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1.
Environ Health ; 19(1): 86, 2020 07 29.
Artigo em Inglês | MEDLINE | ID: mdl-32727483

RESUMO

BACKGROUND: Studies of associations between industrial air emissions and rheumatic diseases, or diseases-related serological biomarkers, are few. Moreover, previous evaluations typically studied individual (not mixed) emissions. We investigated associations between individual and combined exposures to industrial sulfur dioxide (SO2), nitrogen dioxide (NO2), and fine particles matter (PM2.5) on anti-citrullinated protein antibodies (ACPA), a characteristic biomarker for rheumatoid arthritis (RA). METHODS: Serum ACPA was determined for 7600 randomly selected CARTaGENE general population subjects in Quebec, Canada. Industrial SO2, NO2, and PM2.5 concentrations, estimated by the California Puff (CALPUFF) atmospheric dispersion model, were assigned based on residential postal codes at the time of sera collection. Single-exposure logistic regressions were performed for ACPA positivity defined by 20 U/ml, 40 U/ml, and 60 U/ml thresholds, adjusting for age, sex, French Canadian origin, smoking, and family income. Associations between regional overall PM2.5 exposure and ACPA positivity were also investigated. The associations between the combined three industrial exposures and the ACPA positivity were assessed by weighted quantile sum (WQS) regressions. RESULTS: Significant associations between individual industrial exposures and ACPA positivity defined by the 20 U/ml threshold were seen with single-exposure logistic regression models, for industrial emissions of PM2.5 (odds ratio, OR = 1.19, 95% confidence intervals, CI: 1.04-1.36) and SO2 (OR = 1.03, 95% CI: 1.00-1.06), without clear associations for NO2 (OR = 1.01, 95% CI: 0.86-1.17). Similar findings were seen for the 40 U/ml threshold, although at 60 U/ml, the results were very imprecise. The WQS model demonstrated a positive relationship between combined industrial exposures and ACPA positivity (OR = 1.36, 95% CI: 1.10-1.69 at 20 U/ml) and suggested that industrial PM2.5 may have a closer association with ACPA positivity than the other exposures. Again, similar findings were seen with the 40 U/ml threshold, though 60 U/ml results were imprecise. No clear association between ACPA and regional overall PM2.5 exposure was seen. CONCLUSIONS: We noted positive associations between ACPA and industrial emissions of PM2.5 and SO2. Industrial PM2.5 exposure may play a particularly important role in this regard.


Assuntos
Poluentes Atmosféricos/efeitos adversos , Anticorpos Anti-Proteína Citrulinada/metabolismo , Exposição Ambiental/efeitos adversos , Dióxido de Nitrogênio/efeitos adversos , Material Particulado/efeitos adversos , Dióxido de Enxofre/efeitos adversos , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Modelos Teóricos , Quebeque , Análise de Regressão
2.
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
3.
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
4.
Clin Exp Rheumatol ; 38(2): 227-238, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31287408

RESUMO

OBJECTIVES: In this cross-sectional study we investigated antibody titres against cyclic citrullinated peptides derived from filaggrin (anti-CCP) and citrullinated α-enolase (anti-CEP-1) among patients with RA as a function of periodontal findings. METHODS: 107 patients with RA (median age 56 years, 75% females) were included. For periodontal diagnoses missing teeth, periodontal epithelial surface area, periodontal inflamed surface area and periodontal diagnosis according to the working group's guidelines of the Center for Disease Control and Prevention were determined. Subgingival bacterial DNA of five periodontopathic bacteria was assessed by PCR with sequence-specific oligonucleotides. Anti-CCP and anti-CEP-1 antibodies in plasma samples were investigated using enzyme-linked immunosorbent assays. Low resolution human leukocyte antigen (HLA) typing was carried out using PCR with sequence-specific primers. RESULTS: PESA was found associated with a low adjusted odds ratio for anti-CCP positivity (OR=1.002, p=0.040). All patients who were infected with Aggregatibacter actinomycetemcomitans were simultaneously anti-CCP positive (p=0.043). HLA-DRB1*13 lowered the adjusted odds ratio for anti-CCP (OR=0.073, p=0.002) and anti-CEP-1 (OR=0.068, p=0.018) positivity whereas HLA-DRB1*07 indicated a lower risk only for demonstrable anti-CCP antibodies (OR=0.079, p=0.004). HLA-DRB1*04 was associated with increased adjusted odds ratio for anti-CEP-1 positivity (OR=4.154, p=0.005) and the simultaneous proof of both investigated autoantibodies (OR=3.725, p=0.011). CONCLUSIONS: Among patients with RA periodontitis may be a minor risk factor for anti-CCP positivity. Our data first provide evidence that an infection with A. actinomycetemcomitans is associated with an increased formation of anti-CCP. HLA phenotype proved to be a significant risk indicator for both investigated antibodies.


