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Whipple's disease is a rare multisystem disorder that occurs mostly in middle-aged Caucasian males. It may affect any organ of the body but most clinical manifestations are secondary to gastrointestinal and joint involvement. It is caused by infection with the actinomycete, Tropheryma whippelii. The diagnosis is suspected when large aggregates of PAS-positive , bacteria-containing macrophages are seen in the small intestine and/or other affected organs. Granulomas may also be seen.The bacteria exhibit an unusual trilaminar cell wall ultrastructure by electron microscopy. Diagnosis is established by polymerase chain reaction amplification of the 16S rRNA gene sequences of these bacteria in tissue. The organism has been isolated in tissue culture. There is evidence indicating that Tropheryma whippelii is a ubiquitous environmental or commensal organism causing Whipple's disease in a small subset of individuals. Macrophage dysfunction appears to be a prerequisite for the development of Whipple's disease.