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Open AccessArticle

Expression of the Antioxidative Enzyme Peroxiredoxin 2 in Multiple Sclerosis Lesions in Relation to Inflammation

by David Voigt, Uta Scheidt, Tobias Derfuss, Wolfgang Brück and Andreas Junker

Int. J. Mol. Sci. 2017, 18(4), 760; https://doi.org/10.3390/ijms18040760 - 4 Apr 2017

Cited by 29 | Viewed by 5616

Abstract

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by demyelination and axonal damage as well as neuronal degeneration. Since oxygen-derived free radicals are an important factor leading to tissue damage in inflammatory multiple sclerosis (MS) lesions, research on [...] Read more.

Multiple sclerosis is a chronic inflammatory disease of the central nervous system, characterized by demyelination and axonal damage as well as neuronal degeneration. Since oxygen-derived free radicals are an important factor leading to tissue damage in inflammatory multiple sclerosis (MS) lesions, research on antioxidative systems is essential to identify endogenous factors which can possibly counteract oxidative damage. As an important scavenging enzyme family, peroxiredoxins (PRDXs) play a crucial role in preventing oxidative damage; however little is known about their expression and function in MS lesions. In the present study we examined the expression of PRDX2 in white matter lesions of MS patients with long-standing, chronic disease. PRDX2 expression was investigated by immunohistochemistry in the context of oxidative stress and inflammation (determined by microglia/macrophage and T cell infiltration) in ten MS autopsy cases as well as seven control autopsy cases. PRDX2 was found to be upregulated in white matter MS lesions mainly in astrocytes, and its expression level was positively correlated with the degree of inflammation and oxidative stress. Our data suggest that PRDX2 expression contributes to the resistance of astrocytes against oxidative damage. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessArticle

Dimethyl Fumarate Therapy Significantly Improves the Responsiveness of T Cells in Multiple Sclerosis Patients for Immunoregulation by Regulatory T Cells

by Janine Schlöder, Carsten Berges, Felix Luessi and Helmut Jonuleit

Int. J. Mol. Sci. 2017, 18(2), 271; https://doi.org/10.3390/ijms18020271 - 28 Jan 2017

Cited by 26 | Viewed by 9087

Abstract

Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), [...] Read more.

Multiple sclerosis (MS) is a chronic autoimmune disease caused by an insufficient suppression of autoreactive T lymphocytes. One reason for the lack of immunological control is the reduced responsiveness of T effector cells (Teff) for the suppressive properties of regulatory T cells (Treg), a process termed Treg resistance. Here we investigated whether the disease-modifying therapy of relapsing-remitting MS (RRMS) with dimethyl fumarate (DMF) influences the sensitivity of T cells in the peripheral blood of patients towards Treg-mediated suppression. We demonstrated that DMF restores responsiveness of Teff to the suppressive function of Treg in vitro, presumably by down-regulation of interleukin-6R (IL-6R) expression on T cells. Transfer of human immune cells into immunodeficient mice resulted in a lethal graft-versus-host reaction triggered by human CD4⁺ Teff. This systemic inflammation can be prevented by activated Treg after transfer of immune cells from DMF-treated MS patients, but not after injection of Treg-resistant Teff from therapy-naïve MS patients. Furthermore, after DMF therapy, proliferation and expansion of T cells and the immigration into the spleen of the animals is reduced and modulated by activated Treg. In summary, our data reveals that DMF therapy significantly improves the responsiveness of Teff in MS patients to immunoregulation. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessArticle

Contribution of Gray and White Matter Abnormalities to Cognitive Impairment in Multiple Sclerosis

by Xiaofei Zhang, Fangfang Zhang, Dehui Huang, Lei Wu, Lin Ma, Hua Liu, Yujun Zhao, Shengyuan Yu and Jiong Shi

Int. J. Mol. Sci. 2017, 18(1), 46; https://doi.org/10.3390/ijms18010046 - 27 Dec 2016

Cited by 43 | Viewed by 5847

Abstract

Patients with multiple sclerosis (MS) commonly exhibit cognitive impairments (CI). However, the neural mechanisms underlying CI remain unclear. The current study applied diffusion tensor imaging (DTI) and voxel-based morphometric (VBM) magnetic resonance imaging (MRI) techniques to evaluate differences in white matter (WM) integrity [...] Read more.

