We have recognized two forms of histological lesions in diseased sheep gut: a multibacillary (lepromatous) form and a paucibacillary (tuberculoid ) form. We hypothesize that these correspond to different types of immunological responses. Sheep with clinical paratuberculosis (n=19) and healthy control animals (n=16) were used in the study. The proliferative responses of lymphocytes (isolated from the intestinal lamina propria, mesenteric lymph nodes, and peripheral blood) to Mycobacterium aviumparatuberculosis antigens were measured by titrated thymidine uptake. Isolated cells were also cultured with antigen, and the supernatants were assayed for IL-2 activity (IL-2-responsive cell proliferative assay) and IFN-gamma activity (ELISA). Serum samples were assayed for specific antibody. A full necropsy with histological examination of tissues were performed on all animals. A range of immune responses were seen corresponding to the type of histopathology present. The paucibacillary group was characterized by dominant cell-mediated immune (CMI) responses with high levels of IFN-gamma and IL-2, and lower humoral responses suggesting a TH1 type response. The multibacillary group had significantly weaker CMI responses and IFN-gamma and IL-2 levels, with higher antibody levels, suggesting a TH2 type response. These groups correspond to the recognized tuberculoid and lepromatous types of histopathology, respectively. These results suggest that different mechanisms of pathogenesis, corresponding to the type of pathology seen, may operate in ovine paratuberculosis.