GM1 ganglioside inhibits amyloid beta-protein induced-cytokine release.
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Amyloid beta-Protein Precursor↗
Biomedical subjects
T Ariga
Publications and source records attributed to T Ariga.
Is IgG anti-GT1a antibody associated with pharyngeal-cervical-brachial weakness or oropharyngeal palsy in Guillain-Barré syndrome?
The pharyngeal-cervical-brachial variant (PCB) of Guillain-Barré syndrome (GBS) has clinical features similar to those of botulism and diphtheria. Mizoguchi et al. (1994) [Mizoguchi, K., Hase, A., Obi, T., Matsuoka, H., Takatsu, M., Nishimura, Y., Irie, F., Seyama, Y., Hirabayashi, Y., 1994. Two species of antiganglioside antibodies in a patient with a pharyngeal-cervical-brachial variant of Guillain-Barré syndrome. J. Neurol. Neurosurg. Psychiatry 57, 1121-1123] reported a patient with PCB-like symptoms who had serum IgG anti-GT1a antibodies which did not cross-react with GQ1b. We assumed that PCB is associated with anti-GT1a antibodies that do not have reactivity to GQ1b and made a serological study of a PCB patient. We searched for PCB patients prospectively and found one with PCB. This patient had IgG anti-GT1a antibodies which were not absorbed with GQ1b in an absorption study, whereas IgG anti-GT1a antibodies from Fisher's syndrome patients were. The frequency of positive IgG anti-GT1a antibody did not differ in patients with and without bulbar palsy. Our findings indicate that IgG anti-GT1a antibodies which do not cross-react with GQ1b are specifically detectable in PCB and can be used as a diagnostic marker of PCB.
Adult↗
Sulfoglucuronosyl glycolipids as putative antigens for autoimmune inner ear disease.
Autoimmune inner ear disease is diagnosed based on clinical history of fluctuating but progressive sensorineural hearing loss (SNHL) with or without vestibular symptoms occurring over weeks to months. An initial response to steroids or immunosuppressive drugs usually reverses the hearing loss. In search of specific diagnostic and therapeutic markers for autoimmune inner ear diseases, we investigated serum anti-glycolipid antibody activities in these patients by two different methods, HPTLC-immunoblotting and ELISA. We found that 37 out of 74 patients of clinically diagnosed autoimmune inner ear disease (30 of sensorineural hearing loss (SNHL) (group I), 14 of vestibular symptoms only (group II), 30 of Menieres symptoms (with both hearing loss and vestibular symptoms) (group III)) showed positive anti-sulfoglucuronosyl lactosaminyl paragloboside (SGLPG) antibody titers (p < 0.001). On the other hand, anti-sulfoglucuronosyl paragloboside (SGPG) titers were not elevated in these conditions. In contrast, only 3 out of 56 pathological control and 2 out of 28 healthy volunteers had measurable anti-SGLPG antibody titers. We further analyzed the localization of SGLPG in the auditory pathway and found that the antigens existed exclusively in inner ear and the eighth nerve, but not in pons, cerebellum, nor cerebrum. We conclude that the anti-SGLPG antibody represents a novel diagnostic marker for autoimmune inner ear disease and may participate in the pathogenesis of this disease.
Autoantibodies↗
Visible integration of the adenosine deaminase (ADA) gene into the recipient genome after gene therapy.
Gene therapy for patients with adenosine deaminase (ADA) deficiency has become practical in the 1990s, and the exogenous gene has been reported to survive for several years in the recipient genome. To evaluate the integration efficiency of the ADA gene (ADA) into peripheral blood lymphocytes (PBL) of a patient with ADA deficiency who is receiving gene therapy, we performed two-color interphase fluorescence in situ hybridization (FISH) analysis by using digoxigenin-labeled ADA-cDNA and the biotin-labeled lambda-genomic ADA clone as probes. After each of 9 sequential series of gene therapy, interphase nuclei of 100 mononuclear cells from the patient were analyzed, and those of a LASN-producing cell line were used as a control. FISH signals were detected with rhodamine and FITC for the cDNA and the genomic DNA, respectively. The number of PBL giving a transgene signal grew after the sequential gene therapies, and the proportion of signal-positive cells reached about 10%. Our results indicate that the two-color FISH system can be used as a potential aid to monitor the efficiency of the ADA gene therapy.
