RESUMO
OBJECTIVE: This study investigated whether circulating cold-inducible RNA-binding protein (CIRP) could be a biomarker to reflect the current activity, function, and damage status in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: This study selected 39 MPA and 26 GPA patients. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices include the Birmingham Vasculitis Activity Index (BVAS), five-factor score (FFS), the Korean version of the Short-Form 36-Item Health Survey (SF-36) physical component summary (PCS) and mental component summary (MCS), and the vasculitis damage index (VDI). The highest tertile of BVAS was defined as high activity of AAV. RESULTS: The median age of the study subjects was 65.0 years and 53.8% were women. The median BVAS, FFS, SF-36 PCS, MCS, and VDI scores were 12.0, 2.0, 47.5, 50.3, and 3.0, respectively. The median circulating CIRP level was 6.4â¯ng/mL. Among the four AAV-specific indices, circulating CIRP was significantly correlated with BVAS (râ¯= 0.256). Using the receiver operator characteristic curve, the cut-off of circulating CIRP for high activity of AAV was 6.16â¯ng/mL. High activity of AAV was identified more frequently in patients with circulating CIRP ≥â¯6.16â¯ng/mL than in those with circulating CIRP <â¯6.16â¯ng/mL (48.6% vs. 21.4%). In addition, patients with circulating CIRP ≥â¯6.16â¯ng/mL exhibited a significantly higher risk for high activity of AAV than those with circulating CIRP <â¯6.16â¯ng/mL (relative risk 3.474). CONCLUSION: This study suggests the clinical potential of circulating CIRP as a biomarker for reflecting the current BVAS and predicting high activity of AAV in patients with MPA and GPA.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Poliangiite Microscópica , Idoso , Feminino , Humanos , Masculino , Anticorpos Anticitoplasma de Neutrófilos , Biomarcadores , Granulomatose com Poliangiite/diagnóstico , Poliangiite Microscópica/diagnóstico , Proteínas de Ligação a RNARESUMO
Background and Objectives: To investigate whether circulating malondialdehyde (cMDA) at diagnosis could contribute to reflecting cross-sectional comprehensive inflammation or vasculitis activity and further predicting all-cause mortality during follow-up in patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Materials and Methods: This study included 78 patients with AAV. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels were collected as indices reflecting cross-sectional comprehensive inflammation, whereas the Birmingham vasculitis activity score (bVAS), and the five-factor score (FFS) were reviewed as AAV-specific indices. All-cause mortality was considered to be a poor outcome during follow-up. cMDA was measured from stored sera. Results: The median age of the 78 patients (32 men and 46 women) was 63.0 years. The median BVAS, FFS, ESR, and CRP were 5.0, 0, 24.5 mm/h, and 3.4 mg/L, respectively. Six patients died during the median follow-up duration based on all-cause mortality at 26.7 months. At diagnosis, cMDA was significantly correlated with cross-sectional ESR but not with BVAS or FFS. Compared to patients with cMDA < 221.7 ng/mL, those with cMDA ≥ 221.7 ng/mL at diagnosis exhibited an increased relative risk (RR 12.4) for all-cause mortality and further showed a decreased cumulative patient survival rate. Cox analyses revealed that cMDA ≥ 221.7 ng/mL (hazard ratio 24.076, p = 0.007) exhibited an independent association with all-cause mortality during follow-up in patients with AAV. Conclusions: cMDA at diagnosis may be a potential biomarker for predicting all-cause mortality during follow-up by reflecting comprehensive inflammation at diagnosis in patients with AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Biomarcadores , Proteína C-Reativa , Inflamação , Malondialdeído , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/mortalidade , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/complicações , Biomarcadores/sangue , Sedimentação Sanguínea , Proteína C-Reativa/análise , Estudos Transversais , Seguimentos , Inflamação/sangue , Malondialdeído/sangueRESUMO
BACKGROUND: Interest in complications and sequelae following Coronavirus disease 2019 (COVID-19) is increasing. Several articles have reported COVID-19-associated autoimmune diseases and the association between autoantibodies and the severity of COVID-19. Thromboembolic complications are frequent in patients with COVID-19, and the anti-phospholipid antibodies (aPL) is frequently detected. We conducted this study to investigate the prevalence, clinical significance, and persistence of anti-nuclear antibodies (ANA) and aPLs in COVID-19. METHODS: We enrolled patients diagnosed with COVID-19 with oxygen demand and admitted to a tertiary hospital in South Korea between July 2020 and March 2022. ANA and aPLs levels were assessed using an immunoassay kit. RESULTS: A total of 248 patients were enrolled in the study. Among them, five patients were ANA-positive, and 41 were aPL-positive (IgM anti-cardiolipin (aCL) antibody in seven patients, IgG aCL in seven patients, IgM anti-ß2Glycoprotein1 antibody (aß2-GPI) in 32 patients, and IgG aß2-GPI in one patient). Two of five ANA-positive patients, 13 of 32 IgM aß2-GPI-positive patients, 5 of 7 IgM aCL-positive patients, and 2 of 7 IgG aCL-positive patients were eligible for follow-up analysis, and 100%, 69.2%, 40%, and 50% of the patients remained autoantibody-positive, respectively. There were no differences in clinical outcomes between the autoantibody-positive and autoantibody-negative groups, except for the IgG aCL group showing a tendency for worse outcomes. CONCLUSION: A significant proportion of COVID-19 patients with oxygen demand were autoantibody-positive, and autoantibodies persisted for several months after symptom onset. Whether these autoantibodies are related to long-term sequelae in COVID-19 patients requires further investigation.
