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PubMed1984

Enzymatic and nonenzymatic degradation of myelin basic protein.

A procedure for large scale isolation of myelin basic protein (BP) has been modified to insure BP preparations free of neutral proteinase activity. Fractions were monitored by electrophoretic analysis of BP solutions incubated under various conditions of temperature and pH. Maximum degradation of human BP prepared by the old batch procedure occurs at pH 7, approximately 47 degrees C. BP preparations obtained by the new procedure, as well as BP preparations purified by CM-cellulose chromatography, are stable under these conditions. The latter, however, do undergo significant breakdown at pH 9, 100 degrees C. The results suggest that the degradation observed under these conditions is non-enzymatic in nature.

Humans↗
PubMed2003

An immunodominant epitope of myelin basic protein is an amphipathic alpha-helix.

Myelin basic protein is a candidate autoantigen in multiple sclerosis. One of its dominant antigenic epitopes is segment Pro85 to Pro96 (human sequence numbering, corresponding to Pro82 to Pro93 in the mouse). There have been several, contradictory predictions of secondary structure in this region; either beta-sheet, alpha-helix, random coil, or combinations thereof have all been proposed. In this paper, molecular dynamics and site-directed spin labeling in aqueous solution indicate that this segment forms a transient alpha-helix, which is stabilized in 30% trifluoroethanol. When bound to a myelin-like membrane surface, this antigenic segment exhibits a depth profile that is characteristic of an amphipathic alpha-helix, penetrating up to 12 A into the bilayer. The alpha-helix is tilted approximately 9 degrees, and the central lysine is in an ideal snorkeling position for side-chain interaction with the negatively charged phospholipid head groups.

Amino Acid Sequence↗
PubMed1984

Interaction of myelin basic protein with micelles of dodecylphosphocholine.

Interactions of myelin basic protein (MBP) and peptides derived from it with micelles of dodecylphosphocholine (DPC) and perdeuterated DPC have been studied by proton nuclear magnetic resonance (NMR) at 400 MHz and by circular dichroism (CD). When MBP binds to DPC micelles, it acquires about 18% alpha-helicity. The CD spectra of various peptides derived by cleavage of MBP indicate that a major alpha-helical region occurs in residues 85-99 just before the sequence of three prolyl residues 100-102. From line broadenings by fatty acid spin-labels in the micelles and from changes in chemical shifts, the NMR data identify specific residues in MBP that participate in lipid binding. One such sequence is an alpha-helical region from residues 85 to 95, and others occur around methionine-21 and between residues 117 and 135. The different effects of C5, C12, and C16 spin-labels suggest that some segments of the protein may penetrate beyond the dipolar interfacial region of the micelles into the hydrophobic interior, but no part of the protein is protected by the micelles against rapid exchange of its amide groups with the aqueous environment. Even at a lipid to protein molar ratio of 200/1, most NMR resonances from side chains of amino acid residues are not appreciably broadened, suggesting that much of the polypeptide remains highly mobile.

Animals↗
PubMed1991

On the spontaneous adherence of myelin basic protein to T lymphocytes.

We have applied a double tagging system in order to study whether purified myelin basic protein is able to adhere to normal human peripheral T lymphocytes without the need to purify cells. Evaluation of myelin basic protein adherence to peripheral blood mononuclear cells was determined with biotinylated myelin basic protein and fluoresceinated avidin, and lymphocyte population was identified by the corresponding phycoerythrinated monoclonal antibody. The observed adherence of myelin basic protein to T lymphocytes was found to depend on protein conformation.

Animals↗
PubMed1988

Protection from experimental allergic encephalomyelitis conferred by a monoclonal antibody directed against a shared idiotype on rat T cell receptors specific for myelin basic protein.

Immunizing Lewis rats with guinea pig myelin basic protein (MBP) yielded an encephalitogen specific, Ia-restricted, rat-mouse T cell hybridoma 5.10, which was used to establish a clonotypic mAb (10.18) that binds to and precipitates the rat TCR. By two-dimensional gel electrophoresis, the rat TCR was shown to consist of two disulfide-linked peptide chains with mol wt of 48,000 and 39,000. 10.18 binds the majority of cells in MBP-specific T cell lines that are capable of transferring experimental allergic encephalomyelitis (EAE) to Lewis rat recipients, but does not bind to either a purified protein derivative of tuberculin-specific cell line or an OVA-specific line. Furthermore, soluble 10.18 can block antigen-specific stimulation of hybridoma 5.10 but cannot control hybridomas, while immobilized 10.18 stimulates 5.10, but cannot control the hybrids. Though 10.18+ cells are very rare in normal rats, increase of 10.18+ cells is observed in MBP-primed paralyzed rats. Finally, when 10.18 is injected into MBP-primed Lewis rats, EAE is abrogated. We have thus characterized EAE as a "mono-idiotypic" autoimmune disease.

