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Special Issue "Potential Pathogenic Mechanisms of Multiple Sclerosis"

A special issue of Journal of Clinical Medicine (ISSN 2077-0383). This special issue belongs to the section "Immunology".

Deadline for manuscript submissions: closed (30 September 2018)

Special Issue Editors

Guest Editor
Assoc. Prof. Judith Greer

Associate Professor, Centre for Clinical Research, the University of Queensland, Australia
Website | E-Mail
Interests: determining the antigen specificity of the autoimmune response in multiple sclerosis and how it can be targeted in a specific manner to treat disease
Guest Editor
Prof. Pamela McCombe

Professor of Neurology, Faculty of Medicine, the University of Queensland, Australia
Website | E-Mail
Interests: multiple sclerosis, amyotrophic lateral sclerosis

Special Issue Information

Dear Colleagues,

Knowledge of the mechanisms that underlie the development of multiple sclerosis (MS) is important for appropriate therapeutic interventions. However, the initiating events that lead to MS are still unknown, and the relative merits of “outside-in” (i.e., autoimmune) vs. “inside-out” (i.e., primary central nervous system damage) models for development of MS have been debated. Genetics undoubtedly play an important role in susceptibility to MS, but the relative contribution of individual genes remains to be determined, and little is yet known of genes that affect the course of disease. Female gender is one of the major risk factors for MS, but, conversely, some uniquely female events such as pregnancy are protective in MS. Environmental factors (diet, gut flora, stress, exposure to chemicals, toxins or UVB) are also likely to influence the pathogenesis of MS. Even cell types once thought to be of little interest in MS (e.g., neutrophils, platelets) are now being proposed as important players in development of disease. The present Special Issue aims to explore these potential pathogenic mechanisms in more detail.

Assoc. Prof. Judith Greer
Prof. Pamela McCombe
Guest Editors

Manuscript Submission Information

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Keywords

  • Multiple sclerosis
  • autoimmunity
  • primary CNS damage
  • genetics of MS
  • environmental factors
  • gender and MS
  • innate immune cells in MS

Published Papers (9 papers)

