RESUMO
Connective tissue disease-associated interstitial lung disease (CTD-ILD) is a severe manifestation of CTD that leads to significant morbidity and mortality. Clinically, ILD can occur in diverse CTDs. Pathologically, CTD-ILD is characterized by various histologic patterns, such as nonspecific interstitial pneumonia, organizing pneumonia, and usual interstitial pneumonia. Abnormal immune system responses have traditionally been instrumental in its pathophysiology, and various changes in immune cells have been described, especially in macrophages. This article first briefly overviews the epidemiology, clinical characteristics, impacts, and histopathologic changes associated with CTD-ILD. Next, it summarizes the roles of various signaling pathways in macrophages or products of macrophages in ILD, helped by insights gained from animal models. In the following sections, this review returns to studies of macrophages in CTD-ILD in humans for an overall picture of the current understanding. Finally, we direct attention to potential therapies targeting macrophages in CTD-ILD in investigation or in clinical trials, as well as the future directions regarding macrophages in the context of CTD-ILD. Although the field of macrophages in CTD-ILD is still in its infancy, several lines of evidence suggest the potential of this area.
Assuntos
Doenças do Tecido Conjuntivo , Pneumonias Intersticiais Idiopáticas , Fibrose Pulmonar Idiopática , Doenças Pulmonares Intersticiais , Animais , Humanos , Doenças Pulmonares Intersticiais/terapia , Doenças Pulmonares Intersticiais/complicações , Doenças do Tecido Conjuntivo/complicações , Fibrose Pulmonar Idiopática/complicações , MacrófagosRESUMO
BACKGROUND: Genetic and epigenetic factors are strongly associated with the autoimmune disease rheumatoid arthritis (RA). Cyclic AMP response element modulator (CREM), a gene related to immune system regulation, has been implicated in various immune-mediated inflammatory processes, although it remains unknown whether CREM is involved in RA. METHODS: This study enrolled 278 RA patients and 262 controls. Three variants [rs12765063, rs17499247, rs1213386] were identified through linkage disequilibrium and expression quantitative trait locus analysis, and CREM transcript abundance was determined by quantitative real-time polymerase chain reaction. The identified variants were genotyped using the TaqMan Allelic Discrimination assay, and CREM promoter methylation was assessed by bisulphite sequencing. Differences between groups and correlations between variables were assessed with Student's t-tests and Pearson's correlation coefficients. Associations between phenotypes and genotypes were evaluated with logistic regression. RESULTS: Rheumatoid arthritis patients exhibited increased CREM expression (p < .0001), which was decreased by methotrexate (p = .0223) and biologics (p = .0001), but could not be attributed to CREM variants. Interestingly, rs17499247 displayed a significant association with serositis (p = .0377), and rs1213386 increased the risk of lymphadenopathy (p = .0398). Furthermore, seven CpG sites showed decreased methylation in RA (p = .0477~ p < .0001). CONCLUSIONS: Collectively, our results indicate that CREM hypomethylation and CREM upregulation occur in RA and that CREM variants are involved in the development of serositis and lymphadenopathy in RA. This study highlights the novel roles of CREM in RA pathophysiology.
Assuntos
Artrite Reumatoide , Linfadenopatia , Serosite , Artrite Reumatoide/genética , Modulador de Elemento de Resposta do AMP Cíclico/genética , Modulador de Elemento de Resposta do AMP Cíclico/metabolismo , Epigênese Genética , Humanos , Serosite/genéticaRESUMO
Rheumatoid arthritis (RA) is one of the inflammatory joint diseases that display features of articular cartilage destruction. The underlying disturbance results from immune dysregulation that directly and indirectly influence chondrocyte physiology. In the last years, significant evidence inferred from studies in vitro and in the animal model offered a more holistic vision of chondrocytes in RA. Chondrocytes, despite being one of injured cells in RA, also undergo molecular alterations to actively participate in inflammation and matrix destruction in the human rheumatoid joint. This review covers current knowledge about the specific cellular and biochemical mechanisms that account for the chondrocyte signatures of RA and its potential applications for diagnosis and prognosis in RA.
