Browsing by Author "Naves, Rodrigo"

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    Cellular and molecular regulation of the programmed death-1/programmed death ligand system and its role in multiple sclerosis and other autoimmune diseases
    (2021) Ibanez-Vega, Jorge; Vilchez, Constanza; Jimenez, Karin; Guevara, Carlos; Burgos, Paula, I; Naves, Rodrigo
    Programmed Cell Death 1 (PD-1) receptor and its ligands (PD-Ls) are essential to maintain peripheral immune tolerance and to avoid tissue damage. Consequently, altered gene or protein expression of this system of coinhibitory molecules has been involved in the development of cancer and autoimmunity. Substantial progress has been achieved in the study of the PD-1/PD-Ls system in terms of regulatory mechanisms and therapy. However, the role of the PD-1/PD-Ls pathway in neuroinflammation has been less explored despite being a potential target of treatment for neurodegenerative diseases. Multiple Sclerosis (MS) is the most prevalent, chronic, inflammatory, and autoimmune disease of the central nervous system that leads to demyelination and axonal damage in young adults. Recent studies have highlighted the key role of the PD-1/PD-Ls pathway in inducing a neuroprotective response and restraining T cell activation and neurodegeneration in MS. In this review, we outline the molecular and cellular mechanisms regulating gene expression, protein synthesis and traffic of PD-1/PD-Ls as well as relevant processes that control PD-1/PD-Ls engagement in the immunological synapse between antigen-presenting cells and T cells. Also, we highlight the most recent findings regarding the role of the PD-1/PD-Ls pathway in MS and its murine model, experimental autoimmune encephalomyelitis (EAE), including the contribution of PD-1 expressing follicular helper T (TFH) cells in the pathogenesis of these diseases. In addition, we compare and contrast results found in MS and EAE with evidence reported in other autoimmune diseases and their experimental models, and review PD-1/PD-Ls-targeting therapeutic approaches.
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    Diagnostic performance of GM-CSF and IL-2 in response to long-term specific-antigen cell stimulation in patients with active and latent tuberculosis infection
    (2018) Balcells Marty, María Elvira; Ruiz-Tagle, Cinthya; Tiznado, Camila; García Cañete, Patricia; Naves, Rodrigo
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    Estrategia de pesquisa sistemática y seguimiento prolongado revela alto número de nuevas infecciones tuberculosas en contactos adultos en la Región Metropolitana, Chile
    (2020) Balcells Marty, María Elvira; Carvajal, Camila; Fernández, Paula; Ruiz-Tagle, Cinthya; Pizarro, Alejandra; García, Patricia; Peña, Carlos; Cuevas, Gerardo; Naves, Rodrigo
    Background: Contact investigation is cardinal in the control of tuberculosis (TB) since it helps to stop its transmission. In Chile, the National TB Program strategy does not include latent TB infection testing, regular chemoprophylaxis or follow-up in adults. Active TB was found in only 1.2% of contacts at country-level during 2018. Aim: To evaluate the performance of a systematic screening ofadult household contacts with targeted chemoprophylaxis and prolonged active follow-up. Material and Methods: Prospective cohort of household contacts in Santiago. Two face-to-face visits (at 0 and 12 weeks) that included QuantiFERON TB-Gold plus tests (QFT), chest radiography (CXR) at 0 and 24 weeks and, periodic text messaging or phone call follow-up for up to 48 weeks were implemented. Contacts with positive QFT were referred for TB chemoprophylaxis. Results: A total of 200 contacts were enrolled, 69% were migrants. At baseline evaluation, 45% had a positive QFT result and 1.6% had co-prevalent active TB. At follow-up, 13% contacts further converted to QFT (+), and 5.1% more were diagnosed with active TB (mean follow-up time 32 weeks). Of these 10 further active TB cases, 6 (60%) had a negative QFT and all (100%) had normal CXR at baseline; while three cases occurred in QFT converters. Conclusions: In this cohort of household contacts, 6.7 % were diagnosed with active TB (more than 2/3 at follow-up) and 13% had a late QFT (+) conversion. Active and prolonged contacts’ follow-up are essential to detect new infections and tackle the TB epidemic in Chile.