3T3 Cells↗
Successful peripheral T-lymphocyte-directed gene transfer for a patient with severe combined immune deficiency caused by adenosine deaminase deficiency.
Ten patients with adenosine deaminase deficiency (ADA-) have been enrolled in gene therapy clinical trials since the first patient was treated in September 1990. We describe a Japanese ADA- severe combined immune deficiency (SCID) patient who has received periodic infusions of genetically modified autologous T lymphocytes transduced with the human ADA cDNA containing retroviral vector LASN. The percentage of peripheral blood lymphocytes carrying the transduced ADA gene has remained stable at 10% to 20% during the 12 months since the fourth infusion. ADA enzyme activity in the patient's circulating T cells, which was only marginally detected before gene transfer, increased to levels comparable to those of a heterozygous carrier individual and was associated with increased T-lymphocyte counts and improvement of the patient's immune function. The results obtained in this trial are in agreement with previously published observations and support the usefulness of T lymphocyte-directed gene transfer in the treatment of ADA-SCID.
Adenosine Deaminase↗
Elevation of serum IgE level and peripheral eosinophil count during T lymphocyte-directed gene therapy for ADA deficiency: implication of Tc2-like cells after gene transduction procedure.
We have successfully carried out T-cell-directed gene therapy for a boy with severe combined immunodeficiency due to adenosine deaminase deficiency (ADA SCID) and unexpectedly found an elevation of serum IgE level and peripheral eosinophil count during the course. More than 90% of transduced cells cultured for 7-11 days before infusion into the patient were positive for CD8 and expressed Th2-type cytokine genes such as IL-4, IL-5 and IL-13. Furthermore, CD4(+) T-depleted PBMC (peripheral blood mononuclear cells) from the patient synthesized IgE in vitro by stimulation with IL-4. Collectively, these results suggested that Tc2-like cells in the transduced cells have distinct immunological functions to help IgE synthesis and activate eosinophils.
Adenosine Deaminase↗
The role of globo-series glycolipids in neuronal cell differentiation--a review.
Alterations in glycolipid composition as well as glycosyltransferase activities during cellular differentiation and growth have been well documented. However, the underlying mechanisms for the regulation of glycolipid expression remain obscure. One of the major obstacles has been the lack of a well defined model system for studying these phenomena. We have chosen PC12 pheochromocytoma cells as a model because (a) the properties of these cells have been well characterized, and (b) they respond to nerve growth factor (NGF) by differentiating into sympathetic-like neurons and are amenable to well-controlled experimentation. Thus, PC12 cells represent a suitable model for studying changes in glycolipid metabolism in relation to cellular differentiation. We have previously shown that subcloned PC12 cells accumulate a unique series of globo-series neutral glycolipids which are not expressed in parental PC12 cells. This unusual change in glycolipid distribution is accompanied by changes in the activities of specific glycosyltransferases involved in their synthesis and is correlated with neuritogenesis and/or cellular differentiation in this cell line. We have further demonstrated that changes in the glycosyltransferase activities may be modulated by the phosphorylation states of the cells via protein kinase systems. We conclude that these unique globo-series glycolipids may play a functional role in the initiation and/or maintenance of neurite outgrowth in PC12 cells.
Animals↗
Regulation of tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) gene expression in rat hepatocytes in primary culture.