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Autoanticorpos , COVID-19 , Humanos , Prevalência , Relevância Clínica , beta 2-Glicoproteína I , Imunoglobulina G , COVID-19/epidemiologia , Anticorpos Anticardiolipina , Imunoglobulina M , OxigênioRESUMO
OBJECTIVES: This study investigated whether serum soluble interleukin-7 receptor alpha (sIL-7Rα) levels could reflect the simultaneous activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Sixty patients with AAV were included in this study. AAV-related variables and clinical and laboratory data were collected at the two-time points (at early high and late low BVAS) for each patient along with blood sampling. Serum sIL-7Rα levels and the populations of CD3+CD4+ and CD3+CD8+ T cells expressing membranous IL-7Rα (mIL-7Rα) were compared between patients at different time points and between patients and healthy controls. RESULTS: Serum sIL-7Rα levels were significantly lower in AAV patients at early high BVAS than in those at late low BVAS, and the direction of change in serum sIL-7Rα levels increased as BVAS decreased. Serum sIL-7Rα levels were inversely correlated with BVAS, erythrocyte sedimentation rate and C-reactive protein levels. In addition, serum sIL-7Rα levels in AAV patients at early high BVAS exhibited significantly lower levels than those in healthy controls. Particularly, AAV patients at early high BVAS showed significantly increased populations of CD3+ T cells and CD3+CD8+ T cells expressing mIL-7Rα compared to those at late low BVAS. CONCLUSIONS: This study demonstrated that not only serum sIL-7Rα levels but also the populations of CD3+ and CD3+CD8+ T cells expressing m IL-7Rα were negatively correlated with simultaneous BVAS in patients with AAV. Therefore, we suggest that serum sIL-7Rα levels can be an additional and useful biomarker for assessing the simultaneous activity of AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Interleucina-7 , Biomarcadores , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnósticoRESUMO
OBJECTIVES: This study investigated whether soluble Tyro-3 (sTyro-3), sAxl, and sMer could reflect the current activity in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: This study retrospectively reviewed the medical records of 76 patients with MPA and GPA, and measure the serum concentrations of sTyro-3, sAxl, and sMer using the stored serum at AAV diagnosis. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV)-specific indices included Birmingham vasculitis activity index (BVAS), five-factor score, the short-form 36-item health survey, and vasculitis damage index. High AAV activity was defined as the highest tertile of BVAS. RESULTS: The median age of the 47 MPA and 29 GPA patients was 66.0 years and 43.4% were men. The serum concentrations of sTyro-3 and sAxl were significantly correlated with BVAS and the total score of renal manifestation. The serum concentrations of sTyro-3 and sAxl were independently correlated with BVAS (ß=0.343 and ß=0.310, respectively). In addition, the serum concentrations of sTyro-3 and sAxl were independently associated with the renal involvement of MPA and GPA (OR 1.003 and OR 1.055, respectively). CONCLUSIONS: This study demonstrated the potential of the serum concentrations of sTyro-3 and sAxl to reflect the current activity and renal involvement in patients with MPA and GPA.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Poliangiite Microscópica , Masculino , Humanos , Idoso , Feminino , Poliangiite Microscópica/diagnóstico , Estudos Retrospectivos , Anticorpos Anticitoplasma de NeutrófilosRESUMO
OBJECTIVES: Serum galectin levels have been reported to be associated with the activity in autoimmune diseases. This study investigated whether serum levels of galectin (Gal)-1, Gal-3, and Gal-9 could be used as biomarkers in assessing the disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Eighty AAV patients were selected for inclusion in our AAV cohort. AAV-specific indices and clinical and laboratory data were assessed on the same day when blood samples were obtained from the patient and serum levels of Gal-1, Gal-3, and Gal-9 were measured by ELISA from obtained sera. High disease activity was defined as Birmingham vasculitis activity score (BVAS) ≥ 12. The optimal cut-off value of galectins was extrapolated by receiver operator characteristic analysis and linear and logistic regression analyses were performed to evaluate the association between Gal-3, Gal-9, and BVAS. RESULTS: The median values of BVAS, Gal-1, Gal-3, and Gal-9 were 8.0, 38.1 ng/mL, 12.4 ng/mL, and 1017.7 ng/mL, respectively. Serum Gal-3 and Gal-9 levels were correlated with BVAS (r=0.375 and r=0.462), while only serum Gal-9 levels were independently associated with BVAS (ß=0.250) in linear regression analyses. Serum Gal-9 ≥10.28 ng/mL was also associated with high activity of AAV (odds ratio 5.303) in multivariable logistic regression analysis. In addition, serum Gal-1, Gal-3, and Gal-9 levels were found to differ according to ANCA positivity status and the presence of renal manifestations. CONCLUSIONS: These results suggest the potential possibility of serum Gal-9 levels in assessing AAV disease activity.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/diagnóstico , Biomarcadores , Estudos de Coortes , Galectinas , HumanosRESUMO
Serum interleukin- (IL-) 27 level has been reported to increase in patients with several autoimmune diseases; however, its significance in patients with antineutrophil cytoplasmic antibody- (ANCA-) associated vasculitis (AAV) is unknown. In this study, we investigated the associations between serum IL-27, laboratory features, and activity of AAV and evaluate the predictive ability of serum IL-27 level for disease activity. This study included 77 AAV patients, and we collected clinical and laboratory data at blood sampling. Inflammation-related variables included white blood cell, neutrophil, lymphocyte and platelet counts, serum albumin, erythrocyte sedimentation rate, and C-reactive protein levels. Serum IL-27 and IL-18 levels were measured from stored sera using Human Magnetic Luminex® assay. High disease activity of AAV was defined as the highest tertile of Birmingham vasculitis activity score (BVAS) (≥11). The mean age of the enrolled patients was 59.9 years, and 38 (49.4%) were diagnosed as microscopic polyangiitis. In the multivariable analysis, serum albumin (ß = -0.419) and serum IL-27 level (ß = 0.221) were significantly associated with BVAS. Furthermore, patients with renal manifestation exhibited higher serum IL-27 (mean 308.7 pg/mL vs. 105.8 pg/mL) and IL-18 levels (mean 376.7 pg/mL vs. 270.4 pg/mL) than those without. On applying the optimal cut-off of serum IL-27 level for predicting high activity, AAV patients with serum IL - 27 level ≥ 300.8 pg/mL had a significantly higher risk for having high disease activity than those with serum IL - 27 level < 300.8 pg/mL (relative risk 3.380, 95% confidence interval 1.223, 9.345, P = 0.016). These results suggest that serum IL-27 level is associated with the cross-sectional activity and the presence of renal manifestation and could be used to predict high disease activity in patients with AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Interleucina-27 , Interleucinas/sangue , Anticorpos Anticitoplasma de Neutrófilos , Estudos Transversais , Humanos , Pessoa de Meia-IdadeRESUMO
BACKGROUND: This study investigated whether serum progranulin could act as a predictive marker for high disease activity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). METHODS: Fifty-eight AAV patients were included in this study. Clinical and laboratory data were obtained at blood collection. The Short-Form 36-Item Health Survey Physical and Mental Component Summaries (SF-36 PCS and SF-36 MCS), Birmingham Vasculitis activity score (BVAS), Five-Factor Score (FFS), and Vasculitis Damage Index (VDI) were assessed as AAV-specific indices. Whole blood was collected and serum samples were isolated and stored at -80°C. Serum progranulin concentration was quantified by ELISA kits. RESULTS: The median age of patients was 63.0 years (19 men). The median BVAS was 11.0, and the median serum progranulin level was 49.0 ng/ml. Serum progranulin was significantly correlated with BVAS, FFS, erythrocyte sedimentation rate, C-reactive protein level, SF-36 PCS, haemoglobin, and serum albumin. Severe AAV was arbitrarily defined as the highest tertile of BVAS (BVAS ≥16). When the cut-offs of serum progranulin were set as 55.16 ng/ml and 43.01 ng/ml for severe AAV, AAV patients with serum progranulin ≥55.16 and 43.01 ng/ml had significantly higher risks of severe AAV than those without (relative risk (RR) 4.167 and 4.524, respectively). CONCLUSIONS: Progranulin might play an anti-inflammatory role in AAV pathogenesis and serum progranulin could be used as a predictive marker for high activity of AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Progranulinas/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/fisiopatologia , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