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    Galectin-8 as an immunosuppressor in experimental autoimmune encephalomyelitis and a target of human early prognostic antibodies in multiple sclerosis
    (2017) Pardo, Evelyn; Cárcamo, Claudia; Uribe-San Martín, Reinaldo; Ciampi, Ethel; Segovia-Miranda, Fabián; Curkovic-Peña, Cristobal; Montecino, Fabián; Holmes, Christopher; Tichauer, Juan Enrique; Acuña, Eric; Osorio-Barrios, Francisco; Castro, Marjorie; Cortes, Priscilla; Oyanadel, Claudia; Valenzuela, David M.; Pacheco, Rodrigo; Naves, Rodrigo; Soza, Andrea; González, Alfonso
    Galectin-8 (Gal-8) is a member of a glycan-binding protein family that regulates the immune system, among other functions, and is a target of antibodies in autoimmune disorders. However, its role in multiple sclerosis (MS), an autoimmune inflammatory disease of the central nervous system (CNS), remains unknown. We study the consequences of Gal-8 silencing on lymphocyte subpopulations and the development of experimental autoimmune encephalitis (EAE), to then assess the presence and clinical meaning of anti-Gal-8 antibodies in MS patients. Lgals8/Lac-Z knock-in mice lacking Gal-8 expression have higher polarization toward Th17 cells accompanied with decreased CCR6+ and higher CXCR3+ regulatory T cells (Tregs) frequency. These conditions result in exacerbated MOG35-55 peptide-induced EAE. Gal-8 eliminates activated Th17 but not Th1 cells by apoptosis and ameliorates EAE in C57BL/6 wild-type mice. β-gal histochemistry reflecting the activity of the Gal-8 promoter revealed Gal-8 expression in a wide range of CNS regions, including high expression in the choroid-plexus. Accordingly, we detected Gal-8 in human cerebrospinal fluid, suggesting a role in the CNS immune-surveillance circuit. In addition, we show that MS patients generate function-blocking anti-Gal-8 antibodies with pathogenic potential. Such antibodies block cell adhesion and Gal-8-induced Th17 apoptosis. Furthermore, circulating anti-Gal-8 antibodies associate with relapsing-remitting MS (RRMS), and not with progressive MS phenotypes, predicting clinical disability at diagnosis within the first year of follow-up. Our results reveal that Gal-8 has an immunosuppressive protective role against autoimmune CNS inflammation, modulating the balance of Th17 and Th1 polarization and their respective Tregs. Such a role can be counteracted during RRMS by anti-Gal-8 antibodies, worsening disease prognosis. Even though anti-Gal-8 antibodies are not specific for MS, our results suggest that they could be a potential early severity biomarker in RRMS.
