CD4+CD25−mTGFβ+ T cells induced by nasal application of ovalbumin transfer tolerance in a therapeutic model of asthma

Background: Intranasal administration of high amount of allergen was shown to induce tolerance and to reverse the allergic phenotype. However, mechanisms of tolerance induction via the mucosal route are still unclear. Objectives: To characterize the therapeutic effects of intranasal application of ovalbumin (OVA) in a mouse model of bronchial inflammation as well as the cellular and molecular mechanisms leading to protection upon re-exposure to allergen. Methods: After induction of bronchial inflammation, mice were treated intranasally with OVA and re-exposed to OVA aerosols 10 days later. Bronchoalveolar lavage fluid (BALF), T cell proliferation and cytokine secretion were examined. The respective role of CD4+CD25+ and CD4+CD25− T cells in the induction of tolerance was analysed. Results: Intranasal treatment with OVA drastically reduced inflammatory cell recruitment into BALF and bronchial hyperresponsiveness upon re-exposure to allergen. Both OVA- specific-proliferation of T cells, Th1 and Th2 cytokine production from lung and bronchial lymph nodes were inhibited. Transfer of CD4+CD25− T cells, which strongly expressed membrane-bound transforming growth factor β (mTGFβ), from tolerized mice protected asthmatic recipient mice from subsequent aerosol challenges. The presence of CD4+CD25+(Foxp3+) T cells during the process of tolerization was indispensable to CD4+CD25− T cells to acquire regulatory properties. Whereas the presence of IL-10 appeared dispensable in this model, the suppression of CD4+CD25−mTGFβ+ T cells in transfer experiments significantly impaired the down-regulation of airways inflammation. Conclusion: Nasal application of OVA in established asthma led to the induction of CD4+CD25−mTGFβ+ T cells with regulatory properties, able to confer protection upon allergen re-exposur

Bonifacio – Caserne Montlaur

Les fouilles de la Caserne Montlaur font suite à une prescription de diagnostic du Service régional de l’archéologie, en raison des travaux de rénovation importants prévus sur le site. Les résultats positifs de ce diagnostic, réalisé par P. Ferreira (Ferreira et al. 2014), ont permis de mettre au jour quelques inhumations datées du xviiie s., des tranchées de plantations non datées précisément mais attribuées aux périodes médiévales à postmédiévales, ainsi que des niveaux du Néolithique récen..

Globotriaosylsphingosine Accumulation and Not Alpha-Galactosidase-A Deficiency Causes Endothelial Dysfunction in Fabry Disease

BACKGROUND: Fabry disease (FD) is caused by a deficiency of the lysosomal enzyme alpha-galactosidase A (GLA) resulting in the accumulation of globotriaosylsphingosine (Gb3) in a variety of tissues. While GLA deficiency was always considered as the fulcrum of the disease, recent attention shifted towards studying the mechanisms through which Gb3 accumulation in vascular cells leads to endothelial dysfunction and eventually multiorgan failure. In addition to the well-described macrovascular disease, FD is also characterized by abnormalities of microvascular function, which have been demonstrated by measurements of myocardial blood flow and coronary flow reserve. To date, the relative importance of Gb3 accumulation versus GLA deficiency in causing endothelial dysfunction is not fully understood; furthermore, its differential effects on cardiac micro- and macrovascular endothelial cells are not known. METHODS AND RESULTS: In order to assess the effects of Gb3 accumulation versus GLA deficiency, human macro- and microvascular cardiac endothelial cells (ECs) were incubated with Gb3 or silenced by siRNA to GLA. Gb3 loading caused deregulation of several key endothelial pathways such as eNOS, iNOS, COX-1 and COX-2, while GLA silencing showed no effects. Cardiac microvascular ECs showed a greater susceptibility to Gb3 loading as compared to macrovascular ECs. CONCLUSIONS: Deregulation of key endothelial pathways as observed in FD vasculopathy is likely caused by intracellular Gb3 accumulation rather than deficiency of GLA. Human microvascular ECs, as opposed to macrovascular ECs, seem to be affected earlier and more severely by Gb3 accumulation and this notion may prove fundamental for future progresses in early diagnosis and management of FD patients

