Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 18.290
Filtrar
1.
Nat Commun ; 11(1): 4243, 2020 08 25.
Artigo em Inglês | MEDLINE | ID: mdl-32843625

RESUMO

Increased extracellular Ca2+ concentrations ([Ca2+]ex) trigger activation of the NLRP3 inflammasome in monocytes through calcium-sensing receptor (CaSR). To prevent extraosseous calcification in vivo, the serum protein fetuin-A stabilizes calcium and phosphate into 70-100 nm-sized colloidal calciprotein particles (CPPs). Here we show that monocytes engulf CPPs via macropinocytosis, and this process is strictly dependent on CaSR signaling triggered by increases in [Ca2+]ex. Enhanced macropinocytosis of CPPs results in increased lysosomal activity, NLRP3 inflammasome activation, and IL-1ß release. Monocytes in the context of rheumatoid arthritis (RA) exhibit increased CPP uptake and IL-1ß release in response to CaSR signaling. CaSR expression in these monocytes and local [Ca2+] in afflicted joints are increased, probably contributing to this enhanced response. We propose that CaSR-mediated NLRP3 inflammasome activation contributes to inflammatory arthritis and systemic inflammation not only in RA, but possibly also in other inflammatory conditions. Inhibition of CaSR-mediated CPP uptake might be a therapeutic approach to treating RA.


Assuntos
Artrite Reumatoide/imunologia , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Receptores de Detecção de Cálcio/metabolismo , Animais , Calcinose , Cálcio/metabolismo , Células Cultivadas , Humanos , Inflamação , Interleucina-1beta/metabolismo , Camundongos , Monócitos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Fosfatos/metabolismo , Pinocitose , Receptores de Detecção de Cálcio/deficiência , Transdução de Sinais , Células THP-1 , alfa-2-Glicoproteína-HS/metabolismo
2.
Medicine (Baltimore) ; 99(34): e21857, 2020 Aug 21.
Artigo em Inglês | MEDLINE | ID: mdl-32846836

RESUMO

BACKGROUND: Rheumatoid arthritis (RA), as an autoimmune disease, can eventually lead to joint deformity and loss of function, seriously reduce the quality of life of patients and increase economic burden. As a traditional Chinese therapy, warming acupuncture and moxibustion is safe, economical, and has few side effects. At present, some studies have shown that warming acupuncture and moxibustion has a certain effect on RA, but there is no evidence of evidence-based medicine. The purpose of this study was to evaluate the efficacy and safety of warming acupuncture and moxibustion in the treatment of rheumatoid arthritis. METHOD: Randomized controlled trials of warming acupuncture and moxibustion treating RA will be searched in the databases including PubMed, EMBASE, the Cochrane library, Web of science, China National Knowledge Infrastructure (CNKI), WanFang, the Chongqing VIP Chinese Science and Technology Periodical Database (VIP), and China biomedical literature database (CBM) from inception to July, 2020. In addition, Baidu, Google Scholar, International Clinical Trials Registry Platform, and Chinese Clinical Trials Registry will be searched to obtain the gray literature and relevant data that have not yet been published. Two qualified researchers will extract data and assess the risk of bias from included studies independently. Statistical analysis is performed in RevMan 5.3 software. RESULTS: The primary outcome is symptom evaluation including morning stiffness, pain, and joint swelling. The number of joints affected by RA, Rheumatoid factor (RF), erythrocyte sedimentation rate (ESR), C reactive protein (CRP), anti-cyclic peptide containing citrulline (A-CCP), and adverse effects, will be evaluated as secondary outcomes. CONCLUSIONS: This study will compare the efficacy and safety of warming acupuncture and moxibustion with common acupuncture in the treatment of RA, providing reliable evidence for clinical application. OSF REGISTRATION NUMBER: DOI 10.17605/OSF.IO/C8RY9.


