NaYF4 Microstructure, beyond Their Well-Shaped Morphology

International audienceLanthanide doped nanoparticles are widely investigated for their optical properties. However, the sensitivity of the lanthanide ions to the local symmetry, useful when investigating structural environments, becomes a drawback for optimized properties in the case of poorly controlled crystallinity. In this paper, we focus on β-NaYF4 nanorods in order to provide a detailed description of their chemical composition and microstructure. The combination of detailed XRD analysis and TEM observations show that strong variation may be observed from particles from a same batch of synthesis, but also when considering small variations of synthesis conditions. Moreover, also the nanorods observed by SEM exhibit a very nice faceted shape, they are far from being monocrystalline and present significant local deviation of crystalline symmetry and orientation. All these structural considerations, sensitively probed by polarized emission analysis, are crucial to be analyzed for the development of optimal systems toward the targeted applications

Rescue of Pap-Mas in Systemic JIA Using Janus Kinase Inhibitors, Case Report and Systematic Review

Introduction: Biological disease-modifying anti-rheumatic drugs (bDMARDs) targeting interleukin (IL)-6 and IL-1β represent a steroid-sparing first-line therapy used in systemic-onset juvenile idiopathic arthritis (sJIA). Recently, the occurrence of pulmonary alveolar proteinosis (PAP) in sJIA patients was reported with early-onset and exposure to bDMARDs as potential risk factors. We report on a new case with longitudinal immunomonitoring successfully treated by Janus Kinase inhibitors (JAKi) and review past clinical descriptions of this new entity. Methods: We report one case of pulmonary alveolar proteinosis and macrophage activation syndrome (PAP-MAS) with longitudinal immunomonitoring. We then conducted a review of the literature of seven publications reporting 107 cases of PAP-MAS sJIA, and included the main characteristics and evolution under treatment. Results: Of the seven articles analyzed, the incidence of PAP-MAS among sJIA patients varied from 1.28% to 12.9%. We report here a single case among a cohort of 537 sJIA patients followed in the pediatric department of the Hospices Civils de Lyon over the last 15 years. This child presented with all clinical and immunological characteristics of PAP-MAS. After several lines of treatment, he benefited from JAKi and improved with respect to both systemic symptoms and lung disease. In the literature, strategies with monoclonal antibodies targeting either INF-γ or IL-1β/IL-18 have been tested with variable results. Orally taken JAKi presents the advantage of targeting multiple cytokines and avoiding parenteral injections of monoclonal antibodies that may contribute to the pathogenesis. Conclusions: JAKi represent a promising option in the treatment of lung disease associated with sJIA

DNASE1L3 deficiency, new phenotypes, and evidence for a transient type I IFN signaling

peer reviewedBACKGROUND: Deoxyribonuclease 1 like 3 (DNASE1L3) is a secreted enzyme that has been shown to digest the extracellular chromatin derived from apoptotic bodies, and DNASE1L3 pathogenic variants have been associated with a lupus phenotype. It is unclear whether interferon signaling is sustained in DNASE1L3 deficiency in humans. OBJECTIVES: To explore interferon signaling in DNASE1L3 deficient patients. To depict the characteristic features of DNASE1L3 deficiencies in human. METHODS: We identified, characterized, and analyzed five new patients carrying biallelic DNASE1L3 variations. Whole or targeted exome and/or Sanger sequencing was performed to detect pathogenic variations in five juvenile systemic erythematosus lupus (jSLE) patients. We measured interferon-stimulated gene (ISG) expression in all patients. We performed a systematic review of all published cases available from its first description in 2011 to March 24(th) 2022. RESULTS: We identified five new patients carrying biallelic DNASE1L3 pathogenic variations, including three previously unreported mutations. Contrary to canonical type I interferonopathies, we noticed a transient increase of ISGs in blood, which returned to normal with disease remission. Disease in one patient was characterized by lupus nephritis and skin lesions, while four others exhibited hypocomplementemic urticarial vasculitis syndrome. The fourth patient presented also with early-onset inflammatory bowel disease. Reviewing previous reports, we identified 35 additional patients with DNASE1L3 deficiency which was associated with a significant risk of lupus nephritis and a poor outcome together with the presence of anti-neutrophil cytoplasmic antibodies (ANCA). Lung lesions were reported in 6/35 patients. CONCLUSIONS: DNASE1L3 deficiencies are associated with a broad phenotype including frequently lupus nephritis and hypocomplementemic urticarial vasculitis with positive ANCA and rarely, alveolar hemorrhages and inflammatory bowel disease. This report shows that interferon production is transient contrary to anomalies of intracellular DNA sensing and signaling observed in Aicardi-Goutières syndrome or STING-associated vasculitis in infancy (SAVI)