Assuntos
Artrite Reumatoide , Cadeias HLA-DRB1 , Peptídeos Cíclicos/imunologia , Periodontite , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Autoanticorpos , Infecções por Bacteroidaceae/epidemiologia , Infecções por Bacteroidaceae/imunologia , Estudos Transversais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/epidemiologia , Periodontite/imunologia , Periodontite/microbiologia , Prognóstico , Fatores de Risco
5.
Int J Mol Sci ; 20(18)2019 Sep 13.
Artigo em Inglês | MEDLINE | ID: mdl-31540277

RESUMO

The association between rheumatoid arthritis (RA) and periodontal disease (PD) has been the focus of numerous investigations driven by their common pathological features. RA is an autoimmune disease characterized by chronic inflammation, the production of anti-citrullinated proteins antibodies (ACPA) leading to synovial joint inflammation and destruction. PD is a chronic inflammatory condition associated with a dysbiotic microbial biofilm affecting the supporting tissues around the teeth leading to the destruction of mineralized and non-mineralized connective tissues. Chronic inflammation associated with both RA and PD is similar in the predominant adaptive immune phenotype, in the imbalance between pro- and anti-inflammatory cytokines and in the role of smoking and genetic background as risk factors. Structural damage that occurs in consequence of chronic inflammation is the ultimate cause of loss of function and disability observed with the progression of RA and PD. Interestingly, the periodontal pathogen Porphyromonas gingivalis has been implicated in the generation of ACPA in RA patients, suggesting a direct biological intersection between PD and RA. However, more studies are warranted to confirm this link, elucidate potential mechanisms involved, and ascertain temporal associations between RA and PD. This review is mainly focused on recent clinical and translational research intends to discuss and provide an overview of the relationship between RA and PD, exploring the similarities in the immune-pathological aspects and the possible mechanisms linking the development and progression of both diseases. In addition, the current available treatments targeting both RA and PD were revised.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/imunologia , Periodontite/microbiologia , Citocinas/metabolismo , Progressão da Doença , Disbiose/imunologia , Disbiose/microbiologia , Regulação da Expressão Gênica , Humanos , Periodontite/imunologia , Porphyromonas gingivalis/imunologia
6.
Clin Epigenetics ; 11(1): 110, 2019 07 31.
Artigo em Inglês | MEDLINE | ID: mdl-31366403

RESUMO

OBJECTIVE: To compare DNA methylation in subjects positive vs negative for anti-citrullinated protein antibodies (ACPA), a key serological marker of rheumatoid arthritis (RA) risk. METHODS: With banked serum from a random subset (N = 3600) of a large general population cohort, we identified ACPA-positive samples and compared them to age- and sex-matched ACPA-negative controls. We used a custom-designed methylome panel to conduct targeted bisulfite sequencing of 5 million CpGs located in regulatory or hypomethylated regions of DNA from whole blood (red blood cell lysed). Using binomial regression models, we investigated the differentially methylated regions (DMRs) between ACPA-positive vs ACPA-negative subjects. An independent set of T cells from RA patients was used to "validate" the differentially methylated sites. RESULTS: We measured DNA methylation in 137 subjects, of whom 63 were ACPA-positive, 66 were ACPA-negative, and 8 had self-reported RA. We identified 1303 DMRs of relevance, of which one third (402) had underlying genetic effects. These DMRs were enriched in intergenic CpG islands (CGI) and CGI shore regions. Furthermore, the genes associated with these DMRs were enriched in pathways related to Epstein-Barr virus infection and immune response. In addition, 80 (38%) of 208 RA-specific DMRs were replicated in T cells from RA samples. CONCLUSIONS: Sequencing-based high-resolution methylome mapping revealed biologically relevant DNA methylation changes in asymptomatic individuals positive for ACPA that overlap with those seen in RA. Pathway analyses suggested roles for viral infections, which may represent the effect of environmental triggers upstream of disease onset.


Assuntos
Artrite Reumatoide/genética , Metilação de DNA , Redes Reguladoras de Genes , Análise de Sequência de DNA/métodos , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/imunologia , Ilhas de CpG , Epigênese Genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Análise de Regressão
7.
Arch Oral Biol ; 108: 104510, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31446118

RESUMO

OBJECTIVE: The anti-citrullinated protein antibody (ACPA), an autoantibody of rheumatoid arthritis (RA), is very specific in the diagnosis of RA and has been detected in early cases and several years before the onset of the disease. In this study, we focused on ACPA and examined whether it could be detected in saliva whether it is associated with periodontal disease. DESIGN: Porphyromonas gingivalis (Pg) or Escherichia coli (Ec) was administered into the oral cavity of DBA/1JJmsSlc mice. The arthritis index was measured in foot bones, and collected saliva and serum. The amount of ACPA in serum and saliva was measured using ELISA, and antibodies in serum, saliva, and foot bones were detected and analysed by western blotting. RESULT: Histopathological analysis of foot bones of the Pg/RA group detected greater inflammatory cell infiltration than in the RA group, and bone resorption was evident. Furthermore, ELISA results show that the amount of ACPA in serum was significantly higher in the Pg/RA group (P < 0.05), with a tendency to also increase in the saliva. In addition, western blotting results show a 55 kDa citrullinated protein in the serum and saliva of the RA and Pg/RA groups. CONCLUSIONS: We conclude that Pg infection increases ACPA in the serum and is reflected in the saliva, and may be involved in the inflammatory progression of RA.


