Whipple's disease: a macrophage disease.

Whipple’s disease (WD) is a rare systemic disease, first described in 1907 by the American pathologist George H. Whipple as an intestinal lipodystrophy. He reported the fatal illness in a patient with weight loss, chronic cough, fever, and accumulation of fat in the intestine, mesenteric lymph nodes, and stool (121a). The hallmark of the disease is the accrual of periodic-acid Schiff (PAS)-stained foamy macrophages in the lamina propria. Although G. H. Whipple suggested a bacterial etiology in his systematic description of the disease in his index patient (121a), it was not until 1961 that intramacrophagic and free-living bacilli were observed in patient duodenal biopsies (16a). The bacteria present a rod-shaped morphology with a symmetric external membrane that is not found among grampositive bacteria, and yet it differs from the external membrane in gram-negative bacteria because it is devoid of lipopolysaccharide (LPS) (22a). It surrounds a thin homogeneous layer and an internal membrane containing polysaccharides, which are probably responsible for the PAS staining (111). As a result of phylogenetic studies based on the ssr and rpoB gene sequences, the agent, which is now referred to as Tropheryma whipplei, has been placed among the gram-positive bacteria in the Actinobacteria clade. Several environmental studies suggest that T. whipplei is ubiquitous. Indeed, bacterial DNA was detected in 66% of wastewater samples from five different sewage treatment plants in Germany (72a). In 1997, culture of T. whipplei was achieved in interleukin-4 (IL-4)-deactivated macrophages; however, it was not possible to establish stable subcultures (107a). In 2000, our laboratory successfully cultured T. whipplei from the heart valve specimen of a patient with endocarditis in a human fibroblast cell line (HEL) (98). The ability to culture the organism allowed the generation of antibodies against T. whipplei (98) and enumeration of the complete genome sequence for two strains (7a, 101). Analysis of the genome sequence, which is approximately 0.9 Mb in length, revealed deficiencies in the biosynthetic pathways of 16 amino acids. Addition of the missing amino acids to culture medium permitted the axenic culture of T. whipplei (102a). WD is considered to be rare, although no valid estimate of the incidence is available. The disease was diagnosed in a set of patients within a familial context (22, 96), which implies an immunogenetic component in the pathogenesis of WD. Several studies have shown a greater prevalence of HLA-B27 antigen in WD patients (26% versus 8% in European and American populations, respectively) (16, 22), but no causal association between HLA-B27 presence and infection susceptibility has been demonstrated. The classic symptoms of WD include weight loss, diarrhea, and chronic arthropathy. However, it is now known that the disease is often multisystemic, including possible cardiac and central nervous system involvement, and has clinical manifestations that may be varied and nonspecific (Table 1). T. whipplei has been detected in 4% of patients with various gastrointestinal diseases and in 7% of presumably healthy control subjects (2). T. whipplei DNA has also been detected in 40% of subgingival and gingival sulcus samples from healthy individuals (124). The disease is characterized by the persistent bacterial infection of affected tissues, resulting in recurring relapses and gradual exacerbation. PCRbased diagnosis of WD, which is accomplished by detection of the genomic material of T. whipplei, is well defined (30). However, in practice, some studies raise concerns about the diagnostic value of T. whipplei PCR alone. Indeed, peripheral blood mononuclear cells from four patients with active WD (confirmed by PAS-positive intestinal biopsies) were negative by PCR for T. whipplei DNA (74). On the contrary, T. whipplei DNA has been detected in people without WD (28). Diagnosis can also be made by examination of biopsy samples using electron microscopy, which allows visualization of the distinctive trilamellar cell wall of T. whipplei. Serologic tests for the diagnosis of WD are not yet established, because antibodies directed against T. whipplei have been measured in subjects without WD as well as in WD patients (27). Thus, although the diagnosis is usually made by duodenal biopsy, it can simply be overlooked in the early stages of WD or in other forms of the disease when gastrointestinal involvement is not clear.