scholarly journals A Clonal NG2-Glia Cell Response in a Mouse Model of Multiple Sclerosis

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1279 ◽  
Author(s):  
Sonsoles Barriola ◽  
Fernando Pérez-Cerdá ◽  
Carlos Matute ◽  
Ana Bribián ◽  
Laura López-Mascaraque
Keyword(s):  
Multiple Sclerosis ◽  
Brain Damage ◽  
Tissue Repair ◽  
Phenotypic Diversity ◽  
Demyelinating Diseases ◽  
Autoimmune Encephalomyelitis ◽  
Oligodendrocyte Precursor ◽  
Autoimmune Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

NG2-glia, also known as oligodendrocyte precursor cells (OPCs), have the potential to generate new mature oligodendrocytes and thus, to contribute to tissue repair in demyelinating diseases like multiple sclerosis (MS). Once activated in response to brain damage, NG2-glial cells proliferate, and they acquire a reactive phenotype and a heterogeneous appearance. Here, we set out to investigate the distribution and phenotypic diversity of NG2-glia relative to their ontogenic origin, and whether there is a clonal NG2-glial response to lesion in an experimental autoimmune encephalomyelitis (EAE) murine model of MS. As such, we performed in utero electroporation of the genomic lineage tracer, StarTrack, to follow the fate of NG2-glia derived from single progenitors and to evaluate their response to brain damage after EAE induction. We then analyzed the dispersion of the NG2-glia derived clonally from single pallial progenitors in the brain of EAE mice. In addition, we examined several morphological parameters to assess the degree of NG2-glia reactivity in clonally-related cells. Our results reveal the heterogeneity of these progenitors and their cell progeny in a scenario of autoimmune demyelination, revealing the ontogenic phenomena at play in these processes.

scholarly journals Loss of HDAC11 ameliorates clinical symptoms in a multiple sclerosis mouse model

2018 ◽  
Vol 1 (5) ◽  
pp. e201800039 ◽  
Author(s):  
Lei Sun ◽  
Elphine Telles ◽  
Molly Karl ◽  
Fengdong Cheng ◽  
Noreen Luetteke ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Mouse Model ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Immune Cell ◽  
Demyelinating Disease ◽  
Demyelinating Diseases ◽  
Clinical Severity ◽  
Autoimmune Encephalomyelitis ◽  
Immune Mediated ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a chronic, immune-mediated, demyelinating disease of the central nervous system (CNS). There is no known cure for MS, and currently available drugs for managing this disease are only effective early on and have many adverse side effects. Results from recent studies suggest that histone deacetylase (HDAC) inhibitors may be useful for the treatment of autoimmune and inflammatory diseases such as MS. However, the underlying mechanisms by which HDACs influence immune-mediated diseases such as MS are unclear. More importantly, the question of which specific HDAC(s) are suitable drug targets for the potential treatment of MS remains unanswered. Here, we investigate the functional role of HDAC11 in experimental autoimmune encephalomyelitis, a mouse model for MS. Our results indicate that the loss of HDAC11 in KO mice significantly reduces clinical severity and demyelination of the spinal cord in the post-acute phase of experimental autoimmune encephalomyelitis. The absence of HDAC11 leads to reduced immune cell infiltration into the CNS and decreased monocytes and myeloid DCs in the chronic progressive phase of the disease. Mechanistically, HDAC11 controls the expression of the pro-inflammatory chemokine C–C motif ligand 2 (CCL2) gene by enabling the binding of PU.1 transcription factor to the CCL2 promoter. Our results reveal a novel pathophysiological function for HDAC11 in CNS demyelinating diseases, and warrant further investigations into the potential use of HDAC11-specific inhibitors for the treatment of chronic progressive MS.

scholarly journals Transgenic mouse model for central nervous system demyelination.

1991 ◽  
Vol 11 (11) ◽  
pp. 5479-5486 ◽  
Author(s):  
T Yoshioka ◽  
L Feigenbaum ◽  
G Jay
Keyword(s):  
Mhc Class I ◽  
Demyelinating Diseases ◽  
Class I ◽  
Infectious Agents ◽  
Autoimmune Encephalomyelitis ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Central Nervous System Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.

