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• W1988872209 abstract "Pemphigus foliaceus (PF) is an autoimmune skin blistering disease mediated by pathogenic autoantibodies against the desmosomal core glycoprotein desmoglein-1 (Dsg1). This study demonstrated that the O-glycan-specific plant lectin jacalin binds Dsg1 and inhibits the interaction of Dsg1/PF IgG. N-glycosylation is not involved in the interaction of Dsg1/jacalin or Dsg1/PF IgG. Subcutaneous injection of jacalin into neonatal mice drastically reduced PF IgG deposition at the epidermal cell surface and blocked PF IgG-induced skin blisters, both clinically and histologically. Interestingly, another plant lectin, peanut agglutinin, which shares the same carbohydrate specificity toward the O-linked carbohydrate structure known as Thomsen-Friedenreich antigen (TF antigen, Galβ1-3GalNAcα-O-Ser/Thr), also bound Dsg1 and blocked the skin blistering. In contrast, the plant lectin vicia villosa-B4 (VVL-B4), which shares the carbohydrate specificity toward the O-linked monosaccharide known as Thomsen-nouveau antigen (GalNAc-α1-O-Ser/Thr), did not bind Dsg1 and did not show a protective effect against the disease induced by the autoantibodies. Collectively, these results suggest that the binding of jacalin to O-linked TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and abrogates its pathogenicity in vivo. TF-specific binding ligands may have a potential therapeutic value for PF. Pemphigus foliaceus (PF) is an autoimmune skin blistering disease mediated by pathogenic autoantibodies against the desmosomal core glycoprotein desmoglein-1 (Dsg1). This study demonstrated that the O-glycan-specific plant lectin jacalin binds Dsg1 and inhibits the interaction of Dsg1/PF IgG. N-glycosylation is not involved in the interaction of Dsg1/jacalin or Dsg1/PF IgG. Subcutaneous injection of jacalin into neonatal mice drastically reduced PF IgG deposition at the epidermal cell surface and blocked PF IgG-induced skin blisters, both clinically and histologically. Interestingly, another plant lectin, peanut agglutinin, which shares the same carbohydrate specificity toward the O-linked carbohydrate structure known as Thomsen-Friedenreich antigen (TF antigen, Galβ1-3GalNAcα-O-Ser/Thr), also bound Dsg1 and blocked the skin blistering. In contrast, the plant lectin vicia villosa-B4 (VVL-B4), which shares the carbohydrate specificity toward the O-linked monosaccharide known as Thomsen-nouveau antigen (GalNAc-α1-O-Ser/Thr), did not bind Dsg1 and did not show a protective effect against the disease induced by the autoantibodies. Collectively, these results suggest that the binding of jacalin to O-linked TF carbohydrate motifs on Dsg1 impairs the Dsg1/PF autoantibody interactions and abrogates its pathogenicity in vivo. TF-specific binding ligands may have a potential therapeutic value for PF. desmoglein pemphigus foliaceus peanut agglutinin subcutaneous Thomsen-Friedenreich antigen (Galβ1-3GalNAcα-O-Ser/Thr) Thomsen-nouveau antigen (GalNAc-α1-O-Ser/Thr) vicia villosa-B4 lectin The endemic and nonendemic forms of pemphigus foliaceus (PF) are autoimmune blistering skin diseases characterized by superficial blisters, epidermal cell detachment (known as acantholysis) at the level of the granular layer of the epidermis, and IgG autoantibodies bound to the surface of detached keratinocytes (Lever et al., 1953Lever W.F. Smith P.A. Hurley N.A. Effects of intravenous heparin on the plasma lipoproteins in primary hypercholesteremic xanthomatosis and idiopathic hyperlipemia.Science. 