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During initiation of antiviral and antitumor T cell-mediated immune responses, dendritic cells (DCs) cross-present exogenous antigens on major histocompatibility complex (MHC) class I molecules. Cross-presentation relies on the unusual "leakiness" of endocytic compartments in DCs, whereby internalized proteins escape into the cytosol for proteasome-mediated generation of MHC I-binding peptides. Given that type 1 conventional DCs excel at cross-presentation, we searched for cell type-specific effectors of endocytic escape. We devised an assay suitable for genetic screening and identified a pore-forming protein, perforin-2 (Mpeg1), as a dedicated effector exclusive to cross-presenting cells. Perforin-2 was recruited to antigen-containing compartments, where it underwent maturation, releasing its pore-forming domain. Mpeg1-/- mice failed to efficiently prime CD8+ T cells to cell-associated antigens, revealing an important role for perforin-2 in cytosolic entry of antigens during cross-presentation.

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Recently, Bikorimana et al. presented a new vaccine formulation, AccumTM, capable of eliciting efficient T cell-mediated immune responses and controlling tumour growth. AccumTM is designed to facilitate cross-presentation by breaking through endo/lysosomal membranes and enhancing delivery of antigens into the cytosol of dendritic cells (DCs).

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Cross-presentation of antigens by dendritic cells (DCs) is critical for initiation of anti-tumor immune responses. Yet, key steps involved in trafficking of antigens taken up by DCs remain incompletely understood. Here, we screen 700 US Food and Drug Administration (FDA)-approved drugs and identify 37 enhancers of antigen import from endolysosomes into the cytosol. To reveal their mechanism of action, we generate proteomic organellar maps of control and drug-treated DCs (focusing on two compounds, prazosin and tamoxifen). By combining organellar mapping, quantitative proteomics, and microscopy, we conclude that import enhancers undergo lysosomal trapping leading to membrane permeation and antigen release. Enhancing antigen import facilitates cross-presentation of soluble and cell-associated antigens. Systemic administration of prazosin leads to reduced growth of MC38 tumors and to a synergistic effect with checkpoint immunotherapy in a melanoma model. Thus, inefficient antigen import into the cytosol limits antigen cross-presentation, restraining the potency of anti-tumor immune responses and efficacy of checkpoint blockers.

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Inflammasomes are potent innate immune signalling complexes that couple cytokine release with pro-inflammatory cell death. However, pathogens have evolved strategies to evade this cell autonomous system. Here, we show how antibodies combine with innate sensors in primary human macrophages to detect viral infection and activate the inflammasome. Our data demonstrate that antibody opsonisation of virions can activate macrophages in multiple ways. In the first, antibody binding of adenovirus causes lysosomal damage, activating NLRP3 to drive inflammasome formation and IL-1ß release. Importantly, this mechanism enhances virion capture but not infection and is accompanied by cell death, denying the opportunity for viral replication. Unexpectedly, we also find that antibody-coated viruses, which successfully escape into the cytosol, trigger a second system of inflammasome activation. These viruses are intercepted by the cytosolic antibody receptor TRIM21 and the DNA sensor cGAS. Together, these sensors stimulate both NLRP3 inflammasome formation and NFκB activation, driving dose-dependent IL-1ß and TNF secretion, without inducing cell death. Our data highlight the importance of cooperativity between multiple sensing networks to expose viruses to the inflammasome pathway, which is particularly important for how our innate immune system responds to infection in the presence of pre-existing immunity.

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Multivesicular bodies (MVB) are endocytic compartments that enclose intraluminal vesicles (ILVs) formed by inward budding from the limiting membrane of endosomes. In T lymphocytes, ILVs are secreted as Fas ligand-bearing, pro-apoptotic exosomes following T cell receptor (TCR)-induced fusion of MVB with the plasma membrane at the immune synapse (IS). In this study we show that protein kinase C δ (PKCδ), a novel PKC isotype activated by diacylglycerol (DAG), regulates TCR-controlled MVB polarization toward the IS and exosome secretion. Concomitantly, we demonstrate that PKCδ-interfered T lymphocytes are defective in activation-induced cell death. Using a DAG sensor based on the C1 DAG-binding domain of PKCδ and a GFP-PKCδ chimera, we reveal that T lymphocyte activation enhances DAG levels at the MVB endomembranes which mediates the association of PKCδ to MVB. Spatiotemporal reorganization of F-actin at the IS is inhibited in PKCδ-interfered T lymphocytes. Therefore, we propose PKCδ as a DAG effector that regulates the actin reorganization necessary for MVB traffic and exosome secretion.