We have performed a comparative study on tPA and PAI-1 mRNA expression in primary cultures of rat hepatocytes and elucidated the possible regulation of these factors by certain hormonal stimulation. The tPA mRNA increased 2- to 4-fold in the presence of cholera toxin (CT), dibutyryl cyclic AMP (dbcAMP), or 3-isobutyl-1-methyl xanthine (IBMX), but slightly decreased in the presence of dexamethasone. The tPA activity was also changed by these agents in a similar fashion. On the contrary, PAI-1 mRNA decreased with CT, dbcAMP, or IBMX, but increased transiently with dexamethasone. From results obtained with cycloheximide, ongoing protein synthesis was judged to be required for both PAI-1 induction with dexamethasone and PAI-1 suppression with IBMX, but not for the tPA induction with IBMX. Dexamethasone exerted opposite regulatory effects on the tPA mRNA expression depending on its concentration: at 10(-8) to 10(-6) M, it suppressed the expression; whereas at 10(-10) M, it elevated the expression.
1-Methyl-3-isobutylxanthine↗
Genetic analysis of 13 families with X-linked chronic granulomatous disease reveals a low proportion of sporadic patients and a high proportion of sporadic carriers.
X-linked chronic granulomatous disease (X-CGD) is the most common type of CGD, whose responsible gene has been identified and termed as CYBB, according to the gp91-phox, a subunit of cytochrome b558. Although approximately 200 different mutations of the gp91-phox gene have been reported, no precise study of the proportion of sporadic cases in X-CGD, based on molecular genetic analysis, has been reported. We made a genetic analysis of six newly identified X-CGD patients together with that of eight previously reported X-CGD patients. The mutations newly detected were three missense mutations, two splice mutations, and one insertion of 2 bases. All of the mutations were novel. Twelve mothers (two of them came from the same family) and four maternal grandmothers from 13 different X-CGD families were available for further genetic studies. It was revealed that a proportion of sporadic patients was low and that of sporadic carriers was high. These results suggest that the mutation for the disease originates mainly from male gametes.
Alternative Splicing↗
The view of Jehovah's Witnesses on blood substitutes.
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Attitude to Health↗
Role of sphingolipid-mediated cell death in neurodegenerative diseases.
The metazoan nervous system gives rise intradevelopmentally to many more neurons than ultimately survive in the adult. Such excess cells are eliminated through programmed cell death or apoptosis. As is true for cells of other lineages, neuronal survival is sustained by an array of growth factors, such that withdrawal of neurotrophic support results in apoptotic cell death. Apoptosis is therefore believed to represent a beneficial process essential to normal development of central and peripheral nervous system (CNS and PNS) structures. Although the initiation of neuronal apoptosis in response to numerous extracellular agents has been widely reported, the regulatory mechanisms underlying this mode of cell death remain incompletely understood. In recent years, the contribution of lipid-dependent signaling systems, such as the sphingomyelin pathway, to regulation of cell survival has received considerable attention, leading to the identification of lethal functions for the lipid effectors ceramide and sphingosine in both normal and pathophysiological conditions. Moreover, the apoptotic capacities of several cytotoxic receptor systems (e.g., CD120a, CD95) and many environmental stresses (e.g., ionizing radiation, heat-shock, oxidative stress) are now known to derive from the activation of multiple signaling cascades by ceramide or, under some circumstances, by sphingosine. Inappropriate initiation of apoptosis has been proposed to underlie the progressive neuronal attrition associated with various neurodegenerative diseases such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and other neurological disorders that are characterized by the gradual loss of specific populations of neurons. In such pathophysiological states, neuronal cell death can result in specific disorders of movement and diverse impairments of CNS and PNS function. In some autoimmune neurological diseases such as Guillain-Barré syndrome, demyelinating polyneuropathy, and motoneuron disease, persistent immunological attack of microvascular endothelial cells by glycolipid-directed autoantibodies may lead to extensive cellular damages, resulting in increased permeability across brain-nerve barrier (BNB) and/or blood-brain barrier (BBB).
Animals↗
[Study of T cell-directed gene transfer for a patient with ADA deficiency].
We have been undertaking the gene therapy for a 6 year-old boy with ADA deficiency and performed 11 cycles of the infusion of the peripheral T cells transduced with retroviral vector LASN since August 8th 1995. The percentage of the peripheral blood lymphocytes carrying the transduced ADA gene has remained stable at 10% to 20% since the 4th infusion. ADA enzyme activity in his circulating T cells increased to levels comparable to 1/3 of a heterozygous carrier individual and was associated with increased T lymphocytes counts and improvement in both humoral and cellular immune function. The results obtained in this clinical study support the usefulness of T lymphocyte-directed gene transfer in the treatment of ADA deficiency.