1953; 118: 653-654Crossref PubMed Scopus (1) Google Scholar; Beutner et al., 1968Beutner E.H. Prigenzi L.S. Hale W. et al.Immunofluorescent studies of autoantibodies to intercellular areas of epithelia in Brazilian pemphigus foliaceus.Proc Soc Exp Biol Med. 1968; 127: 81-86Crossref PubMed Scopus (72) Google Scholar). The nonendemic form of PF occurs sporadically in many regions of the world and the endemic form, also known as Fogo Selvagem (FS), is common in certain rural areas of Brazil (Aoki et al., 2004Aoki V. Millikan R.C. Rivitti E.A. et al.Environmental risk factors in endemic pemphigus foliaceus (fogo selvagem).J Investig Dermatol Symp Proc. 2004; 9: 34-40Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar). The antiepidermal autoantibodies in both clinical forms of PF are predominantly and in a pathogenic manner IgG4 subclass, as demonstrated by passive transfer of the IgG fraction of these sera into mice (Rock et al., 1989Rock B. Martins C.R. Theofilopoulos A.N. et al.The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).N Engl J Med. 1989; 320: 1463-1469Crossref PubMed Scopus (234) Google Scholar; Futei et al., 2001Futei Y. Amagai M. Ishii K. et al.Predominant IgG4 subclass in autoantibodies of pemphigus vulgaris and foliaceus.J Dermatol Sci. 2001; 26: 55-61Abstract Full Text Full Text PDF PubMed Scopus (99) Google Scholar). Neonatal mice that are injected with PF IgG, IgG4, or Fab' monovalent fragment develop skin blisters and subcorneal vesicles, which recapitulate the clinical and histological features of the human disease in these animals (Roscoe et al., 1985Roscoe J.T. Diaz L. Sampaio S.A. et al.Brazilian pemphigus foliaceus autoantibodies are pathogenic to BALB/c mice by passive transfer.J Invest Dermatol. 1985; 85: 538-541Crossref PubMed Scopus (165) Google Scholar; Rock et al., 1989Rock B. Martins C.R. Theofilopoulos A.N. et al.The pathogenic effect of IgG4 autoantibodies in endemic pemphigus foliaceus (fogo selvagem).N Engl J Med. 1989; 320: 1463-1469Crossref PubMed Scopus (234) Google Scholar, Rock et al., 1990Rock B. Labib R.S. Diaz L.A. Monovalent Fab' immunoglobulin fragments from endemic pemphigus foliaceus autoantibodies reproduce the human disease in neonatal Balb/c mice.J Clin Invest. 1990; 85: 296-299Crossref PubMed Scopus (108) Google Scholar; Espana et al., 1997Espana A. Diaz L.A. Mascaro Jr, J.M. et al.Mechanisms of acantholysis in pemphigus foliaceus.Clin Immunol Immunopathol. 1997; 85: 83-89Crossref PubMed Scopus (43) Google Scholar). The antigen targeted by pathogenic PF autoantibodies is desmoglein-1 (Dsg1), a desmosomal core glycoprotein expressed predominantly in the upper layers of the epidermis (Koulu et al., 1984Koulu L. Kusumi A. Steinberg M.S. et al.Human autoantibodies against a desmosomal core protein in pemphigus foliaceus.J Exp Med. 1984; 160: 1509-1518Crossref PubMed Scopus (171) Google Scholar; Rappersberger et al., 1992Rappersberger K. Roos N. Stanley J.R. Immunomorphologic and biochemical identification of the pemphigus foliaceous autoantigen within desmosomes.J Invest Dermatol. 1992; 99: 323-330Crossref PubMed Scopus (64) Google Scholar). Affinity-purified anti-Dsg1 autoantibodies from PF sera are able to induce epidermal blisters and subcorneal acantholysis in mice passively transferred with these fractions (Amagai et al., 1995aAmagai M. Hashimoto T. Green K.J. et al.Antigen-specific immunoadsorption of pathogenic autoantibodies in pemphigus foliaceus.J Invest Dermatol. 1995; 104: 895-901Crossref PubMed Scopus (225) Google Scholar; Arteaga et al., 2002Arteaga L.A. Prisayanh P.S. Warren S.J. et al.A subset of pemphigus foliaceus patients exhibits pathogenic autoantibodies against both desmoglein-1 and desmoglein-3.J Invest Dermatol. 