Evidence for Transepithelial Dendritic Cells in Human H. pylori Active Gastritis

Abstract

Background: Despite extensive experimental investigation stressing the importance of bacterial interaction with dendritic cells (DCs), evidence regarding direct interaction of Helicobacter pylori or its virulence products with DCs in the human gastric mucosa is lacking. Methods: Human gastric mucosa biopsies, with or without H. pylori infection and active inflammation, were investigated at light and electron microscopy level with immunocytochemical tests for bacterial products (VacA, urease, outer membrane proteins) and DC markers (DC-SIGN, CD11c, CD83) or with the DC-labeling ZnI 2 -OsO 4 technique. Parallel tests with cultured DCs were carried out. Results: Cells reproducing ultrastructural and cytochemical patterns of DCs were detected in the lamina propria and epithelium of heavily infected and inflamed (but not of normal) mucosa, where DC luminal endings directly contact H. pylori and take up their virulence products. Cytotoxic changes (mitochondrial swelling, cytoplasmic vacuolation, autophagy) were observed in intraepithelial DCs and reproduced in cultured DCs incubated with H. pylori broth culture filtrates to obtain intracellular accumulation of VacA and urease. Granulocytes were also seen to contact and heavily phagocytose luminal H. pylori , while macrophages remained confined to basal epithelium, though taking up bacteria and bacterial products. Conclusion: Human DCs can enter H. pylori -infected gastric epithelium, in association with other innate immunity cells, to take up bacteria and their virulence products. This process is likely to be important for bacterial sensing and pertinent immune response; however, it may also generate DC cytotoxic changes potentially hampering their function.

Comparative Analysis of the Interaction of Helicobacter pylori with Human Dendritic Cells, Macrophages, and Monocytes

“…The upregulation of CD80, CD83, CD86, CCR7, and PDL-1 by infected DCs has previously been observed by others (36,47,48,58). Additionally, we observed reduced expression of CD209 (DC-SIGN), which is also expressed on gastric DCs (13,14,63). H. pylori LPS can become modified to contain Lewis blood group antigens (59) that play a role in the attachment to epithelial cells (4).…”

“…Some of the monocytes from each donor were differentiated in vitro to immature DCs through incubation in the presence of recombinant IL-4 and GM-CSF. DCs are prevalent in the human gastric mucosa of H. pyloriinfected patients (63), and DCs isolated from biopsy specimens of infected subjects display an activated phenotype (14,63) and are, in part, monocyte derived (45). Previous studies have shown that H. pylori is able to activate human DCs in vitro (36,47,48,58).…”

Different Bacterial Pathogens, Different Strategies, Yet the Aim Is the Same: Evasion of Intestinal Dendritic Cell Recognition

“…First, DCs are recruited into the gastric mucosa very early on postinfection of mice with H. pylori (66). Second, H. pylori can productively infect bone marrow-derived DCs in vitro (67), and third, DCs in the gastric mucosa of H. pylori-infected individuals can send protrusions into the lumen with which they make direct contacts with H. pylori (67). Even though there is still an ongoing debate as to the exact role of CD4 + T cells during H. pylori infection, these cells are clearly placed at the center of the ensuing immune response (68,69).…”

Helicobacter pylori Cytotoxin-Associated Gene A Impairs Human Dendritic Cell Maturation and Function through IL-10–Mediated Activation of STAT3

“…This inflammatory response toward H. pylori is characterized by the recruitment of different immune cells, mainly dendritic cells (DCs), neutrophils, macrophages, as well as B and T lymphocytes (1) to the site of infection. In fact, human DCs can enter H. pylori-infected gastric epithelium to take up bacteria and their virulence factors (2). DCs not only play a crucial role as primary responders to microbial infection because of their ability of capturing and transferring Ags, but they also determine the type of T cell-mediated response to be mounted (3).…”