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PubMed1985

A double antibody radioimmunoassay for myelin basic protein in cerebrospinal fluid.

Levels of myelin basic protein (MBP) in cerebrospinal fluid (CSF) are useful in assessing the extent of demyelination which has occurred, or is occurring, in a variety of human problems associated with demyelination. Thus, an accurate, specific, simple, and consistent test for detecting MBP in CSF is needed. We describe such a test herein. The radioimmunoassay (RIA) described is a double antibody RIA using human MBP, and rabbit anti-MBP as reagents. The test can be done using only 200 microL of unconcentrated CSF. The test was sensitive to 0.1 microgram MBP/L. Recovery of known amounts of MBP was 97-105%, the within-assay and between-assay reproducibility were excellent. The "normal range" for our MBP-RIA was less than 2 micrograms/L, with a "grey area" between 2.0 and 3.0 micrograms/L.

Animals↗

PubMed1982

Transfer of allergic encephalomyelitis with spleen cells from donors sensitized with myelin basic protein in incomplete Freund's adjuvant.

Myelin basic protein (BP) emulsified in incomplete Freund's adjuvant (BP/IFA) is relatively nonencephalitogenic in Lewis rats. Furthermore, repeated injections of BP/IFA prevent subsequent induction of experimental allergic encephalomyelitis (EAE) by BP emulsified in complete Freund's adjuvant (BP/CFA). In spite of this, spleen cells from rats injected repeatedly with BP/IFA transfer EAE after they are cultured with BP almost as effectively as BP/CFA spleen cells. However, unlike the latter, BP/IFA spleen cells do not proliferate in response to BP in culture. Furthermore, BP/IFA spleen cells are unable to transfer EAE after culture with concanavalin A (Con A), in contrast to BP/CFA spleen cells. Both populations of spleen cells undergo a strong proliferative response to Con A in culture. For BP/IFA cells, at least, a proliferative response to BP in vitro is not a prerequisite for enhanced transfer of EAE in Lewis rats.

Animals↗

PubMed1983

Encephalitogenic activity of the small form of mouse myelin basic protein in the SJL/J mouse.

Mouse myelin basic proteins (MBP) were prepared by ion-exchange chromatography of an acid extract of homogenized, delipidated mouse brain. The use of a linear salt gradient during ion-exchange chromatography gave three peaks, 1, 2, and 3, of MBP. Sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) analysis of these peaks showed that peaks 2 and 3 were a mixture of the large and small forms of mouse MBP, whereas peak 1 was solely the small form. Tryptic peptides of mouse and rat small form MBP were compared by high-performance liquid chromatography. The elution times and absorbances at 210 nm were identical for 16 of 21 peaks derived from small form MBP of the two species. Amino acid analysis showed that 10 corresponding peaks from the small form of mouse and rat MBP had identical amino acid composition. When tested for encephalitogenicity in SJL/J mice, both the mixture of large and small forms of mouse MBP and the small form mouse MBP were highly encephalitogenic.

Amino Acid Sequence↗

PubMed1987

Monoclonal antibodies reactive with myelin basic protein.

New monoclonal antibodies (MAbs) to myelin basic protein (BP) reveal epitopes to be in sequences 22-34, 75-82, 83-96, 118-131 and 125-131. Comparison of these results with those previously reported suggest that almost every sequence of about 10 amino acid residues may be sufficiently antigenic to make a single MAb but that certain regions are immunodominant, strong enough to make practically the same MAb repeatedly. One of these new MAbs (clone 3) has especially interesting reactivity, sharply limited to residues 75-82 in bovine and porcine BP: Lys-Ala-Gln-His-Gly-Arg-Pro. Whales presumably have the same sequence, since their BPs are fully reactive with clone 3 MAb, but all other species of BP, with known sequences of BP, have at least two changes in this sequence. Deletion of Lys75 (as in a tryptic peptide of porcine BP) reduces reactivity with the MAb about 10-fold, whereas substitution of Ala76 by Ser (as in all other species of BP) and either deletion of Gln77 (as in human, monkey and rabbit BP) or His78 (as in the guinea pig and rat BP) or substitution of Pro82 by Thr (as in human, monkey, rat and mouse BP) eliminates reactivity. We speculate that woodchuck and prairie dog BPs in this region closely resemble chicken BP, which has about 2% of the original reactivity. However, squirrel BP is unique, probably having only one of the changes in this region of BP, since it possesses 10-20 times the reactivity of chicken BP but still only 20-50% of the original reactivity with clone 3 MAb, a degree of reactivity not seen with any other species of BP.