Vitamin D (1,25(OH

Studies to identify novel immune-regulatory functions of active vitamin D (1,25(OH) D3) in human CD4 T cells revealed that 1,25(OH) D3 potently induced expression of the gene SERPINA1, encoding the anti-protease α-1-antitrypsin. We confirmed α-1-antitrypsin protein expression by 1,25(OH) D3-treated CD4 T cells, but not in CD8 T cells or monocytes. α-1-Antitrypsin promotes anti-inflammatory IL-10 synthesis in other immune cell populations. We therefore investigated its immune-regulatory effects in CD4 T cells. Plasma-derived α-1-antitrypsin drove IL-10 synthesis by CD4 T cells, which was not dependent on anti-protease activity, but appeared to require a serum-binding factor, since this could not be achieved with recombinant protein. α-1-Antitrypsin is reported to bind complement components, which regulate T cell function. A role for this interaction was therefore probed. Plasma-derived, but not recombinant α-1-antitrypsin contained C3a. Surface Plasmon Resonance and Microscale Thermophoresis demonstrated α-1-antitrypsin binding to C3a. Addition of C3a to CD4 T cells cultured with recombinant α-1-antitrypsin restored induction of IL-10, whereas neutralisation of C3a abrogated IL-10 induced by plasma-derived α-1-antitrypsin. To interrogate an endogenous role for the α-1-antitrypsin-C3a axis in 1,25(OH) D3-driven CD4 T cell IL-10 synthesis, we treated cells from healthy or α-1-antitrypsin-deficient individuals (which transcribe SERPINA1 but do not secrete protein) with 1,25(OH) D3. A significant correlation was identified between SERPINA1 and IL10 gene expression in healthy donor CD4 T cells, which was absent in cells from α-1-antitrypsin-deficient individuals. Therefore, α-1-antitrypsin is required for 1,25(OH) D3-induced IL-10 expression in CD4 T cells, interacting with C3a to drive IL-10 expression. [Abstract copyright: Copyright © 2019. Published by Elsevier Ltd.

Implementing Associations with Ada

Object-oriented programming is a mechanism used to construct modular systems made of reusable components. These systems would be of little use if the objects were all unrelated. This is the reason why the relationships between the objects are one of the major factors in the development of software. Unfortunately, of all the relationships between the objects, the associations are often left aside. Therefore, we investigated a way to implement associations, using a language that does not provide a built-in construct for that purpose. We first give a definition of the associations and then an implementation-oriented taxonomy of the different kinds of associations. Then, according to this taxonomy, we propose a way to implement the associations using Ada 83. We also show, for a particular case, how Ada 9X can be used. The solutions proposed allow to translate all the semantics attached to associations while preserving the integrity of the system to develop

Ex Vivo Monitoring of Antigen-Specific CD4+ T Cells after Recall Immunization with Tetanus Toxoid▿

To monitor antigen-specific CD4+ T cells during a recall immune response to tetanus toxoid (TT), a sequential analysis including ex vivo phenotyping and cytokine flow cytometry, followed by cloning and T-cell-receptor (TCR) spectratyping of cytokine-positive CD4+ T cells, was performed. Grossly, twice as many TT-specific CD4+ T-cell clones, ex vivo derived from the CCR7+/− CD69+ interleukin-2-positive (IL-2+) CD4+ subsets, belonged to the central memory (TCM; CD62L+ CD27+ CCR7+) compared to the effector memory population (TEM; CD62L− CD27− CCR7−). After the boost, a predominant expansion of the TCM population was observed with more limited variations of the TEM population. TCR beta-chain-variable region (BV) spectratyping and sequencing confirmed a large concordance between most frequently expressed BV TCR-CDR3 from ex vivo-sorted CCR7+/− CD69+ IL-2+ CD4+ subsets and BV usage of in vitro-derived TT-specific CD4+ T-cell clones, further demonstrating the highly polyclonal but stable character of the specific recall response to TT. Taken together, ex vivo flow cytometry analysis focused on the CCR7+/− CD69+ IL-2+ CD4+ subsets appears to target the bulk of antigen-specific T cells and to reach an analytical power sufficient to adequately delineate in field trials the profile of the antigen-specific response to vaccine

When nuclear medicine radiological protection meets biological COVID-19 protection

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Colour vision in AIDS patients without HIV retinopathy

Patients suffering from AIDS develop ocular complications, the most frequent being HIV retinopathy. It is however not clear, if functional visual impairments can be observed as early indicators of ocular complications, before clinical diagnosis of HIV retinopathy is made at fundus examination. To address this issue, we measured colour vision in a group of 49 AIDS subjects with normal clinical fundi using the 'two equation method'. This method, combining red-green Rayleigh and the blue-green Moreland metameric matches, enables more complete and quantitative assessments of colour vision than those based on pigmentary tests. Data were collected on our computer controlled colorimeter and compared to those of normal subjects. While most AIDS subjects without HIV retinopathy demonstrated normal colour vision, a significant portion of them had wider matches than normal subjects (11% for the Rayleigh equation and 16% for the Moreland equation). Furthermore, matching ranges of the Moreland equation were significantly correlated with CD4 lymphocyte counts. Patients with low CD4 values tended to produce larger matching ranges than the patients with high CD4 values. A within subject study on 17 patients confirmed this trend and showed that the patients who increased/decreased their CD4 blood counts generally improved/impaired their colour discrimination in the Moreland match. No such correlation was found between the matching ranges of the Rayleigh equation and the CD4 counts. These results show that colour discrimination is slightly reduced in some AIDS subjects, although there are no detectable ocular complications. They also suggest two different types of colour vision impairments in AIDS patients without retinopathy: one reversible process affecting colour discrimination in the blue-green range; and another irreversible process affecting colour discrimination in the red-green range

Does a low feeding level enhance estradiol synthesis in preovulatory follicles of Holstein x Normande dairy cows?

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