Distinct patterns of glia repair and remyelination in antibody‐mediated demyelination models of multiple sclerosis and neuromyelitis optica

Liu, Yiting; Given, Katherine S.; Owens, Gregory P.; Macklin, Wendy B.; Bennett, Jeffrey L.

doi:10.1002/glia.23512

Cited by 24 publications

(16 citation statements)

References 69 publications

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“…Further, CSF of MS patients induced inflammatory demyelination and axonal damage in mice (29,30). We demonstrated that a subset of myelin-specific recombinant antibodies constructed from clonal expanded plasma cells in MS CSF caused robust complementdependent cytotoxicity in oligodendrocytes and induced rapid demyelination in mouse organotypic cerebellar slices (31,32). These studies support the pathogenic effects of CSF IgGs in MS.…”

Section: Increased Intrathecal Synthesis Of Ocb Is the Most Characteristic Feature Of Mssupporting

confidence: 64%

The Role of Antibodies in the Pathogenesis of Multiple Sclerosis

Graner

Kennedy

et al. 2020

Front. Neurol.

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The presence of persistent intrathecal oligoclonal immunoglobulin G (IgG) bands (OCBs) and lesional IgG deposition are seminal features of multiple sclerosis (MS) disease pathology. Despite extensive investigations, the role of antibodies, the products of mature CD19 + B cells, in disease development is still controversial and under significant debate. Recent success of B cell depletion therapies has revealed that CD20 + B cells contribute to MS pathogenesis via both antigen-presentation and T-cell-regulation. However, the limited efficacy of CD20 + B cell depletion therapies for the treatment of progressive MS indicates that additional mechanisms are involved. In this review, we present findings suggesting a potential pathological role for increased intrathecal IgGs, the relation of circulating antibodies to intrathecal IgGs, and the selective elevation of IgG1 and IgG3 subclasses in MS. We propose a working hypothesis that circulating B cells and antibodies contribute significantly to intrathecal IgGs, thereby exerting primary and pathogenic effects in MS development. Increased levels of IgG1 and IgG3 antibodies induce potent antibody-mediated cytotoxicity to central nervous system (CNS) cells and/or reduce the threshold required for antigen-driven antibody clustering leading to optimal activation of immune responses. Direct proof of the pathogenic roles of antibodies in MS may provide opportunities for novel blood biomarker identification as well as strategies for the development of effective therapeutic interventions.

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Section: Increased Intrathecal Synthesis Of Ocb Is the Most Characteristic Feature Of Mssupporting

confidence: 64%

The Role of Antibodies in the Pathogenesis of Multiple Sclerosis

Graner

Kennedy

et al. 2020

Front. Neurol.

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“…Using recombinant monoclonal IgG1, the loss of OPCs is practically complete in NMOSD lesions may present limited remyelination due to several mechanisms: inhibition of differentiation into mature OLGs, inhibition of the migration of OPCs through BBB injury, microglial alterations that limit phagocytosis of myelin debris, or axonal alterations. Using recombinant monoclonal IgG1, the loss of OPCs is practically complete in NMOSD, unlike in multiple sclerosis, in which it decreases to 50% [45]; therefore, with the presence of AQP4-IgG, remyelination may be difficult [46]. Our study presents the limitation that it does not reproduce the pathogenesis of NMOSD, which involves an inflammatory environment with BBB disruption, nor the effects of axonal alteration: it only analyzes the effect of AQP4IgG on cell differentiation and does not consider the effect of AQP4 on the immune response [47].…”

