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PubMed1989

Restricted usage of VH and V kappa genes by murine monoclonal antibodies against 3-fucosyllactosamine.

We are studying the structure and regulation of murine antibodies against the 3-fucosyllactosamine antigenic determinant. Analysis of the sequences of seven BALB/c IgM, kappa monoclonal antibodies (mAb), obtained from four fusions, indicates that these antibodies exhibit restriction in their usage of VH and VL genes. Based on a combination of mRNA sequences and Southern filter hybridization data, all seven light chains are encoded by V kappa 24B and J kappa 1 gene segments. Complete mRNA sequences of the heavy chains revealed that all seven mAb are encoded by VH441, six antibodies are encoded by JH4 and one uses a JH3 gene segment. The VH441 gene segment and all seven mAb contain a potential glycosylation site at Asn 58 in complementarity-determining region (CDR)2. In contrast to the similarity of the VH regions, the heavy chain CDR3 segments exhibit considerable heterogeneity. They are encoded by three D segments, they vary in length from 7-9 amino acids and display differences in their deduced amino acid sequences. The VH441 gene segment also encodes antibodies against four other carbohydrate antigens, levan, galactan, dextran and galactosyl globoside. The use of a single gene segment to encode antibodies against five different antigens suggests that the domain encoded by VH441 might be particularly well adapted for forming sites that bind carbohydrate determinants. Glycosylation of CDR2 might contribute to the unique properties of this VH domain.

Amino Acid Sequence↗

PubMed1989

Glycosphingolipids in lectin-resistant variants of mouse Lewis lung carcinoma cells.

Neutral glycolipids and gangliosides from murine Lewis lung carcinoma cell line LL2 and its lectin-resistant variants, differing in metastatic properties, were studied by fast-atom-bombardment mass spectrometry (FAB-MS), exoglycosidase treatment and an immunostaining procedure. The neutral glycolipids identified in all cell lines studied included CMH, CDH, CTH, asialo GM2, globoside and a glycolipid with a preliminary structure of Hex-Hexl-4HexNAc-Hex-Hex-Cer. The major gangliosides were GM3, GM2, GM1 and GD1a. No qualitative differences in glycosphingolipid expression were found between the metastatic cell lines (LL2 and LL2AAA) and the weakly metastatic variants (LL25, LL28, LL230 and LL2RCA II). Some quantitative differences were observed between the cell lines, e.g., in the level of ganglioside-bound sialic acid, which was not apparently correlated with the metastatic capacities.

Animals↗

PubMed1991

Changes in glycolipids in human renal-cell carcinoma and their clinical significance.

The expression patterns of glycolipids of human renal-cell carcinoma were studied in primary tumors from 23 cases and 5 metastatic lesions from 4 cases using HPTLC (high-performance thin-layer chromatography). The expression pattern of glycolipids in primary tumors was characteristic of the histological cell type. In granular-cell carcinoma, lactosylceramide (CDH), GM3 and the longer-chain gangliosides (gangliosides migrating more slowly than GM3) increased, although in clear-cell carcinoma, CDH and other glycolipids tended to decrease. Globoside decreased in all cases but one, irrespective of cell type. In metastatic lesions of the clear-cell type, the prominent increase in longer-chain gangliosides was characteristic. Furthermore, the same expression pattern as that of metastastatic lesions was shown in 3 of 14 patients with primary clear-cell carcinoma, all of whom developed metastases soon after radical nephrectomy. These studies indicate that the increased expression of the longer-chain gangliosides in primary tumor is one of the factors associated with high metastatic potential, and also predict early post-operative development of metastasis.

Aged↗

PubMed1994

Glycolipids of germ cell tumors: extended globo-series glycolipids are a hallmark of human embryonal carcinoma cells.

