagosomal vacuoles containing undigested cytoplasmic material. Finally, the study of EV cargo evidenced a number of dysregulated molecules in MS patients, including GANAB, IFI35, Cortactin, Septin 2, Cofilin 1, and ARHGDIA, that serve as inflammatory signals in a context of altered vesicular dynamics. We concluded that EM coupled with Western blot analysis applied to PBMCs and vesiculation can enhance our knowledge in the physiopathology of MS.

Consanguineous marriage among familial multiple sclerosis subjects: A national registry-based study

BackgroundThe rising prevalence of familial multiple sclerosis (MS) in Iran has spurred interest in the potential impact of parental consanguinity on the risk of developing the disease. This study aims to aggregate current knowledge on parental consanguinity and its possible effect on MS risk, particularly among familial MS patients from various regions and ethnicities in Iran. The objective is to enhance the understanding of MS genetics and encourage further research in this field. Materials and methodsA cross-sectional study was conducted on clinically definite familial MS (FMS) patients registered in the nationwide MS registry of Iran (NMSRI). Data were extracted and supplemented with structured telephone follow-ups to gather detailed histories of MS in relatives and the familial relationships of the patients' parents. A family penetration score was proposed. Descriptive statistics and inferential statistical tests were used to analyze the data at a significance level of 0.05, adhering to ethical guidelines. ResultsOut of 19,911 individuals registered in the NMSRI, 2307 FMS patients across 13 provinces were included in the final analysis. Among these, 385 (19.3 %) reported parental consanguinity, with 283 (14.2 %) having parents who were cousins and 102 (5.1 %) having parents who were distant relatives. The data showed no significant association between parental kinship and variables such as MS phenotype, number of affected relatives with MS, hospitalization rates, and expanded disability status scale score. Similarly, MS severity did not differ based on parental consanguinity (P-value >0.05). While the rate of consanguineous marriage was higher among patients with an onset age less than 18 years, there was no statistically significant difference in disease onset age based on parental consanguinity status. ConclusionOur study highlights the complexity of factors influencing MS development, including genetic and environmental components. These results highlight the need for further research to achieve a more comprehensive understanding of MS etiology.

Drosophila Evi5 is a critical regulator of intracellular iron transport via transferrin and ferritin interactions

Vesicular transport is essential for delivering cargo to intracellular destinations. Evi5 is a Rab11-GTPase-activating protein involved in endosome recycling. In humans, Evi5 is a high-risk locus for multiple sclerosis, a debilitating disease that also presents with excess iron in the CNS. In insects, the prothoracic gland (PG) requires entry of extracellular iron to synthesize steroidogenic enzyme cofactors. The mechanism of peripheral iron uptake in insect cells remains controversial. We show that Evi5-depletion in the Drosophila PG affected vesicle morphology and density, blocked endosome recycling and impaired trafficking of transferrin-1, thus disrupting heme synthesis due to reduced cellular iron concentrations. We show that ferritin delivers iron to the PG as well, and interacts physically with Evi5. Further, ferritin-injection rescued developmental delays associated with Evi5-depletion. To summarize, our findings show that Evi5 is critical for intracellular iron trafficking via transferrin-1 and ferritin, and implicate altered iron homeostasis in the etiology of multiple sclerosis.

Modulation of multiple sclerosis risk and pathogenesis by the gut microbiota: Complex interactions between host genetics, bacterial metabolism, and diet.

Multiple sclerosis (MS) is an autoimmune disease of the central nervous system, affecting nearly 2 million people worldwide. The etiology of MS is multifactorial: Approximately 30% of the MS risk is genetic, which implies that the remaining ~70% is environmental, with a number of factors proposed. One recently implicated risk factor for MS is the composition of the gut microbiome. Numerous case-control studies have identified changes in gut microbiota composition of people with MS (pwMS) compared with healthy control individuals, and more recent studies in animal models have begun to identify the causative microbes and underlying mechanisms. Here, we review some of these mechanisms, with a specific focus on the role of host genetic variation, dietary inputs, and gut microbial metabolism, with a particular emphasis on short-chain fatty acid and tryptophan metabolism. We put forward a model where, in an individual genetically susceptible to MS, the gut microbiota and diet can synergize as potent environmental modifiers of disease risk and possibly progression, with diet-dependent gut microbial metabolites serving as a key mechanism. We also propose that specific microbial taxa may have divergent effects in individuals carrying distinct variants of MS risk alleles or other polymorphisms, as a consequence of host gene-by-gut microbiota interactions. Finally, we also propose that the effects of specific microbial taxa, especially those that exert their effects through metabolites, are highly dependent on the host dietary intake. What emerges is a complex multifaceted interaction that has been challenging to disentangle in human studies, contributing to the divergence of findings across heterogeneous cohorts with differing geography, dietary preferences, and genetics. Nonetheless, this provides a complex and individualized, yet tractable, model of how the gut microbiota regulate susceptibility to MS, and potentially progression of this disease. Thus, we conclude that prophylactic or therapeutic modulation of the gut microbiome to prevent or treat MS will require a careful and personalized consideration of host genetics, baseline gut microbiota composition, and dietary inputs.