Assuntos
Artrite Reumatoide/patologia , Condrócitos/patologia , Animais , Artrite Reumatoide/imunologia , Condrócitos/imunologia , Modelos Animais de Doenças , Humanos , PrognósticoRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is an autoimmune disease where both genetics and epigenetics are contributing factors. In order to discover genetic and epigenetic associations with RA and its phenotypes, we analysed RNA expression, DNA variations and DNA methylation of programmed cell death 1 (PDCD1) in a cohort of RA patients and healthy controls. METHODS: RA patients (n = 206) and healthy controls (n = 234) were included for analysis of PDCD1 expression, PDCD1 polymorphisms and PDCD1 methylation. Differences in continuous variables between groups were compared by applying t tests. Associations between phenotypes and genotypes were evaluated with contingency tables. Sensitivity analyses were conducted to confirm the robustness of results, considering potential confounding factors and different treatment response definitions. Odds ratio (OR) and 95% confidence interval (95% CI) were calculated. RESULTS: Higher expression of PDCD1 was found in RA compared to controls (P < 0.001), with similar PDCD1 polymorphisms in RA and controls. rs36084323 decreased inadequate response to conventional synthetic disease-modifying antirheumatic drugs (OR = 0.37, 95% CI = 0.19-0.72, P = 0.003), and rs41386349 increased rheumatoid factor seropositivity (OR = 11.89, 95% CI = 1.57-89.87, P = 0.003). Sensitivity analysis adjusting for further potential confounders and using different treatment response definition indicated similar results. Additionally, DNA methylation change at regulatory region of PDCD1 was detected in RA (P = 0.036). CONCLUSION: Altogether, this was the first study to suggest genetic and epigenetic changes of PDCD1 in RA subsets and RA. Independent prospective cohorts are awaited to address the implications of these genetic and epigenetic changes in disease pathogenesis and phenotypes of RA.
Assuntos
Artrite Reumatoide/genética , Receptor de Morte Celular Programada 1/genética , RNA Mensageiro/metabolismo , Anticorpos Antiproteína Citrulinada/imunologia , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Metilação de DNA , Epigênese Genética , Feminino , Expressão Gênica , Humanos , Hidroxicloroquina/uso terapêutico , Leflunomida/uso terapêutico , Masculino , Metotrexato/uso terapêutico , Razão de Chances , Polimorfismo de Nucleotídeo Único , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Fator Reumatoide/imunologia , Sulfassalazina/uso terapêutico , Transcriptoma , Falha de Tratamento , Resultado do TratamentoRESUMO
BACKGROUND: Although dermatomyositis and Sjögren syndrome share serologic autoantibodies and genetic polymorphisms, population data about the incidence of Sjögren syndrome in patients with dermatomyositis is unavailable. We performed a nationwide cohort study to explore the potential relation between dermatomyositis and Sjögren syndrome and, if an association exists, to elucidate whether it varies by sex. METHODS: We identified all patients with newly diagnosed dermatomyositis from the Registry of Catastrophic Illness Database in Taiwan between Jan. 1, 1998, and Dec. 31, 2011. Each patient was matched to, at most, 5 control patients from the National Health Insurance Research Database by age, sex and entry date. Cox regression was used to calculate the hazard ratio (HR) and 95% confidence interval (CI) of Sjögren syndrome after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis. RESULTS: A total of 1602 patients with dermatomyositis and 7981 control patients were enrolled in the study. There was a positive association of having Sjögren syndrome among patients with dermatomyositis after adjusting for age, sex, rheumatoid arthritis, systemic lupus erythematosus and systemic sclerosis (HR 2.67, 95% CI 2.01-3.54). The association was more pronounced in the male cohort (HR 2.69, 95% CI 1.19-6.09). INTERPRETATION: We found a sex differential association of Sjögren syndrome among patients with dermatomyositis independent of age and concomitant autoimmune disease. Further studies are required to determine the clinical importance of this association for both outcomes and therapeutic options.
