International Journal of Molecular Sciences

Editorial

Jump to: Research, Review, Other

152 KiB

Open AccessEditorial

Multiple Sclerosis: From Molecules to Treatment

by Simon A. Broadley

Int. J. Mol. Sci. 2013, 14(4), 7598-7602; https://doi.org/10.3390/ijms14047598 - 8 Apr 2013

Viewed by 5288

Abstract

The treatment of multiple sclerosis has been radically transformed over the past 20 years and this special issue of IJMS, focusing on the molecular aspects of the disease, highlights the growing conformity of the various investigative approaches. It is a very exciting time [...] Read more.

The treatment of multiple sclerosis has been radically transformed over the past 20 years and this special issue of IJMS, focusing on the molecular aspects of the disease, highlights the growing conformity of the various investigative approaches. It is a very exciting time to be involved in the research of this disease. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

Research

Jump to: Editorial, Review, Other

767 KiB

Open AccessArticle

Differential Regulation of CD4+ T Cell Adhesion to Cerebral Microvascular Endothelium by the β-Chemokines CCL2 and CCL3

by Kenneth KY Liu and Katerina Dorovini-Zis

Int. J. Mol. Sci. 2012, 13(12), 16119-16140; https://doi.org/10.3390/ijms131216119 - 30 Nov 2012

Cited by 18 | Viewed by 6765

Abstract

In Multiple sclerosis (MS), circulating lymphocytes cross the blood–brain barrier (BBB) and accumulate at sites of antigenic challenge. This process depends on specific interactions between lymphocytes and cerebral microvascular endothelium that involve endothelial activation by cytokines and the presence of chemokines. Chemokines play [...] Read more.

In Multiple sclerosis (MS), circulating lymphocytes cross the blood–brain barrier (BBB) and accumulate at sites of antigenic challenge. This process depends on specific interactions between lymphocytes and cerebral microvascular endothelium that involve endothelial activation by cytokines and the presence of chemokines. Chemokines play a key role in the orchestration of immune responses, acting both as chemoattractants and activators of leukocyte subsets. In the present study, we investigated the effects of the β-chemokines, CCL2 and CCL3, on the adhesion of CD4+ T cell subsets to human brain microvessel endothelial cells (HBMEC). Chemokines added to the lower compartment of a two-chamber chemotaxis system under confluent resting or cytokine-activated HBMEC, diffused through the culture substrate and bound to the basal surface of HBMEC. The low rate of adhesion of naïve, resting and memory CD4+ T cells to resting HBMEC was significantly upregulated following treatment of HBMEC with TNF-α and IFN-g. Recently activated CD4+ T cells readily adhered to resting monolayers. Concentration gradients of CCL2 upregulated the adhesion of activated CD4+ T cells to cytokine treated but not resting HBMEC. The presence of CCL3 in the lower chamber increased the adhesion of memory T cells to both unstimulated and cytokine-treated HBMEC. These findings emphasize the importance of brain endothelial cell activation and the role of CCL2 and CCL3 in regulating the adhesion of CD4+ T cell subsets to BBB endothelium, thus contributing to the specificity of immune responses in MS. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Graphical abstract

676 KiB

Open AccessArticle

Interleukin-6 Gene Promoter-572 C Allele May Play a Role in Rate of Disease Progression in Multiple Sclerosis

by Jun Yan, Jia Liu, Clement Yihao Lin, ANZGene, Peter A. Csurhes, Michael P. Pender, Pamela A. McCombe and Judith M. Greer

Int. J. Mol. Sci. 2012, 13(10), 13667-13679; https://doi.org/10.3390/ijms131013667 - 22 Oct 2012

Cited by 16 | Viewed by 7739

Abstract

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important [...] Read more.

