Whipple's disease pathophysiology: Difference between revisions

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{{Whipple's disease}}
{{Whipple's disease}}
{{CMG}}; {{AE}} {{SSH}}
{{CMG}}; {{AE}} {{SSH}}
==Overview==
==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.
Whipple’s disease is a rare systemic disease. Therefore, some aspects of [[pathogenesis]] have remained unclear. [[Tropheryma whipplei|''Tropheryma whipplei'']] is usually transmitted through [[oral route]] to human [[Host (biology)|hosts]]. There is no known causative [[genetic]] factor for Whipple's disease. However, [[genetic]] and [[Immunological|immunologic]] factors play important roles in [[clinical]] manifestation of [[Tropheryma whipplei|''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 [[Macrophage|macrophages]] in the [[lamina propria]] that is [[periodic acid-Schiff stain]] positive.


==Pathophysiology==
==Pathophysiology==
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===Pathogenesis===
===Pathogenesis===


*Whipple's disease is a rare bacterial systemic infection caused by [[Tropheryma whipplei]].<ref name="pmid18291339">{{cite journal |vauthors=Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D |title=Whipple's disease: new aspects of pathogenesis and treatment |journal=Lancet Infect Dis |volume=8 |issue=3 |pages=179–90 |year=2008 |pmid=18291339 |doi=10.1016/S1473-3099(08)70042-2 |url=}}</ref>
*Whipple's disease is a rare bacterial systemic infection caused by [[Tropheryma whipplei|''Tropheryma whipplei'']].<ref name="pmid18291339">{{cite journal |vauthors=Schneider T, Moos V, Loddenkemper C, Marth T, Fenollar F, Raoult D |title=Whipple's disease: new aspects of pathogenesis and treatment |journal=Lancet Infect Dis |volume=8 |issue=3 |pages=179–90 |year=2008 |pmid=18291339 |doi=10.1016/S1473-3099(08)70042-2 |url=}}</ref>


*[[Tropheryma whipplei]] is a [[periodic acid-Schiff stain]] positive, gram-positive [[bacillus]] of [[Actinomycetes]] family.<ref name="SchwartzmanSchwartzman2013">{{cite journal|last1=Schwartzman|first1=Sergio|last2=Schwartzman|first2=Monica|title=Whipple's Disease|journal=Rheumatic Disease Clinics of North America|volume=39|issue=2|year=2013|pages=313–321|issn=0889857X|doi=10.1016/j.rdc.2013.03.005}}</ref>
*[[Tropheryma whipplei|''Tropheryma whipplei'']] is a [[periodic acid-Schiff stain]] positive, gram-positive [[bacillus]] of [[Actinomycetes|''Actinomycetes'']] family.<ref name="SchwartzmanSchwartzman2013">{{cite journal|last1=Schwartzman|first1=Sergio|last2=Schwartzman|first2=Monica|title=Whipple's Disease|journal=Rheumatic Disease Clinics of North America|volume=39|issue=2|year=2013|pages=313–321|issn=0889857X|doi=10.1016/j.rdc.2013.03.005}}</ref>


* 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.<ref name="KeitaDiatta2013">{{cite journal|last1=Keita|first1=Alpha Kabinet|last2=Diatta|first2=Georges|last3=Ratmanov|first3=Pavel|last4=Bassene|first4=Hubert|last5=Raoult|first5=Didier|last6=Roucher|first6=Clémentine|last7=Fenollar|first7=Florence|last8=Sokhna|first8=Cheikh|last9=Tall|first9=Adama|last10=Trape|first10=Jean-François|last11=Mediannikov|first11=Oleg|title=Looking for Tropheryma whipplei Source and Reservoir in Rural Senegal|journal=The American Journal of Tropical Medicine and Hygiene|volume=88|issue=2|year=2013|pages=339–343|issn=0002-9637|doi=10.4269/ajtmh.2012.12-0614}}</ref>
* 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.<ref name="KeitaDiatta2013">{{cite journal|last1=Keita|first1=Alpha Kabinet|last2=Diatta|first2=Georges|last3=Ratmanov|first3=Pavel|last4=Bassene|first4=Hubert|last5=Raoult|first5=Didier|last6=Roucher|first6=Clémentine|last7=Fenollar|first7=Florence|last8=Sokhna|first8=Cheikh|last9=Tall|first9=Adama|last10=Trape|first10=Jean-François|last11=Mediannikov|first11=Oleg|title=Looking for Tropheryma whipplei Source and Reservoir in Rural Senegal|journal=The American Journal of Tropical Medicine and Hygiene|volume=88|issue=2|year=2013|pages=339–343|issn=0002-9637|doi=10.4269/ajtmh.2012.12-0614}}</ref>


