The role of regulatory T cells and Interleukin-2 in the pathogenesis and treatment of systemic lupus erythematosus

Eine mangelhafte Produktion des Zytokins Interleukin-2 (IL-2), sowie Veränderungen in der Population der CD4+Foxp3+ regulatorischen T Zellen (Treg) wurden im Zusammenhang mit der Autoimmunkrankheit Systemischer Lupus erythematodes (SLE) beschrieben. Jedoch wurde ein möglicher kausaler Zusammenhang zwischen diesen beiden Auffälligkeiten und der Pathogenese des SLE bis jetzt nicht aufschlussreich untersucht. Durchflusszytometrische Analysen zeigten hier, dass der Anteil an Treg mit hoher Expression der IL-2 Rezeptoruntereinheit CD25, die mit funktioneller und metabolischer Treg Aktivität assoziiert wurde, in SLE Patienten erniedrigt ist. Außerdem ist das homöostatische Gleichgewicht zwischen Treg und konventionellen T Zellen gestört. In vitro Experimente zeigten, dass eine defekte IL-2 Produktion der CD4+ T Zellen für die niedrige CD25 Expression der Treg von SLE Patienten verantwortlich ist, wohingegen Stimulation mit IL-2 in vitro die CD25 Expression der Treg wiederherstellt und auch das Überleben der Treg erhöht. Vor allem niedrige IL-2 Konzentrationen hatten einen selektiven Effekt auf die Treg Population, während andere Lymphozyten nur wenig beeinflusst wurden. Basierend auf diesen Ergebnissen wurde eine klinische Studie mit niedrig dosiertem IL-2 zur Behandlung von Patienten mit refraktärem SLE implementiert. Niedrig dosiertes IL-2 führte zu einer peripheren Expansion suppressiver Treg mit stark erhöhter CD25 Expression und verbesserte das homöostatische Gleichgewicht zwischen Treg und konventionellen T Zellen. Diese Effekte wurden von einer klinischen Remission in drei der fünf mit IL-2 behandelten SLE Patienten begleitet. Zusammenfassend machen die Ergebnisse der vorliegenden Arbeit die Bedeutung des IL-2 Defizits für die Veränderungen in der Treg Population und die Pathogenese des SLE deutlich, und zeigen, dass niedrig dosiertes IL-2 einen sicheren und effizienten neuen Therapieansatz darstellt, der direkt in die Pathogenese des SLE eingreift.A defective production of the cytokine Interleukin-2 (IL-2), as well as abnormalities in the population of CD4+Foxp3+ regulatory T cells (Treg), have been described in association with the autoimmune disease systemic lupus erythematosus (SLE). However, a possible causal relationship between these two features and SLE pathogenesis has not been adequately investigated so far. Here, flow-cytometric analyses showed that the proportion of Treg expressing high levels of the IL-2 receptor subunit CD25, which was associated with functional and metabolic Treg activity, is reduced in SLE patients. In addition, the homeostatic balance between Treg and conventional T cells is disturbed in SLE. In vitro experiments showed that a defective IL-2 production by CD4+ T cells accounts for the low CD25 expression in Treg from SLE patients. In contrast, in vitro stimulation with IL-2 restores CD25 expression in Treg and enhances their survival. Especially low IL-2 concentrations had a selective effect on the Treg population, while other lymphocytes were only marginally affected. Based on these results, a clinical trial with low-dose IL-2 was implemented for the treatment of patients with refractory SLE. Low-dose IL-2 treatment of SLE patients caused a selective peripheral expansion of suppressive Treg with strongly increased CD25 expression levels, and improved the homeostatic balance between Treg and conventional T cells. These effects were accompanied by clinical remission in three of the five SLE patients that were treated with low-dose IL-2 during the course of this study. In summary, this work demonstrates the impact of IL-2 deficiency for the Treg abnormalities and disease pathogenesis in SLE, and it proposes low-dose IL-2 as a safe and efficient novel therapeutic approach, which directly targets SLE pathogenesis

Phonology and intonation

The encoding standards for phonology and intonation are designed to facilitate consistent annotation of the phonological and intonational aspects of information structure, in languages across a range ofprosodic types. The guidelines are designed with the aim that a nonspecialist in phonology can both implement and interpret the resulting annotation

IL-2 Therapy Diminishes Renal Inflammation and the Activity of Kidney-Infiltrating CD4+ T Cells in Murine Lupus Nephritis

