Whipple's disease pathophysiology
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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Sadaf Sharfaei M.D.[2]
Overview
Whipple’s disease is a very rare disease. Therefore, some aspects of pathogenesis have remained unclear. Tropheryma whipplei is usually transmitted through oral route to human hosts. There is no known causative genetic factor for Whipple's disease. However, genetic and immunologic factors play important roles on clinical manifestation of T. whipplei infection.
Pathophysiology
Pathogenesis
- Whipple's disease is a rare bacterial systemic infection caused by Tropheryma whipplei.[1]
- Tropheryma whipplei is a periodic acid-Schiff stain positive, gram-positive bacillus of Actinomycetes family.[2]
- The bacterium lives in soil and wastewater. Farmers and everyone who has any contact with contaminated soil and water are at high risk of the infection.[3]
- It is transmitted through oro-oral and feco-oral routes. The poor sanitation is associated with Tropheryma whipplei infection.[4]
- It is believed that human being is the only host for this bacterium.[5]
- Tropheryma whipplei invades intestines primarily and then every other organ including the heart, CNS, joints, lymph nodes, lungs, eyes, kidneys, bone marrow, and skin. Tissues are infected by macrophage infiltration contaminated by Tropheryma whipplei. Tropheryma whipplei multiplies in macrophages and monocytes.[6] Although there is a massive infiltration of the intestinal mucosa with the bacteria, the immunologic response is not adequate to limit the infection. Bacterium-infected macrophages express less CD11b which leads to inappropriate antigen presentation. These macrophages are unable to turn into mature phagosomes and lower the thioredoxin expression. The impairment in T-helper 1 cells differentiation leads to the inability of the immune system to kill the bacteria.[7][8]
- Tropheryma whipplei infection causes four different clinical manifestations: acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.[9][10]
| Contamination via oro-oral or feco-oral route | |||||||||||||||||||||||||||||||||||||||
| Acute infection | |||||||||||||||||||||||||||||||||||||||
| Antibodies production | |||||||||||||||||||||||||||||||||||||||
| Strong immune response | Insufficient immune response | ||||||||||||||||||||||||||||||||||||||
| Complete eradication | Chronic carrier | Chronic infection | |||||||||||||||||||||||||||||||||||||
| Classic Whipple's disease | Localized infection | ||||||||||||||||||||||||||||||||||||||
| Cure | Relapse | Re-infection | Death | ||||||||||||||||||||||||||||||||||||
Immunologic response
- It is believed that host immunologic response to Tropheryma whipplei plays an important role on the clinical manifestation of the disease.[6]
- Several studies suggested that the defective cellular immunity and humoral immunity may lead to the proliferation of the bacteria and clinical manifestation of the Whipple's disease.[8]
Followings are some of the observations that indicate the immunologic nature of the Whipple's disease:
Defective cellular immunity
- Reduced peripheral T cell proliferation to phytohemagglutinin and concanavalin A[8]
- Decreased functional activity of T helper cells type 1 (Th1)[11]
- Enhanced functional activity of T helper cells type 2 (Th2)[11]
- Enhanced expression of interleukin 4 (IL-4)[11]
- Decreased CD4/CD8 ratio[12][8]
- Reduced Interleukin 12 production by peripheral blood mononuclear cells[13]
- Decreased Interferon gamma secretion by peripheral blood mononuclear cells[13]
Defective humoral immunity
- Increased Immunoglobulin M production in the lamina propria[12]
- Reduced Serum Immunoglobulin G2, an Interferon gamma dependent immunoglobulin subclass, and serum TGF-beta levels[13]
Genetics
There is no known causative genetic factor for Whipple's disease. However, there is an association between Whipple's disease and some immunologic defects.
- Studies showed that individuals with specific HLA type (HLA alleles DRB1*13 and DQB1*06) have a higher risk of Whipple's disease.[9]
Associated Conditions
The most important conditions associated with Whipple's disease include:
- HLA-B27 individuals
- Defective cellular immunity
Gross Pathology
- On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of Whipple's disease.
