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1.
Artigo em Inglês | MEDLINE | ID: mdl-39136831

RESUMO

PURPOSE: To increase knowledge about the varied clinical manifestations of human infection with the emerging tick-borne pathogen Neoehrlichia mikurensis. METHODS: All patients diagnosed in Sweden with N. mikurensis infection during a 10-year period (2013-2023) were investigated regarding their demographic factors, risk factors, comorbidities, clinical signs and symptoms, and laboratory results. Multivariate models were generated using "Orthogonal Projections to Latent Structures-Discriminant Analysis" to identify clinical and immune parameters associated with N. mikurensis infection. RESULTS: During the 10-year period, 134 patients were diagnosed with N. mikurensis infection, 102 of whom were included in this study. Most of the patients (79%) were immunosuppressed. The main comorbidities were malignant B-cell lymphomas, multiple sclerosis, and rheumatoid arthritis. Rituximab therapy (59%) and splenectomy (14%) featured prominently. All patients resided in the southern tick-endemic part of Sweden, yet one-third of them were diagnosed in wintertime when ticks are inactive. Two asymptomatically infected blood donors were identified but transfusion-transmitted infection was not confirmed. Increased levels of C-reactive protein, orosomucoid, and total IgM in serum were associated with neoehrlichiosis. Previously unreported symptoms such as ankle edema, neck pain, numbness, and sudden deafness were detected in some patients. One case of aplastic anemia partially improved after eradication of the infection. CONCLUSIONS: Neoehrlichiosis is a multi-faceted emerging infectious disease.

2.
J Infect Dis ; 211(9): 1476-83, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25429102

RESUMO

BACKGROUND: Seasonal increases in malaria continue in hot spots in Zanzibar. Mass screening and treatment (MSAT) may help reduce the reservoir of infection; however, it is unclear whether rapid diagnostic tests (RDTs) detect a sufficient proportion of low-density infections to influence subsequent transmission. METHODS: Two rounds of MSAT using Plasmodium falciparum-specific RDT were conducted in 5 hot spots (population, 12 000) in Zanzibar in 2012. In parallel, blood samples were collected on filter paper for polymerase chain reaction (PCR) analyses. Data on confirmed malarial parasite infections from health facilities in intervention and hot spot control areas were monitored as proxy for malaria transmission. RESULTS: Approximately 64% of the population (7859) were screened at least once. P. falciparum prevalence, as measured by RDT, was 0.2% (95% confidence interval [CI], .1%-.3%) in both rounds, compared with PCR measured prevalences (for all species) of 2.5% (95% CI, 2.1%-2.9%) and 3.8% (95% CI, 3.2%-4.4%) in rounds 1 and 2, respectively. Two fifths (40%) of infections detected by PCR included non-falciparum species. Treatment of RDT-positive individuals (4% of the PCR-detected parasite carriers) did not reduce subsequent malaria incidence, compared with control areas. CONCLUSIONS: Highly sensitive point-of-care diagnostic tools for detection of all human malaria species are needed to make MSAT an effective strategy in settings where malaria elimination programs are in the pre-elimination phase.


Assuntos
Antimaláricos/uso terapêutico , Malária Falciparum/diagnóstico , Malária Falciparum/tratamento farmacológico , Programas de Rastreamento , Plasmodium falciparum , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Pré-Escolar , Feminino , Humanos , Incidência , Lactente , Masculino , Pessoa de Meia-Idade , Reação em Cadeia da Polimerase/métodos , Estações do Ano , Sensibilidade e Especificidade , Tanzânia/epidemiologia , Adulto Jovem
3.
Arthritis Res Ther ; 26(1): 178, 2024 Oct 11.
Artigo em Inglês | MEDLINE | ID: mdl-39394168

