Specific and nonspecific B-cell function in the small intestines of patients with Whipple's disease

Abstract

Whipple's disease is a chronic multisystemic infection caused by Tropheryma whipplei that is characterized by arthritis, weight loss, and diarrhea. The immunological defects in the duodenal mucosa, the site of major replication of the agent underlying the pathogenesis of Whipple's disease, are poorly understood. Mucosal immunoglobulins are essential for the defense against intestinal pathogens; therefore, we analyzed the B-cell response in duodenal specimens and sera of Whipple's disease patients. Whereas systemic immunoglobulin production was affected only marginally, duodenal biopsy specimens of Whipple's disease patients contained reduced numbers of immunoglobulin-positive plasma cells and secreted less immunoglobulin compared to healthy controls but showed a weak secretory IgA response toward T. whipplei. This T. whipplei-specific intestinal immune response was not observed in controls. Thus, we were able to demonstrate that general mucosal immunoglobulin production in Whipple's disease patients is impaired. However, this deficiency does not completely abolish T. whipplei-specific secretory IgA production that nonetheless does not protect from chronic infection.

FIG. 1.

Immunoglobulin production in duodenal biopsy specimens of Whipple's disease patients compared to healthy subjects, as evidenced by exemplary immunostaining of IgA (colored in red). (A) High number of IgA⁺ plasma cells in a healthy control; (B and C) low number of IgA⁺ plasma cells in a Whipple's disease patient before the start of treatment (B) and in the same Whipple's disease patient after 6 months of antimicrobial treatment (C).

FIG. 2.

Percentage of immunoglobulin-producing plasma cells among all plasma cells in duodenal biopsy specimens from Whipple's disease (WD) patients and healthy controls as determined by immunohistochemistry. (A) Percentage of IgA⁺ plasma cells; (B) percentage of IgG⁺ plasma cells; (C) percentage of IgM⁺ plasma cells. Individual values, medians, and interquartile ranges are shown, and P values were determined by using the Mann-Whitney test.

FIG. 3.

Immunoglobulin concentrations in supernatants of duodenal biopsy specimens obtained from healthy subjects and Whipple's disease patients during or after antimicrobial treatment. (A) IgA; (B) IgG2; (C) IgM. Individual values, medians, and interquartile ranges are shown, and P values were determined by using the Mann-Whitney test. WD, Whipple's disease.

FIG. 4.

Western blot for T. whipplei-specific immunoglobulins. Exemplary Western blots of T. whipplei-specific IgA (lane 1) and IgG (lane 2) in the serum from a Whipple's disease (WD) patient (positive control), secretory IgA in biopsy specimen supernatants from three healthy controls (lanes 3 to 5), and secretory IgA in biopsy specimen supernatants from three Whipple's disease patients (lanes 6 to 8). Arrowheads indicate T. whipplei-antigens recognized by the respective supernatants and sera used as positive controls. C₁ to C₃, healthy subjects; WD₁ to WD₃, Whipple's disease patients.