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PubMed2005

Immunodetection of anti-MAG IgM antibody by cross-reactivity to LA-N-1 neuroblastoma cells.

Demyelinating polyneuropathiy associated with IgM paraproteinemia and high titers of anti-MAG IgM antibodies (MAG-PN) is considered different from chronic inflammatory demyelinating polyneuropathy, particularly because of the poorer response to treatment of MAG-PN patients. Therefore, anti-MAG anitbodies may have relevant prognostic value. Available anti-MAG antibody assays require central nervous system myelin proteins from autopsied human brains. This study investigated the feasibility of detecting anti-MAG antibody by immunofluorescence and flow cytometry using a panel of human neuroblastoma cell lines as targets. We report here on the evaluation of the LA-N-1 cell line as an appropriate substrate for the detection of anti-MAG antibody by indirect immunoflourescence.

Adult↗
PubMed1997

Increased number of unmyelinated axons in optic nerves of adult mice deficient in the myelin-associated glycoprotein (MAG).

We have recently demonstrated that the formation of myelin sheaths in the optic nerve of young postnatal mice deficient in the myelin-associated glycoprotein (MAG) is retarded when compared to age-matched wild-type mice. In the present study, we analyzed whether impaired myelination of retinal ganglion cell axons is detectable in adult MAG mutants. In optic nerves of 2- and 9-month-old MAG-deficient mice, we observed a significantly increased number of unmyelinated axons compared to age-matched wild-type mice. At both ages, unmyelinated axons in optic nerves of MAG mutants were of small caliber. The number of unmyelinated axons decreased significantly in 9-month-old MAG mutants when compared to 2-month-old MAG mutants, indicative of a slow and long-lasting myelination of axons in the mutant. Our observations support the view that MAG is involved in the initiation of myelination in the CNS.

Animals↗
PubMed1999

Variability in the binding of anti-MAG and anti-SGPG antibodies to target antigens in demyelinating neuropathy and IgM paraproteinemia.

Densitometry of immunostained Western blots or thin layer chromatograms and enzyme-linked immunosorbent assays (ELISAs) were used to compare the relative strengths of IgM binding to myelin-associated glycoprotein (MAG), P0 glycoprotein, peripheral myelin protein-22 (PMP-22), sulfate-3-glucuronyl paragloboside (SGPG), and other potential target antigens in a series of eleven patients with sensory or sensorimotor demyelinating neuropathy and IgM paraproteinemia. The IgM from all patients exhibited reactivity with both MAG and SGPG, and there was a statistically significant correlation between the overlay assays and ELISAs for measuring the strength of IgM binding to MAG and to SGPG. However, the data revealed variations in the relative strengths with which the antibodies bound to the potential target antigens and heterogeneity in their fine specificities. First, there was a poor correlation between the strength of binding to MAG and to SGPG, respectively. Second, reactivity with MAG or SGPG in a few of the patients was only detected by one of the two assay systems. Third, about one-third of the patients' IgM absolutely required the sulfate on SGPG for reactivity, whereas the others retained some reactivity after removal of the sulfate. Fourth, IgM from two of the patients exhibited unusually strong reactivity with the proteins of compact myelin, P0 and PMP22. These relative differences in strengths of antibody binding to the potential antigens were compared with the patients' clinical presentations and with their responses to intravenous immunoglobulin (IVIg) therapy in a clinical trial in which they participated. For the most part, these variations did not correlate with clinical presentation, which was relatively homogeneous in this series of patients. However, an inverse relationship was noted between degree of reactivity to MAG by ELISA and response to IVIg. Two of the patients who responded had only mild elevations of IgM antibodies to nerve glycoconjugates and exhibited some unusual immunochemical and clinical characteristics in comparison to the other patients. The results demonstrate differences in the relative strengths with which anti-MAG and anti-SGPG IgM antibodies from different patients bind to potential neural target antigens which may affect pathogenic mechanisms and response to therapy.

Aged↗
PubMed1998

Differential expression of the L- and S-isoforms of myelin associated glycoprotein (MAG) in oligodendrocyte unit phenotypes in the adult rat anterior medullary velum.

