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International Journal of Molecular... Mar 2022Autoimmune demyelinating diseases-including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease,... (Review)
Review
Autoimmune demyelinating diseases-including multiple sclerosis, neuromyelitis optica spectrum disorder, anti-myelin oligodendrocyte glycoprotein-associated disease, acute disseminated encephalomyelitis, and glial fibrillary acidic protein (GFAP)-associated meningoencephalomyelitis-are a heterogeneous group of diseases even though their common pathology is characterized by neuroinflammation, loss of myelin, and reactive astrogliosis. The lack of safe pharmacological therapies has purported the notion that cell-based treatments could be introduced to cure these patients. Among stem cells, mesenchymal stem cells (MSCs), obtained from various sources, are considered to be the ones with more interesting features in the context of demyelinating disorders, given that their secretome is fully equipped with an array of anti-inflammatory and neuroprotective molecules, such as mRNAs, miRNAs, lipids, and proteins with multiple functions. In this review, we discuss the potential of cell-free therapeutics utilizing MSC secretome-derived extracellular vesicles-and in particular exosomes-in the treatment of autoimmune demyelinating diseases, and provide an outlook for studies of their future applications.
Topics: Autoimmune Diseases; Central Nervous System; Extracellular Vesicles; Humans; Mesenchymal Stem Cells; Myelin-Oligodendrocyte Glycoprotein; Neuromyelitis Optica
PubMed: 35409188
DOI: 10.3390/ijms23073829 -
International Journal of Molecular... Jan 2024Multiple sclerosis (MS) is an autoimmune and inflammatory disorder affecting the central nervous system whose cause is still largely unknown. Oligodendrocyte... (Review)
Review
Multiple sclerosis (MS) is an autoimmune and inflammatory disorder affecting the central nervous system whose cause is still largely unknown. Oligodendrocyte degeneration results in demyelination of axons, which can eventually be repaired by a mechanism called remyelination. Prevention of demyelination and the pharmacological support of remyelination are two promising strategies to ameliorate disease progression in MS patients. The cuprizone model is commonly employed to investigate oligodendrocyte degeneration mechanisms or to explore remyelination pathways. During the last decades, several different protocols have been applied, and all have their pros and cons. This article intends to offer guidance for conducting pre-clinical trials using the cuprizone model in mice, focusing on discovering new treatment approaches to prevent oligodendrocyte degeneration or enhance remyelination.
Topics: Humans; Mice; Animals; Cuprizone; Myelin Sheath; Demyelinating Diseases; Remyelination; Oligodendroglia; Multiple Sclerosis; Mice, Inbred C57BL; Disease Models, Animal
PubMed: 38338724
DOI: 10.3390/ijms25031445 -
Neurology(R) Neuroimmunology &... May 2021Neurofilament light protein (NfL) and chitinase 3-like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to...
OBJECTIVE
Neurofilament light protein (NfL) and chitinase 3-like 1 (CHI3L1) are biomarkers for acute neuroaxonal damage and local inflammation, respectively. Thus, we set out to evaluate how these biomarkers were associated with clinical features of demyelinating diseases in parallel with the expression in brain autopsies from patients with similar disease stages, assuming their comparability.
METHODS
NfL and CHI3L1 in CSF and serum CHI3L1 were assessed retrospectively in a cross-sectional cohort of controls (n = 17) and patients diagnosed with MS (n = 224), relapsing (n = 163) or progressive (n = 61); neuromyelitis optica (NMO, n = 7); and acute disseminated encephalomyelitis (ADEM, n = 15). Inflammatory activity was evaluated at the time of sampling, and CSF biomarker levels were related to the degree of inflammation in 22 brain autopsy tissues.
RESULTS
During a clinical attack, the CSF NfL increased in MS, NMO, and ADEM, whereas CHI3L1 was only elevated in patients with NMO and ADEM and in outlier MS patients with extensive radiologic activity. Outside relapses, CHI3L1 levels only remained elevated in patients with progressive MS. CHI3L1 was detected in macrophages and astrocytes, predominantly in areas of active demyelination, and its expression by astrocytes in chronic lesions was independent of lymphocyte infiltrates and associated with active neurodegeneration.
CONCLUSIONS
Both CSF NfL and CHI3L1 augment during acute inflammation in demyelinating diseases. In MS, CHI3L1 may be associated with low-grade nonlymphocytic inflammation and active neurodegeneration and therefore linked to progressive disease.
CLASSIFICATION OF EVIDENCE
This study provides Class III evidence that CSF NfL and CHI3L1 levels increase in inflammatory brain diseases during acute inflammation.
