Papel del hígado en la regulación renal del volúmen extracelular : mediación de un mecanismo humoral

Tesis Univ. Complutense de Madrid, 1983.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEProQuestpu

Papel del hígado en la regulación renal del volúmen extracelular : mediación de un mecanismo humoral

Tesis Univ. Complutense de Madrid, 1983.Depto. de Genética, Fisiología y MicrobiologíaFac. de Ciencias BiológicasTRUEProQuestpu

The Role of CD38 on the Function of Regulatory B Cells in a Murine Model of Lupus

Previous work from our group has shown that Cd38-/- mice develop a milder pristane-induced lupus disease than WT or Art2-/- counterparts, demonstrating a new role for CD38 in promoting aberrant inflammation and lupus-like autoimmunity via a Transient Receptor Potential Melastatin 2 (TRPM2)-dependent apoptosis-driven mechanism. In this study we asked whether CD38 may play a role in the expression and function of regulatory B cells (IL-10-producing B cells or B10 cells). In pristane-treated mice the frequency of spleen CD19+CD1dhiCD5+ B cells, which are highly enriched in B10 cells, was significantly increased in Cd38-/- splenocytes compared to WT, while the frequency of peritoneal plasmacytoid dendritic cells (pDCs), which are major type I Interferon (IFN) producers, was greatly diminished. The low proportion of pDCs correlated with lower amounts of IFN-α in the peritoneal lavage fluids of the Cd38-/- mice than of WT and Art2-/- mice. Functional ex vivo assays showed increased frequencies of IL-10-producing B cells in Cd38-/- splenocytes than in WT upon stimulation with an agonist anti-CD40 mAb. Overall these results strongly suggest that Cd38-/- mice are better suited than WT mice to generate and expand regulatory B10 cells following the appropriate stimulation.Work performed in the Sancho and Zubiaur labs was supported in part by the European Commission in collaboration with the following Funding Agencies: (i) Junta de Andalucía, Consejería Innovación Ciencia y Empresa y Consejería Educación y Ciencia, Project: PC08-CTS-04046 to Jaime Sancho and Mercedes Zubiaur, and (ii) Ministerio de Economía y Competitividad (MINECO), Projects: SAF-2011-27261 and SAF-2017-89801-R to Jaime Sancho and Mercedes Zubiaur. The stay of B.B. and G.R. in Sancho’s lab was supported by National Science Foundation: Grant #HRD-0963629 (G-STEM). USA.; and U.S. Department of Education; Student Aid and Fiscal Responsibility Act; Title III Grant (SAFRA, Part F). Grant SAF-2017-89801-R covers in part the costs to publish in open access

Differential protein expression in peripheral blood mononuclear cells (PBMCs) on patients withd systemic lupus erythematosus (SLE)

Comunicaciones a congreso

El análisis proteómico mediante 2D-DIGE y MS/MS permite discriminar en un mismo experimento entre ratones silvestres (WT) o deficientes CD38 (CD38ko) y entre ratones afectados o no por la artritis inducida por colágeno

Comunicaciones a congreso

Cd38 deficiency ameliorates chronic graft versus Host disease murine lupus via a b-cell dependent mechanism

Trabajo presentado en el II Congreso investigación PTS, celebrado en Granada (España) del 09 al 11 de febrero de 2022.Absence of mouse cell surface receptor CD38 in Cd38-/- mice suggests that this receptor acts as positive regulator of inflammatory and autoimmune responses. Here we report that in the setting of a chronic graft versus host disease (cGVHD) lupus model induced by the transfer of B6.C-H2bm12/KhEg (bm12) spleen cells into co-isogenic Cd38-/- B6 mice causes milder lupus-like autoimmunity with lower levels of anti-ssDNA autoantibodies than the transfer of bm12 spleen cells into WT B6 mice. I In addition, significantly lower percentages of Tfh cells, as well as GC B cells, plasma cells and T-bet+CD11chi B cells are observed in Cd38-/- mice than in WT mice, while the expansion of Treg cells, and Tfr cells is normal, suggesting that the ability of Cd38-/- B cells to respond to allogeneic help from bm12 CD4+ T cells is greatly diminished. The frequencies of T-bet+CD11chi B cells, which are considered the precursors of the autoantibody secreting cells, correlate with anti-ssDNA autoantibody serum levels, with IL-27, and sCD40L. Proteomics profiling of spleens from WT cGVHD mice reflects a STAT1-driven type I IFN-signature, which is absent in Cd38-/- cGVHD mice. Kidney, spleen and liver inflammation was mild and resolved faster in Cd38-/- cGVHD mice than in WT cGVHD mice. We conclude that in B cells CD38 functions as a modulator receptor that controls autoimmune responses

