Oligosaccharide Side Chains on Human Secretory IgA Serve as Receptors for Ricin

Mantis, Nicholas J.; Farrant, Stephanie; Mehta, Simren

doi:10.4049/jimmunol.172.11.6838

Cited by 36 publications

(32 citation statements)

References 51 publications

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“…This is confirmed by our observation that Madin-Darby canine kidney cells stably transfected by pIgR (46) do not get infected when exposed to a mixture of toxin A and SC (data not shown). Our data also agree with previous observations that free SC and/or SIgA inhibit attachment to the gut epithelium of pathogens, including Helicobacter pylori (47), E. coli (48,49), and the ricin toxin (50).…”

Section: Discussionsupporting

confidence: 83%

Glycans on Secretory Component Participate in Innate Protection against Mucosal Pathogens

Perrier

Sprenger

Corthésy

2006

Journal of Biological Chemistry

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In mucosal secretions, secretory component (SC) is found either free or bound to polymeric IgA within the secretory IgA complex. SC displays numerous and various glycans, which are potential ligands for bacterial compounds. We first established that human SC (hSC) purified from colostrum (hSCcol) or produced in Chinese hamster ovary cells (hSCrec) exhibits the same lectin reactivity. Both forms bind to Clostridium difficile toxin A and functionally protect polarized Caco-2 cell monolayers from the cytopathic effect of the toxin. The interaction is mediated by glycans present on hSC and involves galactose and sialic acid residues. hSCcol and hSCrec were also shown to bind enteropathogenic Escherichia coli adhesin intimin and to inhibit its infectivity on HEp-2 cells in a glycan-dependent manner as well. SC remained operative in the context of the whole secretory IgA molecule and can therefore enhance its Fabmediated neutralizing properties. On the contrary, hSC did not interact with three different strains of rotavirus (RF, RRV, and SA11). Accordingly, infection of target MA104 cells with these rotavirus strains was not reduced in the presence of either form of hSC tested. Although not a universal mechanism, these findings identify hSC as a microbial scavenger contributing to the antipathogenic arsenal that protects the body epithelial surfaces.

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Section: Discussionsupporting

confidence: 83%

Glycans on Secretory Component Participate in Innate Protection against Mucosal Pathogens

Perrier

Sprenger

Corthésy

2006

Journal of Biological Chemistry

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“…The sections were then stained with avidin-FITC and visualized by fluorescence microscopy. As observed previously (28), ricin uniformly labeled the luminal surfaces of intestinal villi (Fig. 7A).…”

Section: Anti-rtb But Not Anti-rta Iga Mabs Reduce Ricin Binding Tosupporting

confidence: 64%

Immunoglobulin A Antibodies against Ricin A and B Subunits Protect Epithelial Cells from Ricin Intoxication