Topics: Adult; Aged; Aged, 80 and over; Astrocytes; Biomarkers; Chitinase-3-Like Protein 1; Cohort Studies; Cross-Sectional Studies; Demyelinating Diseases; Disease Progression; Female; Humans; Inflammation; Male; Middle Aged; Multiple Sclerosis, Chronic Progressive; Neurofilament Proteins; Retrospective Studies
PubMed: 33658322
DOI: 10.1212/NXI.0000000000000972 -
Scientific Reports Jul 2023Theiler's murine encephalomyelitis virus (TMEV) induces an acute polioencephalomyelitis and a chronic demyelinating leukomyelitis in SJL mice. C57BL/6 (B6) mice...
Theiler's murine encephalomyelitis virus (TMEV) induces an acute polioencephalomyelitis and a chronic demyelinating leukomyelitis in SJL mice. C57BL/6 (B6) mice generally do not develop TMEV-induced demyelinating disease (TMEV-IDD) due to virus elimination. However, TMEV can persist in specific immunodeficient B6 mice such as IFNβ mice and induce a demyelinating process. The proinflammatory cytokines IL-1β and IL-18 are activated by the inflammasome pathway, which consists of a pattern recognition receptor molecule sensing microbial pathogens, the adaptor molecule Apoptosis-associated speck-like protein containing a CARD (ASC), and the executioner caspase-1. To analyze the contribution of the inflammasome pathway to the resistance of B6 mice to TMEV-IDD, ASC- and caspase-1-deficient mice and wild type littermates were infected with TMEV and investigated using histology, immunohistochemistry, RT-qPCR, and Western Blot. Despite the antiviral activity of the inflammasome pathway, ASC- and caspase-1-deficient mice eliminated the virus and did not develop TMEV-IDD. Moreover, a similar IFNβ and cytokine gene expression was found in the brain of immunodeficient mice and their wild type littermates. Most importantly, Western Blot showed cleavage of IL-1β and IL-18 in all investigated mice. Consequently, inflammasome-dependent activation of IL-1β and IL-18 does not play a major role in the resistance of B6 mice to TMEV-IDD.
Topics: Animals; Mice; Caspase 1; Cytokines; Demyelinating Diseases; Inflammasomes; Interleukin-18; Mice, Inbred C57BL; Mice, Inbred Strains; Theilovirus
PubMed: 37414913
DOI: 10.1038/s41598-023-38152-3 -
Annals of Clinical and Translational... Dec 2021To examine the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS).
OBJECTIVE
To examine the gut microbiota in individuals with and without pediatric-onset multiple sclerosis (MS).
METHODS
We compared stool-derived microbiota of Canadian Pediatric Demyelinating Disease Network study participants ≤21 years old, with MS (disease-modifying drug [DMD] exposed and naïve) or monophasic acquired demyelinating syndrome [monoADS] (symptom onset <18 years), and unaffected controls. All were ≥30 days without antibiotics or corticosteroids. V4 region 16S RNA gene-derived amplicon sequence variants (Illumina MiSeq) were assessed using negative binomial regression and network analyses; rate ratios were age- and sex-adjusted (aRR).
RESULTS
Thirty-two MS, 41 monoADS (symptom onset [mean] = 14.0 and 6.9 years) and 36 control participants were included; 75%/56%/58% were female, with mean ages at stool sample = 16.5/13.8/15.1 years, respectively. Nine MS cases (28%) were DMD-naïve. Although microbiota diversity (alpha, beta) did not differ between participants (p > 0.1), taxa-level and gut community networks did. MS (vs. monoADS) exhibited > fourfold higher relative abundance of the superphylum Patescibacteria (aRR = 4.2;95%CI:1.6-11.2, p = 0.004, Q = 0.01), and lower abundances of short-chain fatty acid (SCFA)-producing Lachnospiraceae (Anaerosporobacter) and Ruminococcaceae (p, Q < 0.05). DMD-naïve MS cases were depleted for Clostridiales vadin-BB60 (unnamed species) versus either DMD-exposed, controls (p, Q < 0.01), or monoADS (p = 0.001, Q = 0.06) and exhibited altered community connectedness (p < 10 Kruskal-Wallis), with SCFA-producing taxa underrepresented. Consistent taxa-level findings from an independent US Network of Pediatric MS Centers case/control (n = 51/42) cohort included >eightfold higher abundance for Candidatus Stoquefichus and Tyzzerella (aRR = 8.8-12.8, p < 0.05) in MS cases and 72%-80% lower abundance of SCFA-producing Ruminococcaceae-NK4A214 (aRR = 0.38-0.2, p ≤ 0.01).
INTERPRETATION
Gut microbiota community structure, function and connectivity, and not just individual taxa, are of likely importance in MS.
