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)

Two peptic fragments (residues 37-88 and 43-88) of guinea pig myelin basic protein which are capable of inducing experimental allergic encephalomyelitis in Lewis rats were cleaved to shorter fragments with alpha-protease (Crotalus atrox proteinase, EC 3.4.24.1) and thermolysin (EC 3.4.24.4). The fragments were isolated, purified, and identified by amino acid composition and NH2- and COOH-terminal residues. The time courses of the reactions, monitored by thin layer electrophoresis of the digests, showed that alpha-protease cleaves peptide (43-88) initially at the Pro(71)-Gln(72) bond, and that the product peptides are subsequently attacked at the Arg(63) -Thr(64), Ser(74)-Gln(75), Arg(78)-Ser(79), and Ser(76)-Gln(80) bonds. No significant cleavages occurred at the -Leu, -Val, and -Ala bonds. These results are in striking contrast to those obtained previously by others workers with other peptide substrates, where selective cleavage at hydrophobic residues occurred. Thermolysin was found to attack peptide (37-88) at the Phe(42)-Phe(43) bond very rapidly; the product peptides were subsequently attacked at the His(60)-Ala(61), Ser(38)-Ile(39)-Tyr(67)-Gly(68), and Pro(84)-Val(85) bonds. These cleavages are compatible with the known specificity of this enzyme. Several of the fragments prepared with these two enzymes, peptides (43-71), (61-88), (75-88), and (72-84) have been used in other studies to locate the encephalitogenic site in the parent peptic peptide.
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PMID:Treatment of an encephalitogenic peptide from guinea pig myelin basic protein with alpha-protease and thermolysin. Isolation of fragments and determination of cleavage sites. 6 52

Two amino acid sequences from the same regions of guinea pig and bovine myelin basic protein which induce experimental allergic encephalomyelitis in Lewis rats were synthesized. The sequences of these two regions may be defined by residues 69 to 84 of the bovine basic protein. The encephalitogenic sequence from guinea pig basic protein (peptide S49), H-Gly-Ser-Leu-Pro-Gln-Lys-Ala-Gin-Arg-Pro-Gin-Asp-Glu-Asn-OH, is a much more potent encephalitogen than that of H-Gly-Ser-Leu-Pro-Gln-Lys-Ala-Gln-Gly-His-Arg-Pro-Gln-Asp-Glu-Asn-OH (peptide S8) found in the bovine protein. The primary structures of the two determinants are similar; however, a Gly-His deletion from the guinea pig sequence is noted. Study of the encephalitogenicity of peptide S49, peptide S8, and the parent proteins suggests that the difference in the encephalitogenic potency of the parent proteins in Lewis rats is due to a natural modification in the primary structure of their respective encephalitogenic determinants.
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PMID:Experimental allergic encephalomyelitis in Lewis rats: chemical synthesis of disease-inducing determinant. 6 39

Copolymer 1 (Cop 1) is a synthetic basic random copolymer of amino acids that has been shown to be effective in suppression of experimental allergic encephalomyelitis and has been proposed as a candidate drug for multiple sclerosis. Cop 1 is immunologically cross reactive with myelin basic protein (BP) and was shown to inhibit murine BP-specific T-cell lines of various H-2 restrictions. In the present study these findings were extended to include human T-cell lines. Cop 1 competitively inhibited the proliferative responses and interleukin 2 secretion of six BP-specific T-cell lines and 13 clones with several DR restrictions and epitope specificities. Conversely, BP inhibited--albeit to a lesser extent--the response of all the Cop 1-specific T-cell lines and clones, irrespective of their DR restrictions. Another random copolymer of tyrosine, glutamic acid, and alanine, denoted TGA, had no effect on these lines. Neither Cop 1 nor BP inhibited the response of lines and clones specific for purified protein derivative. Cop 1 and BP exerted their cross-inhibitory effects only in the presence of antigen-presenting cells. These results suggest that Cop 1 can compete with BP for the binding to human major histocompatibility complex molecules. In view of recent studies implicating BP reactivity in multiple sclerosis, these findings suggest a possible mechanism for the beneficial effect of Cop 1 in this disease.
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PMID:Synthetic copolymer 1 inhibits human T-cell lines specific for myelin basic protein. 137 Mar 47