Early-onset autoimmunity associated with SOCS1 haploinsufficiency

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DOCK11 deficiency in patients with X-linked actinopathy and autoimmunity

International audienceDedicator of cytokinesis (DOCK) proteins play a central role in actin cytoskeleton regulation. This is highlighted by the DOCK2 and DOCK8 deficiencies leading to actinopathies and immune deficiencies. DOCK8 and DOCK11 activate CDC42, a RHO-GTPase involved in actin cytoskeleton dynamics, among many cellular functions. The role of DOCK11 in human immune disease has been long suspected but has never been described so far. We studied eight male patients, from seven unrelated families, with hemizygous DOCK11 missense variants leading to reduced DOCK11 expression. The patients were presenting with early-onset autoimmunity, including cytopenia, systemic lupus erythematosus, skin, and digestive manifestations. Patients’ platelets exhibited abnormal ultrastructural morphology and spreading as well as impaired CDC42 activity. In vitro activated T cells and B lymphoblastoid cell lines (B-LCL) of patients exhibited aberrant protrusions and abnormal migration speed in confined channels concomitant with altered actin polymerization during migration. A DOCK11 knock-down recapitulated these abnormal cellular phenotypes in monocytes-derived dendritic cells (MDDC) and primary activated T cells from healthy controls. Lastly, in line with the patients’ autoimmune manifestations, we also observed abnormal regulatory T cells (Tregs) phenotype with profoundly reduced FOXP3 and IKZF2 expression. Moreover, we found a reduced T cell proliferation and an impaired STAT5B phosphorylation upon IL2 stimulation of the patients’ lymphocytes. In conclusion, DOCK11 deficiency is a new X-linked immune-related actinopathy leading to impaired CDC42 activity and STAT5 activation, and associated with abnormal actin cytoskeleton remodeling as well as Tregs phenotype culminating in immune dysregulation and severe early-onset autoimmunity

Contribution of rare and predicted pathogenic gene variants to childhood-onset lupus: a large, genetic panel analysis of British and French cohorts

International audienceBackgroundSystemic lupus erythematosus (SLE) is a rare immunological disorder and genetic factors are considered important in its causation. Monogenic lupus has been associated with around 30 genotypes in humans and 60 in mice, while genome-wide association studies have identified more than 90 risk loci. We aimed to analyse the contribution of rare and predicted pathogenic gene variants in a population of unselected cases of childhood-onset SLE.MethodsFor this genetic panel analysis we designed a next-generation sequencing panel comprising 147 genes, including all known lupus-causing genes in humans, and potentially lupus-causing genes identified through GWAS and animal models. We screened 117 probands fulfilling American College of Rheumatology (ACR) criteria for SLE, ascertained through British and French cohorts of childhood-onset SLE, and compared these data with those of 791 ethnically matched controls from the 1000 Genomes Project and 574 controls from the FREX Consortium.FindingsAfter filtering, mendelian genotypes were confirmed in eight probands, involving variants in C1QA, C1QC, C2, DNASE1L3, and IKZF1. Seven additional patients carried heterozygous variants in complement or type I interferon-associated autosomal recessive genes, with decreased concentrations of the encoded proteins C3 and C9 recorded in two patients. Rare variants that were predicted to be damaging were significantly enriched in the childhood-onset SLE cohort compared with controls; 25% of SLE probands versus 5% of controls were identified to harbour at least one rare, predicted damaging variant (p=2·98 × 10 −11). Inborn errors of immunity were estimated to account for 7% of cases of childhood-onset SLE, with defects in innate immunity representing the main monogenic contribution.InterpretationAn accumulation of rare variants that are predicted to be damaging in SLE-associated genes might contribute to disease expression and clinical heterogeneity