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)

Monocyte recruitment to the central nervous system (CNS) is a necessary step in the development of pathologic inflammatory lesions in experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. Monocyte chemoattractant protein (MCP)-1, a potent agonist for directed monocyte migration, has been implicated in the pathogenesis of EAE. Here we report that deficiency in CC chemokine receptor (CCR)2, the receptor for MCP-1, confers resistance to EAE induced with a peptide derived from myelin oligodendrocyte glycoprotein peptide 35-55 (MOGp35-55). CCR2(-/)- mice immunized with MOGp35-55 failed to develop mononuclear cell inflammatory infiltrates in the CNS and failed to increase CNS levels of the chemokines RANTES (regulated on activation, normal T cell expressed and secreted), MCP-1, and interferon (IFN)-inducible protein 10 (IP-10) as well the chemokine receptors CCR1, CCR2, and CCR5. Additionally, T cells from CCR2(-/)- immunized mice showed decreased antigen-induced proliferation and production of IFN-gamma compared with wild-type immunized controls, suggesting that CCR2 enhances the T helper cell type 1 immune response in EAE. These data indicate that CCR2 plays a necessary and nonredundant role in the pathogenesis of EAE.
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PMID:Resistance to experimental autoimmune encephalomyelitis in mice lacking the CC chemokine receptor (CCR)2. 1101 48

DAP12 is an ITAM-bearing membrane adaptor molecule implicated in the activation of NK and myeloid cells. In mice rendered DAP12 deficient by targeted gene disruption, lymphoid and myeloid development was apparently normal, although the activating Ly49 receptors on NK cells were downregulated and nonfunctional. To analyze the consequences of DAP12 deficiency in vivo, we examined the susceptibility of DAP12-/- mice to experimental autoimmune encephalomyelitis (EAE). DAP12-/- mice were resistant to EAE induced by immunization with myelin oligodendrocyte glycoprotein (MOG) peptide. Resistance was associated with a strongly diminished production of IFNgamma by myelin-reactive CD4+ T cells due to inadequate T cell priming in vivo. These data suggest that DAP12 signaling may be required for optimal antigen-presenting cell (APC) function or inflammation.
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PMID:DAP12-deficient mice fail to develop autoimmunity due to impaired antigen priming. 1102 32

Eight rhesus monkeys with different MHC backgrounds were immunized with myelin oligodendrocyte glycoprotein (MOG). All developed severe experimental autoimmune encephalomyelitis associated with large inflammatory foci and extensive demyelination. T-cell autoreactivity to MOG was directed against three main epitopes encompassed within amino acids 4-20, 35-50 and 94-116, of which two are also immunodominant epitopes for the autoimmune T cell response to MOG in patients with MS. A strong B cell response to MOG was observed in all monkeys and major epitopes recognized were located within amino acids 4-26, 24-46 and 44-66/54-76.
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PMID:Rhesus monkeys are highly susceptible to experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein: characterisation of immunodominant T- and B-cell epitopes. 1102 37

A role for alpha4 and beta7 integrins in mediating leucocyte entry into the central nervous system in the multiple sclerosis (MS)-like disease experimental autoimmune encephalomyelitis (EAE) has been demonstrated. However, the individual contributions of their respective ligands mucosal addressin cell adhesion molecule-1 (MAdCAM-1), vascular cell adhesion molecule-1 (VCAM-1) and E-cadherin expressed on the blood-brain barrier has not been determined. In the present paper, it is shown that an antibody directed against MAdCAM-1, the preferential ligand for alpha4beta7, effectively prevented the development of a progressive, non-remitting, form of EAE, actively induced by injection of myelin oligodendrocyte glycoprotein peptide (MOG(35-55)) autoantigen. Combinational treatment with both anti-MAdCAM-1, VCAM-1, and intercellular adhesion molecule-1 (ICAM-1) (ligand for integrin lymphocyte function-associated antigen (LFA)-1) mAbs led to more rapid remission than that obtained with anti-MAdCAM-1 antibody alone. However, neither MAdCAM-1 monotherapy, nor combinational antibody blockade was preventative when administered late in the course of disease progression. In conclusion, MAdCAM-1 plays a major contributory role in the progression of chronic EAE and is a potential therapeutic target for the treatment of MS. Critically, antivascular addressin therapy must be given early in the course of disease prior to the establishment of irreversible damage if it is to be effective, as a single treatment modality.
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PMID:Prevention of a chronic progressive form of experimental autoimmune encephalomyelitis by an antibody against mucosal addressin cell adhesion molecule-1, given early in the course of disease progression. 1111 75