The structure of Mengo encephalomyelitis virus was refined at 3 A resolution with a final R-factor of 0.221 and a root-mean-square deviation from idealized bond lengths of 0.019 A for 10 A to 3 A data with F greater than or equal to 3 sigma(F). The Hendrickson-Konnert refinement was restrained by the phases derived from the molecular replacement averaging procedure and constrained by the icosahedral symmetry of the virus. The virus consists of 60 protomers each having three major subunits, VP1, VP2 and VP3, along with one smaller internal protein, VP4. The three major subunits form similar eight-stranded beta-barrel structures. Alterations in the original sequence were found at position 45 in VP1 (Arg to Ala) and at position 58 in VP3 (Met to Val). The residues in loops I and II of VP1 (82 to 102), the "FMDV loop" in VP1 (205 to 213), the flexible loop of VP3 in the putative receptor attachment site (175 to 185) as well as the terminal regions 260 to 268 in VP1, 253 to 256 in VP2 and 13 to 15 in VP4 were built or modified in regions of weak density. The variation in temperature factors at the end of the refinement is over a wide range (from 2 to 80 A2), with the disordered outer and inner regions showing high mobility. Four cis proline residues, 105 in VP1, 85 and 152 in VP2 and 59 in VP3, have been identified. The disulfide bridge Cys86 to Cys88 in VP3 has been characterized. One phosphate ion and 233 water positions were included in the refinement. It is suggested that this phosphate is associated with the receptor attachment site. There are two major hydrogen-bonding networks involving solvent atoms; one involving only the subunits of a protomer, and the other connecting the protomers in a pentamer. The distribution of atom types around the icosahedral symmetry axes shows that the 5-fold channel is more hydrophobic than that along the 3-fold axis and that there are more charged residues around the 2-fold axis. The analysis of contacts between the different subunits supports the assignment of the protomeric unit. The five protomers that form the pentameric unit are held together by interactions involving the smaller VP4 protein and the amino termini of VP1 and VP3. The pentamers are associated by means of the amino-terminal region of the VP2 subunits, the beta F strand of the VP3 subunits, the C terminus of the VP4 subunits and the electrostatic helical (alpha A) interactions of VP2 subunits across the icosahedral 2-fold axes. The superposition of the corresponding subunits of Mengo virus, human rhinovirus 14 and southern bean mosaic virus has provided an improved sequence alignment. The largest structural similarity is between the VP3 subunits of Mengo virus and rhinovirus, while the least similarity is between the VP1 subunits. The various specialized insertions in the different subunits can be associated with specific functional requirements.
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PMID:Structural refinement and analysis of Mengo virus. 215 78

Single intracutaneous injection of 30 micrograms of human basic myelin protein peptide 114-122 (H-Phe-Ser-Trp-Gly-Ala-Glu-Gly-Gln-Arg-OH) with Freund adjuvant induced the onset of encephalomyelitis on day 9-19 after the injection. The lethality was 33%. In autumn the disease was more severe than in summer.
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PMID:[Allergic encephalomyelitis in guinea pigs on the intracutaneous and subcutaneous administration of fragment 114-122 of the human myelin cationic protein]. 243 68

Cop 1 is a synthetic basic random copolymer of L-alanine, L-glutamic acid, L-lysine, and L-tyrosine in a residue molar ratio of 6.0:1.9:4.7:1.0 and with a molecular weight of 21,000 which proved to be effective in specific suppression of experimental allergic encephalomyelitis and has been proposed as a candidate drug against multiple sclerosis. In the present study we further investigated the mechanism of Cop 1 suppressive activity and tested whether Cop 1 could inhibit the specific T-cell response to myelin basic protein (BP). Eight BP-specific T-cell lines and clones with various H-2 restrictions and antigenic specificities were used. The responses of all these lines and clones to BP, as followed by both cell proliferation and interleukin 2 secretion assays, were affected by Cop 1. For one line, a direct cross proliferation with Cop 1 was observed, whereas in the other seven lines and clones, Cop 1 specifically inhibited the responses to BP in a competitive dose-dependent manner. The inhibition of the response to BP is specific to Cop 1, as D-Cop 1 and another random acidic polymer, poly(Tyr,Glu,Ala) (TGA), both of which were previously demonstrated to be ineffective in suppression of experimental allergic encephalomyelitis, did not inhibit the response to BP. Furthermore, Cop 1 specifically inhibited only the response of the T-cell lines and clones to BP. It did not inhibit their response to the mitogen Con A, nor did it inhibit the responses of the purified protein derivative-specific T-cell line and clone. These results suggest that Cop 1 may be effective in suppression of experimental allergic encephalomyelitis, not only because of the selective stimulation of suppressor T cells, as we have previously demonstrated, but also by specific inhibition of BP-specific effector T cells.
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PMID:Specific inhibition of the T-cell response to myelin basic protein by the synthetic copolymer Cop 1. 246 52

We examined a variety of strains of Sindbis virus for the genetic changes responsible for differences in neurovirulence in mice. SV1A (a low passage of the AR339 strain of Sindbis virus), a neuroadapted Sindbis virus (NSV), and two laboratory strains of Sindbis virus (HRSP and Toto1101) were examined. NSV causes severe encephalomyelitis with hind-limb paralysis and high mortality after intracerebral inoculation in weanling mice. In contrast, SV1A causes only mild, nonfatal disease in weanling mice; however, in suckling mice, SV1A causes a fatal encephalomyelitis after either intracerebral or subcutaneous inoculation. The two laboratory strains used have a greatly reduced neurovirulence for suckling mice and are avirulent for weanling mice. The nucleotide sequences and encoded amino acid sequences of the structural glycoproteins of these four strains were compared. Hybrid genomes were constructed by replacing restriction fragments in a full-length cDNA clone of Sindbis virus, from which infectious RNA can be transcribed in vitro, with fragments from cDNA clones of the various strains. These recombinant viruses allowed us to test the importance of each amino acid difference between the various strains for neurovirulence in weanling and suckling mice. Glycoproteins E2 and E1 were of paramount importance for neurovirulence in adult mice. Recombinant viruses containing the nonstructural protein region and the capsid protein region from an avirulent strain and the E1 and E2 glycoprotein regions from NSV were virulent, although they were less virulent than NSV. Furthermore, changes in either E2 (His-55 in NSV to Gln in SV1A) or E1 (Ala-72 in NSV to Val in SV1A and Asp-313 in NSV to Gly in SV1A) reduced virulence. For virulence in suckling mice, we found that a number of changes in E2 and E1 can lead to decreased virulence and that in fact, a gradient of virulence exists.
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PMID:Molecular basis of Sindbis virus neurovirulence in mice. 283 15

