Mucosal Inducible NO Synthase–Producing IgA+ Plasma Cells in Helicobacter pylori–Infected Patients

Abstract

The mucosal immune system is relevant for homeostasis, immunity, and also pathological conditions in the gastrointestinal tract. Inducible NO synthase (iNOS)–dependent production of NO is one of the factors linked to both antimicrobial immunity and pathological conditions. Upregulation of iNOS has been observed in human Helicobacter pylori infection, but the cellular sources of iNOS are ill defined. Key differences in regulation of iNOS expression impair the translation from mouse models to human medicine. To characterize mucosal iNOS-producing leukocytes, biopsy specimens from H. pylori–infected patients, controls, and participants of a vaccination trial were analyzed by immunohistochemistry, along with flow cytometric analyses of lymphocytes for iNOS expression and activity. We newly identified mucosal IgA-producing plasma cells (PCs) as one major iNOS+ cell population in H. pylori–infected patients and confirmed intracellular NO production. Because we did not detect iNOS+ PCs in three distinct infectious diseases, this is not a general feature of mucosal PCs under conditions of infection. Furthermore, numbers of mucosal iNOS+ PCs were elevated in individuals who had cleared experimental H. pylori infection compared with those who had not. Thus, IgA+ PCs expressing iNOS are described for the first time, to our knowledge, in humans. iNOS+ PCs are induced in the course of human H. pylori infection, and their abundance seems to correlate with the clinical course of the infection.

Polarised epithelial monolayers of the gastric mucosa reveal insights into mucosal homeostasis and defence against infection

“…H. pylori can enter deep into the glands and interact with the stem cell compartment where it triggers hyperplasia11 and inflammation. Immune cells such as macrophages, T lymphocytes and B cells then infiltrate the mucosa and target the epithelium,38 exacerbating inflammation. Moreover H. pylori can destabilise the host genome by inducing DNA double-strand breaks and shifting repair mechanisms towards error-prone non-homologous end joining 39 40.…”

B cell depletion therapies in autoimmune disease: advances and mechanistic insights

“…IgA-producing PCs in the mouse intestine can express either TNF or inducible nitrogen oxide synthase (iNOS), and this expression is required for resolution of Citrobacter rodentium infection 63 . PC-derived iNOS, which is induced by the unfolded protein response and contributes to PC survival 64,65 , also plays a role in controlling Helicobacter pylori infection in humans 66 . Lastly, by isolation of intestinal PCs for ex vivo flow…”

“…IgA-producing PCs in the mouse intestine can express either TNF or inducible nitrogen oxide synthase (iNOS), and this expression is required for resolution of Citrobacter rodentium infection 63 . PC-derived iNOS, which is induced by the unfolded protein response and contributes to PC survival 64 , 65 , also plays a role in controlling Helicobacter pylori infection in humans 66 . Lastly, by isolation of intestinal PCs for ex vivo flow cytometry analysis and by immunofluorescence analysis on gut tissue from patients with inflammatory bowel disease, PCs in the intestine have also been shown to produce tissue-damaging molecules such as matrix metalloproteinases and granzyme B in response to inflammation 67 , 68 .…”

Helicobacter pylori-induced adrenomedullin modulates IFN-γ-producing T-cell responses and contributes to gastritis

“…During the infection, gastric epithelial cells produce a variety of cytokines that are involved in the inflammatory gastric environment after infection with H. pylori 3 . Besides, many immune cells, such as neutrophils, lymphocytes, and plasma cells, are releasing inflammatory factors in the stomach of H. pylori infection [4][5][6] . Inflammatory reaction to H. pylori infection shows special characteristics rarely seen in other organs or biological systems, and the mixed acute and chronic inflammatory reactions contribute to H. pylori-associated gastritis, and take place simultaneously during H. pylori infection [7][8][9] .…”