The myelin oligodendrocyte glycoprotein (MOG) is a major target for autoantibody mediated demyelination in experimental autoimmune encephalomyelitis (EAE). In the current review we discuss the epitope specificity of this antibody response, in particular evidence suggesting that pathogenic anti-MOG antibodies are preferentially directed against conformation-dependent epitopes present on the extracellular immunoglobulin domain of the protein. Surprisingly, recent data suggest that this autoimmune response is in part regulated by polymorphisms in the MOG gene itself, an observation that may have important implications for the genetic and immunological stratification of patients with multiple sclerosis.
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PMID:The myelin oligodendrocyte glycoprotein (MOG): a model for antibody-mediated demyelination in experimental autoimmune encephalomyelitis and multiple sclerosis. 1112 2

The well established and characterized animal model for the human demyelinating autoimmune disease multiple sclerosis (MS) is known as experimental autoimmune encephalomyelitis (EAE). EAE is clinically characterized by focal areas of inflammation and demyelination and an infiltrate composed of large numbers of lymphocytes and macrophages, often found in a perivascular localization but also throughout the central nervous system (CNS). Active immunization of mice with several different protein components of myelin, including myelin basic protein (MBP), proteolipid protein (PLP) and myelin oligodendrocyte glycoprotein (MOG), are capable of eliciting an immune response resulting in the quintessential symptoms of EAE: ascending paralysis involving the tail and then the limbs. Depending on the mouse strain and myelin antigen utilized, the disease course can be acute or chronic relapsing, characterized by a rapid onset of hind limb weakness that commonly progresses to paralysis, followed by spontaneous remission starting 7-10 days after the initial appearance of symptoms. EAE can also be induced passively by the adoptive transfer of in vitro activated CD4+ T cell clones or lines, typically of the Th1 phenotype, into irradiated susceptible recipients. The mechanisms involved in the cellular pathogenesis leading to paralysis and demyelination have been extensively studied and are primarily mediated by CD4+ T cells of the Th1 phenotype, with specificity for myelin antigens. Following activation, Th1 CD4 T cells produce in abundance the inflammatory cytokines TNF-alpha, IFN-gamma and lymphotoxin alpha (LT-alpha, also know as TNF-beta). IFN-gamma production is highly correlated with encephalitogenicity and may contribute to disease by up-regulation of adhesion molecules on endothelial cells, facilitating migration of lymphocytes into the CNS; by induction of major histocompatibility complex (MHC) class I and MHC class II molecules on astrocytes, microglial cells and brain endothelium, facilitating antigen (Ag) presentation in the CNS; and by activation of macrophages, leading to production of nitric oxide, a potent cytotoxic molecule. TNF-alpha and LT-alpha are both members of the TNF family of molecules and cause cell death by apoptosis following interaction with their counter-receptors, the TNFR1 and TNFR2, leading to a cascade of proteolytic events culminating in the blebbing of the cytoplasmic membrane, nuclear condensation and DNA fragmentation. Consequently, the production of TNF-alpha and LT-alpha by Th1 clones has been correlated with encephalitogenic potential and antibodies (Abs) to both prevents EAE upon transfer of encephalitogenic clones. Even though substantial evidence exists for the role of inflammatory cytokines in the pathogenesis of EAE, other mechanisms of myelin destruction are thought to exist. To date, many reports have implicated a role for the cell death-inducing ligand pair Fas and Fas-ligand (FasL).
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PMID:Evidence that Fas and FasL contribute to the pathogenesis of experimental autoimmune encephalomyelitis. 1114 Apr 65