*It is transmitted through oro-oral and feco-oral routes. The poor sanitation is associated with [[Tropheryma whipplei|Tropheryma whipplei]] infection.<ref name="KeitaBrouqui2013">{{cite journal|last1=Keita|first1=Alpha Kabinet|last2=Brouqui|first2=Philippe|last3=Badiaga|first3=Sékéné|last4=Benkouiten|first4=Samir|last5=Ratmanov|first5=Pavel|last6=Raoult|first6=Didier|last7=Fenollar|first7=Florence|title=Tropheryma whipplei prevalence strongly suggests human transmission in homeless shelters|journal=International Journal of Infectious Diseases|volume=17|issue=1|year=2013|pages=e67–e68|issn=12019712|doi=10.1016/j.ijid.2012.05.1033}}</ref>  
*It is transmitted through oro-oral and feco-oral routes. The poor sanitation is associated with [[Tropheryma whipplei|''Tropheryma whipplei'']] infection.<ref name="KeitaBrouqui2013">{{cite journal|last1=Keita|first1=Alpha Kabinet|last2=Brouqui|first2=Philippe|last3=Badiaga|first3=Sékéné|last4=Benkouiten|first4=Samir|last5=Ratmanov|first5=Pavel|last6=Raoult|first6=Didier|last7=Fenollar|first7=Florence|title=Tropheryma whipplei prevalence strongly suggests human transmission in homeless shelters|journal=International Journal of Infectious Diseases|volume=17|issue=1|year=2013|pages=e67–e68|issn=12019712|doi=10.1016/j.ijid.2012.05.1033}}</ref>  


*It is believed that human being is the only host for this bacterium.<ref name="MarthMoos2016">{{cite journal|last1=Marth|first1=Thomas|last2=Moos|first2=Verena|last3=Müller|first3=Christian|last4=Biagi|first4=Federico|last5=Schneider|first5=Thomas|title=Tropheryma whipplei infection and Whipple's disease|journal=The Lancet Infectious Diseases|volume=16|issue=3|year=2016|pages=e13–e22|issn=14733099|doi=10.1016/S1473-3099(15)00537-X}}</ref>
*It is believed that human being is the only host for this bacterium.<ref name="MarthMoos2016">{{cite journal|last1=Marth|first1=Thomas|last2=Moos|first2=Verena|last3=Müller|first3=Christian|last4=Biagi|first4=Federico|last5=Schneider|first5=Thomas|title=Tropheryma whipplei infection and Whipple's disease|journal=The Lancet Infectious Diseases|volume=16|issue=3|year=2016|pages=e13–e22|issn=14733099|doi=10.1016/S1473-3099(15)00537-X}}</ref>


