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1.
J Immunol ; 203(1): 208-215, 2019 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-31101665

RESUMO

Mucosal plasma cells (PC) and Ig production are essential to fend pathogens and to maintain mucosal homeostasis. In human Helicobacter pylori infection, mucosal PC express inducible NO synthase (iNOS), which positively correlates with clearance of experimental human infection. To characterize Ig genes and specificities of antral mucosal iNOS+ and iNOS- PC in H. pylori infection, we sequenced rearranged Ig genes from single cell-sorted PC from biopsy specimens of chronically infected patients and analyzed them with respect to their molecular features. The binding specificity of individual PC's Ig was determined following recombinant expression. We identified high rates of somatic hypermutations, especially targeting RGYW/WRCY hotspot motifs in the individual Ig genes, indicating T cell-dependent maturation. For seven of 14 recombinantly expressed Ig, Ag specificity could be determined. Two clones reacted to H. pylori proteins, and five were found to be polyreactive against LPSs, dsDNA, and ssDNA. All specific Ig originated from iNOS+ PC. H. pylori-specific Ig are encoded by V and J family genes previously shown to be also used in rearranged Ig loci of MALT B cell lymphomas. In summary, mucosal iNOS+ PC producing H. pylori-specific Ig accumulate in infection and appear to be a product of T cell-dependent B cell maturation. Moreover, the Ig's molecular features partly resembled that of MALT B cell lymphoma Ig genes, suggestive of a mechanism in which a progressive molecular evolution of pathogen-specific B cells to MALT B cell lymphoma occurs.

2.
Eur Heart J ; 2019 Apr 19.
Artigo em Inglês | MEDLINE | ID: mdl-31004144

RESUMO

AIMS: Heart failure with preserved ejection fraction (HFpEF) and pathological cardiac aging share a complex pathophysiology, including extracellular matrix remodelling (EMR). Protease-activated receptor 2 (PAR2) deficiency is associated with EMR. The roles of PAR1 and PAR2 have not been studied in HFpEF, age-dependent cardiac fibrosis, or diastolic dysfunction (DD). METHODS AND RESULTS: Evaluation of endomyocardial biopsies from patients with HFpEF (n = 14) revealed that a reduced cardiac PAR2 expression was associated with aggravated DD and increased myocardial fibrosis (r = -0.7336, P = 0.0028). In line, 1-year-old PAR2-knockout (PAR2ko) mice suffered from DD with preserved systolic function, associated with an increased age-dependent α-smooth muscle actin expression, collagen deposition (1.7-fold increase, P = 0.0003), lysyl oxidase activity, collagen cross-linking (2.2-fold increase, P = 0.0008), endothelial activation, and inflammation. In the absence of PAR2, the receptor-regulating protein caveolin-1 was down-regulated, contributing to an augmented profibrotic PAR1 and transforming growth factor beta (TGF-ß)-dependent signalling. This enhanced TGF-ß/PAR1 signalling caused N-proteinase (ADAMTS3) and C-proteinase (BMP1)-related increased collagen I production from cardiac fibroblasts (CFs). PAR2 overexpression in PAR2ko CFs reversed these effects. The treatment with the PAR1 antagonist, vorapaxar, reduced cardiac fibrosis by 44% (P = 0.03) and reduced inflammation in a metabolic disease model (apolipoprotein E-ko mice). Patients with HFpEF with upstream PAR inhibition via FXa inhibitors (n = 40) also exhibited reduced circulating markers of fibrosis and DD compared with patients treated with vitamin K antagonists (n = 20). CONCLUSIONS: Protease-activated receptor 2 is an important regulator of profibrotic PAR1 and TGF-ß signalling in the heart. Modulation of the FXa/FIIa-PAR1/PAR2/TGF-ß-axis might be a promising therapeutic approach to reduce HFpEF.

