Article

Impaired Immune Functions of Monocytes and Macrophages in Whipple's Disease

September 2009
Gastroenterology 138(1):210-20

DOI:10.1053/j.gastro.2009.07.066

Source
PubMed

Authors:

Verena Moos

Charité Universitätsmedizin Berlin

Anika Geelhaar

Charité Universitätsmedizin Berlin

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Whipple's disease is a chronic multisystemic infection caused by Tropheryma whipplei. Host factors likely predispose for the establishment of an infection, and macrophages seem to be involved in the pathogenesis of Whipple's disease. However, macrophage activation in Whipple's disease has not been studied systematically so far. Samples from 145 Whipple's disease patients and 166 control subjects were investigated. We characterized duodenal macrophages and lymphocytes immunohistochemically and peripheral monocytes by flow cytometry and quantified mucosal and systemic cytokines and chemokines indicative for macrophage activation. In addition, we determined duodenal nitrite production and oxidative burst induced by T whipplei and by other bacteria. Reduced numbers of duodenal lymphocytes, increased numbers of CD163(+) and stabilin-1(+), reduced numbers of inducible nitric synthase+ duodenal macrophages, and increased percentages of CD163(+) peripheral monocytes indicated a lack of inflammation and a M2/alternatively activated macrophage phenotype in Whipple's disease. Incubation with T whipplei in vitro enhanced the expression of CD163 on monocytes from Whipple's disease patients but not from control subjects. Chemokines and cytokines associated with M2/alternative macrophage activation were elevated in the duodenum and the peripheral blood from Whipple's disease patients. Functionally, Whipple's disease patients showed a reduced duodenal nitrite production and reduced oxidative burst upon incubation with T whipplei compared with healthy subjects. The lack of excessive local inflammation and alternative activation of macrophages, triggered in part by the agent T whipplei itself, may explain the hallmark of Whipple's disease: invasion of the intestinal mucosa with macrophages incompetent to degrade T whipplei.

Intestinal barrier dysfunction mediates Whipple's disease immune reconstitution inflammatory syndrome (IRIS)

Article

Full-text available

Apr 2022

Background & aims: Classical Whipple's disease (CWD) affects the gastrointestinal tract and causes chronic diarrhea, malabsorption, and barrier dysfunction with microbial translocation (MT). Immune reconstitution inflammatory syndrome (IRIS) is a serious complication during antimicrobial treatment of CWD. The pathomechanisms of IRIS have not been identified and mucosal barrier integrity has not been studied in patients with IRIS CWD. Methods: In 96 CWD patients (n = 23 IRIS, n = 73 non-IRIS) and 30 control subjects, we analysed duodenal morphology by histology, measured serum markers of MT, and proinflammatory cytokines in biopsy supernatants, and correlated microbial translocation with T cell reconstitution and activation. Results: Before treatment, duodenal specimens from patients who later developed IRIS exhibited a more pronounced morphological transformation that suggested a disturbed barrier integrity when compared with the non-IRIS group. Villous atrophy was mediated by increased apoptosis of epithelial cells, which was insufficiently counterbalanced by regenerative proliferation of crypt cells. Pretreatment deficiencies in the mucosal secretion of proinflammatory cytokines and chemokines (e.g., IL-6, CCL2) in these patients markedly resolved after therapy induction. High serum levels of lipopolysaccharides (LPS), soluble CD14 (sCD14), and LPS-binding protein (LBP) combined with low endotoxin core antibody (EndoCAb) titres suggested systemic MT in CWD patients developing IRIS. CD4+ T cell count and activation in IRIS CWD patients correlated positively with sCD14 levels and negatively with EndoCAb titres. Furthermore, the degree of intestinal barrier dysfunction and MT was predictive for the onset of IRIS. Conclusion: Prolonged MT across a dysfunctional intestinal mucosal barrier due to severe tissue damage favors dysbalanced immune reconstitution and systemic immune activation in IRIS CWD. Therefore, the monitoring of inflammatory and MT markers in CWD patients might be helpful in identifying patients who are at risk of developing IRIS. Therapeutic strategies to reconstitute the mucosal barrier and control inflammation could assist in the prevention of IRIS.

Review Whipple's disease and Tropheryma whipplei infections: from bench to bedside

Article

Apr 2022
LANCET INFECT DIS

Whipple's disease is a chronic and systemic disease caused by the Gram-positive bacterium Tropheryma whipplei that primarily affects the gastrointestinal tract. Data from the last two decades have substantially increased our knowledge of the spectrum and our understanding of T whipplei infections. Although T whipplei seems ubiquitously present in the environment, Whipple's disease itself is very rare. Remarkably, primary infections can be symptomatic, but most cases result in bacterial clearance and seroconversion. However, some individuals are unable to clear the bacterium leading to persistence and asymptomatic carriage. In very rare cases, which might be associated with a subtle immune defect, T whipplei replication is uncontrolled and manifests as classical Whipple's disease or T whipplei localised infections. In this review, we provide a comprehensive outline of T whipplei infection, including the epidemiology, clinical manifestations, diagnosis, and treatment. We also provide an up-to-date overview of our understanding of the host immune response and pathophysiology and discuss future research avenues to resolve the lacking pieces of the puzzle of T whipplei infections.

Defizienzen in der Interaktion von Makrophagen und T-Lymphozyten bei der Entstehung des Morbus Whipple

Thesis

Jul 2020

Kathleen Sara Weigt

Morbus Whipple (MW) ist eine chronische multisystemische Infektionskrankheit, die durch das Bakterium Tropheryma whipplei verursacht wird. Während asymptomatische Trägerschaften und selbst-limitierende Infektionen mit T. whipplei häufig vorkommen, ist die chronische Manifestation des MW sehr selten. Die geringe Inzidenz des MW bei ubiquitärer Verbreitung der Erreger deutet auf eine Assoziation mit prädisponierenden Faktoren bei der Entstehung der Erkrankung hin. Die zugrundeliegenden Faktoren und Mechanismen der Manifestation sind nicht ausreichend geklärt, sodass die vorliegende Arbeit die T-Zell-Reaktivität auf die Antigenpräsentation sowie die Interaktion von T. whipplei mit peripheren monozytären Zellen (PBMC) in vitro analysierte. Hierbei wiesen allogene PBMC von MW-Patienten bei produktiver Präsentation des T. whipplei GrpE Antigens über den MHC-I-Komplex einen vermehrten Anteil Perforin+ CD8+ T-Zellen auf. Die Interferon-g Produktion zeigte sich nach optimierter GrpE Präsentation mit gesunden Kontrollen vergleichbar, wodurch erstmalig nachgewiesen wurde, dass die verminderte T-Zell-Reaktion in MW-Patienten auf eine Dysfunktion im Zuge der Antigenpräsentation zurückzuführen ist. Die Infektion in vitro differenzierter Makrophagen mit vitalen T. whipplei resultierte in einer Reduktion der HLA-DR und CC-18 Expression. Stimulationen mit Bakterienlysat und -überstand induzierten keine phänotypischen Änderungen, wodurch die Hypothese einer aktiven Immunmodulation durch T. whipplei gestützt wurde. Transkriptomanalysen führten zur Identifikation von 105 Kandidaten-Gene, die die chronische Manifestation des MW bedingen könnten. Die klinische Relevanz der Gene ist in weiteren Studien zu prüfen, ebenso wie die Bedeutung CD14+ depletierter Zellen für die Pathogenese des MW. Diese gelangten im Zuge einer prospektiven Pilotstudie erstmalig in den Fokus und deuten darauf hin, dass neben Monozyten weitere Zellen in die systemische Verbreitung von T. whipplei involviert sind.

Fluorescence In Situ Hybridization for Diagnosis of Whipple’s Disease in Formalin-Fixed Paraffin-Embedded Tissue

Article

Full-text available

Jun 2017

Whipple’s disease (WD) is a rare chronic systemic infection with a wide range of clinical symptoms, routinely diagnosed in biopsies from the small intestine and other tissues by periodic acid–Schiff (PAS) diastase staining and immunohistological analysis with specific antibodies. The aim of our study was to improve the pathological diagnosis of WD. Therefore, we analyzed the potential of fluorescence in situ hybridization (FISH) for diagnosing WD, using a Tropheryma (T.) whipplei-specific probe. 19 formalin-fixed paraffin-embedded (FFPE) duodenal biopsy specimens of 12 patients with treated (6/12) and untreated (6/12) WD were retrospectively examined using PAS diastase staining, immunohistochemistry, and FISH. 20 biopsy specimens with normal intestinal mucosa, Helicobacter pylori, or mycobacterial infection, respectively, served as controls. We successfully detected T. whipplei in tissue biopsies with a sensitivity of 83% in untreated (5/6) and 40% in treated (4/10) cases of WD. In our study, we show that FISH-based diagnosis of individual vital T. whipplei in FFPE specimens is feasible and can be considered as ancillary diagnostic tool for the diagnosis of WD in FFPE material. We show that FISH not only detect active WD but also be helpful as an indicator for the efficiency of antibiotic treatment and for detection of recurrence of disease when the signal of PAS diastase and immunohistochemistry lags behind the recurrence of disease, especially if the clinical course of the patient and antimicrobial treatment is considered.

Peripheral T-Cell Reactivity to Heat Shock Protein 70 and Its Cofactor GrpE from Tropheryma whipplei Is Reduced in Patients with Classical Whipple's Disease

Article

Full-text available

Jul 2017
INFECT IMMUN

Background: Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response towards Tropheryma (T.) whipplei in genetically predisposed individuals. The cofactor GrpE of heat-shock protein 70 (Hsp70) from T. whipplei was previously identified as B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific pro-inflammatory T-cell responses. Methods: Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before CD40L, CD69, perforin, granzyme B, CD107a, and interferon (IFN)γ were determined in T cells by flow cytometry. Results : Upon stimulation with total bacterial lysate or recombinant GrpE or Hsp70 of T. whipplei, the proportions of activated effector CD4 ⁺ T cells, determined as CD40L ⁺ IFNγ ⁺ , were significantly lower in patients with CWD compared to healthy controls; CD8 ⁺ T cells of untreated CWD patients revealed an enhanced activation towards unspecific stimulation and T. whipplei -specific degranulation, though CD69 ⁺ IFNγ ⁺ CD8 ⁺ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei -derived proteins. Conclusions: Hsp70 and its cofactor GrpE are immunogenic in healthy individuals, eliciting effective responses against T. whipplei to control bacterial spreading. The lack of specific T-cell responses against these T. whipplei -derived proteins may contribute to the pathogenesis of CWD.

Clinical Manifestations, Treatment, and Diagnosis of Tropheryma whipplei Infections

Article

Apr 2017

Whipple's disease is a rare infectious disease that can be fatal if left untreated. The disease is caused by infection with Tropheryma whipplei , a bacterium that may be more common than was initially assumed. Most patients present with nonspecific symptoms, and as routine cultivation of the bacterium is not feasible, it is difficult to diagnose this infection. On the other hand, due to the generic symptoms, infection with this bacterium is actually quite often in the differential diagnosis. The gold standard for diagnosis used to be periodic acid-Schiff (PAS) staining of duodenal biopsy specimens, but PAS staining has a poor specificity and sensitivity. The development of molecular techniques has resulted in more convenient methods for detecting T. whipplei infections, and this has greatly improved the diagnosis of this often missed infection. In addition, the molecular detection of T. whipplei has resulted in an increase in knowledge about its pathogenicity, and this review gives an overview of the new insights in epidemiology, pathogenesis, clinical manifestations, diagnosis, and treatment of Tropheryma whipplei infections.

Uptake of Tropheryma whipplei by Intestinal Epithelia

Article

Full-text available

Mar 2023
INT J MOL SCI

Background: Tropheryma whipplei (TW) can cause different pathologies, e.g., Whipple’s disease and transient gastroenteritis. The mechanism by which the bacteria pass the intestinal epithelial barrier, and the mechanism of TW-induced gastroenteritis are currently unknown. Methods: Using ex vivo disease models comprising human duodenal mucosa exposed to TW in Ussing chambers, various intestinal epithelial cell (IEC) cultures exposed to TW and a macrophage/IEC coculture model served to characterize endocytic uptake mechanisms and barrier function. Results: TW exposed ex vivo to human small intestinal mucosae is capable of autonomously entering IECs, thereby invading the mucosa. Using dominant-negative mutants, TW uptake was shown to be dynamin- and caveolin-dependent but independent of clathrin-mediated endocytosis. Complementary inhibitor experiments suggested a role for the activation of the Ras/Rac1 pathway and actin polymerization. TW-invaded IECs underwent apoptosis, thereby causing an epithelial barrier defect, and were subsequently subject to phagocytosis by macrophages. Conclusions: TW enters epithelia via an actin-, dynamin-, caveolin-, and Ras-Rac1-dependent endocytosis mechanism and consecutively causes IEC apoptosis primarily in IECs invaded by multiple TW bacteria. This results in a barrier leak. Moreover, we propose that TW-packed IECs can be subject to phagocytic uptake by macrophages, thereby opening a potential entry point of TW into intestinal macrophages.