The Molecular Architecture and Mode of Action of Clostridium perfringens ε-Toxin

Clostridium perfringens ε-toxin has long been associated with a severe enterotoxaemia of livestock animals, and more recently, was proposed to play a role in the etiology of multiple sclerosis in humans. The remarkable potency of the toxin has intrigued researchers for many decades, who suggested that this indicated an enzymatic mode of action. Recently, there have been major breakthroughs by finding that it is a pore-forming toxin which shows exquisite specificity for cells bearing the myelin and lymphocyte protein (MAL) receptor. This review details the molecular structures of the toxin, the evidence which identifies MAL as the receptor and the possible roles of other cell membrane components in toxin binding. The information on structure and mode of action has allowed the functions of individual amino acids to be investigated and has led to the creation of mutants with reduced toxicity that could serve as vaccines. In spite of this progress, there are still a number of key questions around the mode of action of the toxin which need to be further investigated.

Complete Blood Count in Multiple Sclerosis

Multiple sclerosis (MS) is a chronic disease that affects the central nervous system in primarily young adults. Although the exact etiology of MS is unknown, autoimmune mechanisms are thought to play a crucial role, especially with CD4+ T cells involved in the immune response. Inflammatory reactions involving T cells and macrophages are commonly observed in MS lesions. B lymphocytes, plasma cells, and antibodies also contribute to MS pathogenesis. Neutrophils, lymphocytes, monocytes, and platelets, key immune system components, play roles in inflammatory processes, but their association with MS prognosis remains inconclusive. Due to its heterogeneous nature, clinical manifestations of MS vary depending on the location of the affected central nervous system. While several potential biomarkers have been identified for MS diagnosis and monitoring, none have been universally accepted. Studies have examined complete blood count parameters in MS patients, including erythrocyte, platelet, and leukocyte populations. Changes in these parameters have been observed in MS patients compared to healthy controls and may be related to disease prognosis. For example, increased erythrocyte fragility and altered hemoglobin levels have been reported in MS patients. Leukocyte counts and ratios, such as the neutrophil/lymphocyte ratio, have shown associations with disease severity. Platelet activation and interaction with immune cells have also been implicated in MS pathophysiology. Nevertheless, further research is needed to fully understand the role of complete blood count parameters in MS. Identifying reliable biomarkers for early diagnosis and prognosis prediction would greatly enhance MS management. Moreover, these benefits could lead to substantial improvements in achieving complete recovery of patients, surpassing the focus on current symptomatic treatments.

Article Review: Multiple Sclerosis

Neurology still puzzles about multiple sclerosis (MS). This comprehensive overview explores MS's history, epidemiology, etiology, clinical manifestations, diagnostic tools, and treatment options. From historical awareness to cutting-edge research, we traverse MS's complex world with a focus on the past and future. Genetics, environment, and migration interact to create geographic riddles in MS prevalence. MS's sensory and cognitive symptoms show its significant influence. Advanced imaging technology and diagnostic criteria enable accurate and quick identification. While transformational, disease-modifying treatments require a tailored approach. Advances have left crucial gaps, prompting researchers, physicians, and policymakers to continue. This in-depth investigation of MS combines historical and future perspectives to emphasize the urgency and possibility of solving this complicated neurological puzzle.

