Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy

Fox, James G.; Beck, Paul L.; Dangler, Charles A.; Whary, Mark T.; Wang, Yichen; Shi, Hai Ning; Nagler‐Anderson, Cathryn

doi:10.1038/75015

Cited by 451 publications

(365 citation statements)

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“…28,38 In addition, it has been suggested that the Th1 response may also mediate gastritis and gastric cancer. 39 Several studies have shown that T lymphocytes of Stat6-deficient mice fail to differentiate into Th2 cells in response to IL-4 or IL-13. 40,41 RANKL, a member of the TNF cytokine family, is also specifically expressed in Th1-type T lymphocytes.…”

Section: Discussionmentioning

confidence: 99%

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

et al. 2007

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Pathogenic mechanisms associated with Helicobacter pylori infection enhance susceptibility of the gastric epithelium to carcinogenic conversion. We have characterized the gene expression profiles of gastric biopsies from 69 French Caucasian patients, of which 43 (62%) were infected with H. pylori. The bacterium was detected in 27 of the 42 antral biopsies examined and in 16 of the 27 fundic biopsies. Infected biopsies were selected for the presence of chronic active gastritis, in absence of metaplasia and dysplasia of the gastric mucosa. Infected antral and fundic biopsies exhibited distinct transcriptional responses. Altered responses were linked with: (1) the extent of polymorphonuclear leukocyte infiltration, (2) bacterial density, and (3) the presence of the virulence factors vacA, babA2, and cagA. Robust modulation of transcripts associated with Toll-like receptors, signal transduction, the immune response, apoptosis, and the cell cycle was consistent with expected responses to Gram-negative bacterial infection. Altered expression of interferon-regulated genes (IFITM1, IRF4, STAT6), indicative of major histocompatibility complex (MHC) II-mediated and Th1-specific responses, as well as altered expression of GATA6, have previously been described in precancerous states. Upregulation of genes abundantly expressed in cancer tissues (UBD, CXCL13, LY96, MAPK8, MMP7, RANKL, CCL18) or in stem cells (IFITM1 and WFDC2) may reveal a molecular switch towards a premalignant state in infected tissues. Tissue microarray analysis of a large number of biopsies, which were either positive or negative for the cag-A virulence factor, when compared to each other and to noninfected controls, confirmed observed gene alterations at the protein level, for eight key transcripts. This study provides 'proof-of-principle' data for identifying molecular mechanisms driving H. pylori-associated carcinogenesis before morphological evidence of changes along the neoplastic progression pathway. Modern Pathology (2007) 20, 974-989;

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Section: Discussionmentioning

confidence: 99%

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

et al. 2007

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“…Chronic infections favor immunosuppression, the so-called modulated Th2-response, associated with poor parasite-specific reactivity alongside with the strong production of anti-inflammatory cytokines, such as IL-10 and TGF-b [1]. This helminth-induced immunosuppression may spill over to bystander antigens [3], downmodulate reactivity against other pathogens [4] and impair vaccination efficacy [5]. However, such effects can be beneficial by downregulating inflammatory reactions to allergens and inflammatory disorders of the intestinal tract.…”