Assuntos
Terapia por Acupuntura/métodos , Artrite Reumatoide/terapia , Doenças Autoimunes/complicações , Moxibustão/métodos , Terapia por Acupuntura/efeitos adversos , Anticorpos Anti-Proteína Citrulinada/análise , Artrite Reumatoide/imunologia , Artrite Reumatoide/psicologia , Sedimentação Sanguínea , Proteína C-Reativa/análise , Estudos de Casos e Controles , Efeitos Psicossociais da Doença , Feminino , Humanos , Masculino , Moxibustão/efeitos adversos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como Assunto , Fator Reumatoide/sangue , Segurança , Resultado do Tratamento
3.
PLoS One ; 15(8): e0237072, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32745151

RESUMO

BACKGROUND: Rheumatoid arthritis (RA) is associated with an increased cardiovascular disease (CVD) risk which may start even before diagnosis. To explore this CVD risk prior to RA, we determined multiple risk factors and two 10-year clinical risk scores in a cohort of individuals at-risk of RA. We also analyzed associations with arthritis development and autoantibody status and compared a subset of at-risk individuals to an age and sex matched seronegative control group. METHODS: In a cohort of 555 consecutive arthralgia patients positive for rheumatoid factor (RF) and / or anti-citrullinated protein antibody (ACPA) we retrospectively identified patients with preclinical arthritis (i.e. those who developed arthritis), and non-arthritis patients (those without arthritis development during maximum 5 years follow up). Demographics, CVD risk factors and the 10-year cardiovascular risk according to the SCORE and QRISK3 system were determined at baseline. RESULTS: Preclinical arthritis patients (n = 188) had a higher heart rate (68 vs 63 bpm, p = 0.048) and lower cholesterol (5.2 mmol/l vs 5.5, p = 0.006), HDL (1.0 mmol/l vs 1.1, p0.003) and ApoB (0.85 g/l vs 0.91, p = 0.011) compared to non-arthritis patients (n = 367). Lipid levels were associated with ACPA status in both the preclinical arthritis and non-arthritis group. Ten-year CVD risk scores did not differ between preclinical arthritis and non-arthritis patients, in total, 7% (SCORE) and 8% (QRISK3) of seropositive arthralgia patients were classified as high risk. Seropositive at-risk patients (n = 71) had higher total cholesterol (5.4 vs 4.9, p<0.001), TC/HDL ratio (4.0 vs 3.0, p<0.001), triglycerides (1.4 vs 1.0, p = 0.001), ApoB (1.0 vs 0.9, p = 0.019) and 10-year risk scores (median SCORE 1.0 vs 0.0, p = 0.030 and median QRISK3 4.4 vs 3.1, p<0.001) compared to seronegative controls. CONCLUSION: Our results suggest that lipid changes commence prior to RA diagnosis and that ACPAs might play a role.


Assuntos
Artrite Reumatoide/complicações , Artrite Reumatoide/fisiopatologia , Doenças Cardiovasculares/etiologia , Adulto , Anticorpos Anti-Proteína Citrulinada , Artralgia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Doenças Cardiovasculares/complicações , Doenças Cardiovasculares/fisiopatologia , Estudos de Coortes , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fator Reumatoide/imunologia , Fatores de Risco
4.
Int J Mol Sci ; 21(15)2020 07 23.
Artigo em Inglês | MEDLINE | ID: mdl-32718086

RESUMO

The role of interleukin (IL)-6 in health and disease has been under a lot of scrutiny in recent years, particularly during the recent COVID-19 pandemic. The inflammatory pathways in which IL-6 is involved are also partly responsible of the development and progression of rheumatoid arthritis (RA), opening interesting perspectives in terms of therapy. Anti-IL-6 drugs are being used with variable degrees of success in other diseases and are being tested in RA. Results have been encouraging, particularly when anti-IL-6 has been used with other drugs, such as metothrexate (MTX). In this review we discuss the main immunologic aspects that make anti-IL-6 a good candidate in RA, but despite the main therapeutic options available to target IL-6, no gold standard treatment has been established so far.


Assuntos
Artrite Reumatoide/imunologia , Interleucina-6/metabolismo , Anticorpos Monoclonais/farmacologia , Anticorpos Monoclonais/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Progressão da Doença , Humanos , Interleucina-6/antagonistas & inibidores , Terapia de Alvo Molecular , Transdução de Sinais/efeitos dos fármacos
5.
Mol Immunol ; 125: 1-8, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32610164

