The Role of Antigenic Drive and Tumor-Infiltrating Accessory Cells in the Pathogenesis of Helicobacter-Induced Mucosa-Associated Lymphoid Tissue Lymphoma

Abstract

Gastric B-cell lymphoma of mucosa-associated lymphoid tissue type is closely linked to chronic Helicobacter pylori infection. Most clinical and histopathological features of the tumor can be reproduced by prolonged Helicobacter infection of BALB/c mice. In this study, we have addressed the role of antigenic stimulation in the pathogenesis of the lymphoma by experimental infection with Helicobacter felis, followed by antibiotic eradication therapy and subsequent re-infection. Antimicrobial therapy was successful in 75% of mice and led to complete histological but not "molecular" tumor remission. Although lympho-epithelial lesions disappeared and most gastric lymphoid aggregates resolved, transcriptional profiling revealed the long-term mucosal persistence of residual B cells. Experimental re-introduction of Helicobacter led to very rapid recurrence of the lymphomas, which differed from the original lesions by higher proliferative indices and more aggressive behavior. Immunophenotyping of tumor cells revealed massive infiltration of lesions by CD4(+) T cells, which express CD 28, CD 69, and interleukin-4 but not interferon-gamma, suggesting that tumor B-cell proliferation was driven by Th 2-polarized, immunocompetent, and activated T cells. Tumors were also densely colonized by follicular dendritic cells, whose numbers were closely associated with and predictive of treatment outcome.

Chronic inflammatory disease, lymphoid tissue neogenesis and extranodal marginal zone B-cell lymphomas

“…[174][175][176][177] Oral infection of A/J mice with Helicobacter sp leads to development of hepatic inflammatory lesions containing HEVs, the production of CCL21 and CXCL13 and influx of B and T cells. 177 Infection of BALB/c mice with Helicobacter felis resulted in a massive influx of B cells and lymphoorganogenesis in the stomach.…”

“…177 Infection of BALB/c mice with Helicobacter felis resulted in a massive influx of B cells and lymphoorganogenesis in the stomach. 174,175 It was reported that after 23 months of infection, 25-75% of these mice developed low-or intermediate-grade MZBCLs. In these mice, regression of the infiltrates after anti-bacterial therapy was also demonstrated.…”

“…In these mice, regression of the infiltrates after anti-bacterial therapy was also demonstrated. 174,175 Other investigators have infected BALB/c mice with different 'H. heilmannii' isolates originating from human and animal hosts.…”

“…the presence of centrocyte-like cells and lympho-epithelial lesions, but not on the assessment of monoclonality by Ig gene rearrangement assays nor on any other molecular genetic analyses. 174,175 Transgenic FVB mice expressing the API2-MALT1 fusion gene, driven by the SRα promoter under control of the Eµ Ig heavy chain enhancer, specifically triggered the expansion of splenic MZ B cells. However, the expression of the API2-MALT1 fusion protein alone was not sufficient for the development of lymphomas over a period of 50 weeks.…”

Gastric MALT lymphoma B cells express polyreactive, somatically mutated immunoglobulins

“…Several studies have implicated the abundant population of tumor-infiltrating T cells in providing growth signals to tumor B cells. [10][11][12] In one study, depletion of T cells was shown to abrogate the proliferation of explanted MALT lymphoma cultures. 12 We and others have reported that MALT lymphomas express high levels of interleukin-4 (IL-4) and other T helper 2 cytokines in vivo, supporting a role for T helper 2-polarized T-helper responses in early MALT lymphomagenesis.…”