Ly9 (CD229) cell surface receptor is crucial for the development of spontaneous autoantibody production to nuclear antigens

The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9 (-/-) mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4(+) T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses

Asserta medica ... ad mente[m] ... Hipps. apertendam publicae disputationi

Cartel anunciador de la disertaciónCopia digital. Madrid : Ministerio de Educación, Cultura y Deporte. Subdirección General de Coordinación Bibliotecaria, 2016Fecha en tít. : 1780Texto enmarcado en grab. calc.Grab. calc. de águila bicéfala:"D. Joachimus Rodriguez de Munera, Inventor. Alagarda d. et sculp. Oriolae. P.C. Tip.

Relevance of CD6-Mediated interactions in the regulation of peripheral T-Cell responses and tolerance

The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6(-/-)) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6(-/-)mice together with higher induction of regulatory T cells (T-reg, CD4(+)CD25(+)FoxP3(+)) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6(-/-)mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21(+)CD23(hi)) and T-reg cells. Interestingly, functional analysis of in vivo-generated CD6(-/-)T(reg) cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6(-/-)mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance

Exploring Biginelli-based scaffolds as A2B adenosine receptor antagonists: Unveiling novel structure-activity relationship trends, lead compounds, and potent colorectal anticancer agents

Antagonists of the A(2B) adenosine receptor have recently emerged as targeted anticancer agents and immune checkpoint inhibitors within the realm of cancer immunotherapy. This study presents a comprehensive evaluation of novel Biginelli-assembled pyrimidine chemotypes, including mono-, bi-, and tricyclic derivatives, as A(2B)AR antagonists. We conducted a comprehensive examination of the adenosinergic profile (both binding and functional) of a large compound library consisting of 168 compounds. This approach unveiled original lead compounds and enabled the identification of novel structure-activity relationship (SAR) trends, which were supported by extensive computational studies, including quantum mechanical calculations and free energy perturbation (FEP) analysis. In total, 25 molecules showed attractive affinity (K-i < 100 nM) and outstanding selectivity for A(2B)AR. From these, five molecules corresponding to the new benzothiazole scaffold were below the K-i < 10 nM threshold, in addition to a novel dual A(2A)/A(2B) antagonist. The most potent compounds, and the dual antagonist, showed enantiospecific recognition in the A(2B)AR. Two A(2B)AR selective antagonists and the dual A(2A)AR/A(2B)AR antagonist reported in this study were assessed for their impact on colorectal cancer cell lines. The results revealed a significant and dose-dependent reduction in cell proliferation. Notably, the A(2B)AR antagonists exhibited remarkable specificity, as they did not impede the proliferation of non-tumoral cell lines. These findings support the efficacy and potential that A(2B)AR antagonists as valuable candidates for cancer therapy, but also that they can effectively complement strategies involving A(2A)AR antagonism in the context of immune checkpoint inhibition

Estudio de la fidelidad de clientes aplicado al sector hotelero

En un sector tan competitivo como es el hotelero, la excelencia de productos y servicios juega una importancia decisiva. Ponerse en la piel de los consumidores finales del producto y servicio es vital para comprender mejor de qué manera perciben estos cada uno de los componentes que forman el total. La utilización de estas técnicas tiene un único objetivo: la mejora constante de la calidad y el compromiso pleno con la satisfacción de sus clientes. La gestión de las relaciones con los clientes, y en especial la gestión de su satisfacción, es determinante para el éxito o fracaso de cualquier empresa, tanto en las relaciones con el mercado como en el ámbito de la propia empresa. Las iniciativas para la mejora de la calidad del servicio, basadas únicamente en resultados internos, en las que falta información de los clientes, están inevitablemente condenadas al fracaso. Estas iniciativas se frustran por el desconocimiento de los requerimientos de los clientes y la necesidad de conectar la satisfacción y la medida de los avances internos. Palabras clave: Fidelidad, Clientes, Hoteles

Ly9 (CD229) cell surface receptor is crucial for the development of spontaneous autoantibody production to nuclear antigens

The Signaling Lymphocyte Activation Molecule Family (SLAMF) genes, which encode cell-surface receptors that modulate innate and adaptive immune responses, lay within a genomic region of human and mouse chromosome 1 that confers a predisposition for the development of systemic lupus erythematosus (SLE). Herein, we demonstrate that the SLAMF member Ly9 arises as a novel receptor contributing to the reinforcement of tolerance. Specifically, Ly9-deficient mice spontaneously developed features of systemic autoimmunity such as the production of anti-nuclear antibodies (ANA), -dsDNA, and -nucleosome autoantibodies, independently of genetic background [(B6.129) or (BALB/c.129)]. In aged (10- to 12-month-old) Ly9 (-/-) mice key cell subsets implicated in autoimmunity were expanded, e.g., T follicular helper (Tfh) as well as germinal center (GC) B cells. More importantly, in vitro functional experiments showed that Ly9 acts as an inhibitory receptor of IFN-γ producing CD4(+) T cells. Taken together, our findings reveal that the Ly9 receptor triggers cell intrinsic safeguarding mechanisms to prevent a breach of tolerance, emerging as a new non-redundant inhibitory cell-surface receptor capable of disabling autoantibody responses

Relevance of CD6-Mediated interactions in the regulation of peripheral T-Cell responses and tolerance