RESUMO

BACKGROUND: Follicular helper T (Tfh) cells are a subgroup of activated CD4+ T cells which can assist the formation and maintenance of germinal centers. Follicular regulatory T (Tfr) cells are a new class of regulatory T cells which play a major role in suppressing cells in humoral immunity. In contrast to the role of Tfh cells, Tfr cells can inhibit the function of Tfh cells and B cells. Imbalance of blood Tfr/Tfh ratio resulted in the expansion of auto-reactive B cells and auto-antibody production (). However, the effect of Tfr cells and Tfh cells in the pathogenesis of RA (rheumatoid arthritis) is unclear. The purpose of this study was to investigate the function of Tfr cells and Tfh cells in the pathogenesis of RA. METHODS: We recruited 20 patients fulfilled the the American College of Rheumatology diagnosis criteria and 20 healthy controls (HCs). The number of CD4+CXCR5+Foxp3+ Tfr cells and CD4+CXCR5+ Tfh cells in 20 RA patients were measured by flow cytometry analysis. Furthermore, the correlations between the Tfr/Tfh ratio and the characteristic clinical parameters were assessed. The serum levels of IL-21(interleukin-21), CXCL13 (chemokine (C-X-C motif) ligand 13) and TGF-ß (Transforming growth factor-ß) were measured by ELISA. The formation of ectopic germinal center (GC) of synovial membrane was examined by H&E staining. The transcriptional levels of CXCR5 (C-X-C chemokine receptor type 5), CXCL13, ICOS (inducible co-stimulater) and TGF-ß mRNA were also analyzed. In addition, the expression of Bcl-6 (B-cell lymphoma 6), CXCR5, CXCL13 and ICOS in synovial membrane were examined by immunohistochemistry. RESULTS: RA patients had more Tfh cells in peripheral blood, conversely, the frequency of blood Tfr cells (p < 0.05) and the ratio of Tfr/Tfh were significantly decreased compared to healthy controls (p < 0.05, p < 0.01). Furthermore, the ratio of Tfr/Tfh was negatively correlated with values of ESR (r=-0.57, p < 0.05), RF (r=-0.5275, p < 0.001), CRP (r=-0.4486, p < 0.001), IgG (r=-0.4631, p < 0.05), DAS28 scores (r=-0.5645, p < 0.01), as well as the levels of IL-21(r=-0.7398, p < 0.01), CXCL13 (r=-0.4832, p < 0.05). However, the ratio of Tfr/Tfh was positively with the serum level of TGF-ß (r=0.5115, p < 0.05). Higher mRNA expression of CXCR5, CXCL13, ICOS and lower TGF-ß mRNA expression were observed in RA patients. The serum expression level of IL-21, CXCL13 was significantly increased and expression of TGF-ß was significantly decreased in RA patients. Furthermore, ectopic germinal center formation and higher expression of Bcl-6, CXCR5, ICOS, CXCL13 in the synovial membrane of the joints in RA patients were observed. CONCLUSIONS: The decreased blood CD4+CXCR5+Foxp3+ Tfr cells/CD4+CXCR5+ Tfh cells may be responsible for the immunopathogenesis of RA.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Adulto , Idoso , Citocinas/sangue , Citocinas/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
6.
N Engl J Med ; 383(3): 218-228, 2020 07 16.
Artigo em Inglês | MEDLINE | ID: mdl-32668112

RESUMO

BACKGROUND: Rheumatoid arthritis, like many inflammatory diseases, is characterized by episodes of quiescence and exacerbation (flares). The molecular events leading to flares are unknown. METHODS: We established a clinical and technical protocol for repeated home collection of blood in patients with rheumatoid arthritis to allow for longitudinal RNA sequencing (RNA-seq). Specimens were obtained from 364 time points during eight flares over a period of 4 years in our index patient, as well as from 235 time points during flares in three additional patients. We identified transcripts that were differentially expressed before flares and compared these with data from synovial single-cell RNA-seq. Flow cytometry and sorted-blood-cell RNA-seq in additional patients were used to validate the findings. RESULTS: Consistent changes were observed in blood transcriptional profiles 1 to 2 weeks before a rheumatoid arthritis flare. B-cell activation was followed by expansion of circulating CD45-CD31-PDPN+ preinflammatory mesenchymal, or PRIME, cells in the blood from patients with rheumatoid arthritis; these cells shared features of inflammatory synovial fibroblasts. Levels of circulating PRIME cells decreased during flares in all 4 patients, and flow cytometry and sorted-cell RNA-seq confirmed the presence of PRIME cells in 19 additional patients with rheumatoid arthritis. CONCLUSIONS: Longitudinal genomic analysis of rheumatoid arthritis flares revealed PRIME cells in the blood during the period before a flare and suggested a model in which these cells become activated by B cells in the weeks before a flare and subsequently migrate out of the blood into the synovium. (Funded by the National Institutes of Health and others.).


