Secretory IgA-Mediated Neutralization of Shigella flexneri Prevents Intestinal Tissue Destruction by Down-Regulating Inflammatory Circuits

Abstract

Shigella, a Gram-negative invasive enteropathogenic bacterium responsible for bacillary dysentery, causes the rupture, invasion, and inflammatory destruction of the human colonic mucosa. We explored the mechanisms of protection mediated by Shigella LPS-specific secretory IgA (SIgA), the major mucosal Ab induced upon natural infection. Bacteria, SIgA, or SIgA-S. flexneri immune complexes were administered into rabbit ligated intestinal loops containing a Peyer’s patch. After 8 h, localizations of bacteria, SIgA, and SIgA-S. flexneri immune complexes were examined by immunohistochemistry and confocal microscopy imaging. We found that anti-Shigella LPS SIgA, mainly via immune exclusion, prevented Shigella-induced inflammation responsible for the destruction of the intestinal barrier. Besides this luminal trapping, a small proportion of SIgA-S. flexneri immune complexes were shown to enter the rabbit Peyer’s patch and were internalized by dendritic cells of the subepithelial dome region. Local inflammatory status was analyzed by quantitative RT-PCR using newly designed primers for rabbit pro- and anti-inflammatory mediator genes. In Peyer’s patches exposed to immune complexes, limited up-regulation of the expression of proinflammatory genes, including TNF-α, IL-6, Cox-2, and IFN-γ, was observed, consistent with preserved morphology. In contrast, in Peyer’s patches exposed to Shigella alone, high expression of the same mediators was measured, indicating that neutralizing SIgA dampens the proinflammatory properties of Shigella. These results show that in the form of immune complexes, SIgA guarantees both immune exclusion and neutralization of translocated bacteria, thus preserving the intestinal barrier integrity by preventing bacterial-induced inflammation. These findings add to the multiple facets of the noninflammatory properties of SIgA.

Recombinant Dimeric IgA Antibodies against the Epidermal Growth Factor Receptor Mediate Effective Tumor Cell Killing

“…However, EC 50 of dimeric 225-IgA was significantly lower than EC 50 of monomeric 225-IgA (p , 0.01). In contrast, both 225-IgA isoforms required lower Ab concentrations than the IgG1 Ab (EC 50 : 5.61 6 1.48, 3.66 6 0.45, and 9.98 6 1.90 nM for monomeric IgA, dimeric IgA, and 225-IgG, respectively) with PMN effector cells (Fig. 3C), with dimeric 225-IgA being significantly more effective than its monomeric counterpart (p , 0.05).…”

“…2C, 2D). In this assay, binding of control IgA (EC 50 : 717.5 6 0.57 nM) was lower than that of dimeric 225-IgA, but higher than that of monomeric 225-IgA, which is probably explained by the high polymer content of control IgA (see Fig. 1A, lane 2).…”

“…3A). Binding of dimeric 225-IgA was significantly more effective than binding of monomeric 225-IgA (EC 50 : 498.1 6 0.57 versus 1137 6 29.37 nM; p , 0.001; Supplemental Fig. 2C, 2D).…”

“…For example, i.v. applied or backpack hybridoma-produced dimeric IgA was detected on mucosal surfaces and neutralized their respective target Ags (49)(50)(51). Whether i.v.…”

Vaccines against enteric infections for the developing world

“…SIgA provides the first line of defence against bacterial colonization, virus replication and enterotoxin binding to gut epithelial cells [4]. In addition, SIgA is endowed with antiinflammatory properties [5]. Relatively small amounts of IgG are synthesized in the gastrointestinal tract of healthy individuals, but higher levels are observed in subjects with acute and chronic (inflammatory bowel diseases; coeliac disease) inflammatory conditions mainly through transudation from blood [4,6].…”