| 1. |
- Hansson, Malin, 1967, et al.
(författare)
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DC-LAMP(+) Dendritic Cells Are Recruited to Gastric Lymphoid Follicles in Helicobacter pylori-Infected Individuals
- 2013
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Ingår i: Infection and Immunity. - : American Society for Microbiology. - 0019-9567 .- 1098-5522. ; 81:10, s. 3684-3692
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Tidskriftsartikel (refereegranskat)abstract
- Infection with Helicobacter pylori is associated with development of ulcer disease and gastrointestinal adenocarcinoma. The infection leads to a large infiltration of immune cells and the formation of organized lymphoid follicles in the human gastric mucosa. Still, the immune system fails to eradicate the bacteria, and the substantial regulatory T cell (Treg) response elicited is probably a major factor permitting bacterial persistence. Dendritic cells (DCs) are professional antigen-presenting cells that can activate naive T cells, and maturation of DCs is crucial for the initiation of primary immune responses. The aim of this study was to investigate the presence and localization of mature human DCs in H. pylori-infected gastric mucosa. Gastric antral biopsy specimens were collected from patients with H. pylori-associated gastritis and healthy volunteers, and antrum tissue was collected from patients undergoing gastric resection. Immunohistochemistry and flow cytometry showed that DCs expressing the maturation marker dendritic cell lysosome-associated membrane glycoprotein (DC-LAMP; CD208) are enriched in the H. pylori-infected gastric mucosa and that these DCs are specifically localized within or close to lymphoid follicles. Gastric DC-LAMP-positive (DC-LAMP(+)) DCs express CD11c and high levels of HLA-DR but little CD80, CD83, and CD86. Furthermore, immunofluorescence analyses demonstrated that DC-LAMP(+) DCs are in the same location as FoxP3-positive putative Tregs in the follicles. In conclusion, we show that DC-LAMP(+) DCs with low costimulatory capacity accumulate in the lymphoid follicles in human H. pylori-infected gastric tissue, and our results suggest that Treg-DC interactions may promote chronic infection by rendering gastric DCs tolerogenic.
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| 2. |
- Oertli, Mathias, et al.
(författare)
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DC-derived IL-18 drives Treg differentiation, murine Helicobacter pylori-specific immune tolerance, and asthma protection.
- 2012
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Ingår i: The Journal of clinical investigation. - 1558-8238. ; 122:3, s. 1082-96
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Tidskriftsartikel (refereegranskat)abstract
- Persistent colonization with the gastric bacterial pathogen Helicobacter pylori causes gastritis and predisposes infected individuals to gastric cancer. Conversely, it is also linked to protection from allergic, chronic inflammatory, and autoimmune diseases. We demonstrate here that H. pylori inhibits LPS-induced maturation of DCs and reprograms DCs toward a tolerance-promoting phenotype. Our results showed that DCs exposed to H. pylori in vitro or in vivo failed to induce T cell effector functions. Instead, they efficiently induced expression of the forkhead transcription factor FoxP3, the master regulator of Tregs, in naive T cells. Depletion of DCs in mice infected with H. pylori during the neonatal period was sufficient to break H. pylori-specific tolerance. DC depletion resulted in improved control of the infection but also aggravated T cell-driven immunopathology. Consistent with the mouse data, DCs infiltrating the gastric mucosa of human H. pylori carriers exhibited a semimature DC-SIGN(+)HLA-DR(hi)CD80(lo)CD86(lo) phenotype. Mechanistically, the tolerogenic activity of H. pylori-experienced DCs was shown to require IL-18 in vitro and in vivo; DC-derived IL-18 acted directly on T cells to drive their conversion to Tregs. CD4(+)CD25(+) Tregs from infected wild-type mice but not Il18(-/-) or Il18r1(-/-) mice prevented airway inflammation and hyperresponsiveness in an experimental model of asthma. Taken together, our results indicate that tolerogenic reprogramming of DCs ensures the persistence of H. pylori and protects against allergic asthma in a process that requires IL-18.
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| 3. |
- Flach, Carl-Fredrik, 1977, et al.
(författare)
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Mucosal vaccination increases local chemokine production attracting immune cells to the stomach mucosa of Helicobacter pylori infected mice.