Tumor Necrosis Factor Inhibitors Exacerbate Whipple’s Disease by Reprogramming Macrophage and Inducing Apoptosis

Article

Full-text available

May 2021

Tropheryma whipplei is the agent of Whipple’s disease, a rare systemic disease characterized by macrophage infiltration of the intestinal mucosa. The disease first manifests as arthralgia and/or arthropathy that usually precede the diagnosis by years, and which may push clinicians to prescribe Tumor necrosis factor inhibitors (TNFI) to treat unexplained arthralgia. However, such therapies have been associated with exacerbation of subclinical undiagnosed Whipple’s disease. The objective of this study was to delineate the biological basis of disease exacerbation. We found that etanercept, adalimumab or certolizumab treatment of monocyte-derived macrophages from healthy subjects significantly increased bacterial replication in vitro without affecting uptake. Interestingly, this effect was associated with macrophage repolarization and increased rate of apoptosis. Further analysis revealed that in patients for whom Whipple’s disease diagnosis was made while under TNFI therapy, apoptosis was increased in duodenal tissue specimens as compared with control Whipple’s disease patients who never received TNFI prior diagnosis. In addition, IFN-γ expression was increased in duodenal biopsy specimen and circulating levels of IFN-γ were higher in patients for whom Whipple’s disease diagnosis was made while under TNFI therapy. Taken together, our findings establish that TNFI aggravate/exacerbate latent or subclinical undiagnosed Whipple’s disease by promoting a strong inflammatory response and apoptosis and confirm that patients may be screened for T. whipplei prior to introduction of TNFI therapy.

Human galectin-1 and galectin-3 promote Tropheryma whipplei infection

Article

Full-text available

Jan 2021

Tropheryma whipplei, is an actinobacterium that causes different infections in humans, including Whipple’s disease. The bacterium infects and replicates in macrophages, leading to a Th2-biased immune response. Previous studies have shown that T. whipplei harbors complex surface glycoproteins with evidence of sialylation. However, the exact contribution of these glycoproteins for infection and survival remains obscure. To address this, we characterized the bacterial glycoprofile and evaluated the involvement of human β-galactoside-binding lectins, Galectin-1 (Gal-1) and Galectin-3 (Gal-3) which are highly expressed by macrophages as receptors for bacterial glycans. Tropheryma whipplei glycoproteins harbor different sugars including glucose, mannose, fucose, β-galactose and sialic acid. Mass spectrometry identification revealed that these glycoproteins were membrane- and virulence-associated glycoproteins. Most of these glycoproteins are highly sialylated and N-glycosylated while some of them are rich in poly-N-acetyllactosamine (Poly-LAcNAc) and bind Gal-1 and Gal-3. In vitro, T. whipplei modulates the expression and cellular distribution of Gal-1 and Gal-3. Although both galectins promote T. whipplei infection by enhancing bacterial cell entry, only Gal-3 is required for optimal bacterial uptake. Finally, we found that serum levels of Gal-1 and Gal-3 were altered in patients with T. whipplei infections as compared to healthy individuals, suggesting that galectins are also involved in vivo. Among T. whipplei membrane-associated proteins, poly-LacNAc rich-glycoproteins promote infection through interaction with galectins. T. whipplei modulates the expression of Gal-1 and Gal-3 both in vitro and in vivo. Drugs interfering with galectin–glycan interactions may provide new avenues for the treatment and diagnosis of T. whipplei infections.

Clinical Manifestations and Diagnosis of Axial Spondyloarthritis

Article

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Oct 2020

Background: Axial spondyloarthritis (axSpA) is a chronic, rheumatic disease characterized by inflammation of the sacroiliac joint, spine, and entheses. Axial spondyloarthritis affects up to 1.4% of adults in the United States and is associated with decreased quality of life, increased mortality, and substantial health care-related costs, imposing a high burden on patients, their caregivers, and society. Summary of work: Diagnosing axSpA can be difficult. In this review, we seek to help rheumatologists in recognizing and diagnosing axSpA. Major conclusions: A discussion of challenges associated with diagnosis is presented, including use and interpretation of imaging, reasons for diagnostic delays, differences in disease presentation by sex, and differential diagnoses of axSpA. Future research directions: The early diagnosis of axSpA and advances in available therapeutic options have improved patient care and disease management, but delays in diagnosis and treatment remain common. Additional research and education are critical for recognizing diverse axSpA presentations and optimizing management early in the course of disease.

Late Onset Multiple Acyl-CoA Dehydrogenase Deficiency (MADD) Myopathy Misdiagnosed as Polymyositis

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Feb 2019

Onycholysis—An Uncommon Finding in Kawasaki Disease

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Feb 2019

Peripheral-blood b-cell subset disturbances in inflammatory joint diseases induced by Tropheryma whipplei

Article

Full-text available

Feb 2019
PLOS ONE

Objective To look for abnormalities in circulating B-cell subsets in patients with rheumatic symptoms of Whipple’s disease (WD). Method Consecutive patients seen between 2010 and 2016 for suspected inflammatory joint disease were identified retrospectively. Results of standardized immunological and serological tests and of peripheral-blood B-cell and T-cell subset analysis by flow cytometry were collected. Patients with criteria suggesting WD underwent PCR testing for Tropheryma whipplei, and those with diagnosis of WD (cases) were compared to those without diagnosis (controls). We used ROC curve analysis to evaluate the diagnostic value of flow cytometry findings for WD. Results Among 2917 patients seen for suspected inflammatory joint disease, 121 had suspected WD, including 9 (9/121, 7.4%) confirmed WD. Proportions of T cells and NK cells were similar between suspected and confirmed WD, whereas cases had a lower proportion of circulating memory B cells (IgD⁻CD38low, 18.0%±9.7% vs. 26.0%±14.2%, P = 0.041) and higher ratio of activated B cells over memory B cells (4.4±2.0 vs. 2.9±2.2, P = 0.023). Among peripheral-blood B-cells, the proportion of IgD+CD27- naive B cells was higher (66.2%±18.2% vs. 54.6%±18.4%, P = 0.047) and that of IgD-CD27+ switched memory B cells lower (13.3%±5.7% vs. 21.4%±11.9%, P = 0.023), in cases vs. controls. The criterion with the best diagnostic performance was a proportion of IgD+CD27- naive B cells above 70.5%, which had 73% sensitivity and 80% specificity. Conclusion Our study provides data on peripheral-blood B-cell disturbances that may have implications for the diagnosis and pathogenetic understanding of WD.

Tropheryma whipplei Increases Expression of Human Leukocyte Antigen-G on Monocytes to Reduce Tumor Necrosis Factor and Promote Bacterial Replication

Article

Aug 2018
GASTROENTEROLOGY

Background & aims: Infection with Tropheryma whipplei has a range of effects-some patients can be chronic carriers without developing any symptoms whereas others can develop systemic Whipple disease, characterized by a lack a protective inflammatory immune response. Alterations in major histocompatibility complex, class I, G (HLA-G) function have been associated with several diseases. We investigated the role of HLA-G during T whipplei infection. Methods: Sera, total RNA, and genomic DNA were collected from peripheral blood from 22 patients with classic Whipple's disease, 19 patients with localized T whipplei infections, and 21 asymptomatic carriers. Levels of soluble HLA-G in sera were measured by ELISA and expression of HLA-G and its isoforms were monitored by real-time PCR. HLA-G alleles were identified and compared with a population of voluntary bone marrow donors. Additionally, monocytes from healthy subjects were stimulated with T whipplei and HLA-G expression was monitored by real-time PCR and flow cytometry. Bacterial replication was assessed by PCR in the presence of HLA-G or inhibitor of tumor necrosis factor (TNF, etanercept). Results: HLA-G mRNAs and levels of soluble HLA-G were significantly increased in sera from patients with chronic T whipplei infection compared with sera from asymptomatic carriers and controls. No specific HLA-G haplotypes were associated with disease or T whipplei infection. However, T whipplei infection of monocytes induced expression of HLA-G, which was associated with reduced secretion of TNF, compared with non-infected monocytes. A neutralizing antibody against HLA-G increased TNF secretion by monocytes in response to T whipplei, and a TNF inhibitor promoted bacteria replication. Conclusions: Levels of HLA-G are increased in sera from patients with T whipplei tissue infections, associated with reduced production of TNF by monocytes. This might promote bacteria colonization in patients.

Whipple's Disease: A Case Report with Long-term Endoscopic Follow-up

Article

Full-text available

Feb 2018

A 72-year-old man presented with anorexia and 15-kg weight loss over 3 years. Endoscopy revealed yellow, shaggy mucosa alternating with erythematous, eroded mucosa in the duodenum. Biopsy specimens showed massive infiltration of periodic acid-Schiff-positive macrophages in the lamina propria, consistent with Whipple's disease. The patient was treated with intravenous ceftriaxone for four weeks, followed by oral trimethoprim-sulfamethoxazole. His condition improved, and he gradually gained weight. Although the endoscopic findings improved with continuous trimethoprim-sulfamethoxazole administration, macrophage infiltration of the duodenal mucosa persisted. However, the patient has been symptom-free for eight years.

Whipple’s disease: etiology, pathogenesis, clinic, diagnosis and treatment

Article

Jan 2024

Whipple’s disease is an infectious, systemic and recurrent disease caused by the gram-positive bacterium Tropheryma whipplei. The disease proceeds with a heterogeneous clinical picture, presenting difficulties of timely diagnosis and in the absence of antibacterial therapy can lethal outcome. This review is devoted to the etiology, pathogenesis, epidemiology, clinical picture, modern diagnosis and therapy of Whipple’s disease.

Isolated central nervous system Whipple disease

Article

Full-text available

Oct 2022

Background Whipple disease (WD) is an infection caused by Tropheryma whipplei , which might present in three different forms: classical, localized, and isolated in the central nervous system (CNS). Methods We report the result of a systematic review of the literature on WD unusually presenting with exclusively neurological symptoms, including two previously unpublished cases. A description of two cases with isolated CNS WD was performed, as well as a literature search in Cochrane, Scielo , and PubMed . Results Two male adult patients presented with exclusively neurological symptomatology. Both magnetic resonance imaging (MRI) showed an intracranial mass suggestive of brain tumor. The histopathological examination was consistent with WD, with no systemic involvement. In the review of the literature, 35 cases of isolated CNS WD were retrieved. The median age at diagnosis was 43.5 (IQR 31.5–51.5). In 13 patients, the MRI showed a brain mass consistent with a brain tumor. The most common finding in the biopsy was the periodic-acid Schiff-stained foamy macrophages. Only five cases presented the pathognomonic sign of oculomasticatory myorhythmia. Thirteen cases had an adverse outcome that resulted in death during follow-up, whereas another 13 improved. The other nine patients remained stable or presented moderate improvement. Conclusion Isolated CNS WD is a rare disease that should be considered among the differential diagnosis of CNS mass lesions. Brain biopsy is necessary to establish the diagnosis. It is stressed in the literature that an extended antibiotic course is required to prevent relapses and to control the disease.

Tropheryma whipplei detection by metagenomic next-generation sequencing in bronchoalveolar lavage fluid: A cross-sectional study

Article

Full-text available

Aug 2022

Tropheryma whipplei is the bacterium associated with Whipple’s disease (WD), a chronic systemic infectious disease primarily involving the gastrointestinal tract. T. whipplei can also be detected in different body site of healthy individuals, including saliva and feces. Traditionally, Tropheryma whipplei has a higher prevalence in bronchoalveolar lavage fluid (BALF) of immunocompromised individuals. Few studies have explored the significance of the detection of T. whipplei in BALF. Herein, we retrospectively reviewed 1725 BALF samples which detected for metagenomic next-generation sequencing (mNGS) from March 2019 to April 2022 in Zhuhai, China. Seventy BALs (70/1725, 4.0%) from 70 patients were positive for T. whipplei. Forty-four patients were male with an average age of 50 years. The main symptoms included cough (23/70), expectoration (13/70), weight loss (9/70), and/or dyspnea (8/70), but gastrointestinal symptoms were rare. Chronic liver diseases were the most common comorbidity (n=15, 21.4%), followed by diabetes mellitus (n=13, 18.6%). Only nine patients (12.9%) were immunocompromised. Twenty-four patients (34.3%) were finally diagnosed with reactivation tuberculosis and 15 patients (21.4%) were diagnosed with lung tumors, including 13 primary lung adenocarcinoma and two lung metastases. Fifteen patients (21.4%) had pneumonia. Among the 20 samples, T. whipplei was the sole agent, and Mycobacterium tuberculosis complex was the most common detected other pathogens. Among the non-tuberculosis patients, 31 (31/46, 67.4%) had ground glass nodules or solid nodules on chest CT. Our study indicates that T. whipplei should be considered as a potential contributing factor in some lung diseases. For non-immunocompromised patients, the detection of T. whipplei also needs attention. The mNGS technology improves the detection and attention of rare pathogens. In the future, the infection, colonization, and prognosis of T. whipplei in lung still need to be studied.

Whipple’s disease unmasked by TNF inhibitor therapy for treatment of seronegative rheumatoid arthritis

Article

Jul 2022

We report a patient with seronegative rheumatoid arthritis diagnosed with Whipple’s disease following treatment of tumour necrosis factor inhibitor (TNFI) therapy. Whipple’s disease should be considered in patients with seronegative rheumatoid arthritis and other unexplained multisystem illness. The TNFI therapy and immunosuppressive therapies can unmask latent Whipple’s disease.

