RESUMEN
OBJECTIVES: To quantify survivin and NETs in synovial fluid (SF) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and to assess whether there is a correlation of the quantifications with the exclusion of OA diagnosis and the activity of RA. METHODS: We performed a cross-sectional, observational study, in which 32 patients with RA and 16 with OA were included. Clinical and laboratory data were obtained, in addition to routine analysis of SF and the measurement of SF survivin and NETs. RA activity was assessed by DAS28. RESULTS: Concentrations of survivin (median, 356.9 vs. 49.9 pg/mL; p=0.0006) and NETs (median, 100.7 vs. 49.7 ng/mL; p=0.004) were elevated in the SF of the RA group compared to those of the OA group. ROC curves showed the following values for measurements of survivin and NETs: AUC of 79% and 75% respectively, with sensitivity of 75% and specificity of 78% for both. There was no correlation between survivin and NETs values for both groups, but we found association between SF survivin and serum ACPA for RA patients. CONCLUSIONS: We found an independent association between levels of survivin and NETs in SF with the exclusion of OA diagnosis, but not with RA activity. There was no correlation between survivin and NETs in SF, because we suppose that resistance to apoptosis, mediated by survivin, and NETosis are independently related to the pathophysiology of RA.
Asunto(s)
Artritis Reumatoide , Osteoartritis , Líquido Sinovial , Humanos , Biomarcadores , Estudios Transversales , SurvivinRESUMEN
Intracellular pattern recognition receptors such as the nucleotide-binding oligomerization domain (NOD)-like receptors family members are key for innate immune recognition of microbial infection and may play important roles in the development of inflammatory diseases, including rheumatic diseases. In this study, we evaluated the role of NOD1 and NOD2 on development of experimental arthritis. Ag-induced arthritis was generated in wild-type, NOD1(-/-), NOD2(-/-), or receptor-interacting serine-threonine kinase 2(-/-) (RIPK2(-/-)) immunized mice challenged intra-articularly with methylated BSA. Nociception was determined by electronic Von Frey test. Neutrophil recruitment and histopathological analysis of proteoglycan lost was evaluated in inflamed joints. Joint levels of inflammatory cytokine/chemokine were measured by ELISA. Cytokine (IL-6 and IL-23) and NOD2 expressions were determined in mice synovial tissue by RT-PCR. The NOD2(-/-) and RIPK2(-/-), but not NOD1(-/-), mice are protected from Ag-induced arthritis, which was characterized by a reduction in neutrophil recruitment, nociception, and cartilage degradation. NOD2/RIPK2 signaling impairment was associated with a reduction in proinflammatory cytokines and chemokines (TNF, IL-1ß, and CXCL1/KC). IL-17 and IL-17 triggering cytokines (IL-6 and IL-23) were also reduced in the joint, but there is no difference in the percentage of CD4(+) IL-17(+) cells in the lymph node between arthritic wild-type and NOD2(-/-) mice. Altogether, these findings point to a pivotal role of the NOD2/RIPK2 signaling in the onset of experimental arthritis by triggering an IL-17-dependent joint immune response. Therefore, we could propose that NOD2 signaling is a target for the development of new therapies for the control of rheumatoid arthritis.
