RESUMO
BACKGROUND: Epigenetics, especially DNA methylation, plays an important role in the pathogenesis of primary Sjogren syndrome (pSS). Our study aimed to reveal the role of DNA methylation in peripheral monocytes of pSS patients. METHODS: A total of 11 pSS patients and five age-matched healthy controls (HCs) were included in this study. Monocytes were isolated from peripheral blood mononuclear cells using magnetic microbeads. DNA methylation profiles were generated using Human Methylation 850K BeadChips. RESULTS: In monocytes from pSS patients, we identified 2819 differentially methylated positions (DMPs), comprising 1977 hypomethylated- and 842 hypermethylated-DMPs, corresponding to 1313 unique genes when compared with HCs. IFI44L, MX1, PAARP9, and IFITM1, which influence the interferon (IFN) signaling pathway, were among the genes hypomethylated in pSS. Functional analysis of genes with a minimum of two DMPs showed involvement in antigen binding, transcriptional regulation, cell adhesion, IFN-γ pathway, type I IFN pathway, antigen presentation, Epstein-Barr virus infection, human T-lymphotropic virus type 1 virus infection, and metabolic disease-related pathways. In addition, patients with higher serum IgG levels exhibited enrichment in Notch signaling and metabolic-related pathways. Upon comparing monocytes with salivary gland epithelial cells, an important overlap was observed in the cell cycle, cell senescence, and interleukin-17 signaling pathways. The differentially methylated genes were more enriched in the ribosome- and AMP-activated protein kinase signaling pathway in anti-Ro/SSA and anti-La/SSB autoantibodies double-positive patients. CONCLUSION: Genome-wide DNA methylation profiling revealed significant differences in DNA methylation in monocytes isolated from patients with pSS.
Assuntos
Infecções por Vírus Epstein-Barr , Síndrome de Sjogren , Metilação de DNA/genética , Herpesvirus Humano 4 , Humanos , Leucócitos Mononucleares , Monócitos , Síndrome de Sjogren/genéticaRESUMO
The aim of this study is to investigate the clinical features and outcome of interstitial lung disease (ILD)-onset rheumatoid arthritis (RA) and anti-citrullinated protein antibody (ACPA)-positive ILD-only patients. Arthritis-onset and ILD-onset RA-ILD and ACPA-positive ILD-only patients consecutively admitted to Peking Union Medical College Hospital from January 2008 to December 2017 were enrolled and followed-up. Their demographic, clinical, and laboratory features as well as outcome were collected and analyzed. Compared with arthritis-onset RA-ILD (n = 166, median arthritis-to-ILD interval: 60 months), the ILD-onset RA-ILD (n = 75, median ILD-to-arthritis interval: 2 months) had less rheumatoid nodules and higher titer of ACPA, and manifested more stable ILD (median estimated progression-free survival: 120 vs. 100 months, p = 0.019). Elder age (≥ 65 years) at ILD diagnosis and UIP pattern were associated with ILD progression by both univariate and Cox hazards modeling analysis (p < 0.05). In ACPA-positive ILD-only patients (n = 41), arthritis developed in 7 (17.1%) female patients after a median interval of 24 months. ACPA-positive ILD who subsequently developed arthritis exhibited higher frequency of rheumatoid factor (RF), higher titer of ACPA, and higher levels of ESR and CRP (p < 0.05). Multivariate regression analysis showed that positive RF (OR 12.55, 95% CI 1.31 to 120.48) was the independent risk factor for arthritis development in ACPA-positive ILD-only patients. ILD-onset RA-ILD had more stable ILD compared with arthritis-onset RA-ILD. ACPA-positive ILD patients with positive RF are at increased risk of developing RA.
Assuntos
Anticorpos Antiproteína Citrulinada/sangue , Artrite Reumatoide/imunologia , Fator Reumatoide/sangue , Fatores Etários , Idoso , Artrite Reumatoide/diagnóstico , Artrite Reumatoide/mortalidade , Autoanticorpos/sangue , China/epidemiologia , Estudos de Coortes , Feminino , Humanos , Doenças Pulmonares Intersticiais , Masculino , Pessoa de Meia-Idade , Fatores de Risco , Análise de SobrevidaRESUMO
OBJECTIVES: The objective of this study was to address the biological function of miR-7 in an animal model of systemic lupus erythematosus. METHODS: MRLlpr/lpr lupus mice were administrated antagomiR-7 or a scramble control by tail vein for 5weeks. Three groups of animals' tissues were assessed for lupus manifestations by immunofluorescence and immunohistochemistry, and serum was examined for levels of autoantibodies and inflammatory cytokines. Splenic B cell subsets were assessed for intracellular expression of PI3K signaling by FACS. Finally, the ability of the miR-7 antagomir to regulate the expansion of T follicular helper (Tfh) cells and B cell hyperresponsiveness was further explored. RESULTS: We found that miR-7 was up-regulated in MRLlpr/lpr lupus mice and directly targeted PTEN mRNA in B cells. Up-regulated miR-7 in MRLlpr/lpr lupus B cells was negatively correlated with PTEN expression. Notably, miR-7 antagomir treatment reduced lupus manifestations in MRLlpr/lpr lupus mice. miR-7-mediated down-regulation of PTEN/AKT signaling promoted B cell differentiation into plasmablasts/plasma cells and spontaneous germinal center (GC) formation, whereas miR-7 antagomir normalized splenic B cell subtypes. Besides suppressing the activation of B cells, miR-7 antagomir intervention also down-regulated STAT3 phosphorylation and production of IL-21 and reduced Tfh expansion. CONCLUSION: The above data have demonstrated the critical roles of miR-7 not only in regulating PTEN expression and also B cell and Tfh cell function in lupus-prone MRLlpr/lpr lupus mice. Furthermore, the disease manifestations in MRLlpr/lpr lupus mice are efficiently improved by miR-7 antagomir, indicating miR-7 as a potential treatment strategy in SLE.
