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Journal of Neuroimmunology Nov 2023Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state...
Inhibition of SUMOylation promotes remyelination and reduces IL-17 mediated autoimmune inflammation: Novel approach toward treatment of inflammatory CNS demyelinating disease.
Small ubiquitin like modifiers (SUMO) are reversible posttranslational modifiers of intracellular proteins. In the CNS, expression of myelin genes is regulated by state of SUMOylation of their respective transcription factors. In the immune system, deSUMOylation activates innate immune responses and promotes anti-viral immunity. However, the role played by SUMO in an adaptive immune response and in the development of T cell mediated autoimmune disease has not been previously described. TAK981 is a synthetic small molecule which by forming adducts with SUMO proteins prevents SUMOylation. We examined the expression of myelin genes and their transcription factors following culture with TAK981 in Oligodendrocyte Precursor Cells (OPC). We found that myelin basic protein (MBP), a key myelin protein, is upregulated in OPC in the presence of TAK981. We also found increased expression of transcription factors Sox10 and Myrf, which engage in the expression of MBP. In the Cuprizone model of demyelination/remyelination, animals which were treated with TAK981 showed increased remyelination in areas of demyelination and an increase in the number of maturing oligodendrocytes compared to vehicle treated controls. In in vitro cultures of lymphocytes, TAK981 reduced the expression of TH17 in T cells in mice immunized with MOGp35-55. Following in vivo treatment with TAK981, there was a significant reduction in the clinical and pathological severity in mice immunized to develop experimental allergic encephalitis (EAE). The dual effects of deSUMOylation on remyelination and in regulating an autoimmune adaptive response offers a novel approach to the management of human inflammatory demyelinating diseases such as multiple sclerosis.
Topics: Mice; Humans; Animals; Demyelinating Diseases; Remyelination; Sumoylation; Interleukin-17; Cell Differentiation; Myelin Sheath; Oligodendroglia; Cuprizone; Inflammation; Central Nervous System Diseases; Transcription Factors; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 37813042
DOI: 10.1016/j.jneuroim.2023.578219 -
Neurologic Clinics Feb 2022The spectrum of demyelinating diseases affecting the central nervous system is broad. Although many have a chronic course, neuroinflammatory conditions often present... (Review)
Review
The spectrum of demyelinating diseases affecting the central nervous system is broad. Although many have a chronic course, neuroinflammatory conditions often present with acute to subacute onset symptoms requiring hospitalization when severe. This article reviews the acute phase assessment and management of these disorders, with a particular focus on multiple sclerosis, neuromyelitis optica spectrum disorder, myelin oligodendrocyte glycoprotein antibody disorder, and several atypical demyelinating diseases.
Topics: Autoantibodies; Central Nervous System; Encephalomyelitis, Acute Disseminated; Humans; Multiple Sclerosis; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica
PubMed: 34798965
DOI: 10.1016/j.ncl.2021.08.008 -
Immunology Today Apr 1996
Review
Topics: Animals; Conserved Sequence; Demyelinating Diseases; Encephalomyelitis, Autoimmune, Experimental; Humans; Multiple Sclerosis; Receptors, Antigen, T-Cell, alpha-beta
PubMed: 8871344
DOI: 10.1016/0167-5699(96)80611-6 -
Neurologia Mar 2023The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the...
INTRODUCTION
The C1236T, G2677T/A, and C3435T variants of the ABCB1 gene alter the functioning of P-glycoprotein and the transport of endogenous and exogenous substances across the blood-brain barrier, and act as risk factors for some neurodegenerative diseases. This study aimed to determine the association between demyelinating disease and the C1236T, G2677T/A, and C3435T variants of ABCB1 and its haplotypes and combinations of genotypes.
METHODS
Polymerase chain reaction with restriction fragment length polymorphism analysis (PCR-RFLP) and Sanger sequencing were used to genotype 199 patients with demyelinating disease and 200 controls, all Mexicans of mixed race; frequencies of alleles, genotypes, haplotypes, and genotype combinations were compared between patients and controls. We conducted a logistic regression analysis and calculated chi-square values and 95% confidence intervals (CI); odds ratios (OR) were calculated to evaluate the association with demyelinating disease.