Adenosine Deaminase↗
Ganglioside GD3 and GD3-lactone mediated regulation of the intermolecular organization in mixed monolayers with dipalmitoylphosphatidylcholine.
The interactions of dpPC with ganglioside GD3 and two lactones. GD3LacI or GD3LacII, in lipid monolayers occur with reduced, unaltered, or increased molecular area and surface potential/molecule, respectively. dpPC is fully miscible with GD3 and GD3LacI but films with GD3LacII show immiscibility above 75 mol% lactone. At low proportions of GD3 in mixtures with dpPC, GD3 undergoes condensation and depolarization; dpPC is depolarized and its molecular area is reduced above 50 mol% GD3. GD3LacI forms ideally mixed films with dpPC. Mixtures of dpPC with GD3LacII at mole fractions below 0.3 show increased mean molecular area and surface potential/molecule mostly due to lactone alterations. Between mole fractions of 0.3 and 0.75 the surface parameters of dpPC are altered, and above these proportions both lipids are immiscible. Defined variations of molecular properties induced by ganglioside lactonization are selectively transduced to changes of the intermolecular organization and surface electrostatics in mixed interfaces with dpPC. Thus, changes in the relative proportions of a ganglioside and its lactone forms may act as sensitive biotransducers for membrane-mediated cellular functions, without the need for metabolically altering the concentration of gangliosides.
1,2-Dipalmitoylphosphatidylcholine↗
Induction of tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) as early growth responses in rat hepatocytes in primary culture.
Early growth response with respect to tissue-type plasminogen activator (tPA) and type-1 plasminogen activator inhibitor (PAI-1) gene expression was studied in rat hepatocytes in primary culture. The genes for tPA and PAI-1 could be categorized as a delayed early growth response (DER) gene and an immediate early growth response (IER) gene, respectively. The expression of tPA was much higher in growth-promoting than in static culture conditions (i.e., cultured at low density and/or on a collagen-coated dish), and that of PAI-1 was regulated in the opposite direction. Experiments using dibutyryl cAMP (dbcAMP) and H-89 showed that the cAMP/A-kinase system might be involved in the induction of the early growth response of tPA and in the augmentation of PAI-1 mRNA induction by dbcAMP. These fibrinolytic components, whose expression is closely associated with hepatocyte growth, may play important roles in pathophysiological events in the liver such as liver regeneration.
Animals↗
Antibodies to fucogangliosides in neurological diseases.
We examined serum antibodies to 4 species of fucogangliosides: fucosyl-GM1, fucosyl-GD1b, alpha galactosyl (alpha fucosyl) GM1 and alpha galactosyl (alpha fucosyl) GD1b, in 329 patients with various neurologic diseases, 32 patients with non-neurologic autoimmune diseases and 50 healthy persons. Nine patients with Guillain-Barre syndrome, 2 with amyotrophic lateral sclerosis and 2 with cerebral infarction had IgG anti-fucosyl-GM1 antibody. Five patients with Guillain-Barre syndrome, 1 with cerebral infarction and 1 normal control subject had IgM anti-fucosyl-GM1 antibody, 3 of whom also had IgG anti-fucosyl-GM1 antibody. Sixteen of 17 patients who had IgG or IgM antibody to fucosyl-GM1 showed no sensory dysfunction. Yoshino et al. [J. Neurochem. 1993, 61: 658-663] speculated that anti-fucosyl-GM1 antibody functions in the development of sensory neuropathy, but our results do not support this. Two patients with sensory ataxic neuropathy had high IgM antibody titers to fucosyl-GD1b and alpha galactosyl (alpha fucosyl) GD1b. These fucogangliosides may be the target molecules for serum antibodies in some patients with sensory ataxic neuropathy.
