RASGRP1 is an important guanine nucleotide exchange factor and activator of the RAS-MAPK pathway following T cell antigen receptor (TCR) signaling. The consequences of RASGRP1 mutations in humans are ...unknown. In a patient with recurrent bacterial and viral infections, born to healthy consanguineous parents, we used homozygosity mapping and exome sequencing to identify a biallelic stop-gain variant in RASGRP1. This variant segregated perfectly with the disease and has not been reported in genetic databases. RASGRP1 deficiency was associated in T cells and B cells with decreased phosphorylation of the extracellular-signal-regulated serine kinase ERK, which was restored following expression of wild-type RASGRP1. RASGRP1 deficiency also resulted in defective proliferation, activation and motility of T cells and B cells. RASGRP1-deficient natural killer (NK) cells exhibited impaired cytotoxicity with defective granule convergence and actin accumulation. Interaction proteomics identified the dynein light chain DYNLL1 as interacting with RASGRP1, which links RASGRP1 to cytoskeletal dynamics. RASGRP1-deficient cells showed decreased activation of the GTPase RhoA. Treatment with lenalidomide increased RhoA activity and reversed the migration and activation defects of RASGRP1-deficient lymphocytes.
Immunoglobulin replacement therapy is a life-saving treatment in patients with immunodeficiency and effective in the management of autoimmune disorders. Immunoglobulins are administered intravenously ...or subcutaneously, with the latter route reducing systemic reactions and providing an option for self-infusion, increasing patient convenience, while decreasing patient burden, healthcare utilization, and costs. A major limitation with subcutaneous administrations is the frequency of infusion due to limited volumes administrable into subcutaneous space, necessitating increased drug concentration, absorption, and dispersion. Increasing the concentration of immunoglobulins from 10 to 20% halves the required volume, but leads to higher dynamic viscosity, limiting infusion rate. Recombinant human hyaluronidase increases dispersion and absorption of immunoglobulins allowing administration of ≤ 600 mL per site, but does not change viscosity. Since the viscosity of fluids depends on temperature, we tested the feasibility of in-line warming of immunoglobulin formulations to physiological temperatures. In vitro analysis showed no negative impact of in-line warming to 38 °C on product quality. Subcutaneous infusion studies in pigs confirmed the feasibility of infusion rates of up to 7.5 mL/min with in-line warmed TAK-881, an immunoglobulin 20% facilitated with recombinant human hyaluronidase. In-line pressures were reduced compared with conventional immunoglobulin 20%, and local tolerance was not altered. Reduction of in-line pressures was more pronounced with thinner needle sets, indicating a potential benefit for patients. In summary, an in in-line warming device can circumvent the limitation of high viscosity, while product quality and local tolerance are maintained. The results of the presented studies warrant further testing in a phase 1 clinical study.
Graphical Abstract
Chromatin modifications, such as reversible histone acetylation, play a key role in the regulation of T cell development and function. However, the role of individual histone deacetylases (HDACs) in ...T cells is less well understood. In this article, we show by conditional gene targeting that T cell-specific loss of HDAC1 led to an increased inflammatory response in an in vivo allergic airway inflammation model. Mice with HDAC1-deficient T cells displayed an increase in all critical parameters in this Th2-type asthma model, such as eosinophil recruitment into the lung, mucus hypersecretion, parenchymal lung inflammation, and enhanced airway resistance. This correlated with enhanced Th2 cytokine production in HDAC1-deficient T cells isolated from diseased mice. In vitro-polarized HDAC1-deficient Th2 cells showed a similar enhancement of IL-4 expression, which was evident already at day 3 of Th2 differentiation cultures and restricted to T cell subsets that underwent several rounds of cell divisions. HDAC1 was recruited to the Il4 gene locus in ex vivo isolated nonstimulated CD4(+) T cells, indicating a direct control of the Il4 gene locus. Our data provide genetic evidence that HDAC1 is an essential HDAC that controls the magnitude of an inflammatory response by modulating cytokine expression in effector T cells.
