Glycobiology Advance Access originally published online on November 10, 2005
Glycobiology 2006 16(3):237-243; doi:10.1093/glycob/cwj058
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LacdiNAc- and LacNAc-containing glycans induce granulomas in an in vivo model for schistosome egg-induced hepatic granuloma formation
2 Department of Parasitology, Center of Infectious Diseases, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands; and 3 Department of Pathology, Antwerp University, Universiteitsplein 1, B-2610 Antwerp, Belgium
1To whom correspondence should be addressed; e-mail: c.h.hokke{at}lumc.nl
Received on September 30, 2005; revised on November 7, 2005; accepted on November 8, 2005
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Abstract |
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Schistosomes, major parasitic helminths, express numerous glycoconjugates that provoke humoral and cellular immune responses in the infected human host. The main pathology in schistosomiasis is due to the formation of granulomas around tissue-trapped eggs and the resulting organ damage. By using a mouse model of induction of granulomas by hepatic implantation of antigen-coated beads, it has been determined that the glycan part of schistosomal soluble egg antigens (SEA) initiates granulomogenesis. To identify which individual glycan elements in this complex SEA mixture are granulomogenic, we have tested in the same mouse model conjugates of various synthetic oligosaccharides characteristic for schistosome eggs, including GalNAcß1-4GlcNAc (LacdiNAc, LDN), Galß1-4(Fuc
1-3)GlcNAc (Lewisx), Fuc1-2Fuc1-3GlcNAc (DF-Gn), and Fuc1-3GalNAcß1-4(Fuc1-3)GlcNAc (F-LDN-F). Ribonuclease (RNase) A and B, and different fetuin glycoforms were included as controls. Only beads that carry glycoconjugates with terminal LacdiNAc or Galß1-4GlcNAc (LacNAc, LN) elements gave rise to granulomas, with macrophage, lymphocyte, and eosinophil levels similar to the granulomatous lesions caused by schistosome eggs in a natural infection. Uncoated beads, and beads coated with fucosylated glycoconjugates or glycoconjugates lacking terminally exposed Gal or GalNAc, only attracted a monolayer of macrophages. These results indicate that the formation of hepatic granulomas is triggered specifically by glycoconjugates which carry terminal LacNAc or LacdiNAc, both constituents of the schistosome egg. Key words: carbohydrate antigen / galectin / hepatic granulomas / schistosomiasis
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Introduction |
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Granulomas are localized inflammatory lesions. Their formation is characterized by the recruitment and aggregation of activated mononuclear inflammatory cells and sensitized CD4+ T lymphocytes. This process is the result of both innate and adaptive components of the immune response. Granulomas emerge during chronic inflammation in response to various stimuli including infectious pathogens (Mycobacterium tuberculosis, schistosomes) as well as noninfectious agents (silicosis, berylliosis) (Sneller, 2002
). Pathogen-induced granulomas are in fact host protective, because they isolate the pathogen in immunologically organized focal lesions surrounded by a network of matrix proteins. In schistosomiasis, a major tropical parasitic disease caused by infection with Schistosoma, granulomogenesis around tissue-trapped eggs, however, forms the basis for the development of severe pathology and may lead to fibrosis, hepatosplenomegaly, and portal hypertension (Pearce and MacDonald, 2002).
Schistosomes, in particular their eggs, express numerous proteins and lipids that carry structurally diverse and complex glycans. Analytical studies performed over the past decade have shown that these glycans contain unusual structures such as GalNAcß1-4(Fuc1-2Fuc1-3)GlcNAc (LDN-DF) and Fuc1-3GalNAcß1-4GlcNAc (F-LDN) but more widely occurring elements like Galß1-4(Fuc1-3)GlcNAc (Lewisx), GalNAcß1-4GlcNAc (LacdiNAc, LDN), and GalNAcß1-4(Fuc1-3)GlcNAc (LDN-F) have also been found (Cummings and Nyame, 1999; Hokke and Deelder, 2001; Khoo and Dell, 2001).