Animals↗
PubMed1996

Human T lymphocytes specific for the immunodominant 83-99 epitope of myelin basic protein: recognition of golli MBP HOG 7.

Myelin basic protein (MBP) is a candidate autoantigen in the disease multiple sclerosis. Although MBP was thought to be sequestered behind the blood-brain barrier, isoforms of MBPs have recently been demonstrated in lymphoid tissues. These isoforms, termed golli MBPs, contain sequences that are shared with "classic" MBP within the CNS. In the present study, we have determined that epitopes within golli MBP isoforms may be recognized by human T lymphocyte clones specific for classic MBP. Ten of 12 T-cell clones recognized golli MBP. Although 11 clones were specific for the immunodominant 83-99 sequence, the clones differed with respect to human leukocyte antigen (HLA) restriction, T-helper phenotype, cytolytic activity, and T-cell receptor usage. Greater responses to classic MBP than to golli MBP suggested a difference in the ability of the two proteins to be processed and to present epitopes therein. These data advance the hypothesis that golli MBP sequences expressed within lymphoid tissues may be recognized by classic MBP-specific T lymphocytes during central or peripheral tolerance.

Antibody Specificity↗
PubMedDate not supplied

[Polymorphism of length of tetranucleotide repeat from the 5'-side from the myelin basic protein gene in multiple sclerosis in Russians].

The myelin basic protein gene (MBP) can confer the susceptibility to multiple sclerosis, because its protein product is the main protein component of myelin of the central nervous system and a potential autoimmune antigen in the disease. A possible association of multiple sclerosis with alleles and genotypes of a microsatellite repeat (TGGA)n, located to the 5' side from the first exon of MBP in ethnic Russians (126 patients with reliable multiple sclerosis and 142 healthy controls from Central Russia) was analyzed using the case-control method. Upon separation of the tetranucleotide repeat site amplification products in 1.5% agarose gel, one can see two distinct bands that can be analyzed as two allele groups (A and B). The distribution of allele A and B group frequencies as well as frequency of allele group B and genotype A/A reliably differs in multiple sclerosis patients and healthy controls. Alleles A and the A/A genotype are associated with the development of multiple sclerosis. We also analyzed the association of multiple sclerosis with combined bearing of alleles and genotypes A and B of MBP and groups of alleles of the DRB1 gene of the major histocompatibility complex that correspond to serospecificities DR1-DR18. The comparison of subgroups of multiple sclerosis patients and healthy individuals, formed on the basis of the DRB1 phenotype, has shown a reliable increase in the frequency of allele B in healthy individuals and the genotype A/A frequency in patients, only among DR4- and DR5-positive individuals. No reliable difference was found in the MBP allele and genotype distribution between multiple sclerosis patients and healthy individuals in combined groups of (DR4,DR5)-negative individuals, i.e., no carriers of any phenotype except DR4 and DR5 were revealed. Thus, MBP or some other nearby gene is involved in the multiple sclerosis development in Russians, predominantly (or exclusively) among DR4 and DR5 carriers. In this case, without stratification of analyzed individuals by the MBP alleles, multiple sclerosis is reliably associated only with DR2(15), but not of DR4 and DR5 alleles of DRB1. The results obtained are in favor of the genetic heterogeneity of multiple sclerosis, and suggest the possibility of epistatic interactions between the MBP and DRB1 genes.

Base Sequence↗
PubMed1985

Lipid-induced recognition of a conformational determinant (residues 65 to 83) in myelin basic protein.