RESULTS
The TTT and CGC haplotypes were most frequent in both patients and controls. The G2677 allele was associated with demyelinating disease (OR: 1.79; 95% CI, 1.12-2.86; P = .015), as were the genotypes GG2677 (OR: 2.72; 95% CI, 1.11-6.68; P = .025) and CC3435 (OR: 1.82; 95% CI, 1.15-2.90; P = .010), the combination GG2677/CC3435 (OR: 2.02; 95% CI, 1.17-3.48; P = .010), and the CAT haplotype (OR: 0.21; 95% CI, 0.05-0.66; P = .001). TTTTTT carriers presented the earliest age of onset (23.0 ± 7.7 years, vs 31.6 ± 10.7; P = .0001).
CONCLUSIONS
The GG2677/CC3435 genotype combination is associated with demyelinating disease in this sample, particularly among men, who may present toxic accumulation of P-glycoprotein substrates. In our study, the G2677 allele of ABCB1 may differentially modulate age of onset of demyelinating disease in men and women.
Topics: Female; Humans; Age of Onset; ATP Binding Cassette Transporter, Subfamily B, Member 1; Demyelinating Diseases; Genotype; Risk Factors
PubMed: 35256320
DOI: 10.1016/j.nrleng.2020.05.021 -
Current Opinion in Neurology Jun 2012Identification of autoantigens in demyelinating diseases is essential for the understanding of the pathogenesis. Immune responses against these antigens could be used as... (Review)
Review
PURPOSE OF REVIEW
Identification of autoantigens in demyelinating diseases is essential for the understanding of the pathogenesis. Immune responses against these antigens could be used as biomarkers for diagnosis, prognosis and treatment responses. Knowledge of antigen-specific immune responses in individual patients is also a prerequisite for antigen-based therapies.
RECENT FINDINGS
A proportion of patients with demyelinating disease have antibodies to aquaporin 4 (AQP4) or myelin oligodendrocyte glycoprotein (MOG). Patients with anti-AQP4 have the distinct clinical presentation of neuromyelitis optica (NMO), and these patients often also harbour other autoimmune responses. In contrast, anti-MOG is seen in patients with different disease entities such as childhood multiple sclerosis (MS), acute demyelinating encephalomyelitis (ADEM), anti-AQP4 negative NMO, and optic neuritis, but hardly in adult MS. A number of new candidate autoantigens have been identified and await validation. Antigen-based therapies are mainly aimed at tolerizing T-cell responses against myelin basic protein (MBP) and have shown only modest or no clinical benefit so far.
SUMMARY
Currently, only few patients with demyelinating diseases can be characterized based on their autoantibody profile. The most prominent antigens in this respect are MOG and AQP4. Further research has to focus on the validation of newly discovered antigens as biomarkers.
Topics: Animals; Aquaporin 4; Autoantibodies; Autoantigens; Demyelinating Diseases; Humans
PubMed: 22487571
DOI: 10.1097/WCO.0b013e3283533a64 -
Journal of the Neurological Sciences Aug 2014
Topics: Adult; Antiviral Agents; Demyelinating Diseases; Dimethyl Fumarate; Fumarates; Humans; Immunosuppressive Agents; Interferons; Magnetic Resonance Imaging; Male; Psoriasis
PubMed: 24906711
DOI: 10.1016/j.jns.2014.05.031 -
Archivum Immunologiae Et Therapiae... 2000Multiple sclerosis involves inflammatory immune responses in the central nervous system (CNS) and is considered as an autoimmune disease potentially associated with... (Review)
Review
Multiple sclerosis involves inflammatory immune responses in the central nervous system (CNS) and is considered as an autoimmune disease potentially associated with viral infection. The majority of experimental models rely heavily on the autoimmune components since similar diseases can be induced following immunization with various myelin antigens. A very attractive alternative model is the Theiler's murine encephalomyelitis virus-induced demyelinating disease. This disease is primarily a CD4+ T cell-mediated, inflammatory demyelinating disease induced following viral infection. Virus-specific inflammatory Th1 cell responses, rather than cytotoxic T lymphocyte response, play a critical role in the pathogenic immune responses. The major pathogenic epitopes have been identified and these are correlated with a Th1 type response to the epitopes following viral infection. In addition, the initial virus-specific immune response is followed by the autoimmune responses to myelin antigens. Assessment of cytokines produced locally in the CNS during the course of disease suggests involvement of inflammatory cytokines in the disease. Furthermore, the manipulation of inflammatory cytokine levels by administration of either recombinant cytokines or antibodies to the cytokines strongly influences the induction and/or progression of disease, supporting the importance of these inflammatory cytokines in this virus-induced demyelinating disease.