It has been appreciated since long that schistosome glycoconjugates are major triggers of humoral and cellular immune responses in mammalian hosts (Dunne, 1990). Several recent studies have been seeking information on the contribution of individual, defined glycans to these immunogenic properties. It has been established that antibody responses against LDN, F-LDN, LDN-F, LDN-DF, Fuc1-3GalNAcß1-4(Fuc1-3)GlcNAc (F-LDN-F), Fuc1-2Fuc (DF), and mono- and multimeric Lex elements occur in natural and experimental schistosomiasis (Eberl et al., 2001; van Remoortere et al., 2001, 2003; Naus et al., 2003; Nyame et al., 2003; van Roon et al., 2004). Furthermore, it has been shown that the Lex antigen has immunomodulatory properties: in murine schistosomiasis models, Lex conjugates induce typical immune system mediators such as interleukin-10 (IL-10) (Velupillai and Harn, 1994; Velupillai et al., 2000), and Lex conjugates act as an innate Th2 promotor on dendritic cells via a Toll-like receptor-4 dependent mechanism (Thomas et al., 2003). In addition, conjugates of the LDN-DF antigen were potent inducers of innate immune responses when added to peripheral blood mononuclear cells of naive individuals (van der Kleij et al., 2002).
With respect to hepatic granuloma formation, it has been shown that intact glycosylation of schistosome soluble egg antigens (SEA) is required for the capacity of SEA to initiate granulomas in a standardized in vivo bead model (Weiss et al., 1987; Van de Vijver et al., 2004). In this model, beads injected in the caecal vein of mice induce a synchronized hepatic granulomatous inflammation when they are coated with SEA or adult worm antigens, as well as with keyhole limpet haemocyanin (KLH), a molluscan glycoprotein with considerable immunological carbohydrate cross-reactivity with SEA (Geyer et al., 2005). The cellular characteristics of the bead-induced granulomas are essentially identical to those induced by eggs in a natural infection. Tryptic cleavage of the protein backbone in KLH does not alter its granulomogenic properties in this model, whereas sodium periodate treatment of SEA and KLH to alter the integrity of the carbohydrate chains completely destroys those properties (Van de Vijver et al., 2004). Although these studies clearly demonstrate that granuloma formation is induced by carbohydrates, no information is available on which particular schistosome glycans are involved. Therefore, we tested a series of defined schistosome-related neoglycoproteins (van Remoortere et al., 2000, 2001, 2003; Naus et al., 2003; van Roon et al., 2004, 2005) and natural, nonschistosomal reference glycoproteins in the murine hepatic granulomogenesis model and thus defined the glycan elements present in SEA that harbor granuloma-inducing activities.
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Results |
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Granuloma formation is induced only by asialofetuin- and LDN-coated beads
Agarose beads with the approximate size of Schistosoma mansoni eggs (63–75 µm) were coated with neoglycoconjugates representative for glycan antigens present on glycoproteins and glycolipids from S. mansoni or with different mammalian reference glycoproteins (Table I). Each compound was tested in a standardized in vivo model for hepatic granulomogenesis. BALB/c mice were injected with 20.000 beads and killed at day 16 after injection. Beads were found lodged in the peripheral presinusoidal ramifications of the portal vein. Uncoated beads (Figure 1A) and control beads coated with Bovine serum albumine (BSA) (data not shown) showed no cellular reaction, except for a monolayer of macrophages. With respect to the BSA neoglycoconjugates, a granulomatous response comprising macrophages, multinucleate giant cells, lymphocytes, and eosinophils was exclusively observed surrounding beads coated with the LDN conjugate (Figure 1B). Beads coated with one of the fucosylated neoglycoconjugates LDN-F, F-LDN-F, Lex, Fuc
1-3GlcNAc (F-Gn), Fuc1-2Fuc1-3GlcNAc (DF-Gn), as well as with the GlcNAc (Gn) monosaccharide only elicited a reaction similar to uncoated beads. In the group of beads coated with the mammalian glycoproteins, only asialofetuin evoked a significant granulomatous inflammatory reaction (Figure 1C). Ribonuclease (RNase A) (a nonglycosylated protein), RNase B (its N-glycosylated variant that carries an oligomannosidic N-glycan), native fetuin, and agalactoasialofetuin were only surrounded by a single row of mononuclear cells as observed with the uncoated control beads.