2002; 118: 806-811Abstract Full Text Full Text PDF PubMed Scopus (58) Google Scholar). In spite of the remarkable advances in understanding the molecular mechanisms of autoantibody-induced acantholysis in pemphigus (Rubenstein and Diaz, 2006Rubenstein D.S. Diaz L.A. Pemphigus antibody induced phosphorylation of keratinocyte proteins.Autoimmunity. 2006; 39: 577-586Crossref PubMed Scopus (14) Google Scholar; Kitajima and Aoyama, 2007Kitajima Y. Aoyama Y. A perspective of pemphigus from bedside and laboratory-bench.Clin Rev Allergy Immunol. 2007; 33: 57-66Crossref PubMed Scopus (24) Google Scholar; Sharma et al., 2007Sharma P. Mao X. Payne A.S. Beyond steric hindrance: the role of adhesion signaling pathways in the pathogenesis of pemphigus.J Dermatol Sci. 2007; 48: 1-14Abstract Full Text Full Text PDF PubMed Scopus (57) Google Scholar; Culton et al., 2008Culton D.A. Qian Y. Li N. et al.Advances in pemphigus and its endemic pemphigus foliaceus (Fogo Selvagem) phenotype: a paradigm of human autoimmunity.J Autoimmun. 2008; 31: 311-324Crossref PubMed Scopus (67) Google Scholar; Waschke, 2008Waschke J. The desmosome and pemphigus.Histochem Cell Biol. 2008; 130: 21-54Crossref PubMed Scopus (146) Google Scholar), these knowledge has not been translated into newer therapies of patients. Current therapy of PF patients mainly relies on the use of corticosteroids and immunosuppressive agents. Although these therapies significantly reduce the mortality of the disease, they result in significant morbidity because of side effects. Identifying means of interfering with the autoantibody–antigen interaction may represent an alternative approach to treat autoantibody-mediated autoimmune diseases. While investigating a possible case of IgA pemphigus, we noticed that jacalin-agarose, which was used to precipitate IgA, also precipitated the baculovirus-expressed recombinant Dsg1 ectodomain (rDsg1). Further studies demonstrate that binding of jacalin interferes with PF autoantibody binding and protects mice against PF IgG-induced skin blisters. Aliquots of conditioned culture medium containing baculovirus-expressed human rDsg1 were incubated with agarose beads that were conjugated with jacalin or protein G/A (negative control). Following extensive wash (see Materials and Methods), bound proteins were released by boiling in SDS sample buffer and subjected to immunoblotting (IB). As shown in Figure 1a, jacalin-agarose (lane 1), but not protein G/A-agarose (lane 2), was able to pull-down Dsg1. To demonstrate the carbohydrate-dependency of the binding, we tested the ability of jacalin-specific sugars to elute the bound Dsg1. We found that both melibiose (0.1M) and D-galactose (0.8M) were able to elute the bound Dsg1 (lanes 3 and 4). Moreover, preincubation of jacalin-agarose with D-galactose diminished its binding to Dsg1 (lane 5) as compared with those preincubated with tris-buffered saline (TBS)-Ca2+ buffer alone (lane 6). These results demonstrate that jacalin is able to bind rDsg1 and that the binding is galactose-dependent. Considering possible differences in glycosylation of proteins expressed by insect cells and mammalian epidermal keratinocytes, we examined the interaction of jacalin with Dsg1 extracted from the skin. Tissue lysates from human epidermis and mouse skin were incubated with jacalin-agarose or protein G/A-agarose beads. Proteins bound by the beads were released and analyzed by IB using antibodies to Dsg1. As shown in Figure 1b, the 160-kDa Dsg1 from mouse or human epidermal extracts was precipitated by jacalin-beads (lanes 1 and 2), but not by protein G/A-beads (lanes 3 and 4). Finding that jacalin interacts with the ectodomain of Dsg1 prompted us to investigate whether such interaction could interfere with the binding of PF