Your browser doesn't support javascript.
loading
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 126
Filtrar
1.
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
3.
Nat Rev Rheumatol ; 16(6): 301-315, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32341463

RESUMO

Peptidylarginine deiminases (PADs) have an important role in the pathogenesis of rheumatoid arthritis (RA) owing to their ability to generate citrullinated proteins - the hallmark autoantigens of RA. Of the five PAD enzyme isoforms, PAD2 and PAD4 are the most strongly implicated in RA at both genetic and cellular levels, and PAD inhibitors have shown therapeutic efficacy in mouse models of inflammatory arthritis. PAD2 and PAD4 are additionally targeted by autoantibodies in distinct clinical subsets of patients with RA, suggesting anti-PAD antibodies as possible biomarkers for RA diagnosis and prognosis. This Review weighs the evidence that supports a pathogenic role for PAD enzymes in RA as both promoters and targets of the autoimmune response, as well as discussing the mechanistic and therapeutic implications of these findings in the wider context of RA pathogenesis. Understanding the origin and consequences of dysregulated PAD enzyme activity and immune responses against PAD enzymes will be important to fully comprehend the pathogenic mechanisms involved in this disease and for the development of novel strategies to treat and prevent RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Proteína-Arginina Desiminase do Tipo 2/metabolismo , Proteína-Arginina Desiminase do Tipo 4/metabolismo , Artrite Reumatoide/enzimologia , Artrite Reumatoide/genética , Autoanticorpos/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Citrulinação , Reações Cruzadas , Predisposição Genética para Doença , Humanos , Doenças Pulmonares Intersticiais/imunologia , Proteína-Arginina Desiminase do Tipo 2/genética , Proteína-Arginina Desiminase do Tipo 2/imunologia , Proteína-Arginina Desiminase do Tipo 3/imunologia , Proteína-Arginina Desiminase do Tipo 4/genética , Proteína-Arginina Desiminase do Tipo 4/imunologia , Desiminases de Arginina em Proteínas/genética , Desiminases de Arginina em Proteínas/imunologia , Desiminases de Arginina em Proteínas/metabolismo , Índice de Gravidade de Doença
4.
Sci Rep ; 10(1): 5851, 2020 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-32245990

RESUMO

LL37 exerts a dual pathogenic role in psoriasis. Bound to self-DNA/RNA, LL37 licenses autoreactivity by stimulating plasmacytoid dendritic cells-(pDCs)-Type I interferon (IFN-I) and acts as autoantigen for pathogenic Th17-cells. In systemic lupus erythematosus (SLE), LL37 also triggers IFN-I in pDCs and is target of pathogenic autoantibodies. However, whether LL37 activates T-cells in SLE and how the latter differ from psoriasis LL37-specific T-cells is unknown. Here we found that 45% SLE patients had circulating T-cells strongly responding to LL37, which correlate with anti-LL37 antibodies/disease activity. In contrast to psoriatic Th17-cells, these LL37-specific SLE T-cells displayed a T-follicular helper-(TFH)-like phenotype, with CXCR5/Bcl-6 and IL-21 expression, implicating a role in stimulation of pathogenic autoantibodies. Accordingly, SLE LL37-specific T-cells promoted B-cell secretion of pathogenic anti-LL37 antibodies in vitro. Importantly, we identified abundant citrullinated LL37 (cit-LL37) in SLE tissues (skin and kidney) and observed very pronounced reactivity of LL37-specific SLE T-cells to cit-LL37, compared to native-LL37, which was much more occasional in psoriasis. Thus, in SLE, we identified LL37-specific T-cells with a distinct functional specialization and antigenic specificity. This suggests that autoantigenic specificity is independent from the nature of the autoantigen, but rather relies on the disease-specific milieu driving T-cell subset polarization and autoantigen modifications.


Assuntos
Peptídeos Catiônicos Antimicrobianos/imunologia , Autoanticorpos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Linfócitos T/imunologia , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Antinucleares/imunologia , Formação de Anticorpos/imunologia , DNA/imunologia , Células Dendríticas/imunologia , Feminino , Humanos , Lúpus Eritematoso Sistêmico/etiologia , Masculino , Psoríase/etiologia , Psoríase/imunologia , Células Th17/imunologia
5.
Clin Immunol ; 212: 108360, 2020 03.
Artigo em Inglês | MEDLINE | ID: mdl-32035179

