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Papers by moufida ben nasr

Nature Communications

Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but... more Loss of pancreatic beta cells is a central feature of type 1 (T1D) and type 2 (T2D) diabetes, but a therapeutic strategy to preserve beta cell mass remains to be established. Here we show that the death receptor TMEM219 is expressed on pancreatic beta cells and that signaling through its ligand insulin-like growth factor binding protein 3 (IGFBP3) leads to beta cell loss and dysfunction. Increased peripheral IGFBP3 was observed in established and at-risk T1D/T2D patients and was confirmed in T1D/T2D preclinical models, suggesting that dysfunctional IGFBP3/TMEM219 signaling is associated with abnormalities in beta cells homeostasis. In vitro and in vivo short-term IGFBP3/TMEM219 inhibition and TMEM219 genetic ablation preserved beta cells and prevented/delayed diabetes onset, while long-term IGFBP3/TMEM219 blockade allowed for beta cell expansion. Interestingly, in several patients’ cohorts restoration of appropriate IGFBP3 levels was associated with improved beta cell function. The ...

Transplantation Proceedings, 2011

We explored the influence of polymorphisms in genes encoding the chemokine stromal cell-derived f... more We explored the influence of polymorphisms in genes encoding the chemokine stromal cell-derived factor-1 (SDF-1)/CXCL12 in a cohort of Tunisian patients with malignant hematologic diseases multiple myeloma [MM], non-Hodgkin's lymphoma [NHL], Hodgkin's disease, and acute myeloid leukemia [AML], who underwent stem cell mobilization for autologous transplantation versus a group of healthy donors for allogeneic transplantation. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLp) analysis was used for rapid identification of genotypes. Significant associations for SDF1-3=A polymorphism were observed exclusively in patients with MM and NHL. While there was a lack of all association of SDF-1 polymorphism with AML patients. However, considering that the ability of mobilization varies among subjects, we have observed that the SDF1-3=A allele was associated with good mobilization capacity. Interestingly, the association was mainly observed among healthy allogeneic transplant donors where the analysis was not biased by background disease or chemotherapy (P ϭ .010; odds ratio ϭ 2.603; confidence interval [95%] ϭ 1.239-5.466).

Transfusion Clinique et Biologique, 2008

Disponible sur Internet le 10 juillet 2008 Résumé L'apoptose, forme particulière de mort cellulai... more Disponible sur Internet le 10 juillet 2008 Résumé L'apoptose, forme particulière de mort cellulaire survenant chez la majorité des cellules devenues inutiles ou endommagées, joue un rôle crucial dans le développement des organismes pluricellulaires en assurant le maintien de l'homéostasie cellulaire. Elle intervient dans le processus de développement normal des organismes ainsi que dans la défense immunitaire et la détection des cellules cancéreuses. Un blocage du programme de la machinerie apoptotique pourrait être responsable de certaines maladies neurodégénératives et auto-immunes et jouer un rôle fondamental à différentes étapes de la carcinogenèse. Des études de l'apoptose des cellules souches hématopoïétiques CD34+ qui sont destinées à être greffées aux patients atteints d'hémopathies malignes ont montré que la connaissance de la cinétique de l'apoptose au niveau des cellules souches hématopoïétiques CD34+ après les processus de cryoconservation s'avère indispensable, car elle permet de quantifier le nombre exact de cellules souches hématopoïétiques CD34+ vivantes et donc d'éliminer tout risque associé à l'injection de cellules mortes aux malades. Dans ce travail, nous avons contribué à étudier l'apoptose par cytométrie en flux des cellules souches hématopoïétiques CD34+ avant et après la congélation, en utilisant l'annexine V comme sonde spécifique permettant la détection de la phosphatidylsérine, l'une des caractéristiques majeures de l'apoptose. En revanche, nous avons constaté une induction plus prononcée de l'apoptose au niveau du sang périphérique mobilisé qu'au niveau de la cytaphérèse (après décongélation : 29,79 % de cellules souches hématopoïétiques CD34+ apoptotiques à partir du sang périphérique contre 11,67 % de cellules souches hématopoïétiques CD34+ apoptotiques à partir de cytaphérèse). De plus, nous avons remarqué que les cellules souches hématopoïétiques CD34+ ont un statut de viabilité meilleur que celui des autres cellules mononucléées. Ces résultats mettent en valeur la fiabilité, la simplicité et l'efficacité de la cytométrie en flux quant à l'analyse de l'apoptose des cellules souches hématopoïétiques CD34+ en suivant l'intensité de fluorescence de l'annexine V.

