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Rheumatol Int ; 38(6): 1043-1052, 2018 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-29464314


We examined the functional activity of peripheral blood neutrophils and the complement system activation status in patients with rheumatoid arthritis (RA) undergoing infliximab/methotrexate combined therapy. We studied female RA patients under treatment with infliximab (3-5 mg/kg) and methotrexate (15-25 mg/week) who presented inactive (i-RA; n = 34, DAS-28 ≤ 2.6) or at least moderately active disease (a-RA; n = 29, DAS-28 > 3.2), and age-matched healthy women (n = 38). We measured the levels of reactive oxygen species (ROS) generation (chemiluminescence assay) and membrane expression of FcγRIIa/CD32, FcγRIIIb/CD16, CR1/CD35, and CR3/CD11b receptors (ELISA assay) in neutrophils. We also determined the hemolytic activity of the alternative and classical pathways of the complement system (spectrophotometry), serum levels of C5a and Bb (ELISA assay), and serum chemotactic activity (Boyden chamber). Compared with the control group, i-RA and a-RA patients exhibited: (1) increased neutrophil ROS production and membrane expression of FcγRIIa/CD32, FcγRIIIb/CD16, and CR1/CD35, indicating neutrophil activation; and (2) increased serum chemotactic activity and decreased activity of the alternative complement pathway, indicating systemic complement system activation. The levels of C-reactive protein in a-RA patients were augmented, compared with i-RA patients. Although infliximab/methotrexate combined therapy induced disease remission according to the DAS-28 criteria, both i-RA and a-RA patients still exhibited significant levels of systemic activation of neutrophils and the complement system.

Artrite Reumatoide/imunologia , Ativação do Complemento , Neutrófilos/imunologia , Adulto , Anticorpos Monoclonais/uso terapêutico , Complexo Antígeno-Anticorpo/biossíntese , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Brasil , Feminino , Humanos , Infliximab/uso terapêutico , Metotrexato/uso terapêutico , Pessoa de Meia-Idade , Espécies Reativas de Oxigênio/imunologia , Espécies Reativas de Oxigênio/metabolismo
Clin Exp Rheumatol ; 35(2): 247-254, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-27908303


OBJECTIVES: Neutrophils play a major role in rheumatoid arthritis (RA) pathogenesis. We aimed to evaluate if neutrophil DNA damage in RA patients is associated with the disease activity, autoantibodies status, carriage of the RA shared epitope (SE) and treatment. METHODS: DNA damage was assessed by alkaline comet assay in peripheral blood (77 patients and 55 healthy controls) and in 10 RA synovial fluid neutrophils. Evaluation of the respiratory burst of 30 patients with RA and 30 healthy controls was done. RESULTS: Compared to controls, RA patients exhibited increased neutrophil DNA damage. RA synovial fluid cells DNA damage was increased when compared to OA synovial fluids cells. In addition, our study shows that anti-TNF-α therapy reduces the frequency of DNA damage. Patients with simple or double dose of shared epitope presented a higher frequency of DNA damage compared to patients without the allele. Positive correlation was found between neutrophil DNA damage and DAS-28 and ROS production. CONCLUSIONS: Our results suggest that an increase of respiratory burst of neutrophils reflects the higher levels of DNA damage in neutrophils and a positive correlation between DNA damage and disease activity shows the importance of oxidative stress in the pathogenesis of RA.

Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Dano ao DNA , Epitopos/imunologia , Antígenos HLA/imunologia , Neutrófilos/imunologia , Neutrófilos/patologia , Adulto , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/metabolismo , Autoanticorpos/sangue , Estudos de Casos e Controles , Ensaio Cometa , Dano ao DNA/efeitos dos fármacos , Epitopos/sangue , Epitopos/genética , Feminino , Antígenos HLA/sangue , Antígenos HLA/genética , Humanos , Pessoa de Meia-Idade , Neutrófilos/efeitos dos fármacos , Neutrófilos/metabolismo , Estresse Oxidativo , Espécies Reativas de Oxigênio/metabolismo , Explosão Respiratória , Índice de Gravidade de Doença , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Fator de Necrose Tumoral alfa/imunologia
Int Immunopharmacol ; 21(1): 102-11, 2014 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-24797916


Rheumatoid arthritis (RA) patients usually exhibit immune complex (IC) deposition and increased neutrophil activation in the joint. In this study, we assessed how four flavonols (galangin, kaempferol, quercetin, and myricetin) modulate the effector functions of healthy individuals' and active RA patients' IC-stimulated neutrophils. We measured superoxide anion and total reactive oxygen species production using lucigenin (CL-luc)- and luminol (CL-lum)-enhanced chemiluminescence assays, respectively. Galangin, kaempferol, and quercetin inhibited CL-lum to the same degree (mean IC50=2.5 µM). At 2.5 µM, quercetin and galangin suppressed nearly 65% CL-lum of active RA patients' neutrophils. Quercetin inhibited CL-luc the most effectively (IC50=1.71±0.36 µM). The four flavonols diminished myeloperoxidase activity, but they did not decrease NADPH oxidase activity, phagocytosis, microbial killing, or cell viability of neutrophils. The ability of the flavonols to scavenge hypochlorous acid and chloramines, but not H2O2, depended on the hydroxylation degree of the flavonol B-ring. Therefore, at physiologically relevant concentrations, the flavonols partially inhibited the oxidative metabolism of IC-stimulated neutrophils without affecting the other investigated effector functions. Using these compounds to modulate IC-mediated neutrophil activation is a promising safe therapeutic strategy to control inflammation in active RA patients.

Anti-Inflamatórios/farmacologia , Artrite Reumatoide/tratamento farmacológico , Flavonoides/farmacologia , Quempferóis/farmacologia , Neutrófilos/efeitos dos fármacos , Quercetina/farmacologia , Adulto , Anti-Inflamatórios/química , Complexo Antígeno-Anticorpo/imunologia , Degranulação Celular/efeitos dos fármacos , Células Cultivadas , Feminino , Flavonoides/química , Humanos , Quempferóis/química , Pessoa de Meia-Idade , Neutrófilos/imunologia , Oxirredução/efeitos dos fármacos , Peroxidase/metabolismo , Quercetina/química , Espécies Reativas de Oxigênio/metabolismo , Relação Estrutura-Atividade