RESUMO

Rheumatoid arthritis (RA) is characterized by the production of anti-citrullinated protein antibodies (ACPAs). To gain insights into the relationship between ACPA-expressing B cells in peripheral blood (PB) and synovial tissue (ST), we sequenced the B cell repertoire in paired PB and ST samples from five individuals with established, ACPA+ RA. Bioinformatics analysis of paired heavy- and light-chain sequences revealed clonally-related family members shared between PB and ST. ST-derived antibody repertoires exhibited reduced diversity and increased normalized clonal family size compared to PB-derived repertoires. Functional characterization showed that seven recombinant antibodies (rAbs) expressed from subject-derived sequences from both compartments bound citrullinated antigens and immune complexes (ICs) formed using one ST-derived rAb stimulated macrophage TNF-α production. Our findings demonstrate B cell trafficking between PB and ST in subjects with RA and ST repertoires include B cells that encode ACPA capable of forming ICs that stimulate cellular responses implicated in RA pathogenesis.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Complexo Antígeno-Anticorpo/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Macrófagos/imunologia , Membrana Sinovial/imunologia , Fator de Necrose Tumoral alfa/imunologia , Diversidade de Anticorpos/imunologia , Biologia Computacional , Humanos , Ativação de Macrófagos/imunologia , Membrana Sinovial/citologia
6.
Ann Rheum Dis ; 79(4): 472-480, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32041746

RESUMO

OBJECTIVE: Autoantibodies against antigens carrying distinct post-translational modifications (PTMs), such as citrulline, homocitrulline or acetyllysine, are hallmarks of rheumatoid arthritis (RA). The relation between these anti-modified protein antibody (AMPA)-classes is poorly understood as is the ability of different PTM-antigens to activate B-cell receptors (BCRs) directed against citrullinated proteins (CP). Insights into the nature of PTMs able to activate such B cells are pivotal to understand the 'evolution' of the autoimmune response conceivable underlying the disease. Here, we investigated the cross-reactivity of monoclonal AMPA and the ability of different types of PTM-antigens to activate CP-reactive BCRs. METHODS: BCR sequences from B cells isolated using citrullinated or acetylated antigens were used to produce monoclonal antibodies (mAb) followed by a detailed analysis of their cross-reactivity towards PTM-antigens. Ramos B-cell transfectants expressing CP-reactive IgG BCRs were generated and their activation on stimulation with PTM-antigens investigated. RESULTS: Most mAbs were highly cross-reactive towards multiple PTMs, while no reactivity was observed to the unmodified controls. B cells carrying CP-reactive BCRs showed activation on stimulation with various types of PTM-antigens. CONCLUSIONS: Our study illustrates that AMPA exhibit a high cross-reactivity towards at least two PTMs indicating that their recognition pattern is not confined to one type of modification. Furthermore, our data show that CP-reactive B cells are not only activated by citrullinated, but also by carbamylated and/or acetylated antigens. These data are vital for the understanding of the breach of B-cell tolerance against PTM-antigens and the possible contribution of these antigens to RA-pathogenesis.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Processamento de Proteína Pós-Traducional/imunologia , Receptores de Antígenos de Linfócitos B/imunologia , Acetilação , Idoso , Autoanticorpos/imunologia , Citrulinação/imunologia , Citrulina/análogos & derivados , Citrulina/imunologia , Reações Cruzadas/imunologia , Feminino , Humanos , Imunoglobulina G , Masculino , Pessoa de Meia-Idade , Carbamilação de Proteínas/imunologia
7.
Sci Rep ; 10(1): 3355, 2020 02 25.
Artigo em Inglês | MEDLINE | ID: mdl-32098994

RESUMO

The major environmental risk factor for rheumatoid arthritis (RA) is smoking, which according to a widely accepted model induces protein citrullination in the lungs, triggering the production of anti-citrullinated protein antibodies (ACPA) and RA development. Nevertheless, some research findings do not fit this model. Therefore, we obtained six independent cohorts with 2253 RA patients for a detailed analysis of the association between smoking and RA autoantibodies. Our results showed a predominant association of smoking with the concurrent presence of the three antibodies: rheumatoid factor (RF), ACPA and anti-carbamylated protein antibodies (ACarPA) (3 Ab vs. 0 Ab: OR = 1.99, p = 2.5 × 10-8). Meta-analysis with previous data (4491 patients) confirmed the predominant association with the concurrent presence of the three antibodies (3 Ab vs. 0 Ab: OR = 2.00, p = 4.4 ×10-16) and revealed that smoking was exclusively associated with the presence of RF in patients with one or two antibodies (RF+1+2 vs. RF-0+1+2: OR = 1.32, p = 0.0002). In contrast, no specific association with ACPA or ACarPA was found. Therefore, these results showed the need to understand how smoking favors the concordance of RA specific antibodies and RF triggering, perhaps involving smoking-induced epitope spreading and other hypothesized mechanisms.