Mannose-binding lectin (MBL) is a soluble pattern-recognition molecule, which plays a crucial role in the innate immune system and the activation of lectin complement pathway. Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) is an autoimmune disease affecting the small vasculatures and is characterized by the alteration of innate and adaptive immunity and complement activation. In this study, we investigated whether serum MBL is associated with disease activity of AAV, which was measured by ELISA. Associations between serum MBL and AAV-specific indices, as well as clinical and laboratory data were assessed using Kendall's tau. Among the 80 patients, 42 (52.5%), 21 (26.3), and 17 (21.3%) patients were classified as microscopic polyangiitis (MPA), granulomatosis with polyangiitis (GPA), and eosinophilic granulomatosis with polyangiitis (EGPA), respectively. The median values of erythrocyte sedimentation rate, C-reactive protein, and serum MBL were 36.5 (normal range < 20) mm/h, 2.4 (normal range < 8) mg/dL, and 8.6 ng/mL, respectively. The median serum levels of MBL in MPA, GPA, and EGPA patients were 8.4, 9.3, and 8.2 ng/mL. Correlation analysis showed that serum MBL was associated with Birmingham Vasculitis Activity Score (BVAS) (R = 0.169, p = 0.027), but not with other AAV-specific indices and clinical and laboratory data. In addition, serum MBL was significantly associated with the pulmonary manifestation score based on BVAS (R = 0.247, p = 0.001). In summary, among the AAV-specific indices and clinical and laboratory variables analyzed, serum MBL is correlated with BVAS and pulmonary manifestation score based on the BVAS.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Lectina de Ligação a Manose/sangue , Adulto , Idoso , Idoso de 80 Anos ou mais , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/epidemiologia , Síndrome de Churg-Strauss/sangue , Síndrome de Churg-Strauss/epidemiologia , Síndrome de Churg-Strauss/patologia , Estudos de Coortes , Progressão da Doença , Feminino , Granulomatose com Poliangiite/sangue , Granulomatose com Poliangiite/epidemiologia , Granulomatose com Poliangiite/patologia , Humanos , Masculino , Poliangiite Microscópica/sangue , Poliangiite Microscópica/epidemiologia , Poliangiite Microscópica/patologia , Pessoa de Meia-Idade , Índice de Gravidade de DoençaRESUMO
Lupus nephritis (LN) is the most frequent phenotype in patients with systemic lupus erythematosus (SLE) and has a high rate of progression to end-stage renal disease, in spite of intensive treatment and maintenance therapies. Recent evidence suggests that protease-activated receptor-2 (PAR2) is a therapeutic target for glomerulonephritis. In this study, we performed a cell-based high-throughput screening and identified a novel potent PAR2 antagonist, punicalagin (PCG, a major polyphenol enriched in pomegranate), and evaluated the effects of PCG on LN. The effect of PCG on PAR2 inhibition was observed in the human podocyte cell line and its effect on LN was evaluated in NZB/W F1 mice. In the human podocyte cell line, PCG potently inhibited PAR2 (IC50 = 1.5 ± 0.03 µM) and significantly reduced the PAR2-mediated activation of ERK1/2 and NF-κB signaling pathway. In addition, PCG significantly decreased PAR2-induced increases in ICAM-1 and VCAM-1 as well as in IL-8, IFN-γ, and TNF-α expression. Notably, the intraperitoneal administration of PCG significantly alleviated kidney injury and splenomegaly and reduced proteinuria and renal ICAM-1 and VCAM-1 expression in NZB/W F1 mice. Our results suggest that PCG has beneficial effects on LN via inhibition of PAR2, and PCG is a potential therapeutic agent for LN.
