Role of Mycobacterium avium. subsp. paratuberculosis in the pathogenesis of Crohn's disease

Crohn's disease (CD) is a clinically defined syndrome of unknown etiology. Patients with CD develop chronic relapsing bouts of enteritis. The mechanisms of induction and persistence of inflammation appear to include modulation of the immune response through activation of the IL-23/IL-17 and IL-22 pathways that promote chronic inflammation. Factors that trigger CD are thought to include exposure to specific pathogens, bacteria present in normal microflora of the intestine, or other undefined factors that induce persistent immune mediated inflammation of the bowel. Mycobacterium avium subsp. paratuberculosis (Map) the etiological agent of Johne's disease (JD) is the pathogen most frequently implicated in CD immunopathogenesis. The finding of Map in many patients with CD supports this possibility. It remains unclear, however, how Map could be involved in CD pathogenesis. Elucidation of the mechanisms of pathogenesis mediated by Map in its natural host could provide insight into its potential role in CD pathogenesis. We developed a bovine ileal cannulation model to analyze the mechanisms of JD immunopathogenesis. The studies revealed animals become persistently infected following exposure to Map with no signs of clinical disease during the first year post infection (PI). Map elicited a prominent CD4 T cell response to Map and Map antigens 3 months PI. A similar response was observed in animals at the clinical stage of disease. The CD8 T cell response was more prominent in animals at the clinical stage of disease. Quantitative RT-PCR revealed a complex pattern of expression of genes encoding IFN-γ, IL-17, IL-22, and granulysin PI indicating the presence of CD4 T cells associated with a Type I immune response and Th17 and Th22 CD4 T cells associated with a proinflammatory response. The findings show that persistent infection with Map could play a role in CD pathogenesis.