There are two possible disease outcomes in ovine Johne's Disease. Paucibacillary (PB) disease is defined by lymphocyte infiltration, a Type 1 immune response and few acid fast organisms present within lesions. Multibacillary (MB) disease is defined by macrophage infiltration, a Type 2 immune response and many acid fast organisms. Sheep with severe Johne's Disease were identified from within several small herds, necropsied, and blood and mesenteric lymph node samples harvested. Culture and histology results were used to define two groups; sheep with varying severity PB disease, and sheep with severe MB disease. Samples were further analysed by IFNγ ELISA, IgG1 antibody ELISA, flow cytometry and real-time PCR. This data was correlated with both disease status and disease severity to determine whether these naturally infected sheep have classical PB or MB immune profiles. This data revealed a strong johnin specific proliferative response in the PB diseased group and a less responsive antibody-based response in the MB diseased group. This was demonstrated by high levels of IFNγ protein and mRNA accompanied by increases in all cell populations monitored after stimulation with johnin in PB diseased animals. There were also higher levels of inherent IFNγ mRNA in the blood but not the posterior jejunal lymph node. These observations were in contrast to MB diseased animals which exhibited low levels of IFNγ protein and mRNA, no change in the cell populations monitored after stimulation with johnin, but high IgG1 antibody levels, high circulating levels of BCR+ cells, and high levels of inherent IL-10 mRNA in the posterior jejunal lymph node but not the blood. Interestingly both diseased groups had lower levels of inherent IL-4 mRNA in the blood and posterior jejunal lymph node than the control non-diseased animals. This data will also be compared to data from a current vaccine trial to investigate the effects of vaccination on disease development.