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- 10.1093/glycob/cwy046
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Abstract
Abstract Sialic acids (SAs) are nine-carbon monosaccharides existing at the terminal location of glycan structures on the cell surface and secreted glycoconjugates. The expression levels and linkages of SAs on cells and tissues, collectively known as sialoform, present the hallmark of the cells and tissues of different systems and conditions. Accordingly, detecting or profiling cell surface sialoforms is very critical for understanding the function of cell surface glycans and glycoconjugates and even the molecular mechanisms of their underlying biological processes. Further, it may provide therapeutic and diagnostic applications for different diseases. In the past decades, several kinds of SA-specific binding molecules have been developed for detecting and profiling specific sialoforms of cells and tissues; the experimental materials have expanded from frozen tissue to living cells; and the analytical technologies have advanced from histochemistry to fluorescent imaging, flow cytometry and microarrays. This review summarizes the recent bioaffinity approaches for directly detecting and profiling specific SAs or sialylglycans, and their modifications of different cells and tissues. antibody, lectin, polysialic acid, sialic acid, sialoform Introduction Sialic acids (SAs) are a family of acidic nine-carbon monosaccharides located at the terminal position of glycan structures of many glycoproteins and glycolipids (Varki 2007). They are attached to either a galactose (Gal), or N-acetylgalactosamine (GalNAc) unit via α2,3- or α2,6-linkage, or to a SA via α2,8- or 2,9-linkage on both N- and O-linked glycans. In addition, various substituents present on carbon 4-, 5-, 7-, 8- and 9-positions generate more than 50 SA species (Angata and Varki 2002). N-acetyl neuraminic acid (Neu5Ac) and N-glycolyl neuraminic acid (Neu5Gc) are the major SAs (Figure 1). Humans synthesize Neu5Ac but are incapable of synthesizing Neu5Gc. However, Neu5Gc is identified in humans due to metabolic incorporation from dietary sources (Varki 2001). Given their terminal location and electronegative features, SAs play important roles in both physiological and pathological processes, such as in regulating cellular interactions with ligands, microbes and neighboring cells, and in controlling cellular activation, differentiation, transformation and migration (Murrey and Hsieh-Wilson 2008). Several comprehensive reviews for studying the functions of SAs and sialylglycans have been reported recently (Chen and Varki 2010; Cohen and Varki 2010; Kitajima et al. 2013). The readers are recommended to these reviews for more detailed information and biomedical interests. Fig. 1. View largeDownload slide Bioaffinity approaches for profiling cell surface SAs: (a) lectin binding; (b) antibody recognition; (c) recombinant protein binding combined with chemiluminescence, microscope imaging and/or flow cytometry analysis. Fig. 1. View largeDownload slide Bioaffinity approaches for profiling cell surface SAs: (a) lectin binding; (b) antibody recognition; (c) recombinant protein binding combined with chemiluminescence, microscope imaging and/or flow cytometry analysis. The expression levels and linkages of SAs on a cell or tissue are known as its sialoform and are closely associated with cell property, phenotype, functionality, and thus human health and diseases, such as cancer, inflammation and neurological diseases (Varki 2008). Therefore, detecting and profiling cell surface sialoform is highly significant for understanding the molecular mechanisms of related physiological and pathological processes. In the past, several bioaffinity-based methods for directly detecting specific SAs and sialylglycans and their modifications have been developed, including lectins, antibodies and recombinant SA-binding proteins combined with histochemistry, fluorescent image, flow cytometry and microarray analysis. Lectins are often used to profile cell surface SAs expression as they specifically recognize SAs in different linkages in glycoproteins and glycolipids (Hernandez and Baum 2002). Also, a variety of antibodies have been developed to study the specific types of SAs, sialylglycans and their modifications on cell surfaces (Varki and Varki 2007). In addition, recombinant SA-binding proteins have been developed for detecting specific SAs, sialylglycans and their modifications on the cells or tissues (Langereis et al. 2015). This review summarizes these recent advancements in bioaffinity profiling of specific SAs, sialylglycans and their modifications. Specially, SA-specific lectins, antibodies and recombinant proteins are summarized (Figure 1). Lectin-affinity approaches to determine SAs on cell surface Cell surface SAs, sialylglycans and their modifications can be detected by way of bioaffinity recognition. The most popular bioaffinity approach is the use of lectins that can bind specific SAs and sialylglycans and their modifications. Lectins are sugar-binding proteins that can specifically recognize nonreducing ends of naturally occurring glycans of glycoconjugates, including glycoproteins and glycolipids. Some lectins can specifically recognize terminal SA residues in different linkages and are regarded as a potentially useful tool to study sialoglycoproteins and sialoglycolipids. SA-specific lectins are particularly advantageous because of their ability to discriminate special sialylated complex glycans on cells (Table I). So far, lectins labeled with biotin, FITC and digoxigenin were widely used to analyze the sialoglycoconjugates in histochemistry, blotting, flow cytometry and fluorescence microscopy. In addition, lectin microarray was used for high-throughput profiling of cell surface sialoforms as well. Table I. SA-specific binding lectins Lectin (origin) Specificity References ACG (Agrocybe cylindracea) Neu5Ac(α2,3)Gal, β-Gal Yagi et al. (1997) MAA (Maackia amurensis agglutinin) Neu5Ac(α2,3)Gal/GalNAc Fukasawa et al. (2013) MAH (Maackia amurensis hemagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Kawaguchi et al. (1974), Konami et al. (1994) MAL (Maackia amurensis leukoagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Knibbs et al. (1991), Nicholls et al. (2007), Wang and Cummings (1987), Wang and Cummings (1988) MPA (Macrophomina phaseolina agglutinin) Neu5Ac(α2,3)Gal Bhowal et al. (2005) PSA (Polyporus squamosus) Neu5Ac(α2,6)Gal Mo et al. (2000), Tateno et al. (2004) PVL (Psathyrella velutina) Neu5Ac(α2,3)Gal, GalNAc Ueda et al. (2002) SCA (Sambucus canadensis) Neu5Ac(α2,6)Gal/GalNAc Shibuya et al. (1989) SNA (Sambucus nigra) Neu5Ac(α2,6)Gal/GalNAc Bhavanandan and Katlic (1979), Broekaert et al. (1984) SSA (Sambucus sieboldiana) Neu5Ac(α2,6)Gal/GalNAc Yabe et al. (2009) Saracin (Saraca indica) Neu5Ac(α2,6/3)Galβ1-4GlcNAc Ray and Chatterjee (1995) TJAL (Trichosanthes japonica) Neu5Ac(α2,6)Gal/GalNAc, HSO3(−)-6Galβ1-4GlicNAc Yamashita et al. (1992) WGA (Wheat germ agglutinin) Neu5Ac, GlcNAc(β1,4)GlcNAc Adair and Kornfeld (1974), Gu (1988) ML-1 (Viscum album) Neu5Ac(α2,6)Galβ1-4GlcNAc Muthing et al. (2004) Lectin (origin) Specificity References ACG (Agrocybe cylindracea) Neu5Ac(α2,3)Gal, β-Gal Yagi et al. (1997) MAA (Maackia amurensis agglutinin) Neu5Ac(α2,3)Gal/GalNAc Fukasawa et al. (2013) MAH (Maackia amurensis hemagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Kawaguchi et al. (1974), Konami et al. (1994) MAL (Maackia amurensis leukoagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Knibbs et al. (1991), Nicholls et al. (2007), Wang and Cummings (1987), Wang and Cummings (1988) MPA (Macrophomina phaseolina agglutinin) Neu5Ac(α2,3)Gal Bhowal et al. (2005) PSA (Polyporus squamosus) Neu5Ac(α2,6)Gal Mo et al. (2000), Tateno et al. (2004) PVL (Psathyrella velutina) Neu5Ac(α2,3)Gal, GalNAc Ueda et al. (2002) SCA (Sambucus canadensis) Neu5Ac(α2,6)Gal/GalNAc Shibuya et al. (1989) SNA (Sambucus nigra) Neu5Ac(α2,6)Gal/GalNAc Bhavanandan and Katlic (1979), Broekaert et al. (1984) SSA (Sambucus sieboldiana) Neu5Ac(α2,6)Gal/GalNAc Yabe et al. (2009) Saracin (Saraca indica) Neu5Ac(α2,6/3)Galβ1-4GlcNAc Ray and Chatterjee (1995) TJAL (Trichosanthes japonica) Neu5Ac(α2,6)Gal/GalNAc, HSO3(−)-6Galβ1-4GlicNAc Yamashita et al. (1992) WGA (Wheat germ agglutinin) Neu5Ac, GlcNAc(β1,4)GlcNAc Adair and Kornfeld (1974), Gu (1988) ML-1 (Viscum album) Neu5Ac(α2,6)Galβ1-4GlcNAc Muthing et al. (2004) Table I. SA-specific binding lectins Lectin (origin) Specificity References ACG (Agrocybe cylindracea) Neu5Ac(α2,3)Gal, β-Gal Yagi et al. (1997) MAA (Maackia amurensis agglutinin) Neu5Ac(α2,3)Gal/GalNAc Fukasawa et al. (2013) MAH (Maackia amurensis hemagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Kawaguchi et al. (1974), Konami et al. (1994) MAL (Maackia amurensis leukoagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Knibbs et al. (1991), Nicholls et al. (2007), Wang and Cummings (1987), Wang and Cummings (1988) MPA (Macrophomina phaseolina agglutinin) Neu5Ac(α2,3)Gal Bhowal et al. (2005) PSA (Polyporus squamosus) Neu5Ac(α2,6)Gal Mo et al. (2000), Tateno et al. (2004) PVL (Psathyrella velutina) Neu5Ac(α2,3)Gal, GalNAc Ueda et al. (2002) SCA (Sambucus canadensis) Neu5Ac(α2,6)Gal/GalNAc Shibuya et al. (1989) SNA (Sambucus nigra) Neu5Ac(α2,6)Gal/GalNAc Bhavanandan and Katlic (1979), Broekaert et al. (1984) SSA (Sambucus sieboldiana) Neu5Ac(α2,6)Gal/GalNAc Yabe et al. (2009) Saracin (Saraca indica) Neu5Ac(α2,6/3)Galβ1-4GlcNAc Ray and Chatterjee (1995) TJAL (Trichosanthes japonica) Neu5Ac(α2,6)Gal/GalNAc, HSO3(−)-6Galβ1-4GlicNAc Yamashita et al. (1992) WGA (Wheat germ agglutinin) Neu5Ac, GlcNAc(β1,4)GlcNAc Adair and Kornfeld (1974), Gu (1988) ML-1 (Viscum album) Neu5Ac(α2,6)Galβ1-4GlcNAc Muthing et al. (2004) Lectin (origin) Specificity References ACG (Agrocybe cylindracea) Neu5Ac(α2,3)Gal, β-Gal Yagi et al. (1997) MAA (Maackia amurensis agglutinin) Neu5Ac(α2,3)Gal/GalNAc Fukasawa et al. (2013) MAH (Maackia amurensis hemagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Kawaguchi et al. (1974), Konami et al. (1994) MAL (Maackia amurensis leukoagglutinin) Neu5Ac(α2,3)Gal Geisler and Jarvis (2011), Knibbs et al. (1991), Nicholls et al. (2007), Wang and Cummings (1987), Wang and Cummings (1988) MPA (Macrophomina phaseolina agglutinin) Neu5Ac(α2,3)Gal Bhowal et al. (2005) PSA (Polyporus squamosus) Neu5Ac(α2,6)Gal Mo et al. (2000), Tateno et al. (2004) PVL (Psathyrella velutina) Neu5Ac(α2,3)Gal, GalNAc Ueda et al. (2002) SCA (Sambucus canadensis) Neu5Ac(α2,6)Gal/GalNAc Shibuya et al. (1989) SNA (Sambucus nigra) Neu5Ac(α2,6)Gal/GalNAc Bhavanandan and Katlic (1979), Broekaert et al. (1984) SSA (Sambucus sieboldiana) Neu5Ac(α2,6)Gal/GalNAc Yabe et al. (2009) Saracin (Saraca indica) Neu5Ac(α2,6/3)Galβ1-4GlcNAc Ray and Chatterjee (1995) TJAL (Trichosanthes japonica) Neu5Ac(α2,6)Gal/GalNAc, HSO3(−)-6Galβ1-4GlicNAc Yamashita et al. (1992) WGA (Wheat germ agglutinin) Neu5Ac, GlcNAc(β1,4)GlcNAc Adair and Kornfeld (1974), Gu (1988) ML-1 (Viscum album) Neu5Ac(α2,6)Galβ1-4GlcNAc Muthing et al. (2004) Histochemical study of cell surface SAs with SA-specific lectins Lectin-histochemical staining provides detailed information about the occurrence and distribution of corresponding SA residues in tissues and differentially expressed in different parts of biological samples. In particular, lectin-histochemical staining was often used to study cancer, in which aberrant expression of sialoglycoconjugates was thought to play an important role in cancer progression. Sambucus nigra (SNA) recognizing α2,6-linked SA residues and Maackia amurensis leukoagglutinin (MAL) recognizing α2,3-linked SA residues (Zeng et al. 2009) were effectively used for biochemical and histochemical analyses of sialoglycoconjugates. Dall’Olio et al. (2004) first compared the expression of α2,6-linked SA by SNA-digoxigenin staining of histological sections. Inagaki et al. (2007, 2008) then used biotinylated MAL to investigate the pathological significance of sialylation in colorectal cancer and gastric cancer. In these studies, the sialoglycoproteins in gastric cancer tissues were analyzed with MAL in combination with 2D electrophoresis. Various MAL-positive sialoglycoproteins were detected in cancer tissues but not in noncancer tissues. This result suggests that the MAL-positive sialoglycoproteins detected in gastric cancer tissues have high molecular weights and might contain different numbers of α2,3-linked SA residues in the glycan moieties (Inagaki et al. 2008). Later, Lopez-Morales et al. (2010) used biotinylated MAL and SNA to examine the expression and distribution of SAs in different grades of cervical neoplasia. Recently, Fukasawa et al. (2013) studied the expression of several types of sialylation of glycoconjugates in colorectal cancer tissue specimens with biotinylated MAL, Sambucus sieboldiana (SSA), Maackia amurensis agglutinin (MAA) and monoclonal antibodies, and compared with their clinical pathological features as well. They found that α2,3-sialylated type 2 chain (NeuAcα2,3Galβ1,4GlcNAcβR) structures were predominantly expressed in colorectal tissues associated with malignant transformation, in particular, with lymphatic spread of distal colorectal adenocarcinomas. Overall, detection of sialoglycoconjugates in cancer tissues with SA-binding lectins would be very useful in evaluating the metastatic potential of those cancers and predicting patient prognosis as well. Fig. 2. View largeDownload slide (I) Confocal microscopy analysis of cell surface SA: (A) Raw 264.7 cells at the normal culture condition stained with MAA-FITC (10 μg/mL) and SNA-FITC (20 μg/mL), respectively. DAPI was used to stain nuclei. (B) Raw 264.7 cells treated with 20 μM atorvastatin for 24 h followed by staining with lectins and DAPI. The scale bar represents 10 μm. (II) Determination of cell surface SAs by flow cytometry: (A) Raw 264.7 cells at normal condition stained with MAA-FITC (10 μg/mL) and SNA-FITC (20 μg/mL), respectively. PI staining was used to distinguish living cells and dead cells. (B) Raw 264.7 cells were treated with 20 μM atorvastatin for 24 h then stained with lectins and PI. Data are representative of at least three independent experiments (Wang et al. 2015). Fig. 2. View largeDownload slide (I) Confocal microscopy analysis of cell surface SA: (A) Raw 264.7 cells at the normal culture condition stained with MAA-FITC (10 μg/mL) and SNA-FITC (20 μg/mL), respectively. DAPI was used to stain nuclei. (B) Raw 264.7 cells treated with 20 μM atorvastatin for 24 h followed by staining with lectins and DAPI. The scale bar represents 10 μm. (II) Determination of cell surface SAs by flow cytometry: (A) Raw 264.7 cells at normal condition stained with MAA-FITC (10 μg/mL) and SNA-FITC (20 μg/mL), respectively. PI staining was used to distinguish living cells and dead cells. (B) Raw 264.7 cells were treated with 20 μM atorvastatin for 24 h then stained with lectins and PI. Data are representative of at least three independent experiments (Wang et al. 2015). Flow cytometry and fluorescence microscopy study of cell surface SAs with SA-specific lectins Recently, FITC-labeled lectins were often used to investigate cell surface SAs via cytochemistry, flow cytometry analysis and fluorescence microscopy imaging (Lin et al. 2002; Wang et al. 