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1.
PLoS One ; 15(11): e0241724, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-33237924

RESUMO

INTRODUCTION: Sources of infection of most cases of community-acquired Legionnaires' disease (CALD) are unknown. OBJECTIVE: Identification of sources of infection of CALD. SETTING: Berlin; December 2016-May 2019. PARTICIPANTS: Adult cases of CALD reported to district health authorities and consenting to the study; age and hospital matched controls. MAIN OUTCOME MEASURE: Percentage of cases of CALD with attributed source of infection. METHODS: Analysis of secondary patient samples for monoclonal antibody (MAb) type (and sequence type); questionnaire-based interviews, analysis of standard household water samples for Legionella concentration followed by MAb (and sequence) typing of Legionella pneumophila serogroup 1 (Lp1) isolates; among cases taking of additional water samples to identify the infectious source as appropriate; recruitment of control persons for comparison of exposure history and Legionella in standard household water samples. For each case an appraisal matrix was filled in to attribute any of three source types (external (non-residence) source, residential non-drinking water (RnDW) source (not directly from drinking water outlet), residential drinking water (RDW) as source) using three evidence types (microbiological results, cluster evidence, analytical-comparative evidence (using added information from controls)). RESULTS: Inclusion of 111 study cases and 202 controls. Median age of cases was 67 years (range 25-93 years), 74 (67%) were male. Among 65 patients with urine typable for MAb type we found a MAb 3/1-positive strain in all of them. Compared to controls being a case was not associated with a higher Legionella concentration in standard household water samples, however, the presence of a MAb 3/1-positive strain was significantly associated (odds ratio (OR) = 4.9, 95% confidence interval (CI) 1.7 to 11). Thus, a source was attributed by microbiological evidence if it contained a MAb 3/1-positive strain. A source was attributed by cluster evidence if at least two cases were exposed to the same source. Statistically significant general source types were attributed by calculating the population attributable risk (analytical-comparative evidence). We identified an external source in 16 (14%) cases, and RDW as source in 28 (25%). Wearing inadequately disinfected dentures was the only RnDW source significantly associated with cases (OR = 3.2, 95% CI 1.3 to 7.8) and led to an additional 8% of cases with source attribution, for a total of 48% of cases attributed. CONCLUSION: Using the appraisal matrix we attributed almost half of all cases of CALD to an infectious source, predominantly RDW. Risk for LD seems to be conferred primarily by the type of Legionella rather than the amount. Dentures as a new infectious source needs further, in particular, integrated microbiological, molecular and epidemiological confirmation.

2.
Ann Clin Transl Neurol ; 7(11): 2161-2177, 2020 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-32997393

RESUMO

OBJECTIVE: To assess class I-histone deacetylase (HDAC) inhibition on formation of lipid-accumulating, disease-promoting phagocytes upon myelin load in vitro, relevant for neuroinflammatory disorders like multiple sclerosis (MS) and cerebral X-linked adrenoleukodystrophy (X-ALD). METHODS: Immunohistochemistry on postmortem brain tissue of acute MS (n = 6) and cerebral ALD (n = 4) cases to analyze activation and foam cell state of phagocytes. RNA-Seq of in vitro differentiated healthy macrophages (n = 8) after sustained myelin-loading to assess the metabolic shift associated with foam cell formation. RNA-Seq analysis of genes linked to lipid degradation and export in MS-275-treated human HAP1 cells and RT-qPCR analysis of HAP1 cells knocked out for individual members of class I HDACs or the corresponding enzymatically inactive knock-in mutants. Investigation of intracellular lipid/myelin content after MS-275 treatment of myelin-laden human foam cells. Analysis of disease characteristic very long-chain fatty acid (VLCFA) metabolism and inflammatory state in MS-275-treated X-ALD macrophages. RESULTS: Enlarged foam cells coincided with a pro-inflammatory, lesion-promoting phenotype in postmortem tissue of MS and cerebral ALD patients. Healthy in vitro myelin laden foam cells upregulated genes linked to LXRα/PPARγ pathways and mimicked a program associated with tissue repair. Treating these cells with MS-275, amplified this gene transcription program and significantly reduced lipid and cholesterol accumulation and, thus, foam cell formation. In macrophages derived from X-ALD patients, MS-275 improved the disease-associated alterations of VLCFA metabolism and reduced the pro-inflammatory status of these cells. INTERPRETATION: These findings identify class I-HDAC inhibition as a potential novel strategy to prevent disease promoting foam cell formation in CNS inflammation.

3.
Sci Rep ; 10(1): 10887, 2020 07 02.
Artigo em Inglês | MEDLINE | ID: mdl-32616803

RESUMO

The intesinal microbiome is considered important in human immunodeficiency virus (HIV) pathogenesis and therefore represents a potential therapeutic target to improve the patients' health status. Longitudinal alterations in the colonic mucosa-associated microbiome during simian immunodeficiency virus (SIV) infection were investigated using a 16S rRNA amplicon approach on the Illumina sequencing platform and bioinformatics analyses. Following SIV infection of six animals, no alterations in microbial composition were observed before the viral load peaked in the colon. At the time of acute mucosal SIV replication, the phylum Bacteroidetes including the Bacteroidia class as well as the phylum Firmicutes and its families Ruminococcaceae and Eubacteriaceae became more abundant. Enrichment of Bacteroidetes was maintained until the chronic phase of SIV infection. The shift towards Bacteroidetes in the mucosa-associated microbiome was associated with the extent of SIV infection-induced mucosal CD4+ T cell depletion and correlated with increasing rates of enterocyte damage. These observations suggest that Bacteroidetes strains increase during virus-induced mucosal immune destruction. As Bacteroidetes belong to the lipopolysaccharide- and short chain fatty acids-producing bacteria, their rapid enrichment may contribute to inflammatory tissue damage and metabolic alterations in SIV/HIV infection. These aspects should be considered in future studies on therapeutic interventions.