Zebrafish: A Model Organism to Understand Tumor Angiogenesis Mechanism

Chapter

Jan 2022

Tumor angiogenesis is the most crucial step in the progression of all types of cancers. Preexisted blood vessel vascularizes into new one through sprouting or intussusceptive (splitting) mechanism. This process would facilitate the growth in the size of tumors regulated by VEGF (vascular endothelial growth factor), leading to metastasis, which ultimately increases the severity of cancer. So, it is very important to suppress tumor angiogenesis before the situation gets worse in a cancer patient. A wide variety of in vitro and in vivo models have been used to study the process of tumor angiogenesis and metastasis of cancer. It has helped us to discover new drugs and to find novel therapies for cancer, including anti-angiogenic therapy. Mainly angiogenesis is traditionally modeled in rodents and chick embryo, but of late zebrafish is emerging as the preferred model due its several advantages over the other animals. Zebrafish (Danio rerio) serves as the ideal model to study the various cancers, since it is possible to induce tumor growth or suppression easily, when compared to the other animal models. Also, tumor xenograft model has been studied in zebrafish extensively using many human cancer cell lines. So, in this chapter, we have reviewed some literatures that appreciate zebrafish model to study tumor angiogenesis.KeywordsZebrafishAngiogenesisVEGFTumorXenograftAnti-angiogenic therapy

Codon usage studies and epitope-based peptide vaccine prediction against Tropheryma whipplei

Article

Full-text available

Mar 2022

Background The Tropheryma whipplei causes acute gastroenteritis to neuronal damages in Homo sapiens . Genomics and codon adaptation studies would be helpful advancements of disease evolution prediction, prevention, and treatment of disease. The codon usage data and codon usage measurement tools were deployed to detect the rare, very rare codons, and also synonymous codons usage. The higher effective number of codon usage values indicates the low codon usage bias in T. whipplei and also in the 23S and 16S ribosomal RNA genes. Results In T. whipplei , it was found to hold low codon biasness in genomic sets. The synonymous codons possess the base content in 3rd position that was calculated as A3S% (24.47 and 22.88), C3S% (20.99 and 22.88), T3S% (21.47 and 19.53), and G3S% (33.08 and 34.71) for 23s and 16s rRNA, respectively. Conclusion Amino acids like valine, aspartate, leucine, and phenylalanine hold high codon usage frequency and also found to be present in epitopes KPSYLSALSAHLNDK and FKSFNYNVAIGVRQP that were screened from proteins excinuclease ABC subunit UvrC and 3-oxoacyl-ACP reductase FabG, respectively. This method opens novel ways to determine epitope-based peptide vaccines against different pathogenic organisms.

TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR– and JNK-MAPK–Activated p70S6K Pathway

Article

Sep 2021

IFN-γ, a proinflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-γ production by murine macrophages, IFN-γ production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-γ and IL-12- and IL-18-stimulated monocyte-derived macrophages (M0) produce significant levels of IFN-γ. Further stimulation of IL-12/IL-18-primed macrophages or M1 macrophages with agonists for TLR-2, TLR-3, or TLR-4 significantly enhanced IFN-γ production in contrast to the similarly stimulated M0, M2a, M2b, and M2c macrophages. Similarly, M1 macrophages generated from COVID-19-infected patients' macrophages produced IFN-γ that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-γ production, suggesting that differentiation with IFN-γ plays a key role in IFN-γ induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4-induced IFN-γ production in M1 macrophages. Our results show that TLR-4-induced IFN-γ production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of PI3K, the mammalian target of rapamycin complex 1/2 (mTORC1/2), and the JNK MAPK pathways. These results suggest that M1-derived IFN-γ may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC1/2, PI3K, and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.

Whipple’s disease diagnosed in a patient with suspected sarcoidosis

Article

Full-text available

Mar 2021
INT J INFECT DIS

We present a case of a 51-year-old patient with chronic diarrhea, weight loss, polyarthralgia and diffuse lymphadenopathy. Laboratory work-up showed anemia, leuco- and thrombocytosis, and increased C-reactive protein (CRP). Due to an inconspicuous differential leucocyte count and lymph node biopsy findings showing granulomatous lymphadenopathy, we initially suspected sarcoidosis. Colonoscopy found no abnormalities and duodenal biopsies showed negative Periodic acid-Schiff stains. However, PCR testing on these biopsies revealed tropheryma whipplei DNA. Further PCR testing of urine and cerebrospinal fluid revealed T. whipplei DNA as well. The patient was treated with ceftriaxone for 2 weeks followed by trimethoprim for a year. A rapid improvement of his symptoms was seen.

Selective killing of human M1 macrophages by Smac mimetics alone and M2 macrophages by Smac mimetics and caspase inhibition

Article

Full-text available

Jan 2021

The inflammatory and anti-inflammatory Mϕs have been implicated in many diseases including rheumatoid arthritis, multiple sclerosis, and leprosy. Recent studies suggest targeting Mϕ function and activation may represent a potential target to treat these diseases. Herein, we investigated the effect of second mitochondria-derived activator of caspases (SMAC) mimetics (SMs), the inhibitors of apoptosis (IAPs) proteins, on the killing of human pro- and anti-inflammatory Mϕ subsets. We have shown previously that human monocytes are highly susceptible whereas differentiated Mϕs (M0) are highly resistant to the cytocidal abilities of SMs. To determine whether human Mϕ subsets are resistant to the cytotoxic effects of SMs, we show that M1 Mϕs are highly susceptible to SM-induced cell death whereas M2a, M2b, and M2c differentiated subsets are resistant, with M2c being the most resistant. SM-induced cell death in M1 Mϕs was mediated by apoptosis as well as necroptosis, activated both extrinsic and intrinsic pathways of apoptosis, and was attributed to the IFN-γ-mediated differentiation. In contrast, M2c and M0 Mϕs experienced cell death through necroptosis following simultaneous blockage of the IAPs and the caspase pathways. Overall, the results suggest that survival of human Mϕs is critically linked to the activation of the IAPs pathways. Moreover, agents blocking the cellular IAP1/2 and/or caspases can be exploited therapeutically to address inflammation-related diseases.

Macrophage Polarization Induced by Probiotic Bacteria: a Concise Review

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Full-text available

Sep 2020

Macrophages display remarkable plasticity and can possess distinct functions in response to different environmental stimuli. Classically activated macrophages (M1 macrophages) are pro-inflammatory and have a critical role in host defense against infection, while alternatively activated macrophages (M2 macrophages) suppress inflammatory responses and associated with wound repair. Probiotic bacteria are reported to have a beneficial effect on the host immune status through their ability to modulate the macrophage polarization. Some probiotic strains are reported to activate macrophages to M1 phenotype to kill intracellular pathogens, while some other probiotics can induce M2 macrophages to exert the anti-inflammatory effect. Thus, this review will focus on the immunomodulatory role of probiotics in macrophage polarization and summarize the mode of action of probiotics in regulating macrophage plasticity. The detailed understanding of the immunomodulatory signaling effects of probiotic bacteria will broaden our understanding of how probiotics may regulate the immune system and find their therapeutic potentials for inflammatory diseases.

Epidemiology of Whipple’s Disease in the USA Between 2012 and 2017: A Population-Based National Study

Article

Full-text available

May 2019
DIGEST DIS SCI

Objective Prior studies on the epidemiology of Whipple’s disease are limited by small sample size and case series design. We sought to characterize the epidemiology of Whipple’s disease in the USA utilizing a large population-based database. Methods We queried a commercial database (Explorys Inc, Cleveland, OH), an aggregate of electronic health record data from 26 major integrated healthcare systems in the USA. We identified a cohort of patients with a diagnosis of Whipple’s disease based on systemized nomenclature of medical terminology (SNOMED CT) codes. We calculated the overall and age-, race-, ethnicity, and gender-based prevalence of Whipple’s disease and prevalence of associated diagnoses using univariate analysis. Results A total of 35,838,070 individuals were active in the database between November 2012 and November 2017. Of these, 350 individuals had a SNOMED CT diagnosis of Whipple’s disease, with an overall prevalence of 9.8 cases per 1 million. There was no difference in prevalence based on sex. However, prevalence of Whipple’s disease was higher in Caucasians, non-Hispanics, and individuals > 65 years old. Individuals with a diagnosis of Whipple’s disease were more likely to have associated diagnoses/findings of arthritis, CNS disease, endocarditis, diabetes, malignancy, dementia, vitamin D deficiency, iron deficiency, chemotherapy, weight loss, abdominal pain, and lymphadenopathy. Conclusions To our knowledge, this is the largest study to date examining the epidemiology of Whipple’s disease. In this large population-based study, the overall prevalence of Whipple’s disease in the USA is 9.8 cases per 1 million people. It affects men and women at similar rates and is more common in Caucasians, non-Hispanics, and people > 65 years old.

Whipple’s Disease: Diagnostic Value of rpoB Gene PCR from Peripheral Blood Mononuclear Cells

Article

Full-text available

Jun 2018

Introduction: Chronic infection with Tropheryma whipplei, known as Whipple's disease (WD), classically affects the gastrointestinal tract, but any organ system may be affected, and isolated manifestations occur. Reliable diagnosis based on a combination of periodic acid-Schiff (PAS) staining, T. whipplei-specific immunohistochemistry (IHC), and polymerase chain reaction (PCR) from duodenal biopsies may be challenging in cases without classical gastrointestinal infection, so the need for additional diagnostic materials is urgent. Objective: Our objective was to evaluate additional diagnostic possibilities for WD. Methods: We analyzed samples from 20 patients with WD and 18 control subjects in a prospective observational pilot study. In addition to WD diagnosis by PAS staining, T. whipplei-specific IHC and PCR of duodenal or extra intestinal tissues, whole EDTA blood, peripheral blood mononuclear cells (PBMCs) and PBMC fractions enriched with or depleted of cluster of differentiation (CD)-14+ cells were examined using T. whipplei rpoB gene PCR. Results: Tropheryma whipplei DNA was detected in 35 of 60 (58.3%) preparations from 16 of 20 patients with WD, most of whom lacked gastrointestinal signs and characteristic PAS-positive duodenal macrophages. Conclusion: This study provides evidence for the potential suitability of blood, particularly PBMCs, as material to assist in the diagnosis of WD via rpoB gene real-time PCR. Thus, PCR from blood preparations can be helpful for diagnostic decision making in atypical cases of WD.

Secondary immune thrombocytopenia (ITP) as an initial presentation of Whipple’s disease

Article

Full-text available

Jun 2017

Immune thrombocytopenia (ITP) is a heterogeneous autoimmune disease characterized by low platelet count that has been associated with a number of chronic infections but rarely described as a manifestation of Whipple’s disease (WD). We present a case of Whipple’s disease in a patient initially diagnosed with ITP. A 46-year old male in the fifth decade of life presented with presumed idiopathic ITP and was treated with several therapies including corticosteroids, rituximab, and thrombopoietin receptor agonists. Several years later, he developed weight loss and worsening arthralgias. He was found to have evidence of WD in a jejunal lymph node, the duodenum, and the cerebral spinal fluid (CSF). His diagnosis of WD, as a cause of secondary ITP, came a full 8 years after he was discovered to have thrombocytopenia and over 4 years after he was diagnosed with ITP. WD is an uncommon, multiorgan system disease caused by the actinomycete Tropheryma whipplei. Whipple’s disease presents a diagnostic challenge due to the wide array of possible presenting clinical manifestations, as well as a prolonged time course with separation of symptoms over many years. While T. whipplei is ubiquitous in the environment, few individuals develop clinical disease, raising the prospect that select immunodeficiencies, both singular or in combination, may play a role in infection. While rare, in the appropriate clinical setting, one should consider infection with T. whipplei in addition to other chronic infections as a cause of secondary ITP regardless of how long ago the diagnosis of ITP was made.

Infections intracrâniennes : de l’image au diagnostic

Article

Sep 2017

Whipple's disease: A rare disease that can be spotted by many doctors

Article

Dec 2023
EUR J INTERN MED

Ophthalmic manifestations of Whipple's disease

Article

Oct 2023

Nailyn Rasool

Purpose of review Whipple's disease is an infectious cause of uveitis that may present with nonspecific findings of intraocular inflammation, which can precede the development of neurologic symptoms and signs. Whipple's disease, then, may evade consideration in the differential diagnosis for uveitis. Recent findings Molecular tests can be helpful in identifying the presence of Tropheryma whipplei from ocular specimens. The application of metagenomic sequencing for ocular specimens is promising, as it offers the opportunity to identify the pathogen when suspicion for an intraocular infection is high. Whipple's disease demonstrates the ability to abrogate the host immune response, which gives some insight into its pathogenesis. Summary Whipple's disease should be suspected in patients who have uveitis refractory to anti-inflammatory therapy. Knowledge of this important pathogen can help direct the timely implementation of diagnostic testing.

Co-occurrence of Whipple's disease and hyperparathyroidism - coincidence or causal relationship?

Article

Jan 2023
Z GASTROENTEROL

Zusammenfassung Der Morbus Whipple ist eine seltene Infektionserkrankung mit multiplen klinischen Manifestationen. Die nach dem Erstbeschreiber George Hoyt Whipple benannte Erkrankung wurde 1907 im Rahmen der Autopsie eines 36-Jährigen mit Gewichtsverlust, Diarrhoen und Arthritis entdeckt. Unter dem Mikroskop entdeckte Whipple ein stäbchenförmiges Bakterium in der Darmwand des Patienten, welches erst 1992 als neue Bakterienspezies bestätigt und als Tropheryma whipplei benannt wurde. Ein Rezidiv des Morbus Whipple kann auch Jahre nach der initialen Diagnose auftreten und manifestiert sich häufig mit extraintestinalen Symptomen wie Arthritiden oder Hauteffloreszenzen, Jahre vor einem gastrointestinalen Beschwerdebild. Das im vorliegenden Fall festgestellte, simultane Auftreten mit einem primären Hyperparathyreoidismus ist jedoch ein bislang unbekanntes Krankheitsbild und eröffnet neue Fragen und Perspektiven im Rahmen der Diagnostik und Therapie.