Assuntos
Anticorpos Anti-Proteína Citrulinada , Artrite Reumatoide , Infecções por Bacteroidaceae , Porphyromonas gingivalis , Animais , Anticorpos Anti-Proteína Citrulinada/metabolismo , Infecções por Bacteroidaceae/metabolismo , Ensaio de Imunoadsorção Enzimática , Camundongos , Camundongos Endogâmicos DBA , Peptídeos Cíclicos , Porphyromonas gingivalis/patogenicidade , Saliva
8.
Cells ; 8(7)2019 07 10.
Artigo em Inglês | MEDLINE | ID: mdl-31295951

RESUMO

Mucosal surfaces play a central role in the pathogenesis of rheumatoid arthritis (RA). Several risk factors, such as cigarette smoking, environmental pollution, and periodontitis interact with the host at the mucosal level, triggering immune system activation. Moreover, the alteration of microbiota homeostasis is gaining increased attention for its involvement in the disease pathogenesis, modulating the immune cell response at a local and subsequently at a systemic level. Currently, the onset of the clinical manifest arthritis is thought to be the last step of a series of pathogenic events lasting years. The positivity for anti-citrullinated protein antibodies (ACPAs) and rheumatoid factor (RF), in absence of symptoms, characterizes a preclinical phase of RA-namely systemic autoimmune phase- which is at high risk for disease progression. Several immune abnormalities, such as local ACPA production, increased T cell polarization towards a pro-inflammatory phenotype, and innate immune cell activation can be documented in at-risk subjects. Many of these abnormalities are direct consequences of the interaction between the environment and the host, which takes place at the mucosal level. The purpose of this review is to describe the humoral and cellular immune abnormalities detected in subjects at risk of RA, highlighting their origin from the mucosa-environment interaction.


Assuntos
Artrite Reumatoide/metabolismo , Imunidade nas Mucosas/imunologia , Membrana Mucosa/imunologia , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/fisiopatologia , Autoanticorpos/genética , Autoantígenos/imunologia , Progressão da Doença , Interação Gene-Ambiente , Humanos , Membrana Mucosa/fisiologia , Fator Reumatoide/genética
9.
JAMA Netw Open ; 2(6): e195394, 2019 06 05.
Artigo em Inglês | MEDLINE | ID: mdl-31173126

RESUMO

Importance: The prevalence of periodontitis is increased in patients with rheumatoid arthritis (RA) and periodontopathic bacteria can citrullinate proteins. Periodontitis may, therefore, be an initiator of RA and a target for prevention. Periodontal disease and periodontal bacteria have not been investigated in at-risk individuals with RA autoimmunity but no arthritis. Objective: To examine periodontal disease and periodontopathic bacteria in anti-cyclic citrullinated protein (anti-CCP) antibody-positive at-risk individuals without arthritis. Design, Setting, and Participants: This cross-sectional study took place at a teaching hospital from April 27, 2015, to May 8, 2017. Forty-eight anti-CCP-positive individuals without arthritis (CCP+ at-risk) were recruited nationally. Twenty-six patients with early RA (ERA) and 32 healthy control individuals were recruited locally. Data were analyzed between June 1, 2017, and December 1, 2017. Interventions: Periodontal assessment and examination of joints using ultrasonography. Main Outcomes and Measures: Prevalence of diseased periodontal sites, clinical periodontitis, and periodontal inflamed surface area in CCP+ at-risk individuals compared with patients with ERA and healthy individuals matched for age and smoking. Paired-end sequencing of DNA from subgingival plaque from diseased and healthy periodontal sites was performed and DNA was profiled and analyzed. Results: A total of 48 CCP+ at-risk individuals (mean [SD] age, 51.9 [11.4] years; 31 [65%] female), 26 patients with ERA (mean [SD] age, 54.4 [16.7] years; 14 [54%] female), and 32 healthy individuals (mean [SD] age, 49.4 [15.3] years; 19 [59%] female) were recruited. Of 48 CCP+ at-risk individuals, 46 had no joint inflammation on ultrasonography. Thirty-five CCP+ at-risk individuals (73%), 12 healthy individuals (38%), and 14 patients with ERA (54%) had clinical periodontitis. The median (interquartile range) percentage of periodontal sites with disease was greater in CCP+ at-risk individuals compared with healthy individuals (3.3% [0%-11.3%] vs 0% [0%-0.7%]) and similar to patients with ERA (1.1% [0%-13.1%]). Median (interquartile range) periodontal inflamed surface area was higher in CCP+ at-risk individuals compared with healthy individuals (221 mm2 [81-504 mm2] vs 40 mm2 [12-205 mm2]). Patients with CCP+ at-risk had increased relative abundance of Porphyromonas gingivalis (but not Aggregatibacter actinomycetemcomitans) at healthy periodontal sites compared with healthy individuals (effect size, 3.00; 95% CI, 1.71-4.29) and patients with ERA (effect size, 2.14; 95% CI, 0.77-3.52). Conclusions and Relevance: This study found increased prevalence of periodontitis and P gingivalis in CCP+ at-risk individuals. This suggests periodontitis and P gingivalis are associated with disease initiation and could be targets for preventive interventions in RA.