The transcription factor inhibitor of DNA binding (Id)2 modulates T cell fate decisions, but the molecular mechanism underpinning this regulation is unclear. In this study we show that loss of Id2 ...cripples effector differentiation and instead programs CD8(+) T cells to adopt a memory fate with increased Eomesodermin and Tcf7 expression. We demonstrate that Id2 restrains CD8(+) T cell memory differentiation by inhibiting E2A-mediated direct activation of Tcf7 and that Id2 expression level mirrors T cell memory recall capacity. As a result of the defective effector differentiation, Id2-deficient CD8(+) T cells fail to induce sufficient Tbx21 expression to generate short-lived effector CD8(+) T cells. Our findings reveal that the Id2/E2A axis orchestrates T cell differentiation through the induction or repression of downstream transcription factors essential for effector and memory T cell differentiation.
New Media, Old Issues Balabanić Dr Paško Bilić and Dr. Ivan
French journal for media research (Online),
12/2016
Journal Article
Recenzirano
Odprti dostop
Le document traite de la production des actualités en ligne. En appliquant une démarche critique il élucide les variables politiques, économiques et technologiques structurant la sphère publique et ...numérique. Théoriquement, ce texte a été inspiré par les idées relevant de l'économie politique de la communication. Plus particulièrement, il considère la production et la propriété des médias, le contrôle et les valeurs de production, étendant ainsi le débat PEC dans le domaine de production des actualités en ligne. http://dx.doi.org/10.1111/j.1751-9020.2007.00061.xThe paper addresses online news production. It takes a critical approach and untangles the political, economic and technological variables structuring the digital public sphere. Theoretically, it draws on the ideas developed within the field of political economy of communication (PEC). More specifically, it takes into account media production, media ownership, control and production values and extends the PEC debate into the area of online news production.
Abstract Cell fate specifications during T lymphocyte differentiation result from the orchestrated expression of developmentally regulated genes. Furthermore, epigenetic processes that result in a ...heritable chromatin structure are required for the maintenance of gene expression programs within cells. More and more is known about the basic mechanisms of T cell development and their diversification into various peripheral T cell subsets. Recent research has begun to provide insight into the interactive network of transcription factors as critical regulators of T lymphocyte differentiation. In the past years several members of the BTB domain-containing family of zinc finger proteins (BTB-ZF) have been described to be important for the development and function of hematopoietic cells, and also to contribute to malignant hematopoiesis. This review will provide a brief overview about the role of BTB-ZF proteins during thymocyte development and T cell function.
Heterozygous point mutations in the GT splice donor consensus sequence of exon 11 of the PIK3R1 gene (coding for p85α, p55α, and p50α regulatory subunits of PI3K) lead to exon skipping and thereby to ...an aberrant protein that leaves PI3K hyperactivated. Several patients with this particular variant of PI3 kinase delta syndrome (APDS) suffering from sinopulmonary infections and lymphoproliferation have been described.
(Whole exome) sequencing, evaluation of cellular and clinical phenotypes.
We here report a family with a new heterozygous mutation in this gene, a 9 bp deletion (c.1418_1425+1del) that, however, leads to the same skipping of exon 11. The clinical phenotypes of their members partly overlap features of patients of other reports.
We found a new mutation in PIK3R1 and show how broad the resulting clinical spectrum can be.
Reperfusion of ischaemic tissue provides oxygen and substrates that are necessary for tissue recovery and concurrently removes toxic metabolites. However, reperfusion may induce various detrimental ...processes that may cause further tissue damage. Such deterioration of tissue function after reperfusion is defined as ischaemia-reperfusion injury. The consequences of ischemia-reperfusion injury vary from reversible cell dysfunction to local and remote tissue destruction, multiple organ failure and death. The pathogenesis of ischaemia-reperfusion injury is complex and includes excessive production of reactive oxygen species, activation of neutrophils, activation of complement, involvement of cytokines and other inflammatory mediators, vasoactive substances NO and endothelin. This review discusses the pathophysiology of ischaemia-reperfusion injury, the mechanisms of reactive oxygen species production, and the role of other factors in the pathogenesis of such injury. Several approaches and procedures used in pre-clinical and clinical studies in order to limit ischaemia-reperfusion injury are also presented.
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