An acquired deficiency of interleukin-2 (IL-2) and related disturbances in regulatory T cell (Treg) homeostasis play an important role in the pathogenesis of systemic lupus erythematosus (SLE). Low-dose IL-2 therapy was shown to restore Treg homeostasis in patients with active SLE and its clinical efficacy is currently evaluated in clinical trials. Lupus nephritis (LN), a challenging organ manifestation in SLE, is characterized by the infiltration of pathogenic CD4+ T cells into the inflamed kidney. However, the role of the Treg-IL-2 axis in the pathogenesis of LN and the mode of action of IL-2 therapy in the inflamed kidneys are still poorly understood. Using the (NZB × NZW) F1 mouse model of SLE we studied whether intrarenal Treg are affected by a shortage of IL-2 in comparison with lymphatic organs and whether and how intrarenal T cells and renal inflammation can be influenced by IL-2 therapy. We found that intrarenal Treg show phenotypic signs that are reminiscent of IL-2 deprivation in parallel to a progressive hyperactivity of intrarenal conventional CD4+ T cells (Tcon). Short-term IL-2 treatment of mice with active LN induced an expansion the intrarenal Treg population whereas long-term IL-2 treatment reduced the activity and proliferation of intrarenal Tcon, which was accompanied by a clinical and histological amelioration of LN. The association of these immune pathologies with IL-2 deficiency and their reversibility by IL-2 therapy provides important rationales for an IL-2-based immunotherapy of LN.DFG, SFB 650, Zelluläre Ansätze zur Suppression unerwünschter Immunreaktionen - From Bench to Bedsid

Resilience assessment: controversies about the use of scales

Resiliência é um construto que descreve a capacidade de um indivíduo superar, com relativo sucesso, condições adversas ou situações que envolvem risco ao seu bem-estar, desenvolvimento e saúde mental. Alguns pesquisadores da área interpretam essa definição como uma indicação de que a resiliência é similar a outras variáveis de ajustamento e presumem a sua estabilidade temporal. Isso leva sua avaliação a ser feita frequentemente através de escalas autoadministradas, por vezes questionáveis em termos de sua precisão e validade. Este artigo discute a abrangência e o histórico da resiliência psicológica e as várias formas de sua avaliação. Mais especificamente, o objetivo deste artigo é apresentar argumentos contra a pertinência da utilização de escalas de autorrelato para a mensuração da resiliência, considerando-se o caráter relacional, processual e contextual desse construto. Para tanto, instrumentos disponíveis na literatura para avaliação da resiliência são revisados e discutidos, apontando orientações para a pesquisa na área.Resilience is a construct which describes the capacity of individuals to overcome, with relative success, adverse conditions or risky situations to their well-being, development, and mental health. Some researchers interpret this definition as an indication that resilience is similar to some other adjustment variables and they assume that it presents temporal stability. Resilience is frequently assessed using self-report scales, which may also present validity and reliability problems. The present paper discusses the history and the comprehensiveness of psychological resilience and the different ways of evaluating it. More specifically, the objective of this study is to present arguments against the use of self-report scales to measure resilience, because of the relational, processual and contextual character of such construct. The main instruments available in the literature are reviewed and discussed and new directions for research in the area are suggested.MCT/CNPqMEC/CAPESABENEPI - Associação Brasileira de Neurologia e Psiquiatria InfantilIBICITPPG - Psicologia - UFRGSPró-Reitoria de Pesquisa da UFRGS/Programa de Apoio à Edição de Periódico

Uso de cromatografía en capa fina para caracterización de biodiesel

Biodiesel es un combustible biodegradable derivado de los aceites vegetales o grasas animales, obtenido industrialmente por la reacción de transesterificación o esterificación. Su producción viene aumentando porque su uso reduce las emisiones de gases nocivos para el medio ambiente. El objetivo de este trabajo fue producir biodiesel por esterificación de ácidos grasos dodecanóicos y caracterizarlo utilizando la técnica de cromatografía en capa fina. Los ensayos experimentales se realizaron en la temperatura de 65 °C por 2 horas y la separación de los componentes ocurrió por decantación. El factor de retención (Rf) obtenido fue 0.59 y 0.62 para el ácido graso y el biodiesel, respectivamente. Se concluyó que hubo la formación de biodiesel porque los valores experimentales son similares a de otros estudios. La técnica de cromatografía de capa fina ha demostrado ser satisfactoria para la caracterización cualitativa preliminar de biodiesel producido por esterificación.Biodiesel is a biodegradable fuel derived from vegetable oils or animal fats, industrially obtained by transesterification and esterification reaction. Its production has been increasing because its use reduces the emissions of harmful gases to environment. The objective of this work was to produce biodiesel from the esterification reaction of dodecanoic fatty acid and characterize it using the chromatography thin layer technique. Experimental tests were conducted at temperature of 65°C for 2 hours and the separation of components occurred by decantation. The retention factor (Rf) obtained was 0.59 and 0.62 for the fatty acid and biodiesel, respectively. It was concluded that there was formation of biodiesel because the results were similar to literature data. The thin layer chromatography technique has proved satisfactory for preliminary qualitative characterization of biodiesel produced by esterification.Fil: Cunha, Caroline Barlette da . Universidad Regional Integrada do Alto Uruguai e das Missões (Rio Grande do Sul, Brasil)Fil: Brondani, Michel. Universidade Federal do Rio Grande do Sul (Brasil)Fil: Stracke, Marcelo Paulo. Universidad Regional Integrada do Alto Uruguai e das Missões (Rio Grande do Sul, Brasil)Fil: Hoffmann, Ronaldo. Universidade Federal do Rio Grande do Sul (Brasil)Fil: Mayer, Flávio Dias. Universidade Federal do Rio Grande do Sul (Brasil

