IntroductionGastric mucosa-associated lymphoid tissue (MALT) B-cell lymphoma develops in the context of long-term infection with the Gram-negative gastric bacterium Helicobacter pylori. 1-3 Persistent infection with H pylori causes chronic gastritis that, in some people, can develop into more organized gastric mucosa-associated lymphoid tissue (MALT) with histologic similarity to the Peyer patches of the small intestine. 4 The disease progresses when individual malignant clones grow out, displace the benign lymphoid tissue, and ultimately form the lymphoepithelial lesions that are a hallmark of MALT lymphoma. 5,6 In its early stages, gastric MALT lymphoma is believed to be an antigen-dependent disease; H pylori infection is detectable in a large majority of cases. 1,3,7 Eradication therapy induces tumor regression in approximately 75% of patients at this stage. 8,9 Early-stage low-grade MALT lymphoma is generally considered an indolent tumor due to its slow growth, low proliferation rates, and minimal propensity for spreading. At later stages, however, the tumors can eventually undergo high-grade transformation or acquire one of several known characteristic chromosomal translocations, thereby rendering the lymphoma independent of antigen exposure and refractory to H pylori eradication therapy.In contrast to cases with chromosomal rearrangements, which grow autonomously due to constitutive activation of the nuclear factor B (NF-B) signaling pathway brought about by overexpression of MALT-1, B-cell leukemia 10 (Bcl-10), or production of the Baculovirus IAP repeat-containing 3 (API2)-MALT1 fusion protein (reviewed in Isaacson and Du), 5 little is known about the pathogenesis of early MALT lymphoma. 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. 10,11 An alternative possibility is that early stage MALT lymphoma B cells receive signals via antigenic stimulation through their B-cell receptor (BCR), which would lead to NF-B activation, survival, and proliferation. Indeed, MALT lymphoma cells carry functional, rearranged, and somatically mutated immunoglobulin genes on their surface. 13,14 Sequence analysis of the V H genes suggests that the tumor cells have undergone positive selection in germinal centers. [14][15][16] Intraclonal variation caused by ongoing somatic mutation and/or replacement of a part of the variable heavy segment (receptor revision) has been reported. [15][16][17] Despite these clear results, the search for a target antigen has proven difficult and has yielded controversial results, either providing evidence for reactivity toward certain structures of normal human tissu...