Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0014070 (encephalomyelitis)
 13,017 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oligodendrocyte-specific protein (OSP) is a recently isolated and cloned, 207-aa, hydrophobic, four-transmembrane protein found in CNS myelin. It represents approximately 7% of total myelin protein. The OSP cDNA sequence has no significant homology with previously reported genes, but the predicted protein structure suggests that OSP is a CNS homologue of peripheral myelin protein-22. We previously reported the presence of anti-OSP Abs in the cerebrospinal fluid of relapsing-remitting multiple sclerosis (MS) patients, but not control patient groups. In this study, we tested the ability of a panel of 20-mer peptides with 10-aa overlaps, representing the sequence of murine OSP, to induce experimental autoimmune encephalomyelitis (EAE), an animal model for MS. SJL mice challenged with murine OSP peptides 52-71, 82-101, 102-121, 142-161, 182-201, and 192-207 exhibited clinical EAE. OSP:52-71 elicited severe relapsing-remitting EAE in some individuals. All other encephalitogenic peptides elicited, at most, a loss of tail tonicity from which the mice most often completely recovered. Mononuclear cell infiltrates and focal demyelination characteristic of EAE were evident. T cell proliferative responses were seen with all encephalitogenic peptides except 142-161 and 182-201. OSP peptides 72-91 and 132-151 did not cause clinical EAE, but did elicit robust proliferative responses. B10.PL and PL/J mice challenged with the same OSP peptide doses as SJL mice did not exhibit clinical EAE. These results in the SJL EAE model, together with the results from MS patient clinical samples, make OSP a promising candidate for autoantigenic involvement in MS.
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PMID:Oligodendrocyte-specific protein peptides induce experimental autoimmune encephalomyelitis in SJL/J mice. 1035 5

To investigate the immunogenicity and encephalitogenicity of oligodendrocyte-specific protein (OSP), recombinant soluble mouse OSP (smOSP) was produced from a synthetic gene engineered to lack the sequences coding for the hydrophobic transmembrane domains of the native molecule. SmOSP was immunogenic and encephalitogenic for SJL/J, C3H.SW and C57BL/6J mice, but not PL/J or BALB/c mice. SmOSP-specific T-cells from SJL/J, C3H.SW and C57BL/6J mice induced severe chronic clinical experimental autoimmune encephalomyelitis upon transfer. These findings indicate that autoimmune T-cell responses to OSP should be investigated in the context of multiple sclerosis.
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PMID:T-cells specific for soluble recombinant oligodendrocyte-specific protein induce severe clinical experimental autoimmune encephalomyelitis in H-2(b) and H-2(s) mice. 1071 62

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system (CNS). It is thought that autoimmunity plays a major role in the development of the disease. Despite understanding MS as the cell-mediated autoimmune disease, recent studies suggest a role of humoral response in MS pathogenesis. The contribution of antibodies with anti-MOG specificity in the pathology of EAE (experimental allergic encephalomyelitis), an animal model of MS, in rodents and recently in primates has been demonstrated. B lymphocytes, plasma cells, and autoantibodies reacting with myelin proteins are present in the chronic and active plaques of MS patients. These antibodies, which recognize myelin basic protein (MBP), proteolipid protein (PLP), myelin-associated glycoprotein (MAG), myelin-oligodendrocyte glycoprotein (MOG), oligodendrocyte-specific protein (OSP), 2',3' cyclic nucleotide 3'-phosphodiesterase (CNP), and transaldolase (TAL), have been identified mostly in cerebrospinal fluid and in serum. So far, the antibodies directed against MBP, MOG, and OSP have been characterized in detail. However, the role of autoantibodies in MS pathogenesis is still controversial. A direct role in the demyelination process, by the activation of complement and cytotoxic cells, has been shown only for the anti-MOG antibodies. Identification of the antigens and epitopes targeting the autoimmune response in MS is of great importance, not only for understanding of MS pathology, but also for potential therapeutic use. Recently, antigen therapy trials have been conducted in MS patients. It seems, however, that only the recognition of the individual immunological response in each MS patient, including autoantigens and the subspecificity of autoreactive T and B lymphocytes, can allow for an effective fight against this destructive disease.
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PMID:[Epitopes on myelin proteins recognized by autoantibodies present in multiple sclerosis patients]. 1576 8