Glycolipids of human germ cell tumor lines were analyzed to define the most common immunohistochemical profiles of embryonal carcinoma (EC), differentiated derivatives of EC, yolk sac carcinoma (YC) and choriocarcinoma (CC). Glycolipid composition was examined by high-performance thin-layer chromatography (HPTLC) combined with immunostaining with a panel of anti-carbohydrate monoclonal antibodies (MAbs). All EC cell lines were found to contain high levels of globo-series glycolipids, including globotriosylceramide (Gb3), globoside (Gb4), Gb5 (Gal beta 1-->3Gb4) and GL7 (sialyl Gal beta 1-->3Gb4). Somatic differentiated derivatives (e.g., EC cells treated with retinoic acid) contained decreased levels of globo-series glycolipids and increased levels of lacto- and ganglio-series glycolipids, including GD3, GT3 and GD2. CC cell lines contained relatively large amounts of Gb3 but did not contain extended globo-series glycolipids Gb5 and GL7. CC cell lines also contained a macroglycolipid reactive with the antibody to SSEA-1 (Lex). Glycolipids were not detected in two YC cell lines, while other YC cell lines contained globo-series core glycolipids (Gb3 and Gb4) and gangliosides. We conclude that EC, YC and CC have distinct patterns of membrane glycolipid expression that can be identified by HPTLC and immunostaining. Our results indicate that globo-series glycolipids Gb5 and GL7, which carry stage-specific embryonic antigens 3 and 4 (SSEA-3 and SSEA-4), are a hallmark of human EC cells. Cell lines derived from human germ cell tumors that do not express Gb5 and GL7 deserve to be re-evaluated, since they may represent different stem cells, most likely equivalent to somatic cells and their developmentally committed precursors (e.g., neuroblasts).

Biomarkers, Tumor↗

PubMed1993

Initiation of assembly and association of the structural elements of a bacterial pilus depend on two specialized tip proteins.

Uropathogenic Escherichia coli produce heteropolymeric surface fibers called P pili, which present an adhesin at their tip that specifically recognizes globoside receptors on the host uroepithelium. The initial attachment step is thought to be essential for pathogenesis. P pili are composite fibers consisting of a thin tip fibrillum joined end to end to a rigid helical rod. Here we show that the ordered assembly of these structures requires the activity of two proteins that are minor components of the tip fibrillum, PapF and PapK. PapF is required for the correct presentation of the adhesin at the distal end of the tip fibrillum. PapK regulates the length of the tip fibrillum and joins it to the pilus rod. We propose that these subunits function as adaptors, by providing complementary surfaces to different substructures of the pilus and promoting their proper associations. In addition, the conversion of chaperone-subunit complexes into pili depends on PapF and PapK since a papF- papK- double mutation abolishes piliation. We suggest that in addition to the adaptor functions of PapF and PapK, they are also required to initiate the formation of tip fibrillae and pilus rods.

Adhesins, Escherichia coli↗

PubMed2004

Glycosphingolipid composition of primary cultured human brain microvascular endothelial cells.

Glycosphingolipid (GSL) antigens have been considered to be involved in the pathogenesis of autoimmune neurologic disorders including multiple sclerosis. To establish the GSL pattern specific for endothelial cells forming blood-brain barrier (BBB), we established a method to yield sufficient quantities of highly purified human brain microvascular endothelial cells (HBMECs) and compared their GSL composition to that of human umbilical cord vein endothelial cells (HUVECs), as the representative of endothelial cells not forming BBB. The major gangliosides were GM3 and sialyl paragloboside (LM1), and the major neutral GSLs were lactosylceramide (LacCer), globotriaosylceramide (Gb3), and globoside (Gb4). Trace amounts of GM1, GD1a, GD1b, GT1b, and sulfoglucuronosyl paragloboside (SGPG) could be detected by the high performance thin layer chromatography-overlay method. SGPG was detected only at a nonconfluent state in an amount almost 1/30 that of in nonconfluent HUVECs. Conversely, GM3 and LM1 increased significantly after confluency. The amount of Gb3 in HBMECs was almost as twice that in HUVECs. The significance of these differences in GSL content between HBMECs and HUVECs and between confluent and nonconfluent states is obscure. It might be related, however, to the defense mechanism at the BBB and to the susceptibility of the central nervous system in some disorders that target cell surface GSL, such as hemolytic uremic syndrome.

Aged↗

PubMed1981

Anomalous cell surface structure of sickle cell anemia erythrocytes as demonstrated by cell surface labeling and endo-beta-galactosidase treatment.