JNK1 Deficient Insulin-Producing Cells Are Protected against Interleukin-1 beta-Induced Apoptosis Associated with Abrogated Myc Expression

The relative contributions of the JNK subtypes in inflammatory β-cell failure and apoptosis are unclear. The JNK protein family consists of JNK1, JNK2, and JNK3 subtypes, encompassing many different isoforms. INS-1 cells express JNK1α1, JNK1α2, JNK1β1, JNK1β2, JNK2α1, JNK2α2, JNK3α1, and JNK3α2 mRNA isoform transcripts translating into 46 and 54 kDa isoform JNK proteins. Utilizing Lentiviral mediated expression of shRNAs against JNK1, JNK2, or JNK3 in insulin-producing INS-1 cells, we investigated the role of individual JNK subtypes in IL-1β-induced β-cell apoptosis. JNK1 knockdown prevented IL-1β-induced INS-1 cell apoptosis associated with decreased 46 kDa isoform JNK protein phosphorylation and attenuated Myc expression. Transient knockdown of Myc also prevented IL-1β-induced apoptosis as well as caspase 3 cleavage. JNK2 shRNA potentiated IL-1β-induced apoptosis and caspase 3 cleavage, whereas JNK3 shRNA did not affect IL-1β-induced β-cell death compared to nonsense shRNA expressing INS-1 cells. In conclusion, JNK1 mediates INS-1 cell death associated with increased Myc expression. These findings underline the importance of differentiated targeting of JNK subtypes in the development of inflammatory β-cell failure and destruction

Bridging the gap between low and high mass dwarf galaxies

While the dark matter content within the most massive giant and smallest dwarf galaxies has been probed -- spanning a range of over one million in mass -- an important observational gap remains for galaxies of intermediate mass. This gap covers K band magnitudes of approximately -16 > M_K > -18 (for which dwarf galaxies have B--K ~ 2). On the high mass side of the gap are dwarf elliptical (dE) galaxies, that are dominated by stars in their inner regions. While the low mass side includes dwarf spheroidal (dSph) galaxies that are dark matter-dominated and ultra compact dwarf (UCD) objects that are star-dominated. Evolutionary pathways across the gap have been suggested but remain largely untested because the `gap' galaxies are faint, making dynamical measurements very challenging. With long exposures on the Keck telescope using the ESI instrument we have succeeded in bridging this gap by measuring the dynamical mass for five dwarf galaxies with M_K ~ -17.5 (M_B ~ --15.5). With the exception of our brightest dwarf galaxy, they possess relatively flat velocity dispersion profiles of around 20 km/s. By examining their 2D scaling relations and 3D fundamental manifold, we found that the sizes and velocity dispersions of these gap galaxies reveal continuous trends from dE to dSph galaxies. We conclude that low-luminosity dwarf elliptical galaxies are dominated by stars, not by dark matter, within their half light radii. This finding can be understood if internal feedback processes are operating most efficiently in gap galaxies, gravitationally heating the centrally-located dark matter to larger radii. Whereas external environmental processes, which can strip away stars, have a greater influence on dSph galaxies resulting in their higher dark matter fractions. Abridged.Comment: 20 pages, includes 12 figures, accepted for publication in MNRA

Dynamic aggregation of the mid-sized gadolinium complex {Ph4[Gd(DTTA)(H2O)2]− 3}

A compound binding three Gd3+ ions, {Ph4[Gd(DTTA)(H2O)2]− 3} (where H5DTTA is diethylenetriaminetetraacetic acid), has been synthesized around a hydrophobic center made up of four phenyl rings. In aqueous solution the molecules start to self-aggregate at concentrations well below 1mM as shown by the increase of rotational correlation times and by the decrease of the translational self-diffusion constant. NMR spectra recorded in aqueous solution of the diamagnetic analogue {Ph4[Y(DTTA)(H2O)2]− 3} show that the aggregation is dynamic and due to intermolecular π-stacking interactions between the hydrophobic aromatic centers. From estimations of effective radii, it can be concluded that the aggregates are composed of two to three monomers. The paramagnetic {Ph4[Gd(DTTA)(H2O)2]− 3} exhibits concentration-dependent 1H NMR relaxivities with high values of approximately 50mM−1s−1 (30MHz, 25°C) at gadolinium concentrations above 20mM. A combined analysis of 1H NMR dispersion profiles measured at different concentrations of the compound and 17O NMR data measured at various temperatures was performed using different theoretical approaches. The fitted parameters showed that the increase in relaxivity with increasing concentration of the compound is due to slower global rotational motion and an increase of the Lipari-Szabo order parameter S 2