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)

A 17-residue peptide (Peptide Y) was isolated from the COOH-terminal end of the basic protein of bovine myelin by peptic digestion. This peptide induced experimental allergic encephalomyelitis in the rhesus monkey. Treatment of Peptide Y with cyanogen bromide released three amino acids from the COOH-terminal end and resulted in a tetradecapeptide (Peptide M) which was also encephalitogenic in the rhesus monkey. The sequence of Peptide M is: Phe-Lys-LEU-Gly-Gly-Arg-Asp-Ser-Arg-Ser-Gly-Ser-Pro-Met. Thus a major disease-inducing site active in the rhesus monkey is contained within a 14-residue peptide localized near the COOH-terminal end of the protein. This peptide differs markedly in location and sequence from the 9-residue peptide shown to contain the encephalitogenic determinant for the guinea pig.
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PMID:Allergic encephalomyelitis. Isolation of an encephalitogenic peptide active in the monkey. 4 30

Myelin basic proteins and peptides derived from them by limited cleavage with pepsin were tested for their ability to induce experimental allergic encephalomyelitis (EAE) in Lewis rats. The encephalitogenicity of the weakly active bovine protein was found to be associated with both halves of the molecule, peptides (1-88) and (89-169). Of the four smaller derivates of peptide (1-88), peptides (1-36), (43-88), (1-42), and (37-88), only the last two were active. This demonstrated that the overlap region consisting of residues 37-42 (sequence Asp-Ser-Leu-Gly-Arg-Phe) constitutes an encephalitogenic determinant. Of the two smaller derivatives of peptide (89-169), peptides (111-169) and (89-152), only the last was active. This indicated that the second encephalitogenic determinant begins between residues 88 and 111 and ends before residue 153. This region contains the sequence Leu-Ser-Leu-Ser-Arg-Phe (residues 108-113), which is strikingly similar to that of the first encephalitogenic determinant. Studies involving the extremely encephalitogenic guinea pig protein demonstrated that virtually all of the activity was recovered in the peptides corresponding to bovine peptides (37-88) and (43-88). These peptides, but not those comprising the remainder of the protein, were active in inhibiting the passive transfer of EAE with lymph node cells from donors immunized with guinea pig spinal cord.
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PMID:The location of regions in guinea pig and bovine myelin basic proteins which induce experimental allergic encephalomyelitis in Lewis rats. 4 54

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

This study explores the usage of T cell antigen receptor (TCR) beta chain elements in Lewis rats with experimentally induced allergic encephalomyelitis (EAE). TCRs from 15 different T cell clones and hybridomas derived from animals immunized with myelin basic protein (MBP), and all having specificity for the 21-mer encephalitogenic fragment MBP 68-88, utilized V beta 8.2. In addition, there was a marked conservation of the first two amino acid residues of the junctional complementarity determining region 3 (CDR3) associated with the V beta 8.2 receptors. 12 of 15 contained an aspartic acid followed by serine regardless of the associated J beta element. At the nucleotide level, this conservation of AspSer residues was accomplished with few or no nongermline-encoded nucleotide (N) additions. A similar pattern of AspSer usage and N region nucleotide additions was observed in a number of V beta 8.2 isolates derived from MBP-immunized lymph nodes. In contrast, V beta 8.2 polymerase chain reaction amplified isolates from Lewis T cells activated with concanavalin A or from lymph nodes of complete Freund's adjuvant-immunized animals showed no AspSer utilization (0/31) in the CDR3, and four to nine N region nucleotide additions. We conclude from this finding that AspSer residues in the CDR3, limited N region nucleotide additions, along with V beta 8.2 sequences, contribute to TCR specificity for MBP 68-88. This raises the possibility that encephalitogenic, disease-causing T cells either represent a population that derives from late fetal life or alternatively, that they are rare cells with this particular TCR phenotype contributed to the T cell pool throughout adulthood and are selected by antigen. In either case, the CDR3 AspSer sequences as well as V beta 8.2 sequences are candidates for the receptor target structures recognized by regulator T cells in recovery from and resistance to active EAE. In this respect, a preliminary analysis of TCR utilization in three T cell clones specific for MBP 68-88 isolated from animals recovered from active EAE indicates that while all three use V beta 8.2, only one contains AspSer in the CDR3.
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PMID:Analysis of T cell receptor beta chains in Lewis rats with experimental allergic encephalomyelitis: conserved complementarity determining region 3. 183 12

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

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

Granzymes are a family of serine proteases that are harbored in cytoplasmic granules of activated T lymphocytes and are released upon target cell interaction. Immediate and complete neurite retraction was induced in a mouse neuronal cell line when total extracts of granule proteins were added. This activity was isolated and identified as granzyme A. This protease not only induced neurite retraction at nanomolar concentrations but also reversed the stellation of astrocytes. Both effects were critically dependent on the esterolytic activity of granzyme A. As neurite retraction is known to be induced by thrombin, possible cleavage and activation of the thrombin receptor were investigated. A synthetic peptide spanning the N-terminal thrombin receptor activation sequence was cleaved by granzyme A at the authentic thrombin cleavage site Leu-Asp-Pro-Arg-Ser. Antibodies to the thrombin receptor inhibited both thrombin and granzyme A-mediated neurite retraction. Thus, T-cell-released granzyme A induces cellular responses by activation of the thrombin receptor. As brain-infiltrating CD4+ lymphocytes are the effector cells in experimental allergic encephalomyelitis, granzyme A released in the brain may contribute to the etiology of autoimmune disorders in the nervous system.
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PMID:Granzyme A released upon stimulation of cytotoxic T lymphocytes activates the thrombin receptor on neuronal cells and astrocytes. 805 66