Section: Introductionmentioning

confidence: 99%

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

et al. 2009

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Here, we show that Treg limit intestinal pathology during nematode infection and that they control the onset and magnitude of the anti-parasitic Th Th2 response. Using mice expressing the diptheria toxin receptor under the control of the foxp3 locus, we removed Foxp3 1 Treg during the early phase of infection with Heligmosomoides polygyrus bakeri. Depletion of Treg in infected animals did not affect adult worm burden, but led to increased pathology at the site of infection. Infected, depleted mice displayed higher frequencies of activated CD4 1 T cells and increased levels of the Th2 cytokines IL-4 and IL-13. The stronger parasite-specific Th2 response was accompanied by higher levels of IL-10. Only a moderate change in Th1 (IFN-c) reactivity was detected in worm-infected, Treg-depleted mice. Furthermore, we detected an accelerated onset of parasite-specific Th2 and IL-10 responses in the transient absence of Foxp3 1 Treg. However, adult worm burdens were not affected by the increased Th2-reactivity in Treg-depleted mice. Hence, our data show that Treg restrict the onset and strength of Th2 responses during intestinal worm infection, while increasing primary Th2 responses does not necessarily lead to killing of larvae or accelerated expulsion of adult worms.Key words: Foxp3 . Nematode . Pathology . Th2 response . Treg IntroductionParasitic worms are the most potent inducers of highly polarized Th cell type 2 (Th2) responses. Helminth infections tend to be long lasting and are often associated with insufficient immunity to re-infection [1,2]. Chronic infections favor immunosuppression, the so-called modulated Th2-response, associated with poor parasite-specific reactivity alongside with the strong production of anti-inflammatory cytokines, such as . This helminth-induced immunosuppression may spill over to bystander antigens [3], downmodulate reactivity against other pathogens [4] and impair vaccination efficacy [5]. However, such effects can be beneficial by downregulating inflammatory reactions to allergens and inflammatory disorders of the intestinal tract. Studies in animal models showed that helminths can suppress airway hyperreactivity and colitis [6][7][8] and nematodes have been used to efficiently treat human inflammatory bowel disease in clinical trials [9,10]. 3066In animal models, the beneficial effects of nematode infections on inflammatory disorders were associated with the presence of Treg populations [6,11,12]. However, it is not yet clear whether such Treg suppress anti-parasite immune reactivity and thus contribute to survival and well-being of the worms, or whether they predominantly dampen immunopathology. Several studies investigated the role of Treg in infections with helminths or other parasites and yielded in diverging conclusions (reviewed in [1] and [13]). There is evidence that certain parasites depend on Treg action for their persistence [14][15][16][17]. Other species profit more indirectly from Treg circuits, which control infectioninduced pathology [18][19][20].In a previous study ...

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“…Second, mouse strains susceptible to gastric atrophy, such as C57BL/6 mice, mount strong Th1 cell responses after infection with Helicobacter spp. (74), whereas mouse strains resistant to gastric atrophy, such as BALB/c mice, mount Th2 cell responses. Third, deletion of the gene encoding the Th1 cytokine IFN-γ protects mice from gastric atrophy induced by infection with Helicobacter spp., whereas deletion of the gene encoding the Th2 cytokine IL-4 leads to more severe atrophic gastritis (75).…”

Section: Host Factors That Affect the Development Of Gastric Cancer Gmentioning

confidence: 99%

Inflammation, atrophy, and gastric cancer

Fox

Wang²

2007

J. Clin. Invest.

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694

626

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The association between chronic inflammation and cancer is now well established. This association has recently received renewed interest with the recognition that microbial pathogens can be responsible for the chronic inflammation observed in many cancers, particularly those originating in the gastrointestinal system. A prime example is Helicobacter pylori, which infects 50% of the world's population and is now known to be responsible for inducing chronic gastric inflammation that progresses to atrophy, metaplasia, dysplasia, and gastric cancer. This Review provides an overview of recent progress in elucidating the bacterial properties responsible for colonization of the stomach, persistence in the stomach, and triggering of inflammation, as well as the host factors that have a role in determining whether gastritis progresses to gastric cancer. We also discuss how the increased understanding of the relationship between inflammation and gastric cancer still leaves many questions unanswered regarding recommendations for prevention and treatment.

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Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy

Cited by 451 publications

References 33 publications

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells

Inflammation, atrophy, and gastric cancer

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Concurrent enteric helminth infection modulates inflammation and gastric immune responses and reduces helicobacter-induced gastric atrophy

Cited by 451 publications

References 33 publications

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

Gene expression profiling in human gastric mucosa infected with Helicobacter pylori

Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3+ cells

Inflammation, atrophy, and gastric cancer

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Establishment of nematode infection despite increased Th2 responses and immunopathology after selective depletion of Foxp3⁺ cells