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1.
Acta Neuropathol Commun ; 8(1): 135, 2020 08 13.
Article in English | MEDLINE | ID: mdl-32792006

ABSTRACT

Progressive multi-focal leukoencephalopathy (PML) is a potentially fatal encephalitis caused by JC polyomavirus (JCV). PML principally affects people with a compromised immune system, such as patients with multiple sclerosis (MS) receiving treatment with natalizumab. However, intrathecal synthesis of lipid-reactive IgM in MS patients is associated with a markedly lower incidence of natalizumab-associated PML compared to those without this antibody repertoire. Here we demonstrate that a subset of lipid-reactive human and murine IgMs induce a functional anti-viral response that inhibits replication of encephalitic Alpha and Orthobunyaviruses in multi-cellular central nervous system cultures. These lipid-specific IgMs trigger microglia to produce IFN-ß in a cGAS-STING-dependent manner, which induces an IFN-α/ß-receptor 1-dependent antiviral response in glia and neurons. These data identify lipid-reactive IgM as a mediator of anti-viral activity in the nervous system and provide a rational explanation why intrathecal synthesis of lipid-reactive IgM correlates with a reduced incidence of iatrogenic PML in MS.


Subject(s)
Autoantibodies/cerebrospinal fluid , Immunoglobulin M/cerebrospinal fluid , Leukoencephalopathy, Progressive Multifocal/immunology , Lipids/immunology , Multiple Sclerosis , Animals , Autoantibodies/immunology , Autoantigens/immunology , Humans , Immunocompromised Host/immunology , Immunoglobulin M/immunology , Immunologic Factors/adverse effects , Mice , Mice, Inbred C57BL , Multiple Sclerosis/drug therapy , Multiple Sclerosis/immunology , Natalizumab/adverse effects , Rats , Rats, Sprague-Dawley
2.
Acta Neuropathol Commun ; 2: 168, 2014 Dec 11.
Article in English | MEDLINE | ID: mdl-25589163

ABSTRACT

Chronic demyelination is a pathological hallmark of multiple sclerosis (MS). Only a minority of MS lesions remyelinates completely. Enhancing remyelination is, therefore, a major aim of future MS therapies. Here we took a novel approach to identify factors that may inhibit or support endogenous remyelination in MS. We dissected remyelinated, demyelinated active, and demyelinated inactive white matter MS lesions, and compared transcript levels of myelination and inflammation-related genes using quantitative PCR on customized TaqMan Low Density Arrays. In remyelinated lesions, fibroblast growth factor (FGF) 1 was the most abundant of all analyzed myelination-regulating factors, showed a trend towards higher expression as compared to demyelinated lesions and was significantly higher than in control white matter. Two MS tissue blocks comprised lesions with adjacent de- and remyelinated areas and FGF1 expression was higher in the remyelinated rim compared to the demyelinated lesion core. In functional experiments, FGF1 accelerated developmental myelination in dissociated mixed cultures and promoted remyelination in slice cultures, whereas it decelerated differentiation of purified primary oligodendrocytes, suggesting that promotion of remyelination by FGF1 is based on an indirect mechanism. The analysis of human astrocyte responses to FGF1 by genome wide expression profiling showed that FGF1 induced the expression of the chemokine CXCL8 and leukemia inhibitory factor, two factors implicated in recruitment of oligodendrocytes and promotion of remyelination. Together, this study presents a transcript profiling of remyelinated MS lesions and identified FGF1 as a promoter of remyelination. Modulation of FGF family members might improve myelin repair in MS.


Subject(s)
Brain/physiopathology , Fibroblast Growth Factor 1/metabolism , Multiple Sclerosis/physiopathology , Myelin Sheath/physiology , Spinal Cord/physiopathology , Animals , Astrocytes/physiology , Cells, Cultured , Gene Expression Profiling , Humans , Interleukin-8/metabolism , Leukemia Inhibitory Factor/metabolism , Mice , Mice, Inbred C57BL , Oligodendroglia/physiology , RNA, Messenger/metabolism , Rats, Sprague-Dawley , Rats, Wistar , Tissue Culture Techniques , White Matter/physiopathology
3.
PLoS One ; 7(9): e42667, 2012.
Article in English | MEDLINE | ID: mdl-22984406