Assuntos
Taninos Hidrolisáveis/farmacologia , Nefrite Lúpica/tratamento farmacológico , Nefrite Lúpica/metabolismo , Receptor PAR-2/metabolismo , Animais , Linhagem Celular , Feminino , Humanos , Molécula 1 de Adesão Intercelular/metabolismo , Interleucina-8/metabolismo , Rim/efeitos dos fármacos , Rim/metabolismo , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Células NIH 3T3 , Podócitos/efeitos dos fármacos , Podócitos/metabolismo , Proteinúria/metabolismo , Transdução de Sinais/efeitos dos fármacos , Fator de Necrose Tumoral alfa/metabolismo , Molécula 1 de Adesão de Célula Vascular/metabolismoRESUMO
OBJECTIVES: We investigated whether serum soluble programmed cell death protein 1 (sPD-1) could predict the current activity and severity of antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) based on Birmingham vasculitis activity score (BVAS) in patients with AAV. METHODS: Fifty-nine patients from a monocentric prospective cohort of AAV were included. On the same visit-day, blood samples were collected and isolated sera were stored, BVAS and other AAV-related parameters were assessed, and laboratory tests were performed. We defined the lower limit of the highest tertile of BVAS as the cut-off for severe AAV (BVAS ≥12). Serum sPD-1 was measured from stored serum samples. RESULTS: The mean age was 59.7 years (38 women). The mean BVAS was 8.9 and 18 patients had severe BVAS. Patients with severe AAV exhibited the higher mean serum sPD-1 than those without (380.7 pg/mL vs. 180.3 pg/mL). Serum sPD-1 (r=0.367), white blood cell count (r=0.288), haemoglobin (r=-0.590), serum albumin (r=-0.670) erythrocyte sedimentation rate (ESR) (r=0.339) and C-reactive protein (CRP) (r=0.450) were significantly correlated with BVAS. Moreover, serum sPD-1 was meaningfully correlated with haemoglobin and serum albumin, but not ESR or CRP. In the multivariable linear regression analysis, only serum sPD-1 was significantly associated with BVAS (standardised ß 0.274, p=0.024). We calculated the optimal cut-off of serum sPD-1 for severe AAV as 70.1 pg/mL. Severe AAV were more frequently identified in patients with serum sPD-1 ≥70.1 pg/mL than those without (RR 13.867). CONCLUSIONS: Serum sPD-1 could predict the current activity and severity of AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Proteínas Reguladoras de Apoptose , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/sangue , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/patologia , Sedimentação Sanguínea , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Índice de Gravidade de DoençaRESUMO
We evaluated chemokine expression and its correlation with disease activity in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) (MPA/GPA). Serum CCL2, CCL4, CCL19, CXCL1, CXCL2, and CX3CL1 level in 80 patients were analysed using multiple enzyme-linked immunosorbent assays. Correlations between variables were investigated using Pearson's correlation analysis, and receiver operator curve analysis was performed to identify optimal CX3CL1 values in determining active disease. Multivariate logistic regression analysis was done to evaluate predictors of active disease. CCL4 (r = 0.251, p = 0.025), CXCL1 (r = 0.270, p = 0.015), and CX3CL1 (r = 0.295, p = 0.008) significantly correlated with BVAS, while CX3CL1 was associated with five-factor score (r = - 0.290, p = 0.009). Correlations were revealed between CCL2 and CCL4 (r = 0.267, p = 0.017), CCL4 and CXCL1 (r = 0.368, p < 0.001), CCL4 and CXCL2 (r = 0.436, p < 0.001), and CXCL1 and CXCL2 (r = 0.518, p < 0.001). Multivariate analysis revealed serum CX3CL1 levels > 2408.92 pg/mL could predict active disease (odds ratio, 27.401, p < 0.001). Serum chemokine levels of CCL4, CXCL1, and CX3CL1 showed association with disease activity and especially, CX3CL1 > 2408.92 pg/mL showed potential in predicting active MPA/GPA.
