The role of T cells in the pathogenesis of classical Whipple’s disease

Keywords::

• T cells
• Tropheryma whipplei
• Whipple’s disease

Tropheryma whipplei is a Gram-positive bacterium with a reduced genome closely related to mycobacteria and actinomycetes [1]. T. whipplei lacks a number of essential genes for metabolic pathways [1] and, thus, its survival seems to depend on the symbiosis with a host. Consequently, T. whipplei colonizes, at least temporarily, the GI tract of humans [2]. It is meanwhile known that there are different forms of infection with T. whipplei. On one hand T. whipplei may persist in the GI tract without obvious symptoms [2], induce acute diarrhea in children [3], present with fever and cough [4], or isolated infective endocarditis [5]. The affected subjects consecutively may develop a protective humoral and cellular immune response against T. whipplei[6,7]. Alternatively, the acute infection converts, in very rare cases, to a chronic state and the agent spreads through many organ systems resulting in the clinically well-known classical Whipple’s disease (CWD) with articular and gastrointestinal symptoms [8]. A hallmark of CWD is a massive accumulation of T. whipplei in macrophages of the duodenal lamina propria that appear to be positive in periodic acid-Schiff (PAS) staining [8]. The fact that asymptomatic carriage and self-limiting infection with T. whipplei exist but that only in a minority of cases evolves to chronic manifestations hints at an underlying predisposition of the host. However, the exact nature of host factors permitting chronic systemic infection is a matter of discussion since there are various defects of cell-mediated immunity in CWD patients.

T-cell deficiencies of classical Whipple’s disease patients

It has become obvious that CWD patients reveal a number of dysregulated T-cell functions that have been thought to permit the establishment of a chronic infection with T. whipplei. During active disease CWD patients show a reduced skin reaction to recall antigens and the percentage of CD4⁺ T cells in the peripheral blood and the lamina propria, the tissue with the major pathogen load, is reduced [9,10]. Apparently, as evidence for a diminished activity of CD4⁺ T helper cells of type 1 (Th1), T cells in the peripheral blood as well as in the lamina propria of the duodenum of CWD patients produce only small amounts of IFN-γ [10]. In particular, T. whipplei-specific Th1 reactivity is absent or dramatically reduced in CWD patients before treatment as well as subsequently, whereas healthy subjects exhibit a protective Th1 reactivity against the agent [7]. By contrast, functional Th2 responses that only inefficiently protect from intracellular pathogens increase in lymphocytes from the peripheral blood and the duodenal mucosa of CWD patients [10]. Additional suppression of T-cell activity can be supposed, since regulatory CD4⁺ T cells (Treg) are enumerated in the duodenal mucosa of CWD patients before treatment and reveal an enhanced activity in the peripheral blood of untreated and treated CWD patients [11]. As a consequence of inefficient Th1 activation, the serological reactivity of CWD patients against T. whipplei is reduced compared with asymptomatic carriers or healthy subjects, who exhibit a robust humoral immune response against the agent [6].

A primary T-cell defect does not appear to be the cause for CWD

However, there are several aspects that argue against an initial impairment of T-cell functions being responsible for the establishment of CWD:

• • Clinically, CWD patients do not suffer from opportunistic infections that would be enabled by deficient T-cell functions in general;

• • Immune-suppressed patients with impaired T-cell functions do not acquire CWD more frequently than the general population;

• • The suppressive capacity of Treg in CWD is not specific for T-cell reactions against T. whipplei, but rather reflects a feedback to protect the tissue from inflammatory damage [11];

• • It seems very improbable that the genes that selectively code for T-cell receptors, which are necessary to identify the numerous antigenic epitopes of T. whipplei, are lacking in the repertoire of CWD patients;

• • It seems much more likely that the general immunological milieu generated by infected macrophages after the entry of T. whipplei influences the course of the infection and that T cells are not primarily responsible for deficient immunological clearance of T. whipplei.

Impairment of antigen presenting cells in CWD

Early analyses revealed that macrophages of CWD patients display a persistently diminished ability to degrade intracellular organisms [12], and a reduced expression of the complement receptor 3 α-chain CD11b [9]. More recently, a low production of IL-12 in monocytes further suggested impaired activation of macrophages [13]. And indeed, in the duodenal mucosa of CWD patients preferentially, macrophages with an alternative activated phenotype can be found that express high amounts of IL-10 [14,15]. In addition, monocytes of the peripheral blood of CWD patients reveal an alternative activation that is enhanced by T. whipplei itself [14], in line with the previous observation that T. whipplei replicates in human monocytes that have been deactivated by IL-4 and -10 in vitro[16]. Furthermore, a number of cytokines involved in the differentiation of antigen-presenting cells have been shown to influence survival of T. whipplei. Type I interferon is important to maintain T. whipplei infection in macrophages [17], and IL-16 has been identified as a growth factor for T. whipplei[15]. T. whipplei stimulates the release of IL-16 in human monocyte-derived macrophages, it replicates in macrophages and monocytes after treatment with IL-16, and its growth can be inhibited with antibodies neutralizing IL-16 [15]. IL-16 prevents, in combination with T. whipplei, the maturation of phagosomes and induces macrophage apoptosis [18]. As a result of impaired macrophage functions and the cytokine milieu, invading T. whipplei are ingested but not killed by intestinal macrophages and persist in late phagosomes [14,18].

Not only macrophages, but also dendritic cells, the major antigen-presenting cells in the lamina propria of the duodenum, might be influenced by the anti-inflammatory cytokine milieu induced by T. whipplei itself and by alternative macrophage activation: the absence of IFN-γ and IL-12 combined with the presence of IL-10 and -16 might inhibit maturation and induce the development of tolerogenic dendritic cells.

Most importantly, the cytokine environment generated by alternatively activated macrophages and the deficiency of IL-12 inhibits the development of Th1 cells. Since certain HLA alleles are associated with CWD [19], inefficient presentation of T. whipplei antigens followed by an exhaustion of T cells, due to inadequate stimulation, seems to be more likely than deficient recognition of T. whipplei antigens by T cells. Thus, impaired antigen presentation and insufficient costimulation may be responsible for the failure of immunological clearance of T. whipplei in CWD patients.

T cells in the course of treatment of CWD

Macrophage functions are impaired persistently in CWD patients as the typical PAS-positive, alternatively activated macrophages reside in the duodenal mucosa for months or even years after the initiation of treatment [8], and macrophages reveal a persistent disability to degrade the intracellular organism [12]. By contrast, with the exception of T. whipplei-specific Th1 reactivity [7], most of the T-cell deficiencies recover or at least ameliorate after the initiation of treatment [9,11,13]. However, T cells seem to be responsible for the most important complication during the treatment of CWD. During immune reconstitution inflammatory syndrome in CWD, the suppressed T-cell activity in active disease seems to convert much too quickly to a status of enhanced T-cell activation and thus induces inflammatory damage that can only be treated with immunosuppressive drugs [20].

Conclusion

Malfunction of antigen presenting cells, namely alternative activation of macrophages, deficient antigen presentation, a lack of costimulation, and the absence of an inflammatory response against T. whipplei seem to impair T-cell activation and allow the establishment of a chronic infection with T. whipplei in predisposed patients. T-cell functions appear to be important for the pathogenesis of CWD only secondarily, since they maintain the tolerogenic and anti-inflammatory milieu during infection and also seem to play an important role in the pathogenesis of immune reconstitution inflammatory syndrome – a major complication during the antimicrobial treatment of CWD.

Financial & competing interests disclosure

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.