Reduced Peripheral and MucosalTropheryma whipplei-Specific Th1 Response in Patients with Whipple’s Disease

Abstract

Whipple’s disease is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea, but the CNS and other organs may be affected, too. The incidence of Whipple’s disease is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, it has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple’s disease. However, T. whipplei-specific T cell responses could not be studied until now, because cultivation of the bacteria was established only recently. Thus, the availability of T. whipplei Twist-MarseilleT has enabled the first analysis of T. whipplei-specific reactivity of CD4+ T cells. A robust T. whipplei-specific CD4+ Th1 reactivity and activation (expression of CD154) was detected in peripheral and duodenal lymphocytes of all healthy (16 young, 27 age-matched, 11 triathletes) and disease controls (17 patients with tuberculosis) tested. However, 32 Whipple’s disease patients showed reduced or absent T. whipplei-specific Th1 responses, whereas their capacity to react to other common Ags like tetanus toxoid, tuberculin, actinomycetes, Giardia lamblia, or CMV was not reduced compared with controls. Hence, we conclude that an insufficient T. whipplei-specific Th1 response may be responsible for an impaired immunological clearance of T. whipplei in Whipple’s disease patients and may contribute to the fatal natural course of the disease.

Regulatory T Cells in Patients with Whipple’s Disease

“…For staining of whole blood, Abs were added to 100 ml heparinized blood, incubated for 15 min at room temperature, followed by lysis of erythrocytes and fixation as described previously (10).…”

“…Several immunological aberrations have been found so far in patients with CWD, most of them persisting also after successful eradication of T. whipplei (10)(11)(12)(13)(14). Although an impairment of unspecific proliferation of T cells (15) and a weak IL-12 secretion (11,12) have been described only for the peripheral blood, a reduced CD4 + :CD8 + T cell ratio (15), diminished Th1 reactivity (13), absent T. whipplei-specific Th1 response (10), and alternative macrophage activation (14,16) are likewise apparent in lymphocytes of the duodenal mucosa. In a previous study, it was shown that in the duodenum and the peripheral blood proinflammatory cytokines such as IL-1b and TNF-a are not enhanced in CWD patients compared with healthy controls, whereas an elevated expression of IL-10 of CWD patients may facilitate the chronic infection with T. whipplei (14).…”

“…The low incidence of CWD despite the ubiquitous presence of T. whipplei in the environment and in control persons (7,8) as well as effective humoral and cellular immunological responses against the agent in healthy adults (9,10) indicate predisposing immunological defects in patients with CWD. Several immunological aberrations have been found so far in patients with CWD, most of them persisting also after successful eradication of T. whipplei (10)(11)(12)(13)(14). Although an impairment of unspecific proliferation of T cells (15) and a weak IL-12 secretion (11,12) have been described only for the peripheral blood, a reduced CD4 + :CD8 + T cell ratio (15), diminished Th1 reactivity (13), absent T. whipplei-specific Th1 response (10), and alternative macrophage activation (14,16) are likewise apparent in lymphocytes of the duodenal mucosa.…”

“…The disease is fatal if not treated with appropriate antimicrobials (6). The low incidence of CWD despite the ubiquitous presence of T. whipplei in the environment and in control persons (7,8) as well as effective humoral and cellular immunological responses against the agent in healthy adults (9,10) indicate predisposing immunological defects in patients with CWD. Several immunological aberrations have been found so far in patients with CWD, most of them persisting also after successful eradication of T. whipplei (10)(11)(12)(13)(14).…”

Whipple's Disease in an Afro-Caribbean National

“…It has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple's disease. Recent data demonstrate a persistent defect of the cellular immune response (19).…”