Assuntos
Artrite Reumatoide/sangue , Linfócitos B/fisiologia , Expressão Gênica , Células-Tronco Mesenquimais , Análise de Sequência de RNA/métodos , Adulto , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Feminino , Fibroblastos/metabolismo , Citometria de Fluxo , Humanos , Masculino , Células-Tronco Mesenquimais/metabolismo , Pessoa de Meia-Idade , Gravidade do Paciente , Inquéritos e Questionários , Exacerbação dos Sintomas , Líquido Sinovial/citologia
7.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: covidwho-591986

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
8.
Curr Top Microbiol Immunol ; 426: 119-141, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32483659

RESUMO

Rheumatoid Arthritis (RA) is a chronic systemic autoimmune disease. RA mainly affects the joints, with inflammation of the synovial membrane, characterized by hyperplasia, neo-angiogenesis, and immune cell infiltration that drives local inflammation and, if untreated, can lead to joint destruction and disability. In parallel to the well-known clinical heterogeneity, the underlying synovitis can also be significantly heterogeneous. In particular, in about 40% of patients with RA, synovitis is characterized by a dense lymphocytic infiltrate that can acquire the features of fully functional tertiary lymphoid organs (TLO). These structures amplify autoimmunity and inflammation locally associated with worse prognosis and potential implications for treatment response. Here, we will review the current knowledge on TLO in RA, with a focus on their pathogenetic and clinical relevance.


Assuntos
Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Tecido Linfoide/patologia , Autoimunidade , Humanos , Tecido Linfoide/imunologia , Neovascularização Patológica , Membrana Sinovial/imunologia , Membrana Sinovial/patologia , Sinovite/patologia
10.
Expert Opin Pharmacother ; 21(13): 1527-1536, 2020 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-32515665

RESUMO

INTRODUCTION: The introduction of JAKs inhibitors for the treatment of rheumatoid arthritis represents a promising new era in the management of the disease. New compounds under investigation, like upadacitinib, with greater selectivity for JAK1 inhibition have recently been approved for the treatment of adults with moderately to severely active rheumatoid arthritis who have had an inadequate response or intolerance to conventional synthetic disease-modifying antirheumatic drugs. AREAS COVERED: Herein, the authors review the pharmacological data, the therapeutic efficacy, and safety data of upadacitinib before providing the reader with their critical evaluation and future perspectives. EXPERT OPINION: Upadacitinib was able to accomplish all the primary and secondary end points in most of the trials, with a safety profile that is similar to the other JAK inhibitors. It has also demonstrated superiority over a tumor necrosis factor inhibitor and data on new indications is also favorable. Upadacitinib is a promising new drug for the treatment of rheumatoid arthritis. GLOSSARY: Adalimumab: ADA; American College of Rheumatology: ACR; Assessment of Spondylarthritis International Society 40: ASAS40; Ankylosis Spondylitis: AS; Area under the Curve: AUC; Biological Disease-modifying arthritis drugs: bDMARDs; Clinical disease activity index: CDAI; C Reactive Protein: CRP; Conventional Synthetic Disease-modifying arthritis drugs: csDMARDs; Deep Venous Thrombosis: DVT; Disease arthritis score: DAS.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Compostos Heterocíclicos com 3 Anéis/uso terapêutico , Inibidores de Janus Quinases/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Adulto , Artrite Reumatoide/enzimologia , Artrite Reumatoide/imunologia , Proteína C-Reativa/metabolismo , Quimioterapia Combinada , Humanos , Espondilartrite/tratamento farmacológico , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento
11.
Nat Rev Rheumatol ; 16(8): 465-470, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32561873