Asunto(s)
Artritis Experimental/inmunología , Interleucina-17/metabolismo , Articulación de la Rodilla/inmunología , Proteína Adaptadora de Señalización NOD2/fisiología , Proteína Serina-Treonina Quinasas de Interacción con Receptores/fisiología , Transducción de Señal/inmunología , Animales , Artritis Experimental/metabolismo , Artritis Experimental/patología , Bovinos , Células Cultivadas , Interleucina-17/fisiología , Articulación de la Rodilla/patología , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Proteína Adaptadora de Señalización NOD1/deficiencia , Proteína Adaptadora de Señalización NOD2/deficiencia , Proteína Serina-Treonina Quinasa 2 de Interacción con Receptor , Proteína Serina-Treonina Quinasas de Interacción con Receptores/deficiencia , Albúmina Sérica Bovina/inmunología , Albúmina Sérica Bovina/toxicidad , Transducción de Señal/genéticaRESUMEN
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection is associated with a hyperinflammatory state and lymphocytopenia, a hallmark that appears as both signature and prognosis of disease severity outcome. Although cytokine storm and a sustained inflammatory state are commonly associated with immune cell depletion, it is still unclear whether direct SARS-CoV-2 infection of immune cells could also play a role in this scenario by harboring viral replication. We found that monocytes, as well as both B and T lymphocytes, were susceptible to SARS-CoV-2 infection in vitro, accumulating double-stranded RNA consistent with viral RNA replication and ultimately leading to expressive T cell apoptosis. In addition, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from coronavirus disease 2019 (COVID-19) patients. The rates of SARS-CoV-2-infected monocytes in peripheral blood mononuclear cells from COVID-19 patients increased over time from symptom onset, with SARS-CoV-2-positive monocytes, B cells, and CD4+ T lymphocytes also detected in postmortem lung tissue. These results indicated that SARS-CoV-2 infection of blood-circulating leukocytes in COVID-19 patients might have important implications for disease pathogenesis and progression, immune dysfunction, and virus spread within the host.
Asunto(s)
COVID-19 , SARS-CoV-2 , Síndrome de Liberación de Citoquinas , Humanos , Leucocitos Mononucleares , MonocitosRESUMEN
COVID-19 is a disease of dysfunctional immune responses, but the mechanisms triggering immunopathogenesis are not established. The functional plasticity of macrophages allows this cell type to promote pathogen elimination and inflammation or suppress inflammation and promote tissue remodeling and injury repair. During an infection, the clearance of dead and dying cells, a process named efferocytosis, can modulate the interplay between these contrasting functions. Here, we show that engulfment of SARS-CoV-2-infected apoptotic cells exacerbates inflammatory cytokine production, inhibits the expression of efferocytic receptors, and impairs continual efferocytosis by macrophages. We also provide evidence supporting that lung monocytes and macrophages from severe COVID-19 patients have compromised efferocytic capacity. Our findings reveal that dysfunctional efferocytosis of SARS-CoV-2-infected cell corpses suppresses macrophage anti-inflammation and efficient tissue repair programs and provides mechanistic insights for the excessive production of pro-inflammatory cytokines and accumulation of tissue damage associated with COVID-19 immunopathogenesis.
Asunto(s)
COVID-19 , SARS-CoV-2 , Antiinflamatorios/farmacología , Apoptosis , Humanos , Macrófagos/metabolismo , FagocitosisRESUMEN
OBJECTIVE: To evaluate whether the addition of colchicine to standard treatment for COVID-19 results in better outcomes. DESIGN: We present the results of a randomised, double-blinded, placebo-controlled clinical trial of colchicine for the treatment of moderate to severe COVID-19, with 75 patients allocated 1:1 from 11 April to 30 August 2020. Colchicine regimen was 0.5 mg thrice daily for 5 days, then 0.5 mg twice daily for 5 days. The primary endpoints were the need for supplemental oxygen, time of hospitalisation, need for admission and length of stay in intensive care unit and death rate. RESULTS: Seventy-two patients (36 for placebo and 36 for colchicine) completed the study. Median (and IQR) time of need for supplemental oxygen was 4.0 (2.0-6.0) days for the colchicine group and 6.5 (4.0-9.0) days for the placebo group (p<0.001). Median (IQR) time of hospitalisation was 7.0 (5.0-9.0) days for the colchicine group and 9.0 (7.0-12.0) days for the placebo group (p=0.003). At day 2, 67% versus 86% of patients maintained the need for supplemental oxygen, while at day 7, the values were 9% versus 42%, in the colchicine and the placebo groups, respectively (log rank; p=0.001). Two patients died, both in placebo group. Diarrhoea was more frequent in the colchicine group (p=0.26). CONCLUSION: Colchicine reduced the length of both, supplemental oxygen therapy and hospitalisation. The drug was safe and well tolerated. Once death was an uncommon event, it is not possible to ensure that colchicine reduced mortality of COVID-19. TRIAL REGISTRATION NUMBER: RBR-8jyhxh.