3.
4.
Clin Infect Dis ; 2018 Oct 22.
Artigo em Inglês | MEDLINE | ID: mdl-30351371

RESUMO

Background: Whipple's disease (WD) is a rare infection with Tropheryma whipplei that is fatal if untreated. Diagnosis is challenging and currently based on invasive sampling. In a case of WD diagnosed from a kidney biopsy, we observed morphologically-intact bacteria within the glomerular capsular space and tubular lumens. This raised the questions of whether renal filtration of bacteria is common in WD and whether polymerase chain reaction (PCR) testing of urine might serve as a diagnostic test for WD. Methods: We prospectively investigated urine samples of 12 newly-diagnosed and 31 treated WD patients by PCR. As controls, we investigated samples from 110 healthy volunteers and patients with excluded WD or acute gastroenteritis. Results: Out of 12 urine samples from independent, therapy-naive WD patients, 9 were positive for T. whipplei PCR. In 3 patients, fluorescence in situ hybridization visualized T. whipplei in urine. All control samples were negative, including those of 11 healthy carriers with T. whipplei-positive stool samples. In our study, the detection of T. whipplei in the urine of untreated patients correlated in all cases with WD. Conclusions: T. whipplei is detectable by PCR in the urine of the majority of therapy-naive WD patients. With a low prevalence but far-reaching consequences upon diagnosis, invasive sampling for WD is mandatory and must be based on a strong suspicion. Urine testing could prevent patients from being undiagnosed for years. Urine may serve as a novel, easy-to-obtain specimen for guiding the initial diagnosis of WD, in particular in patients with extra-intestinal WD.

5.
Mol Diagn Ther ; 2018 Jun 07.
Artigo em Inglês | MEDLINE | ID: mdl-29882197

RESUMO

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.

6.
J Infect Dis ; 217(9): 1421-1425, 2018 Apr 11.
Artigo em Inglês | MEDLINE | ID: mdl-29390066

RESUMO

Cell-free and cell-associated human immunodeficiency virus (HIV) may differently affect the immune system and the efficacy of prevention strategies. Here we examined mucosal events in simian immunodeficiency virus (SIV) infection, using infected cells together with cell-free virus and cell-free virus alone. Intravenously inoculated SIV-infected cells disseminated virus to the intestine within 16 hours. Infection with both virus forms accelerated viral dissemination in the intestinal mucosa and the loss of mucosal CD4+ T cells as compared to infection with cell-free virus only. As all natural sources of HIV infection contain both virus forms, future prevention studies should focus on efficacy against both cell-free and cell-associated virus.

8.
Infect Immun ; 85(8)2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28559404

RESUMO

Classical Whipple's disease (CWD) is characterized by the lack of specific Th1 response toward Tropheryma whipplei in genetically predisposed individuals. The cofactor GrpE of heat shock protein 70 (Hsp70) from T. whipplei was previously identified as a B-cell antigen. We tested the capacity of Hsp70 and GrpE to elicit specific proinflammatory T-cell responses. Peripheral mononuclear cells from CWD patients and healthy donors were stimulated with T. whipplei lysate or recombinant GrpE or Hsp70 before levels of CD40L, CD69, perforin, granzyme B, CD107a, and gamma interferon (IFN-γ) were determined in T cells by flow cytometry. 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+ IFN-γ+, were significantly lower in patients with CWD than in healthy controls; CD8+ T cells of untreated CWD patients revealed an enhanced activation toward unspecific stimulation and T. whipplei-specific degranulation, although CD69+ IFN-γ+ CD8+ T cells were reduced upon stimulation with T. whipplei lysate and recombinant T. whipplei-derived proteins. 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.


Assuntos
Proteínas de Bactérias/imunologia , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Proteínas de Choque Térmico HSP70/imunologia , Proteínas de Choque Térmico/imunologia , Tropheryma/imunologia , Doença de Whipple/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/genética , Linfócitos B/patologia , Duodeno/imunologia , Feminino , Citometria de Fluxo , Humanos , Interferon gama/genética , Mucosa Intestinal/imunologia , Leucócitos Mononucleares/efeitos dos fármacos , Ativação Linfocitária , Masculino , Pessoa de Meia-Idade , Tropheryma/química , Tropheryma/genética , Doença de Whipple/fisiopatologia , Adulto Jovem
9.
J Immunol ; 198(1): 481-491, 2017 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-27872210