Patients with multiple sclerosis (MS) commonly exhibit cognitive impairments (CI). However, the neural mechanisms underlying CI remain unclear. The current study applied diffusion tensor imaging (DTI) and voxel-based morphometric (VBM) magnetic resonance imaging (MRI) techniques to evaluate differences in white matter (WM) integrity and gray matter (GM) volume between MS patients with CI and MS patients with cognitive preservation (CP). Neuropsychological assessment and MRI were obtained from 39 relapsing-remitting MS (RRMS) patients and 29 healthy controls (HCs). Patients were classified as CI or CP according to cognitive ability, and demographic characteristics and MRI images were compared. Compared with HCs, MS patients exhibited widespread damage in WM integrity, and GM loss in several regions. Compared with CP patients, CI patients exhibited more extensive WM impairments, particularly in the corpus callosum, cerebellar peduncle, corona radiata, optic radiation, superior longitudinal fasciculus, anterior limb of the internal capsule, and cingulate, as well as decreased GM volume in the bilateral caudate, left insula and right temporal lobe. MS patients with CI exhibited more significant structural abnormalities than those with CP. Widespread impairments of WM integrity and selective GM atrophy both appear to be associated with impaired cognition in RRMS. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessArticle

Dysregulated Homeostasis of Acetylcholine Levels in Immune Cells of RR-Multiple Sclerosis Patients

by Maria Di Bari, Marcella Reale, Marta Di Nicola, Viviana Orlando, Sabrina Galizia, Italo Porfilio, Erica Costantini, Chiara D’Angelo, Serena Ruggieri, Stefano Biagioni, Claudio Gasperini and Ada Maria Tata

Int. J. Mol. Sci. 2016, 17(12), 2009; https://doi.org/10.3390/ijms17122009 - 30 Nov 2016

Cited by 26 | Viewed by 5495

Abstract

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. [...] Read more.

Multiple sclerosis (MS) is characterized by pro-inflammatory cytokine production. Acetylcholine (ACh) contributes to the modulation of central and peripheral inflammation. We studied the homeostasis of the cholinergic system in relation to cytokine levels in immune cells and sera of relapsing remitting-MS (RR-MS) patients. We demonstrated that lower ACh levels in serum of RR-MS patients were inversely correlated with the increased activity of the hydrolyzing enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Interestingly, the expression of the ACh biosynthetic enzyme and the protein carriers involved in non-vesicular ACh release were found overexpressed in peripheral blood mononuclear cells of MS patients. The inflammatory state of the MS patients was confirmed by increased levels of TNFα, IL-12/IL-23p40, IL-18. The lower circulating ACh levels in sera of MS patients are dependent on the higher activity of cholinergic hydrolyzing enzymes. The smaller ratio of ACh to TNFα, IL-12/IL-23p40 and IL-18 in MS patients, with respect to healthy donors (HD), is indicative of an inflammatory environment probably related to the alteration of cholinergic system homeostasis. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessArticle

Internet-Supported Physical Exercise Training for Persons with Multiple Sclerosis—A Randomised, Controlled Study

by Alexander Tallner, René Streber, Christian Hentschke, Marc Morgott, Wolfgang Geidl, Mathias Mäurer and Klaus Pfeifer

Int. J. Mol. Sci. 2016, 17(10), 1667; https://doi.org/10.3390/ijms17101667 - 30 Sep 2016

Cited by 56 | Viewed by 8536

Abstract

Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical [...] Read more.

Physical exercise is effective in improving functional outcomes in persons with multiple sclerosis (pwMS). We evaluated the feasibility and effectiveness of internet-based exercise training (e-training) for pwMS on health-related quality of life (HrQoL). Secondary outcomes were muscle strength, aerobic capacity, lung function, physical activity, and fatigue. This is a randomised, controlled trial with a wait-list control group. Data were collected at baseline, after three and six months, and analysed using a hybrid linear model. One-hundred twenty-six pwMS participated in the home-based aerobic (1×/week) and strength training (2×/week) intervention that was supervised and documented via an internet-platform. The intervention group received e-training for six months, and the control group received e-training after a three months waiting period. Significant differences between the groups were only observed for muscle strength (knee flexion (effect size ES = 0.3, p = 0.003), knee extension (ES = 0.24, p = 0.015)), peak expiratory flow (ES = 0.2, p = 0.039), and sports activity (ES = 0.33, p = 0.001) after three months. E-training had no effect on HrQoL but did on muscle strength, lung function, and physical activity. It is a promising and feasible approach to facilitate large-scale, yet individual, training support. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Disease Activity and Conversion into Multiple Sclerosis after Optic Neuritis Is Treated with Erythropoietin

by Kurt-Wolfram Sühs, Panagiotis Papanagiotou, Katharina Hein, Refik Pul, Kerstin Scholz, Christoph Heesen and Ricarda Diem

Int. J. Mol. Sci. 2016, 17(10), 1666; https://doi.org/10.3390/ijms17101666 - 30 Sep 2016

Cited by 7 | Viewed by 5757

Abstract

Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU [...] Read more.

