85 research outputs found

    Role of VEGF Polymorphisms in the Susceptibility and Severity of Interstitial Lung Disease

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    Biomarker; Interstitial lung disease; Vascular endothelial growth factorBiomarcador; Malaltia pulmonar intersticial; Factor de creixement endotelial vascularBiomarcador; Enfermedad pulmonar intersticial; Factor de crecimiento vascular endotelialThe search for biomarkers that can help to establish an early diagnosis and prognosis of interstitial lung disease (ILD) is of potential interest. VEGF polymorphisms have been implicated in the development of several lung disorders. Consequently, we assessed, for the first time, the role of VEGF polymorphisms in the susceptibility and severity of ILD. A total of 436 Caucasian ILD patients (244 with idiopathic interstitial pneumonias (IIPs) and 192 with non-IIP) and 536 ethnically-matched healthy controls were genotyped for VEGF rs833061, rs1570360, rs2010963, rs3025020, and rs3025039 polymorphisms by TaqMan assays. Pulmonary function tests were collected from all the patients. VEGF serum levels were determined by ELISA in a subgroup of patients. No VEGF genotype, allele, carrier, or haplotype differences were found between ILD patients and controls as well as between IIP and non-IIP patients. However, an association of rs1570360 with IIP in women and also with lung function in IIP patients was found. None of the VEGF polymorphisms were associated with VEGF levels. In conclusion, our results suggest that VEGF does not seem to play a relevant role in ILD, although rs1570360 may influence the severity of ILD in women and a worse outcome in IIP patients.This research was partially supported by a grant from Spanish Society of Pulmonology and Thoracic Surgery (SEPAR 474-2017). S.R.-M. was supported by funds of the RETICS Program (RD16/0012/0009) from the ‚ÄúInstituto de Salud Carlos III‚ÄĚ (ISCIII), co-funded by the European Regional Development Fund. V.P.-C. was supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). B.A.-M. was recipient of a ‚ÄúL√≥pez Albo‚ÄĚ post-residency program funded by Servicio C√°ntabro de Salud. L.L.-G. was supported by funds from IDIVAL (INNVAL 20/06). O.G. was beneficiary of a grant funded by Xunta de Galicia, Conseller√≠a de Educaci√≥n, Universidade e Formaci√≥n Profesional and Conseller√≠a de Econom√≠a, Emprego e Industria (GAIN), GPC IN607B2019/10. R.L.-M. was a recipient of a Miguel Servet type I program fellowship from the ISCIII, co-funded by the ESF, ‚ÄúInvesting in your future‚ÄĚ (grant CP16/00033)

    Modulation of autoimmune arthritis severity in mice by Apolipoprotein E (ApoE) and cholesterol

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    Apolipoprotein E (ApoE) deficiency promoted an exacerbation of autoimmune arthritis in mice by inducing pro-inflammatory immune responses. In this study we analysed the contribution of hypercholesterolemia and/or the absence of ApoE anti-inflammatory properties, unrelated to its function in the control of cholesterol metabolism, towards the acceleration of arthritis in these mutant animals. The induction and severity of collagen type II-induced arthritis (CIA) were compared for B10.RIII wild type (WT), B10.RIII.ApoE+/- , B10.RIII.ApoE-/- and B10.RIII.LDLR-/- mice with different concentrations of circulating ApoE and cholesterol. A 50-70% reduction in serum levels of ApoE was observed in heterozygous B10.RIII.ApoE+/- mice in comparison to B10.RIII.WT, although both strains of mice exhibited similar circulating lipid profiles. This ApoE reduction was associated with an increased CIA severity that remained lower than in homozygous B10.RIII.ApoE-/- mice. An important rise in circulating ApoE concentration was observed in hypercholesterolemic B10.RIII.LDLR-/- mice fed with a normal chow diet, and both parameters further increased with an atherogenic hypercholesterolemic diet. However the severity of CIA in B10.RIII.LDLR-/- mice was similar to that of B10.RIII.WT controls. In conclusion, by comparing the evolution of CIA between several strains of mutant mice with different levels of serum ApoE and cholesterol, our results demonstrate that both hypercholesterolemia and ApoE regulate the intensity of in vivo systemic autoimmune responses. This article is protected by copyright. All rights reserve

    Role of MUC1 rs4072037 polymorphism and serum KL-6 levels in patients with antisynthetase syndrome