Multiple sclerosis (MS) is an inflammatory demyelinating disease affecting the central nervous system. Although the exact pathogenesis of MS is unknown, it is generally considered to be an autoimmune disease, with numerous genetic and environmental factors determining disease susceptibility and severity. One important mediator of immune responses and inflammation is interleukin-6 (IL-6). Previously, elevated levels of IL-6 in mononuclear cells in blood and in brain tissue from MS patients have been reported. Various polymorphisms in the promoter region of the IL6 gene have also been linked with IL-6 protein levels. In MS, several small studies have investigated whether two IL6 promoter polymorphisms (−597 G>A and −174 G>C) correlate with MS susceptibility, but with varying results. In the present study, we analyzed these polymorphisms, together with an additional polymorphism (−572 G>C) in 279 healthy controls and 509 patients with MS. We found no significant differences between MS patients and healthy controls for the different −597 or −174 IL6 promoter alleles or genotypes. There was a slight reduction in the percentage of individuals with MS who carried a C allele at position −572, although this was not significant after correction for multiple comparisons. Interestingly, however, the −572 C allele showed a significant correlation with the MS severity score, suggesting a possible role in disease progression. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

1041 KiB

Open AccessArticle

Effect of High-Dose Vitamin D3 Intake on Ambulation, Muscular Pain and Bone Mineral Density in a Woman with Multiple Sclerosis: A 10-Year Longitudinal Case Report

by Barbara M. Van Amerongen and François Feron

Int. J. Mol. Sci. 2012, 13(10), 13461-13483; https://doi.org/10.3390/ijms131013461 - 19 Oct 2012

Cited by 6 | Viewed by 8917

Abstract

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who [...] Read more.

Mounting evidence correlate vitamin D3 (cholecalciferol) supplementation or higher serum levels of vitamin D (25(OH)D) with a lower risk of developing multiple sclerosis (MS), reduced relapse rate, slower progression or fewer new brain lesions. We present here the case of a woman who was diagnosed with MS in 1990. From 1980 to 2000, her ability to walk decreased from ~20 to 1 km per day. Since January 2001, a vitamin D3 supplement was ingested daily. The starting dose was 20 mcg (800 IU)/day and escalated to 100 mcg (4000 IU)/day in September 2004 and then to 150 mcg (6000 IU)/day in December 2005. Vitamin D3 intake reduced muscular pain and improved ambulation from 1 (February 2000) to 14 km/day (February 2008). Vitamin D intake over 10 years caused no adverse effects: no hypercalcaemia, nephrolithiasis or hypercalciuria were observed. Bowel problems in MS may need to be addressed as they can cause malabsorption including calcium, which may increase serum PTH and 1,25(OH)2D levels, as well as bone loss. We suggest that periodic assessment of vitamin D3, calcium and magnesium intake, bowel problems and the measurement of serum 25(OH)D, PTH, Ca levels, UCa/Cr and bone health become part of the integral management of persons with MS. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

171 KiB

Open AccessArticle

Relation between Pro-inflammatory Cytokines and Acetylcholine Levels in Relapsing-Remitting Multiple Sclerosis Patients

by Marcella Reale, Federica De Angelis, Marta Di Nicola, Elisabetta Capello, Maria Di Ioia, Giovanna De Luca, Alessandra Lugaresi and Ada Maria Tata

Int. J. Mol. Sci. 2012, 13(10), 12656-12664; https://doi.org/10.3390/ijms131012656 - 3 Oct 2012

Cited by 56 | Viewed by 8442

Abstract

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder. Since acetylcholine (ACh) is known to participate in the inflammatory response, we investigated the possible relationship between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis (RR-MS) patients. Levels of ACh and [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disorder. Since acetylcholine (ACh) is known to participate in the inflammatory response, we investigated the possible relationship between pro-inflammatory cytokines and acetylcholine levels in relapsing-remitting multiple sclerosis (RR-MS) patients. Levels of ACh and pro-inflammatory cytokines IL1-β and IL-17 were measured both in cerebrospinal fluid (CSF) and sera of 22 RR-MS patients in the relapsing phase and in 17 control subjects affected by other non-neurological diseases (OND). We observed higher levels of pro-inflammatory cytokines such as IL-1β and IL-17 in both CSF and serum of RR-MS patients compared to control subjects. Moreover, ACh levels were lower in CSF and serum of RR-MS patients compared to levels of control subjects. Although the relationship between high inflammatory cytokine levels and low ACh levels need to be further investigated in the future, our data suggest that IL-1β, and cytokines induced by it, such as IL-17 and ACh, may be involved in the pathogenesis of MS. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