2009; Cui et al. 2011; Bubencikova et al. 2012; Lu et al. 2014). Flow cytometry is a powerful technique for the analysis of multiple parameters of individual cells within heterogeneous populations. Lin et al. (2002) examined the effect of α2,6-sialylation on the adhesion properties of breast carcinoma cells with differential expression level of sialyltransferase ST6Gal-I (ST6GAL1). By confirming the cell surface α2,6-sialylation expression levels with lectins, they concluded that cell surface α2,6-SAs contribute to cell–cell and cell–extracellular matrix adhesion of tumor cells. In another study, Wang et al. measured the different expression of α2,3-linked SA residues in human gastric adenocarcinoma cell lines by flow cytometry using FITC-labeled MAL (Wang et al. 2009). Their results indicated that high expression of α2,3-linked SAs is associated with the metastatic potential of human gastric cancer. Later, Cui et al. (2011) also investigated the expression levels of α2,3-linked SA residues on the cell surface in breast cancer cell lines with different metastatic potentials. In addition, Lu et al. (2014) utilized biotin-conjugated MAA and SNA to confirm the ST6GAL1 knockdown efficiency via examining cell surface SA expression by flow cytometry. Their data indicate that β-galactoside α2,6-sialyltranferase (ST6GAL1) catalyzed the addition of terminal α2,6-sialylation to N-glycans and its increased expression is highly correlated with tumor progression. On the other hand, fluorescent microscopy gives an investigator the ability to visualize desired organelles or unique surface features of a cellular sample of interest. FITC-labeled lectins, or biotinylated lectins together with streptavidin-FITC, are widely used to stain sialoglycoconjugates in biological samples, especially the glycoprotein on cell surface (Emde et al. 2014; Cime-Castillo et al. 2015). Ponnio et al. (2004) developed a confocal microscopy method for identification and localization of cell surface and intracellular sialoglycoconjugates of peripheral blood cells using FITC-labeled WGA, MAA and SNA. Silva et al. (2009) analyzed the expression of cell surface sialoglycoconjugates in Herpetomonasmegaseliae by flow cytometry and fluorescence microscopy using FITC-labeled SNA and MAA. Except the FITC-labeled lectins, tetramethylrhodamine (TRITC), a bright orange-fluorescent dye contrasting to the green fluorescence of the FITC, was widely used to label lectins in recent years (Walski et al. 2014; Strobel et al. 2015). TRITC can be used together with FITC to recognize different kinds of glycoconjugates, especially sialoglycoconjugates on the same biological sample. Our group performed global profiling of the sialylation status of macrophages upon activation with FITC-labeled lectins (Wang et al. 2015). Both flow cytometry and confocal microscopy results showed cell surface α2,3-linked SAs were predominant in normal culture conditions and changed slightly upon activation with atorvastatin for 24 h, while α2,6-linked SAs were negligible under normal culture conditions, but significantly increased upon activation (Figure 2). Meanwhile, the amount of total cellular SAs increased from 369 ± 29 ng/mL to 1.08 (±0.05) × 103 ng/mL upon cell activation as determined by LC–MS/MS method. On the other hand, there was no significant change for secreted free SAs and conjugated SAs in the medium upon cell activation. These results indicated that the cell surface α2,6-sialylation status of macrophages changed distinctly upon cell activation, which may reflect on the biological functions of the cells. The results of this work will contribute to a better understanding of the physiological and pathological roles of SAs in macrophage and in the immune system as well. The level and linkages of cell surface SAs, which are controlled by both sialylation and desialylation processes and environmental cues, can dramatically impact cell properties and represent different cellular statuses. Recently, we systematically examined the sialylation and desialylation profiles of THP-1 monocytes after differentiation to M0 macrophages, and polarization to M1 and M2 macrophages by the combination of flow cytometry and confocal microscopy (Wang et al. 2016). Interestingly, both α2,3- and α2,6-linked SAs on the cell surface of THP-1 monocytes were found to decrease after differentiation to macrophages, which was in accordance with the increased level of free SA in the cell culture medium and the elevated activity of endogenous Neu1 sialidase. Meanwhile, the siaoglycoconjugates inside the cells increased, as confirmed by confocal microscopy and the LC–MS/MS. Further, upon polarization, the cell surface sialylation levels of M1 and M2 macrophages remained the same as M0 macrophages, with a slight decrease of cellular SAs in the M1 macrophages, but an increase in the M2 macrophages were confirmed by LC–MS/MS. Overall, lectin-based assays are very useful for certain types of SAs. However, the use of lectins for assay development is often limited by their low sensitivity, poor specificity and availability as well. Lectin microarray for cell surface SA analysis As described above, lectins were mostly used in techniques such as histochemistry, blots, confocal microscopy and flow cytometry to characterize glycans in serum or cells by focusing on individual glycans. However, these techniques are laborious and inefficient for the high complexity of glycome, and the capacity to measure large sets of samples is limited. For these reasons, high-throughput technologies like lectin microarrays were developed for high-throughput profiling of cell surface glycosylations. Early lectin microarrays were mainly restricted to glycoproteins of cell lysates or serum. Hirabayashi et al. first developed a lectin microarray for direct analysis of the live mammalian cell-surface glycome (Tateno et al. 2007). In this technique, live cells were fluorescent-labeled first and then applied in situ to the lectin microarray consisting of 43 immobilized lectins with distinctive binding specificities. The bound cells were directly detected by an evanescent-field fluorescence scanner in a liquid phase without fixing and permeabilization (Figure 3). They profiled Chinese hamster ovary (CHO) cells and their glycosylation-defective mutant cells, splenocytes of wild-type and β1–3-N-acetylglucosaminyltransferase II knockout. They also compared cell surface glycans of K562 cells before and after differentiation and found a significant increase in the expression of O-glycans on differentiated cells. These results demonstrate that the technique provides a novel strategy for profiling global changes of the mammalian cell surface glycome. Fig. 3. View largeDownload slide (A) Cell surface glycome profiling using lectin microarray. (B) Predicted representative structures of N-glycans, mucin O-glycans, and glycolipids synthesized in the cell. (C) CHO cells and their glycosylation-defective mutants, Lec2, Lec8 and Lec1 in PBS/BSA were allowed to bind to the lectin array (1 × 105 cells/well) and bound cells were scanned with the evanescent-field fluorescent scanner (Tateno et al. 2007). Fig. 3. View largeDownload slide (A) Cell surface glycome profiling using lectin microarray. (B) Predicted representative structures of N-glycans, mucin O-glycans, and glycolipids synthesized in the cell. (C) CHO cells and their glycosylation-defective mutants, Lec2, Lec8 and Lec1 in PBS/BSA were allowed to bind to the lectin array (1 × 105 cells/well) and bound cells were scanned with the evanescent-field fluorescent scanner (Tateno et al. 2007). Suzuki et al. developed a 96-well plate-based lectin array method which was used to