Changes in cerebral lesion load by magnetic resonance imaging (MRI) in patients from a double-blind, placebo-controlled, phase II study on erythropoietin in clinically isolated optic neuritis (ClinicalTrials.gov, NCT00355095) were analyzed. Therefore, patients with acute optic neuritis were assigned to receive either 33,000 IU of recombinant human erythropoietin (IV) daily for three days, or a placebo, as an add-on to methylprednisolone. Of 35 patients, we investigated changes in cerebral lesion load in MRIs obtained at baseline and at weeks 4, 8, and 16. In 5 of the 35 patients, we found conversion into multiple sclerosis (MS) based on MRI progression only. These five patients had received the placebo. Another five patients showed MRI progression together with relapses. Three of these patients had received erythropoietin, and two the placebo. Yet, analyzing the change in absolute numbers of periventricular, juxtacortical, and infratentorial lesions including gadolinium-enhancing lesions, there were no significant differences between the groups. Although effective in terms of retinal nerve fiber layer protection, erythropoietin treatment of acute isolated optic neuritis did not influence further evolution of MRI lesions in the brain when comparing absolute numbers. However, early conversion from clinically isolated syndrome to MS assessed by MRI activity seemed to occur more frequently in the placebo-treated group. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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McDonald Criteria 2010 and 2005 Compared: Persistence of High Oligoclonal Band Prevalence Despite Almost Doubled Diagnostic Sensitivity

by Philipp Schwenkenbecher, Anastasia Sarikidi, Ulrich Wurster, Paul Bronzlik, Kurt-Wolfram Sühs, Peter Raab, Martin Stangel, Refik Pul and Thomas Skripuletz

Int. J. Mol. Sci. 2016, 17(9), 1592; https://doi.org/10.3390/ijms17091592 - 21 Sep 2016

Cited by 33 | Viewed by 6644

Abstract

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral [...] Read more.

The 2010 McDonald criteria were developed to allow a more rapid diagnosis of relapsing-remitting multiple sclerosis (MS) by only one MRI of the brain. Although cerebrospinal fluid (CSF) is not a mandatory part of the latest criteria, the evidence of an intrathecal humoral immunoreaction in the form of oligoclonal bands (OCB) is crucial in the diagnostic workup. To date, the impact of the 2010 McDonald criteria on the prevalence of OCB has not been investigated. We retrospectively evaluated data of 325 patients with a clinical relapse suggestive of demyelination that were treated in a German university hospital between 2010 and 2015. One hundred thirty-six patients (42%) were diagnosed with MS and 189 patients with CIS when the criteria of 2010 were applied. The criteria of 2005 allowed only 70 patients (22%) to be designated as MS. In contrast, the prevalence of OCB was marginal affected in MS patients with 96% for the criteria of 2010 and 98.5% for the criteria of 2005. In conclusion, OCB are prevalent in most MS patients and reflect the chronic inflammatory nature of the disease. We recommend CSF examination to exclude alternative diagnoses and reevaluation of the diagnosis MS in patients with negative OCB. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Regulatory Cell Populations in Relapsing-Remitting Multiple Sclerosis (RRMS) Patients: Effect of Disease Activity and Treatment Regimens

by Maria Rodi, Nikolaos Dimisianos, Anne-Lise De Lastic, Panagiota Sakellaraki, George Deraos, John Matsoukas, Panagiotis Papathanasopoulos and Athanasia Mouzaki

Int. J. Mol. Sci. 2016, 17(9), 1398; https://doi.org/10.3390/ijms17091398 - 25 Aug 2016

Cited by 26 | Viewed by 6505

Abstract

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of autoimmune etiology that results from an imbalance between CNS-specific T effector cells and peripheral suppressive mechanisms mediated by regulatory cells (RC). In this research, we collected blood samples from [...] Read more.