Assuntos
Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Epitopos/imunologia , Estudos Soroepidemiológicos , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/complicações , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Autoanticorpos/imunologia , Feminino , Cadeias HLA-DRB1/imunologia , Humanos , Testes Imunológicos , Masculino , Pacientes , Peptídeos Cíclicos/imunologia , Carbamilação de Proteínas/imunologia , Fator Reumatoide/sangue , Fator Reumatoide/imunologia , Fatores de Risco , Fumar/efeitos adversos
8.
Ann Rheum Dis ; 79(4): 440-444, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32066556

RESUMO

OBJECTIVES: To examine trends in the incidence of rheumatoid arthritis (RA) from 2005 to 2014 overall and by serological status as compared with 1995-2004 and 1985-1994. METHODS: We evaluated RA incidence trends in a population-based inception cohort of individuals aged ≥18 years who first fulfilled the 1987 American College of Rheumatology (ACR) criteria for RA between 1 January 1985 and 31 December 2014. Incidence rates were estimated and were age-adjusted and sex-adjusted to the white population in the USA in 2010. Trends in incidence were examined using Poisson regression methods. RESULTS: The 2005-2014 incidence cohort comprised 427 patients: mean age 55.4 years, 68% female, 51% rheumatoid factor (RF) positive and 50% anti-cyclic citrullinated peptide antibody positive. The overall age-adjusted and sex-adjusted annual RA incidence in 2005-2014 was 41/100 000 population (age-adjusted incidence: 53/100 000 in women and 29/100 000 in men). While these estimates were similar to the 1995-2004 decade, there was a decline in the incidence of RF-positive RA in 2005-2014 compared with the previous two decades (p=0.004), with a corresponding increase in RF-negative cases (p<0.001). Smoking rates declined and obesity rates increased from earlier decades to more recent years. CONCLUSIONS: Significant increase in incidence of RF-negative RA and decrease in RF-positive RA in 2005-2014 compared with previous decades was found using 1987 ACR criteria. The incidence of RA overall during this period remained similar to the previous decade. The changing prevalence of environmental factors, such as smoking, obesity and others, may have contributed to these trends. Whether these trends represent a changing serological profile of RA requires further investigation.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/epidemiologia , Fator Reumatoide/imunologia , Adulto , Idoso , Artrite Reumatoide/imunologia , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Obesidade/epidemiologia , Crescimento Demográfico , Fumar/epidemiologia , Estados Unidos/epidemiologia
9.
Immunol Med ; 43(2): 87-91, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31994996

RESUMO

Abatacept may exert its clinical effect on rheumatoid arthritis (RA) by suppressing anti-cyclic citrullinated peptide (CCP) antibody production. This study was undertaken to test this hypothesis by examining the changes of disease activity of RA and anti-CCP antibody levels over time after starting abatacept. Sixty Japanese RA patients who started abatacept were included in this multicenter, prospective observational study. Simple Disease Activity Index (SDAI) and anti-CCP antibody levels were evaluated at 12, 24, and 52 weeks. The mean SDAI score significantly decreased within 12 weeks after starting abatacept and was maintained thereafter. On the contrary, the mean anti-CCP antibody levels did not change until 52 weeks. At the individual level, there were substantial changes of anti-CCP antibody levels, but these were not correlated with the changes of disease activity at any time points. Thus, abatacept reduces the disease activity of RA independently of modulating anti-CCP antibody production.


Assuntos
Abatacepte/uso terapêutico , Anticorpos Anti-Proteína Citrulinada/metabolismo , Formação de Anticorpos/efeitos dos fármacos , Artrite Reumatoide/dietoterapia , Artrite Reumatoide/imunologia , Abatacepte/farmacologia , Idoso , Anticorpos Anti-Proteína Citrulinada/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
10.
Arthritis Rheumatol ; 72(1): 47-56, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31353807