Cop 1 is a random polymer (molecular weight, 14,000 to 23,000) simulating myelin basic protein. It is synthesized by polymerizing L-alanine, L-glutamic acid, L-lysine, and L-tyrosine. It suppresses but does not induce experimental allergic encephalomyelitis, an animal model of multiple sclerosis. It is not toxic in animals. In a double-blind, randomized, placebo-controlled pilot trial, we studied 50 patients with the exacerbating-remitting form of multiple sclerosis, who self-injected either 20 mg of Cop 1 dissolved in 1 ml of saline or saline alone daily for two years. Six of 23 patients in the placebo group (26 percent) and 14 of 25 patients in the Cop 1 group (56 percent) had no exacerbations (P = 0.045). There were 62 exacerbations in the placebo group and 16 in the Cop 1 group, yielding two-year averages of 2.7 and 0.6 per patient, respectively. Among patients who were less disabled on entry (Kurtzke disability score, 0 to 2), there were 2.7 exacerbations in the placebo group and 0.3 in the Cop 1 group over two years. Among patients who were more affected (Kurtzke disability score, 3 to 6), there was an average of 2.7 exacerbations in the placebo group and 1.0 in the Cop 1 group. Over two years, less disabled patients taking Cop 1 improved an average of 0.5 Kurtzke units; those taking placebo worsened an average of 1.2 Kurtzke units. More disabled patients worsened by 0.3 (Cop 1 group) and 0.4 (placebo group) unit. Irritation at injection sites and rare, transient vasomotor responses were observed as side effects. These results suggest that Cop 1 may be beneficial in patients with the exacerbating-remitting form of multiple sclerosis, but we emphasize that the study is a preliminary one and our data require confirmation by a more extensive clinical trial.
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PMID:A pilot trial of Cop 1 in exacerbating-remitting multiple sclerosis. 330 5

Deletion of certain amino acid residues from the amino acid sequence of the encephalitogenic determinant for guinea pigs, H-Phe-Ser-Trp-Gly-Ala-Glu-Gly-Gln-Lys-OH, destroyed its ability to induce experimental allergic encephalomyelitis (EAE), a cell-mediated autoimmune disease of myelin. The administration of the modified determinant in the form of 4 repeating pentameric sequences, H-(Phe-Ser-Trp-Gln-Lys)4-Gly-OH, activated an antigen-specific T suppressor lymphocyte subset that rendered both presensitized donors and recipients of donor T lymphocytes unresponsive to an encephalitogenic challenge. Treatment of donors or recipients with cyclophosphamide before or after lymphocyte transfer, respectively, obliterated the ability of peptide S42-sensitized T lymphocytes to induce a state of unresponsiveness to an EAE-challenge. The results establish the existence of antigenic determinants for both immunoinduction and immunoregulation of EAE. The immunoregulatory determinant that activates antigen-specific and cyclophosphamide-sensitive suppressor T lymphocyte subset is sequestered within the disease-inducing or T effector determinant.
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PMID:Experimental allergic encephalomyelitis: activation of suppressor T lymphocytes by a modified sequence of the T effector determinant. 616 Nov 72

A single amino acid substitution in the sequence of the encephalitogenic determinant for Lewis rats destroyed its ability to induce experimental allergic encephalomyelitis (EAE) but generated a potent immunoregulatory sequence capable of suppressing the development of both clinical and histologic signs of EAE. The EAE-inducing determinant (synthetic peptide S6) H-Ala-Gln-Gly-His-Arg-Pro-Gln-Asp-Glu-Asn-OH (residues 75 to 84) of the bovine MBP induced clinical and histologic signs of EAE when it was administered at doses of 0.5 micrograms or higher. Gly substituted for the C-terminal Asn during the synthesis of peptide S6 generated the homologous sequence designated by peptide S79. Peptide S79 failed to induce either clinical or histologic signs of EAE even when it was administered at dosages up to 1000 times higher than those of S6. Similarly, rats pretreated with a single dose of S79 were not only unresponsive to an encephalitogenic challenge but also were capable of transferring unresponsiveness to syngeneic recipients with viable donor lymphocytes. The induction of unresponsiveness that was abrogated by pretreatment with cyclophosphamide suggests the development of an S79-sensitive lymphocyte subset that regulates MBP-induced EAE in Lewis rats.
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PMID:Experimental allergic encephalomyelitis in Lewis rats: immunoregulation of disease by a single amino acid substitution in the disease-inducing determinant. 616 28


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