Assuntos
Linfócitos B/imunologia , Linfócitos B/metabolismo , Lúpus Eritematoso Sistêmico/etiologia , Lúpus Eritematoso Sistêmico/metabolismo , Ativação Linfocitária/genética , MicroRNAs/genética , Animais , Biomarcadores , Modelos Animais de Doenças , Suscetibilidade a Doenças , Lúpus Eritematoso Sistêmico/patologia , Camundongos , Camundongos Endogâmicos MRL lpr , PTEN Fosfo-Hidrolase/metabolismo , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismoRESUMO
The chromatin modifier enhancer of zeste homolog 2 (EZH2) methylates lysine 27 of histone H3 (H3K27) and regulates T cell differentiation. However, the potential role of EZH2 in the pathogenesis of rheumatoid arthritis (RA) remains elusive. We analyzed EZH2 expression in PBMC, CD4+ T cells, CD19+ B cell, and CD14+ monocytes from active treatment-naïve RA patients and healthy controls (HC). We also suppressed EZH2 expression using EZH2 inhibitor GSK126 and measured CD4+ T cell differentiation, proliferation and apoptosis. We further examined TGFß-SMAD and RUNX1 signaling pathways in EZH2-suppressed CD4+ T cells. Finally, we explored the regulation mechanism of EZH2 by RA synovial fluid and fibroblast-like synoviocyte (FLS) by neutralizing key proinflammatory cytokines. EZH2 expression is lower in PBMC and CD4+ T cells from RA patients than those from HC. EZH2 inhibition suppressed regulatory T cells (Tregs) differentiation and FOXP3 transcription, and downregulated RUNX1 and upregulated SMAD7 expression in CD4+ T cells. RA synovial fluid and fibroblast-like synoviocytes suppressed EZH2 expression in CD4+ T cells, which was partially neutralized by anti-IL17 antibody. Taken together, EZH2 in CD4+ T cells from RA patients was attenuated, which suppressed FOXP3 transcription through downregulating RUNX1 and upregulating SMAD7 in CD4+ T cells, and ultimately suppressed Tregs differentiation. IL17 in RA synovial fluid might promote downregulation of EZH2 in CD4+ T cells. Defective EZH2 in CD4+ T cells might contribute to Treg deficiency in RA.
Assuntos
Artrite Reumatoide/etiologia , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Proteína Potenciadora do Homólogo 2 de Zeste/deficiência , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Artrite Reumatoide/metabolismo , Artrite Reumatoide/patologia , Linfócitos B/imunologia , Linfócitos B/metabolismo , Biomarcadores , Estudos de Casos e Controles , Citocinas/metabolismo , Histonas/metabolismo , Humanos , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Monócitos/imunologia , Monócitos/metabolismo , Líquido Sinovial/imunologia , Líquido Sinovial/metabolismo , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/citologiaRESUMO
OBJECTIVE: Gut dysbiosis has been reported implicated in ankylosing spondylitis (AS), a common chronic inflammatory disease mainly affects sacroiliac joints and spine. Utilizing deep sequencing on the feces of untreated AS patients, our study aimed at providing an in-depth understanding of AS gut microbiota. METHODS: We analyzed the fecal metagenome of 85 untreated AS patients and 62 healthy controls by metagenomic shotgun sequencing, and 23 post-treatment feces of those AS patients were collected for comparison. Comparative analyses among different cohorts including AS, rheumatoid arthritis and Behcet's disease were performed to uncover some common signatures related to inflammatory arthritis. Molecular mimicry of a microbial peptide was also demonstrated by ELISpot assay. RESULTS: We identified AS-enriched species including Bacteroides coprophilus, Parabacteroides distasonis, Eubacterium siraeum, Acidaminococcus fermentans and Prevotella copri. Pathway analysis revealed increased oxidative phosphorylation, lipopolysaccharide biosynthesis and glycosaminoglycan degradation in AS gut microbiota. Microbial signatures of AS gut selected by random forest model showed high distinguishing accuracy. Some common signatures related to autoimmunity, such as Bacteroides fragilis and type III secretion system (T3SS), were also found. Finally, in vitro experiments demonstrated an increased amount of IFN-γ producing cells triggered by a bacterial peptide of AS-enriched species, mimicking type II collagen. CONCLUSIONS: These findings collectively indicate that gut microbiota was perturbed in untreated AS patients with diagnostic potential, and some AS-enriched species might be triggers of autoimmunity by molecular mimicry. Additionally, different inflammatory arthritis shared some common microbial signatures.