RESUMO

Coronavirus disease 2019 (COVID-19) is an infectious disease, caused by severe acute respiratory syndrome coronavirus 2, which predominantly affects the lungs and, under certain circumstances, leads to an excessive or uncontrolled immune activation and cytokine response in alveolar structures. The pattern of pro-inflammatory cytokines induced in COVID-19 has similarities to those targeted in the treatment of rheumatoid arthritis. Several clinical studies are underway that test the effects of inhibiting IL-6, IL-1ß or TNF or targeting cytokine signalling via Janus kinase inhibition in the treatment of COVID-19. Despite these similarities, COVID-19 and other zoonotic coronavirus-mediated diseases do not induce clinical arthritis, suggesting that a local inflammatory niche develops in alveolar structures and drives the disease process. COVID-19 constitutes a challenge for patients with inflammatory arthritis for several reasons, in particular, the safety of immune interventions during the pandemic. Preliminary data, however, do not suggest that patients with inflammatory arthritis are at increased risk of COVID-19.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/imunologia , Síndrome da Liberação de Citocina/imunologia , Pneumonia Viral/imunologia , Alvéolos Pulmonares/imunologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Antirreumáticos/uso terapêutico , Artralgia , Artrite Reumatoide/tratamento farmacológico , Azetidinas/uso terapêutico , Betacoronavirus , Infecções por Coronavirus/complicações , Infecções por Coronavirus/tratamento farmacológico , Assistência à Saúde , Proteína Antagonista do Receptor de Interleucina 1/uso terapêutico , Interleucina-1beta/imunologia , Interleucina-6/imunologia , Inibidores de Janus Quinases/uso terapêutico , Mialgia , Pandemias , Pneumonia Viral/complicações , Pneumonia Viral/tratamento farmacológico , Reumatologia , Sulfonamidas/uso terapêutico , Inibidores do Fator de Necrose Tumoral/uso terapêutico , Fator de Necrose Tumoral alfa/imunologia
12.
Adv Rheumatol ; 60(1): 32, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32517786

RESUMO

Hydroxychloroquine and chloroquine, also known as antimalarial drugs, are widely used in the treatment of rheumatic diseases and have recently become the focus of attention because of the ongoing COVID-19 pandemic. Rheumatologists have been using antimalarials to manage patients with chronic immune-mediated inflammatory rheumatic diseases for decades. It is an appropriate time to review their immunomodulatory and anti-inflammatory mechanisms impact on disease activity and survival of systemic lupus erythematosus patient, including antiplatelet effect, metabolic and lipid benefits. We also discuss possible adverse effects, adding a practical and comprehensive approach to monitoring rheumatic patients during treatment with these drugs.


Assuntos
Antimaláricos/farmacologia , Artrite Reumatoide/tratamento farmacológico , Cloroquina/farmacologia , Hidroxicloroquina/farmacologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Síndrome Antifosfolipídica/tratamento farmacológico , Síndrome Antifosfolipídica/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Erupção por Droga/etiologia , Interações Medicamentosas , Feminino , Glucose/metabolismo , Cardiopatias/induzido quimicamente , Humanos , Lipídeos/sangue , Lúpus Eritematoso Cutâneo/tratamento farmacológico , Lúpus Eritematoso Cutâneo/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/mortalidade , Masculino , Pandemias , Agregação Plaquetária/efeitos dos fármacos , Pneumonia Viral/tratamento farmacológico , Gravidez , Insuficiência Renal/prevenção & controle , Doenças Retinianas/induzido quimicamente , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia
13.
Cell Prolif ; 53(7): e12824, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32567730

RESUMO

OBJECTIVES: Bone marrow edema is a universal manifestation of rheumatoid arthritis (RA), and its pathological essence is a bone marrow lesion (BML) formed by various bone marrow (BM) immune cells. Neutrophils play an important role in inflammatory arthritis, but the role and mechanism of neutrophils in BML are not clear. MATERIALS AND METHODS: Granulocyte colony-stimulating factor (G-CSF) -/- mice and wild type (WT) C57BL/6 mice were immunized for collagen-induced arthritis (CIA). Histological scores of arthritis were evaluated. Immunohistochemistry staining with anti-Ly6G was conducted. Neutrophil extracellular traps (NETs) in joint sections were determined by immunofluorescence staining. BM neutrophils were isolated for flow cytometry and NETosis induction in vitro. RESULTS: Histological study showed significant neutrophil infiltrations in BML of CIA mice. Inhibition of BM neutrophil production by G-CSF knock out can obstruct the induction of BML and CIA. In addition to abundant infiltrated NETs intra-articular, remarkable NETosis primed BM neutrophils were infiltrated in BML of CIA mice, which was positively related to bone erosion. Neutrophils derived from G-CSF-/- mice have diminished ability of NETs formation in vitro, while G-CSF induction can enhance its capacity of NETs formation. CONCLUSIONS: We propose for the first time that the overproduced BM neutrophils in CIA mice are primed for NETosis in a G-CSF dependent manner, and these pathogenic cells may have an important role in inflammatory arthritis. Blocking this pathological process could be a potential strategy for the treatment of RA.