- 2012
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Ingår i: Vaccine. - : Elsevier BV. - 1873-2518 .- 0264-410X. ; 30:9, s. 1636-1643
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Tidskriftsartikel (refereegranskat)abstract
- Background: Vaccination is an attractive approach for the prevention of Helicobacter pylori infection and disease. In a mouse model, infection induces an accumulation of dendritic cells, macrophages, granulocytes, and B- and T cells to the stomach mucosa, which is further heightened when the infection is preceded by a mucosal immunization. We have studied the chemokines and chemokine receptors guiding infection- and vaccination-induced immune cells to the stomach and their relation to protection against H. pylori infection in mice. Materials and methods: C57BL/6 mice were immunized sublingually with H. pylori lysate antigens and cholera toxin adjuvant or left unimmunized, and then challenged with live H. pylori bacteria. Stomach tissue was taken at 3, 7, 14 and 21 days after challenge and bacterial colonization, chemokine and chemokine receptor gene expression, and influx of cells into the stomach mucosa were evaluated. Results: RT-PCR array screening revealed differential expression of a broad range of chemokine and chemokine receptor genes between immunized and unimmunized mice. A significant upregulation of chemokines known to attract, among other cells, eosinophils (CCL8), T cells (CXCL10, CXCL11) and neutrophils (CXCL2, CXCL5) and of their cognate receptors CCR3, CXCR3 and CXCR2, preceded or coincided with vaccine-induced protection, which was first evident 7 days after infection and was then sustained at the later time-points. Consistent with the increase in chemokines and chemokine receptors flow cytometric analysis indicated a sequential accumulation of CD4+ T cells, eosinophils, neutrophils and CD103+ dendritic cells in the gastric lamina propria of immunized mice. Conclusions: This study provides insights into vaccination-induced chemokines that guide the influx of protective immune cells into the stomach of H. pylori infected mice.
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| 4. |
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| 5. |
- Kirby, Alun C, et al.
(författare)
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In vivo compartmentalization of functionally distinct, rapidly responsive antigen-specific T-cell populations in DNA-immunized or Salmonella enterica serovar Typhimurium-infected mice.
- 2004
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Ingår i: Infection and immunity. - 0019-9567 .- 1098-5522. ; 72:11, s. 6390-400
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Tidskriftsartikel (refereegranskat)abstract
- The location and functional properties of antigen-specific memory T-cell populations in lymphoid and nonlymphoid compartments following DNA immunization or infection with Salmonella were investigated. Epitope-specific CD8+ -T-cell expansion and retention during the memory phase were analyzed for DNA-immunized mice by use of a 5-h peptide restimulation assay. These data revealed that epitope-specific gamma interferon (IFN-gamma)-positive CD8+ T cells occur at higher frequencies in the spleen, liver, and blood than in draining or peripheral lymph nodes during the expansion phase. Moreover, this distribution is maintained into long-term memory. The location and function of both CD4+ and CD8+ Salmonella-specific memory T cells in mice who were given a single dose of Salmonella enterica serovar Typhimurium was also quantitated by an ex vivo restimulation with bacterial lysate to detect the total Salmonella-specific memory pool. Mice immunized up to 6 months previously with S. enterica serovar Typhimurium had bacterium-specific CD4+ T cells that were capable of producing IFN-gamma or tumor necrosis factor alpha (TNF-alpha) at each site analyzed. Similar findings were observed for CD8+ T cells that were capable of producing IFN-gamma, while a much lower frequency and more restricted distribution were associated with TNF-alpha-producing CD8+ T cells. This study is the first to assess the frequencies, locations, and functions of both CD4+ and CD8+ memory T-cell populations in the same Salmonella-infected individuals and demonstrates the organ-specific functional compartmentalization of memory T cells after Salmonella infection.
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| 6. |
- Quiding-Järbrink, Marianne, 1964, et al.
(författare)
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Enhanced M1 macrophage polarization in human Helicobacter pylori-associated atrophic gastritis and in vaccinated mice
- 2010
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Ingår i: PLOS one. - : Public Library of Science (PLoS). - 1932-6203. ; 5:11
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Tidskriftsartikel (refereegranskat)abstract
- Background: Infection with Helicobacter pylori triggers a chronic gastric inflammation that can progress to atrophy and gastric adenocarcinoma. Polarization of macrophages is a characteristic of both cancer and infection, and may promote progression or resolution of disease. However, the role of macrophages and their polarization during H. pylori infection has not been well defined. Methodology/Principal Findings By using a mouse model of infection and gastric biopsies from 29 individuals, we have analyzed macrophage recruitment and polarization during H. pylori infection by flow cytometry and real-time PCR. We found a sequential recruitment of neutrophils, eosinophils and macrophages to the gastric mucosa of infected mice. Gene expression analysis of stomach tissue and sorted macrophages revealed that gastric macrophages were polarized to M1 after H. pylori infection, and this process was substantially accelerated by prior vaccination. Human H. pylori infection was characterized by a mixed M1/M2 polarization of macrophages. However, in H. pylori-associated atrophic gastritis, the expression of inducible nitric oxide synthase was markedly increased compared to uncomplicated gastritis, indicative of an enhanced M1 macrophage polarization in this pre-malignant lesion. Conclusions/Significance These results show that vaccination of mice against H. pylori amplifies M1 polarization of gastric macrophages, and that a similar enhanced M1 polarization is present in human H. pylori-induced atrophic gastritis.