Multiple sclerosis (MS) is a demyelinating disease of the central nervous system (CNS) of autoimmune etiology that results from an imbalance between CNS-specific T effector cells and peripheral suppressive mechanisms mediated by regulatory cells (RC). In this research, we collected blood samples from 83 relapsing remitting MS (RRMS) patients and 45 healthy persons (HC), to assess the sizes of their RC populations, including CD4⁺CD25^highFoxp3⁺ (nTregs), CD3⁺CD4⁺HLA⁻G⁺, CD3⁺CD8⁺CD28⁻, CD3⁺CD56⁺, and CD56^bright cells, and how RC are affected by disease activity (acute phase or remission) and types of treatment (methylprednisolone, interferon, or natalizumab). In addition, we isolated peripheral blood mononuclear cells (PBMC) and cultured them with peptides mapping to myelin antigens, to determine RC responsiveness to autoantigens. The results showed decreased levels of nTregs in patients in the acute phase ± methylprednisolone and in remission + natalizumab, but HC levels in patients in remission or receiving interferon. Patients + interferon had the highest levels of CD3⁺CD4⁺HLA⁻G⁺ and CD3⁺CD8⁺CD28⁻ RC, and patients in the acute phase + methylprednisolone the lowest. Patients in remission had the highest levels of CD3⁺CD56⁺, and patients in remission + natalizumab the highest levels of CD56^bright cells. Only nTregs responded to autoantigens in culture, regardless of disease activity or treatment. The highest suppressive activity was exhibited by nTregs from patients in remission. In conclusion, in RRMS disease activity and type of treatment affect different RC populations. nTregs respond to myelin antigens, indicating that it is possible to restore immunological tolerance through nTreg induction. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Meta-Analysis of Differential Connectivity in Gene Co-Expression Networks in Multiple Sclerosis

by Teresa Maria Creanza, Maria Liguori, Sabino Liuni, Nicoletta Nuzziello and Nicola Ancona

Int. J. Mol. Sci. 2016, 17(6), 936; https://doi.org/10.3390/ijms17060936 - 15 Jun 2016

Cited by 6 | Viewed by 7263

Abstract

Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We [...] Read more.

Differential gene expression analyses to investigate multiple sclerosis (MS) molecular pathogenesis cannot detect genes harboring genetic and/or epigenetic modifications that change the gene functions without affecting their expression. Differential co-expression network approaches may capture changes in functional interactions resulting from these alterations. We re-analyzed 595 mRNA arrays from publicly available datasets by studying changes in gene co-expression networks in MS and in response to interferon (IFN)-β treatment. Interestingly, MS networks show a reduced connectivity relative to the healthy condition, and the treatment activates the transcription of genes and increases their connectivity in MS patients. Importantly, the analysis of changes in gene connectivity in MS patients provides new evidence of association for genes already implicated in MS by single-nucleotide polymorphism studies and that do not show differential expression. This is the case of amiloride-sensitive cation channel 1 neuronal (ACCN1) that shows a reduced number of interacting partners in MS networks, and it is known for its role in synaptic transmission and central nervous system (CNS) development. Furthermore, our study confirms a deregulation of the vitamin D system: among the transcription factors that potentially regulate the deregulated genes, we find TCF3 and SP1 that are both involved in vitamin D3-induced p27Kip1 expression. Unveiling differential network properties allows us to gain systems-level insights into disease mechanisms and may suggest putative targets for the treatment. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Offspring Number Does Not Influence Reaching the Disability’s Milestones in Multiple Sclerosis: A Seven-Year Follow-Up Study

by Emanuele D’Amico, Carmela Leone and Francesco Patti

Int. J. Mol. Sci. 2016, 17(2), 234; https://doi.org/10.3390/ijms17020234 - 12 Feb 2016

Cited by 18 | Viewed by 5192

Abstract

Objectives: data on pregnancy long-term effects on multiple sclerosis (MS) course are still controversial; whether experiencing more than one pregnancy exposes one to risk of the disability‘s accrual is still unknown. We investigated differences existing in terms of disability progression among women with [...] Read more.