Topics: CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Cardiovirus Infections; Cytokines; Demyelinating Diseases; Immunity; Models, Immunological; Multiple Sclerosis; Theilovirus
PubMed: 11140464
DOI: No ID Found -
Neuron Nov 1999
Review
Topics: Animals; Antibody Formation; Cytokines; Demyelinating Diseases; Disease Models, Animal; Encephalomyelitis, Autoimmune, Experimental; Multiple Sclerosis
PubMed: 10595504
DOI: 10.1016/s0896-6273(00)81107-1 -
The Canadian Journal of Neurological... Jan 2012Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and... (Review)
Review
Brain biopsy plays a crucial role in the exploration of suspect white matter lesions in the differential diagnosis of primary central nervous system lymphoma (PCNSL) and inflammatory demyelination. We present the case of a previously healthy, immunocompetent woman, aged fifty-nine, who developed a histologically confirmed demyelinating white matter lesion months prior to the manifestation of a PCNSL. Similar cases of "sentinel lesions" preceding a PCNSL have been reported. In a literature review, we compared the diagnostic features that may be useful to differentiate a PCNSL from inflammatory demyelinating disease in older age. We conclude that the occurrence of large, contrast-enhancing cerebral lesions in older patients with a relapsing-remitting disease course and steroid-resistant vision disorders should lead to the consideration of a PCNSL.
Topics: Brain; Central Nervous System Neoplasms; Demyelinating Diseases; Diagnosis, Differential; Diagnostic Imaging; Humans; Inflammation; Lymphoma; Radiography; Radionuclide Imaging
PubMed: 22384490
DOI: 10.1017/s0317167100012610 -
BMC Pediatrics Jul 2011There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or...
BACKGROUND
There is evidence that at least 5% of Multiple sclerosis (MS) cases manifest in childhood. Children with MS present with a demyelinating episode involving single or multiple symptoms prior to developing a second event (usually within two years) to then meet criteria for diagnosis. There is evidence from adult cohorts that the incidence and sex ratios of MS are changing and that children of immigrants have a higher risk for developing MS. A paediatric population should reflect the vanguard of such changes and may reflect trends yet to be observed in adult cohorts. Studying a paediatric population from the first demyelinating event will allow us to test these hypotheses, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.
METHODS/DESIGN
The Paediatric UK Demyelinating Disease Longitudinal Study (PUDDLS) is a prospective longitudinal observational study which aims to determine the natural history, predictors and outcomes of childhood CNS inflammatory demyelinating diseases. PUDDLS will involve centres in the UK, and will establish a cohort of children affected with a first CNS inflammatory demyelinating event for long-term follow up by recruiting for approximately 5 years. PUDDLS will also establish a biological sample archive (CSF, serum, and DNA), allowing future hypothesis driven research. For example, the future discovery of a biomarker will allow validation within this dataset for the evaluation of novel biomarkers. Patients will also be requested to consent to be contacted in the future. A secondary aim is to collaborate internationally with the International Paediatric Multiple Sclerosis Study Group when future collaborative studies are proposed, whilst sharing a minimal anonymised dataset. PUDDLS is the second of two jointly funded studies. The first (UCID-SS) is an epidemiological surveillance study that already received ethical approvals, and started on the 1st September 2009. There is no direct patient involvement, and UCID-SS aims to determine the UK and Ireland incidence of CNS inflammatory demyelinating disorders in children under 16 years.
DISCUSSION
A paediatric population should reflect the vanguard of MS epidemiological changes and may reflect trends yet to be observed in adult MS cohorts. The restricted window between clinical expression of disease and exposure to environmental factors in children offers a unique research opportunity. Studying a paediatric population from the first demyelinating event will allow us to investigate the changing epidemiology of MS, and may offer further valuable insights into the genetic and environmental interactions in the pathogenesis of MS.
Topics: Biomarkers; Child; Cost of Illness; Demyelinating Diseases; Diagnosis, Differential; Disease Progression; Early Diagnosis; Humans; Longitudinal Studies; Multiple Sclerosis; Prospective Studies; Quality of Life; United Kingdom
PubMed: 21798048
DOI: 10.1186/1471-2431-11-68