Topics: Adolescent; Canada; Case-Control Studies; Child; Child, Preschool; Cohort Studies; Computational Biology; Demyelinating Autoimmune Diseases, CNS; Female; Gastrointestinal Microbiome; Humans; Male; Multiple Sclerosis; RNA, Ribosomal, 16S
PubMed: 34889081
DOI: 10.1002/acn3.51476 -
Multiple Sclerosis and Related Disorders Jun 2021Since March 2020, during the Coronavirus disease 2019 (COVID-19) pandemic, it has been observed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has...
BACKGROUND
Since March 2020, during the Coronavirus disease 2019 (COVID-19) pandemic, it has been observed that the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has neurological involvement with various clinical tables.
METHODS
We present 3 new cases admitted to our clinic with various neurological findings which were affected by SARS-CoV-2.
RESULTS
Imaging studies have shown that inflammatory/demyelinizing lesions appeared in different areas of the central nervous system which were accepted as an atypical demyelinating spectrum associated with Covid 19.
CONCLUSIONS
With increasing experience, it has been suggested that SARS-CoV-2 may also have a neurotrophic effect. The spectrum of neurological involvement is also expanding as the pandemic continues. These 3 cases suggest that the virus plays a role in the clinical onset of the inflammatory/demyelinating disease.
Topics: COVID-19; Central Nervous System; Demyelinating Diseases; Humans; Pandemics; SARS-CoV-2
PubMed: 33770573
DOI: 10.1016/j.msard.2021.102900 -
Multiple Sclerosis and Related Disorders Dec 2022Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs)...
BACKGROUND
Since the start of COVID-19 vaccination worldwide, there have been several reports of inflammatory demyelinating diseases of the central nervous system (CNS-IDDs) following vaccination.
METHODS
We prospectively collected cases of new-onset CNS-IDDs with a temporal relationship between disease onset and COVID-19 vaccination and investigated their proportion among newly registered cases of CNS-IDD over the past year.
RESULTS
Among 117 cases, 10 (8.5%) had their first disease manifestation within one month following COVID-19 vaccination: 2 multiple sclerosis, 2 neuromyelitis optica spectrum disorder, 3 MOG antibody-associated disease, and 3 unclassified CNS-IDDs.
CONCLUSION
This observation suggests that COVID-19 vaccination may trigger the onset of various CNS-IDDs in susceptible individuals.
Topics: Humans; Autoantibodies; Central Nervous System; Central Nervous System Diseases; COVID-19; COVID-19 Vaccines; Demyelinating Autoimmune Diseases, CNS; Neuromyelitis Optica
PubMed: 36037757
DOI: 10.1016/j.msard.2022.104141 -
Annals of Clinical and Translational... Jul 2023Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects...
OBJECTIVE
Metachromatic leukodystrophy is a lysosomal storage disease caused by deficient arylsulfatase A. It is characterized by progressive demyelination and thus mainly affects the white matter. Hematopoietic stem cell transplantation may stabilize and improve white matter damage, yet some patients deteriorate despite successfully treated leukodystrophy. We hypothesized that post-treatment decline in metachromatic leukodystrophy might be caused by gray matter pathology.
METHODS
Three metachromatic leukodystrophy patients treated with hematopoietic stem cell transplantation with a progressive clinical course despite stable white matter pathology were clinically and radiologically analyzed. Longitudinal volumetric MRI was used to quantify atrophy. We also examined histopathology in three other patients deceased after treatment and compared them with six untreated patients.
RESULTS
The three clinically progressive patients developed cognitive and motor deterioration after transplantation, despite stable mild white matter abnormalities on MRI. Volumetric MRI identified cerebral and thalamus atrophy in these patients, and cerebellar atrophy in two. Histopathology showed that in brain tissue of transplanted patients, arylsulfatase A expressing macrophages were clearly present in the white matter, but absent in the cortex. Arylsulfatase A expression within patient thalamic neurons was lower than in controls, the same was found in transplanted patients.
INTERPRETATION
Neurological deterioration may occur after hematopoietic stem cell transplantation in metachromatic leukodystrophy despite successfully treated leukodystrophy. MRI shows gray matter atrophy, and histological data demonstrate absence of donor cells in gray matter structures. These findings point to a clinically relevant gray matter component of metachromatic leukodystrophy, which does not seem sufficiently affected by transplantation.
Topics: Humans; Leukodystrophy, Metachromatic; Cerebroside-Sulfatase; Neurodegenerative Diseases; Hematopoietic Stem Cell Transplantation; Brain; Demyelinating Diseases
PubMed: 37212343
DOI: 10.1002/acn3.51796 -
NeuroImage. Clinical 2022T1w/T2-w ratio has been proposed as a clinically feasible MRI biomarker to assess tissue integrity in multiple sclerosis. However, no data is available in the earliest...