RESUMO

CD8+ T cells in the intestinal mucosa influence the HIV-associated pathogenesis, but little is known about the dynamics of mucosal CD8+ T cell counts and activation of these cells during the course of infection. In this study, mucosal CD8+ T cells in the duodenum were studied at different stages of HIV infection, starting from the seronegative phase. In seronegative acute HIV infection, CD8+ T cell counts increased in the epithelium, but not in the lamina propria. Infiltration of the lamina propria by peripherally expanded CD8+ T cells was observed after seroconversion. Highest increase in the expression of perforin, the rate-limiting molecule for cytotoxic CD8+ T cell activity, was evident in the lamina propria of seronegative acutely HIV-infected patients. The number of perforin-expressing cells in the lamina propria of acutely HIV-infected patients was positively associated with biomarkers of enterocyte damage and microbial translocation. After seroconversion, perforin expression was downregulated in the lamina propria, but not in the epithelium. In conclusion, our findings demonstrate that intraepithelial and lamina propria CD8+ T cells exhibit different dynamics of numerical alteration and cytotoxic activity in HIV-infected patients. Moreover, our results suggest that perforin-dependent cytotoxic mechanisms by CD8+ T cells could impair the intestinal mucosal barrier already in the seronegative phase of acute HIV infection, thereby inducing microbial translocation as one of the earliest pathological events in HIV infection.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Infecções por HIV/imunologia , Soropositividade para HIV/imunologia , Mucosa Intestinal/imunologia , Ativação Linfocitária/imunologia , Adulto , Duodeno/imunologia , Feminino , Citometria de Fluxo , Humanos , Imuno-Histoquímica , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
10.
Eur J Microbiol Immunol (Bp) ; 6(4): 306-311, 2016 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-27980859

RESUMO

Direct effects of Helicobacter pylori (H. pylori) on human CD4+ T-cells hamper disentangling a possible bacterial-mediated interference with major histocompatibility complex class II (MHC-II)-dependent antigen presentation to these cells. To overcome this limitation, we employed a previously described assay, which enables assessing human antigen-processing cell function by using murine T-cell hybridoma cells restricted by human leukocyte antigen (HLA) alleles. HLA-DR1+ monocyte-derived dendritic cells were exposed to H. pylori and pulsed with the antigen 85B from Mycobacterium tuberculosis (M. tuberculosis). Interleukin-2 (IL-2) secretion by AG85Baa97-112-specific hybridoma cells was then evaluated as an integral reporter of cognate antigen presentation. This methodology enabled revealing of interference of H. pylori with the antigen-presenting capacity of human dendritic cells.

11.
J Immunol ; 197(5): 1801-8, 2016 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-27456483

RESUMO

The mucosal immune system is relevant for homeostasis, immunity, and also pathological conditions in the gastrointestinal tract. Inducible NO synthase (iNOS)-dependent production of NO is one of the factors linked to both antimicrobial immunity and pathological conditions. Upregulation of iNOS has been observed in human Helicobacter pylori infection, but the cellular sources of iNOS are ill defined. Key differences in regulation of iNOS expression impair the translation from mouse models to human medicine. To characterize mucosal iNOS-producing leukocytes, biopsy specimens from H. pylori-infected patients, controls, and participants of a vaccination trial were analyzed by immunohistochemistry, along with flow cytometric analyses of lymphocytes for iNOS expression and activity. We newly identified mucosal IgA-producing plasma cells (PCs) as one major iNOS(+) cell population in H. pylori-infected patients and confirmed intracellular NO production. Because we did not detect iNOS(+) PCs in three distinct infectious diseases, this is not a general feature of mucosal PCs under conditions of infection. Furthermore, numbers of mucosal iNOS(+) PCs were elevated in individuals who had cleared experimental H. pylori infection compared with those who had not. Thus, IgA(+) PCs expressing iNOS are described for the first time, to our knowledge, in humans. iNOS(+) PCs are induced in the course of human H. pylori infection, and their abundance seems to correlate with the clinical course of the infection.