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    Biomarkers; Idiopathic inflammatory myopathiesBiomarcadores; Miopat√≠as inflamatorias idiop√°ticasBiomarcadors; Miopaties inflamat√≤ries idiop√†tiquesMucin 1/Krebs von den Lungen-6 (KL-6) is proposed as a serum biomarker of several interstitial lung diseases (ILDs), including connective tissue disorders associated with ILD. However, it has not been studied in a large cohort of Caucasian antisynthetase syndrome (ASSD) patients. Consequently, we assessed the role of MUC1 rs4072037 and serum KL-6 levels as a potential biomarker of ASSD susceptibility and for the differential diagnosis between patients with ILD associated with ASSD (ASSD-ILD‚ÄČ+) and idiopathic pulmonary fibrosis (IPF). 168 ASSD patients (149 ASSD-ILD‚ÄČ+), 174 IPF patients and 523 healthy controls were genotyped for MUC1 rs4072037 T‚ÄČ>‚ÄČC. Serum KL-6 levels were determined in a subgroup of individuals. A significant increase of MUC1 rs4072037 CC genotype and C allele frequencies was observed in ASSD patients compared to healthy controls. Likewise, MUC1 rs4072037 TC and CC genotypes and C allele frequencies were significantly different between ASSD-ILD+ and IPF patients. Additionally, serum KL-6 levels were significantly higher in ASSD patients compared to healthy controls. Nevertheless, no differences in serum KL-6 levels were found between ASSD-ILD+ and IPF patients. Our results suggest that the presence of MUC1 rs4072037 C allele increases the risk of ASSD and it could be a useful genetic biomarker for the differential diagnosis between ASSD-ILD+ and IPF patients.Study partially supported by a grant from Spanish Society of Pulmonology and Thoracic Surgery (SEPAR 474-2017) and from Euronanomed III / Instituto de Salud Carlos III (ISCIII) (AC17/00027) awarded to SC. SR-M is supported by funds of the RETICS Program (RD16/0012/0009) from the ISCIII, co-funded by the European Regional Development Fund. BA-M is recipient of a ‚ÄėL√≥pez Albo‚Äô Post-Residency Programme funded by Servicio C√°ntabro de Salud. VP-C is supported by a pre-doctoral grant from IDIVAL (PREVAL 18/01). LL-G is supported by funds from IDIVAL (INNVAL 20/06). RP-F is supported by funds of START project (FOREUM18/34). DP-P is a recipient of a R√≠o Hortega programme fellowship from the ISCIII, co-funded by the European Social Fund (ESF, ‚ÄėInvesting in your future‚Äô) (CM20/00006). OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS)) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and the European Union FEDER fund (RD16/0012/0014 (RIER) and PI17/00409). He is beneficiary of project funds from the Research Executive Agency (REA) of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, Project 734899‚ÄĒOlive-Net. RL-M is a recipient of a Miguel Servet type I programme fellowship from the ISCIII, co-funded by the ESF (CP16/00033)

    Adipokines, Biomarkers of Endothelial Activation, and Metabolic Syndrome in Patients with Ankylosing Spondylitis

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    Ankylosing spondylitis (AS) is a chronic inflammatory rheumatic disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. AS patients also display a high prevalence of features clustered under the name of metabolic syndrome (MeS). Anti-TNF- őĪ therapy was found to be effective to treat AS patients by suppressing inflammation and also improving endothelial function. Previously, it was demonstrated that a short infusion of anti-TNF- őĪ monoclonal antibodyinfliximab induced a rapid and dramatic reduction in serum insulin levels and insulin resistance along with a rapid improvement of insulin sensitivity in nondiabetic AS patients. The role of adipokines, MeS-related biomarkers and biomarkers of endothelial cell activation and inflammation seem to be relevant in different chronic inflammatory diseases. However, its implication in AS has not been fully established. Therefore, in this review we summarize the recent advances in the study of the involvement of these molecules in CV disease or MeS in AS. The assessment of adipokines and biomarkers of endothelial cell activation and MeS may be of potential relevance in the stratification of the CV risk of patients with AS

    Therapeutic Effects of Anti-Bone Morphogenetic Protein and Activin Membrane-Bound Inhibitor Treatment in Psoriasis and Arthritis