The encephalitogenic potential of oligodendrocyte-specific protein (OSP) in mice, its specific localization in the intralamellar tight junctions in CNS myelin, and the detection of autoreactivity against OSP in multiple sclerosis (MS) strongly suggest the relevance of autoreactivity against OSP in the pathogenesis of MS. In this study, we have characterized the autoimmune T and B cells that are associated with clinicopathological manifestations of OSP-induced MS-like disease in mice by using recombinant soluble mouse OSP (smOSP) and synthetic overlapping peptides spanning smOSP. SJL/J mice immunized with smOSP developed chronic relapsing clinical experimental autoimmune encephalomyelitis accompanied with intense perivascular and parenchymal inflammatory infiltrates, widespread demyelination, axonal loss, and remarkable optic neuritis. The smOSP-primed lymph node cells reacted predominantly against OSP55-80 and to a lesser extent also to OSP22-46 and OSP179-207. Unexpectedly, in vitro selection with smOSP resulted in pathogenic smOSP-specific CD4+ T cells that reacted equally well against OSP55-80, OSP22-46, OSP45-66, and OSP179-207. Fine analysis of the anti-OSP autoimmunity revealed that the disease is primarily associated with CD4+ T cells directed against the major (OSP55-80) and the minor (OSP179-207) encephalitogenic regions that were further delineated, both in vitro and in vivo, to OSP55-66 and OSP194-207, respectively. In contrast, the OSP-induced Abs were predominantly directed against OSP22-46; these Abs were mostly of IgG1 isotype, but high levels of IgG2a and IgG2b and significant levels of IgE were also observed. The reactivity of pathogenic T cells to two encephalitogenic regions, OSP55-80 and OSP179-207, and their diverse TCRVbeta gene repertoire may impose difficulties for epitope-directed or TCR-targeting approaches to immune-specific modulation of OSP-related pathogenesis.
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PMID:Epitope specificity of autoreactive T and B cells associated with experimental autoimmune encephalomyelitis and optic neuritis induced by oligodendrocyte-specific protein in SJL/J mice. 1708 56

Oligodendrocyte-specific protein (OSP)/claudin-11 has been recently implicated in multiple sclerosis pathophysiology. Yet, the pathogenic autoimmunity against OSP has been poorly investigated. We previously showed that OSP-induced experimental autoimmune encephalomyelitis (EAE) and optic neuritis in SJL/J mice are primarily associated with CD4+ T cells reactive against OSP55-80. Dissecting the fine epitope specificity to the level of epitopic residues recognized by OSP-specific encephalitogenic T cells revealed their focused recognition of OSP58M. Accordingly, OSP58M predicted by computer modeling to be a major TCR contact residue shared by the three nonameric core epitopes within OSP55-80, albeit at different MHC-II pockets, was experimentally determined as the primary TCR contact residue crucial for activation and control of encephalitogenic T cells reactive against OSP55-80 or against recombinant OSP. Ala substitution of OSP58M impaired the functional TCR recognition/activation of pathogenic OSP-reactive T cells. Accordingly, the non-stimulatory/non-encephalitogenic pOSP55-58A-66 analogue not only treated EAE induced by pOSP55-80 but also effectively reversed EAE induced by whole OSP. Thus, the selection/activation and control of OSP-pathogenic T cells in H-2(s) mice appeared to be dominated by their predetermined focused recognition of OSP58M. Such a focused recognition by OSP-pathogenic T cells, despite their extensive TCR heterogeneity (Kaushansky, N., Zhong, M. C., Kerlero de Rosbo, N., Hoeftberger, R., Lassmann, H. and Ben-Nun, A. 2006. Epitope specificity of autoreactive T and B cells associated with experimental autoimmune encephalomyelitis and optic neuritis induced by oligodendrocyte-specific protein in SJL/J mice. J. Immunol. 177:7364), may impact profoundly on peripheral self-tolerance to OSP and on altered peptide ligand-mediated immune-specific modulation of the recently described OSP-related autoimmune pathogenesis.
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PMID:Activation and control of pathogenic T cells in OSP/claudin-11-induced EAE in SJL/J mice are dominated by their focused recognition of a single epitopic residue (OSP58M). 1880 57

