A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma

Jennifer Gossmann; Manfred Stolte; Michael Lohoff; Philipp Yu; Roland Moll; Florian Finkernagel; Holger Garn; Cornelia Brendel; Alwina Bittner; Andreas Neubauer; Minh Q Huynh

doi:10.1371/journal.pone.0150411

A Gain-Of-Function Mutation in the Plcg2 Gene Protects Mice from Helicobacter felis-Induced Gastric MALT Lymphoma

PLoS One. 2016 Mar 11;11(3):e0150411. doi: 10.1371/journal.pone.0150411. eCollection 2016.

Authors

Affiliations

¹ Department of Hematology, Oncology and Immunology, Philipps University of Marburg, and University Hospital Giessen and Marburg, Marburg, Germany.
² Institute of Pathology, Kulmbach Hospital, Kulmbach, Germany.
³ Institute of Medical Microbiology, Philipps University of Marburg, Marburg, Germany.
⁴ Institute of Immunology, Philipps University of Marburg, Marburg, Germany.
⁵ Institute of Pathology, Philipps University of Marburg, Marburg, Germany.
⁶ Institute of Molecular Biology and Tumor Research, Philipps University of Marburg, Marburg, Germany.
⁷ Institute of Laboratory Medicine and Pathobiochemistry-Molecular Diagnostics, Philipps University of Marburg, Marburg, Germany.

Abstract

Gastric mucosa-associated lymphoid tissue (MALT) lymphomas develop from a chronic Helicobacter infection. Phospholipase C gamma 2 (PLCG2) is important for B-cell survival and proliferation. We used BALB/c mice with a gain-of-function mutation in the Plcg2 gene (Ali5) to analyze its role in the development of gastric MALT lymphoma. Heterozygous BALB/c Plcg2Ali5/+ and wildtype (WT) mice were infected with Helicobacter felis (H. felis) and observed up to 16 months for development of gastric MALT lymphomas. In contrast to our initial hypothesis, Plcg2Ali5/+ mice developed MALT lymphomas less frequently than their WT littermates after long-term infection of 16 months. Infected Plcg2Ali5/+ mice showed downregulation of proinflammatory cytokines and decreased H. felis-specific IgG1 and IgG2a antibody responses. These results suggested a blunted immune response of Plcg2Ali5/+ mice towards H. felis infection. Intriguingly, Plcg2Ali5/+ mice harboured higher numbers of CD73 expressing regulatory T cells (Tregs), possibly responsible for impaired immune response towards Helicobacter infection. We suggest that Plcg2Ali5/+ mice may be protected from developing gastric MALT lymphomas as a result of elevated Treg numbers, reduced response to H. felis and decrease of proinflammatory cytokines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Cytokines / metabolism
Gene Expression Regulation
Helicobacter Infections / genetics*
Helicobacter Infections / immunology
Helicobacter Infections / veterinary
Helicobacter felis / pathogenicity*
Immunoglobulin G / metabolism
Lymphoma, B-Cell, Marginal Zone / genetics
Lymphoma, B-Cell, Marginal Zone / immunology
Lymphoma, B-Cell, Marginal Zone / virology*
Mice
Mice, Inbred BALB C
Mutation
Phospholipase C gamma / genetics*
Stomach Neoplasms / genetics
Stomach Neoplasms / immunology
Stomach Neoplasms / virology*
T-Lymphocytes, Regulatory / metabolism

Substances

Cytokines
Immunoglobulin G
Phospholipase C gamma

Grants and funding

This work was supported by Landes-Offensive zur Entwicklung Wissenschaftlich-ökonomischer Exzellenz (LOEWE) grant “Tumor and Inflammation” (http://www.imt.uni-marburg.de/loewe/, project A1, to AN); research grant of the University Hospital Giessen and Marburg (UKGM, 11/2013 MR, to JG and MQH); Deutsche Forschungsgemeinschaft (KFO 210, NE 310/14-2, to AN and SFB TR22, 491.000., to ML; http://www.dfg.de); José Carreras Leukämie-Stiftung (https://www.carreras-stiftung.de, AH06-01, to AN); Behring-Röntgen-Stiftung (TP3, 51-0057, to AN and fellowship, 600.000., to ML; http://www.br-stiftung.de). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.