*[[Tropheryma whipplei]] invades [[Intestine|intestines]] primarily and then every other organ including the [[heart]], [[CNS]], [[joints]], [[Lymph node|lymph nodes]], [[lungs]], [[eyes]], [[kidneys]], [[bone marrow]], and [[skin]]. Tissues are infected by [[macrophage]] infiltration contaminated by [[Tropheryma whipplei]]. [[Tropheryma whipplei|Tropheryma whipplei]] multiplies in [[Macrophage|macrophages]] and [[Monocyte|monocytes]].<ref name="pmid8903578">{{cite journal |vauthors=Marth T, Strober W |title=Whipple's disease |journal=Semin. Gastrointest. Dis. |volume=7 |issue=1 |pages=41–8 |year=1996 |pmid=8903578 |doi= |url=}}</ref> 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 [[Th1|T-helper 1]] cells differentiation leads to the inability of the immune system to kill the bacteria.<ref name="DolmansBoel2017">{{cite journal|last1=Dolmans|first1=Ruben A. V.|last2=Boel|first2=C. H. Edwin|last3=Lacle|first3=Miangela M.|last4=Kusters|first4=Johannes G.|title=Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections|journal=Clinical Microbiology Reviews|volume=30|issue=2|year=2017|pages=529–555|issn=0893-8512|doi=10.1128/CMR.00033-16}}</ref><ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>
*[[Tropheryma whipplei|''Tropheryma whipplei'']] invades [[Intestine|intestines]] primarily and then every other organ including the [[heart]], [[CNS]], [[joints]], [[Lymph node|lymph nodes]], [[lungs]], [[eyes]], [[kidneys]], [[bone marrow]], and [[skin]]. Tissues are infected by [[macrophage]] infiltration contaminated by [[Tropheryma whipplei|''Tropheryma whipplei'']]. [[Tropheryma whipplei|''Tropheryma whipplei'']] multiplies in [[Macrophage|macrophages]] and [[Monocyte|monocytes]].<ref name="pmid8903578">{{cite journal |vauthors=Marth T, Strober W |title=Whipple's disease |journal=Semin. Gastrointest. Dis. |volume=7 |issue=1 |pages=41–8 |year=1996 |pmid=8903578 |doi= |url=}}</ref> 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 [[Th1|T-helper 1]] cells differentiation leads to the inability of the immune system to kill the bacteria.<ref name="DolmansBoel2017">{{cite journal|last1=Dolmans|first1=Ruben A. V.|last2=Boel|first2=C. H. Edwin|last3=Lacle|first3=Miangela M.|last4=Kusters|first4=Johannes G.|title=Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections|journal=Clinical Microbiology Reviews|volume=30|issue=2|year=2017|pages=529–555|issn=0893-8512|doi=10.1128/CMR.00033-16}}</ref><ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>


* [[Tropheryma whipplei]] infection causes four different clinical manifestations: acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.<ref name="Marth2009">{{cite journal|last1=Marth|first1=Thomas|title=New Insights into Whipple’s Disease – A Rare Intestinal Inflammatory Disorder|journal=Digestive Diseases|volume=27|issue=4|year=2009|pages=494–501|issn=1421-9875|doi=10.1159/000233288}}</ref><ref name="StreetDonoghue1999">{{cite journal|last1=Street|first1=Sara|last2=Donoghue|first2=Helen D|last3=Neild|first3=GH|title=Tropheryma whippelii DNA in saliva of healthy people|journal=The Lancet|volume=354|issue=9185|year=1999|pages=1178–1179|issn=01406736|doi=10.1016/S0140-6736(99)03065-2}}</ref>
* [[Tropheryma whipplei|''Tropheryma whipplei'']] infection causes four different clinical manifestations: acute infection, asymptomatic carrier state, the classic Whipple’s disease, and localized chronic infection.<ref name="Marth2009">{{cite journal|last1=Marth|first1=Thomas|title=New Insights into Whipple’s Disease – A Rare Intestinal Inflammatory Disorder|journal=Digestive Diseases|volume=27|issue=4|year=2009|pages=494–501|issn=1421-9875|doi=10.1159/000233288}}</ref><ref name="StreetDonoghue1999">{{cite journal|last1=Street|first1=Sara|last2=Donoghue|first2=Helen D|last3=Neild|first3=GH|title=Tropheryma whippelii DNA in saliva of healthy people|journal=The Lancet|volume=354|issue=9185|year=1999|pages=1178–1179|issn=01406736|doi=10.1016/S0140-6736(99)03065-2}}</ref>


