Anti-inflammatory plasma cytokines in children and adolescents with Down syndrome.

Cytokines participate in many physiological processes including the regulation of immune and inflammatory responses. Production of some important cytokines in children with Down syndrome (DS) is depressed or increased. In this study we analysed the selected anti- inflammatory cytokines: interleukin-4 (IL-4), interleukin-10 (IL-10), interleukin-13 (IL-13) in plasma of children and adolescents with DS. The study group consisted of 20 patients with Down syndrome and 33 healthy subjects at the age of 5-17 years. Levels of: IL-4, IL-10 and IL-13 in plasma samples were determined by specific enzyme- linked immunosorbent assay (ELISA) techniques according to manufacturer's instructions. IL-4 was detectable in 25% subjects with Down syndrome and in 28.6% healthy subjects. IL-13 was detectable in 15% patients with Down syndrome and in 15.2% healthy subjects, respectively. IL-10 was detectable in 1 of 20 patients with Down syndrome and in 2 of 33 healthy subjects only. No significant correlations between measurable cytokine levels and age and gender were found. No significant increased concentration of selected anti- inflammatory cytokines were detected

Reduced subcortical glutamate/glutamine in adults with autism spectrum disorders: a [1H]MRS study

Dysfunctional glutamatergic neurotransmission has been implicated in autism spectrum disorder (ASD). However, relatively few studies have directly measured brain glutamate in ASD adults, or related variation in glutamate to clinical phenotype. We therefore set out to investigate brain glutamate levels in adults with an ASD, comparing these to healthy controls and also comparing results between individuals at different points on the spectrum of symptom severity. We recruited 28 adults with ASD and 14 matched healthy controls. Of those with ASD, 15 fulfilled the 'narrowly' defined criteria for typical autism, whereas 13 met the 'broader phenotype'. We measured the concentration of the combined glutamate and glutamine signal (Glx), and other important metabolites, using proton magnetic resonance spectroscopy in two brain regions implicated in ASD--the basal ganglia (including the head of caudate and the anterior putamen) and the dorsolateral prefrontal cortex--as well as in a parietal cortex 'control' region. Individuals with ASD had a significant decrease (P<0.001) in concentration of Glx in the basal ganglia, and this was true in both the 'narrow' and 'broader' phenotype. Also, within the ASD sample, reduced basal ganglia Glx was significantly correlated with increased impairment in social communication (P=0.013). In addition, there was a significant reduction in the concentration of other metabolites such as choline, creatine (Cr) and N-acetylaspartate (NAA) in the basal ganglia. In the dorsolateral prefrontal cortex, Cr and NAA were reduced (P<0.05), although Glx was not. There were no detectable differences in Glx, or any other metabolite, in the parietal lobe control region. There were no significant between-group differences in age, gender, IQ, voxel composition or data quality. In conclusion, individuals across the spectrum of ASD have regionally specific abnormalities in subcortical glutamatergic neurotransmission that are associated with variation in social development

Dual Role of miR-21 in CD4+T-Cells:Activation-Induced miR-21 Supports Survival of Memory T-Cells and Regulates CCR7 Expression in Naive T-Cells

<p>Immune cell-type specific miRNA expression patterns have been described but the detailed role of single miRNAs in the function of T-cells remains largely unknown. We investigated the role of miR-21 in the function of primary human CD4+ T-cells. MiR-21 is substantially expressed in T-cells with a memory phenotype, and is robustly upregulated upon alpha CD3/CD28 activation of both naive and memory T-cells. By inhibiting the endogenous miR-21 function in activated naive and memory T-cells, we showed that miR-21 regulates fundamentally different aspects of T-cell biology, depending on the differentiation status of the T-cell. Stable inhibition of miR-21 function in activated memory T-cells led to growth disadvantage and apoptosis, indicating that the survival of memory T-cells depends on miR-21 function. In contrast, stable inhibition of miR-21 function in activated naive T-cells did not result in growth disadvantage, but led to a significant induction of CCR7 protein expression. Direct interaction between CCR7 and miR-21 was confirmed in a dual luciferase reporter assay. Our data provide evidence for a dual role of miR-21 in CD4+ T cells; Regulation of T-cell survival is confined to activated memory T-cells, while modulation of potential homing properties, through downregulation of CCR7 protein expression, is observed in activated naive T-cells.</p>

Epigenetics in the pathogenesis of RA

Epigenetic modifications can stably alter gene expression and have been shown to be important in the maintenance of cell type-specific functions as well as in cell differentiation, e.g., in T and B cell maturation. In RA, alterations in DNA methylation, histone modifications, and microRNA expression have been found in immune as well as in stromal cells. These changes in the epigenome in RA patients influence key inflammatory and matrix-degrading pathways and are suspected to play a major role in the pathogenesis of RA. In this manuscript, we explain the basic mechanisms of epigenetics, review studies that analyzed epigenetic changes in RA, and assess their potential as therapeutic targets

Mechanisms of naive CD4+ T cell maintenance in the elderly and its implications for Autoimmunity

CD4+ T cells are critical players in the immune system. CD4+ T cells coordinate both innate and adaptive immune responses. When naive CD4+ T cells become activated via their antigen-specific T cell receptor in the presence of costimulation, these cells differentiate into effector and memory T cells. Maintenance of a large and diverse naive CD4+ T cell repertoire over time is thus essential for developing immunity to a multitude of novel antigens. Despite a strong decline in thymic production of naive CD4+ T cells with aging, the circulating pool of naive CD4+ T cells is well-maintained in elderly humans. The preservation of naive CD4+ T cells in aged subjects contrasts sharply with that of naive CD8+ T cells, which decline markedly with age. In the current chapter, the mechanisms facilitating the remarkable maintenance of the naive CD4+ T cell pool with age are discussed. Important mechanisms include recognition of self-peptides by T cell receptors and stimulation by homeostatic cytokines, including interleukin-7 and interleukin-2. Furthermore, we address the implications of naive CD4+ T cell maintenance for the development of autoimmune diseases in the elderly. Lastly, two models for the development of aging-associated autoimmunity are proposed, and suggestions for further investigation are provided