Transgenic mouse model for central nervous system demyelination

1991 ◽  
Vol 11 (11) ◽  
pp. 5479-5486
Author(s):  
T Yoshioka ◽  
L Feigenbaum ◽  
G Jay
Keyword(s):  
Mhc Class I ◽  
Demyelinating Diseases ◽  
Class I ◽  
Infectious Agents ◽  
Autoimmune Encephalomyelitis ◽  
Direct Role ◽  
Histocompatibility Complex ◽  
Central Nervous System Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

A common feature of demyelinating diseases such as multiple sclerosis in humans and experimental autoimmune encephalomyelitis in rodents is the marked elevation in the expression of the major histocompatibility complex (MHC) antigens in the involved sites. By specific targeting of a syngeneic MHC class I gene to oligodendrocytes, we have generated transgenic mice which not only exhibit severe involuntary tremors and develop tonic seizures but also show extensive demyelination in both the brain and the spinal cord. The fact that demyelination in these mice occurs in the absence of immune infiltration dismisses an autoimmune involvement but suggests that the MHC class I antigens play a direct role in inducing disease. Our findings lend support to the possibility that demyelinating diseases are induced by infectious agents such as viruses which can either directly activate MHC gene expression in oligodendroglia or indirectly activate expression through the release by reactive T cells of gamma interferon in the brain.

scholarly journals The Benefits and Detriments of Macrophages/Microglia in Models of Multiple Sclerosis

2013 ◽  
Vol 2013 ◽  
pp. 1-13 ◽  
Author(s):  
Khalil S. Rawji ◽  
V. Wee Yong
Keyword(s):  
Multiple Sclerosis ◽  
Immune Cells ◽  
Neurotrophic Factors ◽  
Neurological Diseases ◽  
Oligodendrocyte Precursor Cells ◽  
Activated Macrophages ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Oligodendrocyte Precursor ◽  
Experimental Autoimmune

The central nervous system (CNS) is immune privileged with access to leukocytes being limited. In several neurological diseases, however, infiltration of immune cells from the periphery into the CNS is largely observed and accounts for the increased representation of macrophages within the CNS. In addition to extensive leukocyte infiltration, the activation of microglia is frequently observed. The functions of activated macrophages/microglia within the CNS are complex. In three animal models of multiple sclerosis (MS), namely, experimental autoimmune encephalomyelitis (EAE) and cuprizone- and lysolecithin-induced demyelination, there have been many reported detrimental roles associated with the involvement of macrophages and microglia. Such detriments include toxicity to neurons and oligodendrocyte precursor cells, release of proteases, release of inflammatory cytokines and free radicals, and recruitment and reactivation of T lymphocytes in the CNS. Many studies, however, have also reported beneficial roles of macrophages/microglia, including axon regenerative roles, assistance in promoting remyelination, clearance of inhibitory myelin debris, and the release of neurotrophic factors. This review will discuss the evidence supporting the detrimental and beneficial aspects of macrophages/microglia in models of MS, provide a discussion of the mechanisms underlying the dichotomous roles, and describe a few therapies in clinical use in MS that impinge on the activity of macrophages/microglia.

Identification of a Val I 45 IIe substitution in the human myelin oligodendrocyte glycoprotein: lack of association with multiple sclerosis

1997 ◽  
Vol 3 (6) ◽  
pp. 377-381 ◽  
Author(s):  
D. Rodriguez ◽  
B. Della Gaspera ◽  
B. Zalc ◽  
J-J. Hauw ◽  
B. Fontaine ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Myelin Oligodendrocyte Glycoprotein ◽  
Demyelinating Diseases ◽  
Target Antigen ◽  
Restriction Enzyme Digestion ◽  
Autoimmune Encephalomyelitis ◽  
Potential Implication ◽  
The Central Nervous System ◽  
Major Target ◽  
Experimental Autoimmune