Experimental autoimmune encephalomyelitis (EAE), an inflammatory demyelinating disease of the CNS, is regarded as an experimental model for multiple sclerosis. The complement has been implicated in the pathogenesis of multiple sclerosis. To clarify the role of C in mouse EAE, we immunized mice deficient in C3 (C3(-/-)) and their wild-type (C3(+/+)) littermates with myelin oligodendrocyte glycoprotein peptide 35-55. C3(-/-) mice were susceptible to EAE as much as the C3(+/+) mice were. No differences were found for the production of IL-2, IL-4, IL-12, TNF-alpha, and IFN-gamma between C3(+/+) and C3(-/-) mice. This finding shows that C3, a key component in C activation, is not essential in myelin oligodendrocyte glycoprotein peptide-induced EAE in mice.
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PMID:Cutting edge: C3, a key component of complement activation, is not required for the development of myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis in mice. 1114 41

TRAIL, the TNF-related apoptosis-inducing ligand, induces apoptosis of tumor cells, but not normal cells; the roles of TRAIL in nontransformed tissues are unknown. Using a soluble TRAIL receptor, we examined the consequences of TRAIL blockade in an animal model of multiple sclerosis. We found that chronic TRAIL blockade in mice exacerbated experimental autoimmune encephalomyelitis induced by myelin oligodendrocyte glycoprotein. The exacerbation was evidenced primarily by increases in disease score and degree of inflammation in the CNS. Interestingly, the degree of apoptosis of inflammatory cells in the CNS was not affected by TRAIL blockade, suggesting that TRAIL may not regulate apoptosis of inflammatory cells in experimental autoimmune encephalomyelitis. By contrast, myelin oligodendrocyte glycoprotein-specific Th1 and Th2 cell responses were significantly enhanced in animals treated with the soluble TRAIL receptor. Based on these observations, we conclude that unlike TNF, which promotes autoimmune inflammation, TRAIL inhibits autoimmune encephalomyelitis and prevents activation of autoreactive T cells.
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PMID:Roles of TNF-related apoptosis-inducing ligand in experimental autoimmune encephalomyelitis. 1114 15

T-cell autoimmunity to myelin basic protein was recently shown to be neuroprotective in injured rat optic nerves. In the present study, using the mouse optic nerve, we examined whether active immunization rather than passive transfer of T-cells can be beneficial in protecting retinal ganglion cells (RGCs) from post-traumatic death. Before severe crush injury of the optic nerve, SJL/J and C3H.SW mice were actively immunized with encephalitogenic or nonencephalitogenic peptides of proteolipid protein (PLP) or myelin oligodendrocyte glycoprotein (MOG), respectively. At different times after the injury, the numbers of surviving RGCs in both strains immunized with the nonencephalitogenic peptides pPLP 190-209 or pMOG 1-22 were significantly higher than in injured controls treated with the non-self-antigen ovalbumin or with a peptide derived from beta-amyloid, a non-myelin-associated protein. Immunization with the encephalitogenic myelin peptide pPLP 139-151 was beneficial only when the disease it induced, experimental autoimmune encephalomyelitis, was mild. The results of this study show that survival of RGCs after axonal injury can be enhanced by vaccination with an appropriate self-antigen. Furthermore, the use of nonencephalitogenic myelin peptides for immunization apparently allows neuroprotection without incurring the risk of an autoimmune disease. Application of these findings might lead to a promising new approach for treating optic neuropathies such as glaucoma.
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PMID:Vaccination for neuroprotection in the mouse optic nerve: implications for optic neuropathies. 1115 Mar 29

One strategy to reestablish self tolerance in autoimmune diseases is based on the use of DNA vaccination to induce ectopic expression of the target autoantigen. We assessed the potential of vaccination with a DNA construct encoding the myelin oligodendrocyte glycoprotein (MOG), an important candidate autoantigen in multiple sclerosis, to induce tolerance and protect against experimental autoimmune encephalomyelitis (EAE). Unexpectedly, mice vaccinated with MOG-DNA developed an exacerbated form of EAE when challenged with either MOG or an unrelated encephalitogen, myelin proteolipid protein. We demonstrate that this is due to the inability of DNA vaccination to tolerize the MOG-specific T cell response and to the concomitant induction of a cytopathic MOG-specific autoantibody response, which is pathogenic, enhancing demyelination, inflammation and disease severity. Our data suggest that tolerogenic strategies for autoimmune diseases based on DNA vaccination should be approached with caution, as the outcome is unpredictable.
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PMID:Myelin oligodendrocyte glycoprotein-DNA vaccination induces antibody-mediated autoaggression in experimental autoimmune encephalomyelitis. 1116 9


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