Stanford, CA -- Research led by Dr. Anne Mueller at Stanford University School of Medicine demonstrates that successful eradication of Helicobacter may not prevent future aggressive gastric lymphoma since resting B cells are left behind. The paper by Mueller et al., "The role of antigenic drive and tumor-infiltrating accessory cells in the pathogenesis of Helicobacter-induced MALT lymphoma," appears in the September issue of The American Journal of Pathology.
Helicobacter pylori, a spiral bacterium of the stomach, infects more than half of the world's population. It is now widely accepted that, aside from gastritis and ulcers, H. pylori is also a causative agent of gastric lymphoma, specifically gastric B cell lymphoma of mucosa-associated lymphoid tissue (MALT). While antibiotic treatment eradicates the bacteria and promotes tumor regression, the effects of re-infection on disease are more severe.
To address the effects of re-infection and the role of immune cells in disease progression, Dr. Mueller's group used a mouse model of Helicobacter-induced MALT lymphoma that employs H. felis to mimic human disease in the mouse. Mice were infected with H. felis and maintained for 18 months before being assigned to one of three treatment groups: 1) no treatment (primarily infected), 2) antibiotic therapy to eradicate bacteria, or 3) antibiotic therapy followed by re-infection.
As expected, low-grade MALT lymphoma occurred in 35% of all infected animals. However, frank MALT lymphoma was more prevalent in re-infected animals (44%) than in primarily infected animals (25%). Transcription profiling identified B cell markers in mice that had been infected at any point in time, even after successful antibiotic treatment, suggesting that resting B cells remain in the gastric mucosa.
Lymphoid aggregates of re-infected animals also contained more proliferating cells than those of primarily infected or antibiotic-treated animals (46% vs. 23.2% or 4.8%, respectively). Closer inspection of the lymphoid aggregates revealed that the tumors were indeed derived from B cells and the main antigen-presenting cells were follicular dendritic cells. Finally, follicular dendritic cell numbers were highest in the tumors of re-infected animals followed by primarily infected and then antibiotic-treated animals, thus correlating with severity of gastric lymphoma.
Because it is the follicular dendritic cells that present antigen to T cells that in turn activate B cell proliferation, follicular dendritic cells appear to be better indicators of tumor behavior than B cells. Thus, follicular dendritic cells represent an untapped target in the fight against recurrent gastric lymphoma.
The significance of the described work is that gastric lymphoma progresses more rapidly upon secondary infection. Because resting B cells are left behind following antibiotic treatment, re-infection by H. pylori promotes the existing B cells to progress quickly into tumors. Therefore, it is important that treated patients be carefully monitored for H. pylori re-infection.
Mueller A, O'Rourke J, Chu P, Chu A, Dixon MF, Bouley DM, Lee A, Falkow S: The role of antigenic drive and tumor-infiltrating accessory cells in the pathogenesis of Helicobacter-induced MALT lymphoma. Am J Pathol 2005, 167:797-812
Research was supported by the National Institutes of Health (US), the Emmy-Noether-Program of the Deutsche Forschungsgemeinschaft (Germany), and J National Health and Medical Research Council (Australia).
The American Journal of Pathology, the official journal of the American Society for Investigative Pathology (ASIP), seeks to publish high-quality original papers on the cellular and molecular mechanisms of disease. The editors accept manuscripts which report important findings on disease pathogenesis or basic biological mechanisms that relate to disease, without preference for a specific method of analysis. High priority is given to studies on human disease and relevant experimental models using cellular, molecular, biological, animal, chemical and immunological approaches in conjunction with morphology.
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