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)

[Arg(91), Ala(96)] MBP(87-99) is an altered peptide ligand (APL) of myelin basic protein (MBP), shown to actively inhibit experimental autoimmune encephalomyelitis (EAE), which is studied as a model of multiple sclerosis (MS). The APL has been rationally designed by substituting two of the critical residues for recognition by the T-cell receptor. A conformational analysis of the APL has been sought using a combination of 2D NOESY nuclear magnetic resonance (NMR) experiments and detailed molecular dynamics (MD) calculations, in order to comprehend the stereoelectronic requirements for antagonistic activity, and to propose a putative bioactive conformation based on spatial proximities of the native peptide in the crystal structure. The proposed structure presents backbone similarity with the native peptide especially at the N-terminus, which is important for major histocompatibility complex (MHC) binding. Primary (Val(87), Phe(90)) and secondary (Asn(92), Ile(93), Thr(95)) MHC anchors occupy the same region in space, whereas T-cell receptor (TCR) contacts (His(88), Phe(89)) have different orientation between the two structures. A possible explanation, thus, of the antagonistic activity of the APL is that it binds to MHC, preventing the binding of myelin epitopes, but it fails to activate the TCR and hence to trigger the immunologic response. NMR experiments coupled with theoretical calculations are found to be in agreement with X-ray crystallography data and open an avenue for the design and synthesis of novel peptide restricted analogues as well as peptide mimetics that rises as an ultimate goal.
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PMID:A putative bioactive conformation for the altered peptide ligand of myelin basic protein and inhibitor of experimental autoimmune encephalomyelitis [Arg91, Ala96] MBP87-99. 1631 Mar 86

CD24 is expressed on a broad range of cells in the immune and central nervous systems and appears to be required for development of experimental autoimmune encephalomyelitis in mice. Association of a CD24 Ala/Val coding polymorphism with susceptibility to and progression of multiple sclerosis was recently reported. We typed this coding polymorphism in a combined cohort of 1,180 cases and 1,168 unrelated and family-based controls from Belgium and the UK, but were unable to confirm either association. Since the CD24 gene is part of a segmental duplication, special care is required for the identification and genotyping of single nucleotide polymorphisms.
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PMID:CD24 Ala/Val polymorphism and multiple sclerosis. 1663 Dec 59

Recent studies claim a central role for Toll-like receptor (TLR) ligands in stimulating autoimmune disease by activation of antigen-presenting cells in the target organ, but it is unclear if and how TLR ligands reach target organs. Most evidence comes from rodent models, and it is uncertain whether this principle holds in primates. Here we identify which cells contain peptidoglycan (PGN) in multiple sclerosis brain and in two nonhuman primate experimental autoimmune encephalomyelitis (EAE) models with different disease courses: acute (rhesus monkey) versus chronic disease (marmoset). Because persistence of TLR ligands in the central nervous system might be consequential for disease progression, we also determined the expression of two major PGN-degrading enzymes, ie, lysozyme and N-acetylmuramyl-l-alanine amidase. Distinct phagocyte subsets, including granulocytes, macrophages, and dendritic cells, contained PGN in the brain and coexpressed the inflammatory cytokine interleukin-12. The number of phagocytes carrying PGN increased in acute and chronic EAE compared with control animals, with the highest number of PGN-containing cells in acute EAE brain. Lytic enzymes were scarcely expressed in monkey and multiple sclerosis brain, favoring PGN persistence. PGN stimulated interleukin-12p70 release by leukocytes from all three primate species. The presence of PGN in the inflamed brain may have major implications because TLR2/Nod ligation potentially promotes inflammation and disease progression.
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PMID:Phagocytes containing a disease-promoting Toll-like receptor/Nod ligand are present in the brain during demyelinating disease in primates. 1707 91