The precipitation by antibodies to intact myelin basic protein (BP) and to synthetic peptides containing a sequence based on the region 65 to 83 of bovine BP, S82, S81, S79, and S24, of intact BP in solution or bound to lipid vesicles was compared, using 125I-BP or 14C-DPPC-labeled lipid-BP vesicles. The antipeptide antibodies were shown earlier to recognize conformational determinants which are not expressed in the intact protein in solution. Several anti-BP antibodies precipitated more of the BP free in solution than when bound to lipid vesicles, suggesting that some of the determinants recognized by these antibodies were either sequestered in the bilayer or were altered in conformation. In contrast, one anti-peptide antisera, which had a high titer for the conformational determinant in two of these peptides, S82 and S81, precipitated the protein to a significant degree when it was bound to PG vesicles, even though it did not react with the intact protein in solution. These results indicated that PG was able to confer on the protein the unique peptide conformation recognized by this antibody. PS was less effective, and other lipids were ineffective at conferring this conformation on the protein, supporting earlier results which showed that the conformation of the protein is influenced by the lipid composition of its environment. None of the other anti-peptide antibodies studied bound to the protein either in solution or in lipid vesicles. These results indicate that the lipid environment can sequester or alter the conformation of some antigenic determinants, preventing recognition by some anti-BP antibodies, and can expose or generate other conformational determinants, allowing recognition by an anti-peptide antiserum.

Animals↗
PubMed2000

Clinical and analytical evaluation of an enzyme immunoassay for myelin basic protein in cerebrospinal fluid.

BACKGROUND: RIA of myelin basic protein (MBP) in cerebrospinal fluid (CSF) is commonly used as a biochemical marker of demyelination in patients with multiple sclerosis (MS). Our aim was to develop a sufficiently sensitive ELISA for MBP and evaluate it clinically in patients with MS. METHODS: The ELISA used anti-bovine MBP antibody coated on plates and biotinylated anti-MBP antibody. The bound antibody complex was quantified with streptavidin-horseradish peroxidase. MBP was determined in CSF from 84 MS patients and 55 patients with other neurological diseases. RESULTS: The respective within- and between-assay CVs were 4.7% and 7.2% at 200 ng/L, and 6. 3% and 8.8% at 2000 ng/L. The detection limit was 30 ng/L. Most of the MS patients with acute exacerbations had markedly increased MBP in the CSF. Longitudinal studies of six MS patients with recurrent exacerbation confirmed this observation. MBP concentrations from 78 MS patients, as tested with our ELISA, correlated well with those obtained by RIA (r = 0.9; P: <0.01), but the detection limit of the ELISA was much lower than that of the RIA. CONCLUSIONS: This convenient ELISA with higher sensitivity than the existing assays is a suitable routine assay that provides a diagnostic indicator of myelin breakdown in the central nervous system; moreover, it is an excellent indicator of MS disease activity.

Adolescent↗
PubMed2005

Assembly of tubulin by classic myelin basic protein isoforms and regulation by post-translational modification.

Myelin basic protein (MBP), a highly cationic protein that maintains the structure of the myelin sheath, associates with tubulin in vivo. The in vitro assembly of tubulin by MBP was examined here using several assays. The unmodified C1 component of 18.5 kDa bovine MBP (bC1) assembled tubulin into microtubules in a dose-dependent manner via filamentous intermediates, and was able simultaneously to promote the formation of microtubule bundles. The critical tubulin concentration in the presence of bC1 was 0.69 +/- 0.05 microM. The effects of post-translational modifications (such as deamidation and phosphorylation) were assayed by comparing the bC1-bC6 components of 18.5 kDa bovine MBP; an increasing level of modification enhanced the ability of MBP to assemble tubulin. The effects of charge reduction via deimination were examined using recombinant murine isoforms emulating the unmodified C1 and deiminated C8 isoforms of 18.5 kDa MBP; both rmC1 and rmC8 exhibited a comparable ability to assemble tubulin. The effects of alternate exon recombination of the classic MBP variants were tested using the recombinant murine 21.5, 17.22, and 14 kDa isoforms. The isoforms containing regions derived from exon II of the classic MBP gene, 21.5 and 17.22 kDa MBP, showed no substantial difference in the extent of tubulin polymerization and bundling when compared to those of 18.5 kDa MBP. The 14 kDa isoform and two terminal deletion mutants of rmC1 were able to induce microtubule polymerization, but not bundling, to the same degree as the longer proteins. Finally, bC1 was shown to disrupt and aggregate planar sheets of crystalline tubulin stabilized by paclitaxel, establishing that these structures are not suitable substrates for the formation of MBP cocrystals.