Myelin/oligodendrocyte glycoprotein (MOG) is a major target antigen in experimental autoimmune encephalomyelitis and it has been suggested that it may as well play a key role in the demyelination process in multiple sclerosis (MS). As MOG variants could be pathogenic in autoimmune demyelinating diseases of the central nervous system, we analysed the coding sequence of MOG in MS patients and described a G→A transition occurring in exon 3 of the human MOG gene. The mutation predicts that isoleucine substitutes for a valine at codon I 45 (Val 145 lle) in the transmembrane region of the protein. This is the first aminoacid substitution reported in human MOG. The polymorphism can be detected by restriction enzyme digestion of genomic DNA or reverse-transcribed PCR amplified products, making it a simple tool to detect a potential implication of MOG alleles in susceptibility to MS by association study. The analysis of 83 unrelated MS patients and 82 unrelated healthy controls showed that the polymorphism is found in similar proportions in MS patients (18%) and controls (14.6%). It is therefore unlikely that the MOG Val 145 lle variant is responsible for genetic susceptibility to MS.

MDC/CCL22 intrathecal levels in patients with multiple sclerosis

2008 ◽  
Vol 14 (4) ◽  
pp. 547-549 ◽  
Author(s):  
D. Galimberti ◽  
C. Fenoglio ◽  
C. Comi ◽  
D. Scalabrini ◽  
M. De Riz ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cerebrospinal Fluid ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Th2 Cells ◽  
Autoimmune Encephalomyelitis ◽  
Disease Subtype ◽  
Male Patients ◽  
Fluid Levels ◽  
The Brain ◽  
Experimental Autoimmune

MDC/CCL22 has been detected in the brain of mice with experimental autoimmune encephalomyelitis. MDC/CCL22 cerebrospinal fluid levels were evaluated in 56 patients with multiple sclerosis (MS) and in 17 controls. No significant differences were found, even when stratifying patients according to the disease subtype. Stratifying by gender, significantly increased MDC/CCL22 levels were observed in female patients when compared with female controls and male patients (109.03 versus 98.54 and 99.37 pg/mL, P = 0.034 and 0.018, respectively). Therefore, MDC/CCL22 is likely to play a role in the development of MS in females only, possibly influencing the intracerebral recruitment of Th2 cells, which produce anti-inflammatory cytokines. Multiple Sclerosis 2008; 14: 547—549. http://msj.sagepub.com

scholarly journals Multiple Sclerosis CD49d+CD154+ As Myelin-Specific Lymphocytes Induced During Remyelination

Cells ◽  
2019 ◽  
Vol 9 (1) ◽  
pp. 15
Author(s):  
Paweł Piatek ◽  
Magdalena Namiecinska ◽  
Małgorzata Domowicz ◽  
Marek Wieczorek ◽  
Sylwia Michlewska ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Cumulative Effect ◽  
Autoimmune Encephalomyelitis ◽  
The Central Nervous System ◽  
Cns Demyelination ◽  
The Brain ◽  
Experimental Autoimmune

Multiple sclerosis (MS) is a demyelinating autoimmune disease of the central nervous system (CNS) mediated by autoreactive lymphocytes. The role of autoreactive lymphocytes in the CNS demyelination is well described, whereas very little is known about their role in remyelination during MS remission. In this study, we identified a new subpopulation of myelin-specific CD49d+CD154+ lymphocytes presented in the peripheral blood of MS patients during remission, that proliferated in vitro in response to myelin peptides. These lymphocytes possessed the unique ability to migrate towards maturing oligodendrocyte precursor cells (OPCs) and synthetize proinflammatory chemokines/cytokines. The co-culture of maturing OPCs with myelin-specific CD49d+CD154+ lymphocytes was characterized by the increase in proinflammatory chemokine/cytokine secretion that was not only a result of their cumulative effect of what OPCs and CD49d+CD154+ lymphocytes produced alone. Moreover, maturing OPCs exposed to exogenous myelin peptides managed to induce CD40-CD154-dependent CD49d+CD154+ lymphocyte proliferation. We confirmed, in vivo, the presence of CD49d+CD154+ cells close to maturating OPCs and remyelinating plaque during disease remission in the MS mouse model (C57Bl/6 mice immunized with MOG35-55) by immunohistochemistry. Three weeks after an acute phase of experimental autoimmune encephalomyelitis, CD49d+/CD154+ cells were found to be co-localized with O4+ cells (oligodendrocyte progenitors) in the areas of remyelination identified by myelin basic protein (MBP) labelling. These data suggested that myelin-specific CD49d+CD154+ lymphocytes present in the brain can interfere with remyelination mediated by oligodendrocytes probably as a result of establishing proinflammatory environment.

