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Entry of secretory immunoglobulin A into Peyer's patch M cells: Targeting of dendritic cells and immunomodulatory properties. Laurent FAVRE (to June 2004), Jacques REY and Blaise CORTHESY
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In addition to being instrumental to the protection of mucosal epithelia, secretory IgA (SIgA) adheres to, and are transported by, intestinal Peyer’s patch (PP) M cells. As a first step to resolve the immunological significance of M cell binding and transport of SIgA, we have thus examined in mice the outcome of SIgA delivered from the intestinal lumen to the cells present in the underlying organized mucosa associated lymphoreticular tissue. We show selective association of SIgA with dendritic cells (DC) and CD4+ T lymphocytes recovered from PP in vitro. In vivo, SIgA associates with, and are internalized by DC in the subepithelial dome region, whereas the interaction with CD4+ T cells is limited to surface binding. Interaction between cells and SIgA is mediated by the IgA moiety and occurs for polymeric and monomeric molecular forms. Targeting of SIgA to PP DC suggests that SIgA-containing immune complexes are not only cleared by peristalsis, but might also enter the body to boost an ongoing immune response in the absence of concomitant inflammation. The immunological consequences of such a transepithelial retro-transport are unknown. We found that oral delivery of SIgA comprising human secretory component and mouse IgA induces hSC-specific antibody and cellular responses in mucosal and peripheral tissues in mice. |
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This takes place in the absence of co-addition of cholera toxin, identifying so far unraveled properties in SIgA as an antigen carrier. Specific immune responses were accompanied by sustained IL-10 and TGF- We propose that in addition to its essential role in immune exclusion, SIgA entering the mucosa through PP may participate to important regulatory functions to preserve the integrity of the intestinal barrier. Together with Th2 and Th3 cell polarization, as well as fine balance of the microbiota, presentation of antigen under non-inflammatory conditions represents another feature of SIgA that allows to govern mucosal homeostasis in the gastrointestinal tract. In terms of humoral immunity at mucosal surfaces, SIgA antibodies appear thus to combine properties of a neutralizing agent (immune exclusion) and of an immunomodulator, underscoring a novel facet of its complex functioning. |
Upper panels (I and II): Outcome of SIgA in vivo after administration in a ligated intestinal loop comprising a PP. Tissue section were prepared and images were obtained by laser scanning confocal microscopy. Colocalization is obtained using red-labeled SIgA and FITC-stained DC. In contrast, fluorescence associated with B cells (green) and red SIgA displays no overlap. The pale yellow rectangle indicates the area under study. SED, subepithelial dome; GC, germinal center; IFR, interfollicular region. White arrows mark yellow spots resulting from colocalization. Lower panels (a and b): Migration of DC from the SED to the interfollicular region of PP. Mice were administered fluorescent green microspheres, then SIgA, and tissue sections were prepared. Association with DC was assessed by staining the cells with a specific antibody labeled in red. Images were obtained by laser scanning confocal microscopy. 2 magnifications shown.
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expression in draining mesenteric lymph nodes (MLN) and spleen. SIgA also triggered migration of DC to the T cell-rich regions of PP, and regulated expression of CD80 and CD86 on DC in PP, MLN and spleen. These results provide evidence that mucosal SIgA re-entering the body exerts a function of antigen delivery that contributes to effector and/or regulatory pathways characteristic of the intestinal mucosal compartment.
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