{{Family tree/start}}
{{Family tree/start}}
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{{Family tree | | | | | | | | | B01 | | | | | | | | |B01= Acute infection}}
{{Family tree | | | | | | | | | B01 | | | | | | | | |B01= Acute infection}}
{{Family tree | | | | | | | | | |!| | | | | | | | | |}}
{{Family tree | | | | | | | | | |!| | | | | | | | | |}}
{{Family tree | | | | | | | | | C01 | | | | | | | | |C01= Antibodies production}}
{{Family tree | | | | | | | | | C01 | | | | | | | | |C01= Antibody production}}
{{Family tree | | | | | |,|-|-|-|^|-|-|-|.| | | | | |}}
{{Family tree | | | | | |,|-|-|-|^|-|-|-|.| | | | | |}}
{{Family tree | | | | | D01 | | | | | | D02 | | | | |D01= Strong immune response| D02= Insufficient immune response}}
{{Family tree | | | | | D01 | | | | | | D02 | | | | |D01= Strong immune response| D02= Insufficient immune response}}
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===Immunologic response===
===Immunologic response===
* It is believed that host [[Immunological|immunologic]] response to [[Tropheryma whipplei]] plays an important role on the clinical manifestation of the disease.<ref name="pmid8903578">{{cite journal |vauthors=Marth T, Strober W |title=Whipple's disease |journal=Semin. Gastrointest. Dis. |volume=7 |issue=1 |pages=41–8 |year=1996 |pmid=8903578 |doi= |url=}}</ref>
* It is believed that host [[Immunological|immunologic]] response to [[Tropheryma whipplei|''Tropheryma whipplei'']] plays an important role on the clinical manifestation of the disease.<ref name="pmid8903578">{{cite journal |vauthors=Marth T, Strober W |title=Whipple's disease |journal=Semin. Gastrointest. Dis. |volume=7 |issue=1 |pages=41–8 |year=1996 |pmid=8903578 |doi= |url=}}</ref>


*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.<ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>  
*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.<ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>  
Followings are some of the observations that indicate the [[Immunological|immunologic]] nature of the Whipple's disease:
Followings are some of the observations that indicate the [[Immunological|immunologic]] nature of the Whipple's disease:
==== Defective cellular immunity ====
==== Defective cellular immunity ====
* Reduced peripheral [[T cell proliferation]] to [[phytohemagglutinin]] and [[concanavalin A]]<ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>
* Reduced [[T cell]] proliferative response<ref name="pmid7519533" />
* Decreased functional activity of [[T helper cells]] type 1 ([[Th1]])<ref name="pmid12404221">{{cite journal |vauthors=Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T |title=Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease |journal=Gastroenterology |volume=123 |issue=5 |pages=1468–77 |year=2002 |pmid=12404221 |doi= |url=}}</ref>
* Decreased [[CD4]]/[[CD8]] ratio<ref name="pmid1378814">{{cite journal |vauthors=Ectors N, Geboes K, De Vos R, Heidbuchel H, Rutgeerts P, Desmet V, Vantrappen G |title=Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestinal mucosa |journal=Histopathology |volume=21 |issue=1 |pages=1–12 |year=1992 |pmid=1378814 |doi= |url=}}</ref>
* Enhanced functional activity of [[T helper cells]] type 2 ([[Th2]])<ref name="pmid12404221">{{cite journal |vauthors=Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T |title=Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease |journal=Gastroenterology |volume=123 |issue=5 |pages=1468–77 |year=2002 |pmid=12404221 |doi= |url=}}</ref>
* Decreased [[T helper cells]] type 1 response and subsequently reduced production of [[interleukin 2]] ([[IL-2]])
* Enhanced expression of [[interleukin 4]] ([[IL-4]]) and functional activity of [[T helper cells]] type 2 ([[Th2]])<ref name="pmid12404221" />
* Increased numbers of regulatory T cells<ref name="pmid21918190">{{cite journal |vauthors=Schinnerling K, Moos V, Geelhaar A, Allers K, Loddenkemper C, Friebel J, Conrad K, Kühl AA, Erben U, Schneider T |title=Regulatory T cells in patients with Whipple's disease |journal=J. Immunol. |volume=187 |issue=8 |pages=4061–7 |year=2011 |pmid=21918190 |doi=10.4049/jimmunol.1101349 |url=}}</ref>
* Increased numbers of regulatory T cells<ref name="pmid21918190">{{cite journal |vauthors=Schinnerling K, Moos V, Geelhaar A, Allers K, Loddenkemper C, Friebel J, Conrad K, Kühl AA, Erben U, Schneider T |title=Regulatory T cells in patients with Whipple's disease |journal=J. Immunol. |volume=187 |issue=8 |pages=4061–7 |year=2011 |pmid=21918190 |doi=10.4049/jimmunol.1101349 |url=}}</ref>
* Decreased [[CD4]]/[[CD8]] ratio<ref name="pmid1378814">{{cite journal |vauthors=Ectors N, Geboes K, De Vos R, Heidbuchel H, Rutgeerts P, Desmet V, Vantrappen G |title=Whipple's disease: a histological, immunocytochemical and electronmicroscopic study of the immune response in the small intestinal mucosa |journal=Histopathology |volume=21 |issue=1 |pages=1–12 |year=1992 |pmid=1378814 |doi= |url=}}</ref><ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>
*Reduced peripheral [[T cell proliferation]] to [[phytohemagglutinin]] and [[concanavalin A]]<ref name="pmid7519533" />
*Enhanced expression of [[interleukin 4]] ([[IL-4]])<ref name="pmid12404221" />
* Up-regulated [[Interleukin 16]] ([[IL-16]]) in [[monocyte]]-derived [[macrophages]] that enhanced [[Tropheryma whipplei|''Tropheryma whipplei'']] replication<ref name="pmid16177102">{{cite journal |vauthors=Desnues B, Raoult D, Mege JL |title=IL-16 is critical for Tropheryma whipplei replication in Whipple's disease |journal=J. Immunol. |volume=175 |issue=7 |pages=4575–82 |year=2005 |pmid=16177102 |doi= |url=}}</ref>
* Reduced [[Interleukin 12]] production by peripheral blood [[mononuclear cells]]<ref name="pmid9247462">{{cite journal |vauthors=Marth T, Neurath M, Cuccherini BA, Strober W |title=Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease |journal=Gastroenterology |volume=113 |issue=2 |pages=442–8 |year=1997 |pmid=9247462 |doi= |url=}}</ref>
 