Assuntos
Microbioma Gastrointestinal , Mediadores da Inflamação/metabolismo , Metagenoma , Metagenômica , Espondilite Anquilosante/etiologia , Espondilite Anquilosante/metabolismo , Autoimunidade , Estudos de Casos e Controles , Suscetibilidade a Doenças , Disbiose , Sequenciamento de Nucleotídeos em Larga Escala , Interações Hospedeiro-Patógeno/imunologia , Humanos , Metagenômica/métodos , Espondilite Anquilosante/patologiaRESUMO
Excessive inflammatory cytokines play crucial roles in the pathogenesis of rheumatoid arthritis (RA), however, the underlying mechanism remains unclear. In this study, we demonstrated that pentaxin 3 (PTX3), an essential component of innate immunity, was elevated in RA and preferentially bound to CD14+ monocytes. C1q promoted the binding and resulted in increased cell proliferation, activation and caspase-1-related late apoptotic cells (7-AAD+annexin V+), as well as enhanced release of inflammatory cytokines including TNF-α, IL-1ß and IL-6. Serum from RA patients, compared with healthy controls, induced gasdermin D (GSDMD)-dependent pyroptosis in monocytes, and this ability was associated with disease activity. Moreover, PTX3 synergized with C1q to promote pyroptosis in RA-serum pre-incubated monocytes by coordinately enhancing NLRP3 inflammasome over-activation and inducing GSDMD cleavage, cell swelling with large bubbles, caspase-1-dependent cell death and inflammatory cytokine release including IL-6. On the other hand, IL-6 promoted PTX3 plus C1q-induced pyroptosis in both normal and RA serum pre-incubated monocytes. These findings collectively implicated an important role of IL-6 in driving PTX3 plus C1q-mediated pyroptosis in RA and shed lights on a potential new treatment strategy targeting pyroptosis-mediated persistent inflammatory cytokine release.
Assuntos
Artrite Reumatoide/imunologia , Proteína C-Reativa/imunologia , Complemento C1q/imunologia , Inflamassomos/imunologia , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Piroptose/imunologia , Componente Amiloide P Sérico/imunologia , Adulto , Idoso , Apoptose/imunologia , Caspase 1/imunologia , Citocinas/imunologia , Feminino , Humanos , Inflamação/imunologia , Receptores de Lipopolissacarídeos/imunologia , Masculino , Pessoa de Meia-Idade , Monócitos/imunologia , Adulto JovemRESUMO
OBJECTIVES: To evaluate the efficacy and safety of antithrombotic prophylaxis and to explore potential risk factors for thrombotic/bleeding events in patients with positive antiphospholipid (aPL) antibodies receiving invasive procedures. METHOD: All aPL-positive patients who underwent invasive procedures in Peking Union Medical College Hospital, from January 2002 to April 2018, were retrospectively enrolled. Demographic features, clinical features, antiphospholipid antibody profiles, types of invasive procedures, and antithrombotic management, as well as complications and outcomes, were systematically reviewed and recorded. RESULTS: A total of 111 aPL-positive patients with 130 invasive procedures were enrolled. One hundred nine (83.8%) cases were on regular antithrombotic therapy which started at least 1 month prior to the invasive procedures, with 58 (44.6%) receiving anticoagulation therapy, 27 (20.8%) receiving antiplatelet therapy, and 24 (18.5%) receiving both. During the periprocedural period, the median time free of antithrombotic therapy was 2.5 days (interquartile range 1.5-6.0 days). Two (1.5%) periprocedural thrombotic events and 18 (13.8%) bleeding events were identified. Large open/laparoscopic surgeries of the thorax and abdomen were associated with a higher risk of bleeding (OR 3.46, 95% CI 1.24-9.67, p = 0.014). All bleeding events were manageable and not life-threatening. CONCLUSIONS: Aggressive antithrombotic therapy was associated with fewer thrombotic events in aPL-positive patients receiving invasive procedures, but might contribute to an increased bleeding rate, especially in large open surgeries. This study justifies more caution in prophylactic antithrombotic therapy in periprocedural aPL-positive patients.
Assuntos
Anticorpos Antifosfolipídeos/sangue , Síndrome Antifosfolipídica/complicações , Fibrinolíticos/uso terapêutico , Hemorragia/etiologia , Trombose/prevenção & controle , Adulto , Anticoagulantes/efeitos adversos , Anticoagulantes/uso terapêutico , Feminino , Fibrinolíticos/efeitos adversos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fatores de Risco , Trombose/etiologia , Adulto JovemRESUMO
OBJECTIVE: This study assessed the relationship between serum albumin (ALB) at start of peritoneal dialysis (PD) and long-term outcomes of continuous ambulatory PD (CAPD) in Anhui Han patients. METHODS: A total of 149 Anhui Han CAPD patients were enrolled in this study and followed up for 3 years. They were initially diagnosed with the end-stage renal disease and underwent surgical PD catheter placement from January 2009 to December 2013. According to serum ALB at start of PD, the patients were divided into two groups: low ALB group (ALB < 35 g/L) and high ALB group (ALB ≥35 g/L). Demographic, hematologic, biochemical, and dialysis-related data were collected. Kaplan-Meier survival analysis and log-rank test were conducted to compare patient mortality, cardiovascular mortality and technique failure between the low ALB group and the high ALB group. Cox regression analysis was performed to analyze the risk factors, calculate the hazard ratio (HR), adjusted HR (AHR) and 95% confidence interval (CI). RESULTS: The low ALB group showed a greater number of diabetes mellitus compared with the high ALB group. Patient mortality, cardiovascular mortality, and technique failure in the high ALB group were significantly lower than those in the low ALB group. In Cox regression analysis, serum ALB < 35 g/L was an independent predictor of patient mortality (AHR 3.043, 95% CI 1.085-8.536, p = 0.034), cardiovascular mortality (AHR 11.587, 95% CI 1.466-91.574, p = 0.020), and technique failure (AHR 3.148, 95% CI 1.603-6.182, p = 0.001) in CAPD patients after adjustment for sex, age, estimated glomerular filtration rate, primary renal disease, diabetes mellitus, and cardiovascular disease. CONCLUSIONS: In Anhui Han patients on CAPD, the levels of serum ALB at start of PD are inversely correlated with patient mortality, cardiovascular mortality, and technique failure, and the long-term outcomes of patients with hypoalbuminemia at start of PD are poor. To improve the long-term outcomes of Anhui Han CAPD patients, patients with hypoalbuminemia at start of PD should be closely monitored.