Assuntos
Granulomatose com Poliangiite , Poliangiite Microscópica , Humanos , Análise Multivariada , Anticorpos Anticitoplasma de NeutrófilosRESUMO
BACKGROUND: Mesenchymal stem cells (MSCs) have immunomodulatory properties and therapeutic effects on autoimmune diseases through their secreted factors, referred to as the secretome. However, the specific key factors of the MSC secretome and their mechanisms of action in immune cells have not been fully determined. Most in vitro experiments are being performed using immune cells, but experiments using natural killer (NK) cells have been neglected, and a few studies using NK cells have shown discrepancies in results. NK cells are crucial elements of the immune system, and adjustment of their activity is essential for controlling various pathological conditions. The aim of this study was to elucidate the role of the adipose tissue-derived stem cell (ADSC) secretome on NK cell activity. METHODS: To obtain the ADSC secretome, we cultured ADSCs in medium and concentrated the culture medium using tangential flow filtration (TFF) capsules. We assessed NK cell viability and proliferation using CCK-8 and CFSE assays, respectively. We analyzed the effects of the ADSC secretome on NK cell activity and pathway-related proteins using a combination of flow cytometry, ELISA, cytotoxicity assay, CD107a assay, western blotting, and quantitative real-time PCR. To identify the composition of the ADSC secretome, we performed LC-MS/MS profiling and bioinformatics analysis. To elucidate the molecular mechanisms involved, we used mRNA sequencing to profile the transcriptional expression of human blood NK cells. RESULTS: The ADSC secretome was found to restrict IL-2-mediated effector function of NK cells while maintaining proliferative potency. This effect was achieved through the upregulation of the inhibitory receptor CD96, as well as downregulation of activating receptors and IL-2 receptor subunits IL-2Rα and IL-2Rγ. These changes were associated with attenuated JAK-STAT and AKT pathways in NK cells, which were achieved through the upregulation of cytokine-inducible SH2-containing protein (CIS, encoded by Cish) and dual specificity protein phosphatase 4 (DUSP4). Furthermore, proteomic analysis revealed twelve novel candidates associated with the immunomodulatory effects of MSCs. CONCLUSIONS: Our findings reveal a detailed cellular outcome and regulatory mechanism of NK cell activity by the ADSC secretome and suggest a therapeutic tool for treating NK-mediated inflammatory and autoimmune diseases using the MSC secretome.
Assuntos
Doenças Autoimunes , Proteínas Proto-Oncogênicas c-akt , Humanos , Interleucina-2/farmacologia , Regulação para Cima , Cromatografia Líquida , Proteômica , Secretoma , Espectrometria de Massas em Tandem , Células-Tronco , Transdução de Sinais , Células Matadoras Naturais , Tecido Adiposo , Fosfatases de Especificidade Dupla , Fosfatases da Proteína Quinase Ativada por MitógenoRESUMO
We investigated the IL-6 receptor (IL-6R) expression on the surface of T cells isolated from peripheral blood mononuclear cells (PBMCs) of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA) patients and measured the serum soluble IL-6R (sIL-6R) levels in these patients. Sera and PBMCs were obtained from 51 patients with MPA (n = 32) and GPA (n = 19), with 25 patients having active disease (defined as a Birmingham Vasculitis Activity Score [BVAS] ≥ 5). The median age of patients was 67.0 years, and 52.9% were women. Serum IL-6 levels were significantly correlated with the BVAS (r = 0.384); however, IL-6R expression on the surface of T cells did not significantly differ based on disease activity. Meanwhile, IL-6R expression on the surface of stimulated CD4+ (median mean fluorescence intensity [MFI] 588.0 vs. 1314.8; p < 0.001), CD4+CD25+ (MFI 853.3 vs. 1527.3; p < 0.001), and CD4+CD45RO+ (MFI 679.5 vs. 1241.5; p < 0.001) T cells was significantly reduced compared with unstimulated conditions. Conversely, patients with active disease exhibited a significantly higher median serum sIL-6R level than those with inactive disease (38.1 ng/mL vs. 34.7 ng/mL; p = 0.029). These results imply that the trans-signalling IL-6 pathway may be more activated than the classical signalling pathway in patients with MPA and GPA, suggesting the therapeutic potential of targeting sIL-6R.