Asunto(s)
Tratamiento Farmacológico de COVID-19 , Colchicina/administración & dosificación , Tiempo de Internación , Terapia por Inhalación de Oxígeno , SARS-CoV-2/genética , Índice de Severidad de la Enfermedad , Adulto , Anciano , COVID-19/mortalidad , COVID-19/virología , Colchicina/efectos adversos , Diarrea/inducido químicamente , Método Doble Ciego , Femenino , Humanos , Unidades de Cuidados Intensivos , Masculino , Persona de Mediana Edad , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Factores de Tiempo , Resultado del TratamientoRESUMEN
Severe cases of COVID-19 are characterized by a strong inflammatory process that may ultimately lead to organ failure and patient death. The NLRP3 inflammasome is a molecular platform that promotes inflammation via cleavage and activation of key inflammatory molecules including active caspase-1 (Casp1p20), IL-1ß, and IL-18. Although participation of the inflammasome in COVID-19 has been highly speculated, the inflammasome activation and participation in the outcome of the disease are unknown. Here we demonstrate that the NLRP3 inflammasome is activated in response to SARS-CoV-2 infection and is active in COVID-19 patients. Studying moderate and severe COVID-19 patients, we found active NLRP3 inflammasome in PBMCs and tissues of postmortem patients upon autopsy. Inflammasome-derived products such as Casp1p20 and IL-18 in the sera correlated with the markers of COVID-19 severity, including IL-6 and LDH. Moreover, higher levels of IL-18 and Casp1p20 are associated with disease severity and poor clinical outcome. Our results suggest that inflammasomes participate in the pathophysiology of the disease, indicating that these platforms might be a marker of disease severity and a potential therapeutic target for COVID-19.
Asunto(s)
COVID-19/patología , COVID-19/virología , Inflamasomas/metabolismo , SARS-CoV-2/fisiología , Índice de Severidad de la Enfermedad , Apoptosis , Comorbilidad , Citocinas/biosíntesis , Humanos , Pulmón/patología , Monocitos/metabolismo , Proteína con Dominio Pirina 3 de la Familia NLR/metabolismo , Cambios Post Mortem , Resultado del TratamientoRESUMEN
OBJECTIVES: Interleukin 33 (IL-33) is a new member of the IL-1 family of cytokines which signals via its receptor, ST2 (IL-33R), and has an important role in Th2 and mast cell responses. This study shows that IL-33 orchestrates neutrophil migration in arthritis. METHODS AND RESULTS: Methylated bovine serum albumin (mBSA) challenge in the knee joint of mBSA-immunised mice induced local neutrophil migration accompanied by increased IL-33R and IL-33 mRNA expression. Cell migration was inhibited by systemic and local treatments with soluble (s)IL-33R, an IL-33 decoy receptor, and was not evident in IL-33R-deficient mice. IL-33 injection also induced IL-33R-dependent neutrophil migration. Antigen- and IL-33-induced neutrophil migration in the joint was dependent on CXCL1, CCL3, tumour necrosis factor alpha (TNFalpha) and IL-1beta synthesis. Synovial tissue, macrophages and activated neutrophils expressed IL-33R. IL-33 induces neutrophil migration by activating macrophages to produce chemokines and cytokines and by directly acting on neutrophils. Importantly, neutrophils from patients with rheumatoid arthritis successfully treated with anti-TNFalpha antibody (infliximab) expressed significantly lower levels of IL-33R than patients treated with methotrexate alone. Only neutrophils from patients treated with methotrexate alone or from normal donors stimulated with TNFalpha responded to IL-33 in chemotaxis. CONCLUSIONS: These results suggest that suppression of IL-33R expression in neutrophils, preventing IL-33-induced neutrophil migration, may be an important mechanism of anti-TNFalpha therapy of inflammation.