Association of OX40L gene polymorphism with multiple sclerosis in Iranians

IntroductionThe exact etiology of multiple sclerosis is unknown but recent studies indicated a link between tumor necrosis factor superfamily member 4 and the disease. Polymorphisms located in the regulatory region of the gene may affect its phenotype. Hence, we aimed to investigate the association of promoter polymorphisms of the gene with multiple sclerosis and also to estimate the frequency of haplotypes in the patients and healthy subjects. MethodsTwo hundred age- and sex-matched subjects including 100 patients and 100 healthy subjects were investigated in the study. Genotype and allele distributions of rs3850641, rs1234313, and rs10912580 polymorphisms in the promoter region of the gene were investigated by polymerase chain reaction-restriction fragment length polymorphism. In addition, haplotype frequencies estimation and linkage disequilibrium analysis were performed by SNPStats web tool. ResultsThe distribution of AA, AG and GG genotypes of rs3850641 was significantly different between the patient and healthy groups (P = 0.009). In addition, frequencies of A and G alleles of rs3850641 were different between the groups (P < 0.001). Also the distribution of rs3850641 genotypes was different between the women of the both groups (P = 0.007). Our analysis revealed that rs3850641 AG (Odds ratio = 0.393, 95 % confidence interval = 0.170–0.907, P = 0.029) and GG (Odds ratio = 0.373, 95 % confidence interval = 0.168–0.830, P = 0.016) genotypes were associated with decreased risk of the disease. However, rs1234313 genotype and allele distributions were not different between the groups. The distribution of rs10912580polymorphism. AA, AG, and GG genotypes was significantly different between the groups (P = 0.007). rs10912580 AG genotype was associated with low risk of the disease (Odds ratio = 0.252, 95 % confidence interval = 0.102–0.623, P = 0.003). The distribution of haplotypes was statistically different between the patient and healthy groups (P < 0.001). A-G-A was the most frequent haplotype among the patients and the estimated frequency was higher than that of the control group (0.5527 versus 0.3739). ConclusionThe distribution of rs3850641 and rs10912580 genotypes was different between the patients and healthy subjects. Moreover, rs3850641 AG and GG genotypes and also rs10912580 AG genotype were associated with low risk of the disease in Iranians. Further studies with large groups are recommended to show whether genotype variation in the patients could alter the response to treatment or not.

Levels of circulating cytokines in children with multiple sclerosis with different effectiveness of interferon therapy

Multiple sclerosis (MS) is a chronic, demyelinating disease that leads to disability. Understanding the etiology of MS contributes to the development of pathogenetic methods of treatment, and the search for informative biomarkers of the effectiveness of treatment will allow the patient to adjust therapy in time. The aim of this work was to determine informative cytokines and cytokine profiles to predict the effectiveness of IFN-β1a therapy in children with MS.Materials and methods. 66 children with MS aged 16 [14.2–17.5] years who are on INFß-1a therapy were examined: group 1 — patients with exacerbation of MS (with active foci of demyelination by MRI), n = 34; group 2 — patients in remission of MS (without active foci), n = 32. The content of cytokines in the blood serum of patients was assessed using the multiplex panel Human Th17 Magnetic Bead Panel.Results: There was a significant increase in cytokine concentrations in patients with exacerbation of MS compared with children in remission: IL5, IL6, IL9, IL12p70, IL17E/IL25, IL21, IL28A, GM-CSF, TNFß. Threshold values for IL9 (AUC = 0,785), IL6 (AUC = 0,750), TNFß (0,740), IL28A (AUC = 0,744) were obtained above which it is possible to predict an exacerbation of MS in patients: IL9 — 3.9 pg/ml (Sn — 70.6, Sp — 71.9), IL6 — 4.0 pg/ml (Sn — 70.6, Sp — 68.8), TNFß — 6.6 pg/ml (Sn — 70.6, Sp — 71.9), IL28A — 243.0 pg/ml (Sn — 70.6, Sp — 71.9). Cytokine profiles associated with T-lymphocytes and their functions were evaluated using z-score.Conclusions. For the first time, an increase in cytokine levels was demonstrated in children with active foci of demyelination compared to patients in remission of MS. An increase in proinflammatory cytokines and cytokine profiles associated with Th1 and Th17, as well as with Th2 and Th22 has been shown. The use of threshold values for IL9, IL6, TNFβ, IL28A will help predict the development of exacerbation in patients with MS.