Amino Acid Sequence↗

PubMed1996

Preferential association of V lambda x light chains with gamma 2a heavy chains in naturally occurring human myelin basic protein reactive antibodies.

Active immunization with myelin basic protein (MBP) induces experimental allergic encephalomyelitis (EAE) in a variety of animal species, including rats and mice. We have previously described the ability of the newly described mouse lambda (lambda) variable (V) region V lambda x, to confer MBP reactivity to an Ab. In this report, we have evaluated the heavy (H) chain isotype distribution of V lambda x-bearing Abs in normal mouse serum. We demonstrate a biased H chain isotype association with V lambda x light (L) chains with a skewing towards gamma 2a and 2b isotypes. The IgG2a restriction in normal mouse Igs is even more evident in V lambda x-containing Abs that bind MBP. This was confirmed by the ability of purified polyclonal IgG2a Abs to bind MBP and the finding that most or all of the IgG2a Abs that bind MBP seem to harbor a V lambda x L chain. The specificity of naturally-occurring V lambda x-bearing Abs with MBP can be localized to a particular epitope encompassing residues 25-34 of the MBP molecule. Furthermore, virtually all of the reactivity of V lambda x-containing Abs with MBP peptide 25-34 is associated with the gamma 2a isotype. Collectively, these results suggest that the interaction of V lambda x with MBP seems to be facilitated by an association with gamma 2a which may reflect preferred VH usage by this isotype. Such unique pairing of particular H chains with V lambda x L chains in Abs that bind MBP may be indicative of a new B-cell component involved in the pathogenesis of EAE.

Animals↗

PubMed1985

Specificity of T lymphocyte lines for peptides of myelin basic protein.

T lymphocyte lines specific for myelin basic protein (BP) can mediate experimental autoimmune encephalomyelitis (EAE), or can protect against the active induction of the disease. To investigate the antigenic fine specificity of guinea pig (GP) BP-specific T cell lines raised from different rat strains, and to determine whether functionally different T lymphocyte lines and clones recognized the same or different regions of the BP molecule, the proliferation responses of line cells were assessed after stimulation with purified peptides of GP-BP. Lewis rat T cell lines and clones selected for responses to whole GP-BP responded selectively to the 68-88 amino acid sequence of GP-BP, but not to the 1-37, 43-67, or 89-169 sequences. The region of GP-BP recognized by Lewis T cells was additionally defined to include the 75-80 amino acid sequence, because a T cell clone responded equally to GP and rat BP which differed by only one amino acid at position 79, but did not respond to human or bovine BP, which had a Gly-His insertion in this region. T lymphocyte lines derived from the F344 and PVG (Weizmann) rat strains shared the same selective response to peptide 68-88, but lines from BN rats responded to an epitope(s) outside of the 68-88 sequence. The functional capacity of the various T cell lines to mediate experimental autoimmune encephalomyelitis (EAE) or to induce resistance against EAE was independent of their specificity for the different GP-BP peptides; lines specific for epitope(s) within or excluded from the 68-88 sequence could be encephalitogenic depending on their strain of origin, and various lines specific for the 68-88 peptide could induce both disease and protection, disease only, or neither activity.

Animals↗

PubMed1986

Biological activity of region 65-102 of the myelin basic protein.

Region 65-102 of the myelin basic protein (MBP) houses a number of antigenic determinants known to induce delayed-type hypersensitivity, experimental allergic encephalomyelitis (EAE), suppressor cell function, and antibodies. In this report we describe the biological activity of synthetic peptides S53, S55, and S49 with sequence homology to region 69-84 of the rat, guinea pig, and bovine MBP. Peptide S53-A, defined by residues 75-84 of the guinea pig (SQRSQDEN) and of the rat (SQRTQDEN) MBP induced clinical signs of disease in Lewis rats. These included weight loss, flaccid tail, "muscle wasting," and hind-leg weakness. Histological examination of brain, spinal cord, and sciatic nerve sections of diseased rats revealed the complete absence of focal and perivascular lymphocytic infiltrates characteristics of demyelinating EAE lesions. Elongation of peptide S53 by three or six residues to residue sequences naturally found at its N-terminal end gave rise to peptides S55S (PQKSQRSQDEN) and S49S (GSLPQKSQRSDQDEN), respectively. Lewis rats challenged with either S55S or S49S developed classical clinical and histological signs of EAE. Severe hind-leg paralysis was accompanied by incontinence and sometimes death. Injected in the form of carrier-free peptide, S53 was a meager B cell immunogen. S53 conjugated with methylated-bovine serum albumin was also a potent immunogen and produced clinical signs of disease without CNS pathology. By comparison, carrier-free S55S and S49S were potent immunogens giving rise to antibodies that cross reacted completely and competitively with S55S but considerably less so with S53. The results show that the sequence of S53 defines an epitope responsible for the formation of anti-S53 antibodies. Elongation of the S53 sequence at its N-terminal end generated an additional epitope which induced cell-mediated immunity responsible for the concomitant development of pathological signs of EAE. It may be concluded that the induction of classical signs of EAE requires specific and defined sequences capable of expressing both B cell and T cell functions.