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    Identification of Recent Tuberculosis Exposure Using QuantiFERON-TB Gold Plus, a Multicenter Study
    (2021) Perez-Recio, Sandra; Pallares, Natalia; Grijota-Camino, Maria D.; Sanchez-Montalva, Adrian; Barcia, Laura; Campos-Gutierrez, Silvia; Pomar, Virginia; Rabunal-Rey, Ramon; Balcells, Maria Elvira; Gazel, Deniz; Montiel, Natalia; Vicente, Diego; Goic-Barisic, Ivana; Schon, Thomas; Paues, Jakob; Marekovic, Ivana; Cacho-Calvo, Juana; Barac, Aleksandra; Goletti, Delia; Garcia-Gasalla, Mercedes; Maria Barcala, Jose; Teresa Tortola, Maria; Anibarro, Luis; Suarez-Toste, Isabel; Moga, Esther; Gude-Gonzalez, Maria J.; Naves, Rodrigo; Karsligil, Tekin; Martin-Penaranda, Tania; Stevanovic, Goran; Trigo, Matilde; Rubio, Veronica; Karaoglan, Ilkay; Bayram, Nazan; Alcaide, Fernando; Tebe, Cristian; Santin, Miguel
    We investigated whether the difference of antigen tube 2 (TB2) minus antigen tube 1 (TB1) (TB22TB1) of the QuantiFERON-TB gold plus test, which has been postulated as a surrogate for the CD81 T-cell response, could be useful in identifying recent tuberculosis (TB) exposure. We looked at the interferon gamma (IFN-g) responses and differences in TB2 and TB1 tubes for 686 adults with QFT-plus positive test results. These results were compared among groups with high (368 TB contacts), low (229 patients with immune-mediated inflammatory diseases [IMID]), and indeterminate (89 asylum seekers or people from abroad [ASPFA]) risks of recent TB exposure. A TB2-TB1 value.0.6 IU.ml(-1) was deemed to indicate a true difference between tubes. In the whole cohort, 13.6%, 10.9%, and 11.2% of cases had a TB2>TB1 result in the contact, IMID, and ASPFA groups, respectively (P = 0.591). The adjusted odds ratios (aORs) for an association between a TB2-TB1 result of >0.6 IU.ml(-1) and risk of recent exposure versus contacts were 0.71 (95% confidence interval [CI], 0.31 to 1.61) for the IMID group and 0.86 (95% CI, 0.49 to 1.52) for the ASPFA group. In TB contact subgroups, 11.4%, 15.4%, and 17.7% with close, frequent, and sporadic contact had a TB2>TB1 result (P = 0.362). The aORs versus the close subgroup were 1.29 (95% CI, 0.63 to 2.62) for the frequent subgroup and 1.55 (95% CI, 0.67 to 3.60) for the sporadic subgroup. A TB2-TB1 difference of.0.6 IU.ml(-1) was not associated with increased risk of recent TB exposure, which puts into question the clinical potential as a proxy marker for recently acquired TB infection.
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    Interferon-gamma ameliorates experimental autoimmune encephalomyelitis by inducing homeostatic adaptation of microglia
    (2023) Tichauer, Juan E.; Arellano, Gabriel; Acuna, Eric; Gonzalez, Luis F.; Kannaiyan, Nirmal R.; Murgas, Paola; Panadero-Medianero, Concepcion; Ibanez-Vega, Jorge; Burgos, Paula I.; Loda, Eileah; Miller, Stephen D.; Rossner, Moritz J.; Gebicke-Haerter, Peter J.; Naves, Rodrigo
    Compelling evidence has shown that interferon (IFN)-gamma has dual effects in multiple sclerosis and in its animal model of experimental autoimmune encephalomyelitis (EAE), with results supporting both a pathogenic and beneficial function. However, the mechanisms whereby IFN-gamma may promote neuroprotection in EAE and its effects on central nervous system (CNS)-resident cells have remained an enigma for more than 30 years. In this study, the impact of IFN-gamma at the peak of EAE, its effects on CNS infiltrating myeloid cells (MC) and microglia (MG), and the underlying cellular and molecular mechanisms were investigated. IFN-gamma administration resulted in disease amelioration and attenuation of neuroinflammation associated with significantly lower frequencies of CNS CD11b(+) myeloid cells and less infiltration of inflammatory cells and demyelination. A significant reduction in activated MG and enhanced resting MG was determined by flow cytometry and immunohistrochemistry. Primary MC/MG cultures obtained from the spinal cord of IFN-gamma-treated EAE mice that were ex vivo re-stimulated with a low dose (1 ng/ml) of IFN-gamma and neuroantigen, promoted a significantly higher induction of CD4(+) regulatory T (Treg) cells associated with increased transforming growth factor (TGF)-beta secretion. Additionally, IFN-gamma-treated primary MC/MG cultures produced significantly lower nitrite in response to LPS challenge than control MC/MG. IFN-gamma-treated EAE mice had a significantly higher frequency of CX3CR1(high) MC/MG and expressed lower levels of program death ligand 1 (PD-L1) than PBS-treated mice. Most CX3CR1(high)PD-L1(low)CD11b(+)Ly6G(-) cells expressed MG markers (Tmem119, Sall2, and P2ry12), indicating that they represented an enriched MG subset (CX3CR1(high)PD-L1(low) MG). Amelioration of clinical symptoms and induction of CX3CR1(high)PD-L1(low) MG by IFN-gamma were dependent on STAT-1. RNA-seq analyses revealed that in vivo treatment with IFN-gamma promoted the induction of homeostatic CX3CR1(high)PD-L1(low) MG, upregulating the expression of genes associated with tolerogenic and anti-inflammatory roles and down-regulating pro-inflammatory genes. These analyses highlight the master role that IFN-gamma plays in regulating microglial activity and provide new insights into the cellular and molecular mechanisms involved in the therapeutic activity of IFN-gamma in EAE.