detect the human anaplastic large cell lymphoma cell surface glycosylations. In this method, 96-well plate was coated with different types of lectins including SA binder like WGA, and cells were applied to each well and shortly incubated. Then, nonadhered cells were removed and adhered cells were stained by crystal violet followed by an absorbance determination (Suzuki and Abe 2014). Most of the current lectin microarrays are primarily constructed from plant lectins. However, they are not all well-suited for studies of human glycosylation because of the extreme complexity of human glycans. For this reason, Sun et al. (2016) constructed a human lectin microarray with 60 human lectins and lectin-like proteins, including SA binding Ig-like lectin, to make up for this deficiency. Except for the method to coat the array with lectins, some researchers also printed cells into microarray slides followed by a lectin-based approach to analyze the cell surface glycosylation profile. Accogli et al. built a lectin-based cell microarray approach to analyze the mammalian granulosa cell surface glycosylation profile. They printed cells into arrays on a microarray slide, incubated with a panel of biotinylated lectins, reacted with fluorescent streptavidin and detected signal intensity by a microarray scanner, to reveal the glycocalyx on cells containing SA terminating glycans and many other kinds of glycans (Accogli et al. 2016). Overall, lectins have provided a very important approach to study cell surface SAs. However, lectins still have several drawbacks. First, many lectins suffer from relatively low affinities. Second, some of the plant lectins are glycosylated and it will complicate the results for study the complex sample, in which endogenous lectins could interact with the glycans of plant lectins (Hsu et al. 2008). Third, many lectins can perturb cells by cross-linking receptors limiting their application in live cells (Hernandez and Baum 2002). Nevertheless, the lectin’s carbohydrate-specific binding ability could offer a biological affinity approach that complements existing mass spectrometer capabilities and retains automated throughput options. Lectins can be used as specific probes for certain derivatives of SA which serve as a useful tool toward potential clinical assays in some physiological and pathological developments. Profiling cell surface SAs with SA-specific antibodies Antibodies are highly useful for studying antigens due to their highly selective and specific interactions. Considerable attention has been paid to the development of anti-SA antibodies for profiling cell surface SAs. In general, carbohydrate antigens are self-antigens and thus have low antigenic potential. The antibody produced is typically a low-affinity immunoglobulin M (IgM) as the poor immune response generated from carbohydrate antigens. For these reasons, many attempts have been made to strengthen the affinity between SAs and the antibody. Some types of SA-related antigens can be recognized by antibodies and are summarized here, including Neu5Ac, Neu5Gc, gangliosides, O-acetylated SAs and SA-containing oligosaccharides sialyl Lewis a (SLea) and sialyl Lewis x (SLex). Anti-Neu5Ac antibodies Neu5Ac is the most ubiquitous SA in nature, and some specific structure with Neu5Ac can be recognized by corresponding anti-Neu5Ac antibodies. A monoclonal antibody named clone HYB4, which could recognize the Neu5Acα2-3 determinant at the nonreducing terminal Gal residue of both glycoproteins and gangliosides, was established by immunization of mice with VI3Neu5AcnLc4Cer. This antibody was firstly applied by Suzuki group to investigate the biochemical properties of influenza virus receptors in A549 cells. It was found that the anti-SA antibody could recognize more diverse glycoproteins containing SA residues than the MAA lectin (Hidari et al. 2013). The clone HYB4 was also used to visualize the Alzheimer’s disease hippocampi by Nagamine et al. to find out if the brains were hypersialylated (Figure 4). They also proved that the anti-SA antibody could detect the status of sialylation with more sensitivity than the lectin MAA (Nagamine et al. 2016). Fig. 4. View largeDownload slide Double immunofluorescence analyses using the anti‐sialic acid (SA) antibody in the hippocampus of Alzheimer’s disease (AD) brains. The Aβ‐positive amyloid core of senile plaques (SPs, rectangle in A, and D) was not stained by the anti‐SA antibody (rectangles in B, C and E, F) in the hippocampus of AD brains. Conversely, the dystrophic neurites (DNs) of SPs were not stained by Aβ (A, D), but were stained by SA (B, C, E, F). The boxed areas in A–C are enlarged in D–F, respectively (Nagamine et al. 2016). Fig. 4. View largeDownload slide Double immunofluorescence analyses using the anti‐sialic acid (SA) antibody in the hippocampus of Alzheimer’s disease (AD) brains. The Aβ‐positive amyloid core of senile plaques (SPs, rectangle in A, and D) was not stained by the anti‐SA antibody (rectangles in B, C and E, F) in the hippocampus of AD brains. Conversely, the dystrophic neurites (DNs) of SPs were not stained by Aβ (A, D), but were stained by SA (B, C, E, F). The boxed areas in A–C are enlarged in D–F, respectively (Nagamine et al. 2016). Anti-Neu5Gc antibodies Neu5Gc is a SA synthesized in most mammals but not in humans. It is derived from the most commonly expressed Neu5Ac, differing from it by only one oxygen atom (Varki 2001). The gene CMAH encoded CMP-N-acetylneuraminic acid hydroxylase is responsible for the conversion of Neu5Ac to Neu5Gc. This gene is inactive due to a deletion mutation in humans. However, it was recently found that Neu5Gc does exist in humans. It was confirmed that Neu5Gc enters the human body primarily through dietary intake of red meat and dairy products (Tangvoranuntakul et al. 2003). Also, Neu5Gc can be incorporated into certain glycoprotein biopharmaceuticals through the use of animal-derived reagents and cell lines during the manufacturing of these glycoprotein products. Neu5Gc is recognized as a foreign, immunogenic molecule by the human immune system and thus causes the formation of circulating antibodies against this nonhuman SA, which can lead to chronic inflammation, cancer and cardiovascular diseases, and possibly reduced stability and efficacy of glycoprotein biopharmaceuticals as well (Alisson-Silva et al. 2016). Therefore, detecting Neu5Gc with antibodies has recently been explored for both basic research and diagnostic applications. Both monoclonal and polyclonal antibodies against Neu5Gc were developed in earlier studies. Monoclonal antibodies are highly specific for certain Neu5Gc containing glycans (Tai et al. 1988), while polyclonal antibodies can recognize specific types of SA (Higashi et al. 1984, 1985, 1988; Hirabayashi et al. 1987; Fukui et al. 1989; Gathuru et al. 1989; Saida et al. 1990; Kawachi and Saida 1992; Mukuria et al. 1994; Kwon et al. 2014). With the affinity-purified chicken polyclonal antibody, Varki et al. first confirmed the human uptake and incorporation of the immunogenic nonhuman dietary Neu5Gc (Tangvoranuntakul et al. 2003). Other types of anti-SA antibody molecules were developed by using Gallus domesticus as the animal model to generate recombinant anti-SA antibody molecules with high affinities towards both Neu5Gc and Neu5Ac (Donohoe et al. 2011). Similarly, affinity-purified anti-Neu5Gc antibodies from individual human sera were used to detect Neu5Gc in mouse tissues (Padler-Karavani et al. 2008). Diaz et al. (2009) found that a low level of cross-reactivity with high densities of other types of SAs could cause background reactivity, so they improved these methods by utilizing sequential columns of immobilized human and chimpanzee serum sialoglycoproteins, followed by specific elution from the latter column by free Neu5Gc to generate anti-Neu5Gc antibodies that allow highly sensitive and specific detection of nonhuman Neu5Gc in human tissues and biotherapeutic products. Recently, Padler-Karavani et al. investigated Neu5Gc expression in nonengineered animal-derived cardiac tissues and in clinically used commercial bioprosthetic heart valves (BHV), and evaluated Neu5Gc immunogenicity on BHV through recognition by human anti-Neu5Gc IgG (Reuven et al. 2016). This research confirmed Neu5Gc expression in native cardiac tissues, as well as in commercial BHV, indicating BHV-Neu5Gc/anti-Neu5Gc may play a role in valve deterioration. Anti-O-acetylated SAs antibodies O-acetylated derivatives of SA (O-AcSA) are among the multiple variations of SA. The most frequently occurring substitutions are O-acetylation at positions C-7, -8 and -9 to form 7-, 8- and -9-O-AcSAs, respectively, thus generating a family of O-AcSAs. 