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    Abstract Objective: The transforming growth factor ? (TGF?) inhibitor BAMBI (bone morphogenetic protein and activin membrane-bound inhibitor) has been shown to control differentiation of CD4+ T lymphocytes into either tolerogenic Treg cells or pathogenic Th17 cells, through the regulation of TGF? and interleukin-2 (IL-2) signaling strength. The present study was undertaken to explore the potential beneficial effects of this strategy of pharmacologic inhibition using novel anti-BAMBI monoclonal antibodies (mAb) in different experimental murine models of chronic skin and joint inflammatory/autoimmune disease. Methods: Development of Saccharomyces cerevisiae mannan-induced psoriatic arthritis (MIP) (n = 18-30 mice per group), imiquimod-induced skin psoriasis (n = 20-30 mice per group), or type II collagen-induced arthritis (CIA) (n = 13-16 mice per group) was analyzed in a total of 2-5 different experiments with either wild-type (WT) or BAMBI-deficient B10.RIII mice that were left untreated or treated with mAb B101.37 (mouse IgG1 anti-BAMBI), a mouse IgG1 anti-TNP isotype control, anti-CD25, or anti-TGF? mAb. Results: Treatment of normal mice with IgG1 anti-BAMBI mAb clone B101.37 led to expansion of Treg cells in vivo, and had both preventive and therapeutic effects in mice with MIP (each P < 0.05 versus controls). The conferred protection against disease progression was found to be mediated by Treg cells, which controlled the activation and expansion of pathogenic IL-17-producing cells, and was dependent on the level of TGF? activity. Furthermore, treatment with B101.37 mAb blocked both the development of skin psoriasis induced by imiquimod and the development of CIA in mice (each P < 0.05 versus controls). Finally, pharmacologic inhibition of BAMBI with the IgM anti-BAMBI mAb B143.14 also potentiated the suppressive activity of Treg cells in vitro (P < 0.001 versus controls). Conclusion: These results in murine models identify BAMBI as a promising new therapeutic target for chronic inflammatory diseases and other pathologic conditions modulated by Treg cells.Funding was provided by grants from the Spanish Ministerio de Econom√≠a y Competitividad (Plan Nacional I+D+i) co-financed by European Development Regional Fund to RM (SAF2017-82905-R) and JM (SAF2016-75195-R). PA and MI were partially supported by grants from ‚ÄúLuchamos por la Vida Foundation‚ÄĚ and the Spanish Ministerio de Econom√≠a y Competitividad (IPT2011-1527-010000) associated with Fibrostatin SL, respectivel

    Relative Risk Chart Score for the Assessment of the Cardiovascular Risk in Young Patients with Ankylosing Spondylitis

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    Objective. To determine if the use of the relative risk (RR) chart score may help to identify young ankylosing spondylitis (AS) patients at high risk of cardiovascular (CV) disease. Methods. 73 AS patients younger than 50 years were assessed. CV risk was calculated according to the total cholesterol systematic coronary risk evaluation (TC-SCORE) and the RR chart score. C-reactive protein (CRP) value at disease diagnosis and carotid ultrasound data were also analyzed. Results. Twenty (27.4%) patients exhibited carotid plaques being classified into the category of very highCVrisk.None of them was found to have a high/very high TC-SCORE. CRP > 3mg/L at disease diagnosis was associated with the presence of carotid plaques (odds ratio 5.66, \u1d45dÔŅĹ = 0.03).Whereas only 5 (14.2%) of the 35 patients with RR = 1 had carotid plaques, 15 (39.5%) of 38 with RR > 1 showed plaques. A model that included the performance of carotid US in patients with RR > 1 who hadCRP> 3mg/L allowed us to identify 60% of very high risk patients, with a specificity of 77.4%. Conclusions. RR chart score assessment may help to identify young AS patients at high risk of CV disease

    Patients with Ankylosing Spondylitis and Low Disease Activity because of Anti-TNF-Alpha Therapy Have Higher TRAIL Levels Than Controls: A Potential Compensatory Effect

