Abstract
The roles of the inflammatory response and production of a proliferation-inducing ligand (APRIL) cytokine in gastric mucosa-associated lymphoid tissue (MALT) lymphomagenesis induced by Helicobacter species infection are not clearly understood. We characterized the gastric mucosal inflammatory response associated with gastric MALT lymphoma (GML) and identified APRIL-producing cells in two model systems: an APRIL transgenic mouse model of GML induced by Helicobacter infection (Tg-hAPRIL) and human gastric biopsy samples from Helicobacter pylori-infected GML patients. In the mouse model, polarization of T helper 1 (tbet), T helper 2 (gata3), and regulatory T cell (foxp3) responses was evaluated by quantitative PCR. In humans, a significant increase in april gene expression was observed in GML compared to gastritis. APRIL-producing cells were eosinophilic polynuclear cells located within lymphoid infiltrates, and tumoral B lymphocytes were targeted by APRIL. Together, the results of this study demonstrate that the Treg-balanced inflammatory environment is important for gastric lymphomagenesis induced by Helicobacter species, and suggest the pro-tumorigenic potential of APRIL-producing eosinophils.
Highlights
The bacterium Helicobacter pylori induces chronic inflammation called gastritis within the gastric mucosa in humans
To understand more fully the pathophysiology of gastric MALT lymphoma (GML) induced by H. pylori infection, an alternative model was implemented in our laboratory that relies on the use of transgenic C57BL6 mice for the human form of the A proliferation-inducing ligand (APRIL) cytokine (Tg-hAPRIL), and infected with Helicobacter sp (H. pylori or H. felis)[19]
We showed that the Tg-hAPRIL mouse model infected with Helicobacter sp closely reproduces the pathology of human GML with the same balanced gastric Th1, Th2, and Treg inflammatory response
Summary
The bacterium Helicobacter pylori induces chronic inflammation called gastritis within the gastric mucosa in humans. In GML, chronic antigenic stimulation by H. pylori on the gastric mucosa induces the formation of B-cell monoclonal infiltrates with a marginal zone immunophenotype[1,3]. Reactive T lymphocytes (predominantly CD4+) are found within the infiltrates These C D4+ cells allow the activation and proliferation of neoplastic B cells via CD40L-CD40 co-stimulation and the secretion of T helper type 2 cytokines such as interleukin 43,4. APRIL is produced by cleavage into a soluble protein by a furin-like protease intracellularly before secretion. It is expressed by many cells of the immune system cells such as neutrophils, eosinophils, and macrophages[10,11,12]. Tumor-infiltrating macrophages are a major source of APRIL in G ML17; the production of APRIL is induced by H. pylori antigens and H. pylori-specific T c ells[17]
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