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Journal of Interferon & Cytokine... Aug 2014There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to... (Review)
Review
There is increasing support for the importance of risk factors such as genetic makeup, obesity, smoking, vitamin D insufficiency, and antibiotic exposure contributing to the development of autoimmune diseases, including human multiple sclerosis (MS). Perhaps the greatest environmental risk factor associated with the development of immune-mediated conditions is the gut microbiome. Microbial and helminthic agents are active participants in shaping the immune systems of their hosts. This concept is continually reinforced by studies in the burgeoning area of commensal-mediated immunomodulation. The clinical importance of these findings for MS is suggested by both their participation in disease and, perhaps of greater clinical importance, attenuation of disease severity. Observations made in murine models of central nervous system demyelinating disease and a limited number of small studies in human MS suggest that immune homeostasis within the gut microbiome may be of paramount importance in maintaining a disease-free state. This review describes three immunological factors associated with the gut microbiome that are central to cytokine network activities in MS pathogenesis: T helper cell polarization, T regulatory cell function, and B cell activity. Comparisons are drawn between the regulatory mechanisms attributed to first-line therapies and those described in commensal-mediated amelioration of central nervous system demyelination.
Topics: Animals; B-Lymphocytes; Central Nervous System; Cytokines; Demyelinating Diseases; Humans; Immune Tolerance; Immunity, Mucosal; Intestines; Lymphocyte Activation; Microbiota; Symbiosis; T-Lymphocyte Subsets; T-Lymphocytes, Regulatory
PubMed: 25084177
DOI: 10.1089/jir.2013.0134 -
Experimental Neurology Sep 2016A variety of growth factors are being explored as therapeutic agents relevant to the axonal and oligodendroglial deficits that occur as a result of demyelinating lesions... (Review)
Review
A variety of growth factors are being explored as therapeutic agents relevant to the axonal and oligodendroglial deficits that occur as a result of demyelinating lesions such as are evident in Multiple Sclerosis (MS). This review focuses on five such proteins that are present in the lesion site and impact oligodendrocyte regeneration. It then presents approaches that are being exploited to manipulate the lesion environment affiliated with multiple neurodegenerative diseases and suggests that the utility of these approaches can extend to demyelination. Challenges are to further understand the roles of specific growth factors on a cellular and tissue level. Emerging technologies can then be employed to optimize the use of growth factors to ameliorate the deficits associated with demyelinating degenerative diseases.
Topics: Animals; Cell Differentiation; Cell Proliferation; Demyelinating Diseases; Humans; Intercellular Signaling Peptides and Proteins; Oligodendroglia
PubMed: 27016070
DOI: 10.1016/j.expneurol.2016.02.023 -
Presse Medicale (Paris, France : 1983) Apr 2015Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple...
Optic neuritis, myelitis and brainstem syndrome accompanied by a symptomatic MRI T2 or FLAIR hyperintensity and T1 hypointensity are highly suggestive of multiple sclerosis (MS) in young adults. They are called "clinically isolated syndrome" (CIS) and correspond to the typical first multiple sclerosis (MS) episode, especially when associated with other asymptomatic demyelinating lesions, without clinical, radiological and immunological sign of differential diagnosis. After a CIS, the delay of apparition of a relapse, which corresponds to the conversion to clinically definite MS (CDMS), varies from several months to more than 10 years (10-15% of cases, generally called benign RRMS). This delay is generally associated with the number and location of demyelinating lesions of the brain and spinal cord and the results of CSF analysis. Several studies comparing different MRI criteria for dissemination in space and dissemination in time of demyelinating lesions, two hallmarks of MS, provided enough substantial data to update diagnostic criteria for MS after a CIS. In the last revision of the McDonald's criteria in 2010, diagnostic criteria were simplified and now the diagnosis can be made by a single initial scan that proves the presence of active asymptomatic lesions (with gadolinium enhancement) and of unenhanced lesions. However, time to conversion remains highly unpredictable for a given patient and CIS can remain isolated, especially for idiopathic unilateral optic neuritis or myelitis. Univariate analyses of clinical, radiological, biological or electrophysiological characteristics of CIS patients in small series identified numerous risk factors of rapid conversion to MS. However, large series of CIS patients analyzing several characteristics of CIS patients and the influence of disease modifying therapies brought important information about the risk of CDMS or RRMS over up to 20 years of follow-up. They confirmed the importance of the initial MRI pattern of demyelinating lesions and of CSF oligoclonal bands. Available treatments of MS (immunomodulators or immunosuppressants) have also shown unequivocal efficacy to slow the conversion to RRMS after a CIS, but they could be unnecessary for patients with benign RRMS. Beyond diagnostic criteria, knowledge of established and potential risk factors of conversion to MS and of disability progression is essential for CIS patients' follow-up and initiation of disease modifying therapies.