RESUMO

OBJECTIVE: Exaggerated neutrophil activation and formation of neutrophil extracellular traps (NETs) are linked to inflammation and autoimmunity, including rheumatoid arthritis (RA). However, whether NETs are present in the circulation of RA patients and contribute to inflammation and disease progression has not been carefully addressed. We undertook this study to assess markers of neutrophil activation and NET formation in plasma samples, investigating whether they add clinical value in improving the determination of prognosis and monitoring in RA patients. METHODS: Markers of neutrophil activation (calprotectin) and cell death (NETs) were analyzed, using enzyme-linked immunosorbent assay, in serum and plasma obtained from patients in 3 cross-sectional RA cohorts and sex-matched healthy controls. A longitudinal inception cohort (n = 247), seen for a median follow-up of 8 years, was used for predictive analyses. RESULTS: Markers of neutrophil activation and cell death were increased in RA patients compared to healthy individuals (P < 0.0001). Calprotectin levels correlated with the Clinical Disease Activity Index (r = 0.53, P < 0.0001) and could be used to distinguish between patients with disease in remission and those with active disease, an observation not seen when examining C-reactive protein levels. A biomarker panel consisting of anti-citrullinated protein antibody and calprotectin could predict erosive disease (odds ratio [OR] 7.5, P < 0.0001) and joint space narrowing (OR 4.9, P = 0.001). NET levels were associated with markers of inflammation (P = 0.0002). Furthermore, NETs and a "neutrophil activation signature" biomarker panel had good predictive value in identifying patients who were developing extraarticular nodules (OR 5.6, P = 0.006). CONCLUSION: Neutrophils undergo marked activation and cell death in RA. Neutrophil biomarkers can provide added clinical value in the monitoring and prognosis of RA patients and may allow for early preventive treatment intervention.


Assuntos
Artrite Reumatoide/imunologia , Armadilhas Extracelulares/microbiologia , Complexo Antígeno L1 Leucocitário/imunologia , Ativação de Neutrófilo/imunologia , Adolescente , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/diagnóstico por imagem , Biomarcadores , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Morte Celular , Feminino , Humanos , Interleucina-6/imunologia , Estudos Longitudinais , Masculino , Pessoa de Meia-Idade , Prognóstico , Adulto Jovem
11.
Scand J Rheumatol ; 49(1): 13-17, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31402744

RESUMO

Objective: Successful rheumatoid arthritis (RA) outcome depends on treatment efficacy in the early stages of the disease and its sustainability. It is thus critical to identify factors predicting treatment persistence with biological agents, such as abatacept. We compared clinical profiles, including early changes in autoantibody titres at 3 months, between patients with RA demonstrating sustained persistence and those discontinuing abatacept treatment.Method: We prospectively enrolled 71 and 78 active RA patients treated with abatacept and tumour necrosis factor inhibitors (TNF-Is), respectively, who had previous disease-modifying anti-rheumatic drug) failure. Clinical characteristics were compared between non-continuation and continuation groups stratified according to abatacept or TNF-I persistence for at least 12 months from treatment initiation.Results: Significantly larger decreases in rheumatoid factor titre and anti-citrullinated protein autoantibody (ACPA) titre were observed in the continuation group of abatacept therapy at 3 months, and early reduction in ACPA titre remained a significant and independent predictor of sustained persistence with abatacept in multivariate analysis. In addition, we obtained the area under the receiver operator characteristics curve of 0.904 from a model including baseline ACPA titre and reduction of ACPA titre at 3 months. Sustained reduction of RA disease activity score at 12 months was significantly and independently associated with reduced ACPA titre at 3 months.Conclusions: Persistence with abatacept and sustained therapeutic response are associated with an early reduction in ACPA titre. Prediction of abatacept continuation and efficacy will facilitate the optimal design of therapy in the early stages of RA.


Assuntos
Abatacepte/administração & dosagem , Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/imunologia , Idoso , Anticorpos Anti-Proteína Citrulinada/imunologia , Antirreumáticos/administração & dosagem , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/tratamento farmacológico , Biomarcadores/sangue , Relação Dose-Resposta a Droga , Feminino , Seguimentos , Humanos , Infusões Intravenosas , Injeções Subcutâneas , Japão , Masculino , Estudos Prospectivos , Resultado do Tratamento , Ultrassonografia
12.
Arthritis Rheumatol ; 72(1): 78-88, 2020 01.
Artigo em Inglês | MEDLINE | ID: mdl-31469249

