The role of antigenic drive and tumor-infiltrating accessory cells in the pathogenesis of helicobacter-induced mucosa-associated lymphoid tissue lymphoma.
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.
Mueller
Anne
A
Department of Microbiology and Immunology, Stanford University Medical School, Stanford, CA 94305, USA. muellera@stanford.edu
O'rourke
Jani
J
Chu
Pauline
P
Chu
Amanda
A
Dixon
Michael F
MF
Bouley
Donna M
DM
Lee
Adrian
A
Falkow
Stanley
S
D000818:Animals; D000900:Anti-Bacterial Agents; D000938:Antigen-Presenting Cells / Q000276:immunology* / Q000473:pathology; D000941:Antigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism / Q000473:pathology; D003713:Dendritic Cells / Q000473:pathology; D004359:Drug Therapy, Combination / Q000494:pharmacology; D005260:Female; D016481:Helicobacter Infections / Q000150:complications*; D044922:Helicobacter felis; D008221:Lymphoid Tissue / Q000473:pathology; D018442:Lymphoma, B-Cell, Marginal Zone / Q000209:etiology* / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D051379:Mice; D008807:Mice, Inbred BALB C; D005810:Multigene Family; D009364:Neoplasm Recurrence, Local; D012008:Recurrence; D012074:Remission Induction; D012720:Severity of Illness Index; D018418:Th2 Cells / Q000473:pathology
D000900:Anti-Bacterial Agents; D000941:Antigens