Advances in Hematopoietic Stem Cell Research, 2012

American Journal of Transplantation

Despite much progress in improving graft outcome during cardiac transplantation, chronic allograf... more Despite much progress in improving graft outcome during cardiac transplantation, chronic allograft vasculopathy (CAV) remains an impediment to long‐term graft survival. MicroRNAs (miRNAs) emerged as regulators of the immune response. Here, we aimed to examine the miRNA network involved in CAV. miRNA profiling of heart samples obtained from a murine model of CAV and from cardiac‐transplanted patients with CAV demonstrated that miR‐21 was most significantly expressed and was primarily localized to macrophages. Interestingly, macrophage depletion with clodronate did not significantly prolong allograft survival in mice, while conditional deletion of miR‐21 in macrophages or the use of a specific miR‐21 antagomir resulted in indefinite cardiac allograft survival and abrogated CAV. The immunophenotype, secretome, ability to phagocytose, migration, and antigen presentation of macrophages were unaffected by miR‐21 targeting, while macrophage metabolism was reprogrammed, with a shift toward oxidative phosphorylation in naïve macrophages and with an inhibition of glycolysis in pro‐inflammatory macrophages. The aforementioned effects resulted in an increase in M2‐like macrophages, which could be reverted by the addition of L‐arginine. RNA‐seq analysis confirmed alterations in arginase‐associated pathways associated with miR‐21 antagonism. In conclusion, miR‐21 is overexpressed in murine and human CAV, and its targeting delays CAV onset by reprogramming macrophages metabolism.

Current Opinion in Pharmacology

The Journal of Immunology

Nature Metabolism

Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hy... more Patients with coronavirus disease 2019 (COVID-19) are reported to have a greater prevalence of hyperglycaemia. Cytokine release as a consequence of severe acute respiratory syndrome coronavirus 2 infection may precipitate the onset of metabolic alterations by affecting glucose homeostasis. Here we describe abnormalities in glycometabolic control, insulin resistance and beta cell function in patients with COVID-19 without any pre-existing history or diagnosis of diabetes, and document glycaemic abnormalities in recovered patients 2 months after onset of disease. In a cohort of 551 patients hospitalized for COVID-19 in Italy, we found that 46% of patients were hyperglycaemic, whereas 27% were normoglycaemic. Using clinical assays and continuous glucose monitoring in a subset of patients, we detected altered glycometabolic control, with insulin resistance and an abnormal cytokine profile, even in normoglycaemic patients. Glycaemic abnormalities can be detected for at least 2 months in patients who recovered from COVID-19. Our data demonstrate that COVID-19 is associated with aberrant glycometabolic control, which can persist even after recovery, suggesting that further investigation of metabolic abnormalities in the context of long COVID is warranted.

Blood

Background: Thalidomide which represents an effective treatment strategy for relapsed/refractory ... more Background: Thalidomide which represents an effective treatment strategy for relapsed/refractory multiple myeloma, actually represents a standard of care also for newly diagnosed multiple myeloma patients. Methods: In the present study, we adopted a gene expression profiling (GEP) strategy in an attempt to predict response (> 50% reduction in serum M protein) to primary therapy with thalidomide-dexamethasone for newly diagnosed multiple myeloma. Plasma cells (CD138+) were purified from bone marrow aspirates from 17 patients at diagnosis, before initiation of treatment with thalidomide-dexamethasone. GEP was performed using the Affymetrix U133 Plus_2 microarray platform. The Affymetrix output (CEL files) was imported into Genespring 7.3 (Agilent technologies) microarray analysis software, where data files were normalized across chips using GCRMA and to the 50th percentile, followed by per gene normalization to median. Criteria of response were those established by Bladè et al. Re...

Scientific Reports

The pancreatic lymph node is critical to the pathogenesis of autoimmune diabetes, as it constitut... more The pancreatic lymph node is critical to the pathogenesis of autoimmune diabetes, as it constitutes the initial site for the priming of autoreactive T cells. In this study, we compared the histopathology of the head pancreatic lymph node (HPLN) to the tail pancreatic lymph node (TPLN) in NOD mice. HPLNs and TPLNs were harvested from 4 week-, 8 week-, and 12 week-old NOD mice, and their microvasculature, extracellular matrix, and immune cell subsets were characterized. The percentages of B cells and antigen-presenting cells (APCs) were much higher in the HPLN, as compared to the TPLN. Notably, the HPLNs of 12 week-old mice were characterized by greater expansion of high endothelial venules (HEVs) and lymphatic vessels in comparison to the TPLNs. Finally, we observed a higher density of extracellular matrix (ECM) fibers surrounding the lymphatic vasculature in the HPLNs than in the TPLNs. These data for the first time demonstrate that the HPLN possesses a different immune microanatomy and organization from the TPLN. These novel observations unveil a major phenotypic difference between two types of LNs from the same organ and may highlight an independent fundamental role played by each PLN during the establishment of T1D.

The Journal of clinical investigation, 2018

Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while N... more Purinergic receptor-7 (P2X7R) signaling controls Th17 and Th1 generation/differentiation, while NOD-like receptor P3 (NLRP3) acts as a Th2 transcriptional factor. Here, we demonstrated the existence of a P2X7R/NLRP3 pathway in T cells that is dysregulated by a P2X7R intracellular region loss-of-function mutation, leading to NLRP3 displacement and to excessive Th17 generation due to abrogation of the NLRP3-mediated Th2 program. This ultimately resulted in poor outcomes in cardiac-transplanted patients carrying the mutant allele, who showed abnormal Th17 generation. Transient NLRP3 silencing in nonmutant T cells or overexpression in mutant T cells normalized the Th profile. Interestingly, IL-17 blockade reduced Th17 skewing of human T cells in vitro and abrogated the severe allograft vasculopathy and abnormal Th17 generation observed in preclinical models in which P2X7R was genetically deleted. This P2X7R intracellular region mutation thus impaired the modulatory effects of P2X7R on N...