L14. Immunomodulatory properties of apoptotic cells.

International audienc

The macrophage in HIV-1 infection: From activation to deactivation?

Macrophages play a crucial role in innate and adaptative immunity in response to microorganisms and are an important cellular target during HIV-1 infection. Recently, the heterogeneity of the macrophage population has been highlighted. Classically activated or type 1 macrophages (M1) induced in particular by IFN-γ display a pro-inflammatory profile. The alternatively activated or type 2 macrophages (M2) induced by Th-2 cytokines, such as IL-4 and IL-13 express anti-inflammatory and tissue repair properties. Finally IL-10 has been described as the prototypic cytokine involved in the deactivation of macrophages (dM). Since the capacity of macrophages to support productive HIV-1 infection is known to be modulated by cytokines, this review shows how modulation of macrophage activation by cytokines impacts the capacity to support productive HIV-1 infection. Based on the activation status of macrophages we propose a model starting with M1 classically activated macrophages with accelerated formation of viral reservoirs in a context of Th1 and proinflammatory cytokines. Then IL-4/IL-13 alternatively activated M2 macrophages will enter into the game that will stop the expansion of the HIV-1 reservoir. Finally IL-10 deactivation of macrophages will lead to immune failure observed at the very late stages of the HIV-1 disease

Cation-Cation Complexes of Pentavalent Uranyl: From Disproportionation Intermediates to Stable Clusters

Three new cation-cation complexes of pentavalent uranyl, stable with respect to the disproportionation reaction, have been prepared from the reaction of the precursor [(UO 2py 5)(KI 2py 2)] n (1) with the Schiff base ligands salen 2-, acacen 2-, and salophen 2- (H 2salen=N,N′- ethylene-bis(salicylideneimine), H 2acacen=N,N′- ethylenebis(acetylacetoneimine), H 2salophen=N,N′-phenylene- bis(salicylideneimine)). The preparation of stable complexes requires a careful choice of counter ions and reaction conditions. Notably the reaction of 1 with salophen 2- in pyridine leads to immediate disproportionation, but in the presence of [18]crown-6 ([18]C-6) a stable complex forms. The solid-state structure of the four tetranuclear complexes, [UO 2(acacen)] 4[μ 8-] 2[K([18]C-6)(py)] 2 (3) and [UO 2(acacen)] 4[μ 8-]·2[K([222])(py) ] (4), [UO 2(salophen)] 4[μ 8-K] 2[μ 5-KI] 2[(K([18]C-6)]·2[K([18]C-6) (thf) 2]·2I (5), and [UO 2(salen) 4][μ 8-Rb] 2[Rb([18]C-6)] 2 (9) ([222]=[222]cryptand, py=pyridine), presenting a T-shaped cation-cation interaction has been determined by X-ray crystallographic studies. NMR spectroscopic and UV/Vis studies show that the tetranuclear structure is maintained in pyridine solution for the salen and acacen complexes. Stable mononuclear complexes of pentavalent uranyl are also obtained by reduction of the hexavalent uranyl Schiff base complexes with cobaltocene in pyridine in the absence of coordinating cations. The reactivity of the complex [U VO 2(salen)(py)][Cp 2Co] with different alkali ions demonstrates the crucial effect of coordinating cations on the stability of cation-cation complexes. The nature of the cation plays a key role in the preparation of stable cation-cation complexes. Stable tetranuclear complexes form in the presence of K + and Rb +, whereas Li + leads to disproportionation. A new uranyl-oxo cluster was isolated from this reaction. The reaction of [U VO 2(salen)(py)][Cp 2Co] (Cp=pentamethylcyclopentadienyl) with its U VI analogue yields the oxo-functionalized dimer [UO 2(salen)(py)] 2[Cp 2Co] (8). The reaction of the [UO 2(salen) 4][μ 8-K] 2[K([18]C-6)] 2 tetramer with protons leads to disproportionation to U IV and U VI species and H 2O confirming the crucial role of the proton in the U V disproportionation. Size matters: Large alkali ions promote the assembly of Schiff base complexes of pentavalent uranyl into three new stable polynuclear cation-cation clusters, while small cations assemble unstable intermediates, resulting in disproportionation (see figure). Protons also promote disproportionation. Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim

A novel <i>TBX19</i> gene mutation in patients with isolated ACTH deficiency from distinct families with a common geographical origin

International audienceIsolated ACTH deficiency (IAD) is a life-threatening condition, particularly in the neonatal period, while a main consequence of undiagnosed isolated ACTH deficiency in survivors is cognitive impairment. TBX19 is involved in the differentiation and proliferation of corticotropic cells and TBX19 mutations are responsible for more than 60% of neonatal cases of IAD. We describe a new variant of the main TBX19 transcript (NM 005149.3, c.840del (p.(Glu280Asp fs*27)), classified as pathogenic, whose pathogenicity is assumed to be due to nonsense mediated decay leading to non-expression of T-box transcription factor TBX19. Moreover we summarize the TBX19 mutations published as individual cases since our last large cohort. Interestingly, this pathogenic variant was identified in four patients from three apparently unrelated families. Two of these families were consanguineous, and after investigations all of three were discovered to have roots in the same mountainous region of northern Morocco, suggesting a founder effect. Early diagnosis, timely treatment (hydrocortisone therapy) and preventive education allowed normal development, growth and quality of life in all patients

Co-Targeting MAP Kinase and Pi3K-Akt-mTOR Pathways in Meningioma: Preclinical Study of Alpelisib and Trametinib

International audienceRecurrent or high-grade meningiomas are an unmet medical need. Recently, we demonstrated that targeting mTOR by everolimus was relevant both in vitro and in humans. However, everolimus induces an AKT activation that may impact the anti-proliferative effect of the drug. Moreover, the MAP kinase pathway was shown to be involved in meningioma tumorigenesis. We therefore targeted both the Pi3k-AKT-mTOR and MAP kinase pathways by using combinations of the Pi3k inhibitor alpelisib and the MEK inhibitor trametinib. Our study was performed in vitro on the human meningioma cell lines and on a large series of primary cultures providing from 63 freshly operated meningiomas including 35 WHO grade 1, 23 grade 2, and five grade 3, half of which presented a NF2 genomic alteration. Alpelisib induced a higher inhibitory effect on cell viability and proliferation than everolimus in all cell lines and 32 randomly selected tumors no matter the genomic status, the histological subtype or grade. Trametinib also strongly inhibited cell proliferation and induced AKT activation. Combined treatment with alpelisib plus trametinib reversed the AKT activation induced by trametinib and induced an additive inhibitory effect irrespective of the cell lines or tumor features. Co-targeting pathways seems promising and may be considered particularly for aggressive meningiom

IGSF1 mutations are the most frequent genetic aetiology of thyrotropin deficiency

International audienceDesign Thyroid-stimulating hormone deficiency (TSHD) is a rare disease. It may be isolated, secondary to abnormalities of genes involved in TSH biosynthesis, or associated with other pituitary deficits or abnormalities of genes involved in pituitary ontogenesis. Several genes are involved in thyrotroph development and function. Objective Our aim was to determine the genetic causes of TSHD, either isolated (ITSHD) or associated with somatotroph deficiency (TSHD-GHD), in the cohort of patients from the GENHYPOPIT network. Methods Next-generation sequencing (NGS) analyses were performed as a panel of genes on a cohort of patients with non-syndromic ITSHD or TSHGHD. The variants were classified according to the American College of Medical Genetics classification reviewed by the NGS-Diag network and correlated with the phenotype. Class 3, 4, and 5 single-nucleotide variants were checked by Sanger sequencing and copy number variants by multiplex ligation-dependent probe amplification (MLPA). Results A total of 64 index cases (22 ITSHD and 42 TSHD-GHD) were included in this cohort. A genetic cause was identified in 26.5% of patients, with 36.3% in the ITSHD group (variants in TSHβ and IGSF1) and 21.4% in TSHD-GHD (variants in IGSF1, TSHβ, TRHR, GH1, POU1F1, and PROP1). Among the pathogenic and likely pathogenic variants identified, 42% were in IGSF1, including six not previously reported. Conclusion Our results show that IGSF1 variants represent the most frequent aetiology of TSH deficiency. Despite a systematic NGS approach and the identification of new variants, most patients remain without a molecular diagnosis. Larger scale studies, such as exome or genome studies, should be considered in the future