Assuntos
Dermatomiosite/epidemiologia , Sistema de Registros , Síndrome de Sjogren/epidemiologia , Adulto , Fatores Etários , Idoso , Idoso de 80 Anos ou mais , Animais , Artrite Reumatoide/epidemiologia , Estudos de Coortes , Feminino , Humanos , Incidência , Lúpus Eritematoso Sistêmico/epidemiologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Modelos de Riscos Proporcionais , Escleroderma Sistêmico/epidemiologia , Distribuição por Sexo , Fatores Sexuais , Taiwan/epidemiologia , Adulto JovemRESUMO
OBJECTIVE: Previous studies showed inconsistent results on the association of systemic sclerosis (SSc) with multiple sclerosis (MS), and are limited by a lack of adjustment for sex and age. The goals of this retrospective cohort study were to evaluate whether SSc is associated with increased incident MS independent of sex and age. METHODS: We enrolled patients with SSc from Taiwan's Registry of Catastrophic Illness Database and referent subjects from the National Health Insurance Research Database. Each SSc patient was matched to at most three referent subjects by sex, age, month and year of initial diagnosis of SSc. Incidence of MS in SSc patients and corresponding 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR) of MS. RESULTS: The study enrolled 1171 patients with SSc and 3409 referent subjects. Patients with SSc had higher incidence of MS than referent subjects (9.35 per 1000 person-years, 95% CI=6.86-11.85; 0.13 per 1000 person-years, 95% CI=0.03-0.37, respectively). Similar results also occurred in both men and women. SSc was associated with increased incidence of MS after adjusting for sex and age (HR: 69.48, 95% CI=21.69-222.54). CONCLUSION: SSc is associated with increased incidence of MS, independent of sex and age of the patients. Multidisciplinary teams should guide the assessment, treatment, and holistic care of SSc patients to reduce its morbidity.
Assuntos
Esclerose Múltipla/etiologia , Escleroderma Sistêmico/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Esclerose Múltipla/epidemiologia , Sistema de Registros , Estudos Retrospectivos , Fatores de Risco , Taiwan/epidemiologiaRESUMO
BACKGROUND: To date, there has been no studies to evaluate the incidence of Crohn's disease in systemic sclerosis patients. The goals of this study were to evaluate the incidence of Crohn's disease and its relationship with sex and age in patients with systemic sclerosis. METHODS: We enrolled patients with systemic sclerosis and controls from Taiwan's Registry of Catastrophic Illness Database and National Health Insurance Research Database. Every systemic sclerosis patient was matched to at most three controls by sex, age, month and year of initial diagnosis of systemic sclerosis. The standardized incidence ratio (SIR) of Crohn's disease in systemic sclerosis patients, and 95% confidence interval (95% CI) were calculated. Cox hazard regression was used to calculate the hazard ratio (HR). RESULTS: The study enrolled 2,829 patients with systemic sclerosis and 8,257 controls. Male and female patients with systemic sclerosis both had lower rates of incident Crohn's disease (SIR: 0.18, 95% CI = 0.05-0.62; SIR: 0.10, 95% CI = 0.05-0.21, respectively). The risk of incident Crohn's disease in systemic sclerosis was still lower than in controls when we stratified the patients according to their ages. In Cox hazard regression, the hazard rates of Crohn's disease were lower in systemic sclerosis patients after adjusting for genders and ages (HR: 0.12, 95% CI = 0.06-0.21, p < 0.001). CONCLUSIONS: Systemic sclerosis is associated with decreased incidence of, irrespective of sex and age of the patients.
Assuntos
Doença de Crohn/diagnóstico , Doença de Crohn/epidemiologia , Vigilância da População , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Feminino , Seguimentos , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Vigilância da População/métodos , Sistema de Registros , Taiwan/epidemiologia , Adulto JovemRESUMO
Different human leukocyte antigen (HLA) genotypes have been known to be associated with the risk of development of Sjögren's syndrome in different populations, but this association has never been reported in Taiwan. We enrolled 1044 subjects (673 patients, 371 controls) and tested their HLA-DR genotypes. We found an increased risk of Sjögren's syndrome in patients carrying HLA-DR8. DR1 and DR14 were associated with increased risk of eye involvement (uveitis, scleritis or optic neuritis), while DR15 was associated with increased risk of interstitial lung disease. DR8 was associated with increased risk of formation of multiple antibodies: anti-Ro, rheumatoid factor and antinuclear antibodies (ANA) reaching titer 1:80 or above. DR9 was associated with decreased risk of formation of anti-La antibodies and increased risk of formation of antithyroglobulin antibodies. DR10 was associated with risk of formation of anticyclic citrullinated peptide (anti-CCP) antibodies, and DR11 was associated with increased risk of formation of anti-La antibodies. Oral ulcer was found to be negatively associated with anti-Ro antibodies and with anti-ENA antibodies. Skin lesions were associated with ANA antibody titer elevation to 1:80 or above. Malignancies of any kind were associated with the presence of cryoglobulin. Females were more likely to be diagnosed at a younger age than males. There was no statistically significant relationship between HLA-DR genotype and age at disease diagnosis. In patients with Sjögren's syndrome in Taiwan, the presence of HLA-DR8 appeared to be a risk factor. In addition, we found several associations between HLA-DR genotype, clinical presentation, and autoantibody status among them.
