[MALT-type B-cell lymphomas escape fas-mediated apoptosis]

Important prognostic factors in primary MALT-lymphomas are stage and grading since the localized low-grade lymphoma may be cured with antibiotic treatment that may result in lymphoma regression as exemplified in Helicobacter eradication (H.p.) in gastric low-grade MALT-lymphomas. For obscure reasons, around 20% of low-grade MALT-lymphomas do not respond to eradication therapy or contain in 25-33% high-grade components as a possible consequence of tumor cell transformation. Given that MALT-lymphoma B-cells are autoimmune in nature and proliferate in response to antigen and T-cell-mediated signals, it is suggestive that autoreactive B-cell lymphoma precursors generated during chronic inflammation escaped the tolerance checkpoint. This mechanism normally operates in healthy individuals through CD40-L/FAS-L expressing activated T-cells and is fundamental in the deletion of harmful B-cells. Analyzing the role of FAS/FAS-L mediated apoptosis in lymphomagenesis, we purified B- and T-cells from low- and high-grade MALT B-cell tumors and tonsillar memory B-cells as control. T-cells were stimulated in vitro to express CD40-L and FAS-L using anti-CD3 antibodies and were subsequently cocultivated with B-cells. Apoptosis was 3 times increased in normal memory B-cells and, to a lesser extent, in a subgroup of low-grade MALT-lymphomas as compared with the spontaneous apoptosis without T-cell coculture. In striking contrast, all primary high-grade MALT-type lymphomas showed increased survival but were resistant to FAS-mediated apoptosis. Furthermore, 40% of low-grade MALT-type lymphomas were resistant to apoptosis and showed mutations in the FAS-gene. The conclusion that self-tolerant high-grade but also a subgroup of low-grade MALT-lymphoma B-cells escaped censoring by the FAS pathway may therefore identify a novel regulatory step in early MALT-lymphomagenesis.