autoantibodies to Dsg1. We tested this possibility by ELISA and immunoprecipitation (IP) assays using a test FS serum (PF-1). ELISA results showed a concentration-dependent inhibition of jacalin on the binding of FS autoantibodies (Figure 2a), and that the inhibition was reversible by D-galactose (Figure 2b). A similar dose-dependent blocking effect on the binding of Dsg1 to FS autoantibodies was also observed by IP analysis (Figure 2c). To assess whether the jacalin inhibition on FS autoantibody binding is applicable to other FS/PF sera, we tested additional samples. Representative IP data are shown in Figure 2d. Among 20 PF/FS sera tested, jacalin significantly reduced Dsg1 binding in 18 samples (90%), and in 2 sera the reduction was modest (one of such sera, PF-2, is shown in lanes 15 and 16). Although jacalin is a well-known O-glycan-specific plant lectin (Hortin, 1990Hortin G.L. Isolation of glycopeptides containing O-linked oligosaccharides by lectin affinity chromatography on jacalin-agarose.Anal Biochem. 1990; 191: 262-267Crossref PubMed Scopus (38) Google Scholar; Tachibana et al., 2006Tachibana K. Nakamura S. Wang H. et al.Elucidation of binding specificity of Jacalin toward O-glycosylated peptides: quantitative analysis by frontal affinity chromatography.Glycobiology. 2006; 16: 46-53Crossref PubMed Scopus (78) Google Scholar), a few studies have suggested that jacalin may also have affinity for N-glycan (Do and Lee, 1998Do S.I. Lee K.Y. Jacalin interacts with Asn-linked glycopeptides containing multi-antennary oligosaccharide structure with terminal alpha-linked galactose.FEBS Lett. 1998; 421: 169-173Abstract Full Text Full Text PDF PubMed Scopus (6) Google Scholar; Bourne et al., 2002Bourne Y. Astoul C.H. Zamboni V. et al.Structural basis for the unusual carbohydrate-binding specificity of jacalin towards galactose and mannose.Biochem J. 2002; 364: 173-180Crossref PubMed Scopus (112) Google Scholar). To evaluate whether jacalin binds to N-glycans on Dsg1, we produced the Dsg1 in High-Five cells in the presence of tunicamycin to inhibit N-glycosylations. As expected, Dsg1 expressed in the presence of tunicamycin showed a reduced molecular weight on SDS–PAGE (Figure 3a, lane 1 vs. lane 2), an indication of N-glycosylation inhibition. We then used the same amount of tunicamycin-treated and nontreated Dsg1 for lectin pull-down assay. As expected, immobilized concanavalin A reacted poorly with tunicamycin-treated Dsg1 (Figure 3a, lanes 3 vs. 4), a further indication of the N-glycosylation inhibition. In contrast, immobilized jacalin was able to precipitate both the tunicamycin-treated and nontreated Dsg1 (Figure 3a, lanes 5 vs. 6). This result demonstrates that N-glycans on Dsg1 are not involved in jacalin binding. We also examined the binding ability of tunicamycin-treated Dsg1 with PF autoantibodies, as the role of N-glycosylation of Dsg1 in PF autoantibody binding has been controversial (Olague-Alcala and Diaz, 1993Olague-Alcala M. Diaz L.A. The epitopes on bovine pemphigus foliaceus antigen are calcium-dependent and located on the peptide backbone of this glycoprotein.Chron Dermatol. 1993; 2: 189-209Google Scholar; Amagai et al., 1995bAmagai M. Ishii K. Hashimoto T. et al.Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent.J Invest Dermatol. 1995; 105: 243-247Crossref PubMed Scopus (84) Google Scholar; Ortiz-Urda et al., 2003Ortiz-Urda S. Elbe-Burger A. Smolle J. et al.The plant lectin wheat germ agglutinin inhibits the binding of pemphigus foliaceus autoantibodies to desmoglein 1 in a majority of patients and prevents pathomechanisms of pemphigus foliaceus in vitro and in vivo.J Immunol. 