RESUMO
Objectives: We investigated whether soluble triggering receptor expressed on myeloid cells-1 (sTREM-1) reflects cross-sectional activity of microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). Methods: Forty-seven MPA and 32 GPA patients with well-documented clinical records and stored sera were enrolled. sTREM-1 levels were evaluated using Magnetic Luminex® assay, and disease activity was assessed using Birmingham vasculitis activity score (BVAS). Patients were divided into two groups according to the upper and lower halves of BVAS. Receiver operator characteristic (ROC) curve analysis was used to identify cut-off for determining upper half of BVAS. Linear and binary logistic regression was performed to evaluate the association between sTREM-1 and disease activity and status. Results: The median age of patients was 67.0 years, and 58.2 % were women. The median BVAS and sTREM-1 were 12.0 and 467.1 pg/mL. sTREM-1 was significantly correlated with BVAS along with five-factor score, Short-Form 36-Item Health Surveys, and C-reactive protein. In multivariable linear regression analysis, erythrocyte sedimentation rate (standardised ß 0.241), and sTREM-1 (standardised ß 0.288) were correlated with BVAS. ROC analysis revealed that the cut-off of sTREM-1 for the upper half of BVAS was 474.1 pg/mL. MPA and GPA patients with sTREM-1 ≥474.1 pg/mL exhibited a significantly higher risk for the upper half of BVAS than those without (relative risk 5.932). Multivariable logistic regression analysis demonstrated sTREM-1 ≥474.1 pg/mL (odds ratio 5.662) was associated with the upper half of BVAS. Conclusion: sTREM-1 reflects the activity of MPA and GPA, suggesting its role as a potential biomarker for assessing disease severity.
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PURPOSE: The present study investigated and compared the antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) activity-predicting ability of the serum concentrations of the four interleukin (IL)-12 family cytokines including IL-23, IL-27, IL-35, and IL-39 in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). MATERIALS AND METHODS: The present study included 70 patients with MPA and GPA. Clinical and laboratory data, particularly Birmingham Vasculitis Activity Score (BVAS), at the time of blood collection were obtained. The serum concentrations of IL-23, IL-27, IL-35, and IL-37 were measured using sera stored at -80â. Patients were divided into two groups: the upper half of BVAS (BVAS ≥12) and the lower half of BVAS (BVAS <12). RESULTS: The serum concentrations of IL-23 and IL-27 reflected AAV activity. Patients with the upper half of BVAS exhibited significantly higher serum concentrations of IL-23 and IL-27 than those without. Patients with the serum concentrations of IL-23 ≥132.1 pg/mL or IL-27 ≥684.7 pg/mL exhibited higher frequency and risk for the upper half of BVAS than those without [relative risks (RR) 5.143 and RR 4.091, respectively]. The serum concentrations of IL-27 were associated with age ≥65 years and proteinase 3-ANCA (or C-ANCA) negativity, whereas, those of IL-23 were associated with MPA. However, the serum concentrations of IL-35 and IL-39 were not useful in predicting AAV activity in this study. CONCLUSION: The present study is the first to demonstrate that among the various members of IL-12 family cytokines, the serum concentrations of IL-23 and IL-27 possess AAV activity-predicting ability.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Granulomatose com Poliangiite , Interleucina-27 , Poliangiite Microscópica , Humanos , Idoso , Interleucina-12 , Citocinas , Anticorpos Anticitoplasma de Neutrófilos , Interleucina-23RESUMO
OBJECTIVES: Acute phase reactants (APRs) are proteins altered by inflammation and are regarded as surrogate markers representing inflammatory status. This study evaluated changes of albumin (Alb), prealbumin (Palb), and ischemia-modified albumin (IMA) in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in response to alterations in disease activity and the correlation between disease activity and Alb, Palb, and IMA. METHODS: Fifty-nine patients with AAV registered in the prospective SHAVE cohort, who had available serial blood samples at least three months apart were included (indicated as pre and post). Correlation analysis and linear regression were carried out to determine the relationship between continuous variables. Alb, Palb, and IMA levels in 40 healthy controls (HCs) were compared with patients with AAV. RESULTS: Comparison of Alb, Palb, and IMA levels in HCs and in patients at initial (pre) and follow-up (post) time points revealed that Alb levels significantly increased following the improvement of disease activity and were comparable between HCs and patients at follow-up (post). Meanwhile, there was no significant difference noted in Palb and IMA levels after the decrease of disease activity. While initial (pre) Alb and Palb were significantly associated with BVAS, a subgroup analysis of patients with new-onset disease showed Palb was no longer significantly associated with Birmingham Vasculitis Activity Score (BVAS). Multivariate linear regression showed Alb level (standardized ß = -0.377; 95% confidence interval: -5.623, -1.260; p = 0.003) was an independent predictor of BVAS at baseline. CONCLUSIONS: Among Alb, Palb, and IMA, we found that Alb could be a useful marker indicating disease activity in patients with AAV.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Albumina Sérica , Anticorpos Anticitoplasma de Neutrófilos , Biomarcadores , Humanos , Pré-Albumina/genética , Estudos Prospectivos , Albumina Sérica HumanaRESUMO