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Research

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Open AccessArticle
Effect of Teriflunomide and Dimethyl Fumarate on Cortical Atrophy and Leptomeningeal Inflammation in Multiple Sclerosis: A Retrospective, Observational, Case-Control Pilot Study
J. Clin. Med. 2019, 8(3), 344; https://doi.org/10.3390/jcm8030344
Received: 30 January 2019 / Revised: 28 February 2019 / Accepted: 7 March 2019 / Published: 12 March 2019
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Abstract
Background: Pathologic changes in cortical gray matter (GM) and leptomeninges contribute to disability worsening in patients with multiple sclerosis (MS), but there is little evidence whether disease-modifying treatments can slow down cortical pathology in MS. Objectives: To investigate the effect of teriflunomide (TFM) [...] Read more.
Background: Pathologic changes in cortical gray matter (GM) and leptomeninges contribute to disability worsening in patients with multiple sclerosis (MS), but there is little evidence whether disease-modifying treatments can slow down cortical pathology in MS. Objectives: To investigate the effect of teriflunomide (TFM) and dimethyl fumarate (DMF) in reducing cortical pathology, as determined by percentage cortical volume change (PCVC) and leptomeningeal contrast enhancement (LMCE) on MRI. Methods: This was a retrospective, single-center, observational study that selected 60 TFM- and 60 DMF-treated MS patients over 24 months. Results: TFM had a lower rate of PCVC compared to DMF over 24 months (−0.2% vs. −2.94%, p = 0.004). Similar results were observed for percentage GM volume change over 0–12 (p = 0.044) and 0–24 (−0.44% vs. −3.12%, p = 0.015) months. No significant differences were found between the TFM and DMF groups in the frequency and number of LMCE foci over the follow-up. TFM showed a numerically lower rate of whole brain atrophy over 24 months (p = 0.077), compared to DMF. No significant clinical or MRI lesion differences between TFM and DMF were detected over follow-up. Conclusions: These findings suggest that TFM has a superior effect on the preservation of cortical GM volume, compared to DMF. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
Open AccessCommunication
Platelet Depletion is Effective in Ameliorating Anxiety-Like Behavior and Reducing the Pro-Inflammatory Environment in the Hippocampus in Murine Experimental Autoimmune Encephalomyelitis
J. Clin. Med. 2019, 8(2), 162; https://doi.org/10.3390/jcm8020162
Received: 23 December 2018 / Revised: 21 January 2019 / Accepted: 27 January 2019 / Published: 1 February 2019
Cited by 1 | PDF Full-text (2340 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted [...] Read more.
The neuropsychiatric symptoms of multiple sclerosis (MS), such as anxiety and depression, can result from disease activity itself as well as psychological reaction to an unfavorable diagnosis. Accordingly, the literature reports evidence of increased anxiety-like behavior in experimental autoimmune encephalomyelitis (EAE), an accepted MS model. Due to the recently described critical role of platelets in inflammation and autoimmune disease, we examined the relationship between platelets, inflammation, and anxiety-like behavior in EAE. In the elevated plus maze, EAE-induced C57BL/6J mice showed decreased time spent in the open arms relative to vehicle-only controls, demonstrating an increase in anxiety-like behavior. This effect occurred in the presence of platelet–neuron association, but absence of lymphocytic infiltration, in the hippocampal parenchyma. Platelet depletion at the pre-clinical disease stage, using antibody-mediated lysis prevented the EAE-induced increase in anxiety-like behavior, while no significant difference in distance moved was recorded. Furthermore, platelet depletion was also associated with reduction of the pro-inflammatory environment to control levels in the hippocampus and prevention of EAE disease symptomology. These studies demonstrate the high efficacy of a platelet-targeting approach in preventing anxiety-like symptoms and clinical manifestations of EAE and have implications for the treatment of neuropsychiatric symptoms in MS. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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Open AccessArticle
Anti-Mycobacterial Antibodies in Paired Cerebrospinal Fluid and Serum Samples from Japanese Patients with Multiple Sclerosis or Neuromyelitis Optica Spectrum Disorder