HUMORAL IMMUNITY IN PATIENTS WITH MULTIPLE SCLEROSIS

Introduction. More than 1 million people in the world suffer from multiple sclerosis (MS). The etiology of MS remains not fully understood. The main role in the pathogenesis of MS belongs to the combination of chronic inflammation and neurodegenerative processes, in the genesis of which autoimmune processes play a significant role. Progress in studying the mechanisms of the pathological process of demyelinating diseases has been achieved mainly thanks to immunological research. One of the manifestations of activation of humoral immunity in MS is increased synthesis of immunoglobulins in brain tissue and cerebrospinal fluid&#x0D; The aim of the study. To study the state of humoral immunity in multiple sclerosis patients with different types of disease course&#x0D; Research methods. 68 patients with a verified diagnosis of multiple sclerosis (MS) based on the MacDonald et al criteria aged 19 to 65 years (37 women, 29 men) were examined. The primary progressive type of the course was established in 19 patients, the secondary-progressive - in 3, the remitting-relapsing type of the course - in 26 patients. The control group consisted of 80 practically healthy male volunteers aged 25-45 years.&#x0D; The concentration of immunoglobulins A, G, M in blood serum was determined by the Mancini method (1965). The content of circulating immune complexes (CIC) in blood serum was determined by the method of precipitation in polyethylene glycol.&#x0D; Results and discussion. The highest content of Ig A was observed in the group of patients with primary progressive form of MS, which was 3.7 times higher than normal values and 1.2 times higher than in the general group of MS patients. In the group of patients with the secondary progressive form of MS, the content of Ig A was 3.1 times higher than in the control group and 1.2 times lower than in the group with the primary progressive form. In the group of patients with relapsing-remitting form of MS, there was an increase in the level of Ig A three times relative to the normal indicator, and a decrease (by 1.2 times) relative to the level in the group with a primary progressive form of MS.&#x0D; The content of Ig M in the blood serum of patients with MS exceeded the norm by 5 times. In the group with the primary progressive form of MS, the level of Ig M was 3.5 times higher than the level in the control group and 1.5 times lower than the level in the group of patients with MS. In patients with secondary progressive form of MS, the content of Ig M was 2.6 times higher than the norm, but 1.3 times lower than the level in the group with primary progressive form of MS and 1.9 times lower than in the group of patients with MS. In patients with the relapsing-remitting form of MS, the level of Ig M was: 4.6 times higher than the level in the control group and 1.7 times higher than the content in patients with the secondary-progressive form of MS, and also 1.3 times higher, than in the group with the primary progressive form.&#x0D; In all groups of patients with MS with different types of the course of the disease, the most pronounced increase in the level of Ig G was noted.&#x0D; The highest level of CIC was recorded in the general group of patients with MS and in the group with secondary progressive form of MS.&#x0D; Conclusions. An imbalance of the humoral link of immunity was observed in patients with multiple sclerosis. A probable increase in the concentration of Ig A in the blood serum of patients with multiple sclerosis indicates the presence of infection of the mucous membranes, which is especially pronounced in patients with the primary progressive form of multiple sclerosis. A significant increase in the content of Ig G in the blood serum of patients with multiple sclerosis indicates a chronic course of the process, which is especially evident in the relapsing-relapsing form of multiple sclerosis. An increased concentration of IgM in the blood serum of patients with multiple sclerosis may indicate an exacerbation of the course of chronic inflammation, especially in the case of relapsing-remitting multiple sclerosis. The detected fluctuations of the average content of CIC in the blood serum of patients with multiple sclerosis did not go beyond the physiological norm.

OVERVIEW OF MULTIPLE SCLEROSIS WITH GUT EPSILON TOXICITY IN HUMAN: SISTEMATIC LITERATURE REVIEW

Background: Multiple Sclerosis (MS) is a complex autoimmune neurodegenerative disorder that afflicts a significant number of individuals worldwide. This formidable disease, which is often life-threatening, imposes a lifelong impact on those diagnosed, altering their existence in profound ways. Methods: The current review is meticulously crafted, drawing upon a multitude of scholarly articles previously disseminated in both national and international academic journals within the same discipline. Results: This disease inflicts substantial damage to the Central Nervous System (CNS), predominantly affecting the myelin sheath of nerve fibers, spinal cord, and eyes, thereby leading to the development of muscle weakness, movement disorders, and visual impairments. Recent observations have unveiled a potential link between a gut bacterium, Clostridium perfringens, and the onset of MS in humans. Conclusion: Given that the precise etiology of Multiple Sclerosis (MS) remains elusive and presents a formidable challenge, this paper endeavors to shed light on the current landscape of the disease. It provides an in-depth exploration of its epidemiology, clinical manifestations, diagnostic procedures, prognosis, and treatment modalities, all underpinned by the most recent advancements in the fields of immunology and medical microbiology about infectious diseases.