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    Intranasal delivery of interferon-β-loaded nanoparticles induces control of neuroinflammation in a preclinical model of multiple sclerosis: A promising simple, effective, non-invasive, and low-cost therapy
    (2021) Gonzalez, Luis F.; Acuna, Eric; Arellano, Gabriel; Morales, Paola; Sotomayor, Paula; Oyarzun-Ampuero, Felipe; Naves, Rodrigo
    Multiple sclerosis (MS) is an autoimmune disease affecting the central nervous system (CNS). Interferon (IFN)-beta constitutes one of the first-line therapies to treat MS, but has limited efficacy due to the injectable systemic administration, short half-life, and limited CNS access. To address these limitations, we developed IFN-beta-loaded chitosan/sulfobutylether-beta-cyclodextrin nanoparticles (IFN-beta-NPs) for delivery of IFN-beta into the CNS via the intranasal (i.n.) route. The nanoparticles (NPs) (approximate to 200 nm, polydispersity approximate to 0.1, and zeta potential approximate to 20 mV) were prepared by mixing two aqueous solutions and associated human or murine IFN-beta with high efficiency (90%). Functional in vitro assays showed that IFN-beta-NPs were safe and that IFN-beta was steadily released while retaining biological activity. Biodistribution analysis showed an early and high fluorescence in the brain after nasal administration of fluorescent probe-loaded NPs. Remarkably, mice developing experimental autoimmune encephalomyelitis (EAE), an experimental model of MS, exhibited a significant improvement of clinical symptoms in response to intranasal IFN-beta-NPs (inIFN-beta-NPs), whereas a similar dose of intranasal or systemic free IFN-beta had no effect. Importantly, inIFN-beta-NPs treatment was equally effective despite a reduction of 78% in the total amount of weekly administered IFN-beta. Spinal cords obtained from inIFN-beta-NPs-treated EAE mice showed fewer inflammatory foci and demyelination, lower expression of antigen-presenting and costimulatory proteins on CD11b(+) cells, and lower astrocyte and microglia activation than control mice. Therefore, IFN-beta treatment at tested doses was effective in promoting clinical recovery and control of neuroinflammation in EAE only when associated with NPs. Overall, inIFN beta-NPs represent a potential, effective, non-invasive, and low-cost therapy for MS.
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    Th1 and Th17 Cells and Associated Cytokines Discriminate among Clinically Isolated Syndrome and Multiple Sclerosis Phenotypes
    (2017) Arellano, Gabriel; Acuña, Eric; Reyes, Lilian I.; Ottum, Payton A.; De Sarno, Patrizia; Villaroel, Luis; Ciampi, Ethel; Uribe San Martín, Reinaldo; Cárcamo Rodríguez, Claudia Andrea; Naves, Rodrigo
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    The interdependent, overlapping, and differential roles of type i and II IFNs in the pathogenesis of experimental autoimmune encephalomyelitis
    (2013) Naves, Rodrigo; Singh, S.; Cashman, K.; Rowse, A.; Axtell, R.; Steinman, L.; Mountz, J.; Steele, C.; De Sarno, P.; Raman, C.