RESUMO

BACKGROUND: Activated fibroblast-like synoviocytes (FLS) are drivers of synovitis and structural joint damage in rheumatoid arthritis (RA). Despite the use of disease-modifying drugs, only about 50% of RA patients reach remission in real-world settings. We used an unbiased approach to investigate the effects of standard-of-care methotrexate (MTX) and a Janus kinase inhibitor, tofacitinib (TOFA), on gene expression in RA-FLS, in order to identify untargeted disease mediators. METHODS: Primary RA-FLS were activated by stimulation with interleukin-1ß (IL-1ß) or platelet-derived growth factor + IL-1ß in the presence or absence of MTX or TOFA, with or without additional inhibitors. Co-cultures of synovial cells were performed in direct and indirect systems. Cells were collected for RNA sequencing or qPCR, and supernatants were analyzed for protein concentrations. RESULTS: Six thousand three hundred fifty genes were differentially expressed, the majority being upregulated, in MTX-treated activated RA-FLS and 970 genes, the majority being downregulated, in TOFA-treated samples. Pathway analysis showed that MTX had largest effects on 'Molecular mechanisms of cancer' and TOFA on 'Interferon signaling'. Targeted analysis of disease-associated genes revealed that MTX increased the expression of cell cycle-regulating genes but also of pro-inflammatory mediators like IL-1α (IL1A) and granulocyte-macrophage colony-stimulating factor, GM-CSF (CSF2). The MTX-promoted expression of CSF2 in activated RA-FLS peaked at 48 h, could be mediated via either NF-κB or AP-1 transcription factors, and was abrogated by IL-1 inhibitors (IRAK4 inhibitor and anakinra). In a co-culture setting, MTX-treatment of activated RA-FLS induced IL1B expression in macrophages. CONCLUSIONS: MTX treatment induces secretion of IL-1 from activated RA-FLS which by autocrine signaling augments their release of GM-CSF. This unexpected effect of MTX might contribute to the persistence of synovitis.


Assuntos
Antirreumáticos , Artrite Reumatoide , Fator Estimulador de Colônias de Granulócitos e Macrófagos , Metotrexato , Transdução de Sinais , Sinoviócitos , Artrite Reumatoide/metabolismo , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Humanos , Metotrexato/farmacologia , Sinoviócitos/efeitos dos fármacos , Sinoviócitos/metabolismo , Fator Estimulador de Colônias de Granulócitos e Macrófagos/metabolismo , Antirreumáticos/farmacologia , Transdução de Sinais/efeitos dos fármacos , Células Cultivadas , Fibroblastos/metabolismo , Fibroblastos/efeitos dos fármacos , Interleucina-1/metabolismo , Comunicação Autócrina/efeitos dos fármacos , Técnicas de Cocultura , Membrana Sinovial/metabolismo , Membrana Sinovial/efeitos dos fármacos , Membrana Sinovial/patologia , Piperidinas , Pirimidinas
4.
Arthritis Res Ther ; 22(1): 245, 2020 10 16.
Artigo em Inglês | MEDLINE | ID: mdl-33066816

RESUMO

BACKGROUND: The majority of CD4+ T helper (Th) cells found in the synovial fluid (SF) of patients with rheumatoid arthritis (RA) express CXCR3, a receptor associated with Th1 cells. In blood, subsets of Th2 and Th17 cells also express CXCR3, but it is unknown if these cells are present in RA SF or how cytokines from these subsets affect cytokine/chemokine secretion by fibroblast-like synoviocytes (FLS) from patients with RA. METHODS: We examined the proportions of Th1, Th2, CXCR3+Th2, Th17, CXCR3+Th17, Th1Th17, peripheral T helper (TPh) and T follicular helper (TFh) cells in paired SF and blood, as well as the phenotype of TPh and TFh cells in RA SF (n = 8), by the use of flow cytometry. We also examined the cytokine/chemokine profile in paired SF and plasma (n = 8) and in culture supernatants of FLS from patients with chronic RA (n = 7) stimulated with Th-associated cytokines, by the use of cytometric bead arrays and ELISA. Cytokine receptor expression in FLS (n = 3) were assessed by the use of RNA sequencing and qPCR. RESULTS: The proportions of Th1 and CXCR3+Th2 cells were higher in SF than in blood (P < 0.05). TPh and PD-1highTFh in RA SF were primarily of a Th1 and a CXCR3+Th2 phenotype. Moreover, the levels of CXCL9, CXCL10, CCL20, CCL2, CXCL8, IL-6 and IL-10 were higher in SF than in plasma (P < 0.05). Lastly, IL-4, IL-13 and IL-17A induced RA FLS to secrete proinflammatory IL-6, CCL2, CXCL1 and CXCL8, while IFNγ mainly induced CXCL10. CONCLUSION: These findings indicate that not only Th1 but also CXCR3+Th2 cells may have a pathogenic role in RA synovial inflammation.