Objectives: data on pregnancy long-term effects on multiple sclerosis (MS) course are still controversial; whether experiencing more than one pregnancy exposes one to risk of the disability‘s accrual is still unknown. We investigated differences existing in terms of disability progression among women with MS (wwMS) who had one or more children after their MS onset. Methods: Monoparous and multiparous wwMS were enrolled from the Catania MS Center, Italy, in a monocenter retrospective study. A Cox proportional hazards model was used to examine the effect of the number of parities on time from MS disease onset to EDSS 4.0 and 6.0. The study protocol was approved by the local Ethical Committee. Results: during the seven years of observation, 32.1% and 23.2% of the monoparous group reached expanded disability disease status (EDSS) 4.0 and 6.0 respectively, compared to 13.3% and 3.3% of the multiparous group (p = 0.057 and p = 0.017; respectively). The Kaplan–Meier curve analysis showed no statistically-significant differences between the two groups in reaching the two milestones. The multiparous group showed a longer time to reach the EDSS 4.0 (3.5 vs. 2.6 years, log-rank 0.57, p = 0.45). The Cox regression analysis showed that the EDSS at the time of first pregnancy (Exp(B) 9.4, CI 4.5–19.7, p< 0.001) and the time from MS onset to first pregnancy (Exp(B) 0.96, CI = 0.93–0.98, p < 0.05) were significant predictors of reaching the EDSS 4.0, whereas a model including only the EDSS one year after the first pregnancy significantly predicted (Exp(B) value of 6.4, CI 2.6–15.4, p < 0.001) the reaching of EDSS 6.0. Conclusions: Our results suggest that experiencing more than one pregnancy could not convey a different clinical outcome in wwMS. Further research is needed to confirm our results. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Review

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Open AccessReview

Excitotoxins, Mitochondrial and Redox Disturbances in Multiple Sclerosis

by Cecilia Rajda, Dániel Pukoli, Zsuzsanna Bende, Zsófia Majláth and László Vécsei

Int. J. Mol. Sci. 2017, 18(2), 353; https://doi.org/10.3390/ijms18020353 - 8 Feb 2017

Cited by 51 | Viewed by 8483

Abstract

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example [...] Read more.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). There is increasing evidence that MS is not only characterized by immune mediated inflammatory reactions, but also by neurodegenerative processes. There is cumulating evidence that neurodegenerative processes, for example mitochondrial dysfunction, oxidative stress, and glutamate (Glu) excitotoxicity, seem to play an important role in the pathogenesis of MS. The alteration of mitochondrial homeostasis leads to the formation of excitotoxins and redox disturbances. Mitochondrial dysfunction (energy disposal failure, apoptosis, etc.), redox disturbances (oxidative stress and enhanced reactive oxygen and nitrogen species production), and excitotoxicity (Glu mediated toxicity) may play an important role in the progression of the disease, causing axonal and neuronal damage. This review focuses on the mechanisms of mitochondrial dysfunction (including mitochondrial DNA (mtDNA) defects and mitochondrial structural/functional changes), oxidative stress (including reactive oxygen and nitric species), and excitotoxicity that are involved in MS and also discusses the potential targets and tools for therapeutic approaches in the future. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessReview

Fingolimod Associated Bilateral Cystoid Macular Edema—Wait and See?

by Refik Pul, Alma Osmanovic, Holger Schmalstieg, Amelie Pielen, Kaweh Pars, Philipp Schwenkenbecher, Kurt Wolfram Sühs, Özlem Yildiz, Benedikt Frank, Martin Stangel and Thomas Skripuletz

Int. J. Mol. Sci. 2016, 17(12), 2106; https://doi.org/10.3390/ijms17122106 - 14 Dec 2016

Cited by 10 | Viewed by 5960

Abstract

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who [...] Read more.

Fingolimod 0.5-mg once-daily is an approved therapy for patients with relapsing–remitting multiple sclerosis (MS). Several pivotal and real-world studies have demonstrated that fingolimod is associated with the development of macular edema (ME). Herein, we present a case of a diabetic MS patient who developed severe bilateral ME during fingolimod treatment. By means of this case study we provide a detailed review about fingolimod associated macular edema (FAME), its current incidence with or without diabetes mellitus, and previous therapy attempts and outcomes in MS patients. Intravitreal administration of antibodies raised against vascular endothelial growth factor A (VEGF-A) has not yet been used in the management of FAME, however, the excellent therapeutic response in our patient may justify the use of anti-VEGF-A agents in combination with cessation of fingolimod to achieve fast resolution of FAME and to prevent visual deficits, particularly in bilateral FAME. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Open AccessReview

Prolactin: Friend or Foe in Central Nervous System Autoimmune Inflammation?

by Massimo Costanza and Rosetta Pedotti

Int. J. Mol. Sci. 2016, 17(12), 2026; https://doi.org/10.3390/ijms17122026 - 2 Dec 2016

Cited by 28 | Viewed by 9137

Abstract

The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its [...] Read more.