ABSTRACT

Schwann cell (SC) transplantation is currently being discussed as a strategy that may promote functional recovery in patients with multiple sclerosis (MS) and other inflammatory demyelinating diseases of the central nervous system (CNS). However this assumes they will not only survive but also remyelinate demyelinated axons in the chronically inflamed CNS. To address this question we investigated the fate of transplanted SCs in myelin oligodendrocyte glycoprotein (MOG)-induced experimental autoimmune encephalomyelitis (EAE) in the Dark Agouti rat; an animal model that reproduces the complex inflammatory demyelinating immunopathology of MS. We now report that SCs expressing green fluorescent protein (GFP-SCs) allografted after disease onset not only survive but also migrate to remyelinate lesions in the inflamed CNS. GFP-SCs were detected more frequently in the parenchyma after direct injection into the spinal cord, than via intra-thecal delivery into the cerebrospinal fluid. In both cases the transplanted cells intermingled with astrocytes in demyelinated lesions, aligned with axons and by twenty one days post transplantation had formed Pzero protein immunoreactive internodes. Strikingly, GFP-SCs transplantation was associated with marked decrease in clinical disease severity in terms of mortality; all GFP-SCs transplanted animals survived whilst 80% of controls died within 40 days of disease.


Subject(s)
Cell Movement , Encephalomyelitis, Autoimmune, Experimental/physiopathology , Encephalomyelitis, Autoimmune, Experimental/therapy , Myelin Sheath/metabolism , Recovery of Function , Schwann Cells/cytology , Schwann Cells/transplantation , Animals , Astrocytes/metabolism , Astrocytes/pathology , Cell Survival , Female , Green Fluorescent Proteins/metabolism , Injections, Spinal , Myelin Sheath/pathology , Myelin-Oligodendrocyte Glycoprotein , Rats , Spinal Cord/blood supply , Spinal Cord/pathology , Spinal Cord/physiopathology , Transduction, Genetic
4.
J Mol Med (Berl) ; 88(8): 753-61, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20445955

ABSTRACT

Multiple sclerosis is thought to be an autoimmune-mediated disease of the central nervous system. For many years, T-cells were regarded as the key players in the pathogenesis, and myelin of white matter was considered as the main victim. However, research during recent years showed a more complex picture. Besides T-cells, also B-cells, antibodies and the innate immunity contribute to the tissue damage. Modern imaging techniques and neuropathological examinations showed that not only myelin but also axons, cortical neurons and nodes of Ranvier are damaged. The autoimmune targets of this widespread injury are so far not known. The identification of the axo-glial proteins contactin-2 and neurofascin provides excellent examples how antibodies can induce axonal injury at the node of Ranvier and how T-cells can destruct cortical integrity. This review will discuss the pathogenic implications of an autoimmune response against these newly discovered antigens.


Subject(s)
Autoantigens/immunology , Multiple Sclerosis/immunology , Multiple Sclerosis/pathology , Animals , Autoantigens/analysis , Autoimmunity , Axons/immunology , Axons/pathology , Cerebral Cortex/immunology , Cerebral Cortex/pathology , Humans , Neuroglia/immunology , Neuroglia/pathology
5.
Ann Neurol ; 51(2): 215-23, 2002 Feb.
Article in English | MEDLINE | ID: mdl-11835378

ABSTRACT

We have explored the use of minocycline, a tetracycline with antiinflammatory properties, to treat chronic relapsing-remitting experimental allergic encephalomyelitis, an animal model of multiple sclerosis. Therapeutic treatment with minocycline dramatically suppresses ongoing disease activity and limits disease progression. Disease suppression is associated with immune deviation in the periphery and with suppression of the inflammatory cascade in the central nervous system. This association is demonstrated by inhibition of microglial activation and metalloproteinase-2 expression, which results in a concomitant decrease in inflammation and demyelination. As an established antiinflammatory drug with neuroprotective properties, minocycline may provide a novel therapeutic agent for relapsing-remitting multiple sclerosis.


Subject(s)
Anti-Bacterial Agents/pharmacology , Encephalomyelitis, Autoimmune, Experimental/drug therapy , Minocycline/pharmacology , Animals , Brain/immunology , Brain/pathology , Chronic Disease , Encephalomyelitis, Autoimmune, Experimental/immunology , Encephalomyelitis, Autoimmune, Experimental/pathology , Female , Immunization , Myelin Proteins , Myelin-Associated Glycoprotein/immunology , Myelin-Oligodendrocyte Glycoprotein , Rats , Recurrence , Th1 Cells/immunology , Th2 Cells/immunology
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