Amino Acid Sequence↗

PubMed1995

Mice doubly deficient in the genes for P0 and myelin basic protein show that both proteins contribute to the formation of the major dense line in peripheral nerve myelin.

In search for the molecular mechanisms underlying the formation of the major dense line in peripheral nerve myelin we investigated mice deficient in the myelin proteins P0 and MBP. In mice lacking both molecules axons were enwrapped by myelin-like processes devoid of the major dense line, while mice deficient in either protein showed, respectively, partial and normal compaction. Mice heterozygous for P0 but devoid of MBP showed myelin of reduced thickness around axons of normal caliber. Both molecules thus contribute to the formation of the major dense line and to the determination of myelin thickness. Furthermore, our observations modify the view that axon caliber is dependent on normal myelin.

Animals↗

PubMed1981

Binding of bacterial endotoxin (LPS) to encephalitogenic myelin basic protein and modulation of characteristic biologic activities of LPS.

Myelin basic protein, isolated from central nervous system tissue and an inducer of experimental allergic encephalomyelitis in animals, has been demonstrated to form a stable molecular complex with the lipid A region of gram-negative bacterial lipopolysaccharides (endotoxins). This binding of endotoxin with myelin basic protein results in generation of lower m.w. aggregates with decreased isopycnic density. A number of lipid A-induced characteristic properties of endotoxin, such as B lymphocyte proliferative response in C3H/St mice, complement activation of normal human serum, Limulus lysate gelation, and lethal effects in mice, are modified as a result of binding of myelin basic protein with lipopolysaccharides.

Animals↗

PubMed2006

Cytokine-neuroantigen fusion proteins: new tools for modulation of myelin basic protein (MBP)-specific T cell responses in experimental autoimmune encephalomyelitis.

Fusion proteins incorporating anti-inflammatory cytokines and immunodominant self antigen as separate domains of a single protein may hold promise for development of antigen-specific tolerogenic vaccines. Proteins incorporating rat sequences of IL-1RA, IL-2, IL-4, IL-10, or IL-13 were expressed as fusion proteins containing the major encephalitogenic region of myelin basic protein (MBP). These fusion proteins were expressed via baculovirus (bv) expression systems and were shown to have cytokine-dependent and antigen-specific biological activity. In the case of the IL-2 and IL-4 fusion proteins, covalent linkage of the cytokine and neuroantigen domains resulted in synergistic antigen presentation. These data indicate that the cytokine domain may be able to modulate APC activity and simultaneously target the covalently tethered NAg for enhanced presentation by certain APC subsets. Cytokine/antigen fusion proteins may represent a novel tool for antigen-specific immune modulation in autoimmune disease.

Amino Acid Sequence↗

PubMed1986

Acid endopeptidase activity of human myelin, elicited by using exogenous myelin basic protein as enzyme substrate.

Purified human myelin was incubated with exogenous myelin basic protein (MBP) at pH 4.0 to see if there is acid proteinase activity associated with myelin. Following incubation for 12 h up to 70% of MBP was degraded. On electrophoresis peptide fragments of MBP between 15.8 and 9.4 kDa were consistent with an endopeptic cleavage of MBP. Unlike the exogenous substrate MBP associated with myelin was only slightly degraded under the experimental conditions used. The results show that proteinase activity associated with isolated myelin may be elicited and further evaluated by using MBP as enzyme substrate.

Aspartic Acid Endopeptidases↗

PubMed1977

The secondary structure of myelin basic protein extracted by deoxycholate.

