Disease relevance of Mbp

• Oral tolerance in myelin basic protein T-cell receptor transgenic mice: suppression of autoimmune encephalomyelitis and dose-dependent induction of regulatory cells [1].
• We have previously shown that orally administered myelin basic protein (MBP) suppresses experimental autoimmune encephalomyelitis in both the Lewis rat and the SJL mouse [2].
• Myelin basic protein-primed T cells of female but not male mice induce nitric-oxide synthase and proinflammatory cytokines in microglia: implications for gender bias in multiple sclerosis [3].
• Myelin basic protein (MBP) and proteolipid protein (PLP), the most abundant proteins of central nervous system (CNS) myelin, have been extensively studied as possible primary target antigens in multiple sclerosis (MS), a primary demyelinating autoimmune disease of the CNS [4].
• Selective expression of foreign genes in glioma cells: use of the mouse myelin basic protein gene promoter to direct toxic gene expression [5].

Psychiatry related information on Mbp

• Shiverer clearly showed deficits in successive reversal learning, while mld showed less deficits in the learning performance [6].

High impact information on Mbp

• We have generated TCR transgenic mice (T/R+) specific for myelin basic protein (MBP) and crossed them to RAG-1-deficient mice to obtain mice (T/R-) that have T cells expressing the transgenic TCR but no other lymphocytes [7].
• High incidence of spontaneous autoimmune encephalomyelitis in immunodeficient anti-myelin basic protein T cell receptor transgenic mice [7].
• We now show that viral persistence is also controlled by a locus close to Ifg on chromosome 10 and possibly by a locus near Mbp on chromosome 18 [8].
• Mice homozygous for the mutation myelin deficient (mld), an allele of shiverer, exhibit decreased CNS myelination, tremors, and convulsions of progressively increasing severity leading to an early death [9].
• Expression of a myelin basic protein gene in transgenic shiverer mice: correction of the dysmyelinating phenotype [10].

Chemical compound and disease context of Mbp

• Glatiramer acetate [copolymer 1 (Cop1)] is a synthetic copolymer designed to mimic MBP which suppresses EAE, is used parenterally to treat multiple sclerosis (MS) and is being tested orally for efficacy in MS [11].
• Passive immunization with T cells reactive to myelin basic protein or active immunization with myelin oligodendrocyte glycoprotein-derived peptide, although neuroprotective after optic nerve injury, was ineffective against glutamate toxicity in mice and rats [12].
• We demonstrate in two models of EAE that orally administered PPARgamma ligand pioglitazone reduced the incidence and severity of monophasic, chronic disease in C57BL/6 mice immunized with myelin oligodendrocyte glycoprotein peptide and of relapsing disease in B10.Pl mice immunized with myelin basic protein [13].
• Transcriptional activity of chimeric MOG- and myelin basic protein-luciferase genes was greater in CG4 cells than in 3T3 fibroblasts or C6 glioblastoma, demonstrating their superiority for functional analysis of myelin gene regulatory elements [14].
• Tumor necrosis factor modulates transcription of myelin basic protein gene through nuclear factor kappa B in a human oligodendroglioma cell line [15].

Biological context of Mbp

• Regulation of cytoskeleton by myelin components: studies on shiverer oligodendrocytes carrying an Mbp transgene [16].
• The present work demonstrates that these IL6RIL6-treated F10.9 cells undergo transdifferentiation to a myelinating glial phenotype characterized by induction of the transcriptional activities of both Po and MBP promoters and accumulation of myelin gene products [17].
• These results indicate that the jp, jpmsd, and qk mutations exhibit qualitatively similar phenotypic effects on MBP gene expression but the magnitude of the effect is proportional to the extent of hypomyelination in each mutant [18].
• Additionally, major histocompatibility complex (MHC) class I and class II mRNA levels were increased in the CNS of MBP/IFN-gamma transgenic mice, and the increase in MHC class I mRNA expression was detected in both white and gray matter regions [19].
• Thus, cytokine plasmid treatment appeared to inhibit MBP-specific pathogenic Thl responses, while enhancing endogenous secretion of protective cytokines [20].

Anatomical context of Mbp

• This suggests that an Mbp gene product may have an important role in regulating the organization and stability of the wild-type oligodendrocyte cytoskeleton [16].
• These results demonstrate that MBP-specific T cells can differentiate in vivo into encephalitogenic or regulatory T cells depending upon the context by which they are exposed to antigen [1].
• Because the presence of neuroantigen-primed T cells within the CNS is necessary for the development of MS, the present study was undertaken to investigate the activation of microglia by myelin basic protein (MBP)-primed T cells of male, female, and castrated male mice [3].
• Myelin basic protein (MBP) plays an essential adhesive role in the formation of compact myelin in the central nervous system (CNS), but not in the peripheral nervous system (PNS) [21].
• We recently demonstrated a predominant response to MOG by peripheral blood lymphocytes from patients with MS tested for their reactivity against various myelin antigens, including MBP and PLP [4].