Quantification of Autoreactive Antibodies in Mice upon Experimental Autoimmune Encephalomyelitis.

Experimental autoimmune encephalomyelitis (EAE) is a disease model that recapitulates the autoimmune disorder multiple sclerosis (MS) at histopathological and molecular levels. EAE is induced by immunizing experimental animals via subcutaneous injection of short myelin peptides together with specific adjuvants to boost the immune response. Like the human counterpart, EAE mice develop demyelinating lesions, immune cell infiltration into the central nervous system (CNS), glia activation and neuronal injury. A consistent body of evidence also supports a mechanistic role for B cell dysfunction in the etiology of both MS and EAE. B cells can serve as antigen-presenting cells as well as a primary source of pro-inflammatory cytokines and autoantibodies. In EAE, antibodies are generated against the myelin peptides that were employed to induce the disease. Such autoantibodies have been shown to mediate either myelin loss or pathogenic T cell reactivation into the CNS. This article describes an efficient ELISA-based protocol to quantify autoantibodies in the serum of C57BL/6J mice immunized with the myelin oligodendrocyte glycoprotein 35-55 (MOG35-55) peptide. The proposed method serves as a powerful tool to investigate the specificity and magnitude of the aberrant humoral response in the context of autoimmune demyelination.

FKBP5 activates mitophagy by ablating PPAR-γ to shape a benign remyelination environment

Multiple sclerosis (MS) is an autoimmune and neurodegenerative disease of the central nervous system (CNS) that is characterized by myelin damage, followed by axonal and ultimately neuronal loss, which has been found to be associated with mitophagy. The etiology and pathology of MS remain elusive. However, the role of FK506 binding protein 5 (FKBP5, also called FKBP51), a newly identified gene associated with MS, in the progression of the disease has not been well defined. Here, we observed that the progress of myelin loss and regeneration in Fkbp5ko mice treated with demyelination for the same amount of time was significantly slower than that in wild-type mice, and that mitophagy plays an important regulatory role in this process. To investigate the mechanism, we discovered that the levels of FKBP5 protein were greatly enhanced in the CNS of cuprizone (CPZ) mice and the myelin-denuded environment stimulates significant activation of the PINK1/Parkin-mediated mitophagy, in which the important regulator, PPAR-γ, is critically regulated by FKBP5. This study reveals the role of FKBP5 in regulating a dynamic pathway of natural restorative regulation of mitophagy through PPAR-γ in pathological demyelinating settings, which may provide potential targets for the treatment of demyelinating diseases.

Early life stress aggravates disease pathogenesis in mice with experimental autoimmune encephalomyelitis: Support for a two-hit hypothesis of multiple sclerosis etiology

Vision problems are one of the earliest diagnosed symptoms of multiple sclerosis (MS). The onset and progression of vision loss and the underlying pathogenesis in MS may be influenced by cumulative psychophysiological stress. Here, we used a two-hit model of stress in female mice to determine if early life stress (ELS, the first hit) influences the response to an immunization that induces experimental autoimmune encephalomyelitis (EAE, the second hit) later in life. We hypothesized that ELS caused by animal transportation from a vendor during early postnatal development represents a co-factor which can exacerbate the clinical severity of EAE. Indeed, adult EAE mice with a history of ELS displayed more severe clinical signs and delayed recovery compared to non-stressed EAE mice. ELS also diminished visual acuity measured by optokinetic responses, as well as locomotion and exploratory behaviours in EAE mice. Notably, ELS accelerated vision loss and caused earlier onset of visual impairments in EAE. Exacerbated functional impairments in stressed EAE mice were highly correlated with circulating corticosterone levels. The findings show that the progression of induced EAE in adulthood can be significantly impacted by adverse early life experiences. These observations emphasize the importance of comprehensive behavioural testing, including non-motor functions, to enhance the translational value of preclinical animal models of MS. Moreover, shipment stress of laboratory animals should be considered a necessary variable in preclinical MS research. The consideration of cumulative lifetime stresses provides a new perspective of MS pathogenesis within a personalized medicine framework.