Immune checkpoint molecules balance immune effector responses with regulatory reactions. We speculated that soluble immune checkpoint molecules are involved in dysregulation of the immune response and autoimmunity. We evaluated the association between soluble immune checkpoint molecules and antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). A total of 56 patients with AAV from a prospective observational cohort and 40 healthy controls (HCs) were analyzed. Soluble PD-1, PD-L1, PD-L2, CTLA-4, CD28, CD80, CD86, ICOS, TIM-3, BTLA, CD40, LAG-3, TLR-2, and CD27 were measured in stored sera using the Milliplex MAP assay. Paired analyses were performed before and after the treatment. AAV-specific indices, including Birmingham vasculitis activity score, five factor score , vasculitis damage index, and blood samples, were collected. Patients with AAV had higher levels of sPD-L1, sCD28, sCD80, sCD86, sICOS, sTIM-3, sLAG-3, sTLR-2, and sCD27 and lower level of sCTLA-4 than HCs (p < 0.05). Patients with AAV had higher serum sCD28, sCD80, sTIM-3, and sCD27 levels than HCs at baseline and decreased after treatment. Furthermore, the serum levels of sCD28 and sTIM-3 were significantly correlated with disease activity. This study demonstrated altered concentrations of serum soluble immune checkpoint molecules in patients with AAV. In particular, sCD28 and sTIM-3 may act as surrogate markers of AAV disease activity.
Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Anticorpos Anticitoplasma de Neutrófilos , Humanos , Proteínas de Checkpoint Imunológico , Antígeno B7-1 , Antígenos CD28 , BiomarcadoresRESUMO
OBJECTIVES: Previous studies have shown that adipokines may serve as potential biomarkers reflecting disease activity in various autoimmune diseases. Here, we investigated the relationship between four adipokines and clinical/laboratory findings in patients with microscopic polyangiitis (MPA) and granulomatosis with polyangiitis (GPA). METHODS: Sera from 63 patients with MPA and GPA who were registered in a prospective cohort were used to detect serum levels of adiponectin, chemerin, resistin, and vaspin using commercial enzyme-linked immunosorbent assay kits. Associations between adipokines and clinical and laboratory data was assessed using Pearson's correlation analysis. RESULTS: The median age was 65.0 years, 24 patients were male, and 42 patients were diagnosed with MPA. The median levels of adiponectin, chemerin, resistin, and vaspin in patient sera were 13.9 ng/mL, 9.2 ng/mL, 23.7 ng/mL, and 0.1 ng/mL, respectively. A significant correlation between chemerin level and five-factor score (FFS) was found (r = 0.320, p = 0.011), and resistin was correlated with both Birmingham vasculitis activity score and FFS (r = 0.256, p = 0.043 and r = 0.320, p = 0.011). Regarding laboratory data, adiponectin level was associated with creatinine, and chemerin level was associated with creatinine, albumin, and erythrocyte sedimentation rate (ESR). On the other hand, resistin was found to be associated with white blood cell count, creatinine, ESR, and C-reactive protein. Age did not have a significant impact on the levels of adipokines. CONCLUSIONS: The expression of adipokines in the sera of patients with MPA and GPA differs depending on clinical and laboratory features, and serum resistin may be suggested as a potential biomarker reflecting disease activity.
Assuntos
Granulomatose com Poliangiite , Poliangiite Microscópica , Adipocinas , Idoso , Biomarcadores/sangue , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND/AIM: We evaluated the relationship between serum alarmin levels and disease-specific indices in patients with anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV). PATIENTS AND METHODS: Sera and data from 79 patients were utilized. For AAV-specific indices, Birmingham vasculitis activity score (BVAS), five-factor score (FFS), and vasculitis damage index (VDI) were collected and serum levels of four alarmins (hepatoma-derived growth factor, high mobility group box protein 1, S100A9, and S100A12) were measured using enzyme-linked immunosorbent assay. Associations between alarmin levels, AAV-specific indices, and inflammatory laboratory markers were assessed. RESULTS: S100A9 levels were significantly correlated with C-reactive protein levels (r=0.316, p=0.005) and S100A12 levels correlated with VDI (r=0.232, p=0.040), which was consistent in a subgroup of patients with myeloperoxidase (perinuclear)-ANCA positivity. No other associations were found between alarmin levels and BVAS, FFS, and VDI. CONCLUSION: The serum S100A12 level was associated with organ damage in AAV, especially in myeloperoxidase (perinuclear)-ANCA-positive patients.