* Decreased [[Interferon gamma]] secretion by peripheral blood [[mononuclear cells]]<ref name="pmid9247462">{{cite journal |vauthors=Marth T, Neurath M, Cuccherini BA, Strober W |title=Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease |journal=Gastroenterology |volume=113 |issue=2 |pages=442–8 |year=1997 |pmid=9247462 |doi= |url=}}</ref><ref name="pmid9867729">{{cite journal |vauthors=Schneider T, Stallmach A, von Herbay A, Marth T, Strober W, Zeitz M |title=Treatment of refractory Whipple disease with interferon-gamma |journal=Ann. Intern. Med. |volume=129 |issue=11 |pages=875–7 |year=1998 |pmid=9867729 |doi= |url=}}</ref>
====Defective macrophagic/phagocytic system====
* Up-regulated [[Interleukin 16]] in monocyte-derived [[macrophages]] that enhanced [[Tropheryma whipplei]] replication<ref name="pmid16177102">{{cite journal |vauthors=Desnues B, Raoult D, Mege JL |title=IL-16 is critical for Tropheryma whipplei replication in Whipple's disease |journal=J. Immunol. |volume=175 |issue=7 |pages=4575–82 |year=2005 |pmid=16177102 |doi= |url=}}</ref>
* Reduced [[Interleukin 12]] ([[IL-12]]) production by peripheral blood [[mononuclear cells]] that leads to decreased functional activity of [[T helper cells]] type 1 ([[Th1]]) and subsequently decreased [[Interferon gamma]] secretion by peripheral blood [[mononuclear cells]]<ref name="pmid9247462">{{cite journal |vauthors=Marth T, Neurath M, Cuccherini BA, Strober W |title=Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease |journal=Gastroenterology |volume=113 |issue=2 |pages=442–8 |year=1997 |pmid=9247462 |doi= |url=}}</ref><ref name="pmid9867729">{{cite journal |vauthors=Schneider T, Stallmach A, von Herbay A, Marth T, Strober W, Zeitz M |title=Treatment of refractory Whipple disease with interferon-gamma |journal=Ann. Intern. Med. |volume=129 |issue=11 |pages=875–7 |year=1998 |pmid=9867729 |doi= |url=}}</ref><ref name="pmid12404221">{{cite journal |vauthors=Marth T, Kleen N, Stallmach A, Ring S, Aziz S, Schmidt C, Strober W, Zeitz M, Schneider T |title=Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease |journal=Gastroenterology |volume=123 |issue=5 |pages=1468–77 |year=2002 |pmid=12404221 |doi= |url=}}</ref>
* Reduced expression of [[complement receptor 3]] ([[CD11b]])<ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>
* Reduced expression of [[complement receptor 3]] ([[CD11b]])<ref name="pmid7519533">{{cite journal |vauthors=Marth T, Roux M, von Herbay A, Meuer SC, Feurle GE |title=Persistent reduction of complement receptor 3 alpha-chain expressing mononuclear blood cells and transient inhibitory serum factors in Whipple's disease |journal=Clin. Immunol. Immunopathol. |volume=72 |issue=2 |pages=217–26 |year=1994 |pmid=7519533 |doi= |url=}}</ref>
* Normal [[phagocytosis]] but impaired [[degradation]]<ref name="pmid9247462">{{cite journal |vauthors=Marth T, Neurath M, Cuccherini BA, Strober W |title=Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease |journal=Gastroenterology |volume=113 |issue=2 |pages=442–8 |year=1997 |pmid=9247462 |doi= |url=}}</ref>


