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Abstract
BackgroundOngoing Helicobacter pylori (HP) infection triggers a chronic active gastritis. Eradicating HP reduces gastric inflammation, but does not eliminate it. We sought to characterize this persistent gastritis, and demonstrate the persistence of HP-specific Th17 responses in individuals previously infected with HP but who no longer had evidence of ongoing infection.Methodology/Principal FindingsStudy subjects were divided into 3 groups 55 individuals had active HP infection (group A), 41 were diagnosed with previous HP infection (group P), and 59 were naïve to HP (group N). Blood and gastric tissue were obtained with written informed consent from all subjects, and immune responses were evaluated using flow cytometry, semi-quantitative real time PCR, immunofluorescent staining, ELISA, and multiplex cytometric bead array for cytokine quantification. Elevated IL-17A responses were observed in patients from group A compared to group N. Interestingly, IL-17A responses remained persistently elevated in the blood and gastric mucosa of individuals from group P, despite the absence of ongoing HP infection. Using purified CD4+ T cells as effectors and antibodies that blocked antigen presentation by MHC Class II, we showed that these persistent IL-17A responses were mediated primarily by HP-specific Th17 cells, rather than other immune cells that have also been described to secrete IL-17A. Gastric mucosal IL-1β levels were also persistently elevated in group P, and neutralisation of IL-1β reduced the HP-specific IL-17A response of purified CD4+ T cells to autologous HP-pulsed antigen presenting cells in vitro, suggesting a functional association between IL-1β and the persistent Th17 response in group P patients.Conclusions/SignificanceDespite lack of ongoing HP infection, HP-specific Th17 cells persist in the blood and gastric mucosa of individuals with past HP infection. We speculate that this persistent inflammation might contribute to gastric mucosal pathology, for example, persistent increased gastric cancer risk despite eradication of HP.
Highlights
Individuals with evidence of past Helicobacter pylori (HP) infection but who no longer had ongoing infection exhibited elevated frequencies of CD3+CD82CCR6+IL-17A+ cells in the blood that was statistically different from individuals who were naive to HP
The frequency of CD3+CD82CCR6+IL-17A+ cells among CD3+CD82 Peripheral Blood Mononuclear Cells (PBMCs) remained elevated in some individuals from group P even if they had been treated for HP more than 10 years ago
Gastric mucosal CD4+IL-17A+ cells remained persistently elevated in some individuals from group P even if they had been treated for HP more than 10 years ago
Summary
Helicobacter pylori (HP) infects the human stomach, and has been associated with various gastric diseases, including gastritis, peptic ulcer disease, gastric adenocarcinoma, and gastric mucosaassociated lymphoma. [1] Infection of the gastric epithelium is sensed by Toll-like receptors and NOD-like receptors, and triggers an inflammatory response characterized by elevated levels of proinflammatory cytokines, e.g. IL-1b, IL-6, IL-8, IL-18, TNF-a, and the recruitment of neutrophils and lymphocytes into the gastric mucosa. [2,3,4] HP evades this vigorous response to establish a persistent infection that co-exists with chronic active inflammation of the gastric mucosa. [3].Gastric mucosal lymphocytes isolated from patients infected with HP contain increased numbers of CD4+ T cells that produce IFNc, consistent with prominent Th1 polarization. [5,6,7] More recently, ongoing HP infection has been associated with upregulation of IL-17A expression in the gastric mucosa. [8,9,10] IL-17A is the most widely studied member of the IL-17 family of cytokines (IL-17A – F), and is produced by Th17 CD4+ T cells as well as other subsets of immune cells. [11,12] Extracellular bacterial and fungal infections elicit strong IL-17A responses that stimulate stromal and epithelial cells to release pro-inflammatory cytokines and chemokines, e.g. TNF-a, IL-1b, IL-6, CXCL1, CXCL2, CCL2, CCL7, CCL20, which recruit neutrophils, macrophages and lymphocytes to the site of infection. [13,14]IL-17A induces expression of matrix metalloproteinases 1, 2, 3, 9, and 13, which regulate inflammation by modulating chemokine activity and establishing chemotactic gradients. [15] On the other hand, pathological persistence of IL-17A responses has been associated with tissue damage in the setting of chronic inflammatory and autoimmune diseases. [12,14] IL-17A has been implicated in the pathogenesis of various cancers, [16,17,18] including gastric cancer, [19,20] the biological basis of this association remains unclear.Even though HP eradication is possible with the use of antimicrobial agents, [21] significant lymphocytic infiltrate can remain in the gastric mucosa more than a decade following successful treatment of HP infection. [22] this chronic lymphocytic infiltrate has not been further characterized. Since chronic IL-17A signaling has pathological associations, we wanted to determine whether IL-17A responses contribute to persistent gastric inflammation after HP eradication, and the types of immune cells that produced IL-17A under these conditions. [8,10] In this study, the association between IL-17A and HP infection was re-evaluated by including patients with past HP infection in the comparison These were individuals without evidence of ongoing HP infection or gastric cancer, but who either had a past history of treatment for HP infection or tested seropositive for HP. By studying such individuals, persistent HPspecific Th17 responses were detected in the blood and gastric mucosa despite absence of ongoing HP infection. We sought to characterize this persistent gastritis, and demonstrate the persistence of HP-specific Th17 responses in individuals previously infected with HP but who no longer had evidence of ongoing infection
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