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]


Whipple’s disease is a rare systemic 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 in clinical manifestation of Tropheryma whipplei infection. Individuals with positive HLA-B27 and defective cellular immunity including AIDS are at risk for Whipple's disease. Impaired macrophage function and cellular immunity are the main factors in replication of the bacteria and disease expansion to every tissue. There is a decreased activity of the T helper cells type 1 and increased activity of the T helper cells type 2. Defective phagocytic system is responsible for replication of bacteria in macrophages and spread of bacteria to other tissues. Characteristic of Whipple's disease is presence of foamy macrophages in the lamina propria that is periodic acid-Schiff stain positive.



  • 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 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
Antibody production
Strong immune response
Insufficient immune response
Complete eradication
Chronic carrier
Chronic infection
Classic Whipple's disease
Localized infection

Immunologic response

Followings are some of the observations that indicate the immunologic nature of the Whipple's disease:

Defective cellular immunity

Defective macrophagic/phagocytic system

Defective humoral immunity


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:

Gross Pathology

  • On endoscopy, pale yellow mucosa with whitish spots, greenish brown and erythematous patches, and both engorged and flattened folds are characteristic findings of Whipple's disease.[17]

Microscopic Pathology

Below images show the characteristic feature of Whipple's disease: foamy macrophages are present in the lamina propria.[19]

Periodic acid-Schiff stain of a small intestinal lesion of Whipple's disease by Ed Uthman from Houston, TX, USA[20]
GMS stain of a small intestinal lesion of Whipple's disease by Ed Uthman from Houston, TX, USA[21]
High magnification micrograph of Whipple's disease. H&E stain. Duodenal biopsy by Nephron[22]
Periodic acid-Schiff stain of a small intestinal lesion of Whipple's disease by Ed Uthman from Houston, TX, USA[23]
Periodic acid-Schiff stain of a small intestinal lesion of Whipple's disease by By Mrwick1[24]
Light microscopy of intestine - Whipples Disease From PEIR - University of Alabama at Birmingham Department of Pathology[25]
Periodic acid-Schiff stain of a small intestinal lesion of Whipple's disease by Ed Uthman from Houston, TX, USA[26]
Acid-fast stain negative bacilli in a patient with Whipple's disease by Ed Uthman from Houston, TX, USA[27]


  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. 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. 6.0 6.1 Marth T, Strober W (1996). "Whipple's disease". Semin. Gastrointest. Dis. 7 (1): 41–8. PMID 8903578.
  7. 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. 8.0 8.1 8.2 8.3 8.4 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. 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.
  10. 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. 11.0 11.1 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.
  12. 12.0 12.1 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.
  13. Schinnerling K, Moos V, Geelhaar A, Allers K, Loddenkemper C, Friebel J, Conrad K, Kühl AA, Erben U, Schneider T (2011). "Regulatory T cells in patients with Whipple's disease". J. Immunol. 187 (8): 4061–7. doi:10.4049/jimmunol.1101349. PMID 21918190.
  14. Desnues B, Raoult D, Mege JL (2005). "IL-16 is critical for Tropheryma whipplei replication in Whipple's disease". J. Immunol. 175 (7): 4575–82. PMID 16177102.
  15. 15.0 15.1 15.2 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.
  16. Schneider T, Stallmach A, von Herbay A, Marth T, Strober W, Zeitz M (1998). "Treatment of refractory Whipple disease with interferon-gamma". Ann. Intern. Med. 129 (11): 875–7. PMID 9867729.
  17. 17.0 17.1 Salkic, Nermin N.; Alibegovic, Ervin; Jovanovic, Predrag (2013). "Endoscopic appearance of duodenal mucosa in Whipple's disease". Gastrointestinal Endoscopy. 77 (5): 822–823. doi:10.1016/j.gie.2013.01.016. ISSN 0016-5107.
  18. 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.
  19. https://commons.wikimedia.org
  20. "File:Whipples Disease, PAS (6881958655).jpg - Wikimedia Commons".
  21. "File:Whipples Disease, GMS (6881505399).jpg - Wikimedia Commons".
  22. "File:Whipple disease -a- high mag.jpg - Wikimedia Commons".
  23. "File:Whipples Disease, PAS (6881958605).jpg - Wikimedia Commons".
  24. "File:Whipple disease.jpg - Wikimedia Commons".
  25. "File:Whipple2.jpg - Wikimedia Commons". External link in |title= (help)
  26. "File:Whipple pas+.jpg - Wikimedia Commons".
  27. "File:Whipples Disease, Kinyoun Carbolfuchsin Acid-Fast Stain (6881505345).jpg - Wikimedia Commons".

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