Assuntos
Infecções por Bacteroidaceae/epidemiologia , Periodontite/epidemiologia , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Infecções por Bacteroidaceae/imunologia , Biomarcadores/metabolismo , Estudos Transversais , Inglaterra/epidemiologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Periodontite/microbiologia , Exame Físico , Porphyromonas gingivalis , Prevalência , Fatores de Risco
10.
Gene ; 712: 143911, 2019 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-31176730

RESUMO

MicroRNA-23b (miR-23b) is associated with inflammation and autoimmune diseases. This study evaluated miR-23b expression and assessed its potential as a biomarker of disease activity for rheumatoid arthritis (RA). Differential expression of microRNAs was determined by miRNA microarray analysis in fibroblast-like synoviocytes (FLSs) from four trauma patients as healthy controls (HCs) and eight RA patients. The microarray results showed elevated expression of miR-23b in FLSs from RA patients and this finding was corroborated by real-time quantitative polymerase chain reaction (RT-qPCR) and in situ hybridization using synovial tissues (STs). Furthermore, we found miR-23b levels in plasma of RA patients were significantly higher than in HCs, and plasma miR-23b levels positively correlated with the erythrocyte sedimentation rate (ESR), hypersensitive C-reactive protein (hs-CRP), C-reactive protein (CRP), DAS28, and platelet (PLT) count (P < 0.05). MiR-23b levels in plasma inversely correlated with the levels of hemoglobin (Hb), total bilirubin (TBIL), direct bilirubin (DBIL), indirect bilirubin (IBIL), total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) (P < 0.05), but not with rheumatoid factor (RF) or anti-cyclic citrullinated peptide antibodies (ACPA) (P > 0.05). Moreover, patients with anorexia showed higher levels of miR-23b in plasma than those without anorexia. Similar results were observed with fatigue. Appropriate treatment for RA not only ameliorated the disease condition but also reversed the elevated plasma miR-23b level remarkably. These results suggest that circulating miR-23b may be a promising biomarker for RA disease activity.


Assuntos
Artrite Reumatoide/sangue , Artrite Reumatoide/genética , MicroRNAs/sangue , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/metabolismo , Bilirrubina/química , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Colesterol/metabolismo , LDL-Colesterol/metabolismo , Feminino , Fibroblastos/metabolismo , Perfilação da Expressão Gênica , Regulação da Expressão Gênica , Hemoglobinas/química , Humanos , Masculino , MicroRNAs/genética , Pessoa de Meia-Idade , Análise de Sequência com Séries de Oligonucleotídeos , Contagem de Plaquetas , Fator Reumatoide/metabolismo , Membrana Sinovial/citologia , Membrana Sinovial/metabolismo
11.
Front Immunol ; 10: 1353, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31249576

RESUMO

Background: The purpose of this study was to determine whether plasma levels of the collagen triple helix repeat containing 1 (CTHRC1) protein can serve as a blood-based biomarker for improved diagnosis of rheumatoid arthritis (RA) patients and monitoring of RA disease activity. Methods: We measured levels of CTHRC1 in the plasma of patients diagnosed with RA, osteoarthritis (OA), reactive arthritis (ReA), as well as in healthy individuals. We then assessed the correlation between CTHRC1 protein and a range of indices including the 28-joint disease activity score (DAS28), rheumatoid factor (RF), C-reactive protein (CRP), anti-citrullinated protein antibodies (ACPA), erythrocyte sedimentation rate (ESR), as well as a panel of cytokines, including interleukin 1 beta (IL-1ß), interleukin 6 (IL-6), interleukin 8 (IL-8), and interferon gamma (IFNγ). Receiver operating characteristic (ROC) analysis was further performed to assess the diagnostic value of CTHRC1. Results: CTHRC1 plasma levels were significantly elevated in RA patients compared to healthy individuals, OA and ReA patients. ROC curve and risk score analysis suggested that plasma CTHRC1 can accurately discriminate patients with RA from healthy controls and may have practical value for RA diagnosis. CTHRC1 levels were positively associated with RF, ACPA, CRP, and disease activity based on the combined index of DAS28 with CRP (DAS28-CRP), and also strongly correlated with IL-1ß, IL-6, IL-8, and IFNγ. Conclusion: Our studies show that CTHRC1 is a sensitive and easy-to-measure plasma marker that differentiates between RA and healthy status and also distinguishes between RA and other forms of arthritis, such as OA and ReA. At the current level of understanding, plasma CTHRC1 levels may improve the diagnosis of RA and these findings warrant confirmation in a larger, more comprehensive patient population.