348 KiB

Open AccessArticle

Interferon-β1b Increases Th2 Response in Neuromyelitis Optica

by Hideto Nakajima, Takafumi Hosokawa, Yoshimitu Doi, Toshiyuki Ikemoto, Shimon Ishida, Fumiharu Kimura and Toshiaki Hanafusa

Int. J. Mol. Sci. 2012, 13(10), 12213-12223; https://doi.org/10.3390/ijms131012213 - 25 Sep 2012

Cited by 6 | Viewed by 6112

Abstract

A Japanese randomized controlled study showed that Interferon â (IFN-â1b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-â (IFN-â1a/IFN-â1b) treatment was not effective in neuromyelitis [...] Read more.

A Japanese randomized controlled study showed that Interferon â (IFN-â1b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-â (IFN-â1a/IFN-â1b) treatment was not effective in neuromyelitis optica (NMO) patients and that the diminished benefit of IFN-â treatment in NMO may be due to different immune responses to IFN-â. We determined longitudinally the expression of CCR5, CXCR3 and CCR4 on CD4+ T and CD8+ T cells in the blood from patients with NMO and MS treated with IFN-â1b. During a 12-month period of IFN-â1b therapy, the annualized relapse rate decreased in MS patients but not in NMO patients. There was no significant difference in the expression of the chemokine receptors between NMO and MS at baseline. The percentages of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of the Th1 response, were decreased in both NMO and MS after treatment. The percentage of CD4+CCR4+ T cells, representative of the Th2 response, was decreased in MS, but those for NMO was significantly increased compared with the pretreatment levels. Our results indicate that IFN-â1b-induced up-modulation of the Th2 response in NMO patients may be the source of differences in the therapeutic response to IFN-â1b therapy. In the present study, Th2 predominance is involved in the pathogenesis of NMO. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

242 KiB

Open AccessArticle

Comparison of Standard 1.5 T vs. 3 T Optimized Protocols in Patients Treated with Glatiramer Acetate. A Serial MRI Pilot Study

by Robert Zivadinov, David Hojnacki, Sara Hussein, Niels Bergsland, Ellen Carl, Jacqueline Durfee, Michael G. Dwyer, Cheryl Kennedy and Bianca Weinstock-Guttman

Int. J. Mol. Sci. 2012, 13(5), 5659-5673; https://doi.org/10.3390/ijms13055659 - 10 May 2012

Cited by 3 | Viewed by 6804

Abstract

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an [...] Read more.

This study explored the effect of glatiramer acetate (GA, 20 mg) on lesion activity using the 1.5 T standard MRI protocol (single dose gadolinium [Gd] and 5-min delay) or optimized 3 T protocol (triple dose of Gd, 20-min delay and application of an off-resonance saturated magnetization transfer pulse). A 15-month, phase IV, open-label, single-blinded, prospective, observational study included 12 patients with relapsing-remitting multiple sclerosis who underwent serial MRI scans (Days −45, −20, 0; the minus ign indicates the number of days before GA treatment; and on Days 30, 60, 90, 120, 150, 180, 270 and 360 during GA treatment) on 1.5 T and 3 T protocols. Cumulative number and volume of Gd enhancing (Gd-E) and T2 lesions were calculated. At Days −45 and 0, there were higher number (p < 0.01) and volume (p < 0.05) of Gd-E lesions on 3 T optimized compared to 1.5 T standard protocol. However, at 180 and 360 days of the study, no significant differences in total and cumulative number of new Gd-E and T 2 lesions were found between the two protocols. Compared to pre-treatment period, at Days 180 and 360 a significantly greater decrease in the cumulative number of Gd-E lesions (p = 0.03 and 0.021, respectively) was found using the 3 T vs. the 1.5 T protocol (p = NS for both time points). This MRI mechanistic study suggests that GA may exert a greater effect on decreasing lesion activity as measured on 3 T optimized compared to 1.5 T standard protocol. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Review

Jump to: Editorial, Research, Other

480 KiB

Open AccessReview

From Identification to Characterization of the Multiple Sclerosis Susceptibility Gene CLEC16A

by Tone Berge, Ingvild Sørum Leikfoss and Hanne F. Harbo

Int. J. Mol. Sci. 2013, 14(3), 4476-4497; https://doi.org/10.3390/ijms14034476 - 25 Feb 2013

Cited by 33 | Viewed by 8204

Abstract

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA) loci were early shown to confer the strongest genetic associations in MS. Now, more [...] Read more.