Patients with Whipple's disease have a high prevalence of Helicobacter pylori infection

Article

Feb 2023
EUR J INTERN MED

Introduction: Whipple's disease is a rare systemic infection due to an impaired immunological response against T. whipplei in genetically predisposed individuals. Since we previously noted development of H. pylori related complications in some patients with Whipple's disease, our aim was to study the prevalence of H. pylori infection and H. pylori related disorders in Whipple's disease. Methods: Whipple's disease patients diagnosed from Jan-2002 to Dec-2021 and two controls per patient, matched for age, gender, ethnicity and year of H. pylori testing were enrolled. Results: 34 patients with Whipple's disease and 68 controls were enrolled. H. pylori infection (13/34 vs 8/68, p<0.01), H. pylori-related gastritis (p<0.01) and gastric atrophy (p = 0.01) were significantly more common in patients with Whipple's disease than controls. H. pylori infection and Whipple's disease were diagnosed synchronously in 6/13 patients, and during follow-up in the remaining 7. Interestingly, these last 7 patients were all on trimethoprim-sulfamethoxazole long-term therapy. Two patients developed H. pylori-related gastric malignancies during follow-up. No patients on doxycycline developed H. pylori infection. Conclusions: H. pylori infection and related disorders are common in patients with Whipple's disease and should always be excluded both at time of diagnosis and during follow-up. These findings should be taken into account when selecting antibiotics for Whipple's disease long-term prophylaxis.

Humoral immunogenicity of COVID-19 vaccines in patients with coeliac disease and other noncoeliac enteropathies compared to healthy controls

Article

Feb 2023
EUR J GASTROEN HEPAT

Objectives: Data are lacking on the immunogenicity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in patients affected by coeliac disease, Whipple's disease and other noncoeliac enteropathies (NCE), characterised by primary or drug-related immunosuppression. We aimed to assess humoral response to SARS-CoV-2 vaccination in these patients compared to controls. Methods: Between December 2021 and January 2022, IgG anti-SARS-CoV-2 spike protein antibodies were measured in serum samples of coeliac disease, Whipple's disease and NCE patients attending our gastroenterology outpatient clinic for follow-up, who had received their first SARS-CoV-2 vaccination dose 3-6-9 (±1) months prior. Humoral response was compared with healthy controls (vaccinated healthcare workers undergoing serological screening), matched for gender, age, and time from first vaccine dose at sample collection. Results: A total of 120 patients [107 coeliac disease; 10 Whipple's disease; 2 common-variable immunodeficiency (CVID); 1 idiopathic villous atrophy; 77 F, 42 ± 16 years] and 240 matched controls (154 F, 43 ± 14 years) were enrolled. At 3, 6 and 9 months, humoral response in coeliac patients was not impaired compared to controls. Inadequate humoral response to vaccination was significantly more common among Whipple's disease patients than controls (P < 0.001). Patients on immunosuppressive therapy had markedly lower IgG anti-SARS-CoV-2 antibody titres (median 14 vs. 520 BAU/mL, P < 0.001). As expected, patients with CVID showed no humoral response to vaccination. Conclusions: Humoral immunogenicity of SARS-CoV-2 vaccines was not reduced in coeliac disease patients compared to controls, although it was in Whipple's disease and CVID patients. Post-vaccination humoral response should be monitored in patients with Whipple's disease and chronic enteropathies on immunosuppressive therapy in order to schedule vaccine booster doses.

Tropheryma

Chapter

May 2011

Thomas Marth

Pharmacological Modeling of Gastrointestinal Disorders in Zebrafish for Drug Discovery and Development

Chapter

May 2022

Zebrafish as a pharmacological model is gaining popularity due to its similarity in both transcriptional and developmental physiology with humans. In this chapter, zebrafish as a relevant model for gastrointestinal tract (GIT) diseases including inflammatory bowel disease (IBD) and GIT cancers is outlined. Information on the relevance of zebrafish models in cancer metastasis, host-microbe interactions, and screening of new drugs is also included in this chapter. In IBD, zebrafish as a tool is used to understand both the pathogenesis and treatment outcomes such as immune suppression or disease regression through drug screening. TgBAC, a transgenic zebrafish line, has revealed two major factors which results into IBD including depletion of epigenetic repression as well as excessive production of tumor necrosis factor. The features of human IBD disease pathology are observed in chemically induced zebrafish models, which are well established and commonly used to test the new chemical entities (NCEs). In addition, zebrafish models are also used to understand IBD immunology including expression of chemokine responses which are difficult to investigate in murine models and to understand intestinal development and GIT transit. Factors such as high fertility, low maintenance, and physiological and developmental similarities in the GIT with humans make zebrafish an efficient model to explore GIT cancers. In addition, comparative genomics to humans, transparent body, and rapidly developing embryos are prominent factors for the successful use of zebrafish models in GIT cancers.KeywordsZebrafishInflammatory bowel diseaseIntestinal cancerHost-microbe interactionsPharmacological model

Whipple’s Disease

Chapter

Jan 2022

Whipple’s disease is a rare, treatable, multisystem bacterial infection with protean manifestations. The causative bacilliform bacterium, Tropheryma whipplei, was once considered rare, but recent evidence demonstrates that it is actually a common commensal. Exposure to the pathogen and asymptomatic gut carriage is frequent; progression to a disease state is largely dependent on dysfunctional host immune responses. Neurological involvement occurs in up to 50% of cases. As illustrated by two clinical cases with video, certain findings can be suggestive of Whipple’s disease of the central nervous system (CNS). In particular, pendular vergence nystagmus, oculomasticatory myorhythmia, and oculofacial-skeletal myorhythmia are pathognomonic. Nearly all patients also exhibit a supranuclear gaze palsy. Diagnosing CNS Whipple’s disease remains exceedingly difficult and relies predominantly on identification of the bacterium within cerebrospinal fluid, usually through polymerase chain reaction. In this chapter we review recent updates in the epidemiology, pathophysiology, diagnosis, and treatment of Whipple’s disease and propose a treatment algorithm based on the most recent clinical evidence.

Selective Induction of Cell Death in Human M1 Macrophages by Smac Mimetics Is Mediated by cIAP-2 and RIPK-1/3 through the Activation of mTORC

Article

Sep 2021

Inflammatory macrophages have been implicated in many diseases, including rheumatoid arthritis and inflammatory bowel disease. Therefore, targeting macrophage function and activation may represent a potential strategy to treat macrophage-associated diseases. We have previously shown that IFN-γ-induced differentiation of human M0 macrophages toward proinflammatory M1 state rendered them highly susceptible to the cytocidal effects of second mitochondria-derived activator of caspases mimetics (SMs), antagonist of the inhibitors of apoptosis proteins (IAPs), whereas M0 and anti-inflammatory M2c macrophages were resistant. In this study, we investigated the mechanism governing SM-induced cell death during differentiation into M1 macrophages and in polarized M1 macrophages. IFN-γ stimulation conferred on M0 macrophages the sensitivity to SM-induced cell death through the Jak/STAT, IFN regulatory factor-1, and mammalian target of rapamycin complex-1 (mTORC-1)/ribosomal protein S6 kinase pathways. Interestingly, mTORC-1 regulated SM-induced cell death independent of M1 differentiation. In contrast, SM-induced cell death in polarized M1 macrophages is regulated by the mTORC-2 pathway. Moreover, SM-induced cell death is regulated by cellular IAP (cIAP)-2, receptor-interacting protein kinase (RIPK)-1, and RIPK-3 degradation through mTORC activation during differentiation into M1 macrophages and in polarized M1 macrophages. In contrast to cancer cell lines, SM-induced cell death in M1 macrophages is independent of endogenously produced TNF-α, as well as the NF-κB pathway. Collectively, selective induction of cell death in human M1 macrophages by SMs may be mediated by cIAP-2, RIPK-1, and RIPK-3 degradation through mTORC activation. Moreover, blocking cIAP-1/2, mTORC, or IFN regulatory factor-1 may represent a promising therapeutic strategy to control M1-associated diseases.

CNS Whipple’s Disease

Chapter

Jan 2021

Whipple’s Disease (WD) was first described by George H. Whipple in 1907. Classic Whipple disease (CWD) is a systemic chronic infection by Tropheryma whipplei (T. whipplei) that can involve various organ systems such as gastrointestinal tract, joints, and central nervous system (CNS). Central nervous system Whipple’s disease (CNS- WD) can be a part of the classical WD, a recurrent phenomenon or an isolated disease. It encompasses a wide array of clinical manifestations depending on the anatomic region affected by the pathological process. Diagnosis is made by polymerase chain reaction testing. It is vital to implement an aggressive mode of treatment to reduce the chances of complications like cognitive impairment, or disease recurrence, even many years later.

Whipple's Disease

Chapter

Jan 2015

ERKRANKUNGEN DER VERDAUUNGSORGANE

Chapter

Jan 2020

In-Silico Proteomic Exploratory Quest: Crafting T-Cell Epitope Vaccine Against Whipple’s Disease

Article

Full-text available

May 2020
INT J PEPT RES THER

Whipple’s disease is one of the rare maladies in terms of spread but very fatal one as it is linked with many disorders (like Gastroenteritis, Endocarditis etc.). Also, current regimens include less effective drugs which require long duration follows up. This exploratory study was conducted to commence the investigation for crafting multi target epitope vaccine against its bacterial pathogen Tropheryma whipplei. The modern bioinformatics tools like VaxiJen, NETMHCII PAN 3.2, ALLERGEN-FP, PATCH-DOCK, TOXIC-PRED, MHCPRED and IEDB were deployed, which makes the study more intensive in analyzing proteome of T. whipplei as these methods are based on robust result generating statistical algorithms ANN, HMM, and ML. This Immuno-Informatics approach leads us in the prediction of two epitopes: VLMVSAFPL and IRYLAALHL interacting with 4 and 6 HLA DRB1 alleles of MHC Class II respectively. VLMVSAFPL epitope is a part of DNA-directed RNA polymerase subunit beta, and IRYLAALHL epitope is a part of membranous protein insertase YidC of this bacterium. Molecular-Docking and Molecular-Simulation analysis yields the perfect interaction based on Atomic contact energy, binding scores along with RMSD values (0 to 1.5 Ǻ) in selection zone. The IEDB (Immune epitope database) population coverage analysis exhibits satisfactory relevance with respect to world population.

Recent advances in understanding inherited deficiencies in immunity to infections

Article

Full-text available

Apr 2020

The immune system is central to our interactions with the world in which we live and importantly dictates our response to potential allergens, toxins, and pathogens to which we are constantly exposed. Understanding the mechanisms that underlie protective host immune responses against microbial pathogens is vital for the development of improved treatment and vaccination strategies against infections. To that end, inherited immunodeficiencies that manifest with susceptibility to bacterial, viral, and/or fungal infections have provided fundamental insights into the indispensable contribution of key immune pathways in host defense against various pathogens. In this mini-review, we summarize the findings from a series of recent publications in which inherited immunodeficiencies have helped illuminate the interplay of human immunity and resistance to infection.

CNS Involvement in Tropheryma whipplei Infection

Chapter

Jan 2020

Emmanuèle Lechapt‐Zalcman

Whipple disease (WD) is a rare systemic infection that is fatal without treatment. Gastrointestinal signs and arthralgia are prominent, but CNS involvement is also frequent and has a bad prognosis. Neurological effects are varied, and include dementia, psychiatric changes, ophthalmoplegia, myoclonus, ataxia, and hypothalamic symptoms. Diagnosis is based on biopsy; the gold standard used to be periodic acid‐Schiff (PAS) staining of duodenal biopsy, but has now been replaced by polymerase chain reaction (PCR) to detect Tropheryma whipplei. Rarely, WD may be confined to the brain (primary isolated encephalitis or relapse of classic WD) and be extremely difficult to recognize. Antimicrobial treatment can be successful, but may be complicated by immune reconstitution inflammatory syndrome (IRIS).

Tropheryma Whipplei Agent of Self-Limiting Infections and Whipple’s Disease

Chapter

Jan 2019

Verena Moos

Uma Breve História do Dia Mundial do Rim no Brasil

Article

Full-text available

Aug 2018
Boletim Acad Nac Med

Chronic Infections of the Small Intestine

Chapter

Nov 2015

The advent of molecular genetic techniques and successful cell culture of the organism towards the end of the 20th century substantially accelerated the understanding of the causative organism, Tropheryma whipplei, and by extension, the underlying clinical condition. Whipple's disease usually is diagnosed at an advanced stage and presents with a variety of clinical manifestations. In classic Whipple's disease small-bowel biopsy usually establishes the diagnosis. The effectiveness of antimicrobials, especially poorly absorbed antibiotics, as the mainstay for treating tropical sprue establishes the central role of enteric bacteria/bacterial overgrowth in the condition. Mycotic infections usually arise from disseminated pulmonary infections and occur usually, but not exclusively, in immunocompromised patients. The differential diagnosis for all mycotic infections of the small intestine is similar and includes other mycotic infections, Crohn's disease, tuberculosis (TB) enteritis, disseminated mycobacterium avium complex (MAC), bacterial typhlitis, intestinal ischemia and carcinoma.

Non-Neoplastic Histiocytic and Dendritic Cell Disorders in Lymph Nodes

Article

Nov 2017
SEMIN DIAGN PATHOL

Benign and malignant proliferations of histiocytes and dendritic cells may be encountered in lymph nodes. Reactive histiocytic and dendritic cell infiltrates occur in response to diverse stimuli and in addition to causing lymphadenopathy, may be present unexpectedly in lymph nodes excised for other indications. This review summarizes the pathogenesis and histopathological features of the various non-neoplastic histiocytic and dendritic cell infiltrates that can occur in lymph nodes.