Erythrocyte surface glycoproteins from patients with various types of sickle cell anemia have been analyzed and compared with those from normal individuals. By hemagglutination with various anti-carbohydrate antibodies, sickle cells showed profound increase of i antigens and moderate increase of GlcNAc beta 1 leads to 3Gal beta 1 leads to 3 Glc structure, whereas antigenicity toward globosidic structure was unchanged. In parallel to these findings, erythrocytes of sickle cell patients have additional sialylated lactosaminoglycan in Band 3. Thus, it can be concluded that erythrocytes of sickle cell patients are characterized by an altered cell surface structure which does not appear to be due to topographical changes of cell surface membrane. It is possible that the anemia or the "stress" hematopoiesis in these patients is responsible for these changes.

Anemia, Sickle Cell↗

PubMed1996

Parvoviruses and bone marrow failure.

Parvovirus B19, the only known human pathogenic parvovirus, is highly tropic to human bone marrow and replicates only in erythroid progenitor cells. The basis of this erythroid tropism is the tissue distribution of the B19 cellular receptor, globoside (blood group P antigen). In individuals with underlying hemolytic disorders, infection with parvovirus B19 is the primary cause of transient aplastic crisis. In immunocompromised patients, persistent B19 infection may develop that manifests as pure red cell aplasia and chronic anemia. B19 infection in utero can result in fetal death, hydrops fetalis or congenital anemia. Diagnosis is based on examination of the bone marrow and B19 virological studies. Treatment of persistent infection with immunoglobulin leads to a rapid, marked resolution of the anemia.

Adult↗

PubMed1997

Successive isolation and separation of the major lipid fractions including gangliosides from single biological samples.

Currently available techniques concerning extraction and characterization of the different lipids from biological specimens are designed for particular families and do not address consecutive isolation of lipid constituents in their globality. We describe here a simple, nondestructive chromatographic procedure that allows efficient elution and further analysis of the major lipid classes (neutral lipids, phospholipids, nonsialylated sphingolipids, and gangliosides) in their natural states from the same starting material. The procedure describes the use of solvent mixtures adapted to silicic acid column chromatography and permits 90-97% recovery of each of the above lipid groups. We have particularly concentrated on optimizing the efficient recovery of the diverse minor forms of gangliosides, free of other contaminants, from relatively small amounts of neural tissue. As model systems we have used in vivo and in vitro preparations of mammalian retina for which only fragmentary data are available on lipid composition. We show that relative to brain, retina contains, for example, twofold more sphingomyelin and sixfold more GD3 ganglioside. In turn, cultured retinal glial cells contain twofold higher levels of globoside and eightfold higher amounts of GM3 ganglioside with respect to intact retina. Compared to previously published techniques, we obtain improved total ganglioside recovery, with enrichment of poly-sialogangliosides. The technique presented here should be widely applicable to analyze global lipid composition of diverse biological samples.

Animals↗

PubMed2001

Structure and functional genomics of lipopolysaccharide expression in Haemophilus influenzae.

The involvement of genes in the lic loci in H. influenzae LPS expression has been known for some time. However, it was not until recently that it was shown that the lic1 locus contains genes required for phase variable expression of phosphocholine substituents, while genes in the lic2 locus and lgtC are required for expression of the globoside trisaccharide, alpha-D-Galp-(1 --> 4)-beta-D-Galp-(1 --> 4)-beta-D-Glcp (i.e., the pK blood group epitope). The availability of the complete sequence of the H. influenzae strain Rd genome has facilitated significant progress in understanding the role of these and other genes in the expression and biosynthesis of LPS. We have employed a comparative structural fingerprinting strategy to establish the structural relationships among LPS from H. influenzae mutant strains in which putative biosynthesis genes were inactivated. Using this functional genomics approach, we have gained considerable insight into the genetic basis for intra-strain and strain-to-strain variation in epitope expression.

Base Sequence↗

PubMed1984

Glycosphingolipids of chicken skeletal muscle in early development and genetic dystrophy.