Assuntos
Artrite Experimental/imunologia , Artrite Reumatoide/imunologia , Medula Óssea/imunologia , Neutrófilos/imunologia , Animais , Células da Medula Óssea/imunologia , Colágeno/imunologia , Armadilhas Extracelulares/imunologia , Fator Estimulador de Colônias de Granulócitos/imunologia , Camundongos , Camundongos Endogâmicos C57BL
14.
Ann Rheum Dis ; 79(9): 1194-1202, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32532752

RESUMO

OBJECTIVES: Porphyromonas gingivalis (P.g.) is discussed to be involved in triggering self-reactive immune responses. The aim of this study was to investigate the autocitrullinated prokaryotic peptidylarginine deiminase (PPAD) from P.g. CH2007 (RACH2007-PPAD) from a rheumatoid arthritis (RA) patient and a synthetic citrullinated PPAD peptide (CPP) containing the main autocitrullination site as potential targets for antibody reactivity in RA and to analyse the possibility of citrullinating native human proteins by PPAD in the context of RA. METHODS: Recombinant RACH2007-PPAD was cloned and expressed in Escherichia coli. Purified RACH2007-PPAD and its enzymatic activity was analysed using two-dimensional electrophoresis, mass spectrometry, immunoblot and ELISA. Autoantibody response to different modified proteins and peptides was recorded and bioinformatically evaluated. RESULTS: RACH2007-PPAD was capable to citrullinate major RA autoantigens, such as fibrinogen, vimentin, hnRNP-A2/B1, histone H1 and multiple peptides, which identify a common RG/RGG consensus motif. 33% of RA patients (n=30) revealed increased reactivity for α-cit-RACH2007-PPAD before RA onset. 77% of RA patients (n=99) presented α-cit-specific signals to CPP amino acids 57-71 which were positively correlated to α-CCP2 antibody levels. Interestingly, 48% of the α-CPP-positives were rheumatoidfactor IgM/anti-citrullinated peptide/protein antibodies (ACPA)-negative. Anti-CPP and α-RACH2007-PPAD antibody levels increase with age. Protein macroarrays that were citrullinated by RACH2007-PPAD and screened with RA patient sera (n=6) and controls (n=4) uncovered 16 RACH2007-PPAD citrullinated RA autoantigens and 9 autoantigens associated with lung diseases. We showed that the α-CPP response could be an important determinant in parenchymal changes in the lung at the time of RA diagnosis (n=106; p=0.018). CONCLUSIONS: RACH2007-PPAD induced internal citrullination of major RA autoantigens. Anti-RACH2007-PPAD correlates with ACPA levels and interstitial lung disease autoantigen reactivity, supporting an infection-based concept for induction of ACPAs via enzymatic mimicry.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Infecções por Bacteroidaceae/imunologia , Epitopos/imunologia , Porphyromonas gingivalis/imunologia , Artrite Reumatoide/microbiologia , Infecções por Bacteroidaceae/microbiologia , Citrulinação/imunologia , Ensaio de Imunoadsorção Enzimática , Humanos , Immunoblotting , Peptídeos/imunologia , Desiminases de Arginina em Proteínas/imunologia
15.
Life Sci ; 254: 117734, 2020 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-32380080

RESUMO

Autophagy is considered as an important intracellular mechanism that degrades cytoplasmic components to furnish additional energy. It has cytoprotective effects through the degradation of intracellular pathogens, damaged organelles, and protein aggregates. On the other hand, there are reports of an association between autophagy and autoimmune diseases. Indeed, it has been evident that autophagy is dysregulated in various autoimmune diseases including rheumatoid arthritis (RA). Autophagy is implicated in the maturation survival and proliferation of various immune and non-immune cells, which play pivotal roles in RA pathogenesis. Additionally, autophagy seems to be involved in citrullination and presentation of citrullinated peptides to T lymphocyte cells. Presentation of citrullinated peptides through MHC compartments to the T cells leads to immune response and chronic inflammation. Evidence suggests that autophagy could be implicated in apoptosis resistance of RA fibroblast-like synoviocyte (RA FLS), osteoclastogenesis, and finally severe bone and cartilage destruction. Since autophagy could be an important phenomenon in RA pathogenesis, we summarized the roles of autophagy in citrullination, osteoclastogenesis, RA FLS cells survival, apoptosis resistance of cells, lymphocyte homeostasis and its clinical outcomes in RA disease.


