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Viral infections
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Sarah Elizabeth Blutt, Mary K. Estes, Satya Dandekar, Phillip D. Smith
The first level of immunity to human rotavirus is an innate susceptibility or resistance to infection based partially on an individuals’ fucosyltransferase 2 (FUT2) genotype. FUT2 controls fucosylation and the expression of ABH histoblood group antigens (HBGAs) at the intestinal mucosa. These carbohydrates function as binding ligands and are thought to be initial receptors required for rotavirus binding to host cells. Susceptibility or resistance to a particular rotavirus strain depends on whether the cell surface in the gut expresses the appropriate binding glycan. Human rotaviruses bind HBGAs, while most animal virus strains bind sialoglycans. The distribution of HBGA types in different human populations affects the prevalence of common rotavirus genotypes across the globe and susceptibility to some strains of animal origin. Innate and adaptive immune cells direct the host response to rotavirus in both primary infection and reinfection (Figure 28.4). Innate immunity that regulates interferon and the induction of interferon (IFN)-stimulated genes also has an important role in modulating rotavirus infection in vitro and in animal models, but its role in humans is not fully understood. Protection from reinfection and disease generally correlates positively with markers of mucosal immunity, including levels of anti-rotavirus intestinal IgA, enteric rotavirus-reactive antibody-secreting cells, and IgA memory cells.
Glycosylation Studies of Monoclonal Immunoglobulin Deposition Disorders
Published in Gilles Grateau, Robert A. Kyle, Martha Skinner, Amyloid and Amyloidosis, 2004
L. A. Omtvedt, L. Royle, G. Husby, K. Sletten, C. Radcliffe, D. J. Harvey, R. A. Dwek, P. M. Rudd
The under-fucosylation of the N-glycans of protein GL-HCDD may render the protein more susceptible to deposition by increased flexibility of the Gal 6’ antenna and thereby revealing amino acids that normally are hidden by the carbohydrate structure and thus lead to enhanced protein-protein interaction that again may lead to protein deposition (8). Furthermore, IgGs without fucose have an increased binding to FCγRINa and this may lead to enhanced cytotoxicity of protein GL (9). In RA, the synovial tissue of affected joints is known to contain activated lymphocytes as well as macrophages, and activated B lymphocytes may be relatively prone to develop clonality (10). This may explain the fact that the patient, diagnosed with seronegativ RA in 1988 prior to be diagnosed with HCDD, developed an overexpression of a monoclonal IgG with a specific oligosaccharide profile. Furthermore, this also indicate that the HCDD may be a consequence of the rheumatoid disease and not the other way around, although this is still elusive (11).The function of the carbohydrate structure in SKA IgG2 remains to be elucidated. However even though the patient continues to produce a monoclonal IgG after the autologous bone marrow transplant, no further progression of amyloid deposit is found. Thus, one may speculate that the pathogenic mechanisms, which govern the progression of this disease, may be other than the glycoprotein alone.
What are the diagnostic capabilities of glycans for breast cancer?
Published in Expert Review of Molecular Diagnostics, 2023
Fucosyltransferases (FUTs) catalyze the addition of fucose moieties to the ends of N-glycan and O-glycan structures, termed as terminal fucosylation, or to the core GlcNAc residue linked to Asn in N-glycan structures, termed as core-fucosylation, respectively. Changes of fucosylation in breast cancer have been noted for many decades. In 1971, Rosato et al. reported that higher concentrations of protein-bound fucose presented in serum of breast cancer patients [77]. Increasing evidence suggested that the altered of fucosylation plays an important role in breast cancer. Reported in one study, a decreased intensity of a bi-antennary-monosialylated N-glycan and an elevated intensity of a fucosylated tri-antennary-tri-asialylated N-glycan were observed in the advanced stages of breast cancer [59] and one monogalactosylated tri-antennary structure containing α1,3-linked fucose (A3FG3S3) showed a twofold increase in serum from breast cancer patients. Following pilot glycoproteomic study of advanced breast cancer serum highlighted several acute-phase proteins including α1-acid glycoprotein, α1-antichymotrypsin, and haptoglobin β-chain as contributors to the increase in the glycan marker [78]. Kyselova et al. suggested that increased sialylation and fucosylation of glycans appeared to be used to diagnose the progression of breast cancer, based on the specific MS-based glycomic profile analysis on serum from different stages of breast cancer [24]. This information indicates specific glycans and glycoforms of proteins may be candidates for improved markers in the monitoring of breast cancer progression.
Aberrant fucosylation enables breast cancer clusterin to interact with dendritic cell-specific ICAM-grabbing non-integrin (DC-SIGN)
Published in OncoImmunology, 2019
Antonela Merlotti, Alvaro López Malizia, Paula Michea, Pierre-Emmanuel Bonte, Christel Goudot, María Sol Carregal, Nicolás Nuñez, Christine Sedlik, Ana Ceballos, Vassili Soumelis, Sebastián Amigorena, Jorge Geffner, Eliane Piaggio, Juan Sabatte
Our present results demonstrate the expression of fucosylated clusterin in breast tumor samples and its ability to interact with DC-SIGN. Fucosylated clusterin was absent or diminished in juxtatumor tissues, suggesting that it might be considered as a cancer associated glycoform. Indeed, aberrant fucosylation of proteins is frequently found in cancer cells.14,15 In spite that we did not analyze whether breast cancer clusterin and seminal plasma clusterin bear identical fucosylated motifs, we demonstrate that clusterin from both sources express terminal fucosylated motifs able to bind DC-SIGN. In fact, our observations suggest that these motifs are responsible for the recognition of tumor clusterin by DC-SIGN. However, due to the low amount of clusterin recovered from tumor samples, we could not assay whether removal of fucose motifs by fucosidases prevent the ability of tumor clusterin to interact with DC-SIGN, as we have previously shown for semen clusterin.10
Influence of N-glycosylation on effector functions and thermal stability of glycoengineered IgG1 monoclonal antibody with homogeneous glycoforms
Published in mAbs, 2019
Ryuta Wada, Makoto Matsui, Nana Kawasaki
Consistent and robust upregulating effects of core defucosylation and the terminal galactosylation were observed in all analysis with respect to FcγRIIIa binding activity. Our observations for core defucosylation were supported by many previous studies investigating both heterogeneous and homogeneous glycoforms.12,13,22,34-42 However, no consensus has been reached regarding the effects of terminal galactosylation, with some reports describing an upregulation36-39,42-44 and no effect45-47 or downregulation48 of FcγRIIIa affinity or ADCC activity. Since our results demonstrated significant statistical interaction between core fucosylation and terminal galactosylation, and are in strong agreement with previous studies utilizing mAbs with highly homogeneous glycoforms,37-39,42 we hypothesize that the interpretation of results could be compromised when evaluating mixtures of different types of glycoform. Our evaluations of the effects of terminal sialylation in FcγRIIIa binding analysis by SPR and ADCC reporter bioassay using N-glycosylated ligand agree with previous reports that have described reduction of FcγRIIIa affinity,13,38,40,46,49,50 but found no evidence of an unchanged affinity as previously reported.30,34,51,52