RESUMO
BACKGROUND: Tripterygium wilfordii Hook F (TwHF) alone or in combination with methotrexate (MTX) has been shown to be more effective than MTX monotherapy in controlling the manifestations in subjects with disease-modifying antirheumatic drug (DMARD)-naïve active rheumatoid arthritis (RA) over a 6-month period. The long-term impact of these therapies on disease activity and radiographic progression in RA has not been examined. METHODS: Patients with DMARD-naïve RA enrolled in the "Comparison of Tripterygium wilfordii Hook F with methotrexate in the Treatment of Active Rheumatoid Arthritis" (TRIFRA) study were randomly allocated into three arms with TwHF or MTX or the two in combination. Clinical indexes and radiographic data at baseline and year 2 was collected and compared using an intent-to-treat (ITT) and a per-protocol (PP) analysis. Two radiologists blinded to the treatment scored the images independently. RESULTS: Of 207 subjects 109 completed the 2-year follow up. The number of subjects withdrawing from the study and the number adhering to the initial regimens were similar among the three groups (p > = 0.05). In the ITT analysis, proportions of patients reaching American College of Rheumatology 50% (ACR50) response criteria were 46.4%, 58.0% and 50.7% in the MTX, TwHF and MTX + TwHF groups (TwHF vs MTX monotherapy, p = 0.004). Similar patterns were found in ACR20, ACR70, Clinical Disease Activity Index good responses, European League Against Rheumatism good response, remission rate and low disease activity rate at year 2. The results of the PP analysis agreed with those in the ITT analysis. The changes in total Sharp scores and joint erosion and joint space narrowing during the 2 years were associated with changes in disease activity measured by the 28-joint count Disease Activity Score and were comparable among the three groups (p > 0.05). Adverse events were similar in the three treatment groups. CONCLUSIONS: During the 2-year therapy period, TwHF monotherapy was not inferior to MTX monotherapy in controlling disease activity and retarding radiological progression in patients with active RA. TRIAL REGISTRATION: This is a follow-up study. Original trial registration: ClinicalTrials.gov , NCT01613079 . Registered on 4 June 2012.
Assuntos
Antirreumáticos/administração & dosagem , Artrite Reumatoide/tratamento farmacológico , Metotrexato/administração & dosagem , Extratos Vegetais/administração & dosagem , Adulto , Idoso , Progressão da Doença , Feminino , Seguimentos , Humanos , Masculino , Pessoa de Meia-Idade , TripterygiumRESUMO
Myelofibrosis usually occurs either as a part of a myelodysplastic syndrome or in conjunction with neoplasia. It is not commonly thought of an autoimmune disease. We reported that p40-/-IL-2Rα-/- (interleukin-12p40 and interleukin-2 receptor alpha double knockout) mice, a mouse model of human primary biliary cholangitis, exhibited features consistent with autoimmune myelofibrosis, including anemia associated with bone marrow fibrosis, and extramedullary hematopoiesis (EMH) including LSK (Lineage-c-Kit+Sca-1+) cells in spleen, liver and peripheral blood. There were also increased LSK cells in bone marrow but they demonstrated impaired hematopoiesis. Importantly effector memory T cells that infiltrated the bone marrow of p40-/-IL-2Rα-/- mice manifested a higher ability to produce IFN-γ. CD8+ T cells, already known to play a dominate role in portal inflammation, were also key for bone marrow dysregulation and EMH. IFN-γ was the key cytokine that induced bone marrow fibrosis, bone marrow failure and EMH. Finally anti-CD8α antibody therapy fully protected p40-/-IL-2Rα-/- mice from autoimmune myelofibrosis. In conclusion, our results demonstrate that CD8+ T cells and IFN-γ are associated with autoimmune myelofibrosis, a finding that may allow targeting of CD8+ T cells and IFN-γ as a therapeutic targets.
