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

We have induced a polyclonal IgG that degrades the HIV-1 surface antigen, glycoprotein gp120, by taking advantage of the susceptibility of SJL mice to a peptide-induced autoimmune disorder, experimental autoimmune encephalomyelitis (EAE). Specific pathogen-free SJL mice were immunized with structural fragments of gp120, fused in-frame with encephalitogenic peptide MBP(85-101). It has resulted in a pronounced disease-associated immune response against antigens. A dramatic increase of gp120 degradation level by purified polyclonal IgG from immunized versus nonimmunized mice has been demonstrated by a newly developed fluorescence-based assay. This activity was inhibited by anti-mouse immunoglobulin antibodies as well as by Ser- and His-reactive covalent inhibitors. A dominant proteolysis site in recombinant gp120 incubated with purified polyclonal IgG from immunized mice was shown by SDS-PAGE. The SELDI-based mass spectrometry revealed that these antibodies exhibited significant specificity toward the Pro484-Leu485 peptide bond. The sequence surrounding this site is present in nearly half of the HIV-I variants. This novel strategy can be generalized for creating a catalytic vaccine against viral pathogens.
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PMID:Induction of a protein-targeted catalytic response in autoimmune prone mice: antibody-mediated cleavage of HIV-1 glycoprotein GP120. 1638 9

Chondroitin sulfate proteoglycan (CSPG), a matrix protein that occurs naturally in the central nervous system (CNS), is considered to be a major inhibitor of axonal regeneration and is known to participate in activation of the inflammatory response. The degradation of CSPG by a specific enzyme, chondroitinase ABC, promotes repair. We postulated that a disaccharidic degradation product of this glycoprotein (CSPG-DS), generated following such degradation, participates in the modulation of the inflammatory responses and can, therefore, promote recovery in immune-induced neuropathologies of the CNS, such as experimental autoimmune encephalomyelitis (EAE) and experimental autoimmune uveitis (EAU). In these pathologies, the dramatic increase in T cells infiltrating the CNS is far in excess of the numbers needed for regular maintenance. Here, we show that CSPG-DS markedly alleviated the clinical symptoms of EAE and protected against the neuronal loss in EAU. The last effect was associated with a reduction in the numbers of infiltrating T cells and marked microglia activation. This is further supported by our in vitro results indicating that CSPG-DS attenuated T cell motility and decreased secretion of the cytokines interferon-gamma and tumor necrosis factor-alpha. Mechanistically, these effects are associated with an increase in SOCS-3 levels and a decrease in NF-kappaB. Our results point to a potential therapeutic modality, in which a compound derived from an endogenous CNS-resident molecule, known for its destructive role in CNS recovery, might be helpful in overcoming inflammation-induced neurodegenerative conditions.
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PMID:A sulfated disaccharide derived from chondroitin sulfate proteoglycan protects against inflammation-associated neurodegeneration. 1639 93

Experimental autoimmune encephalomyelitis (EAE) induced by myelin-oligodendrocyte glycoprotein (MOG) in common marmosets (Callithrix jacchus) is a model for multiple sclerosis. Here, EAE was induced in four common marmosets by 250-300 microg recombinant rat MOG. In addition to a detailed disability scoring, T2- and T1-weighted high-resolution 3D MRI was performed to assess the onset and development of cerebral lesions. The findings were confirmed by histopathology in all animals. Although the animals exhibited a large heterogeneity with regard to onset and localization of lesions and also to disease duration and severity of disability signs, none of the animals revealed any evidence of recovery. A specification of the disability scoring system to account for different aspects of the disease led to a good concurrence of the first MRI-detectable lesion and the onset of central nervous system (CNS) symptoms. The results suggest that MRI monitoring of white matter lesions in conjunction with disability scores that focus on CNS symptoms may be a suitable method to evaluate novel therapeutic interventions even in the presence of pronounced interindividual heterogeneity.
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PMID:Monitoring of EAE onset and progression in the common marmoset monkey by sequential high-resolution 3D MRI. 1640 25

Alpha-fetoprotein (AFP) is a 65-kDa oncofetal glycoprotein found in fetal and maternal fluids during pregnancy. Clinical remissions during pregnancy have been observed in several autoimmune diseases, such as multiple sclerosis (MS), and have been attributed to the presence of pregnancy-associated natural immune-reactive substances, including AFP which can exert immunomodulatory effects on immune cells. In this study, we tested the effect of recombinant human AFP (rhAFP) isolated from transgenic goats, which contain the genomic DNA for hAFP, on experimental autoimmune encephalomyelitis (EAE), the animal model used for the study of MS. RhAFP treatment markedly improved the clinical manifestations of EAE, preventing central nervous system (CNS) inflammation and axonal degeneration. RhAFP exerted a broad immunomodulating activity, influencing the various populations of immune cells. T cells from treated mice had significantly reduced activity towards the encephalitogenic peptide of myelin oligodendrocyte glycoprotein (MOG), exhibiting less proliferation and reduced Th1 cytokine secretion. Moreover, AFP affected the humoral response, causing an inhibition in MOG-specific antibody production. The expression of CD11b, MHC class II and the chemokine receptor CCR5 was also down-regulated. This is the first study demonstrating reduced inflammation and axonal damage exerted by recombinant AFP. In light of our findings, rhAFP may serve as a potential candidate for treatment of MS and other autoimmune diseases.
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PMID:Amelioration of autoimmune neuroinflammation by recombinant human alpha-fetoprotein. 1642 48