The higher prevalence of multiple sclerosis (MS) in females, along with the modulation of disease activity observed during pregnancy and the post-partum period, has suggested a hormonal influence in MS. Even if prolactin (PRL) does not belong to the sex hormones family, its crucial role in female reproduction and lactation has prompted great efforts to understand if PRL could represent a gender factor in the pathogenesis of MS and experimental autoimmune encephalomyelitis (EAE), the animal model for this disease. Extensive literature has documented a remarkable immune-stimulating potential for this hormone, indicating PRL as a disease-promoting factor in MS and EAE. However, recent work has pointed out that PRL is endowed with important neuroprotective and remyelinating properties and has encouraged a reinterpretation of the involvement of this hormone in MS. In this review we summarize both the protective functions that PRL exerts in central nervous system tissue as well as the inflammatory activity of this hormone in the context of autoimmune responses against myelin. Last, we draw future lines of research that might help to better clarify the impact of PRL on MS pathology. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Optical Coherence Tomography and Magnetic Resonance Imaging in Multiple Sclerosis and Neuromyelitis Optica Spectrum Disorder

by Praveena Manogaran, James V. M. Hanson, Elisabeth D. Olbert, Christine Egger, Carla Wicki, Christina Gerth-Kahlert, Klara Landau and Sven Schippling

Int. J. Mol. Sci. 2016, 17(11), 1894; https://doi.org/10.3390/ijms17111894 - 15 Nov 2016

Cited by 26 | Viewed by 8090

Abstract

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool [...] Read more.

Irreversible disability in multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) is largely attributed to neuronal and axonal degeneration, which, along with inflammation, is one of the major pathological hallmarks of these diseases. Optical coherence tomography (OCT) is a non-invasive imaging tool that has been used in MS, NMOSD, and other diseases to quantify damage to the retina, including the ganglion cells and their axons. The fact that these are the only unmyelinated axons within the central nervous system (CNS) renders the afferent visual pathway an ideal model for studying axonal and neuronal degeneration in neurodegenerative diseases. Structural magnetic resonance imaging (MRI) can be used to obtain anatomical information about the CNS and to quantify evolving pathology in MS and NMOSD, both globally and in specific regions of the visual pathway including the optic nerve, optic radiations and visual cortex. Therefore, correlations between brain or optic nerve abnormalities on MRI, and retinal pathology using OCT, may shed light on how damage to one part of the CNS can affect others. In addition, these imaging techniques can help identify important differences between MS and NMOSD such as disease-specific damage to the visual pathway, trans-synaptic degeneration, or pathological changes independent of the underlying disease process. This review focuses on the current knowledge of the role of the visual pathway using OCT and MRI in patients with MS and NMOSD. Emphasis is placed on studies that employ both MRI and OCT to investigate damage to the visual system in these diseases. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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Taking Advantage of Nature’s Gift: Can Endogenous Neural Stem Cells Improve Myelin Regeneration?

by Rainer Akkermann, Janusz Joachim Jadasz, Kasum Azim and Patrick Küry

Int. J. Mol. Sci. 2016, 17(11), 1895; https://doi.org/10.3390/ijms17111895 - 14 Nov 2016

Cited by 9 | Viewed by 6492

Abstract

Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some [...] Read more.

Irreversible functional deficits in multiple sclerosis (MS) are directly correlated to axonal damage and loss. Neurodegeneration results from immune-mediated destruction of myelin sheaths and subsequent axonal demyelination. Importantly, oligodendrocytes, the myelinating glial cells of the central nervous system, can be replaced to some extent to generate new myelin sheaths. This endogenous regeneration capacity has so far mainly been attributed to the activation and recruitment of resident oligodendroglial precursor cells. As this self-repair process is limited and increasingly fails while MS progresses, much interest has evolved regarding the development of remyelination-promoting strategies and the presence of alternative cell types, which can also contribute to the restoration of myelin sheaths. The adult brain comprises at least two neurogenic niches harboring life-long adult neural stem cells (NSCs). An increasing number of investigations are beginning to shed light on these cells under pathological conditions and revealed a significant potential of NSCs to contribute to myelin repair activities. In this review, these emerging investigations are discussed with respect to the importance of stimulating endogenous repair mechanisms from germinal sources. Moreover, we present key findings of NSC-derived oligodendroglial progeny, including a comprehensive overview of factors and mechanisms involved in this process. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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The Gas6/TAM System and Multiple Sclerosis

by Mattia Bellan, Mario Pirisi and Pier Paolo Sainaghi

Int. J. Mol. Sci. 2016, 17(11), 1807; https://doi.org/10.3390/ijms17111807 - 28 Oct 2016

