Crohn's disease (CD) is a clinically defined syndrome of unknown etiology. Although the etiology of CD is not fully understood, genetic and epidemiological studies indicate individuals with one or more allelic variants of genes involved in regulation of the immune response may be at higher risk for developing CD. The factors that induce persistent immune mediated inflammation of the bowel in these individuals are thought to include exposure to specific pathogens, bacteria present in normal microflora of the intestine, or other undefined factors. The mechanisms of induction and persistence of inflammation appear to include modulation of the immune response by regulatory T cells and activation of the IL-23-IL-17 pathway that promotes chronic inflammation. Mycobacterium avium subsp. paratuberculosis (Map) is the pathogen most frequently implicated in playing a role in the pathogenesis of CD. The implications are due to similarities in pathogenesis between CD and Johne's disease in cattle and the increased frequency of finding Map in CD patients over patients of other inflammatory bowel diseases. These findings could indicate Map plays a role in pathogenesis in a subset of genetically susceptible individuals with CD or that, individuals with CD are serving as sentinels that reveal the prevalence of Map in the environment.

Elucidation of the mechanisms of pathogenesis mediated by Map in its natural host could provide an opportunity to clarify the role of Map in CD pathogenesis and also insight into the sequence of events leading to erosion of protective immunity and development of clinical disease. To explore this possibility, we developed a bovine cannulated ileum model to analyze the immune response to bovine and human isolates of Map and determine how Map modulates the immune response during the early and late stages of disease. Comparative studies have revealed no significant differences in the capacity of bovine and human isolates of Map to infect calves. Both types of isolates elicit a prominent CD4 memory T cell response to PPD and soluble Map antigens detectable by flow cytometry 3 months post infection (PI). Morphologic changes in the ileum consistent with disease progression are detectable by 8 - 10 months PI. Although difficult to culture from tissue biopsies, presence of Map is detectable by PCR. Quantitative RT-PCR has revealed a complex pattern of expression of genes encoding IFN-γ, IL-17, and granulysin in experimentally infected animals 10 - 12 months PI indicating the presence of CD4 memory T cells associated with a Type I immune response and Th17 CD4 T cells associated with development of a proinflammatory response. The increase in expression of granulysin suggests the presence of effector memory T cells with bactericidal activity. The findings indicate a detailed analysis of immunopathogenesis of JD will facilitate understanding the role of Map in the pathogenesis of CD.