Coronary-artery Calcium Scores Using Electron Beam CT in Patients with Chronic Renal Failure

We evaluated the risk of coronary-artery disease in patients with chronic renal failure (CRF) by measuring the coronary-artery calcium scores with electron beam CT (EBCT). A total of 81 CRF patients were divided into three groups; pre-dialysis (group I, n=35), hemodialysis (group II, n=31) and peritoneal dialysis (group III, n=15). The several serum biochemical markers and calcium score levels by EBCT were determined. The Ca×P products were significantly higher in groups II (p<0.05) and III (p<0.01) than in group I. The serum calcium levels were significantly higher in group III than in both group I (p<0.01) and II (p<0.05). The serum calcium level in 15 patients with a calcium score > 400 was significantly higher than the 66 patients with a score ≤400 (p<0.01). The calcium score was significantly higher in the 15 patients with cardiovascular complications than in the 66 patients without cardiovascular complications (628.9±904.8 vs. 150.4±350.9, p<0.01). EBCT seemed to be a good diagnostic tool for evaluating the risk of coronary-artery disease "non-invasively" in CRF patients who are at increased risk of cardiovascular morbidity and mortality

NFAT1 and NFκB regulates expression of the common γ-chain cytokine receptor in activated T cells

Abstract Introduction Cytokines of the common γ chain (γc) family are critical for the development, differentiation, and survival of T lineage cells. Cytokines play key roles in immunodeficiencies, autoimmune diseases, allergies, and cancer. Although γc is considered an assistant receptor to transmit cytokine signals and is an indispensable receptor in the immune system, its regulatory mechanism is not yet well understood. Objective This study focused on the molecular mechanisms that γc expression in T cells is regulated under T cell receptor (TCR) stimulation. Methods The γc expression in TCR-stimulated T cells was determined by flow cytometry, western blot and quantitative RT-PCR. The regulatory mechanism of γc expression in activated T cells was examined by promoter-luciferase assay and chromatin immunoprecipitation assays. NFAT1 and NFκB deficient cells generated using CRISPR-Cas9 and specific inhibitors were used to examine their role in regulation of γc expression. Specific binding motif was confirmed by γc promotor mutant cells generated using CRISPR-Cas9. IL-7TgγcTg mice were used to examine regulatory role of γc in cytokine signaling. Results We found that activated T cells significantly upregulated γc expression, wherein NFAT1 and NFκB were key in transcriptional upregulation via T cell receptor stimulation. Also, we identified the functional binding site of the γc promoter and the synergistic effect of NFAT1 and NFκB in the regulation of γc expression. Increased γc expression inhibited IL-7 signaling and rescued lymphoproliferative disorder in an IL-7Tg animal model, providing novel insights into T cell homeostasis. Conclusion Our results indicate functional cooperation between NFAT1 and NFκB in upregulating γc expression in activated T cells. As γc expression also regulates γc cytokine responsiveness, our study suggests that γc expression should be considered as one of the regulators in γc cytokine signaling and the development of T cell immunotherapies. Video Abstrac

Capicua deficiency induces autoimmunity and promotes follicular helper T cell differentiation via derepression of ETV5

High-affinity antibody production through the germinal centre (GC) response is a pivotal process in adaptive immunity. Abnormal development of follicular helper T (T(FH)) cells can induce the GC response to self-antigens, subsequently leading to autoimmunity. Here we show the transcriptional repressor Capicua/CIC maintains peripheral immune tolerance by suppressing aberrant activation of adaptive immunity. CIC deficiency induces excessive development of T(FH) cells and GC responses in a T-cell-intrinsic manner. ETV5 expression is derepressed in Cic null T(FH) cells and knockdown of Etv5 suppresses the enhanced T(FH) cell differentiation in Cic-deficient CD4+ T cells, suggesting that Etv5 is a critical CIC target gene in T(FH) cell differentiation. Furthermore, we identify Maf as a downstream target of the CIC-ETV5 axis in this process. These data demonstrate that CIC maintains T-cell homeostasis and negatively regulates T(FH) cell development and autoimmunity. © The Author(s) 20176

NFAT1 and JunB cooperatively regulate IL-31 gene expression in CD4+ T cells in health and disease

IL-31 is a key mediator of itching in atopic dermatitis (AD) and is preferentially produced by activated CD4+ T cells and Th2 cells. Although pathophysiological functions of IL-31 have been suggested in diverse immune disorders, the molecular events underlying IL-31 gene regulation are still unclear. In this study we identified the transcription start site and functional promoter involved in IL-31 gene regulation in mouse CD4+ T cells. TCR stimulation.dependent IL-31 expression was found to be closely linked with in vivo binding of NFAT1 and JunB to the IL-31 promoter. Although NFAT1 alone enhanced IL-31 promoter activity, it was further enhanced in the presence of JunB. Conversely, knockdown of either NFAT1 or JunB resulted in reduced IL-31 expression. NFAT1-deficient CD4+ T cells showed a significant defect in IL-31 expression compared with wild-type CD4+ T cells. In agreement with these findings, mice subjected to atopic conditions showed much higher levels of IL-31, which were closely correlated with a significant increase in the number of infiltrated NFAT1+CD4+ T cells into the AD ears. Amelioration of AD progression by cyclosporin A treatment was well correlated with downregulation of IL-31 expressions in CD4+ T cells and total ear residual cells. In summary, our results suggest a functional cooperation between NFAT1 and JunB in mediating IL-31 gene expression in CD4+ T cells and indicate that interference with this interaction or their activity has the potential of reducing IL-31.mediated AD symptoms.1891sciescopu