scholarly journals Interactions between Neutrophils, Th17 Cells, and Chemokines during the Initiation of Experimental Model of Multiple Sclerosis

2014 ◽  
Vol 2014 ◽  
pp. 1-8 ◽  
Author(s):  
Dagmara Weronika Wojkowska ◽  
Piotr Szpakowski ◽  
Dominika Ksiazek-Winiarek ◽  
Marcin Leszczynski ◽  
Andrzej Glabinski
Keyword(s):  
Multiple Sclerosis ◽  
Animal Model ◽  
Th17 Cells ◽  
Inflammatory Cell ◽  
Autoimmune Encephalomyelitis ◽  
Preclinical Phase ◽  
Activated T Cell ◽  
Cell Subpopulations ◽  
The Brain ◽  
Experimental Autoimmune

Experimental autoimmune encephalomyelitis (EAE) is an animal model of multiple sclerosis (MS) in which activated T cell and neutrophil interactions lead to neuroinflammation. In this study the expression of CCR6, CXCR2, and CXCR6 in Th17 cells and neutrophils migrating to the brain during EAE was measured, alongside an evaluation of the production of IL-17, IL-23, CCL-20, and CXCL16 in the brain. Next, inflammatory cell subpopulations accumulating in the brain after intracerebral injections of IL-17 or CXCL1, as well as during modulation of EAE with anti-IL-23R or anti-CXCR2 antibodies, were analyzed. Th17 cells upregulate CXCR2 during the preclinical phase of EAE and a significant migration of these cells to the brain was observed. Neutrophils upregulated CCR6, CXCR2, and CXCR6 during EAE, accumulating in the brain both prior to and during acute EAE attacks. Production of IL-17, IL-23, CCL20, and CXCL16 in the CNS was increased during both preclinical and acute EAE. Intracerebral delivery of CXCL1 stimulated the early accumulation of neutrophils in normal and preclinical EAE brains but reduced the migration of Th17 cells to the brain during the preclinical stage of EAE. Modulation of EAE by anti-IL-23R antibodies ameliorated EAE by decreasing the intracerebral accumulation of Th17 cells.

scholarly journals Reduced spinal cord parenchymal cerebrospinal fluid circulation in experimental autoimmune encephalomyelitis

2018 ◽  
Vol 39 (7) ◽  
pp. 1258-1265 ◽  
Author(s):  
Antoine P Fournier ◽  
Maxime Gauberti ◽  
Aurélien Quenault ◽  
Denis Vivien ◽  
Richard Macrez ◽  
...  
Keyword(s):  
Multiple Sclerosis ◽  
Spinal Cord ◽  
Cerebrospinal Fluid ◽  
Experimental Autoimmune Encephalomyelitis ◽  
Fluid Circulation ◽  
Autoimmune Encephalomyelitis ◽  
Cerebrospinal Fluid Circulation ◽  
Csf Circulation ◽  
The Brain ◽  
Experimental Autoimmune

An alteration of parenchymal cerebrospinal fluid circulation (CSF) has been proposed to take part in the pathophysiology of multiple sclerosis. By using an intragate T1-weighted high-resolution MRI of the spinal cord of freely breathing mice injected with a gadolinium chelate in the cisterna magna, we show that a parenchymal CSF circulation exists in the spinal cord, in addition to that originally described in the brain. In experimental autoimmune encephalomyelitis, a model of multiple sclerosis, we show a reduction of parenchymal CSF circulation specifically in the spinal cord but not in the brain.

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