Multiple sclerosis (MS) is an inflammatory, demyelinating disorder of the central nervous system that develops in genetically susceptible individuals, probably triggered by common environmental factors. Human leukocyte antigen (HLA) loci were early shown to confer the strongest genetic associations in MS. Now, more than 50 non-HLA MS susceptibility loci are identified, of which the majority are located in immune-regulatory genes. Single nucleotide polymorphisms (SNPs) in the C-type lectin-like domain family 16A (CLEC16A) gene were among the first non-HLA genetic variants that were confirmed to be associated with MS. Fine-mapping has indicated a primary association in MS and also other autoimmune diseases to intronic CLEC16A SNPs. Here, we review the identification of MS susceptibility variants in the CLEC16A gene region, functional studies of the CLEC16A molecule and the recent progress in understanding the implications thereof for MS development. This may serve as an example of the importance for further molecular investigation of the loci identified in genetic studies, with the aim to translate this knowledge into the clinic. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Graphical abstract

126 KiB

Open AccessReview

Signalling Pathways that Inhibit the Capacity of Precursor Cells for Myelin Repair

by Jennifer K. Sabo and Holly S. Cate

Int. J. Mol. Sci. 2013, 14(1), 1031-1049; https://doi.org/10.3390/ijms14011031 - 7 Jan 2013

Cited by 14 | Viewed by 6245

Abstract

In demyelinating disorders such as Multiple Sclerosis (MS), targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction. Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders. Endogenous precursor cells or exogenous transplanted [...] Read more.

In demyelinating disorders such as Multiple Sclerosis (MS), targets of injury are myelin and oligodendrocytes, leading to severe neurological dysfunction. Regenerative therapies aimed at promoting oligodendrocyte maturation and remyelination are promising strategies for treatment in demyelinating disorders. Endogenous precursor cells or exogenous transplanted cells are potential sources for remyelinating oligodendrocytes in the central nervous system (CNS). Several signalling pathways have been implicated in regulating the capacity of these cell populations for myelin repair. Here, we review neural precursor cells and oligodendrocyte progenitor cells as potential sources for remyelinating oligodendrocytes and evidence for the functional role of key signalling pathways in inhibiting regeneration from these precursor cell populations. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

201 KiB

Open AccessReview

Mast Cells in the Pathogenesis of Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

by Massimo Costanza, Mario P. Colombo and Rosetta Pedotti

Int. J. Mol. Sci. 2012, 13(11), 15107-15125; https://doi.org/10.3390/ijms131115107 - 16 Nov 2012

Cited by 32 | Viewed by 8311

Abstract

Mast cells (MCs) are best known as key immune players in immunoglobulin E (IgE)-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis [...] Read more.

Mast cells (MCs) are best known as key immune players in immunoglobulin E (IgE)-dependent allergic reactions. In recent years, several lines of evidence have suggested that MCs might play an important role in several pathological conditions, including autoimmune disorders such as multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), an animal model for MS. Since their first description in MS plaques in the late 1800s, much effort has been put into elucidating the contribution of MCs to the development of central nervous system (CNS) autoimmunity. Mouse models of MC-deficiency have provided a valuable experimental tool for dissecting MC involvement in MS and EAE. However, to date there is still major controversy concerning the function of MCs in these diseases. Indeed, although MCs have been classically proposed as having a detrimental and pro-inflammatory role, recent literature has questioned and resized the contribution of MCs to the pathology of MS and EAE. In this review, we will present the main evidence obtained in MS and EAE on this topic, and discuss the critical and controversial aspects of such evidence. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

2177 KiB

Open AccessReview

Glatiramer Acetate in Treatment of Multiple Sclerosis: A Toolbox of Random Co-Polymers for Targeting Inflammatory Mechanisms of both the Innate and Adaptive Immune System?

by Babak Jalilian, Halldór Bjarki Einarsson and Thomas Vorup-Jensen

Int. J. Mol. Sci. 2012, 13(11), 14579-14605; https://doi.org/10.3390/ijms131114579 - 9 Nov 2012

Cited by 26 | Viewed by 15346

Abstract

Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA) is a formulation of random polypeptide copolymers [...] Read more.