Assuntos
Artrite Reumatoide/diagnóstico , Biomarcadores/sangue , Proteínas da Matriz Extracelular/sangue , Osteoartrite/diagnóstico , Adulto , Idoso , Anticorpos Anti-Proteína Citrulinada/metabolismo , Citocinas/metabolismo , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Índice de Gravidade de Doença , Regulação para Cima
12.
Clin Chem Lab Med ; 57(11): 1668-1679, 2019 Oct 25.
Artigo em Inglês | MEDLINE | ID: mdl-31141478

RESUMO

Background Previous reviews of the diagnosis for rheumatoid arthritis (RA) have not compared anti-mutated citrullinated vimentin (MCV) with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF) in respect of sensitivity, specificity and the area under the curve (AUC) against disease controls for differential diagnosis. This meta-analysis aims to evaluate the value of anti-MCV in the diagnosis for RA, the combined sensitivity of anti-MCV and anti-CCP, and certain clinical characteristics related to the performance of anti-MCV. Methods Medline, Embase, Cochrane Library and Web of Science were searched for articles published up to 25 August 2018. A total of 33 studies including 6044 RA patients and 5094 healthy or disease controls achieved inclusive criteria. QUADAS-2 was applied to evaluate the quality of the included studies. The bivariate random effects model was employed in primary data synthesis to evaluate the diagnostic performance. Results The sensitivity of anti-MCV, anti-CCP and RF in RA diagnosis against a disease control group was 0.71, 0.71, 0.77, with the specificity of 0.89, 0.95, 0.73, and the AUC of the SROC of 0.89, 0.95, 0.82, respectively. The predesign of the primary study and diagnostic criteria were statistically significant as sources of heterogeneity. Anti-MCV and anti-CCP tests demonstrated a sensitivity of 0.77 when performed in parallel, with a sensitivity of 0.60 when performed in series; whereas, the combination of anti-MCV and RF presented a sensitivity of 0.64 when used in series. Conclusions Anti-MCV demonstrates comparable diagnostic value to anti-CCP and RF, thus it can be an effective diagnostic marker for RA and may be written into the next authoritative criteria.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/diagnóstico , Testes Imunológicos/métodos , Peptídeos Cíclicos/imunologia , Fator Reumatoide/imunologia , Vimentina/imunologia , Artrite Reumatoide/sangue , Feminino , Humanos , Masculino
13.
Arthritis Rheumatol ; 71(10): 1626-1633, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31067000

RESUMO

OBJECTIVE: Anti-citrullinated protein antibodies (ACPAs) are disease-specific biomarkers in rheumatoid arthritis (RA). More than 90% of IgG ACPAs harbor N-linked glycans in the antibody variable (V) domain. The corresponding N-glycosylation sites in ACPA V-region sequences result from somatic hypermutation, a T cell-dependent process. As ample evidence indicates that T cells drive the maturation of the ACPA response prior to arthritis onset, we undertook this study to investigate whether the presence of glycans in IgG ACPA V domains predicts the transition from predisease autoimmunity to overt RA. METHODS: We analyzed 2 independent sets of serum samples obtained from 126 ACPA-positive first-degree relatives (FDRs) of RA patients. Both sets originated from an Indigenous North American population and comprised cross-sectional and longitudinal samples of individuals who did or did not develop inflammatory arthritis. Serum IgG ACPAs were affinity-purified and subjected to ultra high-performance liquid chromatography-based glycan analysis. RESULTS: In both data sets, FDR-derived IgG ACPA displayed markedly lower levels of V domain glycans (<50%) compared to IgG ACPA from RA patients. Notably, FDRs who later developed RA showed extensive V-domain glycosylation before the onset of arthritis. Moreover, IgG ACPA V-domain glycosylation was strongly associated with future development of RA (hazard ratio 6.07 [95% confidence interval 1.46-25.2]; P = 0.013). CONCLUSION: Extensive glycosylation of the IgG ACPA V domain is present in a subset of predisposed FDRs of Indigenous North American RA patients. The presence of this feature substantially increases the risk of RA development. Based on these findings, we propose that glycosylation of the IgG ACPA V domain represents a predictive marker for RA development in ACPA-positive individuals and may serve to better target prevention measures.