Topics: Biomarkers; Demyelinating Diseases; Disease Progression; Humans; Magnetic Resonance Imaging; Multiple Sclerosis; Risk Factors
PubMed: 25813099
DOI: 10.1016/j.lpm.2015.03.002 -
Scientific Reports Aug 2017The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such...
The Aryl hydrocarbon Receptor(AhR) is among the most important receptors which bind pollutants; however it also regulates signaling pathways independently of such exposure. We previously demonstrated that AhR is expressed during development of the central nervous system(CNS) and that its deletion leads to the occurrence of a congenital nystagmus. Objectives of the present study are to decipher the origin of these deficits, and to identify the role of the AhR in the development of the CNS. We show that the AhR-knockout phenotype develops during early infancy together with deficits in visual-information-processing which are associated with an altered optic nerve myelin sheath, which exhibits modifications in its lipid composition and in the expression of myelin-associated-glycoprotein(MAG), a cell adhesion molecule involved in myelin-maintenance and glia-axon interaction. In addition, we show that the expression of pro-inflammatory cytokines is increased in the impaired optic nerve and confirm that inflammation is causally related with an AhR-dependent decreased expression of MAG. Overall, our findings demonstrate the role of the AhR as a physiological regulator of myelination and inflammatory processes in the developing CNS. It identifies a mechanism by which environmental pollutants might influence CNS myelination and suggest AhR as a relevant drug target for demyelinating diseases.
Topics: Animals; Astrocytes; Cytokines; Demyelinating Diseases; Disease Models, Animal; Evoked Potentials, Visual; Genetic Association Studies; Genetic Predisposition to Disease; Inflammation; Inflammation Mediators; Mice; Mice, Knockout; Myelin Sheath; Optic Nerve; Phenotype; Receptors, Aryl Hydrocarbon; Signal Transduction
PubMed: 28851966
DOI: 10.1038/s41598-017-09621-3 -
Multiple Sclerosis and Related Disorders Jun 2021Since March 2020, during the Coronavirus disease 2019 (COVID-19) pandemic, it has been observed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has...
BACKGROUND
Since March 2020, during the Coronavirus disease 2019 (COVID-19) pandemic, it has been observed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has neurological involvement with various clinical tables.
METHODS
We present 3 new cases admitted to our clinic with various neurological findings which were affected by SARS-CoV-2.
RESULTS
Imaging studies have shown that inflammatory/demyelinizing lesions appeared in different areas of the central nervous system which were accepted as an atypical demyelinating spectrum associated with Covid 19.
CONCLUSIONS
With increasing experience, it has been suggested that SARS-CoV-2 may also have a neurotrophic effect. The spectrum of neurological involvement is also expanding as the pandemic continues. These 3 cases suggest that the virus plays a role in the clinical onset of the inflammatory/demyelinating disease.