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| 7. |
- Sundquist, Malin, 1978
(författare)
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Dendritic cell maturation and death during Salmonella infection. Role of pro-inflammatory cytokines and MyD88
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The costimulatory molecules CD80 and CD86 are required for the ability of dendritic cells (DC) to induce both tolerance and immunity. This thesis investigates the control of CD80/CD86 upregulation in vivo on DC during Salmonella infection. After oral Salmonella infection, DC in Peyer?s patches (PP), mesenteric lymph nodes (MLN) and spleen upregulated costimulatory molecules almost simultaneously despite differential seeding of these organs with bacteria. Costimulatory molecules were also induced on TNF/iNOS-producing CD11cintCD11b+ DC that accumulated in infected organs. The CD11cintCD11b+ DC were efficient at bacterial uptake but, in contrast to conventional DC, failed to process and present Salmonella Ag on MHC-II. Using different gene-deficient mice, the pathways controlling CD80/86 upregulation on DC during Salmonella infection were dissected. Upregulation of CD80 was strictly dependent on the Toll-like receptor adaptor MyD88, whereas upregulation of CD86 was mediated by both MyD88-dependent and -independent factors. The pro-inflammatory cytokine TNF was identified as one MyD88-dependent factor required for optimal upregulation of CD80/86 in the MLN. In the absence of MyD88, upregulation of CD86 was mediated by type I interferons. However, the contribution of type I interferons to CD86 upregulation in wild type mice is only marginal, since mice lacking the type I interferon receptor (IFN-??R) showed no major defects in CD80/86 upregulation. Despite the abrogated upregulation of CD80/86 on DC of TNFR1-/-, MyD88-/- or MyD88-/-IFN-??R-/- mice, DC directly associated with bacteria upregulated costimulatory molecules independently of these factors. Pro-inflammatory signaling not only upregulated costimulatory molecules on DC during Salmonella infection, but also mediated DC death. Thus, MyD88-dependent production of TNF induced DC death in Salmonella-infected mice. CD8?+ DC were most susceptible to infection-induced cell death as assessed directly ex vivo by Annexin-V and 7AAD staining, whereas recruited CD11cintCD11b+ DC were completely resistant. Thus, the inflammatory environment imprints a distinct pattern of costimulatory molecules on DC, with MyD88-dependent factors controlling the upregulation of CD80. However, MyD88-dependent factors also induce DC death during Salmonella infection, which is likely to have a negative impact on anti-bacterial immunity.
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| 8. |
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| 9. |
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| 10. |
- Sundquist, Malin, 1978, et al.
(författare)
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Salmonella induces death of CD8alpha(+) dendritic cells but not CD11c(int)CD11b(+) inflammatory cells in vivo via MyD88 and TNFR1.
- 2009
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Ingår i: Journal of leukocyte biology. - : Oxford University Press (OUP). - 0741-5400 .- 1938-3673. ; 85:2, s. 225-34
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Tidskriftsartikel (refereegranskat)abstract
- Dendritic cells (DCs), whose lifespan influences their ability to stimulate the immune system, are potent APCs that are critical for initiating immunity. Here, we show that oral infection with Salmonella enterica serovar Typhimurium induces death of DCs in the gut-draining lymph nodes. Although CD8alpha(+) DCs were sensitive to Salmonella-induced death, CD8alpha(-) DCs and in particular recruited CD11c(int)CD11b(+) inflammatory cells, were resistant. Infecting mice deficient for MyD88 revealed that Salmonella-induced death of CD8alpha(+) DCs was dependent on this adaptor for TLR signaling. In addition, CD8alpha(+) DCs in infected, TNFR1-deficient mice were resistant to Salmonella-induced death. These data, combined with the strict MyD88-dependent production of TNF in Salmonella-infected mice, suggest that MyD88-dependent TNF mediates DC death. As recruited CD11c(int)CD11b(+) cells were resistant to Salmonella-induced death, they could compensate for the infection-induced loss of DCs if they function as APCs. However, in contrast to DCs, CD11c(int)CD11b(+) cells could not present the model antigen OVA expressed in Salmonella to OVA-specific CD4 T cells. These results show that Salmonella induces DC death after oral infection via MyD88 and TNFR1, which could have a negative impact on the initiation of antibacterial immunity.
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