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Witko-Sarsat V.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Witko-Sarsat V.,University of Paris Descartes | Pederzoli-Ribeil M.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Pederzoli-Ribeil M.,University of Paris Descartes | And 3 more authors.
Trends in Immunology | Year: 2011

Recently, unexpected biological features of polymorphonuclear neutrophils have been revealed. In addition to their pivotal role in the defence against pathogens, neutrophils display a high degree of plasticity and contribute to control of adaptive immune responses. An emerging aspect of neutrophils is their ability to modulate their survival in response to both intrinsic and extrinsic factors. This review focuses on recent advances that have uncovered proliferating cell nuclear antigen (PCNA) and other cell cycle regulatory proteins as novel players regulating neutrophil survival. A better understanding of the mechanisms involved in neutrophil fate might pave the way for the identification of new anti-inflammatory molecules. © 2011 Elsevier Ltd.

Bayry J.,Institute National Of La Sante Et Of La Recherche Medicale Unite 872 | Bayry J.,University Pierre and Marie Curie | Bayry J.,University of Paris Descartes | Fournier E.M.,Institute National Of La Sante Et Of La Recherche Medicale Unite 872 | And 32 more authors.
Journal of Autoimmunity | Year: 2011

Common variable immunodeficiency (CVID) is associated with low serum immunoglobulin concentrations and an increased susceptibility to infections and autoimmune diseases. The treatment of choice for CVID patients is replacement intravenous immunoglobulin (IVIg) therapy. IVIg has been beneficial in preventing or alleviating the severity of infections and autoimmune and inflammatory process in majority of CVID patients. Although the mechanisms of action of IVIg given as 'therapeutic high dose' in patients with autoimmune diseases are well studied, the underlying mechanisms of beneficial effects of IVIg in primary immunodeficiencies are not completely understood. Therefore we investigated the effect of 'replacement dose' of IVIg by probing its action on B cells from CVID patients. We demonstrate that IVIg at low doses induces proliferation and immunoglobulin synthesis from B cells of CVID patients. Interestingly, B cell stimulation by IVIg is not associated with induction of B cell effector cytokine IFN-γ and of transcription factor T-bet. Together, our results indicate that in some CVID patients, IVIg rectifies the defective signaling of B cells normally provided by T cells and delivers T-independent signaling for B cells to proliferate. IVIg 'replacement therapy' in primary immunodeficiencies is therefore not a merepassive transfer of antibodies to prevent exclusively the recurrent infections; rather it has an active role in regulating autoimmune and inflammatory responses through modulating B cell functions and thus imposing dynamic equilibrium of the immune system. © 2010 Elsevier Ltd.

Barreau O.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Barreau O.,University of Paris Descartes | Barreau O.,French National Center for Scientific Research | De Reynies A.,Programme Cartes dIdentite des Tumeurs | And 29 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2012

Purpose: Diagnosing malignancy of adrenocortical tumors (ACT) and predicting prognosis in carcinomas are often challenging. Transcriptome markers have recently emerged, providing promising clinical relevance and improved pathophysiological knowledge. Whether tumoral chromosomal alterations provide similar information is not known. The aim was to evaluate the diagnostic and prognostic value of chromosomal alterations in ACT and to identify genes associated with benign and malignant tumorigenesis. Experimental Design: Chromosomal alterations of 86 adenomas and 52 carcinomas were identified by comparative genomic hybridization arrays and/or quantitative PCR. Results: A larger proportion of the genome is altered in carcinomas compared with adenomas (44 vs. 10%, P = 2.10-10). In adenomas, the 9q34 region, which includes the steroidogenic factor 1 locus, is commonly gained and associated with an overexpression of steroidogenic factor 1 (SF-1). In carcinomas, recurrent gains include chromosomes 5, 7, 12, 16, 19, and 20 and recurrent losses chromosomes 13 and 22. Filtering the genes from these regions according to their expression profile identified genes potentially relevant to adrenocortical tumorigenesis. A diagnostic tool was built by combining DNA copy number estimates at six loci (5q, 7p, 11p, 13q, 16q, and 22q). This tool discriminates carcinomas from adenomas in an independent validation cohort (sensitivity 100%, specificity 83%). In carcinomas, the number of chromosomal alterations was not associated with survival (Cox P = 0.84). A prognostic tool based on tumor DNA was designed with a clustering strategy and validated in an independent cohort. Conclusions: Chromosomal alterations in ACT discriminate carcinomas from adenomas and contain prognostic information. Chromosomal alterations alter the expression of genes important for tumorigenesis. Copyright © 2012 by The Endocrine Society.

