On How Fas Apoptosis-Independent Pathways Drive T Cell Hyperproliferation and Lymphadenopathy in lpr Mice

This Document is Protected by copyright and was first published by Frontiers. All rights reserved. it is reproduced with permission.Fas induces massive apoptosis in T cells after repeated in vitro T cell receptor (TCR) stimulation and is critical for lymphocyte homeostasis in Fas-deficient (lpr) mice. Although the in vitro Fas apoptotic mechanism has been defined, there is a large conceptual gap between this in vitro phenomenon and the pathway that leads to in vivo development of lymphadenopathy and autoimmunity. A striking abnormality in lpr mice is the excessive proliferation of CD4+ and CD8+ T cells, and more so of the double-negative TCR+CD4−CD8−B220+ T cells. The basis of lpr T cell hyperproliferation remains elusive, as it cannot be explained by Fas-deficient apoptosis. T cell-directed p21 overexpression reduces hyperactivation/hyperproliferation of all lpr T cell subtypes and lymphadenopathy in lpr mice. p21 controls expansion of repeatedly stimulated T cells without affecting apoptosis. These results confirm a direct link between hyperactivation/hyperproliferation, autoreactivity, and lymphadenopathy in lpr mice and, with earlier studies, suggest that Fas apoptosis-independent pathways control lpr T cell hyperproliferation. lpr T cell hyperproliferation could be an indirect result of the defective apoptosis of repeatedly stimulated lpr T cells. Nonetheless, in this perspective, we argue for an alternative setting, in which lack of Fas would directly cause lpr T cell hyperactivation/hyperproliferation in vivo. We propose that Fas/Fas ligand (FasL) acts as an activation inhibitor of recurrently stimulated T cells, and that its disruption causes overexpansion of T cells in lpr mice. Research to define the underlying mechanism of this Fas/FasL effect could resolve the phenotype of lpr mice and lead to therapeutics for related human syndromes.This work was supported by grants from the Ministry of Economy and Competitivity (MINECO/FEDER PI11/00950 and SAF2016-80803-R to DB, and SAF2013-42289-R and SAF2016-75456-R to CM-A), from the Fundación Alfonso Martin Escudero to CM-A, and from the Community of Madrid (MITIC S2011/BMD2502 to DB and CM-A).Peer reviewe

EAF carbothermic co-reduction of alumina and silica, for the direct production of Al-Si master alloy

Abstract A key alternative for primary aluminum production could be the carbothermic reduction of alumina. Developed concepts face problems with the high solubility of carbon in liquid aluminum, the presence of the oxycarbide slag and the high volatilization of aluminum at elevated processing temperatures. In order to overcome some of these obstacles, in the framework of the ENEXAL FP7 project, research into the co-reduction of alumina and silica was made, aiming at the direct production of Al-Si master alloys. The latter are key commercial products for all casting applications, accounting for approximately 30% of all aluminum demand. As predicted by the thermodynamic study and verified by lab scale EAF experiments, the presence of silicon in the system suppresses volatilization phenomena, limits the oxycarbide slag formation and reduces carbon solubility in the metal phase

Distinct p21 requirements for regulating normal and self-reactive T cells through IFN-γ production.

Self/non-self discrimination characterizes immunity and allows responses against pathogens but not self-antigens. Understanding the principles that govern this process is essential for designing autoimmunity treatments. p21 is thought to attenuate autoreactivity by limiting T cell expansion. Here, we provide direct evidence for a p21 role in controlling autoimmune T cell autoreactivity without affecting normal T cellresponses. We studied C57BL/6, C57BL/6/lpr and MRL/lpr mice overexpressing p21 in T cells, and showed reduced autoreactivity and lymphadenopathy in C57BL/6/lpr, and reduced mortality in MRL/lpr mice. p21 inhibited effector/memory CD4(+) CD8(+) and CD4(-)CD8(-) lpr T cell accumulation without altering defective lpr apoptosis. This was mediated by a previously non-described p21 function in limiting T cell overactivation and overproduction of IFN-γ, a key lupus cytokine. p21 did not affect normal T cell responses, revealing differential p21 requirements for autoreactive and normal T cell activity regulation. The underlying concept of these findings suggests potential treatments for lupus and autoimmune lymphoproliferative syndrome, without compromising normal immunity.This work was supported by grants from the Ministry of Economy and Competitivity (MINECO)/Instituto Carlos III (PI081835 PI11/00950) and the CAM (MITIC S2011/ BMD2502) to DB, and from the MINECO (SAF2010-21205 and PIB2010BZ-00564) and the CAM (MITIC S2011/BMD2502) to CMA.Peer reviewe