Multiple sclerosis is a disease of the central nervous system, resulting in the demyelination of neurons, causing mild to severe symptoms. Several anti-inflammatory treatments now play a significant role in ameliorating the disease. Glatiramer acetate (GA) is a formulation of random polypeptide copolymers for the treatment of relapsing-remitting MS by limiting the frequency of attacks. While evidence suggests the influence of GA on inflammatory responses, the targeted molecular mechanisms remain poorly understood. Here, we review the multiple pharmacological modes-of-actions of glatiramer acetate in treatment of multiple sclerosis. We discuss in particular a newly discovered interaction between the leukocyte-expressed integrin α_Mβ₂ (also called Mac-1, complement receptor 3, or CD11b/CD18) and perspectives on the GA co-polymers as an influence on the function of the innate immune system. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Graphical abstract

376 KiB

Open AccessReview

Experimental and Therapeutic Opportunities for Stem Cells in Multiple Sclerosis

by Rickie Patani and Siddharthan Chandran

Int. J. Mol. Sci. 2012, 13(11), 14470-14491; https://doi.org/10.3390/ijms131114470 - 8 Nov 2012

Cited by 6 | Viewed by 6564

Abstract

Multiple Sclerosis (MS) is an inflammatory demyelinating neurodegenerative disorder of the brain and spinal cord that causes significant disability in young adults. Although the precise aetiopathogenesis of MS remains unresolved, its pathological hallmarks include inflammation, demyelination, axonal injury (acute and chronic), astrogliosis and [...] Read more.

Multiple Sclerosis (MS) is an inflammatory demyelinating neurodegenerative disorder of the brain and spinal cord that causes significant disability in young adults. Although the precise aetiopathogenesis of MS remains unresolved, its pathological hallmarks include inflammation, demyelination, axonal injury (acute and chronic), astrogliosis and variable remyelination. Despite major recent advances in therapeutics for the early stage of the disease there are currently no disease modifying treatments for the progressive stage of disease, whose pathological substrate is axonal degeneration. This represents the great and unmet clinical need in MS. Against this background, human stem cells offer promise both to improve understanding of disease mechanism(s) through in-vitro modeling as well as potentially direct use to supplement and promote remyelination, an endogenous reparative process where entire myelin sheaths are restored to demyelinated axons. Conceptually, stem cells can act directly to myelinate axons or indirectly through different mechanisms to promote endogenous repair; importantly these two mechanisms of action are not mutually exclusive. We propose that discovery of novel methods to invoke or enhance remyelination in MS may be the most effective therapeutic strategy to limit axonal damage and instigate restoration of structure and function in this debilitating condition. Human stem cell derived neurons and glia, including patient specific cells derived through reprogramming, provide an unprecedented experimental system to model MS “in a dish” as well as enable high-throughput drug discovery. Finally, we speculate upon the potential role for stem cell based therapies in MS. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

397 KiB

Open AccessReview

The Role of Neurotrophins in Multiple Sclerosis—Pathological and Clinical Implications

by Alicja Kalinowska-Lyszczarz and Jacek Losy

Int. J. Mol. Sci. 2012, 13(10), 13713-13725; https://doi.org/10.3390/ijms131013713 - 22 Oct 2012