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    Therapeutic role of interferon-γ in experimental autoimmune encephalomyelitis is mediated through a tolerogenic subset of splenic CD11b+ myeloid cells
    (2024) Arellano, Gabriel; Acuña, Eric; Loda, Eileah; Moore, Lindsay; Tichauer Calderón, Juan Enrique; Castillo, Cristian; Vergara, Fabian; Burgos Cañete, Paula Isabel; Peñaloza-MacMaster, Pablo; Miller, Stephen D.; Naves, Rodrigo
    Cumulative evidence has established that Interferon (IFN)-γ has both pathogenic and protective roles in Multiple Sclerosis and the animal model, Experimental Autoimmune Encephalomyelitis (EAE). However, the underlying mechanisms to the beneficial effects of IFN-γ are not well understood. In this study, we found that IFN-γ exerts therapeutic effects on chronic, relapsing-remitting, and chronic progressive EAE models. The frequency of regulatory T (Treg) cells in spinal cords from chronic EAE mice treated with IFN-γ was significantly increased with no effect on Th1 and Th17 cells. Consistently, depletion of FOXP3-expressing cells blocked the protective effects of IFN-γ, indicating that the therapeutic effect of IFN-γ depends on the presence of Treg cells. However, IFN-γ did not trigger direct in vitro differentiation of Treg cells. In vivo administration of blocking antibodies against either interleukin (IL)-10, transforming growth factor (TGF)-β or program death (PD)-1, revealed that the protective effects of IFN-γ in EAE were also dependent on TGF-β and PD-1, but not on IL-10, suggesting that IFN-γ might have an indirect role on Treg cells acting through antigen-presenting cells. Indeed, IFN-γ treatment increased the frequency of a subset of splenic CD11b+ myeloid cells expressing TGF-β-Latency Associated Peptide (LAP) and program death ligand 1 (PD-L1) in a signal transducer and activator of transcription (STAT)-1-dependent manner. Furthermore, splenic CD11b+ cells from EAE mice preconditioned in vitro with IFN-γ and myelin oligodendrocyte glycoprotein (MOG) peptide exhibited a tolerogenic phenotype with the capability to induce conversion of naïve CD4+ T cells mediated by secretion of TGF-β. Remarkably, adoptive transfer of splenic CD11b+ cells from IFN-γ-treated EAE mice into untreated recipient mice ameliorated clinical symptoms of EAE and limited central nervous system infiltration of mononuclear cells and effector helper T cells. These results reveal a novel cellular and molecular mechanism
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    Unraveling the role of micrornas in mycobacterium tuberculosis infection and disease: advances and pitfalls
    (American Society for Microbiology, 2020) Ruiz-Tagle, Cinthya; Naves, Rodrigo; Balcells Marty, María Elvira
    Tuberculosis (TB) is an infectious disease of extremely high epidemiological burden worldwide that is easily acquired through the inhalation of infected respiratory droplets. The complex pathogenesis of this infection spans from subjects never developing this disease despite intense exposure, to others in which immune containment fails catastrophically and severe or disseminated forms of disease ensue. In recent decades, microRNAs (miRNAs) have gained increasing attention due to their role as gene silencers and because of their altered expression in diverse human diseases, including some infections. Recent research regarding miRNAs and TB has revealed that the expression profile for particular miRNAs clearly changes upon Mycobacterium tuberculosis infection and also varies in the different stages of this disease. However, despite the growing number of studies - some of which have even proposed some miRNAs as potential biomarkers - methodological variations and key differences in relevant factors, such as sex and age, cell type analyzed, M. tuberculosis strain, and antimicrobial therapy status, strongly hinder the comparison of data. In this review, we summarize and discuss the literature and highlight the role of selected miRNAs that have specifically and more consistently been associated with M. tuberculosis infection, together with a discussion of the possible gene and immune regulation pathways involved.