Functional Inactivation of CXC Chemokine Receptor 4–mediated Responses through SOCS3 Up-regulation

Hematopoietic cell growth, differentiation, and chemotactic responses require coordinated action between cytokines and chemokines. Cytokines promote receptor oligomerization, followed by Janus kinase (JAK) kinase activation, signal transducers and transactivators of transcription (STAT) nuclear translocation, and transcription of cytokine-responsive genes. These include genes that encode a family of negative regulators of cytokine signaling, the suppressors of cytokine signaling (SOCS) proteins. After binding their specific receptors, chemokines trigger receptor dimerization and activate the JAK/STAT pathway. We show that SOCS3 overexpression or up-regulation, stimulated by a cytokine such as growth hormone, impairs the response to CXCL12, measured by Ca2+ flux and chemotaxis in vitro and in vivo. This effect is mediated by SOCS3 binding to the CXC chemokine receptor 4 receptor, blocking JAK/STAT and Gαi pathways, without interfering with cell surface chemokine receptor expression. The data provide clear evidence for signaling cross-talk between cytokine and chemokine responses in building a functional immune system

Role of Innate and Adaptive Cytokines in the Survival of COVID-19 Patients

SARS-CoV-2 is a new coronavirus characterized by a high infection and transmission capacity. A significant number of patients develop inadequate immune responses that produce massive releases of cytokines that compromise their survival. Soluble factors are clinically and pathologically relevant in COVID-19 survival but remain only partially characterized. The objective of this work was to simultaneously study 62 circulating soluble factors, including innate and adaptive cytokines and their soluble receptors, chemokines and growth and wound-healing/repair factors, in severe COVID-19 patients who survived compared to those with fatal outcomes. Serum samples were obtained from 286 COVID-19 patients and 40 healthy controls. The 62 circulating soluble factors were quantified using a Luminex Milliplex assay. Results. The patients who survived had decreased levels of the following 30 soluble factors of the 62 studied compared to those with fatal outcomes, therefore, these decreases were observed for cytokines and receptors predominantly produced by the innate immune system—IL-1α, IL-1α, IL-18, IL-15, IL-12p40, IL-6, IL-27, IL-1Ra, IL-1RI, IL-1RII, TNFα, TGFα, IL-10, sRAGE, sTNF-RI and sTNF-RII—for the chemokines IL-8, IP-10, MCP-1, MCP-3, MIG and fractalkine; for the growth factors M-CSF and the soluble receptor sIL2Ra; for the cytokines involved in the adaptive immune system IFNγ, IL-17 and sIL-4R; and for the wound-repair factor FGF2. On the other hand, the patients who survived had elevated levels of the soluble factors TNFβ, sCD40L, MDC, RANTES, G-CSF, GM-CSF, EGF, PDGFAA and PDGFABBB compared to those who died. Conclusions. Increases in the circulating levels of the sCD40L cytokine; MDC and RANTES chemokines; the G-CSF and GM-CSF growth factors, EGF, PDGFAA and PDGFABBB; and tissue-repair factors are strongly associated with survival. By contrast, large increases in IL-15, IL-6, IL-18, IL-27 and IL-10; the sIL-1RI, sIL1RII and sTNF-RII receptors; the MCP3, IL-8, MIG and IP-10 chemokines; the M-CSF and sIL-2Ra growth factors; and the wound-healing factor FGF2 favor fatal outcomes of the diseaseThis research was coordinated by ProA Capital and Startlite Foundation, Programa de Actividades de I+D de la Comunidad de Madrid en Biomedicina (B2020/MITICAD-CM), Halekulani S.L., MJR; and Universidad de Alcala COVID-19 UAH 2019/00003/016/001/026 and COVID-19 2021-2020/00003/016/001/027Peer reviewe