Cited by 34 | Viewed by 7620

Abstract

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) with unknown etiology. It was recently suggested that autoimmunity, which had long been considered to be destructive in MS, might also play a protective role in [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory demyelinating and neurodegenerative disease of the central nervous system (CNS) with unknown etiology. It was recently suggested that autoimmunity, which had long been considered to be destructive in MS, might also play a protective role in the CNS of MS patients. Neurotrophins are polypeptides belonging to the neurotrophic factor family. While neurotrophins mediate cell survival and proliferation in the nervous system, they are also expressed within peripheral blood mononuclear cells fraction (PBMCs) of immunological system. In MS additional neurotrophic support from PBMCs might compensate relative neurotrophins deficiency in the damaged CNS tissue that needs to be repaired. Failure to produce the adequate neurotrophins concentrations might result in decreased protection of the CNS, consequently leading to increased atrophy, which is the main determinant of MS patients’ end-point disability. There are several lines of evidence, both from clinical research and animal models, suggesting that neurotrophins play a pivotal role in neuroprotective and neuroregenerative processes that are often defective in the course of MS. It seems that neuroprotective strategies might be used as potentially valuable add-on therapies, alongside traditional immunomodulatory treatment in multiple sclerosis. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

253 KiB

Open AccessReview

MicroRNAs as Active Players in the Pathogenesis of Multiple Sclerosis

by Chiara Fenoglio, Elisa Ridolfi, Daniela Galimberti and Elio Scarpini

Int. J. Mol. Sci. 2012, 13(10), 13227-13239; https://doi.org/10.3390/ijms131013227 - 15 Oct 2012

Cited by 61 | Viewed by 7530

Abstract

MicroRNAs (miRNAs) are a recently discovered group of small noncoding RNAs that regulate gene expression post-transcriptionally. They are highly expressed in cells of the immune system, as well as in the central nervous system, and they are deregulated in various neurological disorders. Emerging [...] Read more.

MicroRNAs (miRNAs) are a recently discovered group of small noncoding RNAs that regulate gene expression post-transcriptionally. They are highly expressed in cells of the immune system, as well as in the central nervous system, and they are deregulated in various neurological disorders. Emerging evidence underlines an involvement of miRNAs in the pathogenesis of Multiple Sclerosis (MS). A number of miRNAs have been found to be dysregulated in blood cells from MS patients, in brain lesions, as well as in biological fluids such as serum and plasma. Despite miRNA altered expression likely showing a high tissue specificity, some profile similarities could be observed for certain miRNAs such as miR-326—such as upregulation in both active lesions and blood—though not for others such as miR-323, which demonstrated upregulation in whole blood, active brain lesions, and T-reg cells, but not in the serum of MS patients. In this review, the possible role of miRNAs in MS pathogenesis will be discussed according to all the available literature, with a particular emphasis on the possibility of considering extracellular miRNAs as a new source for both biomarker identification and therapeutic target discovery. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

1843 KiB

Open AccessReview

Molecular Pathogenesis of Neuromyelitis Optica

by Wajih Bukhari, Michael H Barnett, Kerri Prain and Simon A Broadley

Int. J. Mol. Sci. 2012, 13(10), 12970-12993; https://doi.org/10.3390/ijms131012970 - 11 Oct 2012

Cited by 52 | Viewed by 11768

Abstract

Neuromyelitis optica (NMO) is a rare autoimmune disorder, distinct from multiple sclerosis, causing inflammatory lesions in the optic nerves and spinal cord. An autoantibody (NMO IgG) against aquaporin-4 (AQP4), a water channel expressed on astrocytes is thought to be causative. Peripheral production of [...] Read more.

Neuromyelitis optica (NMO) is a rare autoimmune disorder, distinct from multiple sclerosis, causing inflammatory lesions in the optic nerves and spinal cord. An autoantibody (NMO IgG) against aquaporin-4 (AQP4), a water channel expressed on astrocytes is thought to be causative. Peripheral production of the antibody is triggered by an unknown process in genetically susceptible individuals. Anti-AQP4 antibody enters the central nervous system (CNS) when the blood brain barrier is made permeable and has high affinity for orthogonal array particles of AQP4. Like other autoimmune diseases, Th17 cells and their effector cytokines (such as interleukin 6) have been implicated in pathogenesis. AQP4 expressing peripheral organs are not affected by NMO IgG, but the antibody causes extensive astrocytic loss in specific regions of the CNS through complement mediated cytotoxicity. Demyelination occurs during the inflammatory process and is probably secondary to oligodendrocyte apoptosis subsequent to loss of trophic support from astrocytes. Ultimately, extensive axonal injury leads to severe disability. Despite rapid advances in the understanding of NMO pathogenesis, unanswered questions remain, particularly with regards to disease mechanisms in NMO IgG seronegative cases. Increasing knowledge of the molecular pathology is leading to improved treatment strategies. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