Assuntos
Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/metabolismo , Imunoglobulina G/metabolismo , Região Variável de Imunoglobulina/metabolismo , Índios Norte-Americanos , Polissacarídeos/metabolismo , Adulto , Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Família , Feminino , Glicosilação , Humanos , Imunoglobulina G/imunologia , Masculino , Pessoa de Meia-Idade , Hipermutação Somática de Imunoglobulina , Linfócitos T/imunologia
14.
J Immunol ; 202(11): 3143-3150, 2019 06 01.
Artigo em Inglês | MEDLINE | ID: mdl-31019059

RESUMO

An increased repertoire of potential osteoclast (OC) precursors could accelerate the development of bone-erosive OCs and the consequent bone damage in rheumatoid arthritis (RA). Immature dendritic cells (DCs) can develop into OCs, however, the mechanisms underlying this differentiation switch are poorly understood. We investigated whether protein citrullination and RA-specific anti-citrullinated protein Abs (ACPAs) could regulate human blood-derived DC-OC transdifferentiation. We show that plasticity toward the OC lineage correlated with peptidyl arginine deiminase (PAD) activity and protein citrullination in DCs. Citrullinated actin and vimentin were present in DCs and DC-derived OCs, and both proteins were deposited on the cell surface, colocalizing with ACPAs binding to the cells. ACPAs enhanced OC differentiation from monocyte-derived or circulating CD1c+ DCs by increasing the release of IL-8. Blocking IL-8 binding or the PAD enzymes completely abolished the stimulatory effect of ACPAs, whereas PAD inhibition reduced steady-state OC development, as well, suggesting an essential role for protein citrullination in DC-OC transdifferentiation. Protein citrullination and ACPA binding to immature DCs might thus promote differentiation plasticity toward the OC lineage, which can facilitate bone erosion in ACPA-positive RA.


Assuntos
Artrite Reumatoide/imunologia , Células Dendríticas/fisiologia , Osteoclastos/fisiologia , Anticorpos Anti-Proteína Citrulinada/metabolismo , Antígenos CD1/metabolismo , Diferenciação Celular , Linhagem da Célula , Plasticidade Celular , Transdiferenciação Celular , Células Cultivadas , Citrulinação , Humanos , Interleucina-8/metabolismo , Monócitos/citologia , Desiminases de Arginina em Proteínas/metabolismo
15.
Exp Biol Med (Maywood) ; 244(7): 545-553, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30897958

RESUMO

IMPACT STATEMENT: In view of the partial clinical benefit and significant toxicity of traditional rheumatoid arthritis (RA) treatments, there is a growing trend to use complementary therapy. The antiarthritic activity of soy is related to the effect of soy isoflavones. However, little is known about the antiarthritic activity of soy protein itself. This study demonstrates that soy protein isolate (SPI) and etanercept (ETN), a tumor necrosis factor-α (TNF-α) inhibitor, protect rats against the effects of adjuvant-induced arthritis (AIA) by reducing inflammation (TNF-α and matrix metalloproteinase-3), autoantibody production (anticyclic citrullinated peptide), and lipid peroxidation (malondialdehyde). Only SPI improved dyslipidemia accompanied by RA, giving it the advantage of reducing cardiovascular risk. Additionally, the severity of arthritis-induced pathology, including inflammatory infiltrates, synovial hyperplasia, pannus formation, synovial vascularity, and cartilage erosions, was reduced by both SPI and ETN. This research ascertains the possible antiarthritic effect of SPI, making it a recommended alternative therapy for RA.


Assuntos
Antirreumáticos/uso terapêutico , Artrite Experimental/tratamento farmacológico , Proteínas de Soja/uso terapêutico , Animais , Anticorpos Anti-Proteína Citrulinada/metabolismo , Antirreumáticos/efeitos adversos , Colesterol/metabolismo , Etanercepte/efeitos adversos , Etanercepte/uso terapêutico , Articulações/metabolismo , Masculino , Malondialdeído/metabolismo , Metaloproteinase 3 da Matriz/metabolismo , Ratos , Proteínas de Soja/efeitos adversos , Fator de Necrose Tumoral alfa/metabolismo
16.
J Autoimmun ; 98: 122-131, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30704942