RESUMO

OBJECTIVE: To evaluate the frequency of cell-bound complement activation products (CB-CAPs) as a marker of complement activation in patients with suspected systemic lupus erythematosus (SLE) and the usefulness of this biomarker as a predictor of the evolution of probable SLE into SLE as classified by the American College of Rheumatology (ACR) criteria. METHODS: Patients in whom SLE was suspected by lupus experts and who fulfilled 3 ACR classification criteria for SLE (probable SLE) were enrolled, along with patients with established SLE as classified by both the ACR and the Systemic Lupus International Collaborating Clinics (SLICC) criteria, patients with primary Sjögren's syndrome (SS), and patients with other rheumatic diseases. Individual CB-CAPs were measured by flow cytometry, and positivity rates were compared to those of commonly assessed biomarkers, including serum complement proteins (C3 and C4) and autoantibodies. The frequency of a positive multianalyte assay panel (MAP), which includes CB-CAPs, was also evaluated. Probable SLE cases were followed up prospectively. RESULTS: The 92 patients with probable SLE were diagnosed more recently than the 53 patients with established SLE, and their use of antirheumatic medications was lower. At the enrollment visit, more patients with probable SLE were positive for CB-CAPs (28%) or MAP (40%) than had low complement levels (9%) (P = 0.0001 for each). In probable SLE, MAP scores of >0.8 at enrollment predicted fulfillment of a fourth ACR criterion within 18 months (hazard ratio 3.11, P < 0.01). CONCLUSION: Complement activation occurs in some patients with probable SLE and can be detected with higher frequency by evaluating CB-CAPs and MAP than by assessing traditional serum complement protein levels. A MAP score above 0.8 predicts transition to classifiable SLE according to ACR criteria.


Assuntos
Ativação do Complemento/imunologia , Complemento C3/imunologia , Complemento C4b/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Fragmentos de Peptídeos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Antinucleares/imunologia , Autoanticorpos/imunologia , Linfócitos B/metabolismo , Estudos de Casos e Controles , Complemento C4/imunologia , Complemento C4b/metabolismo , Progressão da Doença , Eritrócitos/metabolismo , Feminino , Citometria de Fluxo , Humanos , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/metabolismo , Estudos Prospectivos , Doenças Reumáticas/imunologia , Fator Reumatoide/imunologia , Síndrome de Sjogren/imunologia , Adulto Jovem
13.
Rheumatology (Oxford) ; 59(4): 852-859, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504962

RESUMO

OBJECTIVE: A 'mucosal connection' in RA presently attracts increasing attention. We recently described the occurrence of secretory antibodies to citrullinated protein (SC-ACPA) in sera from patients with recent-onset RA. The current study was performed to evaluate possible associations between serum levels of secretory ACPA and signs of lung involvement in patients with early, untreated RA. METHODS: One hundred and forty-two RA patients were included as part of the 'LUng Investigation in newly diagnosed RA' study. One hundred and six patients were examined with high-resolution CT (HRCT) and 20 patients underwent bronchoscopy, where bronchial biopsies and bronchoalveolar lavage fluid (BALF) samples were obtained. SC-ACPA in serum and BALF were detected by an enzyme-linked immunoassay. Antibody levels were related to smoking history, pulmonary function, HRCT, BALF cell counts and findings in bronchial biopsies. RESULTS: SC-ACPA occurred in 16% of the serum samples and in 35% of the BALF samples. SC-ACPA levels in serum correlated with SC-ACPA levels in BALF (σ = 0.50, P = 0.027) and were higher among patients with HRCT parenchymal lung abnormalities (P = 0.022) or bronchiectasis (P = 0.042). Also, ever smoking was more frequent among serum SC-ACPA-positive patients (91% vs 67%, P = 0.023), and the SC-ACPA levels correlated with the number of pack-years (σ=0.20, P = 0.020). CONCLUSION: In early, untreated RA, serum levels of SC-ACPA reflect lung involvement in terms of local ACPA levels, smoking and lung abnormalities on HRCT. These findings strengthen the link between mucosal ACPA responses and the lungs in RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Pneumopatias/imunologia , Pulmão/imunologia , Fumar/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/complicações , Artrite Reumatoide/metabolismo , Bronquiectasia/diagnóstico por imagem , Bronquiectasia/etiologia , Bronquiectasia/imunologia , Bronquiectasia/metabolismo , Líquido da Lavagem Broncoalveolar , Broncoscopia , Feminino , Humanos , Imunoglobulina A/imunologia , Imunoglobulina A/metabolismo , Imunoglobulina A Secretora/imunologia , Imunoglobulina A Secretora/metabolismo , Imunoglobulina G/imunologia , Imunoglobulina G/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Pneumopatias/diagnóstico por imagem , Pneumopatias/etiologia , Pneumopatias/metabolismo , Masculino , Pessoa de Meia-Idade , Componente Secretório/imunologia , Componente Secretório/metabolismo , Tomografia Computadorizada por Raios X , Adulto Jovem
14.
Rheumatology (Oxford) ; 59(5): 979-987, 2020 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-31504979