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Quantitative and temporal morphology of the bead-induced granulomas
To quantitate the constituent granuloma cells formed around the LDN- and asialofetuin-coated beads, and to identify the expressed adhesion and extracellular matrix proteins, mouse liver sections were examined by immunophenotyping at day 16 after injection (Table II). Macrophages were the dominant cell type, but eosinophils and lymphocytes were also abundantly present. The bead-induced lesions highly expressed fibronectin and entactin. Type IV collagen was weakly present in the granulomas and the basement membranes of the blood vessels. Moderate to strong immunoreactivity for the adhesion molecules ICAM-1 and its ligand LFA-1 was seen in the granulomas.
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In a time-course experiment, granulomas were examined at 3, 8, 16, 22, and 28 days after injection of asialofetuin-coated beads. With time, a decrease in the cellularity of the asialofetuin-induced granulomas was observed, whereas the collagen became denser (Figure 2). The granuloma size was largest around 16 days after injection. Thereafter, down-regulation of the granulomas with increasing fibrosis occurred.
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Galectin-3 expression in the granulomas
In the bead-induced granulomas, a strongly positive staining for galectin-3 was found in the activated macrophages of the granulomas and in the surrounding Kupffer cells (Figure 3A). Similar patterns were obtained in granulomas caused by S. mansoni eggs in a natural infection (Figure 3B). Immunoreactivity was more pronounced in cells lying close to the LDN-coated beads or the schistosome egg. LDN was mainly localized on the surface of the eggshell, as indicated by staining with the anti-LDN monoclonal antibody (mAb) 273-3F2 (Figure 3C).
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Discussion |
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Granulomatous inflammation is a hypersensitivity reaction (Boros and Warren, 1970
) to protect the host against a variety of invading pathogenic agents, foreign particles, or etiologically unknown factors (Sneller, 2002). Hepatic granuloma formation around eggs in schistosomiasis, a Th2-type immune reaction, is due to the influx into the liver of macrophages, lymphocytes, and eosinophilic granulocytes. Recently, we reported that glycoprotein glycans in SEA play a major role in activating the formation and growth of hepatic granulomas in a standardized in vivo model (Van de Vijver et al., 2004). This study was designed to identify the particular carbohydrate elements that are responsible for the granulomogenic activity of SEA in this model.
Our data demonstrate that among the representative schistosomal glycans and appropriate controls tested, granulomogenic activity is restricted to glycoconjugates with terminal LDN or LN (as in asialofetuin) units. It has been shown that LDN is a constituent of glycans in SEA (Khoo et al., 1997). Importantly, immunofluorescence studies with anti-LDN mAbs have revealed that in schistosome eggs, LDN is located on the outer surface in the egg shell (van Remoortere et al., 2000; van den Berg et al., 2004). It should be noted that like LDN, also LN elements have been identified on schistosome egg glycoproteins (Khoo et al., 1997). Strikingly, LN is also an abundant constituent of mammalian N- and O-glycans, however, often in its sialylated or otherwise substituted form. It is not clear what the individual contribution of the LDN and LN sequences is to the granuloma-inducing properties of SEA.