554 KiB

Open AccessReview

What Do Effective Treatments for Multiple Sclerosis Tell Us about the Molecular Mechanisms Involved in Pathogenesis?

by Katherine A. Buzzard, Simon A. Broadley and Helmut Butzkueven

Int. J. Mol. Sci. 2012, 13(10), 12665-12709; https://doi.org/10.3390/ijms131012665 - 4 Oct 2012

Cited by 28 | Viewed by 15306

Abstract

Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing [...] Read more.

Multiple sclerosis is a potentially debilitating disease of the central nervous system. A concerted program of research by many centers around the world has consistently demonstrated the importance of the immune system in its pathogenesis. This knowledge has led to the formal testing of a number of therapeutic agents in both animal models and humans. These clinical trials have shed yet further light on the pathogenesis of MS through their sometimes unexpected effects and by their differential effects in terms of impact on relapses, progression of the disease, paraclinical parameters (MRI) and the adverse events that are experienced. Here we review the currently approved medications for the commonest form of multiple sclerosis (relapsing-remitting) and the emerging therapies for which preliminary results from phase II/III clinical trials are available. A detailed analysis of the molecular mechanisms responsible for the efficacy of these medications in multiple sclerosis indicates that blockade or modulation of both T- and B-cell activation and migration pathways in the periphery or CNS can lead to amelioration of the disease. It is hoped that further therapeutic trials will better delineate the pathogenesis of MS, ultimately leading to even better treatments with fewer adverse effects. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

297 KiB

Open AccessReview

Environmental Risk Factors for Multiple Sclerosis: A Review with a Focus on Molecular Mechanisms

by Cullen O’Gorman, Robyn Lucas and Bruce Taylor

Int. J. Mol. Sci. 2012, 13(9), 11718-11752; https://doi.org/10.3390/ijms130911718 - 18 Sep 2012

Cited by 152 | Viewed by 16794

Abstract

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and oligodendrocyte loss. There is a global latitude gradient in MS prevalence, and incidence of [...] Read more.

Multiple sclerosis (MS) is a chronic disabling disease of the central nervous system commonly affecting young adults. Pathologically, there are patches of inflammation (plaques) with demyelination of axons and oligodendrocyte loss. There is a global latitude gradient in MS prevalence, and incidence of MS is increasing (particularly in females). These changes suggest a major role for environmental factors in causation of disease. We have reviewed the evidence and potential mechanisms of action for three exposures: vitamin D, Epstein Barr virus and cigarette smoking. Recent advances supporting gene-environment interactions are reviewed. Further research is needed to establish mechanisms of causality in humans and to explore preventative strategies. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

322 KiB

Open AccessReview

Molecular Mechanisms of Oligodendrocyte Injury in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

by Jilpa Patel and Roumen Balabanov

Int. J. Mol. Sci. 2012, 13(8), 10647-10659; https://doi.org/10.3390/ijms130810647 - 23 Aug 2012

Cited by 45 | Viewed by 8110

Abstract

New evidence has emerged over the last decade indicating that oligodendrocyte injury in multiple sclerosis (MS) is not a single unified phenomenon but rather a spectrum of processes ranging from massive immune destruction to a subtle cell death in the absence of significant [...] Read more.