RESUMO
BACKGROUND: Different human leukocyte antigen (HLA)-DR genotypes have been known to be associated with the risk of development of systemic lupus erythematosus (SLE) in different populations, although Lu et al. have reported previously that no correlation exists between the HLA-DR genotype and disease manifestation in SLE patients in Taiwan. We investigated the effects different HLA-DR genotypes had on SLE incidence in Taiwanese patients as to whether risk alleles were associated with different clinical manifestations, and the effects risk alleles had on the age of disease onset. METHODS: Two hundred thirty-four SLE patients and 346 healthy controls were enrolled. HLA-DR genotyping was performed with the HLA FluoGene DRDQ kit for each subject. Chi-square tests and t tests were performed for statistical analysis. RESULTS: HLA-DR2 was significantly more frequently found in SLE patients than in controls (odds ratio [OR] = 2.05, 95% CI, 1.44-2.92, p < 0.001). Notably, HLA-DR6 appeared to trend toward negative correlation with SLE, whereas HLA-DR8 appeared to trend toward positive correlation. HLA-DR2 patients had an earlier onset of disease as well as a higher prevalence of oral ulcer, avascular necrosis of bone, and renal involvement (lupus nephritis). CONCLUSION: HLA-DR2 was associated with SLE susceptibility in this Taiwanese population as well as lower age of disease onset and more severe clinical manifestations.
Assuntos
Antígeno HLA-DR2 , Lúpus Eritematoso Sistêmico , Humanos , Antígeno HLA-DR2/genética , Taiwan , Predisposição Genética para Doença , Antígenos HLA-DR/genética , Lúpus Eritematoso Sistêmico/genética , GenótipoRESUMO
Aim: The activation of NLRP3 inflammasome leads to the stimulation of cytokines and is significantly involved in the pathogenesis and progression of autoimmune diseases. The purpose of this study is to examine the associations of NLRP3 gene polymorphisms with rheumatoid arthritis (RA) and primary Sjogren's syndrome (SS) patients. Methods: A total of 239 patients with RA, 285 patients with primary SS, and 170 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood mononuclear cells, and gene polymorphisms were genotyped through the TaqMan assay. Antinuclear antibody (ANA), anti-Ro, and anti-CCP antibodies were detected using immunofluorescence immunoassay. Results: The T allele of rs4612666 CT elevated the susceptibility to RA disease. The RF titer during diagnosis of RA was significantly high in RA patients with the A allele of rs12079994 G/A polymorphism. The titer of anti-CCP during diagnosis of RA was high in the absence of the C allele of rs10754558 C/G polymorphisms in RA patients. Antinuclear antibody and anti-CCP were positively associated with the A allele of rs12079994 G/A polymorphism in primary SS. The C allele of rs4612666 C/T was negatively associated with ANA in primary SS. Conclusions: The results have shown that NLRP3 gene polymorphisms may play a role in the pathogenesis of RA and primary SS.