Because of the implication of myelin basic protein in some neurological diseases its in vivo structure is of particular interest. The protein is usually isolated using organic solvents and acid solutions and has previously been shown to contain little alpha-helical or beta-structure; but it is not known how the extraction methods influence the structure. Following recent observations that deoxycholate generally causes minimal structural perturbation when used to dissolve membrane proteins, this detergent has been used to extract the basic protein from bovine myelin. The protein contained in deoxycholate washes of myelin has been purified by gel chromatography and its secondary structure examined by circular dichroism spectroscopy. This protein and conventionally prepared bovine and human basic protein to which 1% deoxycholate has been added appear to have the same structure: they contain 8-14% more helical structure than the chloroform/methanol-extracted protein in pH 4.8 acetate buffer or in pH 9.15 Tris buffer. This conformational change is unaffected by addition of 0.25 M NaCl. The helical content will approach the upper limit if, as is expected, these ordered segments are short. It is suggested that basic protein may adopt this more ordered structure in myelin and possess activity not apparent in its water-soluble unordered conformation. Retention of its encephalitogenic activity following severe treatment may result from an ability to rapidly refold to the original conformation rather than from this activity being inherent in the unordered form.

Animals↗

PubMed2002

Protein kinase C inhibitors counteract the ethanol effects on myelin basic protein expression in differentiating CG-4 oligodendrocytes.

Abnormal formation of myelin appears to be one defect contributing to the development of the neuropathology associated with the fetal alcohol syndrome. Using the CG-4 cell line we previously showed that 25-75 mM EtOH downregulates the expression of myelin basic protein (MBP) in differentiating oligodendrocytes (OLGs) without affecting morphological development (Dev. Brain Res. 128 (2001) 9). Here we showed that a relatively low concentration of 12-phorbol-13-myristate acetate (PMA) mimicked the EtOH-caused inhibition of MBP expression without affecting morphology. The inhibition of MBP expression by 100 mM EtOH or 1 nM PMA was completely counteracted by three inhibitors of protein kinase C (PKC), bisindolylmaleimide I, chelerythrine chloride, and calphostin C, indicating that EtOH downregulated MBP expression by activating PKC. We investigated whether the EtOH activation resulted, in part, from upregulation of the expression of PKC isozymes. Of 11 PKC isozymes examined, CG-4 OLGs expressed nine; PKCs alpha, beta1, beta2; delta, epsilon, eta; lambda, zeta; mu; while PKC isozymes gamma and theta were not detected. Only five PKC isozymes, alpha, beta1, beta2, eta, and mu, displayed developmental changes in expression. However, EtOH did not upregulate the early expression of any PKC isozyme during the first 2 days of differentiation, the developmental stage when it downregulates MBP expression in CG-4 cells. The similar effects of PMA and EtOH indicate that EtOH delays MBP expression by activating at least one phorbol ester-sensitive PKC isozyme in oligodendrocytes without upregulating its expression.

Cell Differentiation↗

PubMed1988

Fluorescence spectral resolution of myelin basic protein conformers in complexes with lysophosphatidylcholine.

The structure of (Deibler) myelin basic protein in solution and in a lysolecithin++ lipid complex has been studied by using the emission properties of the single tryptophan residue of the protein (Trp-115). The studies have been carried out using both static and time-resolved fluorescence techniques. Relative to the free protein, the lipid bound myelin basic protein showed a twofold increase in fluorescence intensity and a marked blue-shift in the emission maximum wavelength. The multiexponential fluorescence decays and the decay associated spectra indicated that the protein exists in at least three different conformations both in buffer and in lipids. Fluorescence polarization and acrylamide quenching experiments showed that the tryptophan containing region of the protein is embedded in the lipid matrix. The binding of the protein to the lipid appears to be comparable with that predicted for the interaction of amphipathic helices with nonpolar lipids.

Animals↗

PubMed1986

The role of myelin lipids in experimental allergic encephalomyelitis. Part 2. Influence on disease production by encephalitogenic doses of myelin basic protein.

