CCL28 Is Increased in Human Helicobacter pylori -Induced Gastritis and Mediates Recruitment of Gastric Immunoglobulin A-Secreting Cells

Abstract

Human Helicobacter pylori infection gives rise to an active chronic gastritis and is a major risk factor for the development of duodenal ulcer disease and gastric adenocarcinoma. The infection is accompanied by a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, and following mucosal immunization only H. pylori-infected volunteers mounted a B-cell response in the gastric mucosa. To identify the signals for recruitment of gastric IgA-secreting cells, we investigated the gastric production of CCL28 (mucosaassociated epithelial chemokine) and CCL25 (thymus-expressed chemokine) in H. pylori-infected and uninfected individuals and the potential of gastric B-cell populations to migrate toward these chemokines. Gastric tissue from H. pylori-infected individuals contained significantly more CCL28 protein and mRNA than that from uninfected individuals, while CCL25 levels remained unchanged. Chemokine-induced migration of gastric lamina propria lymphocytes isolated from patients undergoing gastric resection was then assessed using the Transwell system. IgA-secreting cells and IgA ؉ memory B cells from H. pylori-infected tissues migrated toward CCL28 but not CCL25, while the corresponding cells from uninfected patients did not. Furthermore, IgG-secreting cells from H. pylori-infected patients did not migrate to CCL28 but instead to CXCL12 (SDF-1␣). However, chemokine receptor expression did not correlate to the migratory pattern of the different B-cell populations. These studies are the first to show increased CCL28 production during gastrointestinal infection in humans and provide an explanation for the large influx of IgA-secreting cells to the gastric mucosa in H. pylori-infected individuals.Helicobacter pylori is a gram-negative bacterium that infects the human stomach and duodenum and gives rise to active chronic gastritis including the formation of lymphoid follicles (15,20). The infection is widespread and is associated with the development of gastric and duodenal ulcer disease as well as gastric adenocarcinoma and mucosa-associated lymphoid tissue lymphoma. The H. pylori-infected human stomach mucosa contains increased numbers of neutrophils, macrophages, dendritic cells, T cells, and B cells (5,11,15). In particular, H. pylori infection gives rise to a large accumulation of immunoglobulin A (IgA)-secreting cells in the gastric mucosa, many of which are specific for H. pylori virulence factors (28). In parallel, a systemic IgG and IgA response is mounted. However, despite strong immune responses, the bacteria are rarely eliminated from the stomach, and the infection is usually lifelong. As a prerequisite for the development of a vaccine against H. pylori, we have previously investigated the migration of vaccine-specific antibody-secreting cells (ASC) to the stomach mucosa following mucosal immunization with an inactivated cholera vaccine (27,38). In these studies, vaccine-specific IgA and sometimes IgG responses could be detected only in the gastric mucosae of H. pylori-infected in...

Chemokine receptors in gastric MALT lymphoma: loss of CXCR4 and upregulation of CXCR7 is associated with progression to diffuse large B-cell lymphoma

“…In H. pylori-associated gastritis, recruitment of T-and B cells, dendritic cells and neutrophil granulocytes is mediated by a variety of chemokines interacting with their cognate receptors such as CCR7, CCR5, CXCR1 and CXCR4 expressed on infiltrating immunological cells. 30,[36][37][38][39][40][41] Consistent with these findings, we also observed upregulated mRNA transcripts of CCR8, CCR9, CXCR3 and CXCR7.…”

Selective Upregulation of Endothelial E-Selectin in Response toHelicobacter pylori-Induced Gastritis

“…It is less likely, though, that E-selectin is involved in the recruitment of effector B cells to the gastric mucosa, since lymphocytes lack the expression of sialylated Lewis x or Lewis a unless they are transformed by Epstein-Barr virus infection (25). Instead, other factors such as chemokine production may contribute to B-cell accumulation (14). In contrast to our findings, a study reported previously by Hatz et al (15) showed increased levels of expression of the adhesion molecules VCAM-1 and ICAM-1 but no significant increase in the level of expression of E-selectin in H. pyloriinduced gastritis.…”

IL-17A Induces CCL28, Supporting the Chemotaxis of IgE-Secreting B Cells

“…IgE-switched B cells were investigated here, however, it is clear that IgA+ B cells are recruited by CCL28 [4] and that these cells may also be recruited, although they were not the subject of this study. IgG-secreting B cells do not respond to CCL28 (data not shown) [32,48]. Previously, antibodies against CCR4 and CCR3 have been assessed for their capacity to inhibit T cell and eosinophil infiltration, respectively, into the allergic lung [49,50]; this study adds the blockade of CCL28 or CCR10 as additional targets for the treatment of asthma.…”

“…However, the receptors that are involved in the recruitment of IgE-secreting B cells to the lungs have, thus far, remained poorly described. CCL28 is known to induce the chemotaxis of CCR10+ IgA+ ASC, and this interaction is critical in the accumulation of these cells in lactating mammary tissues and to the gastric intestinal tract during infection [31,32]. Hence, it was hypothesized that CCL28 might also play a role in the recruitment of IgE+ B cells in atopy/allergy and that localization of these cells to the lungs might contribute to the population of CCL28 receptor-expressing cells observed.…”