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    TRAIL is a potential biomarker of cardiovascular (CV) disease. Ankylosing spondylitis (AS) is a chronic inflammatory disease associated with metabolic syndrome (MeS) and accelerated atherosclerosis. We assessed whether disease activity, systemic inflammation, and MeS features were associated with circulating TRAIL levels in AS patients undergoing TNF-őĪ antagonist infliximab therapy and if infliximab infusion modified TRAIL levels. Methods. We measured TRAIL serum levels in 30 nondiabetic AS patients without CV disease undergoing anti-TNF-őĪ therapy, immediately before and after an infliximab infusion, and in 48 matched controls. Correlations of TRAIL levels with disease activity, systemic inflammation and MeS features, adipokines, and biomarkers of endothelial activation were evaluated. Changes in TRAIL levels following anti-TNF-őĪ infusion were analyzed. Results. TRAIL levels were higher in AS patients than controls. TRAIL levels displayed an inverse correlation with total and LDL cholesterol. We observed an inverse correlation with QUICKI and a marginal association with HOMA-IR. We also found an inverse correlation with resistin and a marginal association with apelin and OPN. Anti-TNF-őĪ infusion did not change TRAIL levels after 120‚Ä≤. Conclusion. Elevated TRAIL levels in AS patients may be the result of a compensatory mechanism to reduce CV risk in these patients

    Disease activity influences cardiovascular risk reclassification based on carotid ultrasound in patients with psoriatic arthritis

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    ABSTRACT: Objective. Because the addition of carotid ultrasound (US) into composite cardiovascular (CV) risk scores has been found effective for identifying patients with inflammatory arthritis and high CV risk, we aimed to determine whether its use would facilitate the reclassification of patients with psoriatic arthritis (PsA) into the very high Systematic Coronary Risk Evaluation (SCORE) risk category and whether this might be related to disease features. Methods. This was a cross-sectional study involving 206 patients who fulfilled ClASsification for Psoriatic ARthritis criteria for PsA, and 179 controls. We assessed lipid profile, SCORE, disease activity measurements, and the presence of carotid plaques and carotid intima-media thickness by ultrasonography. A multivariable regression analysis, adjusted for classic CV risk factors, was performed to evaluate whether the risk of reclassification could be explained by disease-related features and to assess the most parsimonious combination of risk reclassification predictors. Results. Forty-seven percent of patients were reclassified into a very high SCORE risk category after carotid US compared to 26% of controls (p < 0.001). Patients included in the low SCORE risk category were those who were more commonly reclassified (30% vs 14%, p = 0.002). The Disease Activity Index for PsA (DAPSA) score was associated with reclassification (? 1.10, 95% CI 1.02?1.19; p = 0.019) after adjusting for age and traditional CV risk factors. A model containing SCORE plus age, statin use, and DAPSA score yielded the highest discriminatory accuracy compared to the SCORE-alone model (area under the receiver-operating characteristic curve 0.863, 95% CI 0.789?0.936 vs 0.716, 95% CI 0.668?0.764; p < 0.001). Conclusion. Patients with PsA are more frequently reclassified into the very high SCORE risk category following carotid US assessment than controls. This was independently explained by the disease activity.Funding: This work was supported by a grant to I.F-A. from the Spanish Ministry of Health, Subdirecci√≥n General de Evaluaci√≥n y Fomento de la Investigaci√≥n, Plan Estatal de Investigaci√≥n Cient√≠fica y T√©cnica y de Innovaci√≥n 2013-2016 and by Fondo Europeo de Desarrollo Regional -FEDER - (Fondo de Investigaciones Sanitarias, FIS PI14/00394, PI17/00083) Professor Gonz√°lez-Gay research was supported by European Union FEDER funds and by the ‚ÄúFondo de Investigaci√≥n Sanitaria‚ÄĚ (grants PI06/0024, PS09/00748, PI12/00060, PI15/00525 and PI18/00043) of the ‚ÄėInstituto de Salud Carlos III‚Äô (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Programs RD12/0009 (RIER), RD12/0009/0013 and RD16/0012 from the ‚ÄėInstituto de Salud Carlos III‚Äô (ISCIII, Health Ministry, Spain)

    Angiogenic T Cells: potential biomarkers for the early diagnosis of interstitial lung disease in autoimmune diseases?