9-O-AcSA is considered the most common biologically occurring modification. Chatterjee et al. (1998) purified a kind of IgG antibody using bovine submaxillary mucin, which directed against O-AcSAs in serum of acute lymphoblastic leukemia (ALL) patients, and their binding was totally abolished with de-O-acetylation, confirming their specificity towards O-AcSA determinants. Besides, the specificity of the antibody fraction towards 9-O-AcSA was substantiated by hemagglutination and hemagglutination-inhibition assays (Pal et al. 2000). In another study, anti-9-OAcSGs (9-O-acetylated sialoglycoconjugates) were affinity purified from sera of childhood ALL patients and normal individuals, and their specificity toward the glycotope having terminal 9-O-acetylated SA-linked subterminal N-acetyl galactosamine (GalNAc) in α2,6 manner (9-O-AcSAα2,6GalNAc) was established and substantiated by hemagglutination assay, flow cytometry and confocal microscopy (Bandyopadhyay et al. 2005). Anti-polysialic acid antibodies Polysialic acid (polySia) is a linear homopolymer of α2–8-linked SAs attached on gangliosides and glycoproteins that play a role in cell adhesion and differentiation events in a manner that is dependent on the degree of polymerization (DP). The α2–8-linked polyNeu5Ac chains are often found in microbes and are poorly immunogenic in human and other animals due to structural mimicry (Sarff et al. 1975; Jennings and Lugowski 1981; Mandrell and Zollinger 1982; Frosch et al. 1985). Under special conditions, however, several anti-polySia antibodies have been developed. As early as 1991, anti-polySia antibody was developed by Metzman et al. (1991) to act as the markers of immature neural elements (Metzman et al. 1991). In recent years, anti-oligo/polySia antibodies, which have DP-dependent antigenic specificity, were widely utilized in biological studies for detecting and distinguishing between different oligo/polySia. Here, we summarized some commonly used oligo/polySia-specific antibodies in Table II. With the development of oligo/polySia-specific antibodies, it is more convenient to study oligo/polySia functions and their underlined biological mechanism of either physiological or pathological pathways. Table II. Anti-polysialic acid antibodies Antibody Antigen DPa References mAb.A2B5 Oligo-α(2–8)Neu5Ac 3 Bodey et al. (1990), Gillard et al. (1989), Hanashima et al. (2013), Inoko et al. (2010), Mendez-Otero and Friedman (1996), Schwarz and Futerman (1997), Seddiki et al. (1994), Sim et al. (2011) mAb.5A5 Oligo/poly-α(2–8)Neu5Ac ≥3 Sato et al. (1995) mAb.12E3 Poly-α(2–8)Neu5Ac ≥5 Sato et al. (1995) IgMNOV poly-α(2–9)Neu5NAc or alternating poly-α(2–8)/α(2–9)Neu5NAc 8–10 Kabat et al. (1986) mAb.2-2B Oligo/poly-α(2–8)Neu5Ac 8–10 Mandrell and Zollinger (1982), Rougon et al. (1986) H.46 Oligo/poly-α(2–8)Neu5Ac ≥8 Sato et al. (1995) mAb.735 Poly-α(2–8)Neu5Ac ≥10 Gluer, Schelp, et al. (1998), Gluer, Wunder, et al. (1998), Komminoth et al. (1991), Komminoth et al. (1994), Lackie et al. (1990), Malykh et al. (1999), Michalides et al. (1994), Nagae et al. (2013), Scheidegger et al. (1994), Weisgerber et al. (1990), Zuber et al. (1992) mAb.S2-566 Neu5Acα2→8Neu5Acα2→3Gal Noneb Yasukawa et al. (2007) mAb.4F7 Oligo/poly-α(2–9)Neu5Ac None Escalier et al. (1997), Miyata et al. (2011) mAb.2-4B Neu5Gcα2→(8Neu5Gcα2→)n-1 ≥2 Sato et al. (1998), Yasukawa et al. (2005), Yasukawa et al. (2007) mAb.AC1 (Neu5Gc)n 2–4 Nohara et al. (1997), Yasukawa et al. (2007) mAb.Seam 3 de-N-acetyl sialic acid containing-polysialic acid None Beninati et al. (2004), Nakano et al. (2011), Steirer and Moe (2011) Antibody Antigen DPa References mAb.A2B5 Oligo-α(2–8)Neu5Ac 3 Bodey et al. (1990), Gillard et al. (1989), Hanashima et al. (2013), Inoko et al. (2010), Mendez-Otero and Friedman (1996), Schwarz and Futerman (1997), Seddiki et al. (1994), Sim et al. (2011) mAb.5A5 Oligo/poly-α(2–8)Neu5Ac ≥3 Sato et al. (1995) mAb.12E3 Poly-α(2–8)Neu5Ac ≥5 Sato et al. (1995) IgMNOV poly-α(2–9)Neu5NAc or alternating poly-α(2–8)/α(2–9)Neu5NAc 8–10 Kabat et al. (1986) mAb.2-2B Oligo/poly-α(2–8)Neu5Ac 8–10 Mandrell and Zollinger (1982), Rougon et al. (1986) H.46 Oligo/poly-α(2–8)Neu5Ac ≥8 Sato et al. (1995) mAb.735 Poly-α(2–8)Neu5Ac ≥10 Gluer, Schelp, et al. (1998), Gluer, Wunder, et al. (1998), Komminoth et al. (1991), Komminoth et al. (1994), Lackie et al. (1990), Malykh et al. (1999), Michalides et al. (1994), Nagae et al. (2013), Scheidegger et al. (1994), Weisgerber et al. (1990), Zuber et al. (1992) mAb.S2-566 Neu5Acα2→8Neu5Acα2→3Gal Noneb Yasukawa et al. (2007) mAb.4F7 Oligo/poly-α(2–9)Neu5Ac None Escalier et al. (1997), Miyata et al. (2011) mAb.2-4B Neu5Gcα2→(8Neu5Gcα2→)n-1 ≥2 Sato et al. (1998), Yasukawa et al. (2005), Yasukawa et al. (2007) mAb.AC1 (Neu5Gc)n 2–4 Nohara et al. (1997), Yasukawa et al. (2007) mAb.Seam 3 de-N-acetyl sialic acid containing-polysialic acid None Beninati et al. (2004), Nakano et al. (2011), Steirer and Moe (2011) aDP, degree of polymerization. bNone: Not memtioned. Table II. Anti-polysialic acid antibodies Antibody Antigen DPa References mAb.A2B5 Oligo-α(2–8)Neu5Ac 3 Bodey et al. (1990), Gillard et al. (1989), Hanashima et al. (2013), Inoko et al. (2010), Mendez-Otero and Friedman (1996), Schwarz and Futerman (1997), Seddiki et al. (1994), Sim et al. (2011) mAb.5A5 Oligo/poly-α(2–8)Neu5Ac ≥3 Sato et al. (1995) mAb.12E3 Poly-α(2–8)Neu5Ac ≥5 Sato et al. (1995) IgMNOV poly-α(2–9)Neu5NAc or alternating poly-α(2–8)/α(2–9)Neu5NAc 8–10 Kabat et al. (1986) mAb.2-2B Oligo/poly-α(2–8)Neu5Ac 8–10 Mandrell and Zollinger (1982), Rougon et al. (1986) H.46 Oligo/poly-α(2–8)Neu5Ac ≥8 Sato et al. (1995) mAb.735 Poly-α(2–8)Neu5Ac ≥10 Gluer, Schelp, et al. (1998), Gluer, Wunder, et al. (1998), Komminoth et al. (1991), Komminoth et al. (1994), Lackie et al. (1990), Malykh et al. (1999), Michalides et al. (1994), Nagae et al. (2013), Scheidegger et al. (1994), Weisgerber et al. (1990), Zuber et al. (1992) mAb.S2-566 Neu5Acα2→8Neu5Acα2→3Gal Noneb Yasukawa et al. (2007) mAb.4F7 Oligo/poly-α(2–9)Neu5Ac None Escalier et al. (1997), Miyata et al. (2011) mAb.2-4B Neu5Gcα2→(8Neu5Gcα2→)n-1 ≥2 Sato et al. (1998), Yasukawa et al. (2005), Yasukawa et al. (2007) mAb.AC1 (Neu5Gc)n 2–4 Nohara et al. (1997), Yasukawa et al. (2007) mAb.Seam 3 de-N-acetyl sialic acid containing-polysialic acid None Beninati et al. (2004), Nakano et al. (2011), Steirer and Moe (2011) Antibody Antigen DPa References mAb.A2B5 Oligo-α(2–8)Neu5Ac 3 Bodey et al. (1990), Gillard et al. (1989), Hanashima et al. (2013), Inoko et al. (2010), Mendez-Otero and Friedman (1996), Schwarz and Futerman (1997), Seddiki et al. (1994), Sim et al. (2011) mAb.5A5 