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)

The signaling events involved in T cell trafficking into the central nervous system (CNS) following viral infection are not fully understood. Intracerebral infection of mice with mouse hepatitis virus (MHV) results in an acute encephalomyelitis followed by an immune-mediated demyelinating disease. Although chemokine signaling is critical in promoting T cell infiltration into the CNS and control of viral replication, additional signaling pathways have not been completely explored. DRAK2, a lymphoid-restricted serine/threonine kinase, prevents spurious T cell activation. Yet Drak2- / - mice are resistant to MOG-induced experimental autoimmune encephalomyelitis (EAE), suggesting that DRAK2 may influence T cell trafficking into the CNS. In order to further characterize the molecular mechanisms governing T cell activation and accumulation within the CNS in response to viral infection, MHV was instilled into the CNS of Drak2- / - mice. Drak2-deficient T cells possessed no obvious defects in trafficking into the CNS following MHV infection. Moreover, Drak2-deficient T cell activation, expansion and cytokine production were unimpaired in response to acute MHV infection. These results demonstrate that DRAK2 signaling is dispensable for T cell recruitment into the CNS following viral infection, suggesting that the resistance of Drak2- / - mice to EAE is not due to overt T cell trafficking defects.
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PMID:Anti-viral effector T cell responses and trafficking are not dependent upon DRAK2 signaling following viral infection of the central nervous system. 1736 98

The COX-2 inhibitors Rofecoxib (Rof) and Lumiracoxib (Lum) were evaluated in experimental autoimmune encephalomyelitis (EAE), the model of multiple sclerosis (MS). Administration of Rof and Lum significantly reduced the incidence and severity of EAE, which was associated with the inhibition of MOG 35-55 lymphocyte recall response, anti-MOG 35-55 T cell responses, and modulation of cytokines production. In vitro Rof and Lum inhibited primary T cells proliferation and modulated cytokine production. These findings highlight the fact that Rof and Lum likely prevents EAE by modulating Th1/Th2 response, and suggest its utility in the treatment of MS and other autoimmune diseases.
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PMID:COX-2 inhibitors ameliorate experimental autoimmune encephalomyelitis through modulating IFN-gamma and IL-10 production by inhibiting T-bet expression. 1744 6

It is widely accepted that chronic disabilities in multiple sclerosis (MS) patients are due in part to neuronal damage. The central aim of this study was to characterize axonal disruption in the spinal cord of mice with myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis (MOG-EAE), a model of progressive MS. To accomplish this goal, we induced MOG-EAE in thy1-yellow fluorescent (thy-YFP)-transgenic mice in which all spinal motorneurons express the YFP reporter protein. We demonstrate that a build-up of YFP fluorescence occurs in profiles reminiscent of tortuous fragmented axons and axonal spheroids/globules as seen in various neurodegenerative/neuroinflammatory diseases. Approximately two-thirds of these damaged axons were decorated by the monoclonal antibody SMI 32, which recognizes hypophosphorylated neurofilament-H (hypoP-NF-H), an established marker of CNS axonal pathology. Unexpectedly, one third of damaged axons were hypoP-NF-H negative but could be visualized by their expression of the YFP transgene, whilst the remaining profiles were hypoP-NF-H positive but did not exhibit YFP fluorescence. Thus, using YFP transgenic mice in conjunction with hypoP-NF-H immunoreactivity provides a more comprehensive depiction of axonopathy in the ventral-lateral aspect of lumbosacral spinal cord in MOG-EAE. When YFP fluorescence was used in conjunction with a monoclonal antibody that recognizes CD11b; a marker of subsets of inflammatory cells, we were able to discern evidence of an early inflammatory attack on white matter axons. Finally, we show the accumulation of hyperphosphorylated neurofilament-H (hyperP-NF-H) expression in YFP+, lesioned WM areas and in a subpopulation of neuronal perikarya in the lumbar spinal cords of EAE mice.
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PMID:Enhanced visualization of axonopathy in EAE using thy1-YFP transgenic mice. 1749 38

Complement receptor 2 (CR2) and its physiological ligand, C3d, known for its molecular adjuvant property on the immune response, exhibit opposite effects with regard to autoimmunity. Although CR2 has been implicated in maintaining self-tolerance, recent studies reported a role for C3d signaling to CR2 in tolerance breakdown to self-antigens and the initiation of inflammatory autoimmune pathologies. In the present study, we have investigated the effect of C3d in a model of tolerogenic DNA vaccination encoding the myelin oligodendrocyte glycoprotein (MOG-DNA) which protected mice from the induction of an experimental autoimmune encephalomyelitis (EAE). We show that fusing two or three copies of C3d to MOG overcomes the protective effect of DNA vaccination. Multimeric C3d was able to revert the unresponsiveness state of specific T cells induced by MOG-DNA, independently of a modification in the Th1/Th2 cytokine pattern. Interestingly, the adjuvant effect of C3d was not sufficient to boost the anti-MOG antibody response after DNA vaccination. These findings suggest that C3d might be involved in self-tolerance breakdown and could contribute to the pathogenesis of central nervous system autoimmune disorders.
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PMID:Protective DNA vaccination against myelin oligodendrocyte glycoprotein is overcome by C3d in experimental autoimmune encephalomyelitis. 1752 29

