| 1. |
- Nookaew, Intawat, 1977, et al.
(författare)
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Transcriptome signatures in Helicobacter pylori-infected mucosa identifies acidic mammalian chitinase loss as a corpus atrophy marker
- 2013
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Ingår i: BMC Medical Genomics. - : Springer Science and Business Media LLC. - 1755-8794. ; 6:41
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Tidskriftsartikel (refereegranskat)abstract
- The majority of gastric cancer cases are believed to be caused by chronic infection with the bacterium Helicobacter pylori, and atrophic corpus gastritis is a predisposing condition to gastric cancer development. We aimed to increase understanding of the molecular details of atrophy by performing a global transcriptome analysis of stomach tissue. Biopsies from patients with different stages of H. pylori infection were taken from both the antrum and corpus mucosa and analyzed on microarrays. The stages included patients without current H. pylori infection, H. pylori-infected without corpus atrophy and patients with current or past H. pylori-infection with corpus-predominant atrophic gastritis. Using clustering and integrated analysis, we found firm evidence for antralization of the corpus mucosa of atrophy patients. This antralization harbored gain of gastrin expression, as well as loss of expression of corpus-related genes, such as genes associated with acid production, energy metabolism and blood clotting. The analyses provided detailed molecular evidence for simultaneous intestinal metaplasia (IM) and spasmolytic polypeptide expressing metaplasia (SPEM) in atrophic corpus tissue. Finally, acidic mammalian chitinase, a chitin-degrading enzyme produced by chief cells, was shown to be strongly down-regulated in corpus atrophy. Transcriptome analysis revealed several gene groups which are related to development of corpus atrophy, some of which were increased also in H. pylori-infected non-atrophic patients. Furthermore, loss of acidic chitinase expression is a promising marker for corpus atrophy.
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| 2. |
- Adamsson, Jenni, 1977, et al.
(författare)
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Immune Responses Against Helicobacter pylori in Gastric Cancer Patients and in Risk Groups for Gastric Cancer.
- 2013
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Ingår i: Helicobacter. - : Wiley. - 1523-5378 .- 1083-4389. ; 18:1, s. 73-82
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: It has previously been reported that weak serum IgG but elevated IgA antibody responses against H.pylori may be associated with risk of gastric cancer (GC) development. To search for potential immunologic markers for GC, we analyzed antibody responses against H.pylori in risk groups of cancer development. MATERIAL AND METHODS: Sera and stomach biopsies collected from H.pylori-infected GC patients as well as from patients with gastric ulcer (GU), atrophic gastritis, intestinal metaplasia (IM) and duodenal ulcer and from H.pylori-infected control subjects without atrophy or IM, and in addition from H.pylori-negative subjects were analyzed for IgG and IgA antibodies against three different H.pylori antigen preparations, that is, membrane protein (MP), urease, and CagA. RESULTS: We observed an increased serum IgA/IgG titer ratio against H.pylori anti-MP in GC and GU patients, and against CagA in Hp-infected GC patients and risk groups. Female patients with GC had a higher serum anti-MP IgA/IgG titer ratio and a higher proportion of poorly differentiated cancer compared with male patients. As earlier observed, the non-tumorous mucosa of H.pylori-infected GC patients contained considerably lower levels of total IgA and H.pylori-specific IgA compared with H.pylori-infected controls. Similarly, we observed decreased specific mucosal anti-MP IgA response in patients with IM. CONCLUSION: We observed several differences in local and systemic immunologic responses against H.pylori in H.pylori-infected GC patients and putative GC risk group patients compared with H.pylori-infected controls. These findings may be of importance in efforts to identify risk groups of GC or early stages of GC.
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| 3. |
- Bhuiyan, Taufiqur Rahman, 1974, et al.
(författare)
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Th1 and Th17 responses to Helicobacter pylori in Bangladeshi infants, children and adults
- 2014
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 9:4
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Tidskriftsartikel (refereegranskat)abstract
- Both Th1 and Th17 cells are important components of the immune response to Helicobacter pylori (Hp) in adults, but less is known about T cell responses to Hp during early childhood, when the infection is often acquired. We investigated Th1 and Th17 type responses to Hp in adults, children and infants in Bangladesh, where Hp is highly endemic. IL-17 and IFN-γ mRNA levels in gastric biopsies from Hp-infected Bangladeshi adults were analyzed and compared to levels in infected and uninfected Swedish controls. Since biopsies could not be collected from infants and children, cytokine responses in Bangladeshi infants (6-12 months), children (3-5 years) and adults (>19 years) were instead compared by stimulating peripheral blood mononuclear cells (PBMCs) with a Hp membrane preparation (MP) and analyzing culture supernatants by ELISA and cytometric bead array. We found significantly higher expression of IL-17 and IFN-γ mRNA in gastric mucosa of Hpinfected Bangladeshi and Swedish adults compared to uninfected Swedish controls. PBMCs from all age groups produced IL-17 and IFN-γ after MP stimulation, but little Th2 cytokines. IL-17 and IFN-γ were primarily produced by CD4+ T cells, since CD4 + T cell depleted PBMCs produced reduced amounts of these cytokines. Infant cells produced significantly more IL-17, but similar levels of IFN-γ, compared to adult cells after MP stimulation. In contrast, polyclonal stimulation induced lower levels IL-17 and IFN-γ in infant compared to adult PBMCs and CD4+ T cells. The strong IL-17 production in infants after MP stimulation was paralleled by significantly higher production of the IL-17 promoting cytokine IL-1β from infant compared to adult PBMCs and monocytes. In conclusion, these results show that T cells can produce high levels of IL-17 and IFN-β in response to Hp from an early age and indicate a potential role for IL-1β in promoting Th17 responses to Hp during infancy. © 2014 Bhuiyan et al.