RESUMO

OBJECTIVES: Considering growing evidence of mucosal involvement in RA induction, this study investigated circulating free secretory component (SC) in patients with either recent-onset RA or with ACPA and musculoskeletal pain. METHODS: Two prospective cohorts were studied: TIRA-2 comprising 452 recent-onset RA patients with 3 years of clinical and radiological follow-up, and TIRx patients (n = 104) with ACPA IgG and musculoskeletal pain followed for 290 weeks (median). Blood donors and three different chronic inflammatory diseases served as controls. Free SC was analysed by sandwich ELISA. RESULTS: Serum levels of free SC were significantly higher in TIRA-2 patients compared with TIRx and all control groups (P < 0.01). Among TIRx patients who subsequently developed arthritis, free SC levels were higher compared with all control groups (P < 0.05) except ankylosing spondylitis (P = 0.74). In TIRA-2, patients with ACPA had higher baseline levels of free SC compared with ACPA negative patients (P < 0.001). Free SC status at baseline did not predict radiographic joint damage or disease activity over time. In TIRx, elevated free SC at baseline trendwise associated with arthritis development during follow-up (P = 0.066) but this disappeared when adjusting for confounders (P = 0.72). Cigarette smoking was associated with higher levels of free SC in both cohorts. CONCLUSION: Serum free SC levels are increased in recent-onset RA compared with other inflammatory diseases, and associate with ACPA and smoking. Free SC is elevated before arthritis development among ACPA positive patients with musculoskeletal pain, but does not predict arthritis development. These findings support mucosal engagement in RA development.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/sangue , Dor Musculoesquelética/fisiopatologia , Medição da Dor , Componente Secretório/sangue , Doença Aguda , Adulto , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Autoanticorpos/sangue , Biomarcadores/sangue , Estudos de Casos e Controles , Doença Crônica , Ensaio de Imunoadsorção Enzimática , Feminino , Hospitais Universitários , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Medição de Risco , Índice de Gravidade de Doença , Suécia
15.
Rheumatology (Oxford) ; 59(7): 1505-1513, 2020 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-31628482

RESUMO

OBJECTIVES: 3-hydroxy-3-methylglutaryl coenzyme-A (HMG Co-A) reductase inhibitors (statins) are standard treatment for hyperlipidaemia. In addition to lipid-lowering abilities, statins exhibit multiple anti-inflammatory effects. The objectives of this study were to determine whether treatment of patients with RA with lovastatin decreased CRP or reduced disease activity. METHODS: We conducted a randomized double-blind placebo-controlled 12 week trial of lovastatin vs placebo in 64 RA patients with mild clinical disease activity but an elevated CRP. The primary efficacy end point was the reduction in mean log CRP. Secondary end points included disease activity, RF and anti-CCP antibody titres. Mechanistic end points included levels of serum cytokines. Safety was assessed; hepatic and muscle toxicities were of particular interest. RESULTS: Baseline features were similar between groups. No significant difference in mean log CRP reduction between the two groups was observed, and disease activity did not change from baseline in either treatment group. Mechanistic analyses did not reveal significant changes in any biomarkers. A post hoc analysis of subjects not using biologic therapy demonstrated a significantly greater proportion achieving ⩾20% reduction in CRP from baseline in the lovastatin group compared with placebo (P-value = 0.007). No difference was observed in subjects receiving biologics. Lovastatin was well tolerated with no serious safety concerns. CONCLUSION: This study showed no anti-inflammatory or clinical effects on RA disease activity after 12 weeks of treatment with lovastatin. Lovastatin had a modest effect on CRP in subjects not using biologics, suggesting statins may be anti-inflammatory in selected patients. TRIAL REGISTRATION: ClinicalTrials.gov, http://clinicaltrials.gov, NCT00302952.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Proteína C-Reativa/imunologia , Inibidores de Hidroximetilglutaril-CoA Redutases/uso terapêutico , Lovastatina/uso terapêutico , Adulto , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/fisiopatologia , Método Duplo-Cego , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fator Reumatoide/imunologia , Índice de Gravidade de Doença , Resultado do Tratamento
16.
Arthritis Rheumatol ; 72(6): 903-911, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-31820586