We have previously demonstrated differences in the expression of carbonic anhydrase II (CAII) in oligodendrocyte units myelinating small and large diameter fibres in the anterior medullary velum (AMV) of the adult rat (each unit comprises the cell body, processes and myelin sheaths). Others have indicated that myelin composition may also vary with respect to myelin basic protein (MBP) and proteolipid protein (PLP), and the small (S)- and large (L)-isoforms of myelin associated glycoprotein (MAG). In this study, we have determined the expression of myelin proteins in oligodendrocyte unit phenotypes I-IV, which myelinate fibres ranging in diameter from 0.3-12 microns diameter in the AMV, by using double immunolabelling for Rip, which labels entire units, and MBP, PLP, myelin oligodendrocyte glycoprotein (MOG), L-MAG and S-MAG. We show differences in the expression of L- and S-MAG in units which myelinate different diameter fibres: (1) type I/II units myelinating small diameter fibres had a L-MAG+/S-MAG-/CAII+ phenotype; (2) type II/III units myelinating different diameter fibres had a L-MAG+/S-MAG+/CAII+ phenotype; (3) type III/IV units myelinated large diameter fibres had a L-MAG+/S-MAG+/CAII- phenotype. All units, irrespective of fibre diameter, expressed Rip, MBP, PLP and MOG. The results indicate that type I-IV units may be variants of a single oligodendrocyte population and that phenotypic differences are determined by the diameter of fibres within the unit. The possible significance of metabolic and biochemical differences between oligodendrocytes myelinating small and large diameter axons are discussed with reference to the pathology of demyelination.

Age Factors↗
PubMed1999

Antisense oligodeoxynucleotides targeted to MAG mRNA profoundly alter BP and PLP mRNA expression in differentiating oligodendrocytes: a caution.

The applicability of antisense technology to suppress the expression of myelin associated glycoprotein (MAG) in cultured oligodendrocytes was evaluated. Differentiating oligodendrocyte precursor cells obtained by the shake-off method were exposed to nine unmodified antisense oligodeoxynucleotides (ODNs) targeted to the first seven exons of MAG mRNA. After four days, steady-state levels of MAG, proteolipid protein (PLP) and basic protein (BP) mRNAs were determined by Northern blot analysis. Only ODN annealing to 599-618 nt of the MAG mRNA (the junction of exon 5 and 6) resulted in a significant, 75% decrease in the MAG mRNA level. Unexpectedly, six other anti-MAG ODNs which had no significant effect on the MAG message, greatly increased the level of BP mRNA. The highest upregulation of approximately 12 fold was observed with ODN annealing to 139-168 nt (junction of exon 3 and 4). On the other hand, the 997-1016 ODN decreased the levels of BP and PLP messages by 70-80%. The 599-618 ODN also decreased the PLP mRNA by 85%. The results demonstrate that antisense ODNs targeted to one gene may profoundly alter the expression of other genes, and hence, complicate functional analysis of the targeted protein.

Animals↗
PubMed2002

Multiple MAG peptides are recognized by circulating T and B lymphocytes in polyneuropathy and multiple sclerosis.

Abnormal immune responses to myelin associated glycoprotein (MAG), a component of myelin of the central and peripheral nervous system, have been suggested to play a role in the pathogenesis of multiple sclerosis (MS) and certain types of inflammatory polyneuropathy. To identify possible immunodominant MAG peptides in neuroinflammation, we examined T and B cell responses to five selected synthetic MAG peptides and myelin proteins in 21 patients with non-inflammatory polyneuropathy, 26 patients with MS, 10 optic neuritis patients and 17 healthy subjects. Enzyme-linked immunosorbent spot-forming cell assays were adopted, allowing the detection and enumeration of individual antigen responsive T and B cells in body fluids. Patients with polyneuropathy as well as those with MS had elevated levels of T and B cells recognizing MAG and its peptides. Any of the five MAG peptides under study functioned as immunodominant T and/or B cell epitope in individual subjects. None of the MAG peptides elicited a specific disease-associated T or B cell response. The enhanced T and B cell response to myelin components like MAG may play some role in initiation and/or progression of these diseases, but they could also represent secondary responses associated with myelin damage and indicate tolerization rather than autoaggressive immunity.