Assuntos
Helicobacter pylori/imunologia , Imunoglobulina A/imunologia , Óxido Nítrico Sintase Tipo II/biossíntese , Plasmócitos/enzimologia , Plasmócitos/imunologia , Biópsia , Feminino , Mucosa Gástrica/microbiologia , Infecções por Helicobacter/imunologia , Infecções por Helicobacter/microbiologia , Humanos , Imunoglobulina A/biossíntese , Imuno-Histoquímica , Masculino , Óxido Nítrico/metabolismo , Estudos Prospectivos , Antro Pilórico/microbiologia , Antro Pilórico/patologia
12.
Lancet Infect Dis ; 16(3): e13-22, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26856775

RESUMO

Recent advances in medical microbiology, epidemiology, cellular biology, and the availability of an expanded set of diagnostic methods such as histopathology, immunohistochemistry, PCR, and bacterial culture have improved our understanding of the clinical range and natural course of Tropheryma whipplei infection and Whipple's disease. Interdisciplinary and transnational research activities have contributed to the clarification of the pathogenesis of the disorder and have enabled controlled trials of different treatment strategies. We summarise the current knowledge and new findings relating to T whipplei infection and Whipple's disease.


Assuntos
Tropheryma , Doença de Whipple/microbiologia , Antibacterianos/uso terapêutico , Humanos , Síndrome Inflamatória da Reconstituição Imune , Imunossupressores/efeitos adversos , Doença de Whipple/diagnóstico , Doença de Whipple/tratamento farmacológico
13.
Mol Cell Biol ; 36(3): 462-74, 2016 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-26598605

RESUMO

The class I histone deacetylases (HDACs) HDAC1 and HDAC2 play partially redundant roles in the regulation of gene expression and mouse development. As part of multisubunit corepressor complexes, these two deacetylases exhibit both enzymatic and nonenzymatic functions. To examine the impact of the catalytic activities of HDAC1 and HDAC2, we generated knock-in mice expressing catalytically inactive isoforms, which are still incorporated into the HDAC1/HDAC2 corepressor complexes. Surprisingly, heterozygous mice expressing catalytically inactive HDAC2 die within a few hours after birth, while heterozygous HDAC1 mutant mice are indistinguishable from wild-type littermates. Heterozygous HDAC2 mutant mice show an unaltered composition but reduced associated deacetylase activity of corepressor complexes and exhibit a more severe phenotype than HDAC2-null mice. They display changes in brain architecture accompanied by premature expression of the key regulator protein kinase C delta. Our study reveals a dominant negative effect of catalytically inactive HDAC2 on specific corepressor complexes resulting in histone hyperacetylation, transcriptional derepression, and, ultimately, perinatal lethality.


Assuntos
Histona Desacetilase 2/genética , Histona Desacetilase 2/metabolismo , Camundongos/crescimento & desenvolvimento , Animais , Feminino , Deleção de Genes , Expressão Gênica , Técnicas de Introdução de Genes , Histona Desacetilase 1/genética , Histona Desacetilase 1/metabolismo , Masculino , Camundongos/genética , Camundongos/metabolismo , Camundongos Endogâmicos C57BL , Mutagênese Sítio-Dirigida , Fenótipo , Mutação Puntual , Ativação Transcricional
15.
Clin Vaccine Immunol ; 22(12): 1276-84, 2015 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-26491036

