Tumor-associated macrophages as major source of APRIL in gastric MALT lymphoma

Lymphoid hyperplasia of gastric mucosa associated with Helicobacter pylori (HP) infection represents a pre-neoplastic condition of the mucosa associated lymphoid tissue (MALT) which may evolve to a B cell lymphoma. While it is well established that the initial neoplastic proliferation of B cells is antigen-driven and dependent on the helper activity of HP-specific T cells, it needs to be elucidated which cytokine or soluble factor(s) promote B cell activation and lymphomagenesis. Herein, we originally report that gastric MALT lymphoma express high levels of a proliferation inducing ligand (APRIL), a novel cytokine crucial in sustaining B cell proliferation. By immunohistochemistry, we demonstrate that APRIL is produced almost exclusively by gastric lymphoma-infiltrating macrophages located in close proximity to neoplastic B-cells. We also show that macrophages produce APRIL upon direct stimulation with both HP and HP-specific T cells. Collectively, our results represent the first evidence for an involvement of APRIL in gastric MALT lymphoma development in HP-infected patients.