J. Clin. Med. 2018, 7(12), 522; https://doi.org/10.3390/jcm7120522
Received: 26 October 2018 / Revised: 2 December 2018 / Accepted: 5 December 2018 / Published: 7 December 2018
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Abstract
Local synthesis of antibodies and presence of oligoclonal bands in the cerebrospinal fluid (CSF) are hallmarks of multiple sclerosis (MS). We investigated the frequency of antibodies against mycobacterial and relevant human epitopes in the CSF of patients with MS or neuromyelitis optica spectrum [...] Read more.
Local synthesis of antibodies and presence of oligoclonal bands in the cerebrospinal fluid (CSF) are hallmarks of multiple sclerosis (MS). We investigated the frequency of antibodies against mycobacterial and relevant human epitopes in the CSF of patients with MS or neuromyelitis optica spectrum disorder (NMOSD) and whether these antibodies differed from those present in the serum. Matched serum and CSF samples from 46 patients with MS, 42 patients with NMOSD, and 29 age-matched and sex-matched control subjects were screened retrospectively for the presence of antibodies against Mycobacterium avium subsp. paratuberculosis (MAP) pentapeptide (MAP_5p), MAP_2694295–303, and myelin basic protein (MBP)85–98 peptides by using indirect ELISA. Serum levels of anti-MAP_5p and anti-MAP_2694295–303 antibodies were highly prevalent in patients with MS when compared to patients with NMOSD and controls. Several patients with MS had detectable anti-MAP_5p and anti-MAP_2694295–303 antibodies in the CSF. Furthermore, a group of patients with MS showed intrathecally restricted production of antibodies against these peptides. Women appeared to mount a stronger humoral response to mycobacterial peptides than men. No significant difference in the frequency of anti-MBP85–98 antibodies was found between patients with MS and those with NMOSD. These data highlight the zoonotic potential of MAP, which suggests its involvement in MS etiopathogenesis. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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Open AccessArticle
PLP1 Mutations in Patients with Multiple Sclerosis: Identification of a New Mutation and Potential Pathogenicity of the Mutations
J. Clin. Med. 2018, 7(10), 342; https://doi.org/10.3390/jcm7100342
Received: 27 September 2018 / Revised: 8 October 2018 / Accepted: 9 October 2018 / Published: 11 October 2018
Cited by 1 | PDF Full-text (2298 KB) | HTML Full-text | XML Full-text
Abstract
PLP1 is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in PLP1 result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). However, [...] Read more.
PLP1 is located on the X-chromosome and encodes myelin proteolipid protein (PLP), the most abundant protein in central nervous system myelin. Generally, point mutations in PLP1 result in X-linked dysmyelinating disorders, such as Pelizaeus-Merzbacher disease (PMD) or spastic paraplegia type 2 (SPG2). However, several case studies have identified patients with missense point mutations in PLP1 and clinical symptoms and signs compatible with a diagnosis of multiple sclerosis (MS). To investigate if PLP1 mutations occur relatively frequently in MS, we sequenced the coding regions of PLP1 in 22 female MS patients who had developed disease after the age of 40 and in 42 healthy women, and identified a missense mutation in exon 2 of PLP1 resulting in a Leu30Val mutation in the protein in one of the MS patients. mCherry-tagged plasmids containing wild type or mutant PLP1 sequences of PLP, including two known PMD/SPG2-related mutations as positive controls, were constructed and transfected into Cos-7 cells. In comparison with cells transfected with wild type PLP1, all mutations caused significant accumulation of PLP in the endoplasmic reticulum of the cells and induction of the unfolded protein response—a mechanism that leads to apoptosis of cells expressing mutant proteins. Additionally, in silico analysis of the binding of peptides containing the Leu30Val mutation to the human leukocyte antigen (HLA) molecules carried by the patient harboring this mutation suggested that the mutation could produce several novel immunogenic epitopes in this patient. These results support the idea that mutations in myelin-related genes could contribute to the development of MS in a small proportion of patients. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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Review

