BALB/c (H-2d) and C57BL/6 (H-2b) mice were immunized with one or two doses of allogeneic or syngeneic mucosal antigen (MA) from small intestinal mucosa. This antigen was also characterized by immunoenzymatic assay (ELISA), by SDS-PAGE and by Western blotting. Single-dose immunized mice of either strain, sacrificed 30 days after immunization, synthesized marginal levels of anti-MA antibodies, as assessed by ELISA tests. BALB/c mice receiving two doses of the immunogen produced antibodies at a highly significant level (p < 0.001) when compared to C57BL/6 mice belonging to the same experimental group. BALB/c mice immunized with syngeneic MA gave a humoral anti-MA response similar to that of BALB/c immunized with allogeneic MA. All experimental mice, irrespective of their genetic background or the number of doses of MA received, develop a cell-mediated immune response to MA. BALB/c mice immunized with two doses of allogeneic or syngeneic MA developed lesions mainly located in the small intestine, characterized by macroscopical and microscopical vascular congestion and hemorrhaging, epithelial cell loss, mononuclear cell infiltration of the lamina propria, cryptal degeneration and granuloma formation. Immunochemical analysis showed varying degrees of cross-reactivity between MA, liver and kidney saline extracts when heterologous anti-MA sera were tested by ELISA. Absorption of these sera with mouse liver or kidney saline extract lyophilizates reduced reactivity of anti-MA antibodies, although the degree of residual activity remained high. SDS-PAGE of mouse MA, kidney, and liver extracts revealed the presence of two polypeptidic bands of less than 17 kD molecular weight belonging to MA. Immunoblotting (Western blot) analysis revealed that heterologous or isologous anti-MA antibodies incubated with mouse MA reacted with the same epitopes as well as with others shared by other organs. Absorption of these sera with liver or kidney saline extracts revealed two organ-specific epitopes belonging to MA. Data presented here support the possibility of a genetic control of the susceptibility of BALB/c mice to the development of an acute autoimmune enterocolitis (AEC). This response appears to be a function of the amount of immunogenadministered as well as the genetic background of immunized mice. The presence of a cell-mediated immune response to MA alone, however, is not sufficient for lesions to appear: the histopathological alterations characteristic of AEC are present only in experimental groups where detectable levels of anti-MA antibodies are found. The antibody response seems to be directed against two unique epitopes belongig to MA. They can be tentatively linked to the autoantigens involved in the immune response to MA in this AEC model.