FREQUENT USAGE OF SPECIFIC IMMUNOGLOBULIN VH SEGMENTS IN GASTRIC LOW-GRADE B-CELL LYMPHOMAS OF MALT.

Abstract

Background: Low-grade gastric B-cell lymphomas of the mucosa associated lymphoid tissue(MALT) are frequently associated with chronic H. pylori (Hp) infection. The fact that eradication of Hp induces regression of the lymphoma in the majority of the patients together with the presence of Hp-specific T-cells supports the notion that these lymphomas are Hp-responsive. Recent work suggests that autoreactivity may also be important in the development of lymphomas. In addition, other autoreactive diseases like systemic lupus erythematosus or rheumatoid arthritis are often associated with autoantibodies encoded by specific germline VH segments. This study was initiated to analyze VH segment usage and the pattern of somatic mutations in 25 patients with primary gastric low-grade MALT lymphoma. Methods: PCR on VHDJH rearrangements was performed using genomic DNA and generic primers for the VH-framework and JH regions. Monoclonal PCR-products were cloned and sequenced. Results: The VH-sequences detected were homologous to VH1-family segments in 20% and to VH3 and VH4-family segments in 60% and 20% respectively. All five VH1-sequences were derived from the same germline segment (DP-10, V1-69) and five of the fourteen VH3 sequences used the V3-7 (DP54) segment. Somatic mutations were found in 24 out of 25 sequences, with higher incidence of replacement mutations in the antigen contacting complementarity determinating regions(CDRs). 18 out of 25 germline VH segments had previously been isolated from various autoreactive antibodies. Conclusion: These findings support the notion that gastric MALT lymphomas develop from B-cells that have been exposed to antigen, most likely post germinal center B-cells. The high incidence of VH-alleles associated with autoreactivity and preferrence of specific germline VH segments points to the fact that autoreactivity may be important in the genesis of these lymphomas.