RESUMO
(1) Background: It is widely accepted that aberrant methylation patterns contribute to the development of systemic lupus erythematosus (SLE). Ten-eleven translocation (TET) methylcytosine dioxygenase is an essential enzyme of which there are three members, TET1, 2, and 3, involved in hydroxymethylation, a newly uncovered mechanism of active DNA methylation. The epigenomes of gene transcription are regulated by 5-hydroxymethylcytocine (5-hmC) and TETs, leading to dysregulation of the immune system in SLE. The purpose of this study was to investigate the global hydroxymethylation status in SLE peripheral blood mononuclear cells (PBMCs) and to explore the role of TETs in changing the patterns of methylation. (2) Methods: We collected PBMCs from 101 SLE patients and 100 healthy donors. TaqMan real-time polymerase chain-reaction assay was performed for the detection of 5-methylcytosine (5-mC), 5-hmC, and TET2 mRNA expression and single-nucleotide polymorphism genotyping. The methylation rates in different CpG sites of TET2 promoters were examined using next-generation sequencing-based deep bisulfite sequencing. Putative transcription factors were investigated using the UCSC Genome Browser on the Human Dec. 2013 (GRCh38/hg38) Assembly. (3) Results: 5-mC and 5-hmC were both decreased in SLE. The mRNA expression level of TET2 was notably high and found to be correlated with the levels of immunologic biomarkers that are indicative of SLE disease activity. The analysis of methylation rates in the TET2 promoter revealed that SLE patients had significantly higher and lower rates of methylation in TET2 105146072-154 and TET2 105146218-331, respectively. (4) Conclusions: TET2 may play an important role in 5-mC/5-hmC dynamics in the PBMCs of SLE patients. The epigenetic modification of TET2 promoters could contribute to the pathogenesis of SLE and the intensity of the immunologic reaction.
RESUMO
AIMS: F11R gene encodes junctional adhesion molecule-A protein (JAM-A), which is expressed in various types of cells and is involved in leukocyte extravasation during inflammation. Sjögren's syndrome (SS) is a chronic systemic inflammatory disease that involves lymphocytes invasion of exocrine glands. F11R has been studied in autoimmune diseases, but any association between F11R and SS has not yet been investigated. Therefore, experiments were undertaken to examine the relationships among F11R gene polymorphism, messenger RNA (mRNA) expression and SS patients. METHODS: Three hundred and twenty-nine patients with SS, and 223 healthy controls were enrolled in their recruitment from the Kaohsiung Medical University Hospital. Genomic DNA was extracted from peripheral blood mononuclear cells and gene polymorphisms were genotyped by TaqMan real-time polymerase chain reaction (PCR). F11R mRNA expression was quantitated by quantitative real-time PCR with TaqMan Gene Expression Assay. RESULTS: Our study showed the genotype -688A/C (rs6695707) was not found in relation to SS patients. The odds ratio of -436A/G (rs12567886) genotype was notably associated with less susceptibility of SS in human leukocyte antigen (HLA)-DR2 negative and HLA-DR3 negative individuals. F11R mRNA expression was lower in SS patients than in the cells of healthy controls. CONCLUSION: The result indicated that G allele of -436A/G genotype has the potential protective effect against SS disease condition. F11R mRNA was expressed significantly lower in SS patients.
Assuntos
Moléculas de Adesão Celular/genética , RNA Mensageiro/genética , Receptores de Superfície Celular/genética , Síndrome de Sjogren/genética , Adulto , Alelos , Estudos de Casos e Controles , Feminino , Expressão Gênica , Genótipo , Antígeno HLA-DR2 , Antígeno HLA-DR3 , Humanos , Masculino , Pessoa de Meia-Idade , Polimorfismo Genético , Reação em Cadeia da Polimerase em Tempo Real , Síndrome de Sjogren/sangue , Síndrome de Sjogren/diagnóstico , Síndrome de Sjogren/imunologia , Taq PolimeraseRESUMO
OBJECTIVE: Patients with systemic lupus erythematosus (SLE) often have atherosclerotic complications at a young age but normal low-density lipoprotein (LDL) levels. This study was undertaken to investigate the role of LDL composition in promoting early vascular aging in SLE patients. METHODS: Plasma LDL from 45 SLE patients (SLE-LDL) and from 37 normal healthy controls (N-LDL) was chromatographically divided into 5 subfractions (L1-L5), and the subfraction composition was analyzed. Correlations between subfraction levels and signs of early vascular aging were assessed. Mechanisms of lipid-mediated endothelial dysfunction were explored using in vitro assays and experiments in apoE-/- mice. RESULTS: The L5 percentage was increased 3.4 times in the plasma of SLE patients compared with normal controls. This increased percentage of