HELICOBACTER PYLORI-SPECIFIC TUMOUR-INFILTRATING T CELLS PROVIDE CONTACT DEPENDENT HELP FOR THE GROWTH OF MALIGNANT B CELLS IN LOW-GRADE GASTRIC LYMPHOMA OF MUCOSA-ASSOCIATED LYMPHOID TISSUE

Gastric mucosa-associated lymphoid tissue (MALT) lymphoma is the most common subtype of gastric lymphoma. Most gastric MALT lymphomas are characterized by their association with the Helicobacter pylori (HP) infection and are cured by first-line HP eradication therapy (HPE). Several studies have been conducted to investigate why most gastric MALT lymphomas remain localized, are dependent on HP infection, and show HP-specific intratumoral T-cells (e.g., CD40-mediated signaling, T-helper-2 (Th2)-type cytokines, chemokines, costimulatory molecules, and FOXP3+ regulatory T-cells) and their communication with B-cells. Furthermore, the reason why the antigen stimuli of these intratumoral T-cells with tonic B-cell receptor signaling promote lymphomagenesis of gastric MALT lymphoma has also been investigated. In addition to the aforementioned mechanisms, it has been demonstrated that the translocated HP cytotoxin-associated gene A (CagA) can promote B-cell proliferation through the activation of Src homology-2 domain-containing phosphatase (SHP-2) phosphorylation-dependent signaling, extracellular-signal-regulated kinase (ERK), p38 mitogen-activated protein kinase (MAPK), B-cell lymphoma (Bcl)-2, and Bcl-xL. Furthermore, the expression of CagA and these CagA-signaling molecules is closely associated with the HP-dependence of gastric MALT lymphomas (completely respond to first-line HPE). In this article, we summarize evidence of the classical theory of HP-reactive T-cells and the new paradigm of direct interaction between HP and B-cells that contributes to the HP-dependent lymphomagenesis of gastric MALT lymphomas. Although the role of first-line HPE in the treatment of HP-negative gastric MALT lymphoma remains uncertain, several case series suggest that a proportion of HP-negative gastric MALT lymphomas remains antibiotic-responsive and is cured by HPE. Considering the complicated interaction between microbiomes and the genome/epigenome, further studies on the precise mechanisms of HP- and other bacteria-directed lymphomagenesis in antibiotic-responsive gastric MALT lymphomas are warranted.

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When can complete regression of low-grade gastric lymphoma of mucosa-associated lymphoid tissue be predicted after Helicobacter pylori eradication?

Histopathology ◽

10.1046/j.1365-2559.2000.00927.x ◽

2000 ◽

Vol 37 (2) ◽

pp. 131-140 ◽

Cited By ~ 21

Author(s):

H Yamashita ◽

H Watanabe ◽

Y Ajioka ◽

K Nishikura ◽

K Maruta ◽

...

Keyword(s):

Helicobacter Pylori ◽

Lymphoid Tissue ◽

Gastric Lymphoma ◽

Low Grade ◽

Complete Regression ◽

Helicobacter Pylori Eradication

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Evaluation of the Association of Nine Helicobacter pylori Virulence Factors with Strains Involved in Low-Grade Gastric Mucosa-Associated Lymphoid Tissue Lymphoma

Infection and Immunity ◽

10.1128/iai.72.2.880-888.2004 ◽

2004 ◽

Vol 72 (2) ◽

pp. 880-888 ◽

Cited By ~ 75

Author(s):

Philippe Lehours ◽

Armelle Ménard ◽

Sandrine Dupouy ◽

Bernard Bergey ◽

Fréderique Richy ◽

...

Keyword(s):

Helicobacter Pylori ◽

Gastric Mucosa ◽

Virulence Factors ◽

Malt Lymphoma ◽

Lymphoid Tissue ◽

Gastric Lymphoma ◽

Gastric Malt Lymphoma ◽

Low Grade ◽

H Pylori ◽

Few Data

ABSTRACT Helicobacter pylori has been associated with the development of two malignant diseases: gastric adenocarcinoma and gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Although the cag pathogenicity island, especially the cagA gene, has been linked with adenocarcinoma, few data concerning H. pylori pathogenic factors involved in low-grade gastric MALT lymphoma are available. The goal of this study was to analyze the prevalence of and correlation between genes coding for seven H. pylori virulence factors (cagA, cagE, vacA, iceA, babA, hopQ, and oipA) and two novel adhesins (sabA and hopZ) by comparing a collection of 43 H. pylori strains isolated from patients with low-grade gastric MALT lymphoma to 39 strains isolated from age-matched patients with gastritis only. Our results show that taken individually, none of the nine genes tested can be considered associated with MALT strains and allow us to conclude that MALT pathogenesis is not linked with more proinflammatory H. pylori strains. We demonstrated that in patients infected with strains harboring the iceA1 allele, sabA functional status, and hopZ “off” status, the odds of developing a MALT lymphoma were 10 times higher. However, the low prevalence of such strains (10 of 43 MALT strains) renders this triple association a low-sensitivity marker for MALT strains. Our data confirmed that H. pylori virulence factors are correlated with one another. If the involvement of H. pylori in MALT lymphoma is well established, the pathomechanism by which gastric lymphoma occurs remains to be identified.