RESUMO

OBJECTIVE: The presence of autoantibodies to citrullinated proteins (ACPAs) often precedes the development of rheumatoid arthritis (RA). Citrullines are arginine residues that have been modified by peptidylarginine deiminases (PADs). PAD4 is the target of autoantibodies in RA. ACPAs could arise because PAD4 is recognized by T cells, which facilitate the production of autoantibodies to proteins bound by PAD4. We previously found evidence for this hapten-carrier model in mice. This study was undertaken to investigate whether there is evidence for this model in humans. METHODS: We analyzed antibody response to PAD4 and T cell proliferation in response to PAD4 in 41 RA patients and 36 controls. We tested binding of 65 PAD4 peptides to 5 HLA-DR alleles (DRB1*04:01, *04:02, *04:04, *01:01, and *07:01) and selected 11 PAD4 peptides for proliferation studies using samples from 22 RA patients and 27 controls. Peripheral blood lymphocytes from an additional 10 RA patients and 7 healthy controls were analyzed by flow cytometry for CD3, CD4, CD154, and tumor necrosis factor expression after PAD4 stimulation. RESULTS: Only patients with RA had both antibodies and T cell responses to PAD4. T cell response to peptide 8, a PAD4 peptide, was associated with RA (P = 0.02), anti-PAD4 antibodies (P = 0.057), and the shared epitope (P = 0.05). CONCLUSION: ACPA immunity is associated with antibodies to PAD4 and T cell responses to PAD4 and PAD4 peptides. These findings are consistent with a hapten-carrier model in which PAD4 is the carrier and citrullinated proteins are the haptens.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Haptenos/imunologia , Desiminases de Arginina em Proteínas/imunologia , Alelos , Anticorpos Anti-Proteína Citrulinada/sangue , Artrite Reumatoide/sangue , Autoanticorpos/sangue , Autoimunidade/imunologia , Proliferação de Células , Antígenos HLA-DR/imunologia , Humanos , Proteína-Arginina Desiminase do Tipo 4/imunologia , Linfócitos T/imunologia
17.
Z Rheumatol ; 79(4): 397-403, 2020 May.
Artigo em Inglês | MEDLINE | ID: mdl-31286191

RESUMO

OBJECTIVE: This study aimed to investigate the frequency of the anti-cyclic citrullinated peptide (anti-CCP) antibody in patients with psoriatic arthritis (PsA) and to assess its associations with clinical features of this disease. METHODS: The Medline, EMBASE, and Cochrane databases were searched for studies that examined anti-CCP antibodies in patients with PsA. Meta-analyses of the frequency of the anti-CCP antibody in these patients and its association with polyarthritis, bone erosion, dactylitis, and enthesitis were then performed. RESULTS: Fourteen studies with a combined total of 3291 patients with PsA met the inclusion criteria for this meta-analysis. The pooled overall frequency of anti-CCP antibodies was 9.8% (95% confidence interval [CI] = 7.1-13.3, p < 0.001). Stratification by ethnicity showed that the anti-CCP antibody frequency was lower in Europeans than in non-Europeans (8.5% vs. 14.0%). The meta-analysis showed a significant association of the anti-CCP antibody with polyarthritis (odds ratio [OR] = 4.390, 95% CI = 2.312-8.333, p < 0.001), bone erosion (OR = 2.800, 95% CI = 1.921-4.081, p < 0.001), and dactylitis (OR = 1.958, 95% CI = 1.340-2.861, p < 0.001). However, there was no association between this antibody and enthesitis. CONCLUSIONS: Our meta-analysis demonstrated that the overall frequency of the anti-CCP antibody was 9.8% in patients with PsA, and its presence was associated with increased risks of polyarthritis, bone erosion, and dactylitis, but not of enthesitis.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Psoriásica , Febre Reumática/imunologia , Artrite Psoriásica/epidemiologia , Artrite Psoriásica/imunologia , Autoanticorpos , Humanos , Testes Imunológicos , Razão de Chances , Peptídeos Cíclicos , Febre Reumática/epidemiologia
18.
Adv Wound Care (New Rochelle) ; 9(1): 16-27, 2020 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-31871827