RESUMO

Clinical manifestations of leptospirosis are highly variable: from asymptomatic to severe and potentially fatal. The outcome of the disease is usually determined in the immunological phase, beginning in the second week of symptoms. The underlying mechanisms, predictive factors, and individual immune responses that contribute to clinical variations are not well understood. The aim of this study was to determine the specifics of CD4(+) T-cell reactivity and cytokine release after stimulation with leptospiral antigens in patients with leptospirosis of different disease severities (patients with mild and severe symptoms) and in control subjects (with and without proven exposure to Leptospira). Whole-blood specimens were stimulated with Leptospira antigens in vitro. Subsequently, intracellular staining of cytokines was performed, and flow cytometry was used to assess the expression of CD40 ligand (CD40L) and the production of gamma interferon (IFN-γ), interleukin-10 (IL-10), IL-2, and tumor necrosis factor alpha (TNF-α) by CD4(+) T cells. The production of inflammatory cytokines such as TNF-α by CD4(+) T cells after stimulation with leptospiral antigens was highest in patients with severe disease. In contrast, the ratio of IL-10 production to TNF-α production was higher in exposed subjects than in patients with mild and severe disease. Levels of proinflammatory cytokines such as TNF-α may be useful markers of the severity of the immunological phase of leptospirosis. IL-10 production by T cells after antigen-specific stimulation may indicate a more successful downregulation of the inflammatory response and may contribute to an asymptomatic course of the disease.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Citocinas/imunologia , Leptospirose/diagnóstico , Leptospirose/imunologia , Adulto , Antígenos de Bactérias/imunologia , Infecções Assintomáticas , Ligante de CD40/genética , Ligante de CD40/imunologia , Feminino , Citometria de Fluxo , Humanos , Interferon gama/imunologia , Interferon gama/metabolismo , Interleucina-10/imunologia , Interleucina-10/metabolismo , Interleucina-2/imunologia , Leptospira/imunologia , Leptospirose/microbiologia , Masculino , Pessoa de Meia-Idade , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Adulto Jovem
16.
BMC Gastroenterol ; 15: 62, 2015 May 23.
Artigo em Inglês | MEDLINE | ID: mdl-26001889

RESUMO

BACKGROUND: Although sarcoidosis and celiac disease are both chronic immunologic disorders involving multiple organ systems, reports about association of diseases in individual patients are sparse. While sarcoidosis is a chronic granulomatous disease presumably reflecting an exaggerated response to an unknown antigen, celiac disease is a T cell-driven disease triggered by ingestion of gluten, a protein composite found in wheat and related grains. CASE PRESENTATION: We present three cases with a longstanding history of sarcoidosis that have been additionally diagnosed with celiac-like enteropathy. In two cases, celiac disease was established applying celiac-specific serology and duodenal histology, while one case was revealed as an AIE-75-positive autoimmune enteropathy. The HLA-DR3/DQ2 haplotype was confirmed in both celiac patients, hence confirming previous data of linkage disequilibrium as a cause for disease association. Remarkably, one celiac patient presented with granulomatous nodulae in the ileum, thus reflecting an intestinal sarcoid manifestation. In contrast the patient with an autoimmune enteropathy, was HLA-DQ9/DQ6-positive, also arguing against CD. CONCLUSIONS: Associations of sarcoidosis and celiac disease are rare but do occur. Determining the HLA status in patients with complex autoimmune associations might help classifying involved disease entities.


Assuntos
Doença Celíaca/diagnóstico , Pneumopatias/complicações , Poliendocrinopatias Autoimunes/diagnóstico , Sarcoidose/complicações , Adulto , Biomarcadores/sangue , Doença Celíaca/sangue , Doença Celíaca/complicações , Doença Celíaca/imunologia , Diagnóstico Diferencial , Feminino , Antígenos HLA-DQ/sangue , Haplótipos , Humanos , Pneumopatias/sangue , Pneumopatias/diagnóstico , Pneumopatias/imunologia , Pessoa de Meia-Idade , Poliendocrinopatias Autoimunes/sangue , Poliendocrinopatias Autoimunes/complicações , Poliendocrinopatias Autoimunes/imunologia , Sarcoidose/sangue , Sarcoidose/diagnóstico , Sarcoidose/imunologia
17.
Medicine (Baltimore) ; 94(15): e714, 2015 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-25881849