The acidic and neutral GSL of chicken pectoral muscle and the activities of relevant sialyltransferase and glycosidases have been examined during embryonic and early post-hatching development. At this stage of myogenesis, a prominent shift to the neutral GSL of longer oligosaccharide length involving Forssman glycolipid most prominently and also globoside and GbOse3Cer occurred but the distribution of muscle-type gangliosides was not obviously affected. The glycosidase and sialyltransferase activities decreased dramatically just prior to or at hatching. The fusion-linked change in GSL suggests a role for terminal galactosamine and/or galactose residues in myoblast aggregation. A parallel developmental study of genetic muscular dystrophy revealed similar GSL levels and enzyme activities. A larger proportion of lactosylceramide in dystrophic muscle throughout development suggests a developmental lag in the mutant.

Aging↗

PubMed1980

The specificity of human N-acetyl-beta-D-hexosaminidases towards glycosphincolipids is determined by an activator protein.

It has been very difficult to correlate, on the basis of in vitro measurements of substrate specificities, the glycosphingolipid storage patterns observed in different variants of infantile GM2 gangliosidosis with the hexosaminidase (hex) isoenzyme deficiencies underlying these diseases. However, the in vitro enzyme assays included detergents, which greatly enhanced the enzymic degradation of lipids by breaking down the large lipid micelles that cannot otherwise be attacked by the hydrolases. In vivo, the role of detergent is taken over by water-soluble, low molecular weight proteins, so-called activators, which bind the lipid monomers, thus solubilizing them. It can be shown that the activator protein for the enzymic degradation of ganglioside GM2 has a very strong preference for hex A over hex B; it also acts on glycolipid GA2 and, to a lesser extent, on kidney globoside. This isoenzyme specificity is much less prominent or even reversed when detergents are used to solubilize the substrates. The substrate specificities of hex A and hex B measured in the presence of sufficient amounts of the activator protein most probably reflect the conditions occurring in vivo. They can explain the lipid storage patterns observed in different variants of infantile GM2 gangliosidosis, especially the accumulation of ganglioside GM2 in variant B (where hex B is still present) and the reduced storage of GA2 in the same variant as compared to variants O and AB. The physiological significance of the activator protein is demonstrated in variant AB in which the activator is deficient, resulting in an accumulation of glycolipids GM2 and GA2.

Enzyme Activation↗

PubMed1982

Effects of cell density on the neutral glycolipid composition of cultured human brain and glioma cells.

Density dependent chain elongation of neutral glycosphingolipids (NGSL) is associated with contact inhibition of mitosis in several normal cultured cell lines. Transformed non-neural cell lines which have impaired contact inhibition frequently lose this biochemical response. To determine if either of these phenomena occur in human neural cells we determined NGSL compositions of cultured glioblastoma multiforme and normal fetal brain cells. Fetal cells generally had more total NGSL than the tumor cells. As a percentage of total NGSL, both cell lines at higher cell densities had larger proportions of ceramide trihexoside and globoside, but smaller proportions of cerebroside. This decrease was mainly in non-hydroxy fatty acid cerebroside of glioma cells, but in hydroxy fatty acid cerebroside of normal fetal brain cells. These results demonstrate that although glioblastoma multiforme cells have markedly impaired growth control, they still preserve density dependent chain elongation of NGSL. A role for this phenomenon in normal cellular growth control has yet to be established.

Aged↗

PubMed1989

Glycosphingolipids of human urothelial cell lines with different grades of transformation.

Neutral glycolipids and gangliosides from seven human urothelial cell lines, differing in grades of transformation (TGr), were characterized by fast atom bombardment mass spectrometry, exoglycosidase treatment and an immunostaining procedure. The major neutral glycolipids identified in all cell lines studied included CMH, CDH, CTH, globoside and paragloboside, the gangliosides were GM3, GM2, sialosylparagloboside and GD1a. The following observations were made: 1. GM2 was the major ganglioside in the TGrII cell lines (non-tumorigenic, non-invasive), but a minor component in the TGrIII cell lines (tumorigenic, invasive). 2. All components showed C16:0 and C24:0 as major fatty acids, but in the TGrIII cell lines the fatty acid composition of CMH and some of the gangliosides were more complex showing unsaturated and hydroxy-fatty acids as well.

Antibodies, Monoclonal↗

PubMed1995

Characterisation of the anti-bladder-cancer monoclonal antibody BLCA-8: identification of its antigen as a neutral glycolipid.