New evidence has emerged over the last decade indicating that oligodendrocyte injury in multiple sclerosis (MS) is not a single unified phenomenon but rather a spectrum of processes ranging from massive immune destruction to a subtle cell death in the absence of significant inflammation. Experimentally, protection of oligodendrocytes against inflammatory injury results in protection against experimental autoimmune encephalitis, the animal model of multiple sclerosis. In this review, we will discuss the molecular mechanisms regulating oligodendrocyte injury and inflammatory demyelination. We draw attention to the injurious role of IFN-γ signaling in oligodendrocytes and the pro-inflammatory effect of their death. In conclusion, studying the molecular mechanisms of oligodendrocyte injury is likely to provide new perspective on the pathogenesis of MS and a rationale for cell protective therapies. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

540 KiB

Open AccessReview

The Immunomodulatory and Neuroprotective Effects of Mesenchymal Stem Cells (MSCs) in Experimental Autoimmune Encephalomyelitis (EAE): A Model of Multiple Sclerosis (MS)

by Mohammed A. Al Jumah and Mohamed H. Abumaree

Int. J. Mol. Sci. 2012, 13(7), 9298-9331; https://doi.org/10.3390/ijms13079298 - 24 Jul 2012

Cited by 78 | Viewed by 12343

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti-proliferative, anti-inflammatory and anti-apoptotic effects [...] Read more.

Mesenchymal stem cells (MSCs) are multipotent cells that differentiate into the mesenchymal lineages of adipocytes, osteocytes and chondrocytes. MSCs can also transdifferentiate and thereby cross lineage barriers, differentiating for example into neurons under certain experimental conditions. MSCs have anti-proliferative, anti-inflammatory and anti-apoptotic effects on neurons. Therefore, MSCs were tested in experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS), for their effectiveness in modulating the pathogenic process in EAE to develop effective therapies for MS. The data in the literature have shown that MSCs can inhibit the functions of autoreactive T cells in EAE and that this immunomodulation can be neuroprotective. In addition, MSCs can rescue neural cells via a mechanism that is mediated by soluble factors, which provide a suitable environment for neuron regeneration, remyelination and cerebral blood flow improvement. In this review, we discuss the effectiveness of MSCs in modulating the immunopathogenic process and in providing neuroprotection in EAE. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Other

Jump to: Editorial, Research, Review

494 KiB

Open AccessBrief Report

Prenatal Vitamin D Deficiency Induces an Early and More Severe Experimental Autoimmune Encephalomyelitis in the Second Generation

by Diana Andrea Fernandes de Abreu, Véréna Landel, Adrian G. Barnett, John McGrath, Darryl Eyles and Francois Feron

Int. J. Mol. Sci. 2012, 13(9), 10911-10919; https://doi.org/10.3390/ijms130910911 - 30 Aug 2012

Cited by 18 | Viewed by 6232

Abstract

In a previous study, we demonstrated that mouse adult F₁ offspring, exposed to a vitamin D deficiency during pregnancy, developed a less severe and delayed Experimental Autoimmune Encephalomyelitis (EAE), when compared with control offspring. We then wondered whether a similar response was [...] Read more.

In a previous study, we demonstrated that mouse adult F₁ offspring, exposed to a vitamin D deficiency during pregnancy, developed a less severe and delayed Experimental Autoimmune Encephalomyelitis (EAE), when compared with control offspring. We then wondered whether a similar response was observed in the subsequent generation. To answer this question, we assessed F₂ females whose F₁ parents (males or females) were vitamin D-deprived when developing in the uterus of F₀ females. Unexpectedly, we observed that the vitamin D deficiency affecting the F₀ pregnant mice induced a precocious and more severe EAE in the F₂ generation. This paradoxical finding led us to assess its implications for the epidemiology of Multiple Sclerosis (MS) in humans. Using the REFGENSEP database for MS trios (the patient and his/her parents), we collected the parents’ dates of birth and assessed a potential season of birth effect that could potentially be indicative of the vitamin D status of the pregnant grandmothers. A trend for a reduced number of births in the Fall for the parents of MS patients was observed but statistical significance was not reached. Further well powered studies are warranted to validate the latter finding. Full article

(This article belongs to the Special Issue Recent Advances in the Research of Multiple Sclerosis)

► Show Figures

Journal Menu

Journal Browser

Recent Advances in the Research of Multiple Sclerosis

Share This Special Issue

Special Issue Editor

Special Issue Information

Keywords

Benefits of Publishing in a Special Issue

Published Papers (20 papers)

Editorial

Research

Review

Other

Further Information

Guidelines

MDPI Initiatives

Follow MDPI