Regulatory T Cells in Patients with Whipple's Disease

Classical Whipple’s Disease (CWD) is a rare, multisystemic infection of the duodenal mucosa. Macrophages infected with Tropheryma whipplei, a gram positive bacterium, first attack the intestinal mucosa and then disperse throughout the body to the intestinal epithelium, capillary and lymphatic endothelium, synovium, heart, lungs, liver, brains, eyes and skin. Symptomatic manifestations are most commonly reported in the intestines, and include weight loss, diarrhea, and abdominal pain (Schijf et.al 394). Additionally, T.whipplei infection can spread to the brain and heart and cause inflammation of the heart muscle. [1]

Schinnerling and colleagues argue that host immune deficiency plays a major role in the persistence and systematic spread of CWD. The authors suggest that healthy adults generally display an efficient humoral, or antibody, and cellular immunological response that effectively combats T.whipplei. However, immunological defects are believed to weaken the immune response and enable the pathogen to successfully infect the host [2]. The defects present in the peripheral blood and the duodenal mucosa of CWD patient include, but are not limited to, impairment of T cell proliferation, and diminished Th1 reactivity.

T cells are a type of white blood cell that helps recognize and eradicate invading pathogens that cause disease. Th1 cells are a brand of T cells that specialize in intracellular pathogen disposal. Specifically, Th1 cells secrete IL-2, IFN­-y, and LT, which are cytokines, or signaling chemicals, that initiate a robust inflammatory response. A Th1 response is generally avoided in mucosal tissues because inflammation is an aggressive immune response that can damage the delicate tissue of the mucosa. Consequently, a Th2 response is initiated in the mucosa to avoid cell damage and effectively combat extracellular pathogens. Th2 cells secrete cytokines, such as IL-4, IL-5, and IL-10, to suppress a Th1 response and initiate antibody production. Antibodies neutralize pathogens without damaging surrounding host cells [3].

Previous research has concluded that the immune defects characteristic of CWD patients ultimately cause a downregulation of pro-inflammatory cytokines, such as IL-1B and TNF-a. Pro-inflammatory cytokines initiate a Th1 response. Additionally, CWD patients express elevated levels of IL-10, an anti-inflammatory cytokine, which is believed to dampen the immune response and allow for chronic infection of the CWD bacterium. Notwithstanding, IL-10 also plays a crucial role in downregulating specific inflammatory responses, such as phagocytosis, that can damage the delicate cells of the intestinal mucosa [4]. Ultimately, Schinnerling seeks to explore regulatory T cell (Treg) mechanisms, which activate IL-10 and monitor the immune response in the duodenal mucosa and peripheral blood of CDW patients.

Schinnerling utilized tissue samples of CWD patients in order to determine the varieties of regulatory responses initiated by the host’s immune system. First, researchers assessed the concentration of regulatory T cells in the duodenal mucosa of CWD patients when compared to control subjects. Specifically, immunohistochemical staining, a technique commonly used to identify specific cell surface proteins, was utilized to determine the relative concentrations of Tregs in the lamina propria, connective tissue in the intestinal mucosa. Staining revealed that untreated CWD patients showed increased numbers of Tregs when compared to control subjects. Further testing revealed that Treg concentrations decreased when patients were treated with antibiotics. This data suggests that regulatory T cells are involved in the development of CDW into a chronic infection.

Second, researchers used flow cytometry, a method used to identify and examine microscopic particles, to study the physical characteristics of the CD4 T cells in the peripheral blood of patients infected with T.whipplei. Tests concluded that the CD4 T cells in the peripheral blood of CWD patients express a significantly higher level of two cell surface receptors, CTLA-4 and CD39. CTLA-4 and CD39 are cell surface protein that decreases T cell activation and are believed to suppress an immune response.

Third, duodenal biopsies were collected to determine the levels of pro- and ant-inflammatory cytokines secreted in the small intestine of T.whipplei infected individuals. Schinnerling and colleagues observed that CWD patients expressed lower levels of IFN-y, a pro-inflammatory cytokine that stimulates a Th1 response, while simultaneously expressing high levels of IL-10 and TGF-B, two anti-inflammatory cytokines that suppress an immune response.

Fourth, Schinnerling and colleagues examined an exhaustion marker, PD-1, to determine the cause of the impaired Th1 response in the duodenal mucosa. Increased expression of PD-1 on the CD4 T cells of CWD patients demonstrated that these T cells are anergized, or temporarily inactivated, due to constant stimulation. In other words, the cells are exhausted by the persistence of the chronic T.whipplei infection, and are no longer able to response to the bacterium. Anergized CD4 T cells are prone to receptor-mediated apoptosis, or cell death. However, Th2 cells are insensitive to the cell death mechanism common among anergized CD4 cells, and are therefore favored during the immune response to T.whipplei.

The results of the experiment illustrate increased proliferation and activation of Treg cells in the intestinal mucosa and peripheral blood of CWD patients. Consequently, Schinnerling and colleagues demonstrate a bias towards a Th2 response. In other words, immune regulation ensures that a Th1 response will be reduced in order to protect the delicate mucosal cells from a robust inflammatory response. Regulatory T cell expression will be increased in order to suppress Th1 response. Ultimately, the increase activation of T cells will enable the spread of T.whipplei and will foster the development of a chronic infection.

The present study is important because it effectively demonstrates the disadvantages of a specific type of immune response. Although a Th2 response is appropriate for the intestinal mucosal, it ultimately allows for the development of a chronic infection. Therefore, the immune response favors Th2 over Th1 despite the obvious risks. Future research could examine the effects of a Th1 response in T.whipplei infected patients. Although Tregs favor a Th2, it could be interesting to stimulate a Th1 response to determine if a robust response is more effective despite the damage caused by inflammation.

Works Cited

1. Schinnerling, k., Moos, V. Geelhaar, A. (2011). Regulatory T Cells in Patients with Whipple’s Disease. The Journal of Immunology. http://www.jimmunol.org/content/187/8/4061

2. Gordon, S. Alternative activation of macrophages. Nature Immunology Reviews. 2003 Jan;3(1):23-35. http://www.ncbi.nlm.nih.gov/pubmed/12511873

3. Schifjfl, L.J., Becx, M.C., De Bruin, P.C., Whipple’s disease: easily diagnosed, if considered. Journal of Medicine. http://www.njmonline.nl/getpdf.php?t=a&id=10000372

4. Strausbaugh. L.J., Maiwald, M., Relman, D.A., Whipple's Disease and Tropheryma whippelii: Secrets Slowly Revealed. Clinical Infectious Disease. (2001) 32 (3): 457-463.doi: 10.1086/318512