==== Defective humoral immunity ====
==== Defective humoral immunity ====
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There is no known causative genetic factor for Whipple's disease. However, there is an association between Whipple's disease and some immunologic defects.  
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.<ref name="Marth2009">{{cite journal|last1=Marth|first1=Thomas|title=New Insights into Whipple’s Disease – A Rare Intestinal Inflammatory Disorder|journal=Digestive Diseases|volume=27|issue=4|year=2009|pages=494–501|issn=1421-9875|doi=10.1159/000233288}}</ref>
*Studies showed that individuals with specific [[HLA]] type (HLA alleles DRB1*13 and DQB1*06) have a higher risk of Whipple's disease.<ref name="Marth2009">{{cite journal|last1=Marth|first1=Thomas|title=New Insights into Whipple’s Disease – A Rare Intestinal Inflammatory Disorder|journal=Digestive Diseases|volume=27|issue=4|year=2009|pages=494–501|issn=1421-9875|doi=10.1159/000233288}}</ref>
*


==Associated Conditions==
==Associated Conditions==
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* [[HLA-B27]] individuals  
* [[HLA-B27]] individuals  
* Defective [[cellular immunity]]  
* Defective [[cellular immunity]]  
* [[AIDS|HIV infection]]


==Gross Pathology==
==Gross Pathology==
*On gross pathology, [feature1], [feature2], and [feature3] are characteristic findings of Whipple's disease.
* 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.<ref name="SalkicAlibegovic2013">{{cite journal|last1=Salkic|first1=Nermin N.|last2=Alibegovic|first2=Ervin|last3=Jovanovic|first3=Predrag|title=Endoscopic appearance of duodenal mucosa in Whipple's disease|journal=Gastrointestinal Endoscopy|volume=77|issue=5|year=2013|pages=822–823|issn=00165107|doi=10.1016/j.gie.2013.01.016}}</ref>


==Microscopic Pathology==
==Microscopic Pathology==
*On microscopic histopathological analysis, [[PAS stain|PAS]]-positive [[Macrophage|macrophages]] in the [[lamina propria]] containing non-acid-fast gram-positive [[bacilli]] are characteristic findings of Whipple's disease.<ref name="SchneiderMoos2008">{{cite journal|last1=Schneider|first1=Thomas|last2=Moos|first2=Verena|last3=Loddenkemper|first3=Christoph|last4=Marth|first4=Thomas|last5=Fenollar|first5=Florence|last6=Raoult|first6=Didier|title=Whipple's disease: new aspects of pathogenesis and treatment|journal=The Lancet Infectious Diseases|volume=8|issue=3|year=2008|pages=179–190|issn=14733099|doi=10.1016/S1473-3099(08)70042-2}}</ref>
*On [[microscopic]] [[histopathological]] [[analysis]], [[PAS stain|PAS]]-positive [[Macrophage|macrophages]] in the [[lamina propria]] containing non-acid-fast gram-positive [[bacilli]] are characteristic findings of Whipple's disease.<ref name="SalkicAlibegovic2013" /><ref name="SchneiderMoos2008">{{cite journal|last1=Schneider|first1=Thomas|last2=Moos|first2=Verena|last3=Loddenkemper|first3=Christoph|last4=Marth|first4=Thomas|last5=Fenollar|first5=Florence|last6=Raoult|first6=Didier|title=Whipple's disease: new aspects of pathogenesis and treatment|journal=The Lancet Infectious Diseases|volume=8|issue=3|year=2008|pages=179–190|issn=14733099|doi=10.1016/S1473-3099(08)70042-2}}</ref>