Adult↗
PubMed1991

Cells secreting anti-MAG antibody occur in cerebrospinal fluid and bone marrow in patients with polyneuropathy associated with M component.

Occurrence and distribution of cells secreting antibodies against myelin associated glycoprotein (MAG) were studied in 9 patients with polyneuropathy associated with the monoclonal (M) component in serum. Utilizing an immunospot assay, we found that 4 of 7 patients with polyneuropathy associated with an IgM M component had cells secreting anti-MAG IgM antibody in cerebrospinal fluid (CSF) numbering between 1 per 212 and 1 per 3333 mononuclear cells. All 7 patients had cells secreting anti-MAG IgM antibody in bone marrow (median value 1 per 2000 cells). In contrast, peripheral blood from only 2 of these patients contained low numbers of such cells. One patient with polyneuropathy associated with an IgA M component had cells secreting anti-MAG IgA antibody in CSF, and 1 with an IgG M component had cells secreting anti-MAG IgG antibody in CSF; both patients also had anti-MAG IgM antibodies detectable in CSF only by ELISA. These 2 patients may thus have concurrent intrathecal production of antibodies of 2 different isotypes which are directed against the same or different epitopes of MAG. The production of antibodies directed against a component of myelin occurring in the immediate vicinity of the peripheral nervous system might be involved in the pathogenesis of the polyneuropathy.

Adult↗
PubMed1995

Experimental induction of myelin changes by anti-MAG antibodies and terminal complement complex.

We investigated the role of anti-myelin-associated glycoprotein (MAG) IgM and complement (C) in the pathogenesis of myelin alterations occurring in patients with anti-MAG-associated polyneuropathy. For this purpose, we separately studied the effects of anti-MAG antibodies and terminal C complex (TCC) after injection into the rabbit sciatic nerve. The two different local treatments produced identical ultrastructural abnormalities such as intramyelinic edema, myelin vesiculation and, in particular, separation of the major dense lines with the formation of widely spaced myelin, a peculiar feature encountered in human peripheral nerve disorders with circulating anti-myelin monoclonal IgM. In nerves treated with anti-MAG IgM ultrastructural myelin alterations were concurrent with activation of the rabbit's own C to the formation of TCC. Contrary to the immunological and ultrastructural findings obtained in C-sufficient animals, in C6-deficient rabbits injected with anti-MAG IgM no myelin alterations nor C completion were observed. This study identifies anti-MAG IgM as the mediator and the C as the effector of myelin changes observed in the present model and, for extension, in human neuropathies associated with anti-MAG IgM.

Animals↗
PubMed1985

Experimental autoimmunity to rat male accessory glands (MAG): circulating antibodies, immunoglobulins bound to target glands, and immunoglobulins-secreting cells.

A correlation between spleen B-cell antibody production against MAG antigens and the presence of different antibodies in circulation or antibodies bound to target glands was attempted. The number of 7S and 19S Ig-secreting cells (ISC) found in the spleen and the number of ISC generated after in vitro stimulation of the cells with MAG antigens were evaluated by using the hemolytic plaque assay. Low numbers of 7S and 19S ISC--less than 0.01% of spleen cells--were generated in response to MAG immunization, and no significative increase was observed after in vitro culture of spleen cells with MAG antigens, suggesting that secretory activity of the B-cells can not be improved when liberated from humoral homeostatic mechanisms. The humoral response of MAG-immunized rats, investigated by complement fixation and immunodiffusion assays, has proved negative, and in only two out of 17 rats a weak haemagglutinating activity was observed. Attempts to detect antibodies bound to cellular MAG antigens by immunofluorescence have shown a weak fluorescence in the epithelial cells of the prostate gland in only two rats. In both cases a concomitant tissue damage was observed, but in nine out of 11 cases with histological alterations no fluorescence was observed in the target glands. The medium value of rosette-forming cells (RFC) found in the spleen of MAG-immunized rats did not significantly differ from the value of the HSA-treated control group, although both groups differ in their specific humoral response.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2006

SENSE or k-MAG to accelerate free breathing navigator-guided coronary MR angiography.