Oligo/poly-α(2–8)Neu5Ac ≥3 Sato et al. (1995) mAb.12E3 Poly-α(2–8)Neu5Ac ≥5 Sato et al. (1995) IgMNOV poly-α(2–9)Neu5NAc or alternating poly-α(2–8)/α(2–9)Neu5NAc 8–10 Kabat et al. (1986) mAb.2-2B Oligo/poly-α(2–8)Neu5Ac 8–10 Mandrell and Zollinger (1982), Rougon et al. (1986) H.46 Oligo/poly-α(2–8)Neu5Ac ≥8 Sato et al. (1995) mAb.735 Poly-α(2–8)Neu5Ac ≥10 Gluer, Schelp, et al. (1998), Gluer, Wunder, et al. (1998), Komminoth et al. (1991), Komminoth et al. (1994), Lackie et al. (1990), Malykh et al. (1999), Michalides et al. (1994), Nagae et al. (2013), Scheidegger et al. (1994), Weisgerber et al. (1990), Zuber et al. (1992) mAb.S2-566 Neu5Acα2→8Neu5Acα2→3Gal Noneb Yasukawa et al. (2007) mAb.4F7 Oligo/poly-α(2–9)Neu5Ac None Escalier et al. (1997), Miyata et al. (2011) mAb.2-4B Neu5Gcα2→(8Neu5Gcα2→)n-1 ≥2 Sato et al. (1998), Yasukawa et al. (2005), Yasukawa et al. (2007) mAb.AC1 (Neu5Gc)n 2–4 Nohara et al. (1997), Yasukawa et al. (2007) mAb.Seam 3 de-N-acetyl sialic acid containing-polysialic acid None Beninati et al. (2004), Nakano et al. (2011), Steirer and Moe (2011) aDP, degree of polymerization. bNone: Not memtioned. Anti-gangliosides antibodies Gangliosides are SA-containing glycosphingolipids that are most abundant on the cell surface in the nervous system. Heterogeneity and diversity of the structures in their carbohydrate chains are characteristic hallmarks of these lipids (Yu et al. 2011). Gangliosides can be divided into the following four categories according to the amount of SA contents: GM1-3, GD1-3, GT1/3 and GQ1. Therefore, profiling gangliosides allows the study of gangliosides functions and their underlined biological mechanism of either physiological or pathological pathways. Ganglioside-specific antibodies can be used to detect different kinds of gangliosides on the cell surface specifically and conveniently, providing researchers more convenience in correlational studies. A variety of monoclonal antibodies recognizing gangliosides were developed. Some commonly used gangliosides-specific antibodies are summarized in Table III. Table III. Anti-ganglioside antibodies Gangliosides Antibodies References GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GMB16 Kotani et al. (1992) IgG anti-GM1 mAb Hotta et al. (2014) Fucosyl-GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GM1b GMR6,GMR17 Kotani et al. (1992) GM2 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) DMAb-1, DMAb-2, DMAb-3, and DMAb-5 Bjerkvig et al. (1991) DMF10.62.3, DMF10.167.4 Retter et al. (2005) GMB28 Kotani et al. (1992) KM531 Dohi et al. (1990) KM8969 Nakamura et al. (1999) KM966 Nakamura et al. (1994) L55 Wu et al. (1999) L55-81 MAb Nishinaka et al. (1996) mAb 3–207 Yamaguchi et al. (1990) N-Acetyl- and N-glycolyl-GM2 KM8969 Nakamura et al. (1999) mAb 5-3 Kawashima et al. (1993) MK1-16 Varki (2001) MK2-34 Varki (2001) NeuGc-GM2 GMR14 Kawashima et al. (1993) GM3 GMA1 Kawashima et al. (1993) GMR6 Kotani et al. (1992) HuMab L612 Hoon et al. (1993) N-Glycolyl GM3 14F7 Roque-Navarro et al. (2008) Neu5Ac-GM3 M2590 Hirabayashi et al. (1985) Neu5Gc-GM3 chP3 Talavera et al. (2009) GMR8 Kawashima et al. (1993) P3 Vazquez et al. (1998) GM3 lactone P5-1, P5-3 Ding et al. (1992) GD1a GMR6, GMR17 Kotani et al. (1992) GD1b AGM-1, AGM-2, AGM-3 Watarai et al. (1994) O-Acetyl GD1b 493D4 Zhang et al. (1997) GD2 10B8 Cochonneau et al. (2013) 14G2a Horwacik et al. (2013), Kowalczyk et al. (2009) 220–51 Yoshida et al. (2001) GMA1 Kawashima et al. (1993) KM8969 Nakamura et al. (1999) mAb 3–207 Yamaguchi et al. (1990) O-Acetyl GD2 8B6 Cochonneau et al. (2013) 493D4 Zhang et al. (1997) GD3 GMA1 Kawashima et al. (1993) R-24 Dippold et al. (1984) Neu5Gc-Neu5Gc-GD3 GMR3 Ozawa et al. (1992) O-Acetyl GD3 493D4 Zhang et al. (1997) GT1a GMR11 Kotani et al. (1992) GT1b GMR6, GMR17 Kotani et al. (1992) GT3 18B8 Grunwald et al. (1985) A2B5 Dubois et al. (1990) 9-O-Acetyl GT3 A2B5 Dubois et al. (1990) 493D4 Zhang et al. (1997) GQ1 anti-GQ1 Hashemilar et al. (2014) Gangliosides Antibodies References GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GMB16 Kotani et al. (1992) IgG anti-GM1 mAb Hotta et al. (2014) Fucosyl-GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GM1b GMR6,GMR17 Kotani et al. (1992) GM2 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) DMAb-1, DMAb-2, DMAb-3, and DMAb-5 Bjerkvig et al. (1991) DMF10.62.3, DMF10.167.4 Retter et al. (2005) GMB28 Kotani et al. (1992) KM531 Dohi et al. (1990) KM8969 Nakamura et al. (1999) KM966 Nakamura et al. (1994) L55 Wu et al. (1999) L55-81 MAb Nishinaka et al. (1996) mAb 3–207 Yamaguchi et al. (1990) N-Acetyl- and N-glycolyl-GM2 KM8969 Nakamura et al. (1999) mAb 5-3 Kawashima et al. (1993) MK1-16 Varki (2001) MK2-34 Varki (2001) NeuGc-GM2 GMR14 Kawashima et al. (1993) GM3 GMA1 Kawashima et al. (1993) GMR6 Kotani et al. (1992) HuMab L612 Hoon et al. (1993) N-Glycolyl GM3 14F7 Roque-Navarro et al. (2008) Neu5Ac-GM3 M2590 Hirabayashi et al. (1985) Neu5Gc-GM3 chP3 Talavera et al. (2009) GMR8 Kawashima et al. (1993) P3 Vazquez et al. (1998) GM3 lactone P5-1, P5-3 Ding et al. (1992) GD1a GMR6, GMR17 Kotani et al. (1992) GD1b AGM-1, AGM-2, AGM-3 Watarai et al. (1994) O-Acetyl GD1b 493D4 Zhang et al. (1997) GD2 10B8 Cochonneau et al. (2013) 14G2a Horwacik et al. (2013), Kowalczyk et al. (2009) 220–51 Yoshida et al. (2001) GMA1 Kawashima et al. (1993) KM8969 Nakamura et al. (1999) mAb 3–207 Yamaguchi et al. (1990) O-Acetyl GD2 8B6 Cochonneau et al. (2013) 493D4 Zhang et al. (1997) GD3 GMA1 Kawashima et al. (1993) R-24 Dippold et al. (1984) Neu5Gc-Neu5Gc-GD3 GMR3 Ozawa et al. (1992) O-Acetyl GD3 493D4 Zhang et al. (1997) GT1a GMR11 Kotani et al. (1992) GT1b GMR6, GMR17 Kotani et al. (1992) GT3 18B8 Grunwald et al. (1985) A2B5 Dubois et al. (1990) 9-O-Acetyl GT3 A2B5 Dubois et al. (1990) 493D4 Zhang et al. (1997) GQ1 anti-GQ1 Hashemilar et al. (2014) Table III. Anti-ganglioside antibodies Gangliosides Antibodies References GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GMB16 Kotani et al. (1992) IgG anti-GM1 mAb Hotta et al. (2014) Fucosyl-GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GM1b GMR6,GMR17 Kotani et al. (1992) GM2 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) DMAb-1, DMAb-2, DMAb-3, and DMAb-5 Bjerkvig et al. (1991) DMF10.62.3, DMF10.167.4 Retter et al. (2005) GMB28 Kotani et al. (1992) KM531 Dohi et al. (1990) KM8969 Nakamura et al. (1999) KM966 Nakamura et al. (1994) L55 Wu et al. (1999) L55-81 MAb Nishinaka et al. (1996) mAb 3–207 Yamaguchi et al. (1990) N-Acetyl- and N-glycolyl-GM2 KM8969 Nakamura et al. (1999) mAb 5-3 Kawashima et al. (1993) MK1-16 Varki (2001) MK2-34 Varki (2001) NeuGc-GM2 GMR14 Kawashima et al. (1993) GM3 GMA1 Kawashima et al. (1993) GMR6 Kotani et al. (1992) HuMab L612 Hoon et al. (1993) N-Glycolyl GM3 14F7 Roque-Navarro et al. (2008) Neu5Ac-GM3 M2590 Hirabayashi et al. (1985) Neu5Gc-GM3 chP3 Talavera et al. (2009) GMR8 Kawashima et al. (1993) P3 Vazquez et al. (1998) GM3 lactone P5-1, P5-3 Ding et al. (1992) GD1a GMR6, GMR17 Kotani et al. (1992) GD1b AGM-1, AGM-2, AGM-3 Watarai et al. (1994) O-Acetyl GD1b 493D4 Zhang et al. (1997) GD2 10B8 Cochonneau et al. (2013) 14G2a Horwacik et al. (2013), Kowalczyk et al. (2009) 220–51 Yoshida et al. (2001) GMA1 Kawashima et al. (1993) KM8969 Nakamura et al. (1999) mAb 3–207 Yamaguchi et al. (1990) O-Acetyl GD2 8B6 Cochonneau et al. (2013) 493D4 Zhang et al. (1997) GD3 GMA1 Kawashima et al. (1993) R-24 Dippold et al. (1984) Neu5Gc-Neu5Gc-GD3 GMR3 Ozawa et al. (1992) O-Acetyl GD3 493D4 Zhang et al. (1997) GT1a GMR11 Kotani et al. (1992) GT1b GMR6, GMR17 Kotani et al. (1992) GT3 18B8 Grunwald et al. (1985) A2B5 Dubois et al. (1990) 9-O-Acetyl GT3 A2B5 Dubois et al. (1990) 