Mitogenic autoantibodies in Helicobacter pylori-associated stomach cancerogenesis

Colonization of the bacterium Helicobacter pylori of gastric mucosa plays an important role in stomach carcinogenesis, while the gastric mucosa and nearby lymphoid tissue are active sites of humoral immunity against both bacteria and tumor. In a broad study on the humoral immunity of stomach-cancer patients (5 patients with diffuse- and intestinal-type stomach carcinoma), we immortalized spleen cells by using human hybridoma technology and isolated 11 hybrid clones (9 IgM, 1 IgG and 1 IgA) which react with defined proteins on different stomach-cancer cells and, interestingly, also with distinct proteins on H. pylori; 4 of these antibodies are mitogenic and stimulate the proliferation of stomach-cancer cells in vitro. Furthermore, immunohistochemical studies define these 4 clearly as autoantibodies, in view of their reactivity to normal epithelial cells. Sequence analysis of the genes for the immunoglobulin heavy (V(H)) and light (V(L)) chain variable regions revealed that most of the human antibodies belong to the V(H)3, Vlambda I and III gene families (DP-49, DPL-5 and DPL-23) and are germ-line configured.