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    Background: We explored, for the first time, the contribution of angiogenic T cells (TAng) in interstitial lung disease associated to autoimmune disease (AD-ILD+) as potential biomarkers of the disease, evaluating their role in the underlying vasculopathy and lung fibrosis. Additionally, the relationship of TAng with clinical manifestations and cellular and molecular endothelial dysfunctionrelated biomarkers was assessed. (2) Methods: We included 57 AD-ILD+ patients (21 with rheumatoid arthritis (RA)-ILD+, 21 with systemic sclerosis (SSc)-ILD+ and 15 with other AD-ILD+) and three comparative groups: 45 AD-ILD-- patients (25 RA-ILD-- and 20 SSc-ILD--); 21 idiopathic pulmonary fibrosis (IPF) patients; 21 healthy controls (HC). TAng were considered as CD3+CD184+CD31+ by flow cytometry. (3) Results: A similar TAng frequency was found between AD-ILD+ and IPF, being in both cases lower than that observed in AD-ILD- and HC. A lower TAng frequency was associated with negative Scl-70 status and lower FEV1/FVC ratio in SSc-ILD+, as well as with men in RA-ILD+ and non-specific interstitial pneumonia radiological pattern in other AD-ILD+. No relationship between TAng and endothelial progenitor cells, endothelial cells and vascular endothelial growth factor gene expression and protein levels was disclosed. (4) Conclusions: Our findings suggest TAng as potential biomarkers for the early diagnosis of ILD in AD.Funding: V.P.-C. and S.R.-M. are supported by funds of RETICS Program [RD16/0012/0009, Instituto de Salud Carlos III (ISCIII), co-funded by European Regional Development Fund (ERDF); FG is supported by funds of the RICORS Program (RD21/0002/0025) from ISCIII, co-funded by the European Union; OG is staff personnel of Xunta de Galicia (Servizo Galego de Saude (SERGAS) through a research-staff stabilization contract (ISCIII/SERGAS) and his work is funded by ISCIII and ERDF [RD16/0012/0014 (RIER) and PI17/00409]. He is the beneficiary of project funds from the Research Executive Agency of the European Union in the framework of MSCA-RISE Action of the H2020 Programme, project 734899‚ÄĒOlive-Net. RL-M is a recipient of a Miguel Servet type II Program fellowship from ISCIII, co-funded by the European Social Fund, ‚ÄėInvesting in your future‚Äô (CPII21/00004)

    Lack of Association between ABO, PPAP2B, ADAMST7, PIK3CG, and EDNRA and Carotid Intima-Media Thickness, Carotid Plaques, and Cardiovascular Disease in Patients with Rheumatoid Arthritis

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    Introduction. Rheumatoid arthritis (RA) is a polygenic disease associated with accelerated atherosclerosis and increased cardiovascular (CV) mortality. Recent studies have identified the ABO rs579459, PPAP2B rs17114036, and ADAMTS7 rs3825807 polymorphisms as genetic variants associated with coronary artery disease and the PIK3CG rs17398575 and EDNRA rs1878406 polymorphisms as the most significant signals related to the presence of carotid plaque in nonrheumatic Caucasian individuals. Accordingly, we evaluated the potential relationship between these 5 polymorphisms and subclinical atherosclerosis (assessed by carotid intima-media thickness (cIMT) and presence/absence of carotid plaques) and CV disease in RA. Material and Methods. 2140 Spanish RA patients were genotyped for the 5 polymorphisms by TaqMan assays. Subclinical atherosclerosis was evaluated in 620 of these patients by carotid ultrasonography technology. Results. No statistically significant differences were found when each polymorphism was assessed according to cIMT values and presence/absence of carotid plaques in RA, after adjusting the results for potential confounders. Moreover, no significant differences were obtained when RA patients were stratified according to the presence/absence of CV disease after adjusting for potential confounders. Conclusion. Our results do not confirm association between ABO rs579459, PPAP2B rs17114036, ADAMTS7 rs3825807, PIK3CG rs17398575, and EDNRA rs1878406 and subclinical atherosclerosis and CV disease in RA.European Union FEDER Funds and ‚ÄúFondo de Investigaci√≥n Sanitaria‚ÄĚ (Grants PI06/0024, PS09/00748, and PI12/00060) from ‚ÄúInstituto de Salud Carlos III‚ÄĚ (ISCIII, Health Ministry, Spain). It was also partially supported by RETICS Programs RD12/0009/0013 and RD12/0009/0004 (RIER) from ‚ÄúInstituto de Salud Carlos III‚ÄĚ (ISCIII, Health Ministry, Spain) and in part by grants from the European IMI BTCure Program.Peer reviewe
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