The tested glycans were selected on the basis of data indicating their potential importance as activators and modulators of the immune system in schistosomiasis. LDN, LDN-F, F-LDN-F, Lex, DF-Gn, and F-Gn are all antigenic structures that elicit humoral immune responses in experimental animal, or natural human schistosome infections (Nyame et al., 1999; Eberl et al., 2001; van Remoortere et al., 2001, 2003; Naus et al., 2003; van Roon et al., 2004). Fucosylated neoglycoconjugates including Lex and LDN-DF have been established as immune modulators that induce characteristic cytokine profiles in mononuclear cells (Velupillai and Harn, 1994; van der Kleij et al., 2002). None of these typical schistosomal fucosylated glycans are active in our system showing that they have no involvement in the induction and maintenance of the granulomogenic response in the mouse model. It is possible, however, that normally structures such as Lex contribute to the balance of the granulomatous process by exerting the reported immunomodulatory effects (Velupillai et al., 2000; Okano et al., 2001; Thomas et al., 2003). In schistosome eggs, LDN, Lex, DF and many other glycan elements occur as a complex mixture (van Remoortere et al., 2000; Khoo et al., 2001; Hokke and Yazdanbakhsh, 2005). Experiments with beads that are coated with mixtures of LDN/LN and fucosylated structures could shed light on the potential anti-inflammatory effects of Lex. Previous observations showing that sensitization with Lex-containing neoglycoconjugates increases the volume of the granulomas formed around SEA beads suggest an opposite effect however (Jacobs et al., 1999). Similarly, it will be interesting to incorporate in the system various protein components of the schistosome egg which have been implicated in granuloma formation and egg-induced immunopathology, such as Sm-p40, Sm-PEPCK, and Sm-TPx-1 (Asahi and Stadecker, 2003). At least some of these egg antigens are glycoproteins, and it will be necessary to determine the glycosylation of these individual egg components to fully understand their immunological properties.
In a previous study using the same bead model, we found that KLH glycans induce granulomas, similarly as SEA (Van de Vijver et al., 2004). It has been established that F-LDN-F glycans are responsible for the immunological cross-reactivity of KLH and schistosomes (Geyer et al., 2004; Geyer et al., 2005; Robijn et al., 2005). Therefore, we included F-LDN-F conjugates in this study, and they were not able to induce granulomas. However, structural studies have shown that KLH also abundantly expresses terminal ß-galactose residues (Kurokawa et al., 2002; Geyer et al., 2005), which most likely explains the observed granulomogenic capacity of KLH.
The cellular composition of both the LDN- and asialofetuin-induced granulomas (Table II) was similar to lesions caused by SEA-coated beads or those observed around eggs during murine S. mansoni infections (Edungbola and Schiller, 1979; Van Marck et al., 1980; Pearce and MacDonald, 2002; Van de Vijver et al., 2004). Deposition of the extracellular matrix proteins fibronectin, collagen IV, and entactin, and expression of the adhesion molecules ICAM-1 and LFA-1 were also similar as in the previously described schistosome egg-induced granulomas (Nishimura et al., 1985; Jacobs et al., 1997a,b; Van de Vijver et al., 2004). Moreover, the temporal modulation of the granulomas induced by the asiolofetuin-coated beads is comparable to that of native egg-induced granulomas (Flores-Villanueva et al., 1994; Jacobs et al., 1997b). These observations are in line with our previous conclusions that the bead-induced granuloma formation process strongly resembles granulomogenesis in a natural infection, and they further support the hypothesis that the induction of adhesion and chemotatic molecules which participate in the development of granulomas is triggered by specific carbohydrate structures (Van de Vijver et al., 2004).
In view of our data, it is conceivable that Gal/GalNAc-binding lectins of the host are involved in hepatic granuloma formation. The S-type lectin galectin-3 binds to LDN as well as to LN, and galectin-3 facilitates the uptake of LDN-coated particles by phagocytic cells (van den Berg et al., 2004). Galectins are found on various cell types including macrophages, fibroblasts, and eosinophils (Rabinovich et al., 2002). All galectins bind relatively well to various galactose-containing glycans including LN (Hirabayashi et al., 2002), but galectin-3 may be unique by its capacity to also bind strongly to LDN. Substitution of the GlcNAc residue in LN with fucose to form the Lex trisaccharide abolishes binding of galectin-3, apparently because of steric hindrance by the fucose residue (Hirabayashi et al., 2002; van den Berg et al., 2004), which would explain why Lex-coated beads do not induce granulomas if galectins are involved in their initiation. Immunohistochemical analysis of liver sections indicated high expression levels of galectin-3 in the activated macrophages of the granulomas around LN-coated beads and around native schistosome eggs (Figure 3). In a previous study, it was also found that natural egg granulomas in hamsters contain elevated levels of galectin-3 and that galectin-3 was colocalized with LDN on the egg shell (van den Berg et al., 2004). In schistosomiasis, live eggs not only present various glycans, including LDN, on the egg shell, but also the secretory/excretory glycoconjugates carry a variety of antigenic glycan elements. In the bead model, static expression of glycan antigens is clearly sufficient for induction of granulomas.