The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6(-/-)) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6(-/-)mice together with higher induction of regulatory T cells (T-reg, CD4(+)CD25(+)FoxP3(+)) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6(-/-)mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21(+)CD23(hi)) and T-reg cells. Interestingly, functional analysis of in vivo-generated CD6(-/-)T(reg) cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6(-/-)mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance

Relevance of CD6-Mediated Interactions in the Regulation of Peripheral T-Cell Responses and Tolerance

The CD6 lymphocyte receptor has been involved in the pathophysiology of different autoimmune disorders and is now considered a feasible target for their treatment. In vitro data show the relevance of CD6 in the stabilization of adhesive contacts between T-cell and antigen-presenting cells, and the modulation of T-cell receptor signals. However, the in vivo consequences of such a function are yet undisclosed due to the lack of suitable genetically modified animal models. Here, the in vitro and in vivo challenge of CD6-deficient (CD6−/−) cells with allogeneic cells was used as an approach to explore the role of CD6 in immune responses under relative physiological stimulatory conditions. Mixed lymphocyte reaction (MLR) assays showed lower proliferative responses of splenocytes from CD6−/− mice together with higher induction of regulatory T cells (Treg, CD4+CD25+FoxP3+) with low suppressive activity on T and B-cell proliferation. In line with these results, CD6−/− mice undergoing a lupus-like disorder induced by chronic graft-versus-host disease (cGvHD) showed higher serum titers of anti-double-stranded DNA and nucleosome autoantibodies. This occurred together with reduced splenomegaly, which was associated with lower in vivo bromodesoxyuridine incorporation of spleen cells and with increased percentages of spleen follicular B cells (B2, CD21+CD23hi) and Treg cells. Interestingly, functional analysis of in vivo-generated CD6−/− Treg cells exhibited defective suppressive activity. In conclusion, the data from MLR and cGvHD-induced lupus-like models in CD6−/− mice illustrate the relevance of CD6 in T (and B) cell proliferative responses and, even more importantly, Treg induction and suppressive function in the in vivo maintenance of peripheral tolerance

Valoração ética da cranioplastia com curativo compressivo como forma de limitação de tratamentos de suporte vital

This article analyzes, from a critical perspective, the use of cranioplasty with oppressive binder as a method to limit life support treatment (LLST). Some authors have proposed that this active technique provokes encephalic death, allowing organ donation. Contrasting this procedure with the recommendations of the consent document about treatment of critical patients at the end of life, elaborated by the bioethics group of SEMICYUC, it is shown that the means and ends of this technique do not match with the proper actions of LLST, based on the withdrawal of life support means or in not starting them, considering such means disproportionate or extraordinary in some cases, thus avoiding the therapeutic obstinacy. The definition of LLST allows to clarify the limits in which, in a way ethically fair and with a consensus, the acts at the end of life are included in the medical goals, avoiding the suspicion that these acts may be misinterpreted as justifying an abusive extraction of organs. This article concludes that the direct provocation of encephalic death by the technique of cranioplasty with binder does not appear to fulfill the criteria proper of LLST.Este artículo analiza, desde una postura crítica, la utilización de la craneoplastia de compresión con vendaje como método de limitación de tratamiento de soporte vital (LTSV). Con esta técnica activa, algunos autores han propuesto provocar la muerte encefálica, posibilitando la donación de órganos. Al contrastar este procedimiento con las recomendaciones del documento de consenso sobre el tratamiento al final de la vida del paciente crítico, elaborado por el grupo de bioética de la SEMICYUC, se comprueba que los medios y fines de esta técnica no encajan con las actuaciones propias de la LTSV, que se basan en la retirada de medios de soporte vital o en su no inicio, al considerar dichos medios desproporcionados o extraordinarios en algunos casos, evitando así la obstinación terapéutica. La definición de LTSV permite clarificar los límites en los que, de un modo éticamente correcto y consensuado, las actuaciones al final de la vida se circunscriben a los fines de la medicina, evitando la sospecha de que dichas actuaciones puedan ser malinterpretadas como justificación para una obtención de órganos abusiva. El artículo concluye que la provocación directa de la muerte encefálica mediante la técnica de craneoplastia con vendaje no parece cumplir los criterios propios de la LTSV.Este artigo analisa, a partir de uma postura crítica, a utilização da cranioplastia de compressão com curativo como método de limitação de tratamento de suporte vital (LTSV). Com esta técnica ativa, alguns autores têm proposto provocar a morte encefálica, possibilitando a doação de órgãos. Ao contrastar este procedimento com as recomendações do documento de consenso sobre o tratamento do final de vida do paciente crítico, elaborado pelo grupo de bioética da SEMICYUC, se comprova que os meios e fins desta técnica não encaixam com as atuações próprias da LTSV, que se baseiam na retirada de meios de suporte vital ou em seu não início, ao considerar os ditos meios desproporcionados ou extraordinários em alguns casos, evitando assim a obstinação terapêutica. A definição de LTSV permite esclarecer os limites nos quais, de um modo eticamente correto e aceito, as atuações ao final da vida se circunscrevem às finalidades da medicina, evitando a suspeita de que ditas atuações podem ser mal interpretadas como justificativa para uma obtenção de órgãos abusiva. O artigo conclui que a provocação direta da morte encefálica mediante a técnica da cranioplastia com curativo não parece cumprir os critérios próprios da LTSV