OBJECTIVE: The purpose of this study was to assess the relative merits of reducing the scanning time of navigator-guided (NAV) coronary MR angiography by including, both independently and in combination, two time-saving strategies: k-space weighted motion-adapted gating (k-MAG) and sensitivity encoding (SENSE, factor = 2). SUBJECTS AND METHODS: Coronary arteries of 21 healthy subjects were imaged with four NAV MR angiography sequences: conventional NAV sequence, NAV with the addition of SENSE, NAV with the addition of k-MAG, and NAV with a combination of SENSE and k-MAG. All imaging parameters including the magnetization preparation schemes, prescribed spatial resolution, and acquisition duration per R-R interval were identical for all techniques. The total scanning time, navigator efficiency, visible length of the coronary artery, and subjective image quality were used as metrics for evaluating the performance of the techniques. RESULTS: The results show that the addition of k-MAG to NAV coronary MR angiography (with or without SENSE) improved scan efficiency and decreased scanning time by an average of 17% without compromising the length of coronary artery visible or the image quality. The addition of SENSE to the NAV technique (with or without k-MAG) reduces the scanning time by an average of 50%. CONCLUSION: While the average image quality of coronary arteries was unaffected by the addition of k-MAG to navigator techniques, there was a slight reduction in image quality scores for the navigator sequence with SENSE. Identification of the proximal coronary arteries was not hampered by the addition of k-MAG, SENSE, or both to the NAV coronary MR angiography sequence.

Adult↗
PubMed1986

Myelin-associated glycoprotein (MAG) in the CNS of adult shiverer (Shi/Shi) mice.

Brain fractions of adult control (+/+) and shiverer (Shi/Shi) mice were investigated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) and immunoblotting. Immunostaining with specific antisera against rat brain myelin-associated glycoprotein (MAG) was detected at about the 96-kD region of gels in electrophoresed samples of the total homogenate, low-speed supernatant fraction, and low- and high-speed sedimentable portions of brain from +/+ mice. Reduced immunostaining was observed in the corresponding samples of brain fractions from Shi/Shi mice. The cerebrum, cerebellum, and medulla of +/+ and Shi/Shi mice were examined immunocytochemically for MAG on paraffin-embedded sections. Periaxonal immunostaining for MAG was observed in all the regions and the highest concentrations were in the corpus callosum, in the central cores of cerebellar folia, and in the medulla. Patterns of distribution were similar in +/+ and Shi/Shi mice, although the density of immunostaining around individual axons and the number of immunostained axons were significantly reduced in Shi/Shi mice. In addition, the three brain regions of Shi/Shi mice exhibited oligodendrocyte-like cells that contained immunostaining for MAG in the cytoplasm and periphery of their perikarya. This type of immunostained cell was not observed in +/+ mice. In this study, immunoblotting with brain fractions and immunocytochemistry revealed strong evidence for reduced concentrations of MAG in the CNS of Shi/Shi mice compared to control mice. In addition, there is immunocytochemical evidence for abnormal accumulation of MAG in perikarya of oligodendroglial-like cells, suggesting the possibility of a transport block for myelin proteins in the shiverer mutant.

Animals↗
PubMed1995

Motor conduction parameters in neuropathies associated with anti-MAG antibodies and other types of demyelinating and axonal neuropathies.

We measured residual latency (RL), motor conduction velocity (MCV), and terminal latency index (TLI) in 15 patients with neuropathy and anti-MAG or SGPG antibodies and compared these to values obtained in 103 patients with other types of polyneuropathy (PN) and to 57 normal subjects. Ten patients had anti-MAG antibody titers of 25,600 or higher, and 5 had titers between 800 and 12,600. Patients with the highest titers had longer RL, slower MCV and shorter TLI than those with lower titers, acute or chronic inflammatory demyelinating PN, hereditary neuropathy, and metabolic or axonal neuropathy. In contrast F-wave latencies did not contribute to the differentiation between the groups of demyelinating neuropathies. RL and TLI correlated best with anti-MAG antibody titers, whereas there was a poor correlation with anti-SGPG titers suggesting that MAG more than SGPG may be the antigen in PN, and that the distal nerves are affected more than their proximal segments. The RL rather than TLI turned out to be the best variable to classify the demyelinating type of anti-MAG neuropathy. Sural nerve biopsy in 5 of the patients with the highest titer of anti-MAG antibodies showed deposits of IgM and C3 on the myelin sheaths, pronounced demyelination and widening of the myelin lamellae. In 4 of the patients with lower titers demyelination was absent or less pronounced.