Assuntos
Artrite Reumatoide , Líquido Sinovial , Humanos , Fenótipo , Receptores CXCR3 , Células Th1 , Células Th17 , Células Th2
5.
Front Immunol ; 10: 1384, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31275320

RESUMO

The autoimmune regulator AIRE controls the negative selection of self-reactive T-cells as well as the induction of regulatory T-cells in the thymus by mastering the transcription and presentation of tissue restricted antigens (TRAs) in thymic cells. However, extrathymic AIRE expression of hitherto unknown clinical significance has also been reported. Genetic polymorphisms of AIRE have been associated with rheumatoid arthritis (RA), but no specific disease-mediating mechanism has been identified. Rheumatoid arthritis is characterized by a systemic immune activation and arthritis. Activated fibroblast-like synoviocytes (FLS) are key effector cells, mediating persistent inflammation, and destruction of joints. In this study, we identified AIRE as a cytokine-induced RA risk gene in RA FLS and explored its role in these pathogenic stroma cells. Using RNA interference and RNA sequencing we show that AIRE does not induce TRAs in FLS, but augments the pro-inflammatory response induced by tumor necrosis factor and interleukin-1ß by promoting the transcription of a set of genes associated with systemic autoimmune disease and annotated as interferon-γ regulated genes. In particular, AIRE promoted the production and secretion of a set of chemokines, amongst them CXCL10, which have been associated with disease activity in RA. Finally, we demonstrate that AIRE is expressed in podoplanin positive FLS in the lining layer of synovial tissue from RA patients. These findings support a novel pro-inflammatory role of AIRE at peripheral inflammatory sites and provide a potential pathological mechanism for its association with RA.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Membrana Sinovial/imunologia , Sinoviócitos/metabolismo , Fatores de Transcrição/genética , Células Cultivadas , Quimiocina CXCL10/metabolismo , Humanos , Inflamação/imunologia , Interferon gama/imunologia , Interleucina-1beta/imunologia , Glicoproteínas de Membrana/metabolismo , Polimorfismo de Nucleotídeo Único/genética , Interferência de RNA , RNA Interferente Pequeno/genética , Fator de Necrose Tumoral alfa/imunologia , Proteína AIRE
6.
Arthritis Res Ther ; 20(1): 49, 2018 03 20.
Artigo em Inglês | MEDLINE | ID: mdl-29554943

RESUMO

BACKGROUND: A key feature of joints in rheumatoid arthritis (RA) is the formation of hyperplastic destructive pannus tissue, which is orchestrated by activated fibroblast-like synoviocytes (FLS). We have demonstrated that the RA risk gene and tumor suppressor Limb bud and heart development (LBH) regulates cell cycle progression in FLS. Methotrexate (MTX) is the first-line treatment for RA, but its mechanisms of action remain incompletely understood. Here, we studied the effects of MTX on mitogen-induced FLS proliferation and expression of cell cycle regulators in vitro. METHODS: Primary FLS from patients with RA or osteoarthritis were stimulated with the mitogen platelet-derived growth factor (PDGF) and the cytokine interleukin-1ß (IL-1ß) in the presence or absence of MTX. Cells were then subjected to qPCR for gene expression and cell cycle analysis by flow cytometry. RESULTS: Stimulation with PDGF and IL-1ß increased the percentage of FLS in the G2/M phase and shifted the cell morphology to a dendritic shape. These effects were inhibited by MTX. Furthermore, PDGF + IL-1ß reduced LBH mRNA expression. However, MTX treatment yielded significantly higher transcript levels of LBH, and of CDKN1A (p21) and TP53 (p53), compared to untreated samples upon mitogen stimulation. The expression of DNA methyltransferase-1 (DNMT1) was also higher in the presence of MTX and there was strong correlation between DNMT1 and LBH expression. CONCLUSIONS: Therapeutic concentrations of MTX abolish the effects of PDGF and IL-1ß on tumor suppressor expression and inhibit mitogen-promoted FLS proliferation. These data demonstrate novel and important effects of MTX on pathogenic effector cells in the joint, which might involve epigenetic mechanisms.


Assuntos
Artrite Reumatoide/metabolismo , Fibroblastos/metabolismo , Interleucina-1beta/toxicidade , Metotrexato/farmacologia , Fator de Crescimento Derivado de Plaquetas/toxicidade , Sinoviócitos/metabolismo , Antirreumáticos/farmacologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/patologia , Proliferação de Células/efeitos dos fármacos , Proliferação de Células/fisiologia , Células Cultivadas , Fibroblastos/efeitos dos fármacos , Humanos , Interleucina-1beta/antagonistas & inibidores , Metotrexato/uso terapêutico , Fator de Crescimento Derivado de Plaquetas/antagonistas & inibidores , Sinoviócitos/efeitos dos fármacos
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