Autoantibodies↗
Interaction between cAMP-dependent and insulin-dependent signal pathways in tyrosine phosphorylation in primary cultures of rat hepatocytes.
The present studies were undertaken to determine whether the interaction between cAMP-dependent and insulin-dependent pathways in primary cultures of rat hepatocytes affects biological functions and tyrosine phosphorylation. Quiescent hepatocytes were pretreated with dibutyryl cAMP or cAMP-generating agents such as glucagon, and then treated or not with insulin. Preincubation for 6 h with dibutyryl cAMP or glucagon enhanced the effect of insulin on DNA synthesis, but not the effect of insulin on amino acid transport or glycogen and protein synthesis. Tyrosine phosphorylation of intracellular proteins was determined by immunoblot analysis using an anti-phosphotyrosine antibody. Maximum tyrosine phosphorylation of a 195 kDa protein, which may be a substrate of insulin receptor kinase, of 175-180 kDa proteins, including insulin receptor substrate (IRS)-1, and of 90-95 kDa proteins, including the insulin receptor beta-subunit, was reached within 30 s of incubation with insulin. Pretreatment for about 3 h with dibutyryl cAMP or cAMP-generating agents clearly increased insulin-dependent tyrosine phosphorylation of the 195 kDa protein, but not IRS-1, IRS-2 or the insulin receptor beta-subunit. Because dibutyryl cAMP and cAMP-generating agents did not increase insulin receptor number or its kinase activity, the effect of cAMP on this potentiation of tyrosine phosphorylation is assumed to be exerted at a step distal to insulin receptor kinase activation. The potentiation by cAMP pretreatment of insulin-stimulated tyrosine phosphorylation may in part be secondary to inhibition of phosphotyrosine phosphatase activity, because cAMP pretreatment blunted the effect of Na3VO4 on the net tyrosine phosphorylation of the 195 kDa protein as compared with cells pretreated with no additive. In summary, the interactions between cAMP-dependent and insulin-dependent pathways that lead to augmentation of DNA synthesis appear to parallel the changes in tyrosine phosphorylation. Further studies will be required to determine whether there is a causal relationship between these phenomena.
Amino Acids↗
Characterization of a deletion mutation involving exons 3-7 of the WASP gene detected in a patient with Wiskott-Aldrich syndrome.
A case of Wiskott-Aldrich syndrome (WAS) suspected to have a deletion mutation in the WAS protein (WASP) gene had previously been reported (Ariga et al., 1997). Genomic polymerase chain reaction (PCR) suggested that exons 3-7 of the WASP gene were included in the deletion. Present Southern blot studies confirm that the deletion is approximately 2.0 kb in length, involving exons 3-7 and seemed to have been created by the fusion of introns 2 and 7. To characterize the deletion mutation in detail, we analyzed the PCR-amplified fragments of introns 2 and 7 from normal individuals and the fragment suspected of including the deletion junction from the patient. Sequencing of the patient fragment revealed that the deletion mutation involving exons 3-7 of the WASP gene did, indeed, result from the fusion of introns 2 and 7.
Base Sequence↗
Glycosyltransferase activities in cultured endothelial cells of bovine brain microvascular origin.
Bovine brain microvascular endothelial cells (BMECs) express GM3 (NeuAc) and GM3 (NeuGc) as the major gangliosides, and GM1, GD1a, GD1b, GT1b as well as sialosylparagloboside and sialosyllactosaminylparagloboside as the minor species. To investigate the metabolic basis of this ganglioside pattern, the activities of eight glycosyltransferases (GM3-, GD1a-, GD3-, LM1-, GM2 (NeuAc)-, GM2 (NeuGc)-, LacCer-, and GM1-synthases) in cultured BMECs were studied. It was found that BMECs possessed high activities of GM3- and GD1a-synthases, and low activities of GM2-, GM1-, and GD3-synthases. Thus, the present study provides evidence that endothelial cells are capable of synthesizing gangliosides in situ and that the high content of GM3 in BMEC is closely associated with high activities of GM3-synthase and low activities of GM2-, GM1-, and GD3-synthases.
Animals↗