SLE-L5 was positively correlated with the mean blood pressure (r = 0.27, P = 0.04), carotid intima-media thickness (IMT) (right carotid IMT, r = 0.4, P = 0.004; left carotid IMT, r = 0.36, P = 0.01), pulse wave velocity (r = 0.29, P = 0.04), and blood levels of CD16+ monocytes (r = 0.35, P = 0.004) and CX3CL1 cytokines (r = 0.43, P < 0.001) in SLE patients. Matrix-assisted laser desorption ionization-time-of-flight mass spectrometry analysis revealed that plasma levels of lysophosphatidylcholine (LPC) and platelet-activating factor (PAF) were increased in SLE-LDL and in the SLE-L5 plasma subfraction. Injecting SLE-LDL, SLE-L5, or LPC into young, male apoE-/- mice caused increases in plasma CX3CL1 levels, aortic fatty-streak areas, aortic vascular aging, and macrophage infiltration into the aortic wall, whereas injection of N-LDL or SLE-L1 had negligible effects (n = 3-8 mice per group). In vitro, SLE-L5 lipid extracts induced increases in CX3CR1 and CD16 expression in human monocytes; synthetic PAF and LPC had similar effects. Furthermore, lipid extracts of SLE-LDL and SLE-L5 induced the expression of CX3CL1 and enhanced monocyte-endothelial cell adhesion in assays with bovine aortic endothelial cells. CONCLUSION: An increase in plasma L5 levels, not total LDL concentration, may promote early vascular aging in SLE patients, leading to premature atherosclerosis.
Assuntos
Fatores Etários , Senilidade Prematura/sangue , Endotélio Vascular/fisiopatologia , Lipoproteínas LDL/sangue , Lúpus Eritematoso Sistêmico/sangue , Adulto , Senilidade Prematura/etiologia , Senilidade Prematura/fisiopatologia , Animais , Aterosclerose/etiologia , Espessura Intima-Media Carotídea , Células Endoteliais/metabolismo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/fisiopatologia , Masculino , Camundongos , Pessoa de Meia-Idade , Análise de Onda de Pulso , Fatores de RiscoRESUMO
Using next-generation sequencing to decipher the molecular mechanisms underlying aberrant rheumatoid arthritis synovial fibroblasts (RASF) activation, we performed transcriptome-wide RNA-seq and small RNA-seq on synovial fibroblasts from rheumatoid arthritis (RA) subject and normal donor. Differential expression of mRNA and miRNA was integrated with interaction analysis, functional annotation, regulatory network mapping and experimentally verified miRNA-target interaction data, further validated with microarray expression profiles. In this study, 3049 upregulated mRNA and 3552 downregulated mRNA, together with 50 upregulated miRNA and 35 downregulated miRNA in RASF were identified. Interaction analysis highlighted contribution of miRNA to altered transcriptome. Functional annotation revealed metabolic deregulation and oncogenic signatures of RASF. Regulatory network mapping identified downregulated FOXO1 as master transcription factor resulting in altered transcriptome of RASF. Differential expression in three miRNA and corresponding targets (hsa-miR-31-5p:WASF3, hsa-miR-132-3p:RB1, hsa-miR-29c-3p:COL1A1) were also validated. The interactions of these three miRNA-target genes were experimentally validated with past literature. Our transcriptomic and miRNA interactomic investigation identified gene signatures associated with RASF and revealed the involvement of transcription factors and miRNA in an altered transcriptome. These findings help facilitate our understanding of RA with the hope of serving as a springboard for further discoveries relating to the disease.
RESUMO
BACKGROUND: GADD45 genes are stress sensors in response to cellular stress response, activated signal pathways leading to the stimulation of inflammatory cytokines. This study is to examine the associations of GADD45a and GADD45b genes with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) patients. METHODS: 230 patients of RA, 140 patients of SLE, and 191 healthy controls were enrolled. Genomic DNA was extracted from peripheral blood mononuclear cells and gene polymorphisms were genotyped by TaqMan assay. RNA expression was quantitated with real-time polymerase chain reaction. RESULTS: The RNA expression of the GADD45b gene was significantly lower in RA patients than the control cases (p = 0.03). The odds ratio of GADD45a genotype -589 CC (rs581000) was significantly low (OR = 0.36, 95% CI, 0.15-0.87) in DR4-negative RA patients. The odds ratio of GADD45b genotype -712CT (rs3795024) in DR4-negative RA patients was 0.41 (95% CI, 0.18-0.95). In clinical manifestation, the odds ratio of GADD45b -712CT genotype with anti-RNP antibody was 4.14 (95% CI, 1.10-15.63) in SLE patients. GADD45a genotype -589GG+GC was associated with rheumatoid factor (RF) in SLE patients. CONCLUSIONS: Genotypes GADD45a -589CC and GADD45b -712CT were shown to be less susceptible to RA and related to the disease state in SLE patients.