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Long-Term Persistence of Monoclonal B Cells After Cure of Helicobacter pylori Infection and Complete Histologic Remission in Gastric Mucosa–Associated Lymphoid Tissue B-Cell Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2001.19.6.1600 ◽

2001 ◽

Vol 19 (6) ◽

pp. 1600-1609 ◽

Cited By ~ 83

Author(s):

Christian Thiede ◽

Thomas Wündisch ◽

Birgit Alpen ◽

Beatrix Neubauer ◽

Andrea Morgner ◽

...

Keyword(s):

Helicobacter Pylori ◽

B Cells ◽

Sequence Analysis ◽

Gastric Mucosa ◽

Malt Lymphoma ◽

Lymphoid Tissue ◽

Gastric Malt Lymphoma ◽

Low Grade ◽

H Pylori

PURPOSE: Cure of Helicobacter pylori infection is associated with remission induction in the majority of patients with low-grade gastric mucosa associated lymphoid tissue (MALT) lymphoma in localized stages; however, limited data exist as to whether these patients may be cured of their lymphoma. The present study was performed to investigate whether the polymerase chain reaction (PCR) for the rearranged immunoglobulin heavy chain region may be used to define “molecular” remission. PATIENTS AND METHODS: Ninety-seven patients who suffered from low-grade gastric MALT lymphoma stage IE were observed with central pathology and molecular biology after cure of H pylori infection. PCR was performed with the use of consensus primers for the framework regions 1, 2, and 3 and monoclonality was corroborated by sequence analysis. In selected cases, microdissection was performed to study the origin of the monoclonal B cells. RESULTS: Of the 97 patients, 77 obtained complete endoscopic and histologic remission (CR). Twenty of 44 patients with PCR monoclonality at diagnosis and with sufficient molecular follow-up displayed monoclonal bands for a median time of 20.5 months after CR (range, 0 to 50.4 months). These B cells were related to the original lymphoma clone by sequence analysis. Microdissection analysis identified basal lymphoid aggregates as the source of these monoclonal B cells. Local relapse occurred in and was observed by PCR in four patients. All four patients displayed monoclonal PCR before relapse, and three of these four showed ongoing PCR monoclonality throughout their course, indicating the persistence of malignant cells. CONCLUSION: Half of all patients with gastric MALT lymphoma show long-term PCR monoclonality up to several years after cure of H pylori infection and CR. Patients with monoclonal PCR should be observed closely, whereas long-term PCR negativity may indicate cure of the disease.

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Ongoing somatic mutations and clonal expansions after cure of Helicobacter pylori infection in gastric mucosa-associated lymphoid tissue B-cell lymphoma.

Journal of Clinical Oncology ◽

10.1200/jco.1998.16.12.3822 ◽

1998 ◽

Vol 16 (12) ◽

pp. 3822-3831 ◽

Cited By ~ 38

Author(s):

C Thiede ◽

B Alpen ◽

A Morgner ◽

M Schmidt ◽

M Ritter ◽

...

Keyword(s):

Helicobacter Pylori ◽

B Cells ◽

Gastric Mucosa ◽

B Cell ◽

Lymphoid Tissue ◽

Somatic Mutations ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Low Grade ◽

H Pylori

PURPOSE Although most patients with primary gastric low-grade mucosa-associated lymphoid tissue (MALT) B-cell lymphoma experience complete endoscopic and histologic remission after the cure of Helicobacter pylori infection, in many patients, the polymerase chain reaction (PCR) still detects monoclonal B cells in the gastric mucosa. The present study asked whether the lymphoma immunoglobulin VH (IgVH) sequences remained stable in patients with gastric MALT lymphoma after H pylori eradication. PATIENTS AND METHODS Eight patients with stage EI disease treated with H pylori eradication were analyzed before and at different time points after the cure of the infection. After the amplification of IgVH genes from DNA extracted from gastric biopsy specimens, monoclonal PCR products were cloned and multiple clones (43 to 105) were sequenced per patient. RESULTS Mutations were detected in all lymphoma VH sequences, which suggested germinal center or postgerminal center origin of the lymphoma B cells. In five of the eight patients, clonal heterogeneity was observed at diagnosis or during follow-up. Genealogical analysis of shared and unshared mutations showed that the process of somatic mutations was ongoing after H pylori eradication in four of the five patients who showed clonal instability. Ongoing mutations were observed in three of the four patients who completely responded to H pylori eradication, but in only one of the four patients who did not respond or who partially responded. CONCLUSION In low-grade gastric MALT lymphomas, an ongoing process of somatic hypermutation and antigen selection can be detected after the therapeutic removal of the underlying stimulus H pylori. These data point to the relevance of yet unknown antigens that drive this disease. In addition, they challenge the view that these lymphomas may be cured solely by the eradication of H pylori.

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