Whipple's disease

Chapter

Jan 2013

Whipple's disease is a rare multi-system bacterial infection caused by the bacilliform bacterium, Tropheryma whipplei. Neurological involvement occurs in up to 50 % of cases. As illustrated by two clinical cases, certain findings can be suggestive of Whipple's disease of the central nervous system (CNS). In particular, pendular vergence nystagmus, oculomasticatory myorhythmia and oculo-facioskeletal myorhythmia are pathognomonic of the condition. Nearly all patients also exhibit a supranuclear gaze palsy. Diagnosing the condition remains exceedingly difficult and often relies on identification of the bacterium within cerebrospinal fluid, usually through polymerase chain reaction. In this publication we propose new diagnostic criteria for Whipple's disease of the CNS based on both clinical findings and identification of the bacterium. Imaging of CNS Whipple's disease has evolved and in particular magnetic resonance spectroscopy and diffusion-weighted MRI have an important diagnostic role and may have a role in monitoring response to treatment. There are no agreed treatment schedules for Whipple's disease of the CNS but in addition to new diagnostic criteria, we also propose a treatment algorithm based on the most recent clinical evidence. © Springer Science+Business Media New York 2013. All rights reserved.

Protein losing enteropathy: comprehensive review of the mechanistic association with clinical and subclinical disease states

Article

Full-text available

Jul 2017

Protein losing enteropathy (PLE) has been associated with more than 60 different conditions, including nearly all gastrointestinal diseases (Crohn’s disease, celiac, Whipple’s, intestinal infections, and so on) and a large number of non-gut conditions (cardiac and liver disease, lupus, sarcoidosis, and so on). This review presents the first attempt to quantitatively understand the magnitude of the PLE in relation to the associated pathology for three different disease categories: 1) increased lymphatic pressure (e.g., lymphangiectasis); 2) diseases with mucosal erosions (e.g., Crohn’s disease); and 3) diseases without mucosal erosions (e.g., celiac disease). The PLE with lymphangiectasis results from rupture of the mucosal lymphatics, with retrograde drainage of systemic lymph into the intestinal lumen with the resultant loss of CD4 T cells, which is diagnostic. Mucosal erosion PLE results from macroscopic breakdown of the mucosal barrier, with the epithelial capillaries becoming the rate-limiting factor in albumin loss. The equation derived to describe the relationship between the reduction in serum albumin (CP) and PLE indicates that gastrointestinal albumin clearance must increase by at least 17 times normal to reduce the CP by half. The strengths and limitations of the two quantitative measures of PLE (⁵¹Cr-albumin or α1-antitrypsin [αAT] clearance) are reviewed. αAT provides a simple quantitative diagnostic test that is probably underused clinically. The strong, unexplained correlation between minor decreases in CP and subsequent mortality in seemingly healthy individuals raises the question of whether subclinical PLE could account for the decreased CP and, if so, could the mechanism responsible for PLE play a role in the increased mortality? A large-scale study correlating αAT clearance with serum albumin concentrations will be required in order to determine the role of PLE in the regulation of the serum albumin concentration of seemingly healthy subjects.

Tropheryma whipplei Glycosylation in the Pathophysiologic Profile of Whipple's Disease

Article

Full-text available

Mar 2009

Tropheryma whipplei is a bacterium commonly found in people with Whipple's disease, a rare systemic chronic infection. In the present study, we hypothesized that bacterium glycosylation may impair the immune response. Bacterial extracts were analyzed by glycostaining, and reactive proteins, identified by matrix-assisted laser desorption/ionization-time-of-flight (MALDI-TOF) mass spectometry, were purified to generate antibodies that could be used in immunofluorescence studies. The reactivity of serum samples obtained from patients and asymptomatic carriers was tested against native or deglycosylated bacteria, for which the fate in macrophages was also investigated. To our knowledge, we evidenced, for the first time in T. whipplei, a 110-kDa glycoprotein containing sialic acid. This protein, identified as an Wnt1-inducible signaling pathway (WiSP) protein, is associated with periodic acid-Schiff (PAS) staining in infected intramacrophage biofilm. Consistent with the lack of enzymes required for the glycosylation pathway in this bacterium, the glycoproteins disappear during in vitro axenic subcultures, whereas human transcriptome analysis reveals the up-regulation of corresponding genes within infected macrophages. Proteic antigens are not recognized by the serum samples obtained from patients compared with those obtained from nonsick carriers, and T. whipplei that exhibits a low glycosylation profile does not efficiently multiply in macrophages in vitro. T. whipplei glycosylation is likely to impair antibody-mediated immune recognition in patients. Such an intracellular antigen masking system in bacteria has not previously been described.

Identification of the Uncultured Bacillus of Whipple's Disease

Article

Full-text available

Aug 1992

Whipple's disease is a systemic disorder known for 85 years to be associated with an uncultured, and therefore unidentified, bacillus. We used a molecular genetic approach to identify this organism. The bacterial 16S ribosomal RNA (rRNA) sequence was amplified directly from tissues of five unrelated patients with Whipple's disease by means of the polymerase chain reaction, first with broad-range primers and then with specific primers. We determined and analyzed the nucleotide sequence of the amplification products. A unique 1321-base bacterial 16S rRNA sequence was amplified from duodenal tissue of one patient. This sequence indicated the presence of a previously uncharacterized organism. We then detected this sequence in tissues from all 5 patients with Whipple's disease, but in none of those from 10 patients without the disorder. According to phylogenetic analysis, this bacterium is a gram-positive actinomycete that is not closely related to any known genus. We have identified the uncultured bacillus associated with Whipple's disease. The phylogenetic relations of this bacterium, its distinct morphologic characteristics, and the unusual features of the disease are sufficient grounds for naming this bacillus Tropheryma whippelii gen. nov. sp. nov. Our findings also provide a basis for a specific diagnostic test for this organism.

Deactivation of Macrophages with Interleukin‐4 Is the Key to the Isolation of Tropheryma whippelii

Article

Full-text available

Oct 1997

Whipple's disease is a systemic illness caused by a specific agent. Despite recognition of bacteria in lesions, efforts to isolate the causative agent remained futile. A novel strategy was devised to culture Whipple bacilli in deactivated mononuclear phagocytes. Infected tissue was inoculated into human phagocytes deactivated with interleukin (IL)-4, IL-10, and dexamethasone. Within 8–10 days, diastase-resistant periodic acid-Schiff-positive inclusions appeared, corresponding to intact and degenerating bacteria shown to be Tropheryma whippelii by electron microscopy and molecular analyses. T. whippelii was passaged several times in deactivated monocytes and a monoblastic cell line. Time-kinetics growth studies and comparative polymerase chain reaction analysis documented multiplication of T. whippelii in deactivated macrophages. Complementary studies showed that IL-4 rendered phagocytes permissive for T. whippelii, a strong indication that host factors contribute to the pathogenesis of Whipple's disease. The propagation of T. whippelii will permit microbiologic, immunologic, seroepidemiologic, and therapeutic studies of this pathogen.

Environmental Occurrence of the Whipple’s Disease Bacterium (Tropheryma whippelii)

Article

Full-text available

Mar 1998

Whipple's disease is a systemic disorder in which a gram-positive rod-shaped bacterium is constantly present in infected tissues. After numerous unsuccessful attempts to culture this bacterium, it was eventually characterized by 16S rRNA gene analysis to be a member of the actinomycetes. The name Tropheryma whippelii was proposed. Until now, the bacterium has only been found in infected human tissues, but there is no evidence for human-to-human transmission. Here we report the detection of DNA specific for the Whipple's disease bacterium in 25 of 38 wastewater samples from five different sewage treatment plants in the area of Heidelberg, Germany. These findings provide the first evidence that T. whippelii occurs in the environment, within a polymicrobial community. This is in accordance with the phylogenetic relationship of this bacterium as well as with known epidemiological aspects of Whipple's disease. Our data argue for an environmental source for infection with the Whipple's disease bacterium.

Increased immunoglobulin G production by short term cultured duodenal biopsy samples from HIV infected patients

Article

Full-text available

Mar 1998

Secretory immunity is a major defence mechanism against infections at mucosal surfaces which are common in HIV infected patients. To analyse intestinal immunoglobulin production in HIV infection in comparison with that in saliva and serum. Immunoglobulin G (IgG), A (IgA), and M (IgM) concentrations were determined in supernatants of short term cultured duodenal biopsy samples, serum, and saliva from HIV infected patients (n = 28) and controls (n = 14) by radial immunodiffusion. IgG was increased in the supernatants of short term cultured biopsy samples and saliva from HIV infected patients compared with controls (p < 0.01), but IgA and IgM levels were normal. In contrast, both IgG and IgA concentrations in serum were higher in HIV infected patients than in controls (p < 0.002). No correlation was found between IgA produced by duodenal biopsy specimens and serum IgA. Abnormalities in mucosal immunoglobulin production in HIV infection were surprisingly small, indicating that specific secretory immunity rather than quantitative immunoglobulin production may be impaired. However, increased production of IgG could contribute to mucosal inflammation by complement activation. Our findings of normal mucosal IgA production and the lack of correlation between serum and mucosal IgA argues against an intestinal origin for the increased serum IgA levels in HIV infected patients.

Control of TH2 polarization by the chemokine monocyte chemoattractant protein-1

Article

Full-text available

Apr 2000

Activated T lymphocytes differentiate into effector cells tailored to meet disparate challenges to host integrity. For example, type 1 and type 2 helper (T(H)1 and T(H)2) cells secrete cytokines that enhance cell-mediated and humoral immunity, respectively. The chemokine monocyte chemoattractant protein-1 (MCP-1) can stimulate interleukin-4 production and its overexpression is associated with defects in cell-mediated immunity, indicating that it might be involved in T(H)2 polarization. Here we show that MCP-1-deficient mice are unable to mount T(H)2 responses. Lymph node cells from immunized MCP-1(-/-) mice synthesize extremely low levels of interleukin-4, interleukin-5 and interleukin-10, but normal amounts of interferon-gamma and interleukin-2. Consequently, these mice do not accomplish the immunoglobulin subclass switch that is characteristic of T(H)2 responses and are resistant to Leishmania major. These effects are direct rather than due to abnormal cell migration, because the trafficking of naive T cells is undisturbed in MCP-1(-/-) mice despite the presence of MCP-1-expressing cells in secondary lymphoid organs of wild-type mice. Thus, MCP-1 influences both innate immunity, through effects on monocytes, and adaptive immunity, through control of T helper cell polarization.

Infection of Human Macrophages and Dendritic Cells with Mycobacterium tuberculosis Induces a Differential Cytokine Gene Expression That Modulates T Cell Response

Article

Full-text available

Jul 2001

Macrophages and dendritic cells (DC) play an essential role in the initiation and maintenance of immune response to pathogens. To analyze early interactions between Mycobacterium tuberculosis (Mtb) and immune cells, human peripheral blood monocyte-derived macrophages (MDM) and monocyte-derived dendritic cells (MDDC) were infected with Mtb. Both cells were found to internalize the mycobacteria, resulting in the activation of MDM and maturation of MDDC as reflected by enhanced expression of several surface Ags. After Mtb infection, the proinflammatory cytokines TNF-alpha, IL-1, and IL-6 were secreted mainly by MDM. As regards the production of IFN-gamma-inducing cytokines, IL-12 and IFN-alpha, was seen almost exclusively from infected MDDC, while IL-18 was secreted preferentially by macrophages. Moreover, Mtb-infected MDM also produce the immunosuppressive cytokine IL-10. Because IL-10 is a potent inhibitor of IL-12 synthesis from activated human mononuclear cells, we assessed the inhibitory potential of this cytokine using soluble IL-10R. Neutralization of IL-10 restored IL-12 secretion from Mtb-infected MDM. In line with these findings, supernatants from Mtb-infected MDDC induced IFN-gamma production by T cells and enhanced IL-18R expression, whereas supernatants from MDM failed to do that. Neutralization of IFN-alpha, IL-12, and IL-18 activity in Mtb-infected MDDC supernatants by specific Abs suggested that IL-12 and, to a lesser extent, IFN-alpha and IL-18 play a significant role in enhancing IFN-gamma synthesis by T cells. During Mtb infection, macrophages and DC may have different roles: macrophages secrete proinflammatory cytokines and induce granulomatous inflammatory response, whereas DC are primarily involved in inducing antimycobacterial T cell immune response.

Survival of Tropheryma whipplei, the Agent of Whipple's Disease, Requires Phagosome Acidification

Article

Full-text available

Mar 2002
INFECT IMMUN

Tropheryma whipplei was established as the agent of Whipple's disease in 2000, but the mechanisms by which it survives within host cells are still unknown. We show here that T. whipplei survives within HeLa cells by controlling the biogenesis of its phagosome. Indeed, T. whipplei colocalized with lysosome-associated membrane protein 1, a membrane marker of late endosomal and lysosomal compartments, but not with cathepsin D, a lysosomal hydrolase. This defect in phagosome maturation is specific to live organisms, since heat-killed bacilli colocalized with cathepsin D. In addition, T. whipplei survived within HeLa cells by adapting to acidic pH. The vacuoles containing T. whipplei were acidic (pH 4.7 ± 0.3) and acquired vacuolar ATPase, responsible for the acidic pH of late phagosomes. The treatment of HeLa cells with pH-neutralizing reagents, such as ammonium chloride, N-ethylmaleimide, bafilomycin A1, and chloroquine, increased the intravacuolar pH and promoted the killing of T. whipplei. The ability of T. whipplei to survive in an acidic environment and to interfere with phagosome-lysosome fusion is likely critical for its prolonged persistence in host cells during the course of Whipple's disease. Our results suggest that manipulating the intravacuolar pH may provide a new approach for the treatment of Whipple's disease.