Acute Disease↗
PubMed1986

Renal and extrarenal handling of a new imaging compound (99m-Tc-MAG-3) in the rat.

We investigated the renal clearance, the extrarenal clearance, the biodistribution, the plasma extraction ratio and the imaging quality on a scintillation camera of a new substance: 99mTc-mercaptoacetyltriglycine (MAG-3) in rats. Simultaneously 125I-hippurate (OIH) and 51Cr-EDTA were used as reference substances. In scintillation camera studies, 123I-hippurate served as reference. MAG-3 was prepared by kit labelling without further purification, as it would be used in clinical studies. However in three separate rats, HPLC purified MAG-3 was used. High renal clearance and extraction ratio was found but these were less than that for OIH (1.95 ml/min per 100 g BW vs 2.76 ml/min per 100 g BW and 64% vs 85% respectively). The extrarenal clearance was higher for MAG-3 than for OIH (0.20 ml/min per 100 g BW vs 0.04 ml/min per 100 g BW), presumably because of bile excretion. HPLC purification increased the renal excretion of MAG-3: the clearance was 2.53 ml/min per 100 g BW, the extraction fraction 75%, but the extrarenal clearance was unchanged. The imaging quality was comparable to that of 123I-hippurate in early pictures, but extrarenal activity, presumably representing bile, was observed in late pictures. We conclude that MAG-3 has some potential for the replacement of OIH but clinical studies are necessary to test whether the same conditions and limitations exist in humans.

Animals↗
PubMed2005

Preparation, radiochemical purity control and stability of 99mTc-mertiatide (Mag-3).

BACKGROUND: Scintigraphic image analysis of 99mTc-mertiatide (Mag-3, mercaptoacetyltriglycine) clearance provides the determination of the blood flow, the tubular transit time and the excretion as well from both kidneys. Radiopharmaceutical routine recommends a radiochemical purity control before administration of the product to a patient. The main objective of this study is to develop a Mag-3 labeling procedure that fits better than the previous one in our daily routine production of radiopharmaceuticals. METHODS: Increasing proportions of 99mTc-Mag-3 were measured during the heating and cooling steps of the Mag-3 labeling procedure. HPLC analysis was used to confirm the results of a rapid radiochemical quality control assay on standard ITLC-SG paper. RESULTS: The reconstitution time takes 20-25 minutes from the harvest of pertechnetate to a ready-for-use calibrated patient syringe. The HPLC profile of 99mTc-Mag-3 including its minor impurities remains unchanged for 24-48 hours after reconstitution. CONCLUSIONS: The application of a programmable Peltier-directed device for heating/cooling provides a better control of the temperature course. The procedure proposed fully meets the labeling criteria recommended by the supplier and can be performed with a minimum of attention within a time-span that we formerly needed for solely the radiochemical purity control assay. Moreover, 99mTc-Mag-3 prepared in this way seems to be considerably more stable than mentioned in the manufacturer's instructions.

Chromatography↗
PubMed2006

Unraveling the differential expression of the two isoforms of myelin-associated glycoprotein in a mouse expressing GFP-tagged S-MAG specifically regulated and targeted into the different myelin compartments.