p150/95 (CD11c/CD18, CR4) is a member of the beta(2)-integrin family of adhesion molecules and is considered an important phagocytic receptor. The role of p150/95 in the development of central nervous system demyelinating diseases, including multiple sclerosis, remains unexplored. To determine p150/95-mediated mechanisms in experimental autoimmune encephalomyelitis (EAE), we performed EAE using CD11c-deficient (CD11c(-/-)) mice. EAE in CD11c(-/-) mice was significantly attenuated and characterized by markedly reduced spinal cord T-cell infiltration and interferon-gamma production by these cells. Adoptive transfer of antigen-restimulated T cells from wild-type to CD11c(-/-) mice produced significantly attenuated EAE, whereas transfer of CD11c(-/-) antigen-restimulated T cells to control mice induced a very mild, monophasic EAE. T cells from MOG(35-55) peptide-primed CD11c(-/-) mice displayed an unusual cytokine phenotype with elevated levels of interleukin (IL)-2, IL-4, and IL-12 but reduced levels of interferon-gamma, tumor necrosis factor-alpha, IL-10, IL-17, and transforming growth factor-beta compared with control mice. Overall, CD11c(-/-) T cells from primed mice proliferated comparably to that of control T cells on MOG(35-55) restimulation. Our results indicate that expression of p150/95 is critical on both T cells as well as other leukocytes for the development of demyelinating disease and may represent a novel therapeutic target for multiple sclerosis.
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PMID:p150/95 (CD11c/CD18) expression is required for the development of experimental autoimmune encephalomyelitis. 1752 67

Inflammatory cytokines are implemented in the pathogenesis of experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. We previously demonstrated that glia maturation factor (GMF), a brain protein, isolated, sequenced and cloned in our laboratory, induce expression of proinflammatory cytokine/chemokine in the central nervous system (CNS). We found GMF-deficient (knockout) mice relatively resistant to EAE development after immunization with encephalitogenic MOG peptide 35-55. Consistent with these findings, the expression of proinflammatory cytokines in CNS of mice with EAE differed profoundly between wild type and GMF-knockout mice. In the present study we examined the expressions of six murine signal transducers and activators of transcription (STATs) genes, which are known to regulate the cytokine-dependent signal transduction pathways in autoimmune inflammation. The expressions of STATs genes were evaluated in the brains and spinal cords of wild type and GMF-knockout mice at the peak of EAE by quantitative real-time RT-PCR. Compared to GMF-knockout mice, the expressions of STAT1, STAT2, STAT3, STAT4, STAT5, and STAT6 genes were significantly (P < 0.001) upregulated in the wild type mice exhibiting EAE symptoms. The results are consistent with the diminished development of EAE in the GMF-knockout mice. A significant suppression of STATs expression in GMF-knockout mice suggests GMF as an upstream effector of JAK/STAT signaling.
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PMID:Glia maturation factor regulation of STAT expression: a novel mechanism in experimental autoimmune encephalomyelitis. 1755 29

Microglial activation is emerging as an important etiologic factor and therapeutic target in neurodegenerative and neuroinflammatory diseases. Techniques have been lacking, however, for measuring the different components of microglial activation independently in vivo. We describe a method for measuring microglial proliferation rates in vivo using heavy water (2H2O) labeling, and its application in screening for drugs that suppress neuro-inflammation. Brain microglia were isolated by flow cytometry as F4/80+, CD11b+, CD45(low) cells, and 2H enrichment in DNA was analyzed by gas chromatography/mass spectrometry. Basal proliferation rate was approximately 1%/week and systemic administration of bacterial lipopolysaccharide (LPS) markedly increased this rate in a dose-dependent manner. Induction of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 mice by MOG(35-55) peptide stimulated proliferation of CD45(low) microglia, which could be distinguished from the proliferation of CD45(high) infiltrating monocytes. Minocycline (45 mg/kg/day, i.p.) inhibited resident microglial proliferation in both the LPS and EAE models. Thirteen drugs were then screened for their ability to inhibit LPS-stimulated microglia proliferation. Female C57BL/6 mice were given LPS (1 mg/kg), and concomitant drug treatment while receiving 2H2O label for 7 days. Among the drugs screened, treatment with isotretinoin dose-dependently reduced LPS-induced microglial proliferation, representing an action of retinoids unknown previously. Follow-up studies in the EAE model confirmed that isotretinoin not only inhibited proliferation of microglia but also delayed the onset of clinical symptoms. In conclusion, 2H2O labeling represents a relatively high-throughput, quantitative, and highly reproducible technique for measuring microglial proliferation, and is useful for screening and discovering novel anti-neuroinflammatory drugs.
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PMID:Measurement of brain microglial proliferation rates in vivo in response to neuroinflammatory stimuli: application to drug discovery. 1755 81

