Etiology

Whipple disease is a chronic multisystemic infection caused by Tropheryma whipplei.

This bacterium from the clade of Actinomycetes is ubiquitous in the environment, and healthy people may be carriers.[3][4][12] Thus, host factors have been proposed to be responsible for establishment of infection. The pathogen is most likely transmitted by the fecal-oral route. This theory is substantiated by the association of T whipplei with acute diarrhea in children, the enhanced prevalence of asymptomatic carriage of T whipplei under poor hygienic conditions and in sewage plant workers, and suggestions that healthy people are in regular immunologic contact with T whipplei.[3][22][23]​​​[24][25] However, the natural environmental source has not been defined yet.

Some publications discuss a genetic predisposition for Whipple disease.[11][12]​​​ A human leukocyte antigen association has been identified as a genetic risk factor in a large cohort of patients.[26]​ The idea of a genetic predisposition is further enhanced by the predominance of men (in some studies), the rarity of infections, the relatively high proportion of healthy carriers of Tropheryma whipplei, and the rarity of healthy carriers in others apart from white people.[9][27]

Pathophysiology

A model of the pathogenesis is based on findings on macrophage and T-cell functions of affected patients.[28] Macrophages of patients with Whipple disease display a persistently diminished ability to degrade intracellular organisms, and T. whipplei can prevent maturation of phagosomes.[29][30][31] Low production of interleukin (IL)-12 in monocytes, low serum concentrations of IL-12p40, and reduced expression of CD11b further indicate impaired macrophage functioning.[32][33][34][35] Intestinal macrophages reveal an alternatively activated phenotype.[36][37] Consequently, invading bacteria are ingested but not killed by intestinal macrophages.

In addition, the activity of type 1 helper T cells (Th1) is low in the periphery and the lamina propria of patients with Whipple disease.[38]T whipplei-specific Th1 cells are reduced or absent in the periphery and the mucosa.[24] By contrast, functional Th2 responses increase in peripheral and mucosal lymphocytes, in line with the observation that T whipplei replicates in macrophages deactivated by IL-4 and IL-10.[38][39]

Impaired immunologic clearance of T whipplei results in massive accumulation of the bacteria in macrophages, mainly of the intestinal mucosa, which can be visualized by periodic acid-Schiff staining. Although the organ mainly affected is the GI tract, isolated CNS disease, infective endocarditis, and articular disease can occur. Subcutaneous nodules may develop in rare cases, and early manifestations may also be detected in the lung, liver, or muscle.[40][41][42][43][44][45][46][47]

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