493D4 Zhang et al. (1997) GQ1 anti-GQ1 Hashemilar et al. (2014) Gangliosides Antibodies References GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GMB16 Kotani et al. (1992) IgG anti-GM1 mAb Hotta et al. (2014) Fucosyl-GM1 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) GM1b GMR6,GMR17 Kotani et al. (1992) GM2 AGM-1, AGM-2, AGM-3 Watarai et al. (1994) DMAb-1, DMAb-2, DMAb-3, and DMAb-5 Bjerkvig et al. (1991) DMF10.62.3, DMF10.167.4 Retter et al. (2005) GMB28 Kotani et al. (1992) KM531 Dohi et al. (1990) KM8969 Nakamura et al. (1999) KM966 Nakamura et al. (1994) L55 Wu et al. (1999) L55-81 MAb Nishinaka et al. (1996) mAb 3–207 Yamaguchi et al. (1990) N-Acetyl- and N-glycolyl-GM2 KM8969 Nakamura et al. (1999) mAb 5-3 Kawashima et al. (1993) MK1-16 Varki (2001) MK2-34 Varki (2001) NeuGc-GM2 GMR14 Kawashima et al. (1993) GM3 GMA1 Kawashima et al. (1993) GMR6 Kotani et al. (1992) HuMab L612 Hoon et al. (1993) N-Glycolyl GM3 14F7 Roque-Navarro et al. (2008) Neu5Ac-GM3 M2590 Hirabayashi et al. (1985) Neu5Gc-GM3 chP3 Talavera et al. (2009) GMR8 Kawashima et al. (1993) P3 Vazquez et al. (1998) GM3 lactone P5-1, P5-3 Ding et al. (1992) GD1a GMR6, GMR17 Kotani et al. (1992) GD1b AGM-1, AGM-2, AGM-3 Watarai et al. (1994) O-Acetyl GD1b 493D4 Zhang et al. (1997) GD2 10B8 Cochonneau et al. (2013) 14G2a Horwacik et al. (2013), Kowalczyk et al. (2009) 220–51 Yoshida et al. (2001) GMA1 Kawashima et al. (1993) KM8969 Nakamura et al. (1999) mAb 3–207 Yamaguchi et al. (1990) O-Acetyl GD2 8B6 Cochonneau et al. (2013) 493D4 Zhang et al. (1997) GD3 GMA1 Kawashima et al. (1993) R-24 Dippold et al. (1984) Neu5Gc-Neu5Gc-GD3 GMR3 Ozawa et al. (1992) O-Acetyl GD3 493D4 Zhang et al. (1997) GT1a GMR11 Kotani et al. (1992) GT1b GMR6, GMR17 Kotani et al. (1992) GT3 18B8 Grunwald et al. (1985) A2B5 Dubois et al. (1990) 9-O-Acetyl GT3 A2B5 Dubois et al. (1990) 493D4 Zhang et al. (1997) GQ1 anti-GQ1 Hashemilar et al. (2014) Ganglioside antibodies have great clinical promise for the treatment of cancers as they can directly affect a tumor cell’s growth and/or survival, which are of particular interest for immunotherapy. Rock et al. found that a ganglioside antibody, DMF10.62.3, and a clonally related antibody, DMF10.167.4, can recognize the ganglioside GM2 expressed on a large number of tumor cell lines, including human melanoma and small cell lung carcinoma, but not on normal primary cell lines or most normal tissues (Retter et al. 2005). Interestingly, DMF10.167.4 was able to induce apoptosis and/or block cellular proliferation when cultured in vitro with the human Jurkat T lymphoma, CHL-1 melanoma and SBC-3 small cell lung carcinoma lines. This antibody could prevent murine E710.2.3 lymphoma, human CHL-1 melanoma and SBC-3 small cell lung carcinoma lines from establishing tumors and blocked progression of established CHL-1 and SBC-3 tumors in vivo. This data indicated that monoclonal antibody DMF10.167.4 may have immunotherapeutic potential for cancer treatment. Anti-sialyl Lewis a (SLea) and sialyl Lewis x (SLex) antibodies SLea and SLex are positional isomers and act as ligands for vascular cell adhesion molecules such as E-selectin. One important pathological role for SLea and SLex is to facilitate hematogenous metastasis through mediating adhesion of circulating cancer cells to the vascular endothelium (Trinchera et al. 2017). SLea is well known as carbohydrate antigen 19-9 (CA 19-9) tumor serum marker. For decades it has been used as a prognostic indicator and valuable tool for monitoring pancreatic and gastrointestinal cancers (Goonetilleke and Siriwardena 2007; Kannagi 2007; Galli et al. 2013). The first monoclonal antibody N 19-9 against CA 19-9 was generated in the early 1980s, and was successfully applied to detect CA 19-9 in the sera of patients with digestive cancers (Magnani et al. 1983; Kannagi et al. 1988). The radio immunoassays initially used for the measurement of CA 19-9 in the serum were replaced by enzyme immunoassays, which are now almost all automated in clinical laboratories (Bertsch et al. 2013; Chia et al. 1985). Same as SLea, the monoclonal antibodies for SLex were first reported in the 1980s for cancer diagnostics (Fukushima et al. 1984; Zenita et al. 1988; Pinho et al. 2007). Cancers originated in the lung, ovary and mammary gland showed high expression levels of SLex. Later, these highly specific antibodies, such as CSLEX1, were used to reveal the significant roles of SLex in the inflammatory and immune processes (Munro et al. 1992; Miyara et al. 2015). Another breakthrough in SLex history is the discovery of SLex mediating human sperm binding on the zona pellucida (Pang et al. 2011). SLex is the most abundant terminal sequence on the N- and O-glycans of human zona pellucida, and represents the major carbohydrate ligand for human sperm-egg binding. Detecting cell surface SAs with SA-specific recombinant proteins SAs often serve as receptors recognized by a variety of specific binding proteins of endogenous and exogenous origin for a specific biological process. Therefore, native and recombinant SA-recognizing proteins are capable of detecting specific SA structures and their distributions (Altheide et al. 2006). So far, recombinant SA-specific microbial protein, Siglec-Fc fusion proteins and endoenuraminidase-green fluorescent protein (GFP) fusion proteins were developed for profiling cell surface SAs and are summarized below. SA-specific recombinant microbial proteins The influenza viruses use their cell surface glycoprotein hemagglutinin (HA) to bind host cell surface SAs containing glycans for initial adhesion and infection (Hidari and Suzuki 2010). Influenza C virus HA has two functions: binding 9-O-acetylated SA (9-O-AcSA) and remove the 9-acetyl group following binding (Wang and Veit 2016). Due to this unique property, it is referred as HA-esterase (HE). In the past, heterologously expressed ectodomain of recombinant Influenza C virus HE has proven a useful tool for investigating 9-O-AcSA biological distribution and functions (Klein et al. 1994; Martin et al. 2003). Since then, recombinant SA-binding proteins of the African landsnail Achatinafulica (Mukherjee et al. 2008) and Californian crab Cancer antennarius (Parameswaran et al. 2013) have been used to detect O-AcSA species. It is known that nidovirus HEs resemble influenza C HE fusion protein in that they bind to 9-O-AcSAs in a 9-O-acetyl-dependent fashion and function as sialate-9-O-acetylesterases (de Groot 2006). Langereis et al. (2015) demonstrated that dual-functional nidoviruses HE envelope proteins distinguish between a varieties of closely related O-AcSAs, such as 4-O-AcSAs, 7,9-di-O-AcSAs and 9-O-AcSAs. They expressed a comprehensive set of nidovirus HEs as Fc fusion proteins with the esterase inactivated through an active site Ser-to-Ala substitution. By using soluble forms of HE as lectins and sialate-O-acetylesterases, they successfully validated differential expression of distinct O-Ac-sialoglycan populations in a cell-, tissue- and organ-specific fashion (Figure 5). These findings indicated that SA-O-acetylation/de-O-acetylation may be critical to cell development, homeostasis and function. Most recently, Wasik et al. used these recombinant soluble nidovirus HEs to detect O-acetylated (4-O-acetyl, 9-O-acetyl and 7,9-O-acetyl) SAs on the cells and tissues that are targets for infection by influenza viruses and other viruses in their natural hosts, as well as in some animal models (Wasik et al. 2017). As they reported, 9-O-acetyl (and 7,9-) modified SA forms were found on cells and tissues of many hosts, including mice, humans, ferrets, guinea pigs, pigs, horses, dogs, ducks and embryonated