Microscopic Pathology
- On microscopic histopathological analysis, PAS-positive macrophages in the lamina propria containing non-acid-fast gram-positive bacilli are characteristic findings of Whipple's disease.[14]
Below images show the characteristic feature of Whipple's disease. foamy macrophages are present in the lamina propria.[15]
References
- ↑ Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D (2008). "Whipple's disease: new aspects of pathogenesis and treatment". Lancet Infect Dis. 8 (3): 179–90. doi:10.1016/S1473-3099(08)70042-2. PMID 18291339.
- ↑ Schwartzman, Sergio; Schwartzman, Monica (2013). "Whipple's Disease". Rheumatic Disease Clinics of North America. 39 (2): 313–321. doi:10.1016/j.rdc.2013.03.005. ISSN 0889-857X.
- ↑ Keita, Alpha Kabinet; Diatta, Georges; Ratmanov, Pavel; Bassene, Hubert; Raoult, Didier; Roucher, Clémentine; Fenollar, Florence; Sokhna, Cheikh; Tall, Adama; Trape, Jean-François; Mediannikov, Oleg (2013). "Looking for Tropheryma whipplei Source and Reservoir in Rural Senegal". The American Journal of Tropical Medicine and Hygiene. 88 (2): 339–343. doi:10.4269/ajtmh.2012.12-0614. ISSN 0002-9637.
- ↑ Keita, Alpha Kabinet; Brouqui, Philippe; Badiaga, Sékéné; Benkouiten, Samir; Ratmanov, Pavel; Raoult, Didier; Fenollar, Florence (2013). "Tropheryma whipplei prevalence strongly suggests human transmission in homeless shelters". International Journal of Infectious Diseases. 17 (1): e67–e68. doi:10.1016/j.ijid.2012.05.1033. ISSN 1201-9712.
- ↑ Marth, Thomas; Moos, Verena; Müller, Christian; Biagi, Federico; Schneider, Thomas (2016). "Tropheryma whipplei infection and Whipple's disease". The Lancet Infectious Diseases. 16 (3): e13–e22. doi:10.1016/S1473-3099(15)00537-X. ISSN 1473-3099.
- ↑ 6.0 6.1 Marth T, Strober W (1996). "Whipple's disease". Semin. Gastrointest. Dis. 7 (1): 41–8. PMID 8903578.
- ↑ Dolmans, Ruben A. V.; Boel, C. H. Edwin; Lacle, Miangela M.; Kusters, Johannes G. (2017). "Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections". Clinical Microbiology Reviews. 30 (2): 529–555. doi:10.1128/CMR.00033-16. ISSN 0893-8512.
- ↑ 8.0 8.1 8.2 8.3 Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE (1994). "Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease". Clin. Immunol. Immunopathol. 72 (2): 217–26. PMID 7519533.
- ↑ 9.0 9.1 Marth, Thomas (2009). "New Insights into Whipple's Disease – A Rare Intestinal Inflammatory Disorder". Digestive Diseases. 27 (4): 494–501. doi:10.1159/000233288. ISSN 1421-9875.
- ↑ Street, Sara; Donoghue, Helen D; Neild, GH (1999). "Tropheryma whippelii DNA in saliva of healthy people". The Lancet. 354 (9185): 1178–1179. doi:10.1016/S0140-6736(99)03065-2. ISSN 0140-6736.
- ↑ 11.0 11.1 11.2 Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T (2002). "Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease". Gastroenterology. 123 (5): 1468–77. PMID 12404221.
- ↑ 12.0 12.1 Ectors N, Geboes K, De Vos R, Heidbuchel H, Rutgeerts P, Desmet V, Vantrappen G (1992). "Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestinal mucosa". Histopathology. 21 (1): 1–12. PMID 1378814.
- ↑ 13.0 13.1 13.2 Marth T, Neurath M, Cuccherini BA, Strober W (1997). "Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease". Gastroenterology. 113 (2): 442–8. PMID 9247462.
- ↑ Schneider, Thomas; Moos, Verena; Loddenkemper, Christoph; Marth, Thomas; Fenollar, Florence; Raoult, Didier (2008). "Whipple's disease: new aspects of pathogenesis and treatment". The Lancet Infectious Diseases. 8 (3): 179–190. doi:10.1016/S1473-3099(08)70042-2. ISSN 1473-3099.
- ↑ https://commons.wikimedia.org