Autoantibody responses against conformational epitopes of myelin/oligodendrocyte glycoprotein (MOG) possess myelin destructive potential, as demonstrated in the marmoset model of human multiple sclerosis (MS) and in some rodent models of experimental allergic encephalomyelitis. We have previously characterized monoclonal Fab fragments specific for conformational epitopes of MOG that were derived from a combinatorial antibody library generated from a MOG-immune marmoset. In this paper, we address the molecular heterogeneity of humoral responses against MOG in this outbred model of MS by studying additional antibody clones derived from a genetically unrelated animal. We find that all MOG-specific IgGkappa Fab fragments, unrelated to genetic make-up, utilize a restricted set of variable region genes, IGHV1 and IGHV3 for the H chain and IGKV1, IGKV3, and IGKV5 for the L chain. Despite these restricting factors, diversity within these antibody repertoires can be observed, predominantly within the H-chain CDR3 regions. Our findings suggest that only a limited set of Ig genes is necessary to launch a diverse, destructive humoral immune response against a single CNS antigen in primates. These results are the first to contribute to a better understanding of how myelin-directed and potentially destructive autoantibody responses may develop in human MS.
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PMID:Restrictive and diversifying elements of the anti-myelin/oligodendrocyte glycoprotein antibody response in primate experimental allergic encephalomyelitis. 1652 99

Theiler's murine encephalomyelitis viruses (TMEV) are ubiquitous pathogens of mice, producing either rapidly fatal encephalitis (high-neurovirulence strains) or persistent central nervous system infection and inflammatory demyelination (low-neurovirulence strains). Although a protein entry receptor has not yet been identified, carbohydrate co-receptors that effect docking and concentration of the virus on the cell surface are known for both TMEV neurovirulence groups. Low-neurovirulence TMEV use alpha2,3-linked N-acetylneuramic acid (sialic acid) on an N-linked glycoprotein, whereas high-neurovirulence TMEV use the proteoglycan heparan sulfate (HS) as a co-receptor. While the binding of low-neurovirulence TMEV to sialic acid can be inhibited completely, only a third of the binding of high-neurovirulence TMEV to HS is inhibitable, suggesting that high-neurovirulence strains use another co-receptor or bind directly to the putative protein entry receptor. Four amino acids on the surface (VP2 puff B) of low-neurovirulence strains make contact with sialic acid through non-covalent hydrogen bonds. Since these virus residues are conserved in all TMEV strains, the capsid conformation of this region is probably responsible for sialic acid binding. A persistence determinant that maps within the virus coat using recombinant TMEV is also conformational in nature. Low-neurovirulence virus variants that do not bind to sialic acid fail to persist in the central nervous system of mice, indicating a role for sialic acid binding in TMEV persistence. Analysis of high-neurovirulence variants that do not bind HS demonstrates that HS co-receptor usage influences neuronal tropism in brain, whereas, the HS co-receptor use is not required for the infection of spinal cord anterior horn cells associated with poliomyelitis.
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PMID:Differential usage of carbohydrate co-receptors influences cellular tropism of Theiler's murine encephalomyelitis virus infection of the central nervous system. 1657 21

D6, a promiscuous nonsignaling chemokine binding molecule expressed on the lymphatic endothelium, internalizes and degrades CC chemokines, and D6(-/-) mice demonstrated increased cutaneous inflammation following topical phorbol ester or CFA injection. We report that D6(-/-) mice were unexpectedly resistant to the induction of experimental autoimmune encephalomyelitis due to impaired encephalitogenic responses. Following induction with myelin oligodendroglial glycoprotein (MOG) peptide 35-55 in CFA, D6(-/-) mice showed reduced spinal cord inflammation and demyelination with lower incidence and severity of experimental autoimmune encephalomyelitis attacks as compared with D6(+/+) littermates. In adoptive transfer studies, MOG-primed D6(+/-) T cells equally mediated disease in D6(+/+) or D6(-/-) mice, whereas cells from D6(-/-) mice transferred disease poorly to D6(+/-) recipients. Lymph node cells from MOG-primed D6(-/-) mice showed weak proliferative responses and made reduced IFN-gamma but normal IL-5. CD11c(+) dendritic cells accumulated abnormally in cutaneous immunization sites of D6(-/-) mice. Surprisingly, D6, a "silent" chemokine receptor, supports immune response generation.
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PMID:Cutting edge: the silent chemokine receptor D6 is required for generating T cell responses that mediate experimental autoimmune encephalomyelitis. 1678 91

