Einfluss einer gain-of-function-Mutation im Plcg2-Gen auf eine Helicobacter felis-induzierte gastrale MALT-Lymphom Entwicklung

Gastric marginal zone B cell lymphoma of the MALT (mucosa-associated lymphoid tissue) type is a model disease to understand, how malignant tumors develop out of a chronic bacterial H. pylori infection. Our group was among the first to demonstrate that in most cases low-grade MALT lymphoma patients show long-term remission and cure after elimination of the H. pylori infection. Therefore, eradication of H. pylori is now always the first-line therapy for early stage gastric MALT lymphomas. The interactions of Helicobacter-specific virulence factors and specific host characteristics play a crucial role in the development of MALT lymphomas. Various host gene polymorphisms, which are responsible for the immune response and inflammatory reactions of a H. pylori infection, are associated with an increased inflammatory response and consequently with a higher incidence of MALT lymphomas. In addition, our group has demonstrated that the gene for phospholipase C gamma 2 is overexpressed in gastric MALT lymphoma as compared to chronic gastritis. We therefore asked, whether autoimmune-prone mice with a gain-of-function mutation in the Plcg2 gene are more susceptible to development of H. felis-induced gastric MALT lymphomas. Symptoms of a H. felis infection in mice are very similar to a human H. pylori infection. In contrast to our initial hypothesis, it could be shown that heterozygous Plcg2Ali5/+ mice developed significantly less gastric MALT lymphoma as compared to WT littermates. Infected Plcg2Ali5/+mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific antibody responses. An incisive B-cell defect in Plcg2Ali5/+ mice was ruled out by in vitro experiments. By examining regulatory T-cells in the spleen tissue of both genotypes we found out that Plcg2Ali5/+ mice have a significantly higher number of immunosuppressive CD73-expressing Tregs. This result could explain the decreased immune response of Plcg2Ali5/+ mice towards H. felis infection. Altogether, these data demonstrate for the first time that the gain-of-function mutation in the Plcg2 gene protects against Helicobacter-induced MALT lymphoma development. The experiments and analyses in this study allow to draw the conclusion that higher numbers of Tregs in Plcg2Ali5/+ mice may be responsible for the decreased inflammatory response and consequently for the reduced MALT lymphoma development.