2003; 171: 6244-6250Crossref PubMed Scopus (11) Google Scholar). We tested 12 PF/FS sera (6 PF and 6 FS) by IP, and all reacted well with both tunicamycin-treated and nontreated Dsg1. Representative IP data are shown in Figure 3b. We next examined the binding of jacalin to cryostat sections of human and murine skin by immunofluorescence techniques. Sections of human or mouse skin incubated with FITC-conjugated jacalin produced a “pemphigus-like” staining pattern (Supplementary Figure S1-A online). Preincubation of the human or mouse skin sections with jacalin significantly inhibited PF IgG binding to the epidermis (Supplementary Figure S1-B, panels b and d online) as compared with those preincubated with TBS-Ca2+ buffer alone (Supplementary Figure S1-B, panels a and c online). Download .pdf (.27 MB) Help with pdf files Supplementary Figure S1 We further investigated the in vivo effect of jacalin in the PF mouse model using pathogenic IgG isolated from PF-1, a serum that was significantly inhibited by jacalin (see Figure 2a–c). Control mice (n=4) pretreated with vehicle alone developed blisters, clinically and histologically (Figure 4aA and B) 20hours after PF IgG injections. In contrast, mice pretreated with jacalin (80μgg−1 body weight, n=4; 160μgg−1 body weight, n=4) did not develop skin lesions (Figure 4aD and E). Direct immunofluorescence staining revealed a significant reduction of IgG binding to the epiderms in jacalin-treated mice (Figure 4aF) compared with those of control mice (Figure 4aC). The inhibition of jacalin on the induction of skin lesions in mice was dose dependent (Figure 4b). These results suggest that jacalin affects the in vivo binding of PF autoantibodies to the epidermis and thus inhibits disease. Jacalin is known to have binding specificities for the O-linked disaccharide Thomsen-Friedenreich antigen (TF antigen, Galβ1-3GalNAc-α1-O-Ser/Thr) and the monosaccharide Thomsen-nouveau antigen (Tn antigen, GalNAc-α1-O-Ser/Thr) in either the asialylated or sialylated form. It is known that other lectins have overlapping and distinct binding specificities as jacalin. For example, the peanut agglutinin (PNA) has binding affinity for TF antigen in its asialylated form only, whereas vicia villosa-B4 (VVL-B4) binds specifically to Tn antigen. Therefore, we tested the reactivity of these two lectins with Dsg1 by the lectin pull-down assay. The results showed that PNA, but not VVL-B4, interacted with the epidermal Dsg1 extracted from human or mouse skin (Figure 5a), suggesting that Dsg1 carries the asialylated form of TF antigen but not the Tn antigen. Moreover, preinjection of PNA (80μgg−1 body weight, n=9) abrogated the pathogenicity of PF IgG, whereas preinjection of the same dose of VVL-B4 (n=3) did not show any blocking effect (Figure 5b). Similar to jacalin, subcutaneous (s.c.) injection of PNA or VVL-B4 alone did not cause any abnormal appearance of the mouse skin. Table 1 summarizes the binding specificity of the lectins tested and their effect on PF IgG-induced skin blisters in mice.Table 1In vivo effect of plant lectins in IgG passive transfer mouse model of PFIgGTreatmentOligosaccharide specificityNo. of mice testedNo. of mice with skin blisterNo. of mice without skin blisterPF-1Vehicle15150JacalinGalβ1-3GalNAc-α (asialo or sialo); GalNAc808PNAGalβ1-3GalNAc-α or –β (asialo)911Minimum disease score (0.5+).8VVL-B4GalNAc330PF-2Vehicle660Jacalin652Overall lower disease score (1.25+0.36) compared with those preinjected with vehicle (2.58+0.20) (P<0.01, Student's t-test).1Abbreviations: Gal, galactose; GalNAc, N-acetylglactosamine; Glc, glucose; PF, pemphigus foliaceus; PNA, peanut agglutinin; s.c., subcutaneous; TBS, tris-buffered saline; VVL-B4, vicia villosa-B4 