Associations of Mbp with chemical compounds

• Doxycycline-regulated overexpression of C/EBP-delta was sufficient to induce accumulation of P0 and MBP mRNAs, the effect being selective, because C/EBP-delta did not affect several other genes strongly regulated by IL6RIL6 [22].
• Comparing the extent of total methylation in vivo (sum of all three arginine derivatives), MBP extracted from less-compact myelin (P3A and P3B) showed a level approx. 40% higher than that from compact myelin [23].
• By contrast, the concentrations of P0 glycoprotein and myelin basic proteins were reduced to 27% and 20% of control levels, respectively [24].
• MBPs isolated from dysmyelinating mutant mouse brains, such as jimpy (jp/y) and quaking (qk/qk), contained a much higher level of Me2(asym)Arg relative to the other two methyl derivatives and also in comparison with those levels in the mother brain MBP [23].
• The amounts of NG-methylarginine derivatives in myelin basic protein (MBP) purified from dysmyelinating mutant and different stages of normal myelinating mouse brains have been studied by using h.p.l.c. with a highly sensitive post-column o-phthaldialdehyde derivative-formation method [23].

Physical interactions of Mbp

• The murine Golli-MBP isoform J37 has also been shown to bind CaM in vitro, and an interaction site was predicted in the N-terminal Golli-specific portion of the protein [25].
• In addition, we show that the MBP 3'untranslated region (3'UTR) is necessary and sufficient for binding FMRP, and mediates translation inhibition of a reporter gene by FMRP specifically in oligodendrocytes [26].
• In contrast, surface anti-MOG-MOG complexes redistribute over internal myelin basic protein domains [27].
• These results suggest that ATF-2 coupled to specific signal transduction cascades plays an important regulatory role in MAG expression at a specific stage of shi/shi oligodendrocyte differentiation, and OPCs grow to become myelin-forming cells with numerous cell processes that wraps around an axon to form a thin myelin sheath [28].
• BACKGROUND: Soluble species-specific major histocompatibility complex myelin basic protein91-103 complexes ameliorate disease in a dose-dependent manner when administered to SJL/J mice with chronic relapsing experimental allergic encephalomyelitis [29].

Enzymatic interactions of Mbp

• Myelin-associated glycoprotein was seen periaxonally in both normal myelin sheaths and sheaths which showed extensive splitting and ballooning as seen with toluidine blue stain and myelin basic protein antiserum [30].
• In vitro, both RSK kinases and MBP kinase phosphorylated recombinant RSK and generated nearly identical two-dimensional tryptic phosphopeptide maps [31].
• Furthermore, in in vitro kinase assays, the Esk kinase was shown to phosphorylate both itself and the exogenous substrate myelin basic protein on serine, threonine, and tyrosine residues, confirming that the Esk kinase is a novel member of the serine/threonine/tyrosine family of protein kinases [32].
• IRAK-1 itself, an endogenous substrate with an apparent molecular weight of 24kDa (p24), and exogenous substrates like histone and myelin basic protein are phosphorylated by nuclear located IRAK-1 [33].
• Gelatinase B is present in the cerebrospinal fluid during experimental autoimmune encephalomyelitis and cleaves myelin basic protein [34].

Regulatory relationships of Mbp

• Pax3 repressed a 1.3 kb MBP promoter fragment in cotransfection assays, suggesting that it represses MBP transcription [35].
• In contrast to oral tolerization, s.c. immunization of transgenic animals with MBP in complete Freund's adjuvant induced IFN-gamma-secreting Th1 cells in vitro and experimental encephalomyelitis in vivo [1].
• Inhibition of female T cell contact-mediated microglial expression of proinflammatory molecules by dominant-negative mutants of p65 and C/EBPbeta suggest that female MBP-primed T cells induce microglial expression of proinflammatory molecules through the activation of NF-kappaB and C/EBPbeta [3].
• MBP mRNA levels remained well below control levels in jp/Y brain polyribosomes throughout early postnatal development [36].
• Our data suggest that incorporation of this MOBP isoform into shiverer myelin may be influenced by the presence of MBP or be a consequence of a disrupted MDL [37].

Other interactions of Mbp

• At monthly intervals after immunization with p139-151, responses to PLP 249-273, MBP 87-99, and PLP 137-198 were sequentially accumulated in al mice examined [38].
• An inverse correlation was observed between expression of Pax3 RNA and myelin basic protein (MBP) [35].
• Furthermore, the developmental change between the two molecular forms of MAG (p72MAG/p67MAG) was delayed in mld mice [39].
• However, the data suggest the presence of a peptide core between MBP 21-26 (HARHGF), which contains similar elements to the previously defined encephalitogenic MOG 1-22 and PLP 56-70 peptides [40].
• These studies suggest that microglial activation of C/EBPbeta but not NF-kappaB by T cell:microglial contact is a gender-specific event and that male MBP-primed T cells are not capable of inducing microglial expression of proinflammatory molecules due to their inability to induce the activation of C/EBPbeta in microglia [3].

Analytical, diagnostic and therapeutic context of Mbp

• In the present study, we investigated the cellular requirements for the generation of active suppression following oral administration of MBP in SJL and (PLJ x SJL)F1 mice [2].
• Total messenger RNA (mRNA) and myelin basic protein (MBP)-specific mRNA from brains of these three mutants have been analyzed by in vitro translation and immunoprecipitation with antibody to MBP [18].
• The MBP-related polypeptides that accumulate in vivo have also been analyzed in the three mutants by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by immunoblotting with antibody to MBP [18].
• However, MBP and PLP polypeptides could not be detected by western blot or immunocytochemical staining at either the permissive or nonpermissive temperature [41].
• In general, the MBP mRNA levels measured directly by Northern blot and "dot" blot analyses correlated well with the indirect in vitro translation measurements [36].

References