Oligodendrocytes are important for not only nerve conduction but also central nervous system (CNS) development and neuronal survival in a variety of conditions. Kallikrein-related peptidase 6 (KLK6) is expressed in oligodendrocytes in the CNS and its expression is changed in several physiological and pathological conditions, especially following spinal cord injury (SCI) and experimental autoimmune encephalomyelitis. In this study, we investigated the functions of KLK6 in oligodendrocyte lineage cell development and the production of myelin proteins using KLK6-deficient (KLK6(-/-)) mice. KLK6(-/-) mice were born without apparent defects and lived as long as wild-type (WT) mice. There was no significant difference in the numbers of oligodendrocyte precursor cells and mature oligodendrocytes in the adult naive spinal cord between WT and KLK6(-/-) mice. However, there were fewer mature oligodendrocytes in the KLK6(-/-) spinal cord than in the WT spinal cord at postnatal day 7 (P7). Expression of myelin basic protein (MBP) and oligodendrocyte-specific protein/claudin-11, major myelin proteins, was also decreased in the KLK6(-/-) spinal cord compared with the WT spinal cord at P7-21. Moreover, after SCI, the amount of MBP in the damaged spinal cords of KLK6(-/-) mice was significantly less than that in the damaged spinal cords of WT mice. These results indicate that KLK6 plays a functional role in oligodendrocyte development and the expression of myelin proteins.
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PMID:In vivo analysis of kallikrein-related peptidase 6 (KLK6) function in oligodendrocyte development and the expression of myelin proteins. 2337 68

Optic neuritis (ON), inflammation of the optic nerve, is strongly associated with multiple sclerosis. ON pathology is characterized by attack of autoreactive T cells against optic nerve antigens, resulting in demyelination, death of retinal ganglion cells, and cumulative visual impairment. A model of experimental autoimmune encephalomyelitis (EAE) was utilized to study the onset and progression of ON and the neuroprotective efficacy of oral treatment with the calpain inhibitor SNJ 1945. EAE was actively induced in B10.PL mice with myelin basic protein on Days 0 and 2, and mice received twice daily oral dosing of SNJ 1945 from Day 9 until sacrificing (Day 26). Visual function was determined by electroretinogram recordings and daily measurement of optokinetic responses (OKR) to a changing pattern stimulus. Optic nerve and retinal histopathology was investigated by immunohistochemical and luxol fast blue staining. EAE mice manifested losses in OKR thresholds, a measurement of visual acuity, which began early in the disease course. There was a significant bias toward unilateral OKR impairment among EAE-ON eyes. Treatment with SNJ 1945, initiated after the onset of OKR threshold decline, improved visual acuity, pattern electroretinogram amplitudes, and paralysis, with attenuation of retinal ganglion cell death. Furthermore, calpain inhibition spared oligodendrocytes, prevented degradation of axonal neurofilament protein, and attenuated reactive astrocytosis. The trend of early, unilateral visual impairment in EAE-ON parallels the clinical presentation of ON exacerbations associated with multiple sclerosis. Calpain inhibition may represent an ideal candidate therapy for the preservation of vision in clinical ON. As in multiple sclerosis (MS) patients, optic neuritis (ON) and early, primarily monocular loss in spatial acuity is observed in a rodent model (EAE, experimental autoimmune encephalomyelitis). Daily oral treatment with the calpain inhibitor SNJ 1945 preserves visual acuity and preserves retinal ganglion cells (Brn3a, brain-specific homeobox/POU domain protein 3A) and their axons (MOSP, myelin oligodendrocyte-specific protein). Calpain inhibition may represent a candidate therapy for the preservation of vision in ON.
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PMID:Calpain inhibition reduces structural and functional impairment of retinal ganglion cells in experimental optic neuritis. 2751 91