et al. 2006

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Epithelial cells of the respiratory and gastrointestinal tracts are extremely vulnerable to the cytotoxic effects of ricin, a Shiga-like toxin with ribosome-inactivating properties. While mucosal immunity to ricin correlates with secretory immunoglobulin A (IgA) antibody levels in vivo, the potential of IgA to protect epithelial cells from ricin in vitro has not been examined due to the unavailability of well-defined antitoxin IgA antibodies. Here we report the characterization of four monoclonal IgA antibodies (IgA MAbs) produced from the Peyer's patches and mesenteric lymph nodes of BALB/c mice immunized intragastrically with ricin toxoid. Two IgA MAbs (33G2 and 35H6) were active against ricin's lectin subunit (RTB), and two (23D7 and 25A4) reacted with the toxin's enzymatic subunit (RTA). All four IgA MAbs neutralized ricin in a Vero cell cytotoxicity assay, blocked toxin-induced interleukin-8 release by the human monocyte/macrophage cell line 28SC, and protected polarized epithelial cell monolayers from ricin-mediated protein synthesis inhibition. 33G2 and 35H6 reduced ricin binding to the luminal surfaces of human intestinal epithelial cells to undetectable levels in tissue section overlay assays, whereas 23D7 had no effect on toxin attachment. 23D7 and 25A4 did, however, reduce ricin transcytosis across MDCK II cell monolayers, possibly by interfering with intracellular toxin transport. We conclude that IgA antibodies against RTA and RTB can protect mucosal epithelial cells from ricin intoxication.Recent bioterrorism incidents in the United States and abroad have alerted public health officials to the need for vaccines and therapies against pathogens and toxins previously deemed to be of little concern (2, 7, 27). Ricin, for example, is an extremely potent toxin that is easily purified in high concentrations from its natural source, the castor bean (Ricinus communis). Ricin (molecular weight, 64,000) is a relatively simple toxin consisting of an enzymatic A subunit (RTA) and a binding B subunit (RTB) joined by a disulfide bond (32). Its potency is attributed in part to the fact that RTB is a bivalent lectin with specificities for ubiquitous glycoproteins and glycolipids containing ␤(1-3)-linked galactose or N-acetylgalactosamine residues (4), which enable the toxin to bind and be internalized by all known cell types. The toxic properties of ricin are further compounded by RTA, which is an extremely efficient N-glycosidase specific for a highly conserved adenine residue in the so-called sarcin/ricin loop of eukaryotic 28S rRNA (9). Due to the absence of a specific vaccine or therapy, treatment of individuals intoxicated with ricin is strictly supportive (3).As an agent of bioterrorism, it is feared that ricin will be disseminated by aerosol or food/water supplies, thereby potentially exposing humans via the respiratory or gastrointestinal tract. It is known from animal studies that both mucosal compartments are susceptible to ricin intoxication. Monkeys or rodents exposed to aerosolized ricin (ϳ20 to 40 g/k...

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“…Carbohydrate side chains in SIgA have been shown to interact with Helicobacter pylori (75), Escherichia coli through type I fimbrial lectin (76,77), and the ricin toxin (78). Free SC in milk is able on its own to prevent adhesion of enteropathogenic E. coli, of Clostridium difficile toxin A, and of Streptococcus pneumoniae CbpA to epithelial cells (79,80), a mechanism that identically depends on carbohydrates abundantly present on the surface of SC (81).…”

Section: Siga and Breastfeedingmentioning

confidence: 99%

Roundtrip Ticket for Secretory IgA: Role in Mucosal Homeostasis?

Corthésy¹

2007

The Journal of Immunology

195

148

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An important activity of mucosal surfaces is the production of Ab referred to as secretory IgA (SIgA). SIgA serves as the first line of defense against microorganisms through a mechanism called immune exclusion. In addition, SIgA adheres selectively to M cells in intestinal Peyer’s patches, thus mediating the transepithelial transport of the Ab molecule from the intestinal lumen to underlying gut-associated organized lymphoid tissue. In Peyer’s patches, SIgA binds and is internalized by dendritic cells in the subepithelial dome region. When used as carrier for Ags in oral immunization, SIgA induces mucosal and systemic responses associated with production of anti-inflammatory cytokines and limits activation of dendritic cells. In terms of humoral immunity at mucosal surfaces, SIgA appears thus to combine properties of a neutralizing agent (immune exclusion) and of a mucosal immunopotentiator inducing effector immune responses in a noninflammatory context favorable to preserve local homeostasis of the gastrointestinal tract.

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Oligosaccharide Side Chains on Human Secretory IgA Serve as Receptors for Ricin

Cited by 36 publications

References 51 publications

Glycans on Secretory Component Participate in Innate Protection against Mucosal Pathogens

Glycans on Secretory Component Participate in Innate Protection against Mucosal Pathogens

Immunoglobulin A Antibodies against Ricin A and B Subunits Protect Epithelial Cells from Ricin Intoxication

Roundtrip Ticket for Secretory IgA: Role in Mucosal Homeostasis?

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