Assuntos
Doenças Autoimunes/imunologia , Medula Óssea/patologia , Linfócitos T CD8-Positivos/imunologia , Colangite/imunologia , Cirrose Hepática Biliar/imunologia , Fígado/fisiologia , Mielofibrose Primária/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Modelos Animais de Doenças , Fibrose , Hematopoese Extramedular , Humanos , Memória Imunológica , Interferon gama/metabolismo , Subunidade p40 da Interleucina-12/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Receptores de Interleucina-2/genéticaRESUMO
AIM: To retrospectively investigate the features of renal involvements in patients with primary Sjögren's syndrome (pSS) with biopsy results. METHODS: A total of 2096 pSS inpatients at Peking Union Medical College Hospital in China from 2005 to 2015 were identified. Patients with biopsy-proven renal involvement (SS-renal) and matched controls (SS-only) were recruited. The clinical and pathologic features as well as treatments and outcomes were systematically analyzed. RESULTS: One hundred and three pSS nephritis (inpatients had biopsy-proven renal involvement. Tubulointerstitial 53, 51.5%) was the prominent pathologic pattern with glomerulonephritis (GN) present in 50 (48.5%) of the renal lesions. The patterns of GN lesions included membranous nephropathy (37, 35.9%), mesangial proliferative glomerulonephritis (six, 5.8%) or immunoglobulin A nephropathy (three, 2.9%), minimal change disease (four, 3.9%) and focal segmental glomerulosclerosis (three, 2.9%). Compared to SS-only patients, SS-renal patients had fewer dry eyes and positive objective xerostomia (P < 0.05). They presented with a significantly lower incidence of interstitial lung disease (ILD), leukocytopenia and elevated immunoglobulin G levels (P < 0.05). They received a larger initial dosage of corticosteroid and had a higher mortality rate (P < 0.05). CONCLUSION: This Chinese SS-renal population with biopsy results has diverse pathologic patterns and distinct clinical features. They are characterized with prominent renal-associated and mild SS-associated features. They received more vigorous treatment but had poorer prognosis.
Assuntos
Glomerulonefrite/patologia , Rim/patologia , Nefrite Intersticial/patologia , Nefrose Lipoide/patologia , Síndrome de Sjogren/patologia , Corticosteroides/administração & dosagem , Adulto , Biópsia , China , Feminino , Imunofluorescência , Glomerulonefrite/tratamento farmacológico , Glomerulonefrite/imunologia , Glomerulonefrite/mortalidade , Humanos , Rim/efeitos dos fármacos , Rim/imunologia , Masculino , Pessoa de Meia-Idade , Nefrite Intersticial/tratamento farmacológico , Nefrite Intersticial/imunologia , Nefrite Intersticial/mortalidade , Nefrose Lipoide/tratamento farmacológico , Nefrose Lipoide/imunologia , Nefrose Lipoide/mortalidade , Prognóstico , Estudos Retrospectivos , Síndrome de Sjogren/tratamento farmacológico , Síndrome de Sjogren/imunologia , Síndrome de Sjogren/mortalidadeRESUMO
OBJECTIVES: To explore the role of Vδ2 T cells in the pathogenesis of rheumatoid arthritis (RA). METHODS: Sixty-eight patients with RA, 21 patients with osteoarthritis and 21 healthy controls were enrolled in the study. All patients with RA fulfilled the 2010 American College of Rheumatology/European League Against Rheumatism criteria for RA. Peripheral Vδ2T population, chemokine receptor expression and proinflammatory cytokine secretion were quantified by flow cytometry. The infiltration of Vδ2 T cells within the synovium was examined by immunohistochemistry and flow cytometry. The effect of tumour necrosis factor (TNF)-α and interleukin (IL)-6 on Vδ2 T migration was determined by flow cytometry and transwell migration assay. RESULTS: Peripheral Vδ2T cells, but not Vδ1 T cells, were significantly lower in patients with RA, which was negatively correlated with disease activity gauged by Disease Activity Score in 28 joints. Vδ2 T cells from RA accumulated in the synovium and produced high levels of proinflammatory cytokines including interferon-γ and IL-17. Phenotypically, Vδ2 T cells from RA showed elevated chemotaxis potential and expressed high levels of chemokine receptors CCR5 and CXCR3, which was driven by increased serum TNF-α through nuclear factor kappa B signalling. In vivo, TNF-α neutralising therapy dramatically downregulated CCR5 and CXCR3 on Vδ2 T cells and repopulated the peripheral Vδ2 T cells in patients with RA. CONCLUSIONS: High levels of TNF-α promoted CCR5 and CXCR3 expression in Vδ2 T cells from RA, which potentially infiltrated into the synovium and played crucial roles in the pathogenesis of RA. Targeting Vδ2 T cells might be a potential approach for RA.