Assuntos
Artrite Reumatoide/patologia , Autofagia , Artrite Reumatoide/imunologia , Artrite Reumatoide/terapia , Humanos
16.
PLoS One ; 15(5): e0233781, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459816

RESUMO

OBJECTIVE: Cases of inflammatory bowel disease (IBD) during treatment with interleukin (IL)-17 antagonists have been reported from trials in psoriasis, psoriatic arthritis, and ankylosing spondylitis. The aim of this study was to assess the overall risk for development of IBD due to IL-17 inhibition. DESIGN: Systematic review and meta-analysis of studies conducted 2010-2018 of treatment with IL-17 antagonists in patients with psoriasis, psoriatic arthritis, ankylosing spondylitis, and rheumatoid arthritis. We compared risk of IBD development in anti-IL-17 treated patients compared to placebo treatments. We also computed incident rates of IBD overall. A 'worst case scenario' defining subjects ambiguous for prevalent versus incident cases for the latter was also applied. RESULTS: Sixty-six studies of 14,390 patients exposed to induction and 19,380 patients exposed to induction and/or maintenance treatment were included. During induction, 11 incident cases of IBD were reported, whereas 33 cases were diagnosed during the entire treatment period. There was no difference in the pooled risk of new-onset IBD during induction studies for both the best-case [risk difference (RD) 0.0001 (95% CI: -0.0011, 0.0013)] and worst-case scenario [RD 0.0008 (95% CI: -0.0005, 0.0022)]. The risk of IBD was not different from placebo when including data from maintenance and long-term extension studies [RD 0.0007 (95% CI: -0.0023, 0.0036) and RD 0.0022 (95% CI: -0.0010, 0.0055), respectively]. CONCLUSIONS: The risk for development of IBD in patients treated with IL-17 antagonists is not elevated. Prospective surveillance of patients treated with IL-17 antagonists with symptom and biomarker assessments is warranted to assess for onset of IBD in these patients.


Assuntos
Anticorpos Monoclonais , Artrite Psoriásica , Artrite Reumatoide , Doenças Inflamatórias Intestinais , Interleucina-17/antagonistas & inibidores , Espondilite Anquilosante , Anticorpos Monoclonais/efeitos adversos , Anticorpos Monoclonais/uso terapêutico , Artrite Psoriásica/tratamento farmacológico , Artrite Psoriásica/epidemiologia , Artrite Psoriásica/imunologia , Artrite Psoriásica/patologia , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Feminino , Humanos , Doenças Inflamatórias Intestinais/induzido quimicamente , Doenças Inflamatórias Intestinais/epidemiologia , Doenças Inflamatórias Intestinais/imunologia , Interleucina-17/imunologia , Masculino , Ensaios Clínicos Controlados Aleatórios como Assunto , Espondilite Anquilosante/tratamento farmacológico , Espondilite Anquilosante/epidemiologia , Espondilite Anquilosante/imunologia , Espondilite Anquilosante/patologia
17.
PLoS One ; 15(5): e0233159, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32459801

RESUMO

BACKGROUND: CD4-positive T cells are the main target of human T-cell leukemia virus type 1 (HTLV-1). Interferon-γ release assays rely on the fact that T-lymphocytes release this cytokine when exposed to tuberculosis-specific antigens and are useful in testing for latent tuberculosis infection before initiating biologic therapy, such as anti-tumor necrosis factor agents. However, the reliability of interferon-γ release assays in detecting tuberculosis infection among HTLV-1-positive patients with rheumatoid arthritis (RA) remains unclear. The present study aimed to evaluate the use of the T-SPOT.TB assay in HTLV-1-positive RA patients. METHODS: Overall, 29 HTLV-1-positive RA patients and 87 age- and sex-matched HTLV-1-negative RA patients (controls) were included from the HTLV-1 RA Miyazaki Cohort Study. Results of the T-SPOT.TB assay for latent tuberculosis infection screening were collected from medical records of patients. RESULTS: Approximately 55% of the HTLV-1-positive RA patients showed invalid T-SPOT.TB assay results (odds ratio: 108, 95% confidence interval: 13.1-890, p < 0.0001) owing to a spot count of >10 in the negative controls. HTLV-1 proviral load values were significantly higher in patients with invalid results compared with those without invalid results (p = 0.003). CONCLUSION: HTLV-1 infection affects T-SPOT.TB assay results in RA patients. Assay results in HTLV-1 endemic regions should be interpreted with caution when screening for latent tuberculosis infection before initiation of biologic therapy.