Topics: COVID-19; Central Nervous System; Demyelinating Diseases; Humans; Pandemics; SARS-CoV-2
PubMed: 33770573
DOI: 10.1016/j.msard.2021.102900 -
Revue Neurologique Jun 2018Multiple sclerosis (MS) arises in people who have a genetic susceptibility to environmental factors and events, which ultimately trigger the disease. It is thought that... (Review)
Review
Multiple sclerosis (MS) arises in people who have a genetic susceptibility to environmental factors and events, which ultimately trigger the disease. It is thought that peripheral immune cells are mobilized and enter the CNS through the impaired blood-brain barrier in the subarachnoid space, as acute lesions show large numbers of macrophages and CD8+ T cells and, to a lesser extent, CD4+ T cells, B cells and plasma cells. Demyelination is mostly localized to focal lesions in early relapsing-remitting (RR) MS, whereas other areas of white matter appear normal. Over time, T-cell and B-cell infiltration becomes more diffuse and axonal injury more widespread, leading to self-perpetuating atrophy in both white and gray matter. With disease progression, inflammatory processes are predominantly driven by the action of CNS resident microglia cells. In addition, there is evidence that meningeal lymphoid-like structures can form and contribute to late-stage inflammation. In general, however, despite dynamic changes over time in MS pathology, lesions do not appear to differ significantly in the different classic forms of MS already identified. While all treatments approved for MS management target inflammatory components of RRMS, the B-cell-depleting antibody ocrelizumab is the first such treatment approved recently for primary progressive (PP) MS. However, recent pathological and imaging findings have prompted reconsideration of the clinical phenotypes of MS patients proposed by Lublin's 2013 classification, including clinical and MRI signs of activity, and new imaging biomarkers of remyelination are now being investigated for new strategies of MS management.
Topics: Blood-Brain Barrier; Brain; Demyelinating Diseases; Disease Progression; Humans; Inflammation; Multiple Sclerosis; Neurology
PubMed: 29680179
DOI: 10.1016/j.neurol.2018.03.006 -
Multiple Sclerosis and Related Disorders Nov 2014To evaluate the prevalence of and associated factors impacting vitamin D insufficiency and deficiency in childhood versus adult-onset demyelinating disease.
OBJECTIVE
To evaluate the prevalence of and associated factors impacting vitamin D insufficiency and deficiency in childhood versus adult-onset demyelinating disease.
METHODS
We conducted a retrospective, cross-sectional, chart-review, cohort study on geographically-similar pediatric, young adult, and adult patients with a diagnosis of demyelinating disease identified at the University of Virginia from 2008 to 2013. Group prevalence of vitamin D insufficiency and deficiency as well as relevant factors associated with vitamin D status was analyzed and compared.
RESULTS
We identified 24 childhood-onset (CO), 33 young adult-onset (Y-AO), and 59 adult-onset (AO) cases. There was no difference in the prevalence of vitamin D insufficiency or deficiency between the cohorts. Non-Caucasian race and elevated body mass index were significantly associated with low vitamin D levels, regardless of age of onset. In regression models, race and obesity were independent predictors of vitamin D status. The prevalence of obesity was significantly higher in the childhood-onset cohort (CO=58.5%; Y-AO=31%; AO=34%; p=0.02).
CONCLUSIONS
Our findings demonstrate no difference in the prevalence of vitamin D insufficiency/deficiency between childhood and adult-onset demyelinating disease, suggesting age at disease onset is irrelevant to vitamin D status in demyelinating disease. Both race and obesity are independent factors associated with vitamin D insufficiency/deficiency, regardless of age of disease onset. Obesity, independent of gender, is significantly higher in children compared to adult patients diagnosed with multiple sclerosis and may have a role in the development of childhood-onset demyelinating disease.
Topics: Adolescent; Adult; Age of Onset; Child; Cross-Sectional Studies; Demyelinating Diseases; Female; Humans; Male; Middle Aged; Obesity; Prevalence; Retrospective Studies; Risk Factors; Vitamin D; Vitamin D Deficiency; Young Adult
PubMed: 25891547
DOI: 10.1016/j.msard.2014.07.004 -
Multiple Sclerosis and Related Disorders Oct 2021Radiologically Isolated Syndrome (RIS) likely represents the earliest detectable form of multiple sclerosis (MS). There are recognized risk factors for conversion of RIS...
BACKGROUND
Radiologically Isolated Syndrome (RIS) likely represents the earliest detectable form of multiple sclerosis (MS). There are recognized risk factors for conversion of RIS to clinically definite central nervous system (CNS) demyelinating disease. We aim to characterize a new clinical cohort with RIS and to analyze previously established risk factors for conversion to clinically definite disease.
METHODS
A medical records search was performed for patients who were diagnosed with RIS by their treating neurologist at our institution in Boston, USA, from January 2005 to April 2020. Demographic data, clinical outcomes, and treatment courses were analyzed. The time to first clinical event representing a demyelinating disease attack or last follow up without clinically definite disease was calculated for each person. Hazard ratios (HRs) for known risk factors for the conversion of RIS to clinically definite disease were calculated using Cox proportional hazards models.
RESULTS
Of 89 patients, the median age at RIS diagnosis was 41.0 years (76% female, 8% with a family history of MS and 16% of any autoimmune disorder, 66% never smokers, 40% BMI >30 kg/m, 45% with spinal cord MRI lesions). Clinically definite disease was observed in 16 patients (18%) during follow-up (median time to first event 3.4 years; median follow-up duration of full cohort 3.8 years). Median EDSS for those who developed clinically definite disease was 1.25 (range: 0-4) at most recent follow up. Of 84 patients with longitudinal brain imaging, 42 (50%) had new demyelinating lesions. Gadolinium-enhancing lesions were seen in 36 patients (43%) at either baseline (n=24) or follow-up (n=12). Most patients had at least one T1-hypointense lesion (n=70, 83%). Five patients underwent ultra-high field MRI (7 Tesla); all were positive for central vein sign, two demonstrated leptomeningeal enhancement, and one was found to have cortical lesions. Out of 30 patients with susceptibility-weighted imaging acquired during routine clinical care, 8 had at least one paramagnetic rim positive lesion. Previously reported risk factors for conversion to MS were not significant: age ≤37 years HR 1.3 (95% confidence interval (CI), 0.47-3.5), male sex 1.5 (95% CI, 0.41-5.2), and spinal cord lesions 1.3 (0.47-3.4). Nearly one-third of RIS patients (n=26) took a disease modifying therapy (DMT) for MS (median total treatment duration on any DMT=2.7 years). The sub-cohort treated with a DMT had a statistically significantly greater number of recognized risk factors for conversion to clinically definite disease compared with the untreated group (p=0.028). Most patients took a DMT for MRI changes demonstrating new demyelinating disease activity (n=16). Dimethyl fumarate (n=9) and glatiramer acetate (n=7) were the most frequently prescribed DMTs. A second-line DMT was started in 10 patients.
CONCLUSION
We characterize a new cohort of RIS patients, demonstrating time to clinically evident demyelinating disease from RIS diagnosis of approximately 3.4 years. Our data suggest that early use of a DMT in RIS may mitigate the impact of recognized risk factors on the occurrence of clinically evident disease and reduce the likelihood of conversion to clinically definite CNS demyelinating disease in high-risk individuals.
Topics: Adult; Cohort Studies; Demyelinating Diseases; Disease Progression; Female; Humans; Magnetic Resonance Imaging; Male; Multiple Sclerosis; Retrospective Studies
PubMed: 34365315
DOI: 10.1016/j.msard.2021.103183 -
Journal of Neuroinflammation Jul 2017Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive...