Barreau O.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Barreau O.,French National Center for Scientific Research | Barreau O.,University of Paris Descartes | Assie G.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | And 29 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2013

Purpose: DNA methylation is a mechanism for gene expression silencing in cancer. Limited information is available for adrenocortical tumors. Abnormal methylation at the IGF2/H19 locus is common in adrenocortical carcinomas. Our aim was to characterize the methylation in adrenocortical carcinomas at a whole-genome scale and to assess its clinical significance and its impact on gene expression. Experimental Design: Methylation patterns of CpG islands in promoter regions of 51 adrenocortical carcinomas and 84 adenomas were studied by the Infinium Human Methylation 27 Beadchip (Illumina, San Diego, CA). Methylation of 33 genes was studied by methylation-specific multiplex ligation-dependent probe amplification (MRC-Holland, Amsterdam, The Netherlands) in 15 carcinomas. Gene expression data were available for 87 tumors from a previous study (HG-U133Plus2.0 AffymetrixGeneChip; Affymetrix, Santa Clara, CA). Clinical information, including patient features and survival, were available for all tumors. Results: Methylation was higher in carcinomas than in adenomas (t test P = 3.1 × 10-9). Unsupervised clustering of DNA methylation profiles identified two groups of carcinomas, one with an elevated methylation level, evoking a CpG island methylator phenotype (CIMP). The subgroup of hypermethylated carcinomas was further divided in two subgroups, with different levels of methylation (CIMP-high and CIMP-low). This classification could be confirmed by methylation-specific multiplex ligation-dependent probe amplification. Hypermethylation was associated with a poor survival (Cox model P = 0.02). The transcriptome/methylation correlation showed 1741 genes (of 12,250) negatively correlated; among the top genes were H19 and other tumor suppressors (PLAGL-1, G0S2, and NDRG2). Conclusions: This genome-wide methylation analysis reveals the existence of hypermethylated adrenocortical carcinomas, with a poorer prognosis. Hypermethylation in these tumors is important for silencing specific tumor suppressor genes. Copyright © 2013 by The Endocrine Society.

Witko-Sarsat V.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Witko-Sarsat V.,University of Paris Descartes | Mocek J.,Institute National Of La Sante Et Of La Recherche Medicale Unite 1016 | Mocek J.,University of Paris Descartes | And 14 more authors.
Journal of Experimental Medicine | Year: 2010

Neutrophil apoptosis is a highly regulated process essential for inflammation resolution, the molecular mechanisms of which are only partially elucidated. In this study, we describe a survival pathway controlled by proliferating cell nuclear antigen (PCNA), a nuclear factor involved in DNA replication and repairing of proliferating cells. We show that mature neutrophils, despite their inability to proliferate, express high levels of PCNA exclusively in their cytosol and constitutively associated with procaspases, presumably to prevent their activation. Notably, cytosolic PCNA abundance decreased during apoptosis, and increased during in vitro and in vivo exposure to the survival factor granulocyte colony-stimulating factor (G-CSF). Peptides derived from the cyclin-dependent kinase inhibitor p21, which compete with procaspases to bind PCNA, triggered neutrophil apoptosis thus demonstrating that specific modification of PCNA protein interactions affects neutrophil survival. Furthermore, PCNA overexpression rendered neutrophil-differentiated PLB985 myeloid cells significantly more resistant to TNF-related apoptosis-inducing ligand- or gliotoxin-induced apoptosis. Conversely, a decrease in PCNA expression after PCNA small interfering RNA transfection sensitized these cells to apoptosis. Finally, a mutation in the PCNA interdomain-connecting loop, the binding site for many partners, significantly decreased the PCNA-mediated antiapoptotic effect. These results identify PCNA as a regulator of neutrophil lifespan, thereby highlighting a novel target to potentially modulate pathological inflammation. © 2010 Witko-Sarsat et al.

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