Biopolymers↗
PubMed1987

Experimental allergic encephalomyelitis in mice: presence of myelin basic protein in cerebrospinal fluid.

The concentration of myelin basic protein (MBP) in cerebrospinal fluid (CSF) correlates with the development of experimental allergic encephalomyelitis following intradermal injection with encephalitogen in adjuvant; MBP is absent in controls inoculated with adjuvants only. The presence of MBP is a sensitive indicator of disease inasmuch as CNS-inoculated mice with neurologic signs had an average of 0.29 ng/microliter of MBP in their CSF and controls, including normal or adjuvants only, had an average of 0.03 ng/microliter. The amount present per microliter of CSF, as well as the absolute amount, obtained from an individual mouse do not always reflect the severity of disease as indicated by clinical signs and the pathology observed in a sampling of the neuraxis. The presence of MBP does correlate with demyelination, although the extent of pathology observed by light microscopy in the mouse model is minimal, associated only with the inflammatory response, and does not extend beyond the zone of the perivascular cuff.

Animals↗
PubMed2002

Mutations in the rat myelin basic protein gene are associated with specific alterations in other myelin gene expression.

The Long Evans shaker (les) rat is a myelin basic protein (MBP) mutant that exhibits severe central nervous system (CNS) dysmyelination. We used a combination of immunohistochemistry, immunoblot and Northern blot analyses to determine the effect of MBP deficits on the expression of other CNS myelin genes in this mutant. Immunohistochemistry revealed a marked reduction in all major myelin proteins and differences in their intracellular distribution. Immunoblots confirmed the decreased expression of these proteins and indicated that relative levels of proteolipid protein (PLP) and DM20 were altered in this mutant. Quantitation of mRNA levels indicated that decreases in PLP and DM20 were a result of changes in mRNA levels but detected no change in other myelin gene transcripts.

Animals↗
PubMed1998

The constitutive heat shock protein-70 is required for optimal expression of myelin basic protein during differentiation of oligodendrocytes.

To further elucidate the role of the constitutive heat shock protein-70 (HSC70) as a chaperone for the synthesis of myelin basic protein (MBP), HSC70 content was decreased in oligodendrocyte precursor cells prior to MBP expression either by transfection with an antisense oligonucleotide specific for HSC70, or by exposure to low levels of quercetin, a bioflavonoid known to decrease synthesis of HSC70. As these cells underwent differentiation in vitro, antisense treatment decreased HSC70 levels to 66% of controls. At the same time, a sharp induction resulted in the stress-inducible heat shock protein-70 (HSP70). Levels of two other stress proteins increased as well, namely, the 25-kDa heat shock protein (HSP25) and the 78-kDa glucose regulated protein (GRP78). MBP synthesis proceeded over a normal time course, but at only 50% of control values. As HSC70 content returned to normal, MBP synthesis was also restored to normal levels. Quercetin reduced the expression of HSC70 to an even greater extent than transfection, and prevented the induction of HSP70. In contrast to antisense-treated cells, MBP synthesis was essentially blocked in quercetin-treated cells even though levels of HSP25 and GRP78 increased. Taken together, these observations (a) indicate that HSP70 partially compensates for decreased chaperoning of nascent MBP by HSC70 (HSC70 and HSP70 are closely related and perform similar functions); (b) preclude the involvement of HSP25 and GRP78 in MBP synthesis; and (c) emphasize the requirement of HSC70 for optimal synthesis of MBP.

Animals↗
PubMed1994

Healthy monozygous twins do not recognize identical T cell epitopes on the myelin basic protein autoantigen.

The T cell response against myelin basic protein (MBP) has been extensively studied in humans because of its putative role in the pathophysiology of multiple sclerosis (MS). Higher concordance rates in monozygous twins as well as an increased risk in relatives suggest the role of genetic factors in MS susceptibility. Very little is known about the shaping of T cell repertoire towards self antigens in humans and their contribution to disease susceptibility in autoimmune disorders. Here we report the comparative T cell epitope recognition patterns towards the MBP auto-antigen in healthy identical twins. We have established MBP-specific T cell lines from eight sets of twins and characterized their fine epitope specificity. Intra-pair comparison showed the co-existence of shared as well as distinct epitopes in six of eight pairs and a complete absence of concordant epitope recognition within two other pairs. These findings indicate that important differences in T cell repertoires against a self antigen may be observed between genetically identical healthy individuals, rendering difficult the interpretation of the differences which may be observed between identical twins discordant for an autoimmune disease.