RESUMO

OBJECTIVE: Neutrophil extracellular traps (NET), produced by activated polymorphonuclear neutrophils (PMN), are supposed to play a role in the pathogenesis of rheumatoid arthritis (RA), a chronic inflammatory autoimmune disease characterized by anti-citrullinated protein antibodies (ACPA). Indeed, NET contain citrullinated autoantigens and some RA autoantibodies recognize NET. However, the mechanisms by which NET trigger or perpetuate the inflammatory process in RA are hitherto not elucidated. We hypothesized that, in addition to citrullination, NET might also contain stimulatory proteins and directly activate inflammatory target cells, as PMN and macrophages. METHODS: NET antigenic and inflammatory properties were analyzed in 157 healthy donors (HD) and RA patients, the largest analysis reported so far. Primary PMN and monocyte-derived macrophages were isolated and immunoglobulin G (IgG) purified. NET were induced (NETosis), isolated and quantified. NET antigenicity was analyzed by fluorescence microscopy. PMN and macrophages were stimulated with NET with/without ACPA, C1q, LL-37 or lipopolysaccharide (LPS) and cell activation was estimated by flow cytometry and ELISA. RESULTS: PMN from RA patients produced more NET than HD PMN. We next dissected how NET mechanistically affect inflammatory cells. Particularly, we show for the first time that RA and HD NET activated both resting macrophages and PMN, but importantly RA NET were more stimulatory, leading to secretion of inflammatory cytokines and up-regulation of HLA/CD86/CD11b. IgG from ACPA-positive RA patients specifically recognized RA and even HD NET. Nevertheless, NET-induced cell activation occurs independently of immune complex formation with ACPA. Likewise, endosomal acidification was not required. Notably, we also report that complement C1q increased the NET stimulatory activity on macrophages only, due to higher expression of C1q receptors, which was further supported by the LL-37 antimicrobial peptide. In contrast, NET specifically inhibited interleukin (IL)-6 secretion by LPS-activated macrophages and not PMN, especially with C1q/LL-37. This inhibition was not mediated by NET-derived proteases or LPS neutralization and was associated with the simultaneous induction of IL-10 secretion. CONCLUSION: We show that NET possess both pro- and anti-inflammatory properties depending on target cells, their activation levels and C1q/LL-37. Thus, independently of ACPA, NET modulate RA chronic inflammation via this new dual activity we identified. In addition, NET may trigger autoimmunity in RA as ACPA recognize NET antigens but not non-activated PMN. Therefore, we conclude that excess of NETosis together with enhanced NET activity participate to RA pathogenesis at different levels.


Assuntos
Peptídeos Catiônicos Antimicrobianos/metabolismo , Artrite Reumatoide/imunologia , Complemento C1q/metabolismo , Armadilhas Extracelulares/metabolismo , Inflamação/imunologia , Neutrófilos/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Anti-Proteína Citrulinada/metabolismo , Peptídeos Catiônicos Antimicrobianos/imunologia , Autoimunidade , Células Cultivadas , Complemento C1q/imunologia , Feminino , Humanos , Imunomodulação , Masculino , Pessoa de Meia-Idade
17.
Joint Bone Spine ; 86(5): 562-567, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-30685537

RESUMO

The identification in 1998 of the main antigenic substrate recognized by autoantibodies was a dramatic turning point in our understanding of rheumatoid arthritis (RA) biology. Now, two decades later, antibodies to citrullinated proteins are viewed no longer as mere biomarkers for RA, but also as major pathophysiological factors involved in the development of bone loss and joint pain. These pathogenic effects are ascribable to abnormal autoantibody glycosylation via a pathway involving the Th17T cells. In the future, abnormal autoantibody glycosylation may serve as a disease activity biomarker and suggest novel treatment strategies.


Assuntos
Anticorpos Anti-Proteína Citrulinada/imunologia , Artrite Reumatoide/imunologia , Autoanticorpos/imunologia , Autoimunidade , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Glicosilação , Humanos
18.
Ann Rheum Dis ; 78(1): 43-50, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30297331

RESUMO

OBJECTIVES: To use high-resolution imaging to characterise palindromic rheumatism (PR) and to compare the imaging pattern observed to that seen in new-onset rheumatoid arthritis (NORA). METHODS: Ultrasound (US) assessment of synovitis, tenosynovitis and non-synovial extracapsular inflammation (ECI) was performed during and between flares in a prospective treatment-naive PR cohort. MRI of the flaring region was performed where possible. For comparison, the same US assessment was also performed in anticyclic citrullinated peptide (CCP) positive individuals with musculoskeletal symptoms (CCP+ at risk) and patients with NORA. RESULTS: Thirty-one of 79 patients with PR recruited were assessed during a flare. A high frequency of ECI was identified on US; 19/31 (61%) of patients had ECI including 12/19 (63%) in whom ECI was identified in the absence of synovitis. Only 7/31 (23%) patients with PR had synovitis (greyscale ≥1 and power Doppler ≥1) during flare. In the hands/wrists, ECI was more prevalent in PR compared with NORA and CCP+ at risk (65% vs 29 % vs 6%, p<0.05). Furthermore, ECI without synovitis was specific for PR (42% PR vs 4% NORA (p=0.003) and 6% CCP+ at risk (p=0.0012)). Eleven PR flares were captured by MRI, which was more sensitive than US for synovitis and ECI. 8/31 (26%) patients with PR developed RA and had a similar US phenotype to NORA at progression. CONCLUSION: PR has a distinct US pattern characterised by reversible ECI, often without synovitis. In patients presenting with new joint swelling, US may refine management by distinguishing relapsing from persistent arthritis.