Asunto(s)
Antirreumáticos/farmacología , Artritis Reumatoide/inmunología , Interleucinas/inmunología , Infiltración Neutrófila/inmunología , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Animales , Artritis Experimental/tratamiento farmacológico , Artritis Experimental/inmunología , Artritis Reumatoide/tratamiento farmacológico , Factores Quimiotácticos/inmunología , Quimiotaxis de Leucocito/inmunología , Citocinas/inmunología , Regulación de la Expresión Génica/inmunología , Humanos , Proteína 1 Similar al Receptor de Interleucina-1 , Interleucina-33 , Interleucinas/biosíntesis , Interleucinas/genética , Activación de Macrófagos/inmunología , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BL , ARN Mensajero/genética , Receptores de Interleucina , Membrana Sinovial/inmunologíaRESUMEN
Although SARS-CoV-2 severe infection is associated with a hyperinflammatory state, lymphopenia is an immunological hallmark, and correlates with poor prognosis in COVID-19. However, it remains unknown if circulating human lymphocytes and monocytes are susceptible to SARS-CoV-2 infection. In this study, SARS-CoV-2 infection of human peripheral blood mononuclear cells (PBMCs) was investigated both in vitro and in vivo . We found that in vitro infection of whole PBMCs from healthy donors was productive of virus progeny. Results revealed that monocytes, as well as B and T lymphocytes, are susceptible to SARS-CoV-2 active infection and viral replication was indicated by detection of double-stranded RNA. Moreover, flow cytometry and immunofluorescence analysis revealed that SARS-CoV-2 was frequently detected in monocytes and B lymphocytes from COVID-19 patients, and less frequently in CD4 + T lymphocytes. The rates of SARS-CoV-2-infected monocytes in PBMCs from COVID-19 patients increased over time from symptom onset. Additionally, SARS-CoV-2-positive monocytes and B and CD4+T lymphocytes were detected by immunohistochemistry in post mortem lung tissue. SARS-CoV-2 infection of blood circulating leukocytes in COVID-19 patients may have important implications for disease pathogenesis, immune dysfunction, and virus spread within the host.
RESUMEN
OBJECTIVE: Infiltration of neutrophils into the joints plays an important role in bone erosion and articular destruction in rheumatoid arthritis (RA). Neutrophil trafficking during inflammation is a process that involves activation of chemotactic receptors. Recent findings suggest that changes in chemotactic receptor patterns could occur in neutrophils under certain inflammatory conditions. The aim of this study was to evaluate the gain of responsiveness of neutrophils to CCL2 in RA patients and to assess the role of CCL2 in driving neutrophil infiltration into the joints. METHODS: Neutrophils were purified from the peripheral blood of patients with RA or from mice with antigen-induced arthritis (AIA). Expression of CCR2 was evaluated using polymerase chain reaction, flow cytometry, and immunofluorescence analyses. In vitro chemotaxis to CCL2 was assayed to evaluate the functional significance of de novo CCR2 expression. The murine AIA model was used to evaluate the in vivo role of CCR2 in neutrophil infiltration into the joints. RESULTS: High CCR2 expression and responsiveness to CCL2 were observed in neutrophils from the blood of patients with early RA and in neutrophils from the blood and bone marrow of mice with AIA. Genetic deficiency or pharmacologic inhibition of CCR2 protected against the infiltration of neutrophils into the joints. This protection was not associated with an impairment of the neutrophil chemotactic ability or CXC chemokine production in the joints. Moreover, adoptive transfer of wild-type mouse neutrophils to CCR2-deficient mice restored neutrophil infiltration and the articular mechanical hyperalgesia associated with joint inflammation. CONCLUSION: These findings suggest that CCR2 is directly involved in the detrimental infiltration of neutrophils into the joints in patients with RA, showing a new inflammatory role of CCR2 during RA flares or active disease.
Asunto(s)
Artritis Reumatoide/patología , Artritis Reumatoide/fisiopatología , Movimiento Celular/fisiología , Articulaciones/patología , Neutrófilos/patología , Receptores CCR2/metabolismo , Animales , Artritis Reumatoide/metabolismo , Estudios de Casos y Controles , Movimiento Celular/efectos de los fármacos , Quimiocina CCL2/farmacología , Quimiotaxis/fisiología , Modelos Animales de Enfermedad , Femenino , Humanos , Técnicas In Vitro , Articulaciones/metabolismo , Masculino , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Infiltración Neutrófila/efectos de los fármacos , Infiltración Neutrófila/fisiología , Neutrófilos/efectos de los fármacos , Neutrófilos/metabolismo , Receptores CCR2/deficiencia , Receptores CCR2/genética , Índice de Severidad de la EnfermedadRESUMEN
Vários estudos observacionais apontam forte associação entre hiperglicemia nos pacientes hospitalizados e desfechos clínicos desfavoráveis, incluindo tempo de internação prolongado, infecção, incapacidade após alta hospitalar e morte. A Associação Americana de Endocrinologistas Clínicos (AACE) e a Associação Americana de Diabetes(ADA) sugerem que a insulinoterapia seja iniciada para o tratamento de hiperglicemia persistente a partir de níveis de glicemia de 180 mg/dL. Para a maioria dos pacientes não críticos internados, a metaglicêmica pré-prandial é <140 mg/dL e a casual <180mg/dL. O esquema de insulinização basal-bolus em associação com doses corretivas ou suplementares para o controle da hiperglicemia pré-prandial é a abordagem recomendada. O plano de alta, a educação do paciente durante a internação e a comunicação clara com os cuidadoressão fundamentais para garantir transição segura para o manejo ambulatorial da glicemia.