RESUMO

Objective: Neutrophil extracellular traps (NETs) are associated with impaired wound healing in diabetes. This study evaluates the association between NET-specific markers and wound healing among diabetic foot ulcer (DFU) patients treated in a multidisciplinary setting. Approach: Clinical data of diabetic patients with active foot ulcers who presented to our team between January 1, 2016 and June 30, 2017 were recorded. The diabetic ulcer severity score (DUSS) and wound, ischemia, and foot infection (WIfI) score were calculated. NET-specific markers in plasma and wound tissues were tested. The capacity for plasma and platelets to prime neutrophils to release NETs was assessed. The prognostic value of NET-specific markers for wound healing was evaluated. Results: NET-specific markers were significantly higher in DFU patients than in diabetic patients without DFU or healthy controls and were found to correlate positively with DUSS or WIfI score. Elastase levels in ulcer tissue significantly increased in wounds with infections and delayed healing. Higher levels of NET release were observed after the stimulation of plasma or platelets from ulcer-related vessels than from nonulcer-related vessels of the DFU patients. Citrullinated histone 3 (citH3) was identified as a risk factor for wound healing impairment and amputation. The patients with the highest quartile of citH3 levels presented significantly lower healing rates and higher amputation rates than those with the lower three quartiles. Innovation: This study extended current knowledge of NETs on wound healing in DFU patients. Conclusion: NET-specific markers negatively correlated with wound healing in DFU patients, and citH3 is a potential marker.


Assuntos
Biomarcadores/sangue , Armadilhas Extracelulares/imunologia , Úlcera do Pé/sangue , Cicatrização/imunologia , Idoso , Idoso de 80 Anos ou mais , Amputação/estatística & dados numéricos , Anticorpos Anti-Proteína Citrulinada/imunologia , Pé Diabético/patologia , Feminino , Histonas/metabolismo , Humanos , Estudos Interdisciplinares/normas , Masculino , Pessoa de Meia-Idade , Equipe de Assistência ao Paciente , Prognóstico , Estudos Retrospectivos , Fatores de Risco , Índice de Gravidade de Doença
19.
Can Respir J ; 2019: 7262065, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31885749

RESUMO

Objective: The absolute and relative changes of peripheral NK and T subsets are unclear in rheumatoid arthritis (RA) associated with pulmonary interstitial fibrosis (RA-ILD). To investigate the clinical risk factors, especially the changes of lymphocyte subsets, in RA-ILD in order to make early diagnosis and achieve prevention of the pulmonary interstitial lesions. Methods: A total of 100 RA and 100 RA-ILD patients were enrolled. Rheumatoid factor, anti-cyclic citrulline peptide antibody, erythrocyte sedimentation rate, immunoglobulin, and C-reactive protein were examined. The percentage and absolute number of NK, T, B, Treg, Th1, Th2, and Th17 cells in peripheral blood were determined by flow cytometry. Results: RA-ILD is more common in older and male RA patients and/or those with higher autoantibody titers. Flow cytometry showed that the absolute and relative numbers of CD56+ NK cells were significantly higher in RA-ILD (280.40 ± 180.51 cells/µl vs. 207.66 ± 148.57 cells/µl; 16.62 ± 8.56% vs. 12.11 ± 6.47%), whereas the proportion of T cells and CD4+ T cells was lower in peripheral blood of RA-ILD patients (69.82 ± 9.30%; 39.44 ± 9.87 cells/µl) than that in RA patients (74.45 ± 8.72%; 43.29 ± 9.10 cells/µl). Conclusions: The occurrence of RA-ILD is closely related to the older male patients with high titer of various self-antibodies. Imbalance of CD3-CD56+ NK cells and T cells with other subsets were found in RA-ILD patients, which, together with older age, male, and high levels of autoantibodies should be considered as risk factors of pulmonary interstitial lesions.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Células Matadoras Naturais/imunologia , Doenças Pulmonares Intersticiais/imunologia , Fibrose Pulmonar/imunologia , Fator Reumatoide/imunologia , Linfócitos T/imunologia , Adulto , Fatores Etários , Idoso , Artrite Reumatoide/complicações , Linfócitos B/imunologia , Sedimentação Sanguínea , Proteína C-Reativa/imunologia , Estudos de Casos e Controles , Feminino , Citometria de Fluxo , Humanos , Imunoglobulina A/imunologia , Imunoglobulina G/imunologia , Imunoglobulina M/imunologia , Doenças Pulmonares Intersticiais/complicações , Contagem de Linfócitos , Masculino , Pessoa de Meia-Idade , Fibrose Pulmonar/complicações , Fatores Sexuais , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Células Th1/imunologia , Células Th17/imunologia , Células Th2/imunologia
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA
...