BACKGROUND
Multiple sclerosis is a neuroinflammatory demyelinating and neurodegenerative disease of the central nervous system characterized by recurrent and progressive demyelination/remyelination cycles, neuroinflammation, oligodendrocyte loss, demyelination, and axonal degeneration. Cyclic phosphatidic acid (cPA) is a natural phospholipid mediator with a unique cyclic phosphate ring structure at the sn-2 and sn-3 positions of the glycerol backbone. We reported earlier that cPA elicits a neurotrophin-like action and protects hippocampal neurons from ischemia-induced delayed neuronal death. We designed, chemically synthesized, and metabolically stabilized derivatives of cPA: 2-carba-cPA (2ccPA), a synthesized compound in which one of the phosphate oxygen molecules is replaced with a methylene group at the sn-2 position. In the present study, we investigated whether 2ccPA exerts protective effects in oligodendrocytes and suppresses pathology in the two most common mouse models of multiple sclerosis.
METHODS
To evaluate whether 2ccPA has potential beneficial effects on the pathology of multiple sclerosis, we investigated the effects of 2ccPA on oligodendrocyte cell death in vitro and administrated 2ccPA to mouse models of experimental autoimmune encephalomyelitis (EAE) and cuprizone-induced demyelination.
RESULTS
We demonstrated that 2ccPA suppressed the CoCl-induced increase in the Bax/Bcl-2 protein expression ratio and phosphorylation levels of p38MAPK and JNK protein. 2ccPA treatment reduced cuprizone-induced demyelination, microglial activation, NLRP3 inflammasome, and motor dysfunction. Furthermore, 2ccPA treatment reduced autoreactive T cells and macrophages, spinal cord injury, and pathological scores in EAE, the autoimmune multiple sclerosis mouse model.
CONCLUSIONS
We demonstrated that 2ccPA protected oligodendrocytes via suppression of the mitochondrial apoptosis pathway. Also, we found beneficial effects of 2ccPA in the multiperiod of cuprizone-induced demyelination and the pathology of EAE. These data indicate that 2ccPA may be a promising compound for the development of new drugs to treat demyelinating disease and ameliorate the symptoms of multiple sclerosis.
Topics: Animals; Anti-Inflammatory Agents; Apoptosis; Cell Differentiation; Cell Line, Transformed; Cuprizone; Demyelinating Diseases; Disease Models, Animal; Female; Gene Expression Regulation; Humans; MAP Kinase Signaling System; Male; Mice; Mice, Inbred C57BL; Monoamine Oxidase Inhibitors; Myelin Sheath; NLR Family, Pyrin Domain-Containing 3 Protein; Phosphatidic Acids; Proto-Oncogene Proteins c-bcl-2; p38 Mitogen-Activated Protein Kinases
PubMed: 28732510
DOI: 10.1186/s12974-017-0923-5 -
Reviews in the Neurosciences Jan 2018Demyelinating diseases, such as multiple sclerosis (MS), are kinds of common diseases in the central nervous system (CNS), and originated from myelin loss and axonal... (Review)
Review
Demyelinating diseases, such as multiple sclerosis (MS), are kinds of common diseases in the central nervous system (CNS), and originated from myelin loss and axonal damage. Oligodendrocyte dysfunction is the direct reason of demyelinating lesions in the CNS. Nitric oxide (NO) plays an important role in the pathological process of demyelinating diseases. Although the neurotoxicity of NO is more likely mediated by peroxynitrite rather than NO itself, NO can impair oligodendrocyte energy metabolism through mediating the damaging of mitochondrial DNA, mitochondrial membrane and mitochondrial respiratory chain complexes. In the progression of MS, NO can mainly mediate demyelination, axonal degeneration and cell death. Hence, in this review, we extensively discuss endangerments of NO in oligodendrocytes (OLs), which is suggested to be the main mediator in demyelinating diseases, e.g. MS. We hypothesize that NO takes part in MS through impairing the function of monocarboxylate transporter 1, especially causing axonal degeneration. Then, it further provides a new insight that NO for OLs may be a reliable therapeutic target to ameliorate the course of demyelinating diseases.
Topics: Animals; Humans; Mitochondrial Diseases; Multiple Sclerosis; Myelin Sheath; Nitric Oxide; Oligodendroglia
PubMed: 28822986
DOI: 10.1515/revneuro-2017-0033