A monoclonal antibody, BLCA-8, was raised against the human bladder cancer cell line, UCRU-BL-17CL. By flow cytometry and immunoperoxidase staining, this antibody was found to possess high specificity for bladder tumours, some reactivity with fetal tissues, and no reactivity with normal bladder, or any normal or malignant tissue. This high specificity and the stability of the antigen to the urinary environment suggest that BLCA-8 may have potential for use as an anti-bladder-cancer therapeutic agent. By thin-layer chromatography and autoradiography, BLCA-8 was found to bind four components within the neutral lipid fraction of a bladder cancer cell line, UCRU-BL-17/23 alpha. These components had RF values of 0.22, 0.16/0.15 (doublet), 0.12 and 0.08, and migrated below globoside, indicating the presence of more than four sugars. By enzyme-linked immunosorbent assay and thin-layer chromatography it was found that the binding of BLCA-8 to the lipid extract was increased by both mild alkaline hydrolysis and enzymatic treatments, indicating that adjacent phospholipids and glycolipids interfere with the accessibility of the antibody-binding site. Full biochemical characterisation of the BLCA-8 antigen is currently underway.

Antibodies, Monoclonal↗

PubMed1992

Glycolipids of a human glioma cell line bearing receptors for platelet-derived growth factor (PDGF).

Glycolipids of U-1242 MG were characterized because results of previous studies showed that exogenous gangliosides, especially GM3, inhibit PDGF-stimulated growth of this human glioma cell line. GM3 and GM2 are the major gangliosides; both separate as doublets with thin-layer chromatography. The major neutral glycolipid is glucocerebroside with nonhydroxy fatty acids, but paragloboside, ceramide dihexoside, globoside, and asialoGM2 (GA2) are also present. The coexistence in U-1242 MG of these gangliosides and the PDGF receptor, whose mitogenic signal is modulated by GM3 in these cells, suggests a possible functional relationship among them with respect to growth regulation.

Chromatography, Thin Layer↗

PubMed1999

Gangliosides and neutral glycolipids in ependymal, neuronal and primitive neuroectodermal tumors.

Neutral glycolipid and ganglioside compositions were determined on 11 ependymal tumors, 12 medulloblastomas, 6 other neuronal tumors of the brain, 4 peripheral neuroblastomas, 1 cerebral primitive neuroectodermal tumor (PNET), and 1 PNET of the thoracic wall. Within the group of tumors that can demonstrate neuronal phenotypes, there was an association between the degree of neuronal differentiation usually demonstrated by these tumors and the proportions of both GD1a and 1b-pathway gangliosides. The amount of globoside also correlated with the amount of 1b pathway gangliosides. Patients with medulloblastomas whose 1b gangliosides made up over 15% of the total gangliosides survived longer that those with lower proportions of 1b gangliosides. The only gangliosides in the choroid plexus papilloma were GM3 and GD1a, but other ependymal tumors had significant amounts of GD1b and its metabolic precursors. Ependymoma and anaplastic ependymoma had similar neutral glycolipid compositions, which were different from subependymoma, which lacked ceramide monohexoside and ceramide dihexoside. These differences in glycolipid compositions suggest that there may be fundamental biological differences between these types of ependymal tumors.

Adult↗

PubMed1991

Isolation and characterization of the major glycosphingolipids from the liver of the rainbow trout (Oncorhynchus mykiss): identification of an abundant source of 9-O-acetyl GD3.

The carbohydrate structures of the major glycosphingolipids from the liver of the rainbow trout Oncorhynchus mykiss have been examined. We have isolated and identified four major neutral (glucosylceramide, galactosylceramide, lactosylceramide, and globoside) and five acidic (sulfatide, GM3, GM2, GD1a, and 9-O-Acetyl GD3) glycosphingolipids from trout liver. They have been characterized by 1H nuclear magnetic resonance spectroscopy, methylation analysis, fast atom bombardment mass spectrometry, and specific monoclonal antibodies. Significantly, the relatively scarce ganglioside 9-O-acetyl GD3 was found to comprise approximately 23% of the total ganglioside content of normal rainbow trout liver. 9-O-Acetyl GD3 is, however, abundant in human melanoma and as such, trout liver may be a suitable source of this antigen.

Acetylation↗