chicken egg tissues and membranes. However, 4-O-AcSAs were found in the respiratory tissues of a few animals, being primarily displayed in horse and guinea pig, but not in humans or pigs. These results suggest that these SAs variants may influence virus tropisms by altering and selecting their cell interactions. Overall, SA-specific recombinant proteins can be powerful tools for detecting specific SAs on cells and tissues. Fig. 5. View largeDownload slide Differential expression of O-AcSA in cultured cells and tissues as detected by lectin-immunofluorescence assay (L-IFA): (A) Double L-IFA on HEK293T and HeLa cells stained for P4- and LUN-type SAs (merged images). (B) Immunohistochemical staining of cross-sections of mouse brain with P4 (DAB) and LUN (VectorRed). Images in pseudo-colors (hematoxylin [Htx], blue; P4 and LUN in red or green as indicated) were created by spectral analysis. P4-type SAs: 9-O-AcSAs; LUN-type SAs: 7,9-di-O-AcSAs (Langereis et al. 2015). Fig. 5. View largeDownload slide Differential expression of O-AcSA in cultured cells and tissues as detected by lectin-immunofluorescence assay (L-IFA): (A) Double L-IFA on HEK293T and HeLa cells stained for P4- and LUN-type SAs (merged images). (B) Immunohistochemical staining of cross-sections of mouse brain with P4 (DAB) and LUN (VectorRed). Images in pseudo-colors (hematoxylin [Htx], blue; P4 and LUN in red or green as indicated) were created by spectral analysis. P4-type SAs: 9-O-AcSAs; LUN-type SAs: 7,9-di-O-AcSAs (Langereis et al. 2015). Recombinant Siglec-Fc fusion proteins SA-binding immunoglobulin-like lectins (Siglecs) are members of the Ig superfamily that recognize SA residues of glycoproteins. The recombinant Siglec proteins can be used in the detection of cell surface SAs. Siglec-E is a mouse CD33-related Siglec that preferentially binds to SA residues of the cellular glycocalyx. Crocker group expressed and purified a series of recombinant Siglec-Fc fusion proteins comprising the Fc portion of human IgG1 and the extracellular region of either Siglec-E, Siglec-F, CD22 (Siglec-2), or the first three extracellular domains of sialoadhesin (Sn (1–3)) to study the binding affinities to the SAs in N-glycans on T-lymphocytes (Redelinghuys et al. 2011). Recently, Neuman et al. used Siglec-E:Fc fusion protein to detect the neurons and astrocytes glycocalyx (Claude et al. 2013). In this study, neurons and astrocytes were incubated with the Siglec-E:Fc fusion protein and examined by confocal image, which showed Siglec-E:Fc fusion protein binding. However, removal of SAs by sialidase led to a decreased binding of Siglec-E:Fc to neurons (Figure 6A) and astrocytes (Figure 6B). Therefore, Siglec-E:Fc fusion can be used for cell surface SA study. Together with other data, they found that Siglec-E recognizes the intact neuronal glycocalyx and has neuroprotective function by preventing phagocytosis and the associated oxidative burst (Claude et al. 2013). Fig. 6. View largeDownload slide Binding of Siglec-E to sialic acid residues of neural cells. Neurons/astrocytes were either untreated or treated with sialidase and then incubated with the Siglec-E:Fc fusion protein. Removal of sialic acids by sialidase led to a decreased binding of Siglec-E:Fc to neurons (A) and astrocytes (B). Representative images of three independent experiments are shown (Claude et al. 2013). Fig. 6. View largeDownload slide Binding of Siglec-E to sialic acid residues of neural cells. Neurons/astrocytes were either untreated or treated with sialidase and then incubated with the Siglec-E:Fc fusion protein. Removal of sialic acids by sialidase led to a decreased binding of Siglec-E:Fc to neurons (A) and astrocytes (B). Representative images of three independent experiments are shown (Claude et al. 2013). Except for the ordinary fusion proteins of the Siglec and the Fc portion, in vitro complexes of lectin-peroxidase-Fc fusion proteins were also generated for proximity labeling using polyclonal anti-IgG Fc. Wu et al. developed a proximity labeling method to identify counter-receptors on cell membranes for both membrane and soluble lectins based on horseradish peroxidase-catalyzed biotinylation. Typically, asialoadhesin (Sn, Siglec-1, CD169)-horseradish peroxidase-human IgG1 Fc recombinant protein was created and used in this study. It was proven that this structure could bind with the human erythrocyte glycoproteins that are heavily sialylated (Wu et al. 2017). Recombinant endoenuraminidase-GFP fusion proteins Endoneuraminidase-N (Endo-N) is a bacteriophage-derived enzyme which can specifically cleave α2,8-linked polySia (Finne and Makela 1985; Rutishauser et al. 1985). It has been shown that the removal of polySia with Endo-N results in an accumulation of neuroblasts in the SVZ and RMS (Ono et al. 1994; Petridis et al. 2004). Jokilammi et al. cloned a catalytically inactive endosialidase known to bind but not degrade polySia, and fused it with the GFP. This fusion protein could be used as a molecular beacon to detect the polySia through fluorescence microscopy, binding assays and immunoblots, which offers the opportunity to test clinical samples for polySia in cells rapidly and conveniently (Jokilammi et al. 2004). This technology was then used as a standard protocol to detect the polySia expression on the cell surface, including murine bone marrow cells (Stamatos et al. 2014) and human bone marrow-derived mesenchymal stromal cells (Skog et al. 2016). Summary The expression level and linkage of cell surface SAs, known as cell surface sialoform represent a specific cellular status and function. The development of selective and unique approaches for visualization, identification and characterization of cell surface SAs play key roles for fully understanding of the role of cell surface SAs and glycans in biological processes. In the past, lectins, antibodies and recombinant proteins have been developed for histomchemistry, fluorescent imaging, flow cytometry and microarray investigations of cell surface specific SAs, sialyglycans and their modifications. More specific SA-recognizing molecules with the ability to distinguish the SA linkage and conjugated sugar sequence are much needed. These molecules help to better understand the function of cell surface SAs, glycans and glycoconjugates and their underlying mechanism of either physiological or pathological processes. The advantage of these bioaffinity approaches is their specificity to a SA with specific modification, and ultimately, these advanced approaches will open the door for clinical diagnostic applications by detecting specific sialoform of the cells and tissues of different diseases. Acknowledgements This work was supported by Dr. John C. Vitullo’s Pilot and Bridge Program Award from the Center for Gene Regulation in Health and Disease (GRHD) and Faculty Research Development Award at Cleveland State University (X.L.S.). This work was partially supported by grant from The National Natural Science Foundation of China (31771627, H.N.). Conflict of interest statement None declared. Abbreviations ALL acute lymphoblastic leukemia BHV bioprosthetic heart valves DP degree of polymerization Endo-N endoneuraminidase-N gal galactose GalNAc N-acetylgalactosamine GFP green fluorescent protein HA hemagglutinin HE HA-esterase IgM immunoglobulin M MAL Maackia amurensis leukoagglutinin Neu5Ac N-acetyl neuraminic acid Neu5Gc N-glycolyl neuraminic acid polySia polysialic acid SAs sialic acids SLea sialyl Lewis a SLex sialyl Lewis x SNA Sambucus nigra References Accogli G , Desantis S , Martino NA , Dell’Aquila ME , Gemeiner P , Katrlik J . 2016 . 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Published: Dec 1, 2018