Hartley guinea pig CNS myelin lipids (TL) were combined with an encephalitogenic dose (50 micrograms) of myelin basic protein (MBP) and injected together with complete Freund's adjuvant (CFA) into juvenile strain 13 guinea pigs. All the animals developed acute EAE and recovered, but only 50% had a single mild relapse during an observation period of 12 months. To determine the effect of individual myelin lipids on EAE, purified fractions comprising the galactocerebrosides (GC) or gangliosides (GANG) were combined with 50 micrograms MBP together with phosphatidyl choline (PC) and cholesterol (CHOL) and injected with CFA into juvenile Hartley guinea pigs. Control animals received MBP mixed with PC and CHOL or MBP alone, in CFA. The incidence of acute EAE was similar in all groups, but the highest percent recovery (69%) was seen in animals immunized with the MBP-GC combination. All animals that developed acute EAE in the control groups died. Histologically, CNS myelin breakdown was present during the acute attack except in the MBP control group. Parameters of cell-mediated immunity (CMI) showed good correlation with the clinicopathological findings in animals that received MBP-GC or MBP alone. In most animals, serum anti-MBP antibodies were detected as early as 10 days post-immunization (p.i.) whereas anti-lipid antibodies were found at 90 days p.i. Animals that received MBP-PC did not show any positive CMI or serum antibodies although they developed severe disease. The results indicate that myelin lipids, especially the galactocerebrosides, contribute to the development of chronic EAE; however, the mechanism by which this occurs is still obscure.

Animals↗

PubMed1989

Semple rabies vaccine: presence of myelin basic protein and proteolipid protein and its activity in experimental allergic encephalomyelitis.

Myelin basic protein (MBP) as a cause of postvaccinal encephalomyelitis (PVE) due to Semple rabies vaccine (SRV) has been suggested in previous reports. No actual measurement of MBP in SRV was done. In this study we detected MBP and PLP in the vaccine using immunological methods. The vaccine was found to contain 28 micrograms MBP per ml vaccine. Inoculation with SRV plus adjuvant resulted in the development of experimental allergic encephalomyelitis (EAE) in 2 of 3 guinea pigs. For control, chick embryo vaccine (CEV) was used and MBP was not detected. EAE was not induced in animals inoculated with it. These results suggest that MBP in vaccines may play a decisive role in the production of PVE.

Animals↗

PubMed2002

Identification of Golli and myelin basic proteins in human brain during early development.

The myelin basic protein gene (Mbp) encodes for the major myelin structural proteins and it is included in the Golli-Mbp gene complex. Previously, we observed MBP-like proteins in the human central nervous system (CNS) at developmental stages preceding myelination. In an effort to distinguish between Golli (HOG5 and HOG7) and MBP mRNAs and to determine their spatiotemporal distribution, we performed in situ hybridization using two human Golli specific probes: one corresponding to exon 5a absent from all MBP transcripts, and the other corresponding to exon 5c specific for HOG5. HOG7 transcript was observed first, in 5 gestational week-old embryos, whereas both Golli transcripts were detected at 6-7 weeks gestation in the proliferative zones of the entire CNS. Golli proteins immunoreactivity was observed in microglia and early neurons of the developing telencephalon. During midgestation (17-22 weeks gestation), at the onset of myelination, MBP and Golli mRNAs were observed in the telencephalic subventricular zone and occasionally in the future cerebral cortex. Developmental expression of the human Golli-Mbp indicates that the two Golli proteins have different onset of expression, distribution and possibly function. These results support the hypothesis that at least one of them, HOG7, may be involved in the regulation of early neurogenesis, while both may have additional, still undefined function at the onset of myelination.

Brain↗

PubMed1984

Immunochemical cross-reactivity between intact purified myelin basic protein (MBP) and the synthetic encephalitogenic peptide S49.

Three antisera to myelin basic protein--a rabbit antiserum pool against rat myelin, a rabbit antiserum pool against rat myelin basic protein (MBP), and a monkey antiserum against bovine MBP--were found to contain detectable levels of antibodies that would bind radiolabeled S49 (GSLPQKAQRPQDENG). Strongly encephalitogenic in Lewis rat, S49 is a synthetic peptide representing residues 69-84 of bovine MBP with a deletion of glycine-76 and histidine-77 to make it analogous to rat and guinea pig MBPs. The rabbit antimyelin antiserum and the monkey anti-MBP antiserum contained antibodies directed against a non-sequential determinant that required asparagine 84, the glycine-histidine deletion, and residues 69-71 for maximal activity. S49-reactive antibodies from the rabbit anti-MBP antiserum were directed solely against a sequential determinant comprising residues 69-71, S49-reactive antibodies from all three antisera reacted in liquid phase with purified intact rat, guinea pig, and bovine MBP showing that the determinant is exposed for B cell recognition even in bovine MBP and can serve both as immunogen and reactant.

Amino Acid Sequence↗