Adult↗
PubMed1994

Monoclonal and polyclonal antibody responses to the myelin basic protein epitope present in human urine.

The myelin basic protein (MBP)-like material (MBPLM) in human urine is expressed in a cryptic epitope(s) present in MBP peptide 80-89 and absent or inaccessible in intact MBP. These features of urinary MBPLM have made it difficult to produce reagents for its further characterization. Using an immunogen of keyhole limpet hemocyanin conjugated to MBP peptide cys 74-89, polyclonal antiserum to urinary MBPLM was prepared. With the same immunogen and screening with urine, the product from one of over 1600 wells from the original fusion, produced monoclonal antibody (mAb) which could detect urinary MBPLM. By radioimmunoassay two rabbit polyclonal reagents recognized a cryptic epitope in MBP peptide 84-89 while the two mAbs recognized another cryptic epitope in MBP peptide 80-85. Both could be used for quantitation of MBPLM in urine. These and previous results indicate the presence of at least three epitopes, one noncryptic and two cryptic, in the decapeptide of MBP 80-89. Of the two cryptic epitopes, the one near the carboxyl-terminal is dominant to that in the amino-terminal portion. The detection of urinary MBPLM with reagents with two different specificities suggests the presence of two or more small MBP peptides in urine.

Amino Acid Sequence↗
PubMed1994

Structural features of myelin basic protein mRNAs influence their translational efficiencies.

The myelin basic protein (MBP) gene expresses several alternatively spliced products with the same 5' and 3' untranslated regions (UTRs). It has been reported that its expression may be regulated not only at the transcriptional level but also at the translational level during development. We engineered several MBP mRNA deletion mutants with 5' (-48, -37, -27, -22, and -10) and 3' UTRs of differing lengths and examined the translational efficiencies of these constructs in cell-free systems. The translational efficiencies of the constructs differed significantly over a range of almost 10-fold. A deletion of 11 nucleotides from the 5' end of the natural (i.e., -48) MBP mRNA resulted in an approximate fourfold reduction in translational efficiency. Further truncation of the 5' UTR increased the translational efficiencies of the constructs as has been observed with many RNAs. These results suggest that there may be a positive control element between -48 and -37 nucleotides in the 5' UTR of MBP mRNA. The effects of modifying the lengths of the 5' UTR on the translational efficiency of mRNAs encoding the 21.5-kDa and 14-kDa MBPs were the same, suggesting that the effect observed was not unique to the 21.5-kDa MBP mRNA. Truncating the 3' UTR of four different alternatively spliced MBP mRNAs also altered their translational efficiencies. Thus, the 5' and 3' UTRs of MBP mRNAs appear to influence the translation of these mRNAs, and such factors may be involved in the translational regulation of MBP gene expression.

Animals↗
PubMed1987

Inefficient transcription of the myelin basic protein gene possibly causes hypomyelination in myelin-deficient mutant mice.

A hereditary dysmyelination mutation, named myelin deficient (mld), is considered to be allelic to shiverer, a deletion mutation of the myelin basic protein (MBP) gene. The present study showed that MBP expression is greatly reduced in mld, but that it is still detectable. Northern blot analysis revealed that the pronounced decrease in the MBP level in mld resulted from a reduced mRNA level and was not caused by deletion of a large portion of the MBP gene as in shiverer. Southern blot studies with BamHI-digested chromosomal DNA suggested some part of the MBP gene, at least the 5'-portion, was duplicated in mld. These results indicated that the mld and shiverer mutations were different from each other, even though genetic allelism between the two was reconfirmed. We also examined the developmental pattern of the gene expression of MBP and that of another protein, myelin proteolipid protein (PLP), specifically expressed in the oligodendrocyte, in mld by RNA dot blot study. The mRNA level of MBP in mld was greatly reduced during the active myelination stages, gradually increasing and remaining constant in the later stages. The PLP-mRNA content in mld was almost normal (60-80% that of control) at any stage of development. All these findings imply that the primary defect in mld is due to reduced transcriptional activity of the MBP gene.

Alleles↗