Axonal degeneration is a major contributor to non-remitting deficits in multiple sclerosis, and there is thus considerable current interest in the development of strategies that might prevent axonal loss in neuroinflammatory disease. Dysregulation of sodium ion homeostasis has been implicated in mechanisms leading to axonal degeneration, and several studies have shown that blockade of sodium channels can ameliorate axon damage following anoxic, traumatic and nitric oxide-induced CNS injury. Two sodium channel blockers, phenytoin and flecainide, have been reported to protect axons in experimental autoimmune encephalomyelitis (EAE) for 30 days, but long-term protective effects have not been studied. We demonstrate here that oral administration of phenytoin provides long-term (up to 180 days) protection for spinal cord corticospinal tract (CST) and dorsal column (DC) axons in both monophasic (C57/BL6 mice) and chronic-relapsing (Biozzi mice) murine EAE. Untreated C57/BL6 mice exhibit a 40-50% loss of CST and DF axons at 90 and 180 days post-EAE induction via myelin-oligodendrocyte glycoprotein (MOG) injection. In contrast, only 4% of DF axons are lost at 90 days, and only 8% are lost at 180 days in phenytoin-treated C57/BL6 mice with EAE; only 21-29% of CST axons are lost at 90 and 180 days in phenytoin-treated C57/BL6 mice with EAE. Attenuation of dorsal column compound action potentials was ameliorated and clinical status was also significantly enhanced with phenytoin treatment at 90 and 180 days in this model. In addition, inflammatory cell infiltration into the dorsal columns was reduced in phenytoin-treated mice with EAE compared with untreated mice with EAE. Similar results were obtained in Biozzi mice with chronic-relapsing EAE followed for 120 days post-injection. These observations demonstrate that phenytoin provides long-term protection of CNS axons and improves clinical status in both monophasic and chronic-relapsing models of neuroinflammation.
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PMID:Long-term protection of central axons with phenytoin in monophasic and chronic-relapsing EAE. 1713 43

Experimental autoimmune encephalomyelitis (EAE) induced with recombinant human myelin/oligodendrocyte glycoprotein in the common marmoset is a useful preclinical model of multiple sclerosis in which white matter lesions can be well visualized with MRI. In this study we characterized lesion progression with quantitative in vivo MRI (4.7 T; T(1) relaxation time +/- Gd-DTPA; T(2) relaxation time; magnetization transfer ratio, MTR, imaging) and correlated end stage MRI presentation with quantitative ex vivo MRI (formaldehyde fixed brains; T(1) and T(2) relaxation times; MTR) and histology. The histopathological characterization included axonal density measurements and the numeric quantification of infiltrated macrophages expressing markers for early active [luxol fast blue (LFB) or migration inhibition factor-related protein-14 positive] or late active/inactive [periodic acid Schiff (PAS) positive] demyelinating lesion. MRI experiments were done every two weeks until the monkeys were sacrificed with severe EAE-related motor deficits. Compared with the normal appearing white matter, lesions showed an initial increase in T(1) relaxation times, leakage of Gd-DTPA and decrease in MTR values. The progressive enlargement of lesions was associated with stabilized T(1) values, while T(2) initially increased and stabilized thereafter and MTR remained decreased. Gd-DTPA leakage was highly variable throughout the experiment. MRI characteristics of the cortex and (normal appearing) white matter did not change during the experiment. We observed that in vivo MTR values correlated positively with the number of early active (LFB+) and negatively with late active (PAS+) macrophages. Ex vivo MTR and relaxation times correlated positively with the number of PAS-positive macrophages. None of the investigated MRI parameters correlated with axonal density.
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PMID:Quantitative MRI-pathology correlations of brain white matter lesions developing in a non-human primate model of multiple sclerosis. 1694 76

The precise mechanisms leading to CNS inflammation and myelin destruction in both multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE) remain the subject of intense debate. In both MS and EAE, autoantibodies (autoAbs) are thought to be involved in tissue destruction through recruiting Fc receptor (FcR)-bearing cells or direct cytotoxic effects through the activation of the complement pathway. Whereas intrathecal immunoglobulin (Ig) production and Ig deposition in inflammatory lesions is a hallmark of MS, mice deficient in B cells and Igs develop severe EAE. Paradoxically, mice of the same genetic background but deficient in FcRgamma are EAE-resistant. We found that the functional expression of FcRgamma on systemic accessory cells, but not CNS-resident cells, appears to be vital for the development of CNS inflammation, independent of antigen-presenting cell function or Ab involvement. On the other hand, we found that the injection of antimyelin oligodendrocyte glycoprotein-Abs drastically worsens disease severity, inflammation, and demyelination. Using FcRgamma(-/-) and C1q(-/-) mice, we could definitively establish that the demyelinating capacity of such autoAb in vivo relies entirely on complement activation and is FcR-independent.
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PMID:Autoantibody-mediated demyelination depends on complement activation but not activatory Fc-receptors. 1712 89


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