Multiple sclerosis (MS) is considered to be primarily an inflammatory autoimmune disease. Over the last 5 years, our view of the pathogenesis of MS has evolved considerably. The axonal damage was recognized as an early event in the disease process and as an important determinant of long-term disability. Therefore, the antiinflammatory and neuroprotective strategies are thought to represent promising approach to the therapy of MS. The therapeutic potential of glatiramer acetate (GA), a synthetic amino acid polymer composed of a mixture of L-glutamic acid, L-lysine, L-alanine, and L-tyrosine in defined proportions, in MS has been apparent for many years. GA has been shown to be effective in preventing and suppressing experimental allergic encephalomyelitis (EAE), the animal model of MS. GA has been, therefore, evaluated in several clinical studies and found to alter the natural history of relapsing-remitting (RR)MS by reducing the relapse rate and affecting disability. These findings were confirmed in open-label follow-up trials covering more than 10 years of treatment. The trials demonstrated sustained efficacy for GA in slowing the progression of disability. The clinical therapeutic effect of GA is consistent with the results of magnetic resonance imaging (MRI) findings from various clinical centers. At a daily standard dose of 20 mg, s.c., GA was generally well tolerated. The induction of GA-reactive T-helper 2-like regulatory suppressor cells is thought to be the main mechanism of the therapeutic action of this drug. In addition, it was recently shown that GA-reactive T cells produce neurotrophic factors (e.g., brain-derived neurotrophic factor [BDNF]) that protect neurons and axons in the area of injury.
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PMID:Glatiramer acetate in multiple sclerosis: a review. 1762 71

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

PPARs belong to a receptor family of ligand-activated transcription factors involved in the regulation of inflammation. A crucial role both for PPARgamma and for PPARalpha for the regulation of autoimmunity has been clearly demonstrated, as receptor agonists had beneficial effects on several CD4(+) T cell mediated autoimmune diseases including experimental autoimmune encephalomyelitis (EAE), the animal model of multiple sclerosis. We investigated the association of two common single nucleotide polymorphisms in the PPARA (Leu162Val) and the PPARG (Pro12Ala) genes in 116 patients with clinically definite multiple sclerosis (MS) and 211 age-matched healthy controls. The Ala allele of the PPARG Pro12Ala polymorphism was strongly associated with delayed disease onset (44.1+/-5.3 years vs 34.5+/-4.2 years; p=0.006). No significant differences were found in genotype distributions and allele frequencies of the PPARA Leu162Val and the PPARG Pro12Ala polymorphisms between MS patients and healthy controls, respectively. Our population-based study demonstrates that the Pro12Ala polymorphism resulting in an amino acid exchange in the N-terminal sequence of PPARgamma may influence the onset of MS.
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PMID:Association of the PPARgamma gene polymorphism Pro12Ala with delayed onset of multiple sclerosis. 1897 77

Sindbis virus (SINV), the prototype alphavirus, contains a macro domain in the highly conserved N-terminal region of nonstructural protein 3 (nsP3). However, the biological role of the macro domain is unclear. Mutations of amino acids 10 and 24 from asparagine to alanine in the ADP-ribose binding region of the macro domain impaired SINV replication and viral RNA synthesis particularly in neurons, but did not alter binding of poly(ADP-ribose). Mutation at position 10 had the greatest effect and caused nsP3 instability in neurons, decreased SINV-induced death of mature, but not immature neurons, and attenuated virulence in 2 week-old, but not 5 day-old mice. A compensatory mutation at amino acid 31 in the macro domain of nsP3, as well as reversion of mutated amino acid 10, occurred during replication of double mutant SINV in vitro and in vivo. The nsP3 macro domain is important for SINV replication and age-dependent susceptibility to encephalomyelitis.
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PMID:The nsP3 macro domain is important for Sindbis virus replication in neurons and neurovirulence in mice. 1939 54