BACKGROUND
T1w/T2-w ratio has been proposed as a clinically feasible MRI biomarker to assess tissue integrity in multiple sclerosis. However, no data is available in the earliest stages of the disease and longitudinal studies analysing clinical associations are scarce.
OBJECTIVE
To describe longitudinal changes in T1-w/T2-w in patients with clinically isolated syndrome (CIS) and multiple sclerosis, and to investigate their clinical associations.
METHODS
T1-w/T2-w images were generated and the mean value obtained in the corresponding lesion, normal-appearing grey (NAGM) and white matter (NAWM) masks. By co-registering baseline to follow-up MRI, evolved lesions were assessed; and by placing the mask of new lesions to the baseline study, the pre-lesional tissue integrity was measured.
RESULTS
We included 171 CIS patients and 22 established multiple sclerosis patients. In CIS, evolved lesions showed significant T1-w/T2-w increases compared to baseline (+7.6%, P < 0.001). T1-w/T2-w values in new lesions were lower than in pre-lesional tissue (-28.2%, P < 0.001), and pre-lesional tissue was already lower than baseline NAWM (-7.8%, P < 0.001). In CIS at baseline, higher NAGM T1-w/T2-w was associated with multiple sclerosis diagnosis, and longitudinal decreases in NAGM and NAWM T1-w/T2-w were associated with disease activity. In established multiple sclerosis, T1-w/T2-w was inversely correlated with clinical disability and disease duration.
CONCLUSION
A decrease in T1-w/T2-w ratio precedes lesion formation. In CIS, higher T1-w/T2-w was associated with multiple sclerosis diagnosis. In established multiple sclerosis, lower T1-w/T2-w values were associated with clinical disability. The possible differential impact of chronic inflammation, iron deposition and demyelination should be considered to interpret these findings.
Topics: Brain; Demyelinating Diseases; Humans; Longitudinal Studies; Magnetic Resonance Imaging; Multiple Sclerosis; White Matter
PubMed: 35202997
DOI: 10.1016/j.nicl.2022.102967 -
Journal of Neuroinflammation Oct 2023Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including...
BACKGROUND
Neuromyelitis optica spectrum disorder (NMOSD) stands out among CNS inflammatory demyelinating diseases (CIDDs) due to its unique disease characteristics, including severe clinical attacks with extensive lesions and its association with systemic autoimmune diseases. We aimed to investigate whether characteristics of B cell receptors (BCRs) differ between NMOSD and other CIDDs using high-throughput sequencing.
METHODS
From a prospective cohort, we recruited patients with CIDDs and categorized them based on the presence and type of autoantibodies: NMOSD with anti-aquaporin-4 antibodies, myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) with anti-myelin oligodendrocyte glycoprotein antibodies, double-seronegative demyelinating disease (DSN), and healthy controls (HCs). The BCR features, including isotype class, clonality, somatic hypermutation (SHM), and the third complementarity-determining region (CDR3) length, were analyzed and compared among the different disease groups.
RESULTS
Blood samples from 33 patients with CIDDs (13 NMOSD, 12 MOGAD, and 8 DSN) and 34 HCs were investigated for BCR sequencing. Patients with NMOSD tended to have more activated BCR features compare to the other disease groups. They showed a lower proportion of unswitched isotypes (IgM and IgD) and a higher proportion of switched isotypes (IgG), increased clonality of BCRs, higher rates of SHM, and shorter lengths of CDR3. Notably, advanced age was identified as a clinical factor associated with these activated BCR features, including increased levels of clonality and SHM rates in the NMOSD group. Conversely, no such clinical factors were found to be associated with activated BCR features in the other CIDD groups.
CONCLUSIONS
NMOSD patients, among those with CIDDs, displayed the most pronounced B cell activation, characterized by higher levels of isotype class switching, clonality, SHM rates, and shorter CDR3 lengths. These findings suggest that B cell-mediated humoral immune responses and characteristics in NMOSD patients are distinct from those observed in the other CIDDs, including MOGAD. Age was identified as a clinical factor associated with BCR activation specifically in NMOSD, implying the significance of persistent B cell activation attributed to anti-aquaporin-4 antibodies, even in the absence of clinical relapses throughout an individual's lifetime.
Topics: Humans; Neuromyelitis Optica; Aquaporin 4; Prospective Studies; Myelin-Oligodendrocyte Glycoprotein; Autoantibodies; Receptors, Antigen, B-Cell
PubMed: 37794409
DOI: 10.1186/s12974-023-02896-6