The class II major histocompatibility complex molecule I-A(g7) is strongly linked to the development of spontaneous insulin-dependent diabetes mellitus (IDDM) in non obese diabetic mice and to the induction of experimental allergic encephalomyelitis in Biozzi AB/H mice. Structurally, it resembles the HLA-DQ molecules associated with human IDDM, in having a non-Asp residue at position 57 in its beta chain. To identify the requirements for peptide binding to I-A(g7) and thereby potentially pathogenic T cell epitopes, we analyzed a known I-A(g7)-restricted T cell epitope, hen egg white lysozyme (HEL) amino acids 9-27. NH2- and COOH-terminal truncations demonstrated that the minimal epitope for activation of the T cell hybridoma 2D12.1 was M12-R21 and the minimum sequence for direct binding to purified I-A(g7) M12-Y20/K13-R21. Alanine (A) scanning revealed two primary anchors for binding at relative positions (p) 6 (L) and 9 (Y) in the HEL epitope. The critical role of both anchors was demonstrated by incorporating L and Y in poly(A) backbones at the same relative positions as in the HEL epitope. Well-tolerated, weakly tolerated, and nontolerated residues were identified by analyzing the binding of peptides containing multiple substitutions at individual positions. Optimally, p6 was a large, hydrophobic residue (L, I, V, M), whereas p9 was aromatic and hydrophobic (Y or F) or positively charged (K, R). Specific residues were not tolerated at these and some other positions. A motif for binding to I-A(g7) deduced from analysis of the model HEL epitope was present in 27/30 (90%) of peptides reported to be I-A(g7)-restricted T cell epitopes or eluted from I-A(g7). Scanning a set of overlapping peptides encompassing human proinsulin revealed the motif in 6/6 good binders (sensitivity = 100%) and 4/13 weak or non-binders (specificity = 70%). This motif should facilitate identification of autoantigenic epitopes relevant to the pathogenesis and immunotherapy of IDDM.
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PMID:A peptide-binding motif for I-A(g7), the class II major histocompatibility complex (MHC) molecule of NOD and Biozzi AB/H mice. 909 75

We synthesized single amino acid-substituted peptide analogues of guinea pig myelin basic protein (MBP) 73-86 to study the importance of aspartic acid at residue 82 (QKSQRSQDENPV), which previous reports have suggested is a critical TCR contact residue. Whereas the wild-type 73-86 peptide elicited severe experimental autoimmune encephalomyelitis (EAE) in the Lewis rat, none of the peptide analogues with substitutions at position 82 were capable of inducing EAE. The inability to cause EAE was not due to a failure to bind MHC or to elicit T cell proliferation and cytokine secretion. T cells specific for MBP73-86 did not cross-react with any of the analogues tested, further indicating the importance of this residue in T cell responses to 73-86. Analysis by flow cytometry showed that only the wild-type 73-86 peptide was capable of recruiting V beta 8.2+ T cells, which have been shown previously to be important for disease induction. Reduced expression of the V beta 8.2 TCR was also seen in Lewis rats protected from EAE by coimmunization of MBP73-86 with 73-86(82D-->A), despite an increase in cytokine production when both peptides were present during in vitro culture. The data indicate that aspartic acid 82 is a critical TCR contact residue and is required for the recruitment of V beta 8.2+ T cells and the encephalitogenic activity of MBP73-86.
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PMID:Critical requirement for aspartic acid at position 82 of myelin basic protein 73-86 for recruitment of V beta 8.2+ T cells and encephalitogenicity in the Lewis rat. 991 5

Experimental allergic encephalomyelitis (EAE) is induced in susceptible animals by immunodominant determinants of myelin basic protein (MBP), such as guinea pig sequence MBP72-85. Two linear and one cyclic analogues based on MBP72-85 have been synthesized and evaluated for EAE induction in Lewis rats. The linear peptide Gln1-Lys2-Ser3-Gln4-Arg5-Ser6-Gln7-+ ++Asp8-Glu9-Asn10-Pro11-Val12 (1) was found to induce EAE, while substitution of the Asp residue at position 8 with Ala resulted in an analogue (2) which suppressed the induction of EAE by its parent peptide. Nuclear magnetic resonance studies of analogue 1 in dimethyl sulfoxide (DMSO) using TOCSY/ROESY techniques revealed a head-to-tail intramolecular interaction (ROE connectivity between betaVal12-gammaGln1), indicating a pseudocyclic conformation for the immunogenic peptide 1. A conformational model was developed using NMR constraints and molecular dynamics. Based on this model, a novel amide-linked cyclic analogue has been designed and synthesized by connecting the side-chain amino and carboxyl groups of Lys and Glu at positions 2 and 9, respectively, of linear analogue 1. The cyclic analogue (3) had similar activity to the linear peptide 1, and the EAE effects induced by cyclic analogue 3 were completely suppressed by co-injection with the Ala81-substituted analogue 2 in Lewis rats. The similar potencies of analogues 1 and 3 support the proposed cyclic comformation suggested for analogue 1 from NMR studies and computer modeling and provides the basis for designing more potent molecules with improved properties such as increased resistance to degradation.15 The present findings suggest that a cyclic conformation for the MBP72-85 epitope positions the carboxyl group of Asp81 correctly and presumably other side groups of the peptide such as Arg78 in a manner which enables functional binding of the trimolecular complex MHC-peptide-T cell receptor resulting in EAE.
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PMID:Design and synthesis of a potent cyclic analogue of the myelin basic protein epitope MBP72-85: importance of the Ala81 carboxyl group and of a cyclic conformation for induction of experimental allergic encephalomyelitis. 1019 61


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