Reduced Tropheryma whipplei-specific Th1-reactivity of patients with Whipple's disease might be provoked by disturbed functions of dendritic cells and monocytes

Aims: Whipple's disease (WD) is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea. The incidence of WD is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, host factors indicated by immune deficiencies might be responsible for the development of WD.

Methods: The recent establishment of the strain T. whipplei Twist-MarseilleT has enabled the analysis of T. whipplei-specific reactivity. Thus, we compared CD4+ T-cell reactions of (I) WD-patients (n=40), (II) healthy subjects (n=30), and (III) healthy subjects excreting T. whipplei (n=12) in peripheral blood (PBMC) and duodenal lymphocytes (LPL). In addition, the phenotype of circulating dendritic cells (DC) and monocyte functions were characterized.

Results: Every healthy subject exhibited T. whipplei-specific CD4+IFNγ+CD69+ PBMC and LPL (mean: 0,23% and 2,6%). In contrast, WD-patients showed a significantly reduced reaction against the pathogen (0,03% PBMC, 0% LPL, p<0,001). Healthy T. whipplei-secretors also revealed a diminished reactivity compared to non-secretors (0,1% PBMC, p<0,001) that nonetheless was enhanced compared to WD-patients (p=0,03). The reactivity to Cytomegalovirus, tuberculin, G. lamblia, and actinomycetes closely related to T. whipplei was not reduced in WD-patients. T. whipplei-specific Th2 reactivity was detected in none of the subjects. Although monocytes of WD-patients revealed a similar capacity of phagocytosis, the oxidative burst induced by internalized bacteria was significantly reduced compared to healthy subjects. Additionally, we detected a diminished percentage of circulating CD11+ DC in fresh blood of WD-patients (0,11%) compared to controls (0,19%), while the percentage of CD123+ DC was similar (both 0,09%).

Conclusion: Exposure to the bacteria induces T. whipplei-specific reactivity in healthy subjects. However, asymptomatic colonization of the gastrointestinal tract with T. whipplei diminishes the specific reactivity that gets completely lost during active WD. Disturbed degradation of bacteria and reduced activity of DC and monocytes in WD-patients seems to result in weak T. whipplei-specific Th1 reactivity and deficient protection against the pathogen.