Src homology 2 domain-containing protein tyrosine phosphatase (SHP) substrate-1 (SHPS-1) is a transmembrane protein that binds the protein tyrosine phosphatases SHP-1 and SHP-2 through its cytoplasmic region and is expressed on the surface of CD11c(+) dendritic cells (DCs) and macrophages. In this study, we show that mice that express a mutant form of SHPS-1 lacking most of the cytoplasmic region are resistant to experimental autoimmune encephalomyelitis (EAE) in response to immunization with a peptide derived from myelin oligodendrocyte glycoprotein (MOG (35-55)). The MOG (35-55)-induced proliferation of, and production of IFN-gamma, IL-2, and IL-17, by T cells from immunized SHPS-1 mutant mice were reduced compared with those apparent for wild-type cells. The abilities of splenic DCs from mutant mice to stimulate an allogenic MLR and to prime Ag-specific T cells were reduced. Both IL-12-stimulated and TLR-dependent cytokine production by DCs of mutant mice were also impaired. Finally, SHPS-1 mutant mice were resistant to induction of EAE by adoptive transfer of MOG (35-55)-specific T cells. These results show that SHPS-1 on DCs is essential for priming of naive T cells and the development of EAE. SHPS-1 is thus a potential therapeutic target in inflammatory disorders of the CNS and other autoimmune diseases.
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PMID:Resistance to experimental autoimmune encephalomyelitis and impaired T cell priming by dendritic cells in Src homology 2 domain-containing protein tyrosine phosphatase substrate-1 mutant mice. 1761 77

In this study, axial (lambda(parallel)) and radial (lambda(perpendicular)) diffusivities derived from diffusion tensor imaging (DTI) were used to evaluate white matter injury in brains of mice affected by experimental autoimmune encephalomyelitis (EAE). Sixteen female C57BL/6 mice were immunized with amino acids 35-55 of myelin oligodendrocyte glycoprotein (MOG(35-55)). Three months after immunization, optic nerve and tract were severely affected with 19% and 18% decrease in lambda(parallel) respectively, suggesting the presence of axonal injury. In addition, a 156% and 86% increase in lambda( perpendicular) was observed in optic nerve and tract respectively, suggestive of myelin injury. After in vivo DTI, mice were perfusion fixed and immunohistochemistry for the identification of myelin basic protein (MBP) and phosphorylated neurofilament (pNF) was performed to verify the presence of axonal and myelin injury. The present study demonstrated that the visual pathway is selectively affected in MOG(35-55) induced murine EAE and these injuries are non-invasively detectable using lambda(parallel) and lambda( perpendicular).
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PMID:Selective vulnerability of cerebral white matter in a murine model of multiple sclerosis detected using diffusion tensor imaging. 1768 44

It is obvious that the central nervous system plays a role in the regulation of an immune response. However, the mechanisms of this regulation are poorly understood. The goal of the present study was to examine the role of one of the neurotransmitters - dopamine, in this process. We used experimental autoimmune encephalomyelitis (EAE), an autoimmune disease with its effector phase in the CNS, as a model to study the effect of central dopamine depletion on the development of an immune response. Dopamine depletion was achieved by treatment with 1-methyl-4-phenyl-1, 2, 3, 6-tetrahydropiridine (MPTP; 40 mg/kg), whereas EAE was elicited by immunization with MOG 35-55 (150 microg) in complete Freund's adjuvant (CFA), supplemented with Mycobacterium tuberculosis. As determined by HPLC, striatal dopamine contents in mice treated with MPTP were significantly lower compared to vehicle-treated controls. Remarkably, striatal depletion of dopamine prior to EAE induction resulted in an earlier onset of the disease and an augmentation of its clinical signs. Moreover, the striatal dopamine-depleted mice demonstrated an increased concentration of IL-1beta and decreased concentration of TGFbeta in the spinal cord, compared to EAE mice. Since MPTP itself does not have any direct effect on immune cells, it strongly suggests that the observed changes in EAE induction and progression after MPTP administration depended on lower dopamine level. Further studies are required to find out the cellular mechanism of the dopamine action.
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PMID:MPTP-induced central dopamine depletion exacerbates experimental autoimmune encephalomyelitis (EAE) in C57BL mice. 1768 15


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