RESUMO

Classic Whipple disease (CWD) is a systemic infection caused by Tropheryma whipplei. Different diagnostic tools have been developed over the last decades: periodic acid-Schiff (PAS) staining, T whipplei-specific polymerase chain reaction (PCR), and T whipplei-specific immunohistochemistry (IHC). Despite all these advances, CWD is still difficult to diagnose because of a variety of clinical symptoms and possibly a long time span between first unspecific symptoms and the full-blown clinical picture of the disease. Herein, we report an observational cohort study summarizing epidemiologic data, clinical manifestations, and diagnostic parameters of 191 patients with CWD collected at our institution. Gastrointestinal manifestations are the most characteristic symptoms of CWD affecting 76% of the cohort. Although the small bowel was macroscopically conspicuous in only 27% of cases, 173 (91%) patients presented with characteristic histological changes in small bowel biopsies (in 2 patients, these changes were only seen within the ileum). However, 18 patients displayed normal small bowel histology without typical PAS staining. In 9 of these patients, alternative test were positive from their duodenal specimens (ie, T whipplei-specific PCR and/or IHC). Thus, in 182 patients (95%) a diagnostic hint toward CWD was obtained from small bowel biopsies. Only 9 patients (5%) were diagnosed solely based on positive T whipplei-specific PCR and/or IHC of extraintestinal fluids (eg, cerebrospinal fluid, synovial fluid) or extraintestinal tissue (eg, lymph node, synovial tissue), respectively. Thus, despite efforts to diagnose CWD from alternative specimens, gastroscopy with duodenal biopsy and subsequent histological and molecular-biological examination is the most reliable diagnostic tool for CWD.


Assuntos
Tropheryma , Doença de Whipple/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Líquido Cefalorraquidiano/microbiologia , Estudos de Coortes , Diagnóstico Diferencial , Feminino , Gastroenteropatias/fisiopatologia , Gastroscopia , Testes Hematológicos , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase , Doença de Whipple/líquido cefalorraquidiano , Doença de Whipple/fisiopatologia
18.
Dtsch Med Wochenschr ; 140(6): 428-32, 2015 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-25774735

RESUMO

Within the last years the understanding of infection with Tropheryma whipplei was significantly enhanced by improvement of molecular biology, microbiology and immunology. The following entities of infection or carriage, respectively, with T. whipplei must be differentiated: besides in the context of classical Whipple's disease (CWD), the rare chronic infection with T. whipplei (estimated incidence: 1 : 1,000,000), T. whipplei can be detected more frequently in stool specimens of children with acute gastroenteritis or asymptomatic carriers, or as a cause of isolated endocarditis. However, infection with T. whipplei only rarely results in CWD. T. whipplei was well characterized, raised in vitro and its genome completely sequenced within the last two decades. Very interesting is the resistance of the agent against glutaraldehyde.The histological detection within duodenal biopsies with "Periodic Acid Schiff" (PAS) staining still is first choice for the diagnosis of CWD. Today PCR or immunohistochemistry can identify the agent more specifically. In cases of isolated organ manifestations of e. g. joints or central nervous system the agent needs to be identified from specimen from the affected sites. Successful treatment can be achieved in most of the cases by antimicrobial therapy and first prospective treatment trials are published. However, neuronal CWD still can be progressive lethal and an immune reconstitution inflammatory syndrome (IRIS) might complicate the course of treatment and in worst case end fatal. Thus, because of the complexity of the disease a specialised reference centre should be consulted for diagnosis and treatment of CWD.


Assuntos
Antibacterianos/uso terapêutico , Anti-Inflamatórios/uso terapêutico , Tropheryma , Doença de Whipple/diagnóstico , Doença de Whipple/tratamento farmacológico , Humanos , Doença de Whipple/microbiologia
19.
Infect Immun ; 83(2): 482-91, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25385798