Assuntos
Artrite Reumatoide/diagnóstico por imagem , Imagem por Ressonância Magnética/estatística & dados numéricos , Fenótipo , Ultrassonografia Doppler/estatística & dados numéricos , Adulto , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/genética , Artrite Reumatoide/imunologia , Feminino , Humanos , Cápsula Articular/diagnóstico por imagem , Imagem por Ressonância Magnética/métodos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Exacerbação dos Sintomas , Sinovite/diagnóstico por imagem , Sinovite/genética , Sinovite/imunologia , Tenossinovite/diagnóstico por imagem , Tenossinovite/genética , Tenossinovite/imunologia , Ultrassonografia Doppler/métodos
19.
Mol Pharm ; 15(12): 5565-5573, 2018 12 03.
Artigo em Inglês | MEDLINE | ID: mdl-30289723

RESUMO

Autoreactive B cells are thought to play a pivotal role in many autoimmune diseases. Rheumatoid arthritis (RA) is an autoimmune disease affecting ∼1% of the Western population and is hallmarked by the presence of anticitrullinated proteins antibodies (ACPA) produced by autoreactive B cells. We intend to develop a method to target and selectively eliminate these autoreactive B cells using a sequential antigen prodrug targeting strategy. As ACPA-expressing B cells are thought to play essential roles in RA-disease pathogenesis, we used this B cell response as a prototype to analyze the feasibility to generate a construct consisting of a biologically silenced, that is, blocked, antigen connected to a cytotoxic prodrug. Blocking of the antigen is considered relevant as it is anticipated that circulating autoantibodies will otherwise clear the antigen-prodrug before it can reach the target cell. The antigen-prodrug can only bind to the autoantigen-specific B cell receptor (BCR) upon enzymatic removal of the blocking group in close proximity of the B cell surface. BCR binding ultimately induces antigen-specific cytotoxicity after internalization of the antigen. We have synthesized a cyclic citrullinated peptide (CCP) antigen suitable for BCR binding and demonstrated that binding by ACPA was impaired upon introduction of a carboxy- p-nitrobenzyl (CNBz) blocking group at the side chain of the citrulline residue. Enzymatic removal of the CNBz moiety by nitroreductase fully restored citrulline-specific recognition by both ACPA and ACPA-expressing B cells and showed targeted cell death of CCP-recognizing B cells only. These results mark an important step toward antigen-specific B cell targeting in general and more specifically in RA, as successful blocking and activation of citrullinated antigens forms the basis for subsequent use of such construct as a prodrug in the context of autoimmune diseases.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Linfócitos B/efeitos dos fármacos , Epitopos de Linfócito B/administração & dosagem , Peptídeos Cíclicos/imunologia , Pró-Fármacos/administração & dosagem , Anticorpos Anti-Proteína Citrulinada/imunologia , Anticorpos Anti-Proteína Citrulinada/metabolismo , Artrite Reumatoide/sangue , Artrite Reumatoide/imunologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Linhagem Celular , Epitopos de Linfócito B/química , Estudos de Viabilidade , Humanos , Terapia de Alvo Molecular/métodos , Pró-Fármacos/química , Receptores de Antígenos de Linfócitos B/antagonistas & inibidores , Receptores de Antígenos de Linfócitos B/imunologia , Receptores de Antígenos de Linfócitos B/metabolismo
20.
J Immunol ; 201(11): 3211-3217, 2018 12 01.
Artigo em Inglês | MEDLINE | ID: mdl-30373852

RESUMO

Quantification of Abs toward a single epitope is critical to understanding immunobiological processes. In autoimmunity, the prognostic value of the serological profiles of patients draws much attention, but the detection of Abs toward a single epitope is not well controlled. Particularly, the rheumatoid arthritis (RA)-specific anti-citrullinated protein/peptide Abs (ACPA) are specific to a two-atom change on arginyl residues and are considered a heterogeneous family of Abs. As a model, we studied ACPA to decipher how peptide features used as immunosorbent impact Ab detection. We synthesized 30 peptides encompassing immunodominant epitopes of citrullinated fibrin differing by their length and biotin location and tested them using ELISA with 120 sera from RA and non-RA rheumatic disease controls, generating over 3000 experimental measurements. We showed that minor molecular changes in peptide chemical structure had dramatic consequences. Even when peptides exhibited the same epitope, measured Ab titers were extremely variable, and patients' seropositivity was discordant in up to 50% of cases. The distance between epitope and biotin was the most critical parameter for efficient Ab detection irrespective of biotin position or peptide length. Finally, we identified a 15-mer peptide bearing a single citrullinated epitope detecting almost all ACPA-positive sera, thus revealing a high degree of homogeneity in RA autoimmune response. This integrative analysis deciphers the dramatic impact of the molecular design of peptide-based technologies for epitope-specific Ab quantification. It provides a model for assay development and highlights that the studies using such technologies can give a wrong perception of biological processes and therefore that medical use of data must be cautious.


Assuntos
Artrite Reumatoide/imunologia , Epitopos/química , Fibrina/química , Imunoadsorventes/química , Peptídeos/química , Sorologia/métodos , Anticorpos Anti-Proteína Citrulinada/metabolismo , Citrulinação , Erros de Diagnóstico , Ensaio de Imunoadsorção Enzimática , Epitopos/imunologia , Fibrina/imunologia , Humanos , Imunidade Humoral , Peptídeos/imunologia
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