RESUMO
Using next-generation sequencing to decipher methylome and transcriptome and underlying molecular mechanisms contributing to rheumatoid arthritis (RA) for improving future therapies, we performed methyl-seq and RNA-seq on peripheral blood mononuclear cells (PBMCs) from RA subjects and normal donors. Principal component analysis and hierarchical clustering revealed distinct methylation signatures in RA with methylation aberrations noted across chromosomes. Methylation alterations varied with CpG features and genic characteristics. Typically, CpG islands and CpG shores were hypermethylated and displayed the greatest methylation variance. Promoters were hypermethylated and enhancers/gene bodies were hypomethylated, with methylation variance associated with expression variance. RA genetically associated genes preferentially displayed differential methylation and differential expression or interacted with differentially methylated and differentially expressed genes. These differentially methylated and differentially expressed genes were enriched with several signaling pathways and disease categories. 10 genes (CD86, RAB20, XAF1, FOLR3, LTBR, KCNH8, DOK7, PDGFA, PITPNM2, CELSR1) with concomitantly differential methylation in enhancers/promoters/gene bodies and differential expression in B cells were validated. This integrated analysis of methylome and transcriptome identified novel epigenetic signatures associated with RA and highlighted the interaction between genetics and epigenetics in RA. These findings help our understanding of the pathogenesis of RA and advance epigenetic studies in regards to the disease.
RESUMO
The hallmark of nonlinear complexity phenomena in magnetohydrodynamic and plasma turbulence as well as all natural sciences is the appearance of intermittent fluctuating events. We introduce here a unique procedure that is both physically explicable and quantitatively accurate in deciphering the multifractal characteristics of intermittency. The generic character of the procedure provides a natural connection between the suggested spectrum based on rank order and the idea of one-parameter scaling for monofractals. We demonstrate the utility of this method using results obtained from a large scale two-dimensional magnetohydrodynamic simulation mimicking solar wind turbulence.
RESUMO
OBJECTIVE: Past studies have shown common pathologic characteristics and shared immunologic features between polymyositis (PM) and amyotrophic lateral sclerosis (ALS). To explore the potential relationship between the 2 diseases, we performed a nationwide cohort study. METHODS: We identified all newly diagnosed patients with PM from Taiwan's Registry of Catastrophic Illness Database between January 1, 1998 and December 31, 2011. Each PM patient was matched to ≤5 control patients from the National Health Insurance Research Database by sex, age, and entry date. Cumulative incidence of ALS was calculated by the Kaplan-Meier method and compared using the log rank test. Cox hazard regression was used to calculate the hazard ratio of ALS. RESULTS: A total of 1,778 PM patients and 8,124 control patients were enrolled. PM patients had a higher cumulative incidence of ALS (P < 0.001). There was a positive correlation in being diagnosed with ALS in patients previously diagnosed with PM when stratified by sex. Consistent trends were conserved across different age strata. The strength of this association remained statistically significant after adjusting for sex, age, and concomitant autoimmune diseases (hazard ratio 25.72 [95% confidence interval 2.95-224.58]; P = 0.003). CONCLUSION: This study demonstrates that a diagnosis of PM increased the likelihood of a subsequent ALS diagnosis, independent of sex, age, and concomitant autoimmune diseases. Future studies are warranted to clarify the underlying biologic mechanisms and to translate them into clinical therapeutic options.