Cited by 37 | Viewed by 8320

Abstract

Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done [...] Read more.

Growth arrest specific 6 (Gas6) is a multimodular circulating protein, the biological actions of which are mediated by the interaction with three transmembrane tyrosine kinase receptors: Tyro3, Axl, and MerTK, collectively named TAM. Over the last few decades, many progresses have been done in the understanding of the biological activities of this highly pleiotropic system, which plays a role in the regulation of immune response, inflammation, coagulation, cell growth, and clearance of apoptotic bodies. Recent findings have further related Gas6 and TAM receptors to neuroinflammation in general and, specifically, to multiple sclerosis (MS). In this paper, we review the biology of the Gas6/TAM system and the current evidence supporting its potential role in the pathogenesis of MS. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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The Inflammatory Role of Platelets: Translational Insights from Experimental Studies of Autoimmune Disorders

by Susann Pankratz, Stefan Bittner, Beate E. Kehrel, Harald F. Langer, Christoph Kleinschnitz, Sven G. Meuth and Kerstin Göbel

Int. J. Mol. Sci. 2016, 17(10), 1723; https://doi.org/10.3390/ijms17101723 - 14 Oct 2016

Cited by 24 | Viewed by 6398

Abstract

Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The [...] Read more.

Beyond their indispensable role in hemostasis, platelets have shown to affect the development of inflammatory disorders, as they have been epidemiologically and mechanistically linked to diseases featuring an inflammatory reaction in inflammatory diseases like multiple sclerosis, rheumatoid arthritis and inflammatory bowel disorders. The identification of novel molecular mechanisms linking inflammation and to platelets has highlighted them as new targets for therapeutic interventions. In particular, genetic and pharmacological studies have identified an important role for platelets in neuroinflammation. This review summarizes the main molecular links between platelets and inflammation, focusing on immune regulatory factors, receptors, cellular targets and signaling pathways by which they can amplify inflammatory reactions and that make them potential therapeutic targets. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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The Immunology of Neuromyelitis Optica—Current Knowledge, Clinical Implications, Controversies and Future Perspectives

by Michalina Jasiak-Zatonska, Alicja Kalinowska-Lyszczarz, Slawomir Michalak and Wojciech Kozubski

Int. J. Mol. Sci. 2016, 17(3), 273; https://doi.org/10.3390/ijms17030273 - 2 Mar 2016

Cited by 109 | Viewed by 17981

Abstract

Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder [...] Read more.

Neuromyelitis optica (NMO) is an autoimmune, demyelinating disorder of the central nervous system (CNS) with typical clinical manifestations of optic neuritis and acute transverse myelitis attacks. Previously believed to be a variant of multiple sclerosis (MS), it is now considered an independent disorder which needs to be differentiated from MS. The discovery of autoantibodies against aquaporin-4 (AQP4-IgGs) changed our understanding of NMO immunopathogenesis and revolutionized the diagnostic process. AQP4-IgG is currently regarded as a specific biomarker of NMO and NMO spectrum disorders (NMOsd) and a key factor in its pathogenesis. Nevertheless, AQP4-IgG seronegativity in 10%–25% of NMO patients suggests that there are several other factors involved in NMO immunopathogenesis, i.e., autoantibodies against aquaporin-1 (AQP1-Abs) and antibodies against myelin oligodendrocyte glycoprotein (MOG-IgGs). This manuscript reviews current knowledge about NMO immunopathogenesis, pointing out the controversial issues and showing potential directions for future research. Further efforts should be made to broaden our knowledge of NMO immunology which could have important implications for clinical practice, including the use of potential novel biomarkers to facilitate an early and accurate diagnosis, and modern treatment strategies improving long-term outcome of NMO patients. Full article

(This article belongs to the Special Issue Advances in Multiple Sclerosis 2016)

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