RESUMO

Accumulation of Tropheryma whipplei-stuffed macrophages in the duodenum, impaired T. whipplei-specific Th1 responses, and weak secretion of interleukin-12 (IL-12) are hallmarks of classical Whipple's disease (CWD). This study addresses dendritic cell (DC) functionality during CWD. We documented composition, distribution, and functionality of DC ex vivo or after in vitro maturation by fluorescence-activated cell sorting (FACS) and by immunohistochemistry in situ. A decrease in peripheral DC of untreated CWD patients compared to healthy donors was due to reduced CD11c(high) myeloid DC (M-DC). Decreased maturation markers CD83, CD86, and CCR7, as well as low IL-12 production in response to stimulation, disclosed an immature M-DC phenotype. In vitro-generated monocyte-derived DC from CWD patients showed normal maturation and T cell-stimulatory capacity under proinflammatory conditions but produced less IL-12 and failed to activate T. whipplei-specific Th1 cells. In duodenal and lymphoid tissues, T. whipplei was found within immature DC-SIGN(+) DC. DC and proliferating lymphocytes were reduced in lymph nodes of CWD patients compared to levels in controls. Our results indicate that dysfunctional IL-12 production by DC provides suboptimal conditions for priming of T. whipplei-specific T cells during CWD and that immature DC carrying T. whipplei contribute to the dissemination of the bacterium.


Assuntos
Células Dendríticas/imunologia , Subunidade p35 da Interleucina-12/biossíntese , Células Th1/imunologia , Doença de Whipple/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/biossíntese , Antígeno B7-2/biossíntese , Antígeno CD11c/biossíntese , Moléculas de Adesão Celular/biossíntese , Proliferação de Células , Duodeno/imunologia , Duodeno/microbiologia , Feminino , Citometria de Fluxo , Humanos , Imunoglobulinas/biossíntese , Subunidade p35 da Interleucina-12/imunologia , Subunidade p35 da Interleucina-12/metabolismo , Lectinas Tipo C/biossíntese , Linfonodos/imunologia , Ativação Linfocitária/imunologia , Macrófagos/imunologia , Macrófagos/microbiologia , Masculino , Glicoproteínas de Membrana/biossíntese , Pessoa de Meia-Idade , Receptores CCR7/biossíntese , Receptores de Superfície Celular/biossíntese , Tropheryma/imunologia , Tropheryma/patogenicidade , Doença de Whipple/microbiologia , Doença de Whipple/mortalidade
20.
J Acquir Immune Defic Syndr ; 66(1): 7-15, 2014 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-24378723

RESUMO

BACKGROUND: Knowledge about HIV infection in older persons is becoming increasingly important. CD4⁺ T cells are essential for protective immunity, but little is known about the effect of age on the CD4⁺ T-cell impairment in HIV infection. METHODS: Treatment-naive patients aged older than 50 or younger than 40 years were studied for absolute and relative frequencies of CD31⁺ naive and CD31⁻ naive CD4⁺ T cells, central memory, effector memory, and terminally differentiated CD4⁺ T cells, and compared with age-matched controls. In addition, cellular proliferation and cytokine secretion properties were determined. CD4⁺ T-cell reconstitution was analyzed in older and younger patients with <350 or ≥ 350 CD4⁺ T cells per microliter at initiation of combination antiretroviral therapy (cART). RESULTS: CD4⁺ T cells of older but not younger HIV-infected patients showed age-inappropriate low levels of CD31⁻ naive cells, increased levels of effector memory cells, and enhanced interferonγ and interleukin-17 secretion. Impaired CD4⁺ T-cell composition persisted in patients who initiated cART at <350 CD4⁺ T cells per microliter. In patients with CD4⁺ T cells ≥ 350 per microliter, alterations were less pronounced and were reversible with cART. Compared with age-matched controls, total CD4⁺ T-cell counts did not differ between treated younger and older HIV-infected patients. CONCLUSIONS: These data demonstrate that aging enhances the CD4⁺ T-cell impairment in HIV-infected persons mainly by a loss of CD31⁻ naive cells, accumulation of effector memory cells, and increased pro-inflammatory effector functions. Age-related changes in CD4⁺ T-cell composition can be prevented by an early initiation of cART.


Assuntos
Linfócitos T CD4-Positivos/imunologia , Infecções por HIV/imunologia , Subpopulações de Linfócitos T/imunologia , Adulto , Fatores Etários , Idoso , Antirretrovirais/uso terapêutico , Proliferação de Células , Citocinas/metabolismo , Feminino , Infecções por HIV/tratamento farmacológico , Humanos , Masculino , Pessoa de Meia-Idade , Molécula-1 de Adesão Celular Endotelial a Plaquetas/análise , Adulto Jovem
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