lectin.Neonatal mice were preinjected (s.c.) with vehicle (TBS-Ca2+) or lectins for 2hours followed by pathogenic PF IgG injection (s.c.). Pathogenic IgG from two patients' sera was used. PF-1 serum showed a remarkable inhibition in Dsg1 binding by jacalin, whereas PF-2 showed a marginal reduction in Dsg1 binding by jacalin. Animals were evaluated 20hours after PF IgG injection. Jacalin: 80–160μgg−1 body weight; PNA and VVL-B4: 160μgg−1 body weight.1 Minimum disease score (0.5+).2 Overall lower disease score (1.25+0.36) compared with those preinjected with vehicle (2.58+0.20) (P<0.01, Student's t-test). Open table in a new tab Abbreviations: Gal, galactose; GalNAc, N-acetylglactosamine; Glc, glucose; PF, pemphigus foliaceus; PNA, peanut agglutinin; s.c., subcutaneous; TBS, tris-buffered saline; VVL-B4, vicia villosa-B4 lectin. Neonatal mice were preinjected (s.c.) with vehicle (TBS-Ca2+) or lectins for 2hours followed by pathogenic PF IgG injection (s.c.). Pathogenic IgG from two patients' sera was used. PF-1 serum showed a remarkable inhibition in Dsg1 binding by jacalin, whereas PF-2 showed a marginal reduction in Dsg1 binding by jacalin. Animals were evaluated 20hours after PF IgG injection. Jacalin: 80–160μgg−1 body weight; PNA and VVL-B4: 160μgg−1 body weight. As described above, two patients' sera, including PF-2, showed a modest reduction on the binding of Dsg1 by IP when preincubated with jacalin. We expected that jacalin would have a lesser inhibitory effect on the pathogenicity of these PF autoantibodies. We tested this hypothesis in mice using pathogenic IgG prepared from PF-2 serum. Out of six animals preinjected with jacalin, five developed skin blisters, but the disease score was significantly reduced (P<0.01, Student's t-test) compared with those pretreated with vehicle (Table 1). Jacalin is a plant lectin that is highly specific for the α-O-glycoside of the terminal disaccharide TF carbohydrate motif (asialylated or sialylated) and its monosaccharide precursor Tn antigen (Mahanta et al., 1990Mahanta S.K. Sastry M.V. Surolia A. Topography of the combining region of a Thomsen-Friedenreich-antigen-specific lectin jacalin (Artocarpus integrifolia agglutinin). A thermodynamic and circular-dichroism spectroscopic study.Biochem J. 1990; 265: 831-840Crossref PubMed Scopus (76) Google Scholar; Kabir, 1998Kabir S. Jacalin: a jackfruit (Artocarpus heterophyllus) seed-derived lectin of versatile applications in immunobiological research.J Immunol Methods. 1998; 212: 193-211Crossref PubMed Scopus (105) Google Scholar; Tachibana et al., 2006Tachibana K. Nakamura S. Wang H. et al.Elucidation of binding specificity of Jacalin toward O-glycosylated peptides: quantitative analysis by frontal affinity chromatography.Glycobiology. 2006; 16: 46-53Crossref PubMed Scopus (78) Google Scholar). Immobilized jacalin is often used for isolation of IgA1 from human serum and purifying other O-glycosylated proteins (Roque-Barreira and Campos-Neto, 1985Roque-Barreira M.C. Campos-Neto A. Jacalin: an IgA-binding lectin.J Immunol. 1985; 134: 1740-1743PubMed Google Scholar; Hortin, 1990Hortin G.L. Isolation of glycopeptides containing O-linked oligosaccharides by lectin affinity chromatography on jacalin-agarose.Anal Biochem. 1990; 191: 262-267Crossref PubMed Scopus (38) Google Scholar). In this study, we found that jacalin-agarose beads precipitated the rDsg1 (Figure 1a) as well as the native Dsg1 from human and mouse epidermal lysates (Figure 1b). We demonstrated that the binding between jacalin and Dsg1 is galactose-dependent ((Figure 1a), but N-glycosylation-independent (Figure 3a), supporting the notion that jacalin has no or extremely low affinity for N-glycans (Hortin and Trimpe, 1990Hortin G.L. Trimpe B.L. Lectin affinity chromatography of proteins bearing O-linked oligosaccharides: application of jacalin-agarose.Anal Biochem. 