Assuntos
Artrite Reumatoide/imunologia , Linfócitos T CD4-Positivos/imunologia , Infecções por HTLV-I/imunologia , Vírus Linfotrópico T Tipo 1 Humano/imunologia , Testes de Liberação de Interferon-gama , Tuberculose/imunologia , Idoso , Idoso de 80 Anos ou mais , Artrite Reumatoide/microbiologia , Artrite Reumatoide/patologia , Artrite Reumatoide/virologia , Linfócitos T CD4-Positivos/patologia , Feminino , Infecções por HTLV-I/microbiologia , Infecções por HTLV-I/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Tuberculose/microbiologia , Tuberculose/patologia , Tuberculose/virologia
18.
Nat Rev Rheumatol ; 16(6): 316-333, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32393826

RESUMO

Rheumatoid arthritis (RA) is a chronic immune-mediated disease that primarily affects the synovium of diarthrodial joints. During the course of RA, the synovium transforms into a hyperplastic invasive tissue that causes destruction of cartilage and bone. Fibroblast-like synoviocytes (FLS), which form the lining of the joint, are epigenetically imprinted with an aggressive phenotype in RA and have an important role in these pathological processes. In addition to producing the extracellular matrix and joint lubricants, FLS in RA produce pathogenic mediators such as cytokines and proteases that contribute to disease pathogenesis and perpetuation. The development of multi-omics integrative analyses have enabled new ways to dissect the mechanisms that imprint FLS, have helped to identify potential FLS subsets with distinct functions and have identified differences in FLS phenotypes between joints in individual patients. This Review provides an overview of advances in understanding of FLS biology and highlights omics approaches and studies that hold promise for identifying future therapeutic targets.


Assuntos
Artrite Reumatoide/imunologia , Reabsorção Óssea/imunologia , Cartilagem Articular/imunologia , Fibroblastos/imunologia , Membrana Sinovial/imunologia , Sinoviócitos/imunologia , Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Linfócitos B/imunologia , Reabsorção Óssea/metabolismo , Caderinas/metabolismo , Cartilagem Articular/metabolismo , Metilação de DNA , Células Endoteliais/metabolismo , Epigênese Genética , Fibroblastos/metabolismo , Humanos , Macrófagos/imunologia , Terapia de Alvo Molecular , Monócitos/imunologia , Neovascularização Patológica/imunologia , Neovascularização Patológica/metabolismo , Osteogênese , Proteínas Tirosina Fosfatases/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo , Sinoviócitos/metabolismo , Linfócitos T/imunologia
19.
Rheumatol Int ; 40(6): 991-995, 2020 06.
Artigo em Inglês | MEDLINE | ID: covidwho-88672

RESUMO

In December 2019, numerous coronavirus disease 2019 (COVID-19) cases were reported in Wuhan, China, which has since spread throughout the world. However, its impact on rheumatoid arthritis (RA) patients is unknown. Herein, we report a case of COVID-19 pneumonia in a 61-year-old female RA patient who was receiving conventional disease-modifying antirheumatic drugs (cDMARDs). The patient presented with a 4-day history of myalgia and febrile sensation. COVID-19 was confirmed by real-time polymerase chain reaction (PCR). Chest X-ray showed increased opacity on the right lower lung area, and C-reactive protein level was slightly elevated. The patient was treated with antiviral agents (lopinavir/ritonavir), and treatment with cDMARDs was discontinued except hydroxychloroquine. Her symptoms and laboratory results gradually improved. Three weeks later, real-time PCR for COVID-19 showed negative conversion, and the patient was discharged without any complications.


Assuntos
Artrite Reumatoide/imunologia , Infecções por Coronavirus/tratamento farmacológico , Lopinavir/uso terapêutico , Pneumonia Viral/tratamento farmacológico , Ritonavir/uso terapêutico , Antirreumáticos/efeitos adversos , Antirreumáticos/uso terapêutico , Artrite Reumatoide/complicações , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/virologia , China , Infecções por Coronavirus/complicações , Combinação de Medicamentos , Feminino , Humanos , Hidroxicloroquina/uso terapêutico , Hospedeiro Imunocomprometido , Pessoa de Meia-Idade , Pandemias , Pneumonia Viral/complicações , Reação em Cadeia da Polimerase em Tempo Real , Resultado do Tratamento
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA