Regulatory B Cell Function Is Suppressed by Smoking and Obesity in H. pylori-Infected Subjects and Is Correlated with Elevated Risk of Gastric Cancer.

Guanggang Li,Shihang Zheng,David Z Song,Robert S Downey,Hasi Wulan,Zhendong Zheng,Ji J Yuan,Anna J Jankowska,Zongchang Song,Thomas B Learch,Paul A Paik,Gary M Goodman,Ming L Tsao,Paul T Maceachern,Yaron M Rabinowitz

doi:10.1371/journal.pone.0134591

Abstract

Helicobacter pylori infection occurs in more than half of the world’s population and is the main cause for gastric cancer. A series of lifestyle and nutritional factors, such as tobacco smoking and obesity, have been found to elevate the risk for cancer development. In this study, we sought to determine the immunological aspects during H. pylori infection and gastric cancer development. We found that B cells from H. pylori-infected patients presented altered composition and function compared to uninfected patients. IL-10-expressing CD24+CD38+ B cells were upregulated in H. pylori-infected patients, contained potent regulatory activity in inhibiting T cell pro-inflammatory cytokine secretion, and responded directly to H. pylori antigen stimulation. Interestingly, in H. pylori-infected smoking subjects and obese subjects, the number of IL-10+ B cells and CD24+CD38+ B cells were reduced compared to H. pylori-infected asymptomatic subjects. Regulatory functions mediated by CD24+CD38+ B cells were also impaired. In addition, gastric cancer positive patients had reduced IL-10-producing B cell frequencies after H. pylori-stimulation. Altogether, these data suggest that in H. pylori-infection, CD24+CD38+ B cell is upregulated and plays a role in suppressing pro-inflammatory responses, possibly through IL-10 production, a feature that was not observed in smoking and obese patients.

Highlights

Helicobacter pylori (H. pylori) is a kind of Gram-negative pathogenic bacteria found in more than half of the world’s population and preferentially inhibits the upper gastrointestinal tract, including the stomach epithelium and the duodenum tract[1,2]
We found that the ex vivo expression of IL-2, interferon gamma (IFN-g) and tumor necrosis factor alpha (TNF-a) by B cells were increased in H. pylori-infected smoking subjects and obese subjects than that in healthy subjects (Fig 2A)
We performed T cell-B cell coculture experiments and found that T cells in CD24+CD38+ B cell-depleted co-cultures secreted higher levels of proinflammatory cytokines than T cells co-cultured with whole B cells, while T cells cocultured with CD24+CD38+ B cells only had the lowest pro-inflammatory cytokine production

Summary

Introduction

Helicobacter pylori (H. pylori) is a kind of Gram-negative pathogenic bacteria found in more than half of the world’s population and preferentially inhibits the upper gastrointestinal tract, including the stomach epithelium and the duodenum tract[1,2]. The precise mechanism of cancer development as a result of H. pylori infection is not well defined, but chronic untreated inflammation in the upper gastrointestinal tract is thought to contribute to the continued damage of the stomach epithelium[4,5]. Inflammationassociated signaling molecules, such as tumor necrosis factor alpha (TNF-a), have been found to promote gastric tumorigenesis and is upregulated in H. pylori infection[6]. Other pro-inflammatory cytokines secreted by T cells, including IL-2, IL-17, and interferon gamma (IFN-g), are upregulated in H. pylori infection and are associated with increased risk of gastric tumorigenesis[7,8,9,10]. A series of other factors, such as continuous exposure to tobacco smoking and obesity, are positively correlated with increased gastric cancer risk, though the underlying mechanism is unclear[3,11]

Methods

Results

Conclusion