Theiler's murine encephalomyelitis virus (TMEV) was used to investigate the distribution of P2 proteins in host cells and examine the effect of amino acid substitutions in conserved residues of the 2C protein on virus growth. The distribution of viral proteins 2B, 2C and 2BC with marker proteins of the endoplasmic reticulum (ER) and/or Golgi suggest an association with membranes of the secretory pathway. Similar results were obtained for truncated 2C and 2BC proteins with C-terminal deletions suggesting that the N-terminal region of the 2C protein is important in dictating distribution patterns. The significance of the high degree of conservation of this 2C region throughout the Picornaviridae was investigated by substituting conserved amino acid residues for alanine to create six mutant strains. Substitution mutations E(8)A, W(18)A and W(29)A abolished the ability of the virus to induce cytopathic effect (CPE) in BHK-21 cells. K(14)A, R(4)A and I(23)A delayed the onset and progression of CPE compared to the wild-type (WT) virus, and decreased virus yield. Immunofluorescence analysis of cells transiently expressing mutant 2C proteins revealed that the distribution of 2C was affected by substituting K(14), W(18) and I(23) for alanine indicating that specific conserved residues in 2C dictate protein distribution and virus growth.
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PMID:Amino acid substitutions within the 2C coding sequence of Theiler's Murine Encephalomyelitis virus alter virus growth and affect protein distribution. 1972 3

Neuromyelitis optica (NMO) is characterized by concurrence of optic neuritis and transverse myelitis, which is typically associated with a spinal cord lesion extending three or more vertebral segments. NMO is an inflammatory, demyelinating central nervous system disorder, and although it has a relapsing course in more than 90% of patients, it differs from multiple sclerosis in that it is more severe, usually spares the brain, and is associated with a longitudinally extensive lesion on spinal cord magnetic resonance imaging (MRI). Furthermore, NMO is associated with a highly specific serum marker called anti-aquaporin-4 antibody, which is believed to have a central pathogenetic role in NMO. Treatment with B-cell specific monoclonal antibody (rituximab) and plasma exchanges appears to reduce the severity and frequency of attacks in NMO, and therefore, B-cell autoimmunity as well as a humoral mechanism may be involved in the pathogenesis of NMO. Glatiramer acetate (GA; also known as Copaxone, COP-1) is a synthetic copolymer of a pool of peptides composed of random sequences of four amino acids: glutamine, lysine, alanine, and tyrosine. GA-specific T-helper 1- (Th1) and 2-type (Th2) cells produce brain-derived neurotrophic factor (BDNF), which may affect neuronal survival and myelin repair. GA treatment also leads to sustained augmentation of BDNF, neurotrophin (NT)-3, and NT-4 expression in various brain regions as demonstrated by histological analysis of immunostained brain sections and BDNF elevation after GA treatment on both protein and mRNA levels. GA-Th2 activation may also have a neuroprotective role in the course of NMO. Furthermore, B cells from GA-treated mice suppress experimental autoimmune encephalomyelitis. The pathogenesis of NMO is largely unknown. However, there is some evidence that B-cell autoimmunity, activation of eosinophils, and B-cell activating factor play important roles, based on neurotrophic factors, neuroprotection, anti-inflammation, and B-cell modulation, GA is thus a hypothetic potential treatment agent for NMO.
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PMID:Glatiramer acetate could be a hypothetical therapeutic agent for neuromyelitis optica. 2139 45

We have previously shown that P2X7 receptor blockade prevents ATP excitotoxicity in oligodendrocytes and ameliorates chronic experimental autoimmune encephalomyelitis. Here, we have explored the putative association of functionally relevant single nucleotide polymorphisms of the P2X7 receptor gene with multiple sclerosis. We found that T allele of rs17525809 polymorphism, which yields an Ala-76 to Val change in the extracellular domain, is more frequent in multiple sclerosis patients than in controls. Importantly, P2X7 variants with Val show a gain-of-function consisting in higher calcium permeability, larger electrophysiological responses and higher ethidium uptake, and enhance the effect of the also gain-of-function His-155 to Tyr substitution (rs208294) in the haplotype formed by these two variants. These findings may contribute to define the genetic background predisposing for multiple sclerosis and its pathophysiology.
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PMID:Gain-of-function of P2X7 receptor gene variants in multiple sclerosis. 2190 9


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