Assuntos
Artrite Reumatoide/fisiopatologia , Quimiotaxia , Receptores de Antígenos de Linfócitos T gama-delta , Membrana Sinovial/citologia , Linfócitos T/fisiologia , Artrite Reumatoide/genética , Estudos de Casos e Controles , Movimento Celular/fisiologia , Citometria de Fluxo , Humanos , Interleucina-6/metabolismo , Osteoartrite/genética , Osteoartrite/fisiopatologia , Receptores CCR5/metabolismo , Receptores CXCR3/metabolismo , Fator de Necrose Tumoral alfa/metabolismoRESUMO
CXC Chemokine Receptor 3 (CXCR3) is functionally pleiotropic and not only plays an important role in chemotaxis, but also participates in T cell differentiation and may play a critical role in inducing and maintaining immune tolerance. These observations are particularly critical for autoimmune cholangitis in which CXCR3 positive T cells are found around the portal areas of both humans and mouse models of primary biliary cholangitis (PBC). Herein, we investigated the role of CXCR3 in the pathogenesis of autoimmune cholangitis. We have taken advantage of a unique CXCR3 knockout dnTGFßRII mouse to focus on the role of CXCR3, both by direct observation of its influence on the natural course of disease, as well as through adoptive transfer studies into Rag-/- mice. We report herein that not only do CXCR3 deficient mice develop an exacerbation of autoimmune cholangitis associated with an expanded effector memory T cell number, but also selective adoptive transfer of CXCR3 deficient CD8+ T cells induces autoimmune cholangitis. In addition, gene microarray analysis of CXCR3 deficient CD8+ T cells reveal an intense pro-inflammatory profile. Our data suggests that the altered gene profiles induced by CXCR3 deficiency promotes autoimmune cholangitis through pathogenic CD8+ T cells. These data have significance for human PBC and other autoimmune liver diseases in which therapeutic intervention might be directed to chemokines and/or their receptors.
Assuntos
Autoimunidade/genética , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Cirrose Hepática Biliar/genética , Cirrose Hepática Biliar/imunologia , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Receptores CXCR3/deficiência , Animais , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Citocinas/sangue , Citocinas/metabolismo , Modelos Animais de Doenças , Perfilação da Expressão Gênica , Memória Imunológica , Ligantes , Cirrose Hepática Biliar/metabolismo , Cirrose Hepática Biliar/patologia , Camundongos , Camundongos Knockout , Receptores CXCR3/metabolismoRESUMO
Aberrant expression of CXCR4 has been indicated to play a role in the pathogenesis of systemic lupus erythematosus (SLE), but the mechanism of CXCR4 dysregulation in SLE is unclear. This study is aimed to explore the clinical significance and possible mechanisms of abnormal CXCR4 expression on B cells from patients with untreated SLE. Expression of CXCR4 on peripheral B cells was determined by flow cytometry and western blotting. Freshly isolated B cells were cultured with exogenous interleukin 21(IL-21) in the presence or absence of CD40 ligand (CD40L) plus anti-IgM antibody (aIgM), and changes in CXCR4 expression were detected. Involvement of phosphatidylinositol 3 kinase (PI3K)/Akt and Janus kinase/Signal transducer and activator of transcription (JAK/STAT) signaling pathways was assessed by adding blocking agents Ly294002 and AG490. Since CD63 is reported to mediate endosomal recruitment of CXCR4 and BCL6 is capable of silencing CD63 gene transcription, we also measured BCL6 and CD63 gene transcription with real-time PCR. It was shown that CXCR4 expression on B cells was significantly upregulated in SLE patients, especially in those with lupus nephritis, and was positively correlated with SLE Disease Activity Index scores and negatively with the serum complement 3 levels (P<0.05). Downregulation of CXCR4 by IL-21 was intact. In contrast, a similar effect of aIgM plus CD40L in downregulating CXCR4 expression was defective in SLE patients but was restored by co-stimulation with IL-21 in vitro. Both Ly294002 and AG490 promoted downregulation of surface CXCR4 expression on B cells from SLE patients (P=0.078 and P=0.064). Furthermore, B cells from SLE patients exhibited diminished CD63 mRNA and enhanced BCL6 mRNA expression (both P<0.05). To sum up, CXCR4 was overexpressed on SLE B cells, positively correlating with disease activity and kidney involvement. Overactivation of the PI3K/Akt and JAK/STAT pathways as well as defective CD63 synthesis may contribute to CXCR4 dysregulation in SLE.
Assuntos
Linfócitos B/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Nefrite Lúpica/imunologia , Receptores CXCR4/genética , Tetraspanina 30/metabolismo , Adolescente , Adulto , Anticorpos Anti-Idiotípicos/metabolismo , Ligante de CD40/metabolismo , Células Cultivadas , Feminino , Humanos , Interleucinas/metabolismo , Masculino , Pessoa de Meia-Idade , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Proto-Oncogênicas c-bcl-6/genética , Proteínas Proto-Oncogênicas c-bcl-6/metabolismo , Receptores CXCR4/metabolismo , Fatores de Transcrição STAT/metabolismo , Tetraspanina 30/genética , Regulação para Cima , Adulto JovemRESUMO
AIM: To explore the pathogenesis of primary biliary cholangitis (PBC) by identifying candidate autoantibodies in serum samples by proteomics and bioinformatics. METHODS: Nine antimitochondrial antibody (AMA)-positive PBC patients and nine age- and sex-matched AMA-negative PBC patients were recruited. Antigen enrichment technology was applied to capture autoantigens of human intrahepatic biliary epithelial cells (HiBECs) that are recognized by autoantibodies from the sera of PBC patients. Candidate autoantigens were identified by label-free mass spectrometry. Bioinformatics analysis with MaxQuant software (version 1.5.2.8), DAVID platform, and Cytoscape v.3.0 allowed illustration of pathways potentially involved in the pathogenesis of PBC. RESULTS: In total, 1081 candidate autoantigen proteins were identified from the PBC patient pool. Among them, 371 were determined to be significantly differentially expressed between AMA-positive and -negative PBC patients (P < 0.05). Fisher's exact test was performed for enrichment analysis of Gene Ontology protein annotations (biological processes, cellular components, and molecular functions) and the Kyoto Encyclopedia of Genes and Genomes pathways. Significantly different protein categories were revealed between AMA-positive and -negative PBC patients. As expected, autoantigens related to mitochondria were highly enriched in AMA-positive PBC patients. However, lower levels of AMA were also detected in AMA-negative PBC patients. In addition, autoantigens of AMA-negative PBC patients were mainly involved in B-cell activation, recognition of phagocytosis, and complement activation. CONCLUSION: AMA-negative PBC individuals may not exist, but rather, those patients exhibit pathogenesis pathways different from those of AMA-positive PBC. Comprehensive research is needed to confirm these observations.
Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Colangite/imunologia , Mitocôndrias/imunologia , Proteômica/métodos , Autoanticorpos/imunologia , Células Cultivadas , Colangite/sangue , Biologia Computacional , Ensaio de Imunoadsorção Enzimática , Células Epiteliais/imunologia , Humanos , Fígado/citologia , Fígado/imunologia , Espectrometria de Massas/métodos , Projetos Piloto , SoftwareRESUMO
AIMS: To compare the efficacy and tolerability of azathioprine (AZA), mycophenolate mofetil (MMF), and cyclophosphamide (CTX) in patients with neuromyelitis optica spectrum disorder (NMOSD). METHODS: We performed a prospective cohort analysis of relapses, disability, and adverse events in NMOSD patients treated with AZA, MMF, or CTX (n=119, 38, and 41, respectively). All the patients were co-treated with oral prednisone. RESULTS: A significant reduction in relapse rate was found in patients taking AZA (p<0.001), MMF (p<0.001) or CTX (p=0.01). MMF was associated with a lower risk of relapse than AZA, but this difference was not statistically significant (p=0.08). AZA and MMF decreased the mean Expanded Disability Status Scale (EDSS) scores significantly (AZA: p=0.02; MMF: p=0.01), whereas CTX did not. Compared with AZA, MMF had a significantly lower risk of treatment discontinuation due to drug-related adverse events (p=0.02), whereas CTX had a comparable risk (p=0.35). CONCLUSIONS: MMF is a good first-line treatment option for NMOSD and AZA remains a valuable first-line drug if its side effects are tolerable while CTX can be a treatment option for patients who cannot tolerate AZA and MMF.
Assuntos
Azatioprina/uso terapêutico , Ciclofosfamida/uso terapêutico , Imunossupressores/uso terapêutico , Ácido Micofenólico/uso terapêutico , Neuromielite Óptica/tratamento farmacológico , Adulto , Azatioprina/efeitos adversos , Ciclofosfamida/efeitos adversos , Avaliação da Deficiência , Feminino , Humanos , Imunossupressores/efeitos adversos , Estimativa de Kaplan-Meier , Masculino , Ácido Micofenólico/efeitos adversos , Prednisolona/uso terapêutico , Estudos Prospectivos , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is a newly recognized systemic disease that can involve multiple organs and various clinical phenotypes. The purpose of this study was to analyze different types of organ involvement in IgG4-RD patients in China. METHODS: We conducted a prospective cohort study on IgG4-RD patients to analyze the clinical manifestations and rare features of IgG4-RD. Patients were grouped into different types according to organ involvement regarding organ number and organ site. The constituent ratio in different types was also analyzed. RESULTS: A total of 200 IgG4-RD patients, with a male:female ratio of 2.08:1, were grouped into different types. Cases having involvement of two or three organs were the most common whereas the fewest number of patients had multi-organ (≥4) involvement. Serum IgG4 and IgE levels, IgG4/IgG ratio, and percentage of eosinophils increased as the number of involved organs increased. In addition, constituent ratio analysis revealed that patients with salivary gland/lacrimal gland swelling, who also constituted the largest number of IgG4-RD patients, had higher serum IgG4 concentrations and IgG4/IgG values, had higher percentage of Eos, and were more likely to have had a history of allergies relative to patients with internal organ involvement. CONCLUSIONS: The characteristic feature of IgG4-RD is multiple organ involvement with various clinical manifestations and different types. Although serum IgG4 levels increased with the number of involved organs, serum IgG4 levels were higher for those patients with salivary gland/lacrimal gland swelling compared with those with internal organ involvement. Thus, valuable clues to the differential diagnosis of IgG4-RD could be obtained by examining the clinical patterns of organ involvement.