5.
Int J Mol Sci ; 20(19)2019 Sep 28.
Artigo em Inglês | MEDLINE | ID: mdl-31569415

RESUMO

Campylobacter jejuni (C. jejuni) is the most common cause of foodborne gastroenteritis worldwide. The bacteria induce diarrhea and inflammation by invading the intestinal epithelium. Curcumin is a natural polyphenol from turmeric rhizome of Curcuma longa, a medical plant, and is commonly used in curry powder. The aim of this study was the investigation of the protective effects of curcumin against immune-induced epithelial barrier dysfunction in C. jejuni infection. The indirect C. jejuni-induced barrier defects and its protection by curcumin were analyzed in co-cultures with HT-29/B6-GR/MR epithelial cells together with differentiated THP-1 immune cells. Electrophysiological measurements revealed a reduction in transepithelial electrical resistance (TER) in infected co-cultures. An increase in fluorescein (332 Da) permeability in co-cultures as well as in the germ-free IL-10-/- mouse model after C. jejuni infection was shown. Curcumin treatment attenuated the C. jejuni-induced increase in fluorescein permeability in both models. Moreover, apoptosis induction, tight junction redistribution, and an increased inflammatory response-represented by TNF-α, IL-1ß, and IL-6 secretion-was observed in co-cultures after infection and reversed by curcumin. In conclusion, curcumin protects against indirect C. jejuni-triggered immune-induced barrier defects and might be a therapeutic and protective agent in patients.


Assuntos
Anti-Inflamatórios não Esteroides/farmacologia , Infecções por Campylobacter/imunologia , Campylobacter jejuni/imunologia , Curcumina/farmacologia , Membrana Mucosa/efeitos dos fármacos , Membrana Mucosa/imunologia , Animais , Apoptose , Infecções por Campylobacter/microbiologia , Linhagem Celular , Técnicas de Cocultura , Citocinas/biossíntese , Células Epiteliais/efeitos dos fármacos , Células Epiteliais/metabolismo , Humanos , Interleucina-10/genética , Interleucina-10/metabolismo , Mucosa Intestinal/efeitos dos fármacos , Mucosa Intestinal/imunologia , Mucosa Intestinal/metabolismo , Camundongos , Camundongos Knockout , Membrana Mucosa/microbiologia , Proteínas de Junções Íntimas/genética , Proteínas de Junções Íntimas/metabolismo , Junções Íntimas/genética , Junções Íntimas/metabolismo
6.
J Immunol ; 203(1): 208-215, 2019 07 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.


Assuntos
Infecções por Helicobacter/imunologia , Helicobacter pylori/fisiologia , Mucosa Intestinal/imunologia , Linfoma de Zona Marginal Tipo Células B/imunologia , Plasmócitos/imunologia , Antro Pilórico/imunologia , Linfócitos T/imunologia , Adulto , Proteínas de Bactérias/imunologia , Doença Crônica , Epitopos , Feminino , Humanos , Imunoglobulinas/metabolismo , Lipopolissacarídeos/imunologia , Linfoma de Zona Marginal Tipo Células B/genética , Masculino , Pessoa de Meia-Idade , Óxido Nítrico Sintase Tipo II/metabolismo , Hipermutação Somática de Imunoglobulina , Adulto Jovem
8.
Eur Heart J ; 40(40): 3318-3332, 2019 Oct 21.
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.

9.
Clin Infect Dis ; 68(7): 1089-1097, 2019 03 19.
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.


Assuntos
Técnicas de Diagnóstico Molecular/métodos , Reação em Cadeia da Polimerase/métodos , Tropheryma/isolamento & purificação , Urina/microbiologia , Doença de Whipple/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Tropheryma/genética , Adulto Jovem
10.
Mol Diagn Ther ; 22(4): 459-469, 2018 08.
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.


Assuntos
Proteínas de Bactérias/genética , Leucócitos Mononucleares/microbiologia , Reação em Cadeia da Polimerase , Tropheryma/genética , Doença de Whipple/diagnóstico , Doença de Whipple/microbiologia , Adulto , Idoso , Proteínas de Bactérias/metabolismo , Biomarcadores , Separação Celular , Feminino , Humanos , Imuno-Histoquímica , Imunofenotipagem , Leucócitos Mononucleares/metabolismo , Masculino , Pessoa de Meia-Idade , RNA Ribossômico 16S/genética , Sensibilidade e Especificidade
11.
J Infect Dis ; 217(9): 1421-1425, 2018 04 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.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , Mucosa Intestinal/citologia , Mucosa Intestinal/virologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/fisiologia , Animais , DNA Viral/isolamento & purificação , Macaca mulatta , RNA Viral/isolamento & purificação , Carga Viral , Replicação Viral/fisiologia
13.
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
14.
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
15.
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.

16.
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
17.
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
18.
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
20.
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
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