The second-generation antipsychotic drug aripiprazole modulates the serotonergic system in pancreatic islets and induces beta cell dysfunction in female mice

[Aims/hypothesis]: Second-generation antipsychotic (SGA) drugs have been associated with the development of type 2 diabetes and the metabolic syndrome in patients with schizophrenia. In this study, we aimed to investigate the effects of two different SGA drugs, olanzapine and aripiprazole, on metabolic state and islet function and plasticity. [Methods]: We analysed the functional adaptation of beta cells in 12-week-old B6;129 female mice fed an olanzapine- or aripiprazole-supplemented diet (5.5–6.0 mg kg−1 day−1) for 6 months. Glucose and insulin tolerance tests, in vivo glucose-stimulated insulin secretion and indirect calorimetry were performed at the end of the study. The effects of SGAs on beta cell plasticity and islet serotonin levels were assessed by transcriptomic analysis and immunofluorescence. Insulin secretion was assessed by static incubations and Ca2+ fluxes by imaging techniques. [Results]: Treatment of female mice with olanzapine or aripiprazole for 6 months induced weight gain (p<0.01 and p<0.05, respectively), glucose intolerance (p<0.01) and impaired insulin secretion (p<0.05) vs mice fed a control chow diet. Aripiprazole, but not olanzapine, induced serotonin production in beta cells vs controls, likely by increasing tryptophan hydroxylase 1 (TPH1) expression, and inhibited Ca2+ flux. Of note, aripiprazole increased beta cell size (p<0.05) and mass (p<0.01) vs mice fed a control chow diet, along with activation of mechanistic target of rapamycin complex 1 (mTORC1)/S6 signalling, without preventing beta cell dysfunction. [Conclusions/interpretation]: Both SGAs induced weight gain and beta cell dysfunction, leading to glucose intolerance; however, aripiprazole had a more potent effect in terms of metabolic alterations, which was likely a result of its ability to modulate the serotonergic system. The deleterious metabolic effects of SGAs on islet function should be considered while treating patients as these drugs may increase the risk for development of the metabolic syndrome and diabetes.This work was funded by H2020 Marie Sklodowska-Curie ITN-TREATMENT (Grant Agreement 721236, European Commission). We also acknowledge grants RTI2018-094052-B-100/ AEI/10.13039/501100011033 (Ministerio de Ciencia e Innovación y Fondo Europeo de Desarrollo Regional [FEDER]) and S2017/BMD-3684 (Comunidad de Madrid, Spain), and grants from Fundación Ramón Areces (Spain) and CIBERDEM (ISCIII, Spain)

A novel isoform of the Ly108 gene ameliorates murine lupus

Studies of human systemic lupus erythematosus patients and of murine congenic mouse strains associate genes in a DNA segment on chromosome 1 with a genetic predisposition for this disease. The systematic analysis of lupus-prone congenic mouse strains suggests a role for two isoforms of the Ly108 receptor in the pathogenesis of the disease. In this study, we demonstrate that Ly108 is involved in the pathogenesis of lupus-related autoimmunity in mice. More importantly, we identified a third protein isoform, Ly108-H1, which is absent in two lupus-prone congenic animals. Introduction of an Ly108-H1–expressing transgene markedly diminishes T cell–dependent autoimmunity in congenic B6.Sle1b mice. Thus, an immune response–suppressing isoform of Ly108 can regulate the pathogenesis of lupus.Peer Reviewe