Exploitation of Kaolin as an Alternative Source in Alumina Production

The extensive consumption of aluminum, combined with the shortage of the existing raw materials, and particularly bauxite, necessitates the exploitation of alternative raw materials for the production of alumina. The present paper focuses on the possible use of kaolin, as an abundant, cheap and high-aluminum content raw material, in alumina production, via the application of the Aranda-Mastin technology in the leaching step. From this point of view, leaching experiments were conducted on untreated kaolin and thermally treated, metakaolin, applying atmospheric pressure, temperature of 90 °C and with an aqueous solution of a low HCl concentration as the leaching agent. Leaching, in the aforementioned conditions, is an industrially applied process, characterized by highly efficient aluminum dissolution in the case of metakaolin with low silicon dissolution at a short retention time, but with respectively lower achieved results for untreated kaolin. In order to raise the aluminum dissolution rate from untreated material, temporal and subsequently chemical intensification was applied. The analysis indicated a higher aluminum dissolution rate, up to 70%, with the application of a high acid concentration of leaching agent, performed for a long retention time that could be further improved

Utilizing Recyclable Task-Specific Ionic Liquid for Selective Leaching and Refining of Scandium from Bauxite Residue

Ionic liquids (ILs) have attracted great interest in the field of extractive metallurgy mainly because they can be utilized in low temperature leaching processes where they exhibit selectivity and recyclability. A major drawback in mixed aqueous-IL systems, is IL dissolution in the aqueous phase, which leads to IL losses, increasing the overall processing cost. This study advances the method for recovering scandium (Sc) from bauxite residue (BR) using as leaching agent the IL betainium bistriflimide, [Hbet][Tf2N] mixed with water, which has been reported in previous publications. Ionic liquid leachate (IL-PLS) was prepared by leaching BR with a mixture of [Hbet][Tf2N]-H2O and subjected to different stripping experiments using hydrochloric acid. The advancement, presented in this work, is related with the optimization of the metal extraction (stripping) from the IL-PLS, where an aqueous solution with high Sc concentration and minimum metal impurities and minimum IL co-extraction is produced. It is further proven that the metal cation extraction is defined by the stoichiometry of the acidic solution and the dissolution (losses) of the IL in the aqueous phase can be minimized by adjusting the volume ratio and the acid concentration. A two-step stripping process described, achieves the selective increase of Sc concentration by 8 times in the aqueous solution, while maintaining cumulative IL losses to similar levels as the optimum 1 step non-Sc selective stripping process

Exploitation of Kaolin as an Alternative Source in Alumina Production

The extensive consumption of aluminum, combined with the shortage of the existing raw materials, and particularly bauxite, necessitates the exploitation of alternative raw materials for the production of alumina. The present paper focuses on the possible use of kaolin, as an abundant, cheap and high-aluminum content raw material, in alumina production, via the application of the Aranda-Mastin technology in the leaching step. From this point of view, leaching experiments were conducted on untreated kaolin and thermally treated, metakaolin, applying atmospheric pressure, temperature of 90 °C and with an aqueous solution of a low HCl concentration as the leaching agent. Leaching, in the aforementioned conditions, is an industrially applied process, characterized by highly efficient aluminum dissolution in the case of metakaolin with low silicon dissolution at a short retention time, but with respectively lower achieved results for untreated kaolin. In order to raise the aluminum dissolution rate from untreated material, temporal and subsequently chemical intensification was applied. The analysis indicated a higher aluminum dissolution rate, up to 70%, with the application of a high acid concentration of leaching agent, performed for a long retention time that could be further improved