1990; 188: 271-277Crossref PubMed Scopus (88) Google Scholar; Arockia Jeyaprakash et al., 2005Arockia Jeyaprakash A. Jayashree G. Mahanta S.K. et al.Structural basis for the energetics of jacalin-sugar interactions: promiscuity versus specificity.J Mol Biol. 2005; 347: 181-188Crossref PubMed Scopus (56) Google Scholar). Although Dsg1 is known to be N-glycosylated (Koch et al., 1991Koch P.J. Goldschmidt M.D. Walsh M.J. et al.Complete amino acid sequence of the epidermal desmoglein precursor polypeptide and identification of a second type of desmoglein gene.Eur J Cell Biol. 1991; 55: 200-208PubMed Google Scholar; Olague-Alcala and Diaz, 1993Olague-Alcala M. Diaz L.A. The epitopes on bovine pemphigus foliaceus antigen are calcium-dependent and located on the peptide backbone of this glycoprotein.Chron Dermatol. 1993; 2: 189-209Google Scholar; Amagai et al., 1995bAmagai M. Ishii K. Hashimoto T. et al.Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent.J Invest Dermatol. 1995; 105: 243-247Crossref PubMed Scopus (84) Google Scholar; Ortiz-Urda et al., 2003Ortiz-Urda S. Elbe-Burger A. Smolle J. et al.The plant lectin wheat germ agglutinin inhibits the binding of pemphigus foliaceus autoantibodies to desmoglein 1 in a majority of patients and prevents pathomechanisms of pemphigus foliaceus in vitro and in vivo.J Immunol. 2003; 171: 6244-6250Crossref PubMed Scopus (11) Google Scholar), its possible modification by O-linked oligosaccharides is less defined. The observation that Dsg1 interacts with jacalin and PNA but not VVL-B4 (Figure 5a) indicates that Dsg1 carries O-linked disaccharide TF antigen (asialylated) but not the monosaccharide Tn antigen. By competition ELISA and IP, we showed that jacalin was able to inhibit the binding of PF autoantibodies to Dsg1 in concentration- and galactose-dependent manners (Figure 2a–c). A significant inhibitory effect was observed in the majority of patients' sera tested (90%, n=20, Figure 2d) including PF-1, which was used throughout the study. Jacalin also markedly inhibited the binding of PF autoantibodies to human and mouse epidermis (Supplementary Figure S1 online). Furthermore, preinjection (s.c.) of jacalin into mice diminished the in vivo binding of PF-1 autoantibody to the epidermis and blocked skin disease (Figure 4). Interestingly, injection (s.c.) of jacalin alone did not cause any abnormal effect on mouse skin (data not shown), suggesting that binding of jacalin does not impair the adhesive function of Dsg1. Another lectin PNA, which shares the same carbohydrate specificity for the O-linked asialylated TF antigen but not the sialylated form, interacted with Dsg1 and blocked PF-1 autoantibody-induced skin blisters in mice (Figure 5). In contrast, lectin VVL-B4, which shares the carbohydrate specificity for the O-linked Tn antigen, did not interact with Dsg1 and did not show any beneficial effect on the disease induced by PF-1 IgG (Figure 5). These data suggest that binding of the O-linked TF carbohydrate motif of Dsg1 by jacalin and PNA can abrogate the pathogenicity of PF autoantibodies. However, there are a few PF sera (2 out of 20), in which the Dsg1–PF autoantibody interaction was modestly inhibited by jacalin, and the in vivo protective effect of jacalin on disease was less effective as demonstrated with PF-2 serum (Table 1). The molecular mechanism involved in the inhibitory effects of jacalin on PF autoantibody binding to Dsg1 is not clear. It is known that pathogenic PF autoantibodies bind calcium-dependent conformational epitopes located in the NH2-terminal region (EC1-2 or 1-161 residues) of Dsg1 (Eyre and Stanley, 1987Eyre R.W. Stanley J.R. Human autoantibodies against a desmosomal protein complex with a calcium-sensitive epitope are characteristic of pemphigus foliaceus patients.J Exp Med. 1987; 165: 1719-1724Crossref PubMed Scopus (126) Google Scholar; Kowalczyk et al., 1995Kowalczyk A.P. Anderson J.E. Borgwardt J.E. et al.Pemphigus sera recognize conformationally sensitive epitopes in the amino-terminal region of desmoglein-1.J Invest Dermatol. 