In addition to the galectins, various other lectins have been characterized as receptors in macrophages and other inflammatory cells to date. DC-SIGN, a C-type lectin expressed in dendritic cells, has been described as a receptor for S. mansoni egg antigens via the 1-3-fucosylated structures Lex and LDN-F (van Die et al., 2003). This study reveals that neither Lex nor LDN-F gave rise to granuloma formation, indicating that DC-SIGN is not directly involved in the induction of the granulomas in our system. Another relevant hepatic C-type lectin, the asialoglycoprotein receptor, mediates uptake of desialylated glycoproteins that bear terminal galactose residues and—with even higher affinity—terminal GalNAc (Ashwell and Harford, 1982). However, this asialoglycoprotein receptor is not expressed in schistosomal or bead-induced granulomas (unpublished data).
In conclusion, this study indicates for the first time that specific carbohydrate elements, LDN and LN, act as primary drivers of hepatic granuloma formation. This result opens up new avenues and potential lines for research to the underlying mechanisms involved. Whether these glycans or the corresponding lectins are potential targets for intervention in the immunopathology of schistosomiasis will be an exiting research question to further examine.
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Materials and methods |
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Animals
Six-week-old male BALB/c mice were obtained from Iffa Credo, St.-Germain sur L’Arbresle, France. All animals received food and water ad libitum and were maintained in the animal care facility at Antwerp University under pathogen-free conditions. All experiments were conducted in compliance with the guidelines of the Ethical Committee of the University of Antwerp under the supervision of an animal welfare officer.
Neoglycoconjugates, mammalian model glycoproteins, and antigen-coated beads
BSA conjugates of spacer-linked oligosaccharides were prepared as previously described (van Remoortere et al., 2000, 2003; Naus et al., 2003; van Roon et al., 2005). The obtained neoglycoproteins designated LDN, LDN-F, F-LDN-F, Lex, Gn, F-Gn, and DF-Gn (Table I), contained between 5 and 14 mol glycan per mol BSA. BSA, RNase A and B, fetuin and asialofetuin were purchased from Sigma (Saint Louis, MO). Agalactoasialofetuin was prepared from asialofetuin by enzymatic degalactosylation with jackbean ß-galactosidase (Sigma). Agarose beads were coated with the neoglycoproteins and the mammalian model glycoproteins as described in full elsewhere (Van de Vijver et al., 2004). Homogeneous binding of all proteins and glycoproteins to the beads was ascertained by protein staining using the Bradford and ninhydrin methods.
Implantation of antigen-coated beads in the murine liver
Twenty thousand antigen-coated beads suspended in sterile PBS were injected in the caecal vein according to the technique described previously (Van Marck et al., 1980; Jacobs et al., 1997b). Unloaded beads and BSA-coated beads served as negative controls. Six mice were used for every batch of beads. The animals were killed 16 days after injection, when hepatic granulomas reach their maximum size (Jacobs et al., 1997b). To evaluate the temporal effect on the growth and down-regulation of the hepatic granulomas, additional BALB/c mice injected with asialofetuin-coated beads were killed 3, 8, 16, 22, and 28 days after injection.
Infection of mice
Twelve BALB/c mice were infected with 
80 cercariae of a Puerto Rican strain of S. mansoni using the ring method of Smithers and Terry (1976). The animals were killed in three groups at 8, 12, and 16 weeks after infection.