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| 4. |
- Geahlen, J. H., et al.
(författare)
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Evolution of the human gastrokine locus and confounding factors regarding the pseudogenicity of GKN3
- 2013
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Ingår i: Physiological Genomics. - : American Physiological Society. - 1094-8341 .- 1531-2267. ; 45:15, s. 667-683
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Tidskriftsartikel (refereegranskat)abstract
- In a screen for genes expressed specifically in gastric mucous neck cells, we identified GKN3, the recently discovered third member of the gastrokine family. We present confirmatory mouse data and novel porcine data showing that mouse GKN3 expression is confined to mucous cells of the corpus neck and antrum base and is prominently expressed in metaplastic lesions. GKN3 was proposed originally to be expressed in some human populations and a pseudogene in others. To investigate that hypothesis, we studied human GKN3 evolution in the context of its paralogous genomic neighbors, GKN1 and GKN2. Haplotype analysis revealed that GKN3 mimics GKN2 in patterns of exonic SNP allocation, whereas GKN1 appeared to be more stringently selected. GKN3 showed signatures of both directional selection and population based selective sweeps in humans. One such selective sweep includes SNP rs10187256, originally identified as an ancestral tryptophan to premature STOP codon mutation. The derived (nonancestral) allele went to fixation in Asia. We show that another SNP, rs75578132, identified 5 bp downstream of rs10187256, exhibits a second selective sweep in almost all Europeans, some Latinos, and some Africans, possibly resulting from a reintroduction of European genes during African colonization. Finally, we identify a mutation that would destroy the splice donor site in the putative exon3-intron3 boundary, which occurs in all human genomes examined to date. Our results highlight a stomach-specific human genetic locus, which has undergone various selective sweeps across European, Asian, and African populations and thus reflects geographic and ethnic patterns in genome evolution.
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| 5. |
- 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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| 6. |
- Lindgren, Åsa, 1979, et al.
(författare)
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CD8- natural killer cells are greatly enriched in the human gastrointestinal tract and have the capacity to respond to bacteria.
- 2010
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Ingår i: Journal of innate immunity. - : S. Karger AG. - 1662-8128 .- 1662-811X. ; 2:3, s. 294-302
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Tidskriftsartikel (refereegranskat)abstract
- Natural killer (NK) cells can be activated to produce IFN-gamma by lysate from Helicobacter pylori in combination with IL-12. Furthermore, NK cells in the gastrointestinal mucosa are likely to encounter H. pylori as well as other bacteria and may play a role in the mucosal innate immune defense. In this report, we show that in marked contrast to peripheral blood, the large majority of NK cells of human gastrointestinal mucosa lack CD8 expression. Importantly, we show that CD8(-) and CD8(+) NK cells have different functional properties; although the cytotoxic capacity of the different NK cell populations was equal, only CD8(-) NK cells were capable of responding by IFN-gamma production to stimulation with lysates from H. pylori and other bacteria - this was not due to an intrinsic defect in IFN-gamma production by CD8(+) NK cells. We propose that CD8(-) CD16(-) CD56(bright) NK cells constitute a subset of NK cells that is present in the gastrointestinal mucosa and is especially adapted to responding to bacterial infection by production of cytokines. These findings may have important implications for the understanding of NK cell subsets and the innate defense against gastrointestinal bacterial infections.
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| 7. |
- Lindgren, Åsa, 1979, et al.
(författare)
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Impaired IFN-gamma Production after Stimulation with Bacterial Components by Natural Killer Cells from Gastric Cancer Patients
- 2011
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Ingår i: Experimental Cell Research. - : Elsevier BV. - 0014-4827. ; 317:6, s. 849-858
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Tidskriftsartikel (refereegranskat)abstract
- Gastric adenocarcinoma is a major health problem world-wide, as this is the second most common cause of cancer death in the world. It has been estimated that infection by Helicobacter pylori cause at least half of the gastric cancers. Previously, we have demonstrated that H. pylori antigens directly activate NK cells to secrete IFN-γ. There is also a marked synergistic effect in NK cells stimulated with bacterial lysate and low levels of IL-12, a cytokine which is produced by macrophages and dendritic cells in the H. pylori-infected stomach. The present study was designed to investigate whether NK cells from gastric cancer patients display an altered ability to respond to components from H. pylori and other bacteria. The results show that NK cells from peripheral blood of gastric cancer patients have a severely suppressed ability to produce IFN-γ after stimulation with H. pylori lysate and the synthetic bacterial lipoprotein FSL-1. Furthermore, the synergistic effect of IL-12 and lysate is absent in gastric cancer patients, unless the concentration of IL-12 is increased 10-fold. We also demonstrate that there is a similar lack of IFN-γ production from NK cells isolated from the gastric mucosa of cancer patients. In addition, we propose that the observed suppression is due to tumour-derived TGF-β and that increased expression of the transcription factor GATA-3 may be responsible for the TGF-β induced suppression.