Repeatability of flow cytometric and classical measurement of phagocytosis and respiratory burst in bovine polymorphonuclear leukocytes

Article

Full-text available

Feb 2004
VET IMMUNOL IMMUNOP

Five methods for measurement of phagocytosis and respiratory burst activity of bovine blood polymorphonuclear leukocytes (PMNs) were evaluated. Eight cows were repeatedly sampled over a two week period and parallel samples tested in all five assays to assess the repeatability and stability of the methods. In the flow cytometric phagocytosis assay, ingestion of fluorescein labeled bacteria was measured, and in the flow cytometric assay for respiratory burst, oxidation of a dye by reactive oxygen species was recorded. In the classical assays, bactericidal effect on opsonized, live bacteria was quantified by the conversion of an indicator substance, superoxide anion production was assayed by the reduction of cytochrome c, whereas myeloperoxidase activity was determined with a radioactive iodination assay. The results showed that the Phagotest, Bursttest, cytochrome c and iodination assays gave repeatable results when samples were run in the same setup on the same day. Although day-to-day variability was significant in all assays, the described methods comprise a panel of useful tests for the evaluation of phagocytosis and respiratory burst activity in bovine PMNs. The flow cytometric methods represent a convenient alternative to the classical methods for measurement of phagocytosis and respiratory burst in bovine blood PMNs.

Reduced Peripheral and Mucosal Tropheryma whipplei-Specific Th1 Response in Patients with Whipple's Disease

Article

Full-text available

Sep 2006

Whipple's disease is a rare infectious disorder caused by Tropheryma whipplei. Major symptoms are arthropathy, weight loss, and diarrhea, but the CNS and other organs may be affected, too. The incidence of Whipple's disease is very low despite the ubiquitous presence of T. whipplei in the environment. Therefore, it has been suggested that host factors indicated by immune deficiencies are responsible for the development of Whipple's disease. However, T. whipplei-specific T cell responses could not be studied until now, because cultivation of the bacteria was established only recently. Thus, the availability of T. whipplei Twist-Marseille(T) has enabled the first analysis of T. whipplei-specific reactivity of CD4(+) T cells. A robust T. whipplei-specific CD4(+) Th1 reactivity and activation (expression of CD154) was detected in peripheral and duodenal lymphocytes of all healthy (16 young, 27 age-matched, 11 triathletes) and disease controls (17 patients with tuberculosis) tested. However, 32 Whipple's disease patients showed reduced or absent T. whipplei-specific Th1 responses, whereas their capacity to react to other common Ags like tetanus toxoid, tuberculin, actinomycetes, Giardia lamblia, or CMV was not reduced compared with controls. Hence, we conclude that an insufficient T. whipplei-specific Th1 response may be responsible for an impaired immunological clearance of T. whipplei in Whipple's disease patients and may contribute to the fatal natural course of the disease.

Tropheryma whipplei in the Environment: Survey of Sewage Plant Influxes and Sewage Plant Workers

Article

Full-text available

Jan 2007
APPL ENVIRON MICROB

We studied the prevalence of Tropheryma whipplei in influxes to 46 sewage treatment plants and in stool, mouthwash fluids, and dental plaques of 64 healthy workers in those facilities and 146 disease control patients. T. whipplei was found in sewage water, in stool of healthy individuals, and significantly more often in stool of workers exposed to sewage water.

Prevalence of Asymptomatic Tropheryma whipplei Carriage among Humans and Nonhuman Primates

Article

Full-text available

Mar 2008

The reservoir of the agent of Whipple disease is unknown. Asymptomatic carriage of Tropheryma whipplei in human stool and saliva is controversial. Stools and saliva specimens from 231 workers at a sewage treatment facility and from 10 patients with Whipple disease, stool specimens from 102 healthy people, and stool specimens from 127 monkeys or apes were tested for T. whipplei DNA by a quantitative real-time polymerase chain reaction with probe detection. Genotyping and culture of T. whipplei-positive samples were performed. Asymptomatic carriage in stool was found in humans (ranging from a prevalence of 4% in the control group to 12% among a subgroup of sewer workers) but not in monkeys and apes. The T. whipplei load in stool was significantly lower in carriers than in patients with Whipple disease (P < .001). There was a significant prevalence gradient associated with employment responsibilities at the sewage treatment facility: workers who cleaned the underground portion of the sewers were more likely than other workers to carry T. whipplei in stool. Seven of 9 sewer workers tested positive 8 months later. Patients with Whipple disease were significantly more likely to have T. whipplei-positive saliva specimens (P = .005) and had a significantly greater T. whipplei load in saliva (P = .015), compared with asymptomatic stool carriers from the sewage facility. All non-stool carriers had T. whipplei-negative saliva specimens. T. whipplei strains were heterogeneic among sewer workers but identical within individual workers. Chronic asymptomatic carriage of T. whipplei occurs in humans. Bacterial loads are lower in asymptomatic carriers, and the prevalence of carriage increases with exposure to sewage.

Patients with psoriatic arthritis have an increased number of lymphocytes in the duodenal mucosa in comparison with patients with psoriasis vulgaris

Conference Paper

Jul 2007

Objective. To determine if there is evidence of inflammation in the duodenal mucosa in patients with psoriatic arthritis (PsA) and to compare the results with those in patients with psoriasis vulgaris (PsV). Methods. Nineteen consecutive patients with PsA underwent gastroduodenoscopy, and biopsy specimens were taken from the duodenal and gastric mucosa. In addition to routine processing, the duodenal mucosal specimens were stained for CD3+, CD8+ and CD4+ T lymphocytes, tryptase-positive mast cells, and EG2-positive eosinophil granulocytes. The results were compared with those in duodenal mucosal specimens from patients with PsV and patients with irritable bowel syndrome. Results. Compared with PsV patients (without antibodies against gliadin), patients with PsA had a highly significant increase in intraepithelial CD3+ and CD8+ lymphocytes and also in CD4+ lymphocytes in the lamina propria in the villi. The lymphocyte increase was not related to presence of IgA antibodies against gliadin, endomysium, or transglutaminase, or to concomitant gastritis. Patients with PsA and PsV showed a pronounced increase in mast cells and eosinophil granulocytes. Conclusion. The increased lymphocyte infiltration in the duodenal mucosa in PsA, but not in PsV, might indicate different pathogenetic mechanisms in these psoriasis variants.

Macrophage activation and polarization

Article

Jan 2008

Macrophages are widely distributed immune system cells that play an indispensable role in homeostasis and defense. They can be phenotypically polarized by the microenvironment to mount specific functional programs. Polarized macrophages can be broadly classified in two main groups: classically activated macrophages (or M1), whose prototypical activating stimuli are IFNgamma and LPS, and alternatively activated macrophages (or M2), further subdivided in M2a (after exposure to IL-4 or IL-13), M2b (immune complexes in combination with IL-1beta or LPS) and M2c (IL-10, TGFbeta or glucocorticoids). M1 exhibit potent microbicidal properties and promote strong IL-12-mediated Th1 responses, whilst M2 support Th2-associated effector functions. Beyond infection M2 polarized macrophages play a role in resolution of inflammation through high endocytic clearance capacities and trophic factor synthesis, accompanied by reduced pro-inflammatory cytokine secretion. Similar functions are also exerted by tumor-associated macrophages (TAM), which also display an alternative-like activation phenotype and play a detrimental pro-tumoral role. Here we review the main functions of polarized macrophages and discuss the perspectives of this field.

Intraepithelial leukocytes of the intestinal mucosa in normal man and in Whipple's disease: A light- and electron-microscopic study

Article

Jan 1982

Intraepithelial lymphocytes (IEL) of the intestinal mucosa of normal man and of patients with Whipple's disease were studied by light microscopy of 1-m-thick sections, and by electron microscopy of thin sections. IEL in normal human intestine tend to be elongated in outline, have few cytoplasmic organelles, have compact nuclei, and are unattached to epithelial cells. IEL in Whipple's disease are more likely to be activated in appearance, ie, to be larger and to contain more cytoplasmic organelles than IEL of normal intestine. The number of IEL/100 intestinal epithelial cells is similar in normal man and in patients with Whipple's disease. Other intraepithelial (IE) cells found in normal intestine include eosinophils and mast cells, and we note for the first time the presence of IE macrophages. There are no globule leukocytes in the intestine of normal man or of patients with Whipple's disease. Other IE cells found in the intestine in Whipple's disease include eosinophils, polymorphonuclear (PMN) leukocytes, and macrophages in untreated disease and intraepithelial macrophages in treated disease. These IE cells may be involved in the acute and chronic immune responses of the intestine.

Alternatively activated macrophages actively inhibit proliferation of peripheral blood lymphocytes and CD4+ T cells in vitro

Article

Dec 1997

We compared the immunological functions of interferon-gamma (IFN-gamma)-induced, classically activated macrophages (caM phi) and of interleukin-4 (IL-4)- and glucocorticoid-induced, alternatively activated macrophages (aaM phi) in a human co-culture system in vitro. Proliferation of peripheral blood leucocytes (PBL) or CD4+ T cells mediated by optimal doses of phytohaemagglutinin (PHA) or concanavalin A (Con A) was only marginally influenced by caM phi, but was strongly inhibited by aaM phi. The degree of lymphocyte proliferation sustained in the presence of caM phi was gradually reduced in a dose-dependent fashion by the addition of aaM phi. Flow cytometric analysis revealed that expression of costimulatory molecules such as CD11a, CD40, CD54, CD58, CD80 and CD86 did not vary significantly between caM phi and aaM phi and was low for CD58, CD80 and CD86. As shown by reverse transcriptase-polymerase chain reaction (RT-PCR) analysis, IL-10 was expressed in caM phi, aaM phi and control macrophages; the level of expression of IL-10 was slightly enhanced in aaM phi. Neither neutralizing anti-IL-10 antibodies, indomethacin nor NG-monomethyl-L-arginine (NMMLA) was able to reverse aaM phi-mediated inhibition of lymphocyte proliferation. Of several agents interfering with various second messenger pathways, cAMP and the Ca(2+)-ionophore A23187 inhibited differentiation of cultured human monocytes into phenotypically mature aaM phi expressing MS-1 high molecular weight protein (MS-1-HMWP) and RM 3/1 antigen, and prevented the suppressive action of aaM phi on lymphocyte proliferation. In conclusion, these results who that aaM phi actively inhibit mitogen-mediated proliferation of PBL and CD4+ T cells independently of the expression of costimulatory molecules and of IL-10, NO or prostaglandin synthesis, and that inhibition of phenotypic differentiation of aaM phi is paralleled by a lack of functional maturation. Thus, fully matured aaM phi may be functional in down-regulating CD4+ T-cell-mediated immune reactions by an as yet unknown mechanism.

Whipple GH. A hitherto undescribed disease characterized anatomically by deposits of fat and fatty acids in the intestinal and mesenteric lymphatic tissues

Article

Jan 1907
Bull Johns Hopkins Hosp

George Hoyt WHIPPLE

Ho, V.W. & Sly, L.M. Derivation and characterization of murine alternatively activated (M2) macrophages. Methods Mol. Biol. 531, 173-185

Article

Feb 2009
Meth Mol Biol

Diversity in macrophage responsiveness to inflammatory stimuli has resulted in the description of a new paradigm wherein macrophages are referred to as polarized into one of two distinct phenotypes, classically activated (M1) macrophages and alternatively activated (M2) macrophages. Classically activated, M1 or "killer" macrophages are thought to play a critical role in destroying foreign organisms and tumor cells, while alternatively activated M2 or "healer" macrophages are thought to be important in debris scavenging, wound healing, and angiogenesis. M2 macrophages may also play key roles in chronic infections, tumorigenesis, and tumor metastasis. It is therefore important to establish models of M1 and M2 polarized macrophages to study their characteristics and amenability to manipulation. M1 macrophages are typically derived from myeloid progenitors with murine macrophage-colony-stimulating factor (M-CSF, also known as CSF-1), while M2 macrophages are thought to be derived from mature M1 macrophages by treatment with interleukin-4 (IL-4) or IL-13. M2 macrophages can also be isolated from SH2-containing inositol 5'-phosphatase (SHIP)-/- mice by harvesting macrophages from peritoneal lavage fluids or they can be derived from SHIP-/- bone marrow aspirate cells with addition of 5% human serum. Upon stimulation with lipopolysaccharide (LPS), M1 macrophages produce high levels of proinflammatory cytokines, low levels of anti-inflammatory cytokines, and high levels of inducible nitric oxide synthase (iNOS), which leads to nitric oxide (NO) production. M2 macrophages, on the other hand, express high levels of M2 markers Ym1 and arginase I (ArgI) and, upon stimulation with LPS, produce relatively lower levels of proinflammatory cytokines and NO and higher levels of anti-inflammatory cytokines. In this chapter, we describe methods used in our laboratory to generate and characterize alternatively activated (M2) macrophages.

Impaired bacterial degradation by monocytes and macrophages from a patient with Whipple's disease

Article

Dec 1985
GASTROENTEROLOGY

A patient with Whipple's disease is described, and multiparameter flow cytometric examinations of several of the patient's phagocyte functions 3 and 9 mo after the start of oxytetracycline therapy are reported. Almost no intracellular degradation of Escherichia coli or Streptococcus pyogenes proteins and DNA occurred after ingestion by the patient's monocytes and macrophages. In addition, only minor digestion of phagocytized zymosan particles was detected. The mononuclear intracellular degradation was equally impaired 3 and 9 mo after the start of therapy. The monocyte and macrophage phagocytosis and intracellular killing, and all granulocyte phagocyte functions tested, were normal. The impaired mononuclear degradation of ingested material that was measured is consistent with the accumulation of periodic acid-Schiff-positive bacterial degradation products seen in macrophages of affected tissues in vivo, and suggests a key role of macrophage dysfunction in the pathogenesis of Whipple's disease.