Light microscopy and immunohistochemistry
Liver specimens fixed in 10% buffered formalin were processed for light microscopy and studied as hematoxylin-eosin or as trichrome Masson stained sections. Immunophenotyping of the constituent granuloma cells was performed on 6-µm thick cryostat sections using anti-mouse antibodies directed against macrophages (F4/80, Serotec, Oxford, UK), T lymphocytes (CD4, BD Biosciences, PharMingen, San Diego, CA) and B lymphocytes (CD23, BD Biosciences). The anti-murine eosinophilic granulocyte marker, anti-mMBP-1, was a kind gift of Drs. Jamie and Nancy Lee, Mayo Clinic Scottsdale, AZ. Adhesion and extracellular matrix proteins were evaluated using anti-mouse antibodies directed against fibronectin (Telios Pharmaceuticals, San Diego, CA), collagen type IV (Institut Pasteur, Lyon, France), entactin (Boehringer Ingelheim, Heidelberg, Germany), intercellular adhesion molecule-1 (ICAM-1, R & D Systems, Minneapolis, MN) and lymphocyte function-associated antigen-1 (LFA-1, R & D Systems). Galectin-3 expression in the granulomas was visualized using a goat anti-mouse galectin-3 antibody (R & D Systems). Indirect immunoperoxidase (Perox) and alkaline phosphatase anti-alkaline phosphatase (APAAP) were the applied staining procedures. Secondary antibodies for the Perox technique were peroxidase-conjugated goat anti-rat IgG, goat anti-rabbit IgG, and rabbit anti-goat IgG (Rockland, Gilbertsville, PA). Secondary and tertiary antibodies for the APAAP technique were rabbit anti-rat IgG, the rat APAAP complex (Dako, Glostrup, Denmark), alkaline phosphatase-labeled polymer conjugated to goat anti-rabbit/anti-mouse Ig (Envision System–AP, Dako). Immunohistochemistry for galectin-3 and LDN was also carried out on 4-µm thick formalin-fixed paraffin-embedded liver sections of S. mansoni-infected animals. The LDN-reactive mAb 273-3F2 (van Remoortere et al., 2000) was applied. All sections were examined using a conventional light microscope.
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Acknowledgments |
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We thank Dieuwke Kornelis, Gunther Vrolix, Liliane Moeneclaey, and Frank Rylant for their technical assistance. Dr. J.P. Kamerling (Bijvoet Center, Utrecht) is gratefully acknowledged for providing some of the synthetic glycans. This work has been supported by the Funds of Scientific Research (FWO), Flanders (grant 1.5069.01). K.K.V. is a research assistant/aspirant of the FWO, Flanders, Belgium.
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Abbreviations |
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APAAP, alkaline phosphatase anti-alkaline phosphatase; BSA, bovine serum albumin; DF, Fuc
1-2Fuc; DF-Gn, Fuc1-2Fuc1-3GlcNAc; F-Gn, Fuc1-3GlcNAc; F-LDN, Fuc1-3GalNAcß1-4GlcNAc; F-LDN-F, Fuc1-3GalNAcß1-4(Fuc1-3)GlcNAc; Gn, GlcNAc; ICAM-1, intercellular adhesion molecule-1; KLH, keyhole limpet haemocyanin; LDN or LacdiNAc, GalNAcß1-4GlcNAc; LDN-DF, GalNAcß1-4(Fuc1-2Fuc1-3)GlcNAc; LDN-F, GalNAcß1-4(Fuc1-3)GlcNAc; Lewisx or Lex, Galß1-4(Fuc1-3)GlcNAc; LFA-1, lymphocyte function-associated antigen-1; LN or LacNAc, Galß1-4GlcNAc; mAb, monoclonal antibody; PBS, phosphate-buffered saline; Perox, indirect immunoperoxidase; RNase, ribonuclease; SEA, soluble egg antigens |
References |
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