Below images show the characteristic feature of Whipple's disease. foamy [[Macrophage|macrophages]] are present in the [[lamina propria]].<ref>https://commons.wikimedia.org</ref>
Below images show the characteristic feature of Whipple's disease: foamy [[Macrophage|macrophages]] are present in the [[lamina propria]].<ref>https://commons.wikimedia.org</ref>
{|
|[[image:Whipple disease PAS stain-m1.jpg|thumb|300px|[[Periodic acid-Schiff stain]] of a [[small intestinal]] lesion of Whipple's disease by Ed Uthman from Houston, TX, USA<ref name="urlFile:Whipples Disease, PAS (6881958655).jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=30104677 |title=File:Whipples Disease, PAS (6881958655).jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|[[image:Whipple disease GMS stain.jpg|thumb|320px|[[GMS stain]] of a [[small intestinal]] lesion of Whipple's disease by Ed Uthman from Houston, TX, USA<ref name="urlFile:Whipples Disease, GMS (6881505399).jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=30104665 |title=File:Whipples Disease, GMS (6881505399).jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|[[image:Whipple disease HE.jpg|thumb|320px|High magnification micrograph of Whipple's disease. H&E stain. [[Duodenal]] [[biopsy]] by Nephron<ref name="urlFile:Whipple disease -a- high mag.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=15357467 |title=File:Whipple disease -a- high mag.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|-
|[[image:Whipple disease PAS positive3.jpg|thumb|300px|[[Periodic acid-Schiff stain]] of a [[small intestinal]] lesion of Whipple's disease by Ed Uthman from Houston, TX, USA<ref name="urlFile:Whipples Disease, PAS (6881958605).jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=30104682 |title=File:Whipples Disease, PAS (6881958605).jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|[[image:Whipple disease PAS positive1.jpg|thumb|300px|[[Periodic acid-Schiff stain]] of a [[small intestinal]] lesion of Whipple's disease by By Mrwick1<ref name="urlFile:Whipple disease.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=7403165 |title=File:Whipple disease.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|[[image:Light microscopy of intestine-Whipples Disease.jpg .jpg|thumb|300 px|top|[[Light microscopy]] of [[intestine]] - Whipples Disease From PEIR - University of Alabama at Birmingham Department of Pathology<ref name="urlFile:Whipple2.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=2235609 |title=File:Whipple2.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|-
|[[image:Whipple disease PAS positive2.jpg|thumb|300px|[[Periodic acid-Schiff stain]] of a [[small intestinal]] lesion of Whipple's disease by Ed Uthman from Houston, TX, USA<ref name="urlFile:Whipple pas+.jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=7403191 |title=File:Whipple pas+.jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|[[image:Whipple disease Acid fast stain.jpg|thumb|300 px|top|[[Acid-fast stain]] negative [[bacilli]] in a patient with Whipple's disease by Ed Uthman from Houston, TX, USA<ref name="urlFile:Whipples Disease, Kinyoun Carbolfuchsin Acid-Fast Stain (6881505345).jpg - Wikimedia Commons">{{cite web |url=https://commons.wikimedia.org/w/index.php?curid=30104666 |title=File:Whipples Disease, Kinyoun Carbolfuchsin Acid-Fast Stain (6881505345).jpg - Wikimedia Commons |format= |work= |accessdate=}}</ref>]]
|}


==References==
==References==
{{Reflist|2}}
{{Reflist|2}}
 
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[[Category:Medicine]]
[[Category:Gastroenterology]]
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Latest revision as of 00:44, 30 July 2020

Whipple's disease Microchapters

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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 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.

Pathophysiology

Pathogenesis

  • 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
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cure
 
Relapse
 
Re-infection
 
Death
 

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

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:

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]

References

  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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