Cross-reactivity between Mycobacterium avium subspecies paratuberculosis 4027 peptide and Human IRF5 may contribute to Multiple Sclerosis in Iranian patients

BackgroundThe etiology of Multiple sclerosis (MS) is complicated and can be affected by several environmental factors, such as Mycobacterium avium subspecies paratuberculosis (MAP) infection in genetically predisposed individuals. The link between MAP and MS depends on host genetic and epigenetic aspects and population-based features that require further investigation. We aimed to study the possible role of MAP in triggering MS using molecular and serological methods. Materials and methodsThis case-control study examined 200 blood samples (100 MS patients and 100 HCs) to search for the MAP-specific IS900 gene. In addition, ELISA was conducted to determine the humoral response against MAP_402718-32 and its human IRF5424–434 peptide homolog. ResultsThe frequency of MAP detection based on the molecular method in MS patients and HCs was 48 % and 13 %, respectively (p < 0.0001). The presence of antibodies against MAP_402718-32 and IRF5424–434 was 55 % and 65 % in MS patients versus 9 % and 7 % in HCs, respectively (p < 0.0001). A good correlation was observed between MAP_4027 and IRF5 antibodies (r = 0.5782, p < 0.0001), indicating that the same antibodies recognized common peptide epitopes. ConclusionOur research revealed a significant association between MAP and MS, highlighting the possible role of MAP as an important infection trigger factor of MS. It is hypothesized that cross-reactivity between MAP4027 and IRF5 may dysregulate immune homeostasis.

Simultaneous Isolation of Principal Central Nervous System-Resident Cell Types from Adult Autoimmune Encephalomyelitis Mice.

Experimental autoimmune encephalomyelitis (EAE) is the most common murine model for multiple sclerosis (MS) and is frequently used to further elucidate the still unknown etiology of MS in order to develop new treatment strategies. The myelin oligodendrocyte glycoprotein peptide 35-55 (MOG35-55) EAE model reproduces a self-limiting monophasic disease course with ascending paralysis within 10 days after immunization. The mice are examined daily using a clinical scoring system. MS is driven by different pathomechanisms with a specific temporal pattern, thus the investigation of the role of central nervous system (CNS)-resident cell types during disease progression is of great interest. The unique feature of this protocol is the simultaneous isolation of all principal CNS-resident cell types (microglia, oligodendrocytes, astrocytes, and neurons) applicable in adult EAE and healthy mice. The dissociation of the brain and the spinal cord from adult mice is followed by magnetic-activated cell sorting (MACS) to isolate microglia, oligodendrocytes, astrocytes, and neurons. Flow cytometry was used to perform quality analyses of the purified single-cell suspensions confirming viability after cell isolation and indicating the purity of each cell type of approximately 90%. In conclusion, this protocol offers a precise and comprehensive way to analyze complex cellular networks in healthy and EAE mice. Moreover, required mice numbers can be substantially reduced as all four cell types are isolated from the same mice.

Impact of Alcohol Consumption on Multiple Sclerosis Using Model-based Standardization and Misclassification Adjustment Via Probabilistic Bias Analysis.

The etiology of multiple sclerosis (MS) is still not well-demonstrated, and assessment of some risk factors like alcohol consumption has problems like confounding and measurement bias. To determine the causal effect of alcohol consumption on MS after adjusting for alcohol consumption misclassification bias and confounders. In a population-based incident case-control study, 547 patients with MS and 1057 healthy people were recruited. A minimally sufficient adjustment set of confounders was derived using the causal directed acyclic graph. The probabilistic bias analysis method (PBAM) using beta, logit-logistic, and triangular probability distributions for sensitivity/specificity to adjust for misclassification bias in self-reporting alcohol consumption and model-based standardization (MBS) to estimate the causal effect of alcohol consumption were used. Population attributable fraction (PAF) estimates with 95% Monte Carlo sensitivity analysis (MCSA) intervals were calculated using PBAM and MBS analysis. Bootstrap was used to deal with random errors. The adjusted risk ratio (95% MCSA interval) from the probabilistic bias analysis and MBS between alcohol consumption and MS using the three distribution was in the range of 1.93 (1.07 to 4.07) to 2.02 (1.15 to 4.69). The risk difference (RD) in all three scenarios was 0.0001 (0.0000 to 0.0005) and PAF was in the range of 0.15 (0.010 to 0.50) to 0.17 (0.001 to 0.47). After adjusting for measurement bias, confounding, and random error alcohol consumption had a positive causal effect on the incidence of MS.