Assuntos
Doenças Autoimunes/patologia , Imunoglobulina G/sangue , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/complicações , Eosinófilos/metabolismo , Feminino , Humanos , Imunoglobulina E/sangue , Rim/patologia , Aparelho Lacrimal/patologia , Pulmão/patologia , Masculino , Pessoa de Meia-Idade , Hipófise/patologia , Estudos Prospectivos , Próstata/patologia , Glândulas Salivares/patologia , Glândula Tireoide/patologia , Útero/patologia , Adulto JovemRESUMO
OBJECTIVES: To compare the efficacy and safety of Tripterygium wilfordii Hook F (TwHF) with methotrexate (MTX) in the treatment of active rheumatoid arthritis (RA). METHODS: Design: a multicentre, open-label, randomised controlled trial. All patients were assessed by trained investigators who were unaware of the therapeutic regimen. INTERVENTION: 207 patients with active RA were randomly allocated (1:1:1) to treatment with MTX 12.5â mg once a week, or TwHF 20â mg three times a day, or the two in combination. At week 12, if reduction of the 28-joint count Disease Activity Score (DAS28) was <30% in the monotherapy groups, the patient was switched to MTX+TwHF. The primary efficacy point was the proportion of patients achieving an American College of Rheumatology (ACR) 50 response at week 24. RESULTS: 174/207 (84.1%) patients completed 24â weeks of the trial. In an intention-to-treat analysis, the proportion of patients reaching the ACR50 response criteria was 46.4% (32/69), 55.1% (38/69) and 76.8% (53/69), respectively, in the MTX, TwHF and MTX+TwHF groups (TwHF vs MTX monotherapy, p=0.014; MTX+TwHF vs MTX monotherapy, p<0.001). Similar statistically significant patterns at week 24 were found for ACR20, ACR70, clinical Disease Activity Index good responses, EULAR good response, remission rate and low disease activity rate. Significant improvement in the Health Assessment Questionnaire and 36-item Short-Form Health Survey questionnaire scores from baseline to week 24 was seen in each treatment arm (p<0.05), though no significant difference was found among the treatment arms (p>0.05). The result of per-protocol analysis agreed with that seen in the intention-to-treat analysis. Seven, three and five women in the TwHF, MTX and combination groups, respectively, developed irregular menstruation (TwHF vs MTX monotherapy, p=0.216). CONCLUSIONS: TwHF monotherapy was not inferior to, and MTX+TwHF was better than, MTX monotherapy in controlling disease activity in patients with active RA. TRIAL REGISTRATION NUMBER: NCT01613079.
Assuntos
Antirreumáticos/uso terapêutico , Artrite Reumatoide/tratamento farmacológico , Metotrexato/uso terapêutico , Fitoterapia , Extratos Vegetais/uso terapêutico , Tripterygium , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Método Simples-Cego , Resultado do TratamentoRESUMO
Both ankylosing spondylitis (AS) and Takayasu's arteritis (TA) are infrequent, and their association is even more rare. Our objective was to assess their association and characteristics in our patients. We conducted retrospective analysis of our hospital inpatients from June 2000 to July 2011 who had both AS and TA. We used modified New York criteria for ankylosing spondylitis (1984) as AS diagnosis criterion and American College of Rheumatology Classification Criteria for Takayasu's Arteritis as TA diagnosis criterion. All clinical data, lab data, and radiological data were collected. Six patients were included in our study because they fulfilled our AS and TA criteria, four males and 2 females, aged from 18 to 35 years old. Four patients were HLA-B27 positive and 2 were negative. All patients' inflammatory markers such as erythrocyte sedimentation rate and C-reactive protein were high. The clinical characteristics of patients with both diseases did not seem to be different from that of patients with AS or TA alone in China. All patients were first diagnosed as AS, then found TA 3-20 years later. After diagnosed those patients having AS and TA, patients were given prednisone and cyclophosphamide and their symptoms improved gradually. Our study provides further evidence of the association of TA with AS. We should know that some AS patients can do have TA. To AS patients who have fever, bruit, or pulselessness, we should suspect that they have TA.
Assuntos
Antígeno HLA-B27/imunologia , Espondilite Anquilosante/complicações , Arterite de Takayasu/complicações , Adolescente , Adulto , Angiografia , Feminino , Humanos , Masculino , Estudos Retrospectivos , Espondilite Anquilosante/diagnóstico por imagem , Espondilite Anquilosante/imunologia , Arterite de Takayasu/diagnóstico por imagem , Arterite de Takayasu/imunologia , Adulto JovemRESUMO
OBJECTIVE: To explore the correlation between labial salivary gland focus score (FS) and severity of Sjögren's syndrome patients. METHODS: From January 2009 to December 2010, a total of 77 patients with primary Sjögren's syndrome were recruited to undergo minor salivary gland biopsy, Schirmer's test, unstimulated whole salivary flow, organ function and serological test. Focus score was calculated for all biopsy samples. And the correlation between focus score and serological test and organ function damage was evaluated. RESULTS: Their pathological examinations revealed focal lymphocytic sialadenitis (n = 62), 10 cases with non-specific or sclerosing chronic sialadenitis (n = 10) and normal features (n = 5). Among 62 cases with focal lymphocytic sialadenitis, 46 cases had FS ≥ 1 and another 16 FS < 1. The median FS was 2.4 ± 2.5 . FS ≥ 1 was strongly associated with unstimulated whole salivary flow rates and ocular staining score (P < 0.05), but not significantly with dry mouth or eyes. FS was significantly correlated with serum immunoglobin G (IgG), immunoglobin M (IgM) and rheumatoid factor level (P < 0.05). Those with positive anti-SSA had higher FS level than those with negative anti-SSA antibody (P < 0.05). In addition, FS level was not significantly associated with organ function damage. CONCLUSION: Prior to determining FS, distinguishing focal lymphocytic sialadenitis from other types of sialadenitis is essential in assessing salivary gland biopsy. And the FS level might be associated with disease activity and positive anti-SSA. No correlation exists between FS and organ function damage.