[Whipple's disease]

Article

Sep 1985
J Norweg Med Assoc

Whipple's Disease Demonstration of a Persisting Monocyte and Macrophage Dysfunction

Article

Jul 1988

A patient with Whipple's disease has been followed up for 4 years. Primary involvement was limited to the small intestines, and accumulation of periodic acid-Schiff-positive material, containing typical more or less intact bacillary bodies, was demonstrated within macrophages of affected tissue. After initial oxytetracycline treatment and clinical remission, the patient relapsed, with multiorgan affections. The antibiotic regimen was changed to chloramphenicol, followed by continuous trimethoprim-sulfamethoxazole. Flow cytometric studies showed persisting impairment of monocyte and macrophage intracellular degradation of bacteria during all the 4 years tested. After relapse, reduced activity of several brush border enzymes was demonstrated in distal duodenal biopsy specimens. After 17 months of continuous trimethoprim-sulfamethoxazole therapy complete clinical remission, regression of histopathologic abnormalities, and restoration of duodenal enzyme activities had occurred. The results demonstrate a persisting dysfunction of mononuclear phagocytes from a patient with Whipple's disease, suggesting a primary abnormality of cell-mediated immunity which may promote the susceptibility to the causative bacillus.

Active induction of unresponsiveness (tolerance) to DNFB by in vivo ultraviolet-exposed epidermal cells is dependent upon infiltrating class II MHC+ CD11bbright monocytic/macrophagic cells

Article

Jan 1995

Contact sensitizers, tumor Ags, and microbial pathogens presented through UV-exposed skin result in T cell-mediated immune tolerance (inhibition of acquisition of responsiveness) to these normally potent immunogens. The APC in UV-exposed skin that delivers the signals inducing tolerance remains highly controversial and is the subject of this study. Application of the contact sensitizer, 2,4-dinitro-1-fluorobenzene (DNFB), to C3H/HeN mice immediately after a single dose of 72 mJ/cm2 UVB (138 mJ/cm2 total UVB) resulted in unresponsiveness to an initial DNFB ear challenge, but failed to block the development of responsiveness after a second sensitization on previously unexposed skin (no tolerance). A state of tolerance could only be achieved if a delay of 72 h was allowed to elapse between the UV exposure and the initial sensitization. Epidermal cell suspensions (EC) were prepared from the skin of normal controls and from skin exposed to the same UV dose 3 days before (UV-EC). Three days after in vivo UV exposure, Langerhans cells (CD11blow Ia+) were depleted, and CD11bbright Ia+ macrophages had appeared in the epidermis along with GR-1+ neutrophils. Intracutaneous injection of 2,4 dinitrobenzenesulfonic acid (DNBSO3)-haptenated UV-EC, but not normal controls, resulted in the induction of locally inducible Ag-specific tolerance to DNFB, indicating the presence and dominance of tolerogenic signal within in vivo-irradiated epidermis. Removal of CD11b+ and class II MHC+ cells within UV-EC showed that a CD11b+ class II MHC+ population was indeed critical for tolerance induction. In addition, tolerance induction by UV-EC was not a result of surviving, UV-exposed Langerhans cells, because haptenated 3-day cultured EC from epidermis removed 5 h after UV exposure (before leukocytic infiltration) failed to induce a tolerogenic state. In conclusion, the ability of UV-exposed skin to induce peripheral adult tolerance to a normally potent immunogen is critically dependent on inflammatory class II MHC+, CD11bbright monocytic/macrophagic cells that infiltrate UV-irradiated skin at the same time the ability to tolerize is acquired.

Impaired monocyte function in patients successfully treated for Whipple's disease

Article

Jan 1996
Acta Gastroenterol Latinoam

Peripheral blood mononuclear cells (monocytes) from patients with Whipple's disease in long-term remission were tested for their ability to handle intracellular microorganisms. Phagocytosis and lysis of Candida tropicalis by monocytes of patients (n = 12) and controls (n = 8) were quantified after 30 min of incubation. Phagocytosis was similar in both groups but intracellular killing of Candida tropicalis was significatively lower in patients (p < 0.001). We concluded that our study showed an in vitro defect in the intracellular killing function of monocytes in subjects in remission many years after diagnosis of Whipple's disease. The defective function did not seem to be related to relapse or to the susceptibility to other infections.

Nitric Oxide and Macrophage Function

Article

Feb 1997

At the interface between the innate and adaptive immune systems lies the high-output isoform of nitric oxide synthase (NOS2 or iNOS). This remarkable molecular machine requires at least 17 binding reactions to assemble a functional dimer. Sustained catalysis results from the ability of NOS2 to attach calmodulin without dependence on elevated Ca2+. Expression of NOS2 in macrophages is controlled by cytokines and microbial products, primarily by transcriptional induction. NOS2 has been documented in macrophages from human, horse, cow, goat, sheep, rat, mouse, and chicken. Human NOS2 is most readily observed in monocytes or macrophages from patients with infectious or inflammatory diseases. Sustained production of NO endows macrophages with cytostatic or cytotoxic activity against viruses, bacteria, fungi, protozoa, helminths, and tumor cells. The antimicrobial and cytotoxic actions of NO are enhanced by other macrophage products such as acid, glutathione, cysteine, hydrogen peroxide, or superoxide. Although the high-output NO pathway probably evolved to protect the host from infection, suppressive effects on lymphocyte proliferation and damage to other normal host cells confer upon NOS2 the same protective/destructive duality inherent in every other major component of the immune response.

Defects of monocyte interleukin 12 production and humoral immunity in Whipple's disease

Article

Aug 1997
GASTROENTEROLOGY

Whipple's disease (WD) is a systemic infection in which the causative bacteria typically accumulate within macrophages. The aim of this study was to test whether this macrophage dysfunction is the cause or result of previously shown T-cell defects. In vitro production of interleukin (IL)-12, IL-10, tumor necrosis factor alpha, interferon gamma (IFN-gamma), and transforming growth factor beta (TGF-beta) from purified monocytes and peripheral blood mononuclear cells, cytokine expression on duodenal biopsy specimens, and serum cytokine and immunoglobulin (Ig) levels were tested in 9 patients with WD. Reduced monocyte IL-12 production and decreased IFN-gamma secretion by peripheral blood mononuclear cells in vitro were found, as well as reduced immunohistological staining for IL-12 and IFN-gamma, but no decrease in other cytokines in patients with WD. A similar but less severe defect in 2 relatives with WD argued for a genetic basis of this abnormality. Serum IgG2, an IFN-gamma-dependent Ig subclass, and serum TGF-beta levels were reduced in patients with WD. The described monocyte defects in WD may result in a secondary reduction of IFN-gamma production and IgG2 serum levels. This provides a rationale for additive immunotherapy in patients with antibiotic-refractory WD.

[Expression of macrophage markers in childhood and adult Langerhans histiocytosis (LCH)]

Article

Jul 1997

In the diagnosis of the Langerhans cell histiocytosis several monocyte and macrophag markers have been tested in the recent years. We compared the expression of macrophage and lymphoid markers in childhood and adult type Langerhans cell histiocytosis. Ten childhood and 11 adult cases were tested using paraffin sections of biopsy samples. We have examined 6 markers: the S-100, Lysozyme, CD68 macrophag and the CD1a, CD4, HLA-DR lymphoid markers. We have found that the CD68 marker was more frequently positive than the other examined macrophag markers, and proved to be almost as reliable as the recently discovered CD1a. The most interesting result was that the expression of the markers was different in the childhood and adult type of the disease. On the basis of our experience the possibility arise that the phenotype of the childhood and adult type of the Langerhans cell histiocytosis is different.

Other Functions, Other Genes

Article

Mar 1999
IMMUNITY

Mucosal cytokine expression, cellular markers and adhesion molecules in inflammatory bowel disease

Article

Apr 1999
EUR J GASTROEN HEPAT

To relate proinflammatory cytokines to leukocyte surface markers and adhesion molecules in the same paraffin-embedded biopsy specimen in inflammatory bowel disease (IBD) of varying activity. Biopsies of seven cases of Crohn's disease, seven patients with ulcerative colitis, one case of intestinal infection and six control subjects were studied. We performed in situ hybridization on sections of tissue using probes specific to interleukin-1beta (IL-1beta), interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF alpha). Leucocyte markers and adhesion molecules were investigated in subsequent slides of selected specimens by immunohistochemistry. Cytokine mRNA was found in large numbers of cells throughout the inflamed intestine but also in some macroscopically unaffected tissue specimens. Transcripts were predominantly located within the lamina propria where immunohistochemistry of parallel sections revealed numerous macrophages and the presence of endothelial adhesion molecules. The expression of the different cytokines was closely related to each other and to histological but not to macroscopic (endoscopic) activity. The synthesis of IL-1beta IL-6 and TNF alpha mRNA is coordinately regulated. Cytokine production is located mostly in the lamina propria at sites that are rich in macrophages and show abundant staining of vascular adhesion molecules. This cascade of immune events is related to inflammatory cell infiltration in both Crohn's disease and ulcerative colitis.

Cultivation of the Bacillus of Whipple's Disease

Article

Mar 2000

Whipple's disease is a systemic bacterial infection, but to date no isolate of the bacterium has been established in subculture, and no strain of this bacterium has been available for study. Using specimens from the aortic [corrected] valve of a patient with endocarditis due to Whipple's disease, we isolated and propagated a bacterium by inoculation in a human fibroblast cell line (HEL) with the use of a shell-vial assay. We tested serum samples from our patient, other patients with Whipple's disease, and control subjects for the presence of antibodies to this bacterium. The bacterium of Whipple's disease was grown successfully in HEL cells, and we established subcultures of the isolate. Indirect immunofluorescence assays showed that the patient's serum reacted specifically against the bacterium. Seven of 9 serum samples from patients with Whipple's disease had IgM antibody titers of 1:50 or more, as compared with 3 of 40 samples from the control subjects (P<0.001). Polyclonal antibodies against the bacterium were generated by inoculation of the microorganism into mice and were used to detect bacteria in the excised cardiac tissue from our patient on immunohistochemical analysis. The 16S ribosomal RNA gene of the cultured bacterium was identical to the sequence for Tropheryma whippelii identified previously in tissue samples from patients with Whipple's disease. The strain we have grown is available in the French National Collection. We cultivated the bacterium of Whipple's disease, detected specific antibodies in tissue from the source patient, and generated specific antibodies in mice to be used in the immunodetection of the microorganism in tissues. The development of a serologic test for Whipple's disease may now be possible.

Quantitation of intraepithelial lymphocytes in human duodenum: What is normal?

Article

May 2002

An increase in intraepithelial lymphocytes (IELs) is mandatory for the histological diagnosis of coeliac disease (CD). Currently, duodenal biopsies are used almost exclusively to establish the diagnosis, yet published work continues to cite an upper limit of 40 lymphocytes/100 epithelial cells, a figure derived from jejunal biopsies over 30 years ago. Aim: To establish the normal range for IEL counts in distal duodenal biopsies. Twenty subjects (seven men, 13 women; median age, 34 years; range, 20-65) with a normal sugar permeability test and concurrent distal duodenal biopsies were identified. The number of IELs and epithelial cell nuclei in an uninterrupted length of surface (villous) epithelium (> 500 cells) was counted. An image analysis system was used to assess villous architecture by calculating the villous height to crypt depth ratio. The range of IEL counts in 20 subjects was 1.8-26/100 villous epithelial cells, with a mean value of 11 and SD of 6.8. The mean villous to crypt ratio was 1.82 (SD, 0.38; range, 1.22-2.46). There was no correlation between IEL counts and villous to crypt ratio (Spearman rank correlation, -0.066; p = 0.80). These results suggest that 25 IELs/100 epithelial cells (mean +2 SD) should be taken as the upper limit of the normal range for duodenal mucosa.

Immunohistological detection of Tropheryma whipplei (Whipple bacillus) in lymph nodes

Article

Oct 2002
AM J MED

Dysregulated peripheral and mucosal Th1/Th2 response in Whipple's disease

Article

Nov 2002
GASTROENTEROLOGY

An impaired monocyte function and impaired interferon (IFN)-gamma production has been suggested as a possible pathogenetic factor in Whipple's disease (WD) and as a cause for the delayed elimination of Tropheryma whipplei in some patients. We studied, in a series of 20 WD patients with various degrees of disease activity, cellular immune functions. We found an increased in vitro production of interleukin (IL)-4 by peripheral mononuclear blood cells as determined by enzyme-linked immunosorbent assay, but reduced secretion of IFN-gamma and IL-2 as compared with age- and sex-matched controls. In addition, we observed a significantly reduced monocyte IL-12 production in response to various stimuli in WD patients whereas other cytokines were comparable with controls; these immunologic alterations were not significantly different in patients with various disease activities. At the mucosal level, we found decreased CD4 T-cell percentage and a significantly impaired IFN-gamma secretion. Our data define a defective cellular immune response in a large series of WD patients and point to an important pathogenetic role of impaired Th1 responses. The decreased monocyte IL-12 levels may result in reduced peripheral and mucosal IFN-gamma production and lead to an increased susceptibility to T. whipplei infection in certain hosts.

Genome-based design of a cell-free culture medium for Tropheryma whipplei

Article

Sep 2003
LANCET

Empirical approaches have guided the development of bacterial cultures. The availability of sequenced genomes now provides opportunities to define culture media for growth of fastidious pathogens with computer modelling of metabolic networks. A key issue is the possibility of growing host-dependent bacteria in cell-free conditions. The sequenced Tropheryma whipplei genome was analysed to identify specific metabolic deficiencies. We used this information to design a comprehensive medium that allowed three established T whipplei strains from culture with human cells and one new strain from a clinical sample to grow axenically. Genomic information can, therefore, provide sufficient clues for designing axenic media for fastidious and uncultured pathogens.