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Open AccessReview
The Diversity of Encephalitogenic CD4+ T Cells in Multiple Sclerosis and Its Animal Models
J. Clin. Med. 2019, 8(1), 120; https://doi.org/10.3390/jcm8010120
Received: 3 January 2019 / Revised: 15 January 2019 / Accepted: 15 January 2019 / Published: 19 January 2019
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Abstract
Autoreactive CD4+ T cells, which target antigens in central nervous system (CNS) myelin, are widely believed to play a critical role in the pathogenesis of multiple sclerosis (MS) in concert with other immune effectors. This theory is supported by data from animal model [...] Read more.
Autoreactive CD4+ T cells, which target antigens in central nervous system (CNS) myelin, are widely believed to play a critical role in the pathogenesis of multiple sclerosis (MS) in concert with other immune effectors. This theory is supported by data from animal model experiments, genome-wide association studies, and immune profiles of individuals with MS. Furthermore, disease modifying agents that target lymphocytes significantly reduce the rate of MS clinical exacerbations. However, the properties of myelin-reactive CD4+ T cells that are critical for their pathogenic activities are not understood completely. This article reviews the literature on encephalitogenic CD4+ T cells, with an emphasis on T-helper (Th) lineage and cytokine production. An increased understanding of the spectrum of encephalitogenic T cells and how they differ from protective subsets is necessary for the development of the next generation of more effective and safer immunomodulatory therapies customized for individuals with MS and related disorders. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
Open AccessReview
Innate Immune Responses and Viral-Induced Neurologic Disease
J. Clin. Med. 2019, 8(1), 3; https://doi.org/10.3390/jcm8010003
Received: 2 November 2018 / Revised: 12 December 2018 / Accepted: 18 December 2018 / Published: 20 December 2018
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Abstract
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by chronic neuroinflammation, axonal damage, and demyelination. Cellular components of the adaptive immune response are viewed as important in initiating formation of demyelinating lesions in MS patients. This notion is [...] Read more.
Multiple sclerosis (MS) is a disease of the central nervous system (CNS) characterized by chronic neuroinflammation, axonal damage, and demyelination. Cellular components of the adaptive immune response are viewed as important in initiating formation of demyelinating lesions in MS patients. This notion is supported by preclinical animal models, genome-wide association studies (GWAS), as well as approved disease modifying therapies (DMTs) that suppress clinical relapse and are designed to impede infiltration of activated lymphocytes into the CNS. Nonetheless, emerging evidence demonstrates that the innate immune response e.g., neutrophils can amplify white matter damage through a variety of different mechanisms. Indeed, using a model of coronavirus-induced neurologic disease, we have demonstrated that sustained neutrophil infiltration into the CNS of infected animals correlates with increased demyelination. This brief review highlights recent evidence arguing that targeting the innate immune response may offer new therapeutic avenues for treatment of demyelinating disease including MS. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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Open AccessReview
The Emerging Role of Neutrophil Granulocytes in Multiple Sclerosis
J. Clin. Med. 2018, 7(12), 511; https://doi.org/10.3390/jcm7120511
Received: 2 November 2018 / Revised: 26 November 2018 / Accepted: 29 November 2018 / Published: 3 December 2018
Cited by 2 | PDF Full-text (2865 KB) | HTML Full-text | XML Full-text
Abstract
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong autoimmune, neurodegenerative, and neuroinflammatory component. Most of the common disease modifying treatments (DMTs) for MS modulate the immune response targeting disease associated T and B cells and while [...] Read more.
Multiple sclerosis (MS) is a demyelinating disease of the central nervous system with a strong autoimmune, neurodegenerative, and neuroinflammatory component. Most of the common disease modifying treatments (DMTs) for MS modulate the immune response targeting disease associated T and B cells and while none directly target neutrophils, several DMTs do impact their abundance or function. The role of neutrophils in MS remains unknown and research is ongoing to better understand the phenotype, function, and contribution of neutrophils to both disease onset and stage of disease. Here we summarize the current state of knowledge of neutrophils and their function in MS, including in the rodent based MS model, and we discuss the potential effects of current treatments on these functions. We propose that neutrophils are likely to participate in MS pathogenesis and their abundance and function warrant monitoring in MS. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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Open AccessReview
The Short and Long-Term Effects of Pregnancy on Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis
J. Clin. Med. 2018, 7(12), 494; https://doi.org/10.3390/jcm7120494
Received: 1 October 2018 / Revised: 21 November 2018 / Accepted: 21 November 2018 / Published: 28 November 2018
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Abstract
The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS [...] Read more.
The role of pregnancy in multiple sclerosis (MS) is of importance because many patients with MS are young women in the childbearing age who require information to inform their reproductive decisions. Pregnancy is now well-known to be associated with fewer relapses of MS and reduced activity of autoimmune encephalomyelitis (EAE). However, in women with multiple sclerosis, this benefit is not always sufficient to protect against a rebound of disease activity if disease-modulating therapy is ceased for pregnancy. There is concern that use of assisted reproductive therapies can be associated with relapses of MS, but more data are required. It is thought that the beneficial effects of pregnancy are due to the pregnancy-associated changes in the maternal immune system. There is some evidence of this in human studies and studies of EAE. There is also evidence that having been pregnant leads to better long-term outcome of MS. The mechanism for this is not fully understood but it could result from epigenetic changes resulting from pregnancy or parenthood. Further studies of the mechanisms of the beneficial effects of pregnancy could provide information that might be used to produce new therapies. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
Open AccessReview
Can the Fact That Myelin Proteins Are Old and Break down Explain the Origin of Multiple Sclerosis in Some People?
J. Clin. Med. 2018, 7(9), 281; https://doi.org/10.3390/jcm7090281
Received: 11 July 2018 / Revised: 11 September 2018 / Accepted: 12 September 2018 / Published: 14 September 2018
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Abstract
Recent discoveries may change the way that multiple sclerosis (MS) is viewed, particularly with regard to the reasons for the untoward immune response. The fact that myelin proteins are long-lived, and that by the time we are adults, they are extensively degraded, alters [...] Read more.
Recent discoveries may change the way that multiple sclerosis (MS) is viewed, particularly with regard to the reasons for the untoward immune response. The fact that myelin proteins are long-lived, and that by the time we are adults, they are extensively degraded, alters our perspective on the reasons for the onset of autoimmunity and the origin of MS. For example, myelin basic protein (MBP) from every human brain past the age of 20 years, is so greatly modified, that it is effectively a different protein from the one that was laid down in childhood. Since only a subset of people with such degraded MBP develop MS, a focus on understanding the mechanism of immune responses to central nervous system (CNS) antigens and cerebral immune tolerance appear to be worthwhile avenues to explore. In accord with this, it will be productive to examine why all people, whose brains contain large quantities of a “foreign antigen”, do not develop MS. Importantly for the potential causation of MS, MBP from MS patients breaks down differently from the MBP in aged controls. If the novel structures formed in these MS-specific regions are particularly antigenic, it could help explain the origin of MS. If verified, these findings could provide an avenue for the rational synthesis of drugs to prevent and treat MS. Full article
(This article belongs to the Special Issue Potential Pathogenic Mechanisms of Multiple Sclerosis)
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