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| 8. |
- Lindgren, Åsa, 1979, et al.
(författare)
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Interferon-gamma secretion is induced in IL-12 stimulated human NK cells by recognition of Helicobacter pylori or TLR2 ligands
- 2011
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Ingår i: Innate Immunity. - 1753-4267. ; 17:2, s. 191-203
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori induce a chronic inflammation in the human gastric mucosa characterized by increased production of interferon-gamma (IFN-γ). The presence of natural killer (NK) cells in the human gastric mucosa and the ability of NK cells to produce IFN-γ suggest an important role of NK cells in the immune response directed towards H. pylori infection. Since NK cells previously have been shown to respond to bacterial components with IFN-γ production, we investigated the mechanisms for the recognition of H. pylori. We found that inhibition of MyD88 homodimerization resulted in decreased production of IFN-γ and that inhibition of the p38 MAPK decreased the production as well as the secretion of IFN-γ. Further studies indicated an involvement of Toll-like receptors (TLRs), in particular TLR2. Finally, we showed that the H. pylori specific membrane bound lipoprotein HpaA induced IFN-γ production from NK cells through recognition by TLR2. In conclusion, we suggest an involvement of TLR2 in the recognition of H. pylori by human NK cells and that HpaA is a TLR2 ligand important for recognition.
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| 9. |
- Skoog, Emma C, 1983, et al.
(författare)
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Human Gastric Mucins Differently Regulate Helicobacter pylori Proliferation, Gene Expression and Interactions with Host Cells. : Effects of gastric mucins on Helicobacter pylori
- 2012
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Ingår i: PLoS One. - : Public Library of Science (PLoS). - 1932-6203. ; 7:5
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Tidskriftsartikel (refereegranskat)abstract
- Helicobacter pylori colonizes the mucus niche of the gastric mucosa and is a risk factor for gastritis, ulcers and cancer. The main components of the mucus layer are heavily glycosylated mucins, to which H. pylori can adhere. Mucin glycosylation differs between individuals and changes during disease. Here we have examined the H. pylori response to purified mucins from a range of tumor and normal human gastric tissue samples. Our results demonstrate that mucins from different individuals differ in how they modulate both proliferation and gene expression of H. pylori. The mucin effect on proliferation varied significantly between samples, and ranged from stimulatory to inhibitory, depending on the type of mucins and the ability of the mucins to bind to H. pylori. Tumor-derived mucins and mucins from the surface mucosa had potential to stimulate proliferation, while gland-derived mucins tended to inhibit proliferation and mucins from healthy uninfected individuals showed little effect. Artificial glycoconjugates containing H. pylori ligands also modulated H. pylori proliferation, albeit to a lesser degree than human mucins. Expression of genes important for the pathogenicity of H. pylori (babA, sabA, cagA, flaA and ureA) appeared co-regulated in response to mucins. The addition of mucins to co-cultures of H. pylori and gastric epithelial cells protected the viability of the cells and modulated the cytokine production in a manner that differed between individuals, was partially dependent of adhesion of H. pylori to the gastric cells, but also revealed that other mucin factors in addition to adhesion are important for H. pylori-induced host signaling. The combined data reveal host-specific effects on proliferation, gene expression and virulence of H. pylori due to the gastric mucin environment, demonstrating a dynamic interplay between the bacterium and its host.
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| 10. |
- Svensson, Helena, 1979, et al.
(författare)
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Accumulation of CCR4 CTLA-4 FOXP3CD25 Regulatory T Cells in Colon Adenocarcinomas Correlate to Reduced Activation of Conventional T Cells.
- 2012
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Ingår i: PloS one. - : Public Library of Science (PLoS). - 1932-6203. ; 7:2
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Tidskriftsartikel (refereegranskat)abstract
- Colorectal cancer usually gives rise to a specific anti-tumor immune response, but for unknown reasons the resulting immunity is not able to clear the tumor. Recruitment of activated effector lymphocytes to the tumor is important for efficient anti-tumor responses, while the presence of regulatory T cells (Treg) down-modulate tumor-specific immunity. We therefore aimed to determine homing mechanisms and activation stage of Treg and effector T cell infiltrating colon tumors compared to cells from the unaffected mucosa in patients suffering from colon adenocarcinoma.
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