Several observational studies suggest a strong association between inpatient hyperglycemia (with or without diabetes) and adverse clinical outcomes, including prolonged hospitalization, infection, disability after hospital discharge and death.The American Association of Clinical Endocrinologists (AACE) and American Diabetes Association (ADA) suggest that insulin therapy is initiated for the treatment of persistent hyperglycemia from glucose levels of 180mg/dL. For most noncritically inpatients, usually the goal of premeal blood glucose should be<140mg/dL and random blood glucose < 180mg/dL. The scheme of basal-bolus insulin, in combination with corrective or additional doses to control premeal hyperglycemia is the recommended approach. Discharge planning, patient education and clear communication with outpatient providers are critical forensuring a safe transition to outpatient glycemic management.
Asunto(s)
Humanos , Terapia Convulsiva , Diabetes Mellitus , Hiperglucemia , HipoglucemiaRESUMEN
Artrites são manifestações clínicas de uma série de doenças. Sua classificação etiológica é muitas vezes difícil e depende de história clínica e exame físico cuidadosos. Artrite séptica e gota se apresentam mais comumente como monoartrite aguda e quadros reacionais são geralmente poliarticulares. A internação hospitalar é fator de risco para o desenvolvimento tanto de artrites reacionais quanto para crises de gota e artrite séptica. O diagnóstico precoce é muito importante a fim de iniciar o tratamento precocemente, alívio dos sintomas e preservação da funcionalidade articular. A punção do líquido sinoviale sua análise são de fundamental importância diagnóstica nos quadros de monoartrite aguda.
Arthritis are clinical manifestations of plenty of diseases. Its etiological classification is many timesdifficult and depends on careful clinical history and physical examination. Gout and skeptical arthritispresents commonly as acute monoarthritis and reactional arthritis are often polyarticular. Hospitalaradmission is a risk factor to the development of reactional arthritis, crisis of gout and septical arthritis.Early diagnosis is imperative to start early treatment, symptom relief and articular function preservation.Synovial fluid aspiration and its analysis are of critical diagnostic importance in cases of acute monoarthritis.
Asunto(s)
Humanos , Artritis/clasificación , Artritis/diagnósticoRESUMEN
A dengue é uma arbovirose transmitida principalmente pela picada do mosquito Aedes aegypti. Pode ser assintomática ou apresentar amplo espectro clínico, variando de doença febril autolimitada até formas graves, que podem evoluir com choque circulatório e óbito. Para evitar esse desfecho, a precocidade no diagnóstico da doença e na detecção de sinais de alarme, que indicam evolução desfavorável; assim como a instituição de tratamento adequado, são fundamentais. Não há tratamento específico, ele é apenas sintomático e de suporte. Até o momento, não existe vacina disponível para prevenção da doença, sendo o controle do vetor a medida mais efetiva.
Dengue is an arbovirus transmitted mainly by the bite of the mosquito Aedes aegypti. It can be asymptomaticor present a wide clinical spectrum, ranging from self-limited febrile illness to severe forms that could evolve with circulatory shock and death. In order to avoid this outcome, early diagnosis of disease and the detection of warning signs that indicate unfavorable, as well as adequate treatment are essential,There is no specific treatment, it is only symptomatic and supportive. Up to now, there is no vaccine available for prevention of disease, vector control the most effective measure.