Upon interaction with immobilized antigens, B cells form an immune synapse where actin remodeling and re-positioning of the microtubule-organizing center (MTOC) together with lysosomes can facilitate antigen extraction. B cells have restricted cytoplasmic space, mainly occupied by a large nucleus, yet the role of nuclear morphology in the formation of the immune synapse has not been addressed. Here we show that upon activation, B cells re-orientate and adapt the size of their nuclear groove facing the immune synapse, where the MTOC sits, and lysosomes accumulate. Silencing the nuclear envelope proteins Nesprin-1 and Sun-1 impairs nuclear reorientation towards the synapse and leads to defects in actin organization. Consequently, B cells are unable to internalize the BCR after antigen activation. Nesprin-1 and Sun-1-silenced B cells also fail to accumulate the tethering factor Exo70 at the center of the synaptic membrane and display defective lysosome positioning, impairing efficient antigen extraction at the immune synapse. Thus, changes in nuclear morphology and positioning emerge as critical regulatory steps to coordinate B cell activation.
Upon interaction with immobilized antigens B cells form an immune synapse, where actin remodeling and re-positioning of the microtubule-organizing center (MTOC) together with lysosomes can facilitate antigen extraction. B cells have restricted cytoplasmic space, mainly occupied by a large nucleus, yet the role of nuclear morphology in the formation of the immune synapse has not been addressed. Here we show that, upon activation, B cells re-orientate and adapt the size of their nuclear groove facing the immune synapse, where the MTOC sits and lysosomes accumulate. Silencing nuclear envelope proteins, Nesprin-1 and Sun-1, impairs nuclear reorientation towards the synapse and leads to defects in actin organization at this level. Consequently, B cells are unable to internalize the BCR after antigen activation. Nesprin-1 and Sun-1-silenced B cells also fail to accumulate the tethering factor Exo70 at the center of the synaptic membrane and display defective lysosome positioning, impairing efficient antigen extraction at the immune synapse. Thus, changes in nuclear morphology and positioning emerge as critical regulatory steps to coordinate B cell activation.
Introduction: Cancer progression and metastatic spread is modulated by the tumor microenvironment. Cancer-associated fibroblasts (CAF) are the most abundant cell type within the tumor microenvironment. Little is known about the specific mechanisms by which CAF would exert its cancer progression, through the high secretory capacity of soluble pro-tumorigenic molecules and remodeling of the extracellular matrix. Recent studies in our laboratory have shown for the first time that CAF derived from patients without metastasis express a different genetic profile than those with metastases (mCAF). This study seeks to evaluate the contribution of mCAF to tumor progression through its immunomodulatory role. Methodology: mCAFs were obtained from patients with metastatic disease and BAF from benign patients. The fibroblasts were functionally characterized by the generation of fibroblast-derived matrices (FDM) and secretory profiles by cytokine array. CD8 T lymphocytes were obtained from healthy patients and treated with fibroblast-secretome. Markers were studied by flow cytometry: activation (CD25 and CD69) and repression (LAG3 and PD1). The migration of CD8 T lymphocytes was studied by transwell and agarose drop migration assay. Results and conclusion: FDM of mCAF are different in their composition and organization. Furthermore, the secretome of each type of fibroblast presents a differential effect on the activation of CD8 T cells according to the markers highlighted. Regarding migration, it has been observed that the mCAF-secretome can attract lymphocytes. However, it would lead them to apoptosis. Our results suggest that mCAF, within the tumor microenvironment, has an immunomodulatory role on CD8 T lymphocytes. Acknowledgment: Beca Doctorado Nacional ANID 21181427 Citation Format: Muriel Antonieta Núñez, Oreste Corrales, Victoria Velasquez, Daniel Ernst, Montecinos Viviana, Francisco Nualart, María Isabel Yuseff, Javier Cerda-Infante. CAF contributes to cancer progression through its immunomodulatory role within the tumor microenvironment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4640.
BackgroundOn September 7th 2015, the European Medicines Agency (EMA) and the Spanish Agency for Medicines and Health Products (AEMPS) notified a drug safety warning (DSW) through a communication to healthcare professionals on the use of mirabegron. It showed new recommendations for its use in relation to the risk of increased blood pressure.PurposeTo detect patients under mirabegron treatment with an increased risk of hypertension. To make a notification to physicians.Material and methodsRetrospective study involving patients who were prescribed mirabegron from February–July 2015 in a health area of 450.000 inhabitants. The following data were obtained by querying the electronic prescription billing system (Microstrategy): sanitary identification number (NUHSA) of patients under mirabegron treatment, prescribers and their medical service. Furthermore, we obtained the NUHSA of patients under main therapeutic groups of antihypertensive drugs (AD) treatment: angiotensin converting enzyme inhibitors, angiotensin II-receptor antagonists and calcium antagonists. Patients under mirabegron treatment and any AD were both identified. These patients were defined as patients with increased risk of hypertension during treatment with mirabegron. We did a report that included: a summary of the DSW, an analysis of the prescribing physicians and patients with increased risk of adverse reaction (AR). This report was sent to all physicians.ResultsAfter analysing 6 months, 810 patients were treated with mirabegron. 41.5% of them (N=336) belonged to the Urology service, while the other prescriptions were evenly distributed among other services. The Urology service was considered urgent to send the report. From all the patients under mirabegron treatment, 45% (N=365) had been treated with any AD, implying a higher risk for the AR or possibility of having already had it. A report was sent by pharmacist to show data of patients under both drugs treatment and physicians prescribing mirabegron. It will help to revise the prescriptions when necessary. The report included information about other treatment options.ConclusionFive out of ten patients under mirabegron treatment can be considered as risk population for hypertension. The analysis allows prioritisation on the diffusion of information identifying patients at risk and main prescribers. Further studies would be necessary to confirm the impact of this intervention.References and/or AcknowledgementsCP-Betmiga-07-septiembre-2015.pdf. Consulted: 8/09/2015.No conflict of interest.
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