Assuntos
Esclerose Lateral Amiotrófica/diagnóstico , Esclerose Lateral Amiotrófica/epidemiologia , Polimiosite/diagnóstico , Polimiosite/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Bases de Dados Factuais/tendências , Feminino , Humanos , Incidência , Masculino , Pessoa de Meia-Idade , Sistema de Registros , Taiwan/epidemiologia , Adulto JovemRESUMO
The presence of interleukin (IL)-17-related cytokines correlates with rheumatoid arthritis (RA) pathogenesis. Epigenetic modifications, including histone acetylation, regulate gene expression in RA pathogenesis. Tumour necrosis factor-alpha (TNF-α) inhibitors such as etanercept and adalimumab, represent a breakthrough in RA treatment. We aimed to investigate the effects of etanercept and adalimumab on human Th17-polarized cells and the possible intracellular regulators of these effects, including the Th17-specific transcription factors signal transducer, activator of transcription 3 (STAT3), retinoid-related orphan receptor γ-T (RORγt) and epigenetic modification. Human CD4+ T cells from healthy subjects and patients with RA were pretreated with TNF-α inhibitors and then being polarized into IL-17-producing cells. The Th17-related cytokine levels in the culture supernatants were determined with an enzyme-linked immunosorbent assay. Intracellular signalling was investigated by western blot, real-time RT-PCR, and chromatin immunoprecipitation. Th17-polarized cells from patients with RA produced more IL-17A, IL-17F and IL-22 than those from healthy subjects. Etanercept and adalimumab suppressed IL-17A, IL-17F and IL-22 levels in Th17-polarized cells from healthy subjects and patients with RA. Western blot analysis revealed that etanercept and adalimumab decreased mitogen-activated protein kinase-phospho-p38, nuclear factor-κB-phospho-p65, phospho-STAT3 and RORγt levels. Etanercept and adalimumab decreased histone (H)3 and H4 acetylation in the RORγt gene promotor region by decreasing the recruitment of the acetyltransferases p300, CBP and PCAF. The present study broadens our knowledge of the mechanisms underlying the immunomodulatory effects of TNF-α inhibitors in rheumatoid arthritis treatment.
Assuntos
Adalimumab/uso terapêutico , Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Etanercepte/uso terapêutico , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Células Th17/efeitos dos fármacos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Acetilação , Artrite Reumatoide/imunologia , Artrite Reumatoide/metabolismo , Proteína de Ligação a CREB/metabolismo , Estudos de Casos e Controles , Células Cultivadas , Relação Dose-Resposta a Droga , Histonas/metabolismo , Humanos , Interleucina-17/metabolismo , Interleucinas/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Fosforilação , Regiões Promotoras Genéticas , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Th17/imunologia , Células Th17/metabolismo , Fatores de Tempo , Fator de Transcrição RelA/metabolismo , Fator de Necrose Tumoral alfa/imunologia , Fator de Necrose Tumoral alfa/metabolismo , Fatores de Transcrição de p300-CBP/metabolismo , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismo , Interleucina 22RESUMO
The treatment of rheumatoid arthritis (RA) with tumor necrosis factor-alpha (TNF-α) inhibitors could lead to adverse effects. Therefore, the identification of downstream therapeutic targets is important. Monocyte chemoattractant protein-1 (MCP-1, also called CCL2) is related to RA disease activity, and epigenetic modifications are hypothesized to regulate gene expression in RA pathogenesis. We studied the effects of two TNF-α inhibitors, etanercept and adalimumab, on CCL2 expression and the potentially associated intracellular mechanisms, including epigenetic regulation. Etanercept and adalimumab decreased CCL2 production in THP-1 cells and human primary monocytes, as detected using enzyme-linked immunosorbent assays, and these changes in the CCL2 levels were independent of the TNF-α levels. Etanercept and adalimumab suppressed mitogen-activated protein kinase (MAPK) phospho-p38, phospho-JNK, phospho-ERK and nuclear factor-κB (NF-κB) phospho-p65, as demonstrated using western blot analyses. The investigation of epigenetic modifications using chromatin immunoprecipitation revealed that etanercept and adalimumab down-regulated acetylation of histone (H)3 and H4 in the CCL2 promoter region by decreasing the recruitment of the NF-κB associated acetyltransferases p300, CBP and PCAF. Etanercept and adalimumab also down-regulated trimethylation of H3K4, H3K27, H3K36 and H3K79 in the CCL2 promoter region by decreasing the expression of the related methyltransferases WDR5 and Smyd2. We demonstrated that TNF-α inhibitors exert immunomodulatory effects on CCL2 expression in human monocytes via MAPKs, NF-κB and epigenetic modifications. These findings broaden the mechanistic knowledge related to TNF-α inhibitors and provide novel therapeutic targets for RA.