Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by inhibiting inflammatory circuits

Project Leader

Blaise CORTHESY, Ph.D., M.E.R.

Short CV

In collaboration with
Armelle Phalipon and Philippe Sansonetti,
Institut Pasteur Paris, France
and Séverine Boullier, INRA, Toulouse, France.

Past project's Collaborator

Khalil KADAOUI (to August 2006)

We have previously shown that translocation across Peyer’s patches of Shigella flexneri (a Gram-negative invasive enteropathogenic bacterium causing the rupture, invasion, and inflammatory destruction of the colonic mucosa) in association with SIgA prevents local inflammation, and limits dissemination of the bacterium-antibody complex to draining mesenteric lymph nodes. We thus wanted to continue evaluating the mechanisms of protection mediated by Shigella flexneri LPS-specific SIgA that is the major mucosal antibody induced upon natural infection. At the methodological level, bacteria, SIgA or SIgA-S. flexneri immune complexes were administered into rabbit ligated intestinal loops containing a Peyer’s patch. After 8 hours, localization of bacteria, SIgA and SIgA-S. flexneri immune complexes were examined by histology, immunohistochemistry, and confocal microscopy imaging. Local inflammatory status was analyzed by histology and quantitative RT-PCR performed on lamina propria samples, using newly designed primers for rabbit pro- and anti-inflammatory cytokine genes. We found that anti-LPS SIgA antibodies, via immune exclusion, largely prevent S. flexneri-induced inflammation responsible for the destruction of the intestinal barrier.

As previously shown in mice, we further established that SIgA-S. flexneri immune complexes entered rabbit Peyer’s patches and were internalized by dendritic cells located within the subepithelial dome region, demonstrating that the retro-transport of SIgA-based immune complexes took place in another species than mouse. In contrast to S. flexneri alone, the expression of pro-inflammatory genes including TNF-, IL-6, Cox-2, and IFN- were not up-regulated by the immune complexes remaining localized within the dome region, indicating that neutralizing SIgA turns off the pro-inflammatory properties of S. flexneri in the Peyer’s patch (Figure 1). Both immune exclusion and SIgA-mediated translocation of bacteria into Peyer’s patches ensure the preservation of the intestinal barrier integrity by preventing bacterial-induced inflammation. These findings add to the multiple facets of the non-inflammatory properties of SIgA at mucosal surfaces. These series of data allowed us to conclude that in the case of pathogens, passive transfer of SIgA-based immune complexes could provide a “shield” during a period when the neonatal immune system is not mature enough to respond actively. Similarly, the presence of natural or pre-existing SIgA after a recall challenge might permit to keep inducing mucosal antibody production against a variety of microbial antigens, while minimizing any pro-inflammatory, deleterious effects on the integrity of the mucosal barrier.

Figure 1

Binding to SIgAC5 restricts the Shigella-induced expression of proinflammatory mediators in PPs. cDNA from PP samples were prepared and the level of mRNA transcripts was quantified by quantitative PCR, using a standard plasmid for each gene. All the results were normalized using HPRT gene expression. Each symbol corresponds to samples recovered from the same rabbit with close and open symbols corresponding to Shigella- and Shigella-SIgA-administered ileal loops, respectively. Black bars indicate the average. Differences are statistically significant for the four proinflammatory mediators tested (*, p

Publication
  • Boullier S., Tanguy M., Kadaoui K.A., Caudet C., Sansonetti P., Corthésy B. and Phalipon, A. Secretory IgA-mediated neutralization of Shigella flexneri prevents intestinal tissue destruction by down-regulating inflammatory circuits. J. Immunol. 2009, 183: 5879-5885. PubMed
 Dernière mise à jour le 26/06/2018 à 09:16