The two myelin-associated glycoprotein (MAG) isoforms are cell adhesion molecules that differ only in their cytoplasmic domains, but their specific roles are not well understood. In this study, we present a transgenic mouse line that specifically expresses GFP-tagged S-MAG correctly regulated and targeted into the myelin sheath allowing the specific discrimination of L- and S-MAG on the subcellular level. Here, we describe the differential expression pattern and spatial distribution of L- and S-MAG during development as well as in the adult central and peripheral nervous system. In peripheral nerves, where S-MAG is the sole isoform, we observed S-MAG concentrated in different ring-like structures such as periaxonal and abaxonal rings, and discs spanning through the compact myelin sheath perpendicular to the axon. In summary, our data provide new insight in the subcellular distribution of the two isoforms fundamental for the understanding of their specific functions in myelin formation and maintenance.

Animals↗
PubMed2002

Encephalitogenic and immunogenic potential of myelin-associated glycoprotein (MAG), oligodendrocyte-specific glycoprotein (OSP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) in ABH and SJL mice.

Synthetic peptides of myelin-associated glycoprotein (MAG), oligodendrocyte-specific glycoprotein (OSP) and 2',3'-cyclic nucleotide 3'-phosphodiesterase (CNPase) were screened for their ability to induce experimental allergic encephalomyelitis (EAE) in ABH (H-2A(g7)) and SJL (H-2(s)) mice. The use of overlapping 16mer MAG peptides identified residues 97-112 as a T-cell and encephalitogenic epitope in ABH mice which induced clinical and histological signs of acute EAE. Immunization of SJL mice with MAG peptides failed to induce disease whereas immunization of SJL mice with synthetic peptides of OSP induced major T-cell responses to OSP 73-88 and 81-96. Another epitope, OSP 57-72, that induced EAE, failed to induce T-cell responses in mice immunised with peptides based on the whole sequence supporting a role for cryptic epitopes. In comparison, whilst immunization of ABH mice with OSP revealed two immunodominant T-cell epitopes (49-64 and 137-152), an encephalitogenic epitope was not identified. Similarly, immunization of both SJL and ABH mice with CNPase peptides induced T-cell responses to several epitopes. However, these were not encephalitogenic. This study is the first to identify an encephalitogenic epitope of MAG and immunodominant epitopes of MAG, OSP and CNPase in SJL and ABH mice. The ability of both cryptic and noncryptic peptide epitopes of these myelin antigens to initiate EAE suggests that mice at least are not tolerant to some regions of MAG and OSP and that such specific autoimmune responses may play an important role in the pathogenesis of immune-mediated neurological diseases such as multiple sclerosis.

2',3'-Cyclic-Nucleotide Phosphodiesterases↗
PubMed2000

S100beta inhibits the phosphorylation of the L-MAG cytoplasmic domain by PKA.

The myelin-associated glycoprotein (MAG) is a cell adhesion molecule expressed by myelinating glia, existing as two isoforms that differ only by their cytoplasmic domains. We have studied the in vitro phosphorylation of recombinant rat MAG cytoplasmic domains by three kinases for which consensus sequences exist within this domain, revealing phosphorylation of the L-MAG-specific domain by protein kinase A (PKA). Phosphorylation of the L-MAG cytoplasmic domain by PKA was decreased in the presence of S100beta, providing a functional significance to the interaction between L-MAG and S100beta, and further indicating that L-MAG may play a role in myelinating glial cell signalling processes.

Animals↗
PubMed1998

Expression of glycosylated recombinant human myelin-associated glycoprotein on a neuroblastoma cell line and its reactivity with HNK-1 but not human anti-MAG antibodies.

A correctly glycosylated myelin-associated glycoprotein (MAG) must express the carbohydrate epitope HNK-1, which is the target antigen for IgM antibodies in some patients with neuropathy. We transfected a human MAG cDNA clone into the neuroblastoma cell line SK-N-SH and verified by immunoblot the expression of the HNK-1 epitope on the recombinant molecule. By the same method and by indirect immunofluorescence we did not find any reactivity of human anti-MAG IgM antibodies with glycosylated recombinant MAG and transfected neuroblastoma cells. These findings suggest that the mere presence of the HNK-1 epitope is probably not sufficient for MAG to be recognized by human antibodies and that other factors such as the concentration or fine structure of this epitope in MAG, which mostly depend on the cellular context, may be also critical for this reactivity.

Antibodies↗