Section: Discussionmentioning

confidence: 99%

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

Gómez‐Pinedo¹,

García-Ávila²,

Gallego-Villarejo³

et al. 2021

IJMS

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Introduction: AQP4 (aquaporin-4)–immunoglobulin G (IgG)-mediated neuromyelitis optica spectrum disorder (NMOSD) is an inflammatory demyelinating disease that affects the central nervous system, particularly the spinal cord and optic nerve; remyelination capacity in neuromyelitis optica is yet to be determined, as is the role of AQP4–IgG in cell differentiation. Material and Methods: We included three groups—a group of patients with AQP4–IgG-positive neuromyelitis optica, a healthy group, and a sham group. We analyzed differentiation capacity in cultures of neurospheres from the subventricular zone of mice by adding serum at two different times: early and advanced stages of differentiation. We also analyzed differentiation into different cell lines. Results and Conclusions: The effect of sera from patients with NMOSD on precursor cells differs according to the degree of differentiation, and probably affects oligodendrocyte progenitor cells from NG2 cells to a lesser extent than cells from the subventricular zone; however, the resulting oligodendrocytes may be compromised in terms of maturation and possibly limited in their ability to generate myelin. Furthermore, these cells decrease in number with age. It is very unlikely that the use of drugs favoring the migration and differentiation of oligodendrocyte progenitor cells in multiple sclerosis would be effective in the context of neuromyelitis optica, but cell therapy with oligodendrocyte progenitor cells seems to be a potential alternative.

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“…This hypothesis has been substantiated by experiments on ex vivo brain cultures treated with recombinant antibodies from MS or NMO patient CSF in combination with human complement. It could be demonstrated that axons in demyelinated brain culture lesions treated with MS rAb were rapidly remyelinated, whereas lesions in NMO rAb-treated tissue were repopulated with astrocytes and pre-myelinating oligodendrocytes, but did not show substantial remyelination of preserved axons [ 52 ].…”

Section: Discussionmentioning

confidence: 99%

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination

Lohrberg

Winkler

Franz

et al. 2020

acta neuropathol commun

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Demyelinated lesions in human pons observed after osmotic shifts in serum have been referred to as central pontine myelinolysis (CPM). Astrocytic damage, which is prominent in neuroinflammatory diseases like neuromyelitis optica (NMO) and multiple sclerosis (MS), is considered the primary event during formation of CPM lesions. Although more data on the effects of astrocyte-derived factors on oligodendrocyte precursor cells (OPCs) and remyelination are emerging, still little is known about remyelination of lesions with primary astrocytic loss. In autopsy tissue from patients with CPM as well as in an experimental model, we were able to characterize OPC activation and differentiation. Injections of the thymidine-analogue BrdU traced the maturation of OPCs activated in early astrocyte-depleted lesions. We observed rapid activation of the parenchymal NG2+ OPC reservoir in experimental astrocyte-depleted demyelinated lesions, leading to extensive OPC proliferation. One week after lesion initiation, most parenchyma-derived OPCs expressed breast carcinoma amplified sequence-1 (BCAS1), indicating the transition into a pre-myelinating state. Cells derived from this early parenchymal response often presented a dysfunctional morphology with condensed cytoplasm and few extending processes, and were only sparsely detected among myelin-producing or mature oligodendrocytes. Correspondingly, early stages of human CPM lesions also showed reduced astrocyte numbers and non-myelinating BCAS1+ oligodendrocytes with dysfunctional morphology. In the rat model, neural stem cells (NSCs) located in the subventricular zone (SVZ) were activated while the lesion was already partially repopulated with OPCs, giving rise to nestin+ progenitors that generated oligodendroglial lineage cells in the lesion, which was successively repopulated with astrocytes and remyelinated. These nestin+ stem cell-derived progenitors were absent in human CPM cases, which may have contributed to the inefficient lesion repair. The present study points to the importance of astrocyte-oligodendrocyte interactions for remyelination, highlighting the necessity to further determine the impact of astrocyte dysfunction on remyelination inefficiency in demyelinating disorders including MS.

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Distinct patterns of glia repair and remyelination in antibody‐mediated demyelination models of multiple sclerosis and neuromyelitis optica

Cited by 24 publications

References 69 publications

The Role of Antibodies in the Pathogenesis of Multiple Sclerosis

The Role of Antibodies in the Pathogenesis of Multiple Sclerosis

Sera from Patients with NMOSD Reduce the Differentiation Capacity of Precursor Cells in the Central Nervous System

Lack of astrocytes hinders parenchymal oligodendrocyte precursor cells from reaching a myelinating state in osmolyte-induced demyelination

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