1995; 105: 147-152Crossref PubMed Scopus (75) Google Scholar; Sekiguchi et al., 2001Sekiguchi M. Futei Y. Fujii Y. et al.Dominant autoimmune epitopes recognized by pemphigus antibodies map to the N-terminal adhesive region of desmogleins.J Immunol. 2001; 167: 5439-5448Crossref PubMed Scopus (143) Google Scholar; Li et al., 2003Li N. Aoki V. Hans-Filho G. et al.The role of intramolecular epitope spreading in the pathogenesis of endemic pemphigus foliaceus (fogo selvagem).J Exp Med. 2003; 197: 1501-1510Crossref PubMed Scopus (144) Google Scholar). These epitopes are unlikely to be composed of the carbohydrate moieties as the bacterial-expressed Dsg1 ectodomain, which had no glycosylation modifications, was still recognized by PF sera (Dmochowski et al., 1994Dmochowski M. Hashimoto T. Amagai M. et al.The extracellular aminoterminal domain of bovine desmoglein 1 (Dsg1) is recognized only by certain pemphigus foliaceus sera, whereas its intracellular domain is recognized by both pemphigus vulgaris and pemphigus foliaceus sera.J Invest Dermatol. 1994; 103: 173-177Crossref PubMed Scopus (28) Google Scholar). It is possible that jacalin binds the TF carbohydrate motifs of Dsg1 and spatially masks the major epitopes recognized by PF autoantibodies, thereby inhibiting the subsequent binding of PF autoantibodies. Alternatively, the binding of jacalin to Dsg1 may induce conformational changes of Dsg1, which impairs its interaction with PF autoantibodies. Identification of the position of the O-glycosylation sites on Dsg1 may help to understand the mechanism of action of jacalin. Potential O-glycosylation sites are predicted to be located in the membrane-proximal EC5 domain and possibly in other domains (EC1-4), depending on which predicting programs/methods are used (http://www.turing.cs.iastate.edu/EnsembleGly; http://www.cbs.dtu.dk/services/netoglyc; http://www.comp.chem.nottingham.ac.uk/glyco). Further experimental determination of the O-glycosylation sites on Dsg1 may shed light into the inhibitory mechanism. Two putative N-glycosylation sites (residues 61 and 131) are identified within the NH2-terminal region of Dsg1, where PF autoantibodies bind. The influence of the N-lined glycosylation on PF autoantibody binding has been examined with conflicting results reported. Although earlier studies showed that the binding of PF autoantibodies to Dsg1 is N-glycosylation-independent (Olague-Alcala and Diaz, 1993Olague-Alcala M. Diaz L.A. The epitopes on bovine pemphigus foliaceus antigen are calcium-dependent and located on the peptide backbone of this glycoprotein.Chron Dermatol. 1993; 2: 189-209Google Scholar; Amagai et al., 1995bAmagai M. Ishii K. Hashimoto T. et al.Conformational epitopes of pemphigus antigens (Dsg1 and Dsg3) are calcium dependent and glycosylation independent.J Invest Dermatol. 1995; 105: 243-247Crossref PubMed Scopus (84) Google Scholar), a recent study by Ortiz-Urda et al., 2003Ortiz-Urda S. Elbe-Burger A. Smolle J. et al.The plant lectin wheat germ agglutinin inhibits the binding of pemphigus foliaceus autoantibodies to desmoglein 1" @default.
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