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In general, the use of angle-diversity receivers makes it possible to reduce the impact of ambient light noise, path loss and multipath distortion, in part by exploiting the fact that they often receive the desired signal from different directions. Angle-diversity detection can be performed using a composite receiver with multiple detector elements looking in different directions. These are called non-imaging angle-diversity receivers. In this paper, a comparison of three non-imaging angle-diversity receivers as input sensors of nodes for an indoor infrared (IR) wireless sensor network is presented. The receivers considered are the conventional angle-diversity receiver (CDR), the sectored angle-diversity receiver (SDR), and the self-orienting receiver (SOR), which have been proposed or studied by research groups in Spain. To this end, the effective signal-collection area of the three receivers is modelled and a Monte-Carlo-based ray-tracing algorithm is implemented which allows us to investigate the effect on the signal to noise ratio and main IR channel parameters, such as path loss and rms delay spread, of using the three receivers in conjunction with different combination techniques in IR links operating at low bit rates. Based on the results of the simulations, we show that the use of a conventional angle-diversity receiver in conjunction with the equal-gain combining technique provides the solution with the best signal to noise ratio, the lowest computational capacity and the lowest transmitted power requirements, which comprise the main limitations for sensor nodes in an indoor infrared wireless sensor network.

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Se trata de un paciente de 62 años, tabaquista crónico, portador de estenosis mitral reumática grave que descompenso con insuficiencia cardiaca derecha. Obtuvo mejora con tratamiento clínico, habiendo entretanto, indicación quirúrgica de reemplazo valvular mitral.

It is a 62 years-old patient, inveterate smoker, serious rheumatic mitral stenosis who decompensated with right heart failure. There was clinical improvement with clinical treatment, however there was indication for surgical mitral valve replacement.

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La primera fístula de la arteria coronaria (FAC) fue descrita en 1865 por Krause. Es una anomalía con una incidencia de 0,1% de la población adulta sometida a angiografía coronaria. Se caracteriza por la comunicación anormal entre una arteria coronaria y una cámara cardiaca o grandes vasos. Por lo general son congénitas y el cuadro clínico es silencioso, pero pueden presentarse como una enfermedad coronaria obstructiva, aunque las arterias coronarias estén libres de obstrucciones. El diagnóstico es normalmente hecho de forma casual. Se presenta el caso clínico de una paciente de 59 años de edad, con un cuadro clínico de inicio súbito, caracterizado por dolor torácico opresivo acompañado de cansancio en reposo. Diagnosticada y tratada como "angina de pecho". La cineangiocoronariografía mostró coronarias libres de aterosclerosis, evidenciando la presencia de una fístula entre la arteria descendente anterior y el tronco de la arteria pulmonar.

The first coronary artery fistula (FAC) was reported in 1865 by Krause. It is an anomaly with incidence less than 1% in angiographic studies. Characterized by abnormal communication between a coronary artery and a cardiac chamber or great vessels. They are usually congenital with silent clinical, but it can present as an obstructive coronary disease although the coronary arteries remain free of obs-truction. The diagnosis is usually made incidentally during coronary angiography. We introduce the clinical case of 59 years old woman who presented an event of sudden oppressive chest pain, accompanied by fatigue at rest. Diagnosed and treated as an angina pectoris. The coronary cineangiography showed a coronary free of atherosclerosis, demonstrating the presence of a fistula between the anterior descending artery and the main pulmonary artery.

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We present a comparison between the modified Monte Carlo algorithm (MMCA) and a recently proposed ray-tracing algorithm named as photon-tracing algorithm. Both methods are compared exhaustively according to error analysis and computational costs. We show that the new photon-tracing method offers a solution with a slightly greater error but requiring from considerable less computing time. Moreover, from a practical point of view, the solutions obtained with both algorithms are approximately equivalent, demonstrating the goodness of the new photon-tracing method.

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