Differential Eμ enhancer activity and expression of BOB.I/OBF.I, Oct2, PU.I, and immunoglobulin in reactive B-cell populations, B-cell non-Hodgkin lymphomas, and Hodgkin lymphomas

Article

Jan 2004

It has previously been demonstrated that in cultured and in situ tumour cells of classical Hodgkin lymphoma (cHL), the immunoglobulin (Ig) promoter is inactive and its transcription factors Oct2 and/or BOB.1/OBF.1 are down-regulated. In this study, the analysis of these transcription factors has been extended to a broad spectrum of B-cell malignancies and the findings have been related to the situation in normal B-cells of various differentiation stages and to the expression of Ig. Furthermore, an additional Ig transcription factor, PU.1, recently described to be absent from cHL, and a further regulatory element of the Ig gene, the intronic Emu enhancer, have been studied. BOB.1/OBF.1 and Oct2 were present in all B-cells expressing Ig, whereas PU.1 proved to be absent from late B-cell differentiation stages and from a subset of germinal centre B-cells. Interestingly, there were several normal (eg germinal centre centroblasts and monocytoid B-cells) and malignant B-cell populations (eg a proportion of diffuse large B-cell lymphomas, DLBCLs) that were Ig-negative, despite their BOB.1/OBF.1 and Oct2 expression. This study further shows that absence of PU.1 alone, as well as inactivation of the intronic Emu enhancer, is not sufficient to down-regulate Ig transcription. Taken together, the simultaneous absence of PU.1, Oct2, and/or BOB.1/OBF.1 is unique to Hodgkin and Reed-Sternberg (HRS) cells and cannot be detected in normal B-cell subsets or B-cell non-Hodgkin lymphomas (B-NHLs). This supports the concept that the down-regulation of Ig in cHL does not reflect a physiological situation, but a defect probably closely linked to the pathogenesis of cHL.

CCL2, a product of mice early after systemic inflammatory response syndrome (SIRS), induces alternatively activated macrophages capable of impairing antibacterial resistance of SIRS mice

Article

Sep 2004

Infection associated with systemic inflammatory response syndrome (SIRS) is a major cause of morbidity and mortality in patients with major surgery, polytrauma, and severe burn injury. In previous studies, mice with severe pancreatitis (a mouse model of SIRS, SIRS mice) have been shown to be greatly susceptible to various infections. In the present study, a mechanism involved in the impaired resistance of SIRS mice to infectious complications was investigated. Sera from SIRS mice impaired the resistance of normal mice to infectious complications induced by cecal ligation and puncture (CLP). CC chemokine ligand 2 (CCL2) was detected in sera of SIRS mice. Resident macrophages (RMphi) cultured with SIRS mouse sera converted to alternatively activated macrophages (AAMphi), which were also demonstrated in mice treated with recombinant murine CCL2. However, AAMphi were not demonstrated in mice injected with SIRS mouse sera and anti-CCL2 monoclonal antibody (mAb) in combination. Furthermore, normal mice that received SIRS mouse sera and anti-CCL2 mAb resisted CLP-induced infectious complications. These results indicate that the resistance of SIRS mice to infectious complications is impaired by AAMphi generated from RMphi in response to SIRS-associated CCL2 production.

Decreased levels of interleukin-12p40 in the serum of patients with Whipple's disease

Article

Mar 2006

An impaired production of interleukin (IL)-12 and T cell interferon-gamma (IFN-gamma) of in vitro stimulated monocytes has been discussed as a pathogenic factor in Whipple's disease (WD). It is unclear whether this defect of cellular immunity is translated to the humoral immune system and to serum correlates. We analyzed the serum of 40 patients with Whipple's disease in various degrees of disease activity by sandwich enzyme-linked immunosorbent assay for differences in cytokine and cell adhesion molecule concentrations compared with age- and sex-matched controls. We observed a highly significant reduction of IL-12p40 levels (patients, 0.18+/-0.05 ng/ml (mean+/-SEM); controls, 3.19+/-0.39 ng/ml; p<0.01) in all stages of disease activity, whereas the concentration of IL-12p70 was comparable with controls. Furthermore, we observed a slight decrease in tumour necrosis factor alpha (TNF-alpha) concentrations in the serum of patients (patients, 6.36+/-0.90 pg/ml; controls, 10.5+/-1.23 pg/ml; p<0,05). The levels of other cytokines such as IFN-gamma, IL-2, IL-13 and transforming growth factor beta, as well as soluble cell adhesion molecules lymphocyte function-associated antigen 3 and intercellular adhesion molecule 1, were not significantly different compared with controls. Levels of immunoglobulin G2 (IgG2) measured in the serum of WD patients were below normal in 24 of 29 patients and were even below the 95% confidence interval in 10 patients. Our data demonstrate a persistent defect of the cellular immune response with decreased serum concentrations of IL-12p40 and TNF-alpha and decreased IgG2 levels in a large group of WD patients. These data support as in vivo finding the results obtained in previous investigations with stimulated monocytes/lymphocytes. The isolated decrease in IL-12p40 may hint at possible defects in the IL-12/IFN-gamma promoter system.

Increased cytokine transcripts in pouchitis reflect the degree of inflammation but not the underlying entity

Article

Aug 2006

After ileopouch anal anastomosis (IPAA), 10-40% of patients with ulcerative colitis (UC) but only 5% of patients with familial adenomatous polyposis (FAP) develop pouchitis. Immunoregulatory abnormalities might be of importance in the pathogenesis of the disease. Therefore, we characterized cytokine and chemokine transcripts in inflamed and non-inflamed pouches in patients with UC compared to those with FAP and Crohn's disease (CD). Mucosal biopsies were taken from 87 patients with IPAA [UC (n=70), CD (n=8) or FAP (n=9)]. Patients with active ileal CD (n=14), active UC (n=17) and non-inflammatory conditions (n=12) served as controls. The expression of 20 gene transcripts was quantified using real-time polymerase chain reaction. Pro-inflammatory cytokines and chemokines are significantly increased in IPAA patients with acute pouchitis. This increase is independent of the underlying disease (UC or CD) and reflects the degree of inflammation. A good correlation between pouchitis activity (using the Pouchitis Disease Activity Index) and the MRP-14, interleukin-8, macrophage inflammatory protein-2alpha and matrix metalloproteinase-1 transcripts was observed. Our data support the view that pouchitis reflects an inflammatory process that is different from that of underlying inflammatory bowel diseases, as the cytokine and chemokine patterns in pouchitis are neither typical of CD nor of UC, but maybe due to bacterial intestinal microflora overgrowth in the pouch lumen. Quantification of transcript levels allows an estimation of the extent of mucosal inflammation and may become helpful in the evaluation of the disease, especially in clinical trials.

IL-16 Is Critical for Tropheryma whipplei Replication in Whipple's Disease

Article

Nov 2005

Whipple's disease (WD) is a rare systemic disease caused by Tropheryma whipplei. We showed that T. whipplei was eliminated by human monocytes but replicated in monocyte-derived macrophages (Mphi) by inducing an original activation program. Two different host molecules were found to be key elements for this specific pattern. Thioredoxin, through its overexpression in infected monocytes, was involved in bacterial killing because adding thioredoxin to infected Mphi inhibited bacterial replication. IL-16, which was up-regulated in Mphi, enabled T. whipplei to replicate in monocytes and increased bacterial replication in Mphi. In addition, anti-IL-16 Abs abolished T. whipplei replication in Mphi. IL-16 down-modulated the expression of thioredoxin and up-regulated that of IL-16 and proapoptotic genes. In patients with WD, T. whipplei replication was higher than in healthy subjects and was related to high levels of circulating IL-16. Both events were corrected in patients who successfully responded to antibiotics treatment. This role of IL-16 was not reported previously and gives an insight into the understanding of WD pathophysiology.

Whipple Disease: Intestinal Infiltrating Cells Exhibit a Transcriptional Pattern of M2/Alternatively Activated Macrophages

Article

Dec 2005

Whipple disease (WD) is a rare systemic disease caused by Tropheryma whipplei and is characterized by the presence of foamy macrophages with periodic acid‐Schiff–positive inclusions in tissues such as lamina propria. For the first time, we report the gene‐expression profile of macrophages in intestinal lesions from a patient with WD. Microarray and real‐time polymerase chain reaction revealed that genes encoding CCL18, cathepsins, scavenger receptor, interleukin‐10, and lipid metabolites were up‐regulated in intestinal lesions. This transcriptional pattern corresponds to that of M2/alternatively activated macrophages. Our results suggest that the T helper 2 response in the intestinal environment may account for the pathophysiological properties of WD.

Whipple's Disease: a Macrophage Disease

Article

Mar 2006

Patients with psoriatic arthritis have an increased number of lymphocytes in the duodenal mucosa in comparison with patients with psoriasis vulgaris

Article

Jun 2006

To determine if there is evidence of inflammation in the duodenal mucosa in patients with psoriatic arthritis (PsA) and to compare the results with those in patients with psoriasis vulgaris (PsV). Nineteen consecutive patients with PsA underwent gastroduodenoscopy, and biopsy specimens were taken from the duodenal and gastric mucosa. In addition to routine processing, the duodenal mucosal specimens were stained for CD3+, CD8+ and CD4+ T lymphocytes, tryptase-positive mast cells, and EG2-positive eosinophil granulocytes. The results were compared with those in duodenal mucosal specimens from patients with PsV and patients with irritable bowel syndrome. Compared with PsV patients (without antibodies against gliadin), patients with PsA had a highly significant increase in intraepithelial CD3+ and CD8+ lymphocytes and also in CD4+ lymphocytes in the lamina propria in the villi. The lymphocyte increase was not related to presence of IgA antibodies against gliadin, endomysium, or transglutaminase, or to concomitant gastritis. Patients with PsA and PsV showed a pronounced increase in mast cells and eosinophil granulocytes. The increased lymphocyte infiltration in the duodenal mucosa in PsA, but not in PsV, might indicate different pathogenetic mechanisms in these psoriasis variants.

Whipple's Disease

Article

Feb 2007
NEW ENGL J MED

In 2000, Tropheryma whipplei was finally identified as the cause of Whipple's disease, a chronic condition with protean manifestations that was first described in 1907. This review discusses the epidemiology, pathogenesis, diagnosis, and treatment of this rare and elusive chronic disease.

Macrophage activation and polarization. Front Biosci : J Virtual Libr

Article

Feb 2008
FRONT BIOSCI

Whipple’s Disease: new aspects of pathogenesis and treatment

Article

Apr 2008
LANCET INFECT DIS

100 years after its first description by George H Whipple, the diagnosis and treatment of Whipple's disease is still a subject of controversy. Whipple's disease is a chronic multisystemic disease. The infection is very rare, although the causative bacterium, Tropheryma whipplei, is ubiquitously present in the environment. We review the epidemiology of Whipple's disease and the recent progress made in the understanding of its pathogenesis and the biology of its agent. The clinical features of Whipple's disease are non-specific and sensitive diagnostic methods such as PCR with sequencing of the amplification products and immunohistochemistry to detect T whipplei are still not widely distributed. The best course of treatment is not completely defined, especially in relapsing disease, neurological manifestations, and in cases of immunoreconstitution after initiation of antibiotic treatment. Patients without the classic symptoms of gastrointestinal disease might be misdiagnosed or insufficiently treated, resulting in a potentially fatal outcome or irreversible neurological damage. Thus, we suggest procedures for the improvement of diagnosis and an optimum therapeutic strategy.

Serological microarray for a paradoxical diagnostic of Whipple’s disease

Article

Aug 2008
EUR J CLIN MICROBIOL

Whipple's disease is a systemic chronic infection caused by Tropheryma whipplei. Asymptomatic people may carry T. whipplei in their digestive tract and this can be determined by PCR, making serological diagnosis useful to distinguish between carriers and patients. Putative antigenic proteins were selected by computational analysis of the T. whipplei genome, immunoproteomics studies and from literature. After expression, putative T. whipplei antigens were screened by microimmunofluorescence with sera of immunized rabbit. Selected targets were screened by microarray using sera from patients and carriers. Paradoxically, with 19 tested recombinant proteins and a glycosylated native protein of T. whipplei, a higher immune response was observed with asymptomatic carriers. In contrast, quantification of human IgA exhibited a higher reaction in patients than in carriers against 10 antigens. These results were used to design a diagnostic test with a cut-off value for each antigen. A blind test assay was performed and was able to diagnose 6/8 patients and 11/12 carriers. Among people with positive T. whipplei PCR of the stool, patients differ from carriers by having positive IgA detection and a negative IgG detection. If confirmed, this serological test will distinguish between carriers and patients in people with positive PCR of the stool.

Impaired bacterial degrada-tion by monocytes and macrophages from a patient with treated Whipple's disease

Jan 1985
1139-1146

Bjerknes R Laerum Od
Degaard

Bjerknes R, Laerum OD, Degaard S. Impaired bacterial degrada-tion by monocytes and macrophages from a patient with treated Whipple's disease. Gastroenterology 1985;89:1139 –1146.

Other functions, other genes: alternative activation of antigen-presenting cells

Jan 1999
137

Goerdt

Goerdt S, Orfanos CE. Other functions, other genes: alternative activation of antigen-presenting cells. Immunity 1999;10:137-142.

Derivation and characterization of murine alternatively activated (M2) macrophages

Jan 2009
173-185

Vw Ho
Lm Sly

Ho VW, Sly LM. Derivation and characterization of murine alternatively activated (M2) macrophages. Methods Mol Biol 2009; 531:173–185.

Quantitation of intraepithelial lymphocytes in human duodenum: what is normal?

Jan 2002
393

Hayat

Impaired Immune Functions of Monocytes and Macrophages in Whipple's Disease

Abstract

No full-text available

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