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Rak S.,Gothenburg University | Worm M.,Charité - Medical University of Berlin | Lescaille G.,University Hospital la Pitie Salpetriere | Lescaille G.,University Paris Diderot | And 7 more authors.
Allergy: European Journal of Allergy and Clinical Immunology | Year: 2015

Background A detailed characterization of human oral immune cells is needed to better understand local mechanisms associated with allergen capture following oral exposure. Methods Oral immune cells were characterized by immunohistology and immunofluorescence in biopsies obtained from three healthy individuals and 23 birch pollen-allergic patients with/without oral allergy syndrome (OAS), at baseline and after 5 months of sublingual allergen immunotherapy (AIT). Results Similar cell subsets (i.e., dendritic cells, mast cells, and T lymphocytes) were detected in oral tissues from healthy and birch pollen-allergic individuals. CD207+ Langerhans cells (LCs) and CD11c+ myeloid dendritic cells (DCs) were found in both the epithelium and the papillary layer of the Lamina propria (LP), whereas CD68+ macrophages, CD117+ mast cells, and CD4+/CD8+ T cells were rather located in both the papillary and reticular layers of the LP. Patterns of oral immune cells were identical in patients with/without OAS, except lower numbers of CD207+ LCs found in oral tissues from patients with OAS, when compared to OAS- patients (P < 0.05). A 5-month sublingual AIT had a limited impact on oral immune cells, with only a significant increase in IgE+ cells in patients from the active group. Colocalization experiments confirmed that such IgE-expressing cells mostly encompass CD68+ macrophages located in the LP, and to a lesser extent CD207+ LCs in the epithelium. Conclusion Two cell subsets contribute to antigen/allergen uptake in human oral tissues, including (i) CD207+ LCs possibly involved in the physiopathology of OAS and (ii) CD68+ macrophages likely critical in allergen capture via IgE-facilitated mechanisms during sublingual AIT. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.


Guy J.,University Hospital of Dijon | Antony-Debre I.,University Hospital Henri Mondor | Benayoun E.,University Hospital Henri Mondor | Arnoux I.,University Hospital La Timone | And 8 more authors.
British Journal of Haematology | Year: 2013

The World Health Organization 2008 Classification emphasizes myeloperoxidase (MPO) detection as sufficient for assigning a blast population to the myeloid lineage. Published MPO positivity thresholds are 10% for flow cytometry (FCM) but 3% for cytochemistry. Here we re-evaluated the FCM-MPO threshold by comparing retrospectively 128 acute lymphoblastic leukaemias and 75 acute myeloid leukaemias without maturation, all assessed by benzidine-based cytochemistry. A 13% threshold was found to be relevant using an isotype control as background-reference (sensitivity 95·1%, specificity 91·7%). Residual normal lymphocytes proved to be an advantageous alternative reference, a threshold of 28% yielding improved 97·4% sensitivity and 96·1% specificity. © 2013 John Wiley & Sons Ltd.


PubMed | University of Minnesota, University Utrecht, Radboud University Nijmegen, Texas Tech University Health Sciences Center and 13 more.
Type: | Journal: Journal of medical genetics | Year: 2017

Cohesinopathies are rare neurodevelopmental disorders arising from a dysfunction in the cohesin pathway, which enables chromosome segregation and regulates gene transcription. So far, eight genes from this pathway have been reported in human disease. STAG1 belongs to the STAG subunit of the core cohesin complex, along with five other subunits. This work aimed to identify the phenotype ascribed to STAG1 mutations.Among patients referred for intellectual disability (ID) in genetics departments worldwide, array-comparative genomic hybridisation (CGH), gene panel, whole-exome sequencing or whole-genome sequencing were performed following the local diagnostic standards.A mutation in STAG1 was identified in 17 individuals from 16 families, 9 males and 8 females aged 2-33years. Four individuals harboured a small microdeletion encompassing STAG1; three individuals from two families had an intragenic STAG1 deletion. Six deletions were identified by array-CGH, one by whole-exome sequencing. Whole-exome sequencing found de novo heterozygous missense or frameshift STAG1 variants in eight patients, a panel of genes involved in ID identified a missense and a frameshift variant in two individuals. The 17 patients shared common facial features, with wide mouth and deep-set eyes. Four individuals had mild microcephaly, seven had epilepsy.We report an international series of 17 individuals from 16 families presenting with syndromic unspecific ID that could be attributed to a STAG1 deletion or point mutation. This first series reporting the phenotype ascribed to mutation in STAG1 highlights the importance of data sharing in the field of rare disorders.


Cherai M.,University Hospital La Pitie Salpetriere | Hamel Y.,Paris-Sorbonne University | Baillou C.,Paris-Sorbonne University | Baillou C.,French Institute of Health and Medical Research | And 15 more authors.
Cell Transplantation | Year: 2015

Natural regulatory T cells (Tregs) may have a great therapeutic potential to induce tolerance in allogeneic cells and organ transplantations. In mice, we showed that alloantigen-specific Tregs (spe-Tregs) were more efficient than polyclonal Tregs (poly-Tregs) in controlling graft-versus-host disease (GVHD). Here we describe a clinical-grade compliant method for generating human spe-Tregs. Tregs were enriched from leukapheresis products with anti-CD25 immunomagnetic beads, primed twice by allogeneic mature monocyte-derived dendritic cells (mDCs), and cultured during 3 weeks in medium containing interleukin 2 (IL-2), IL-15, and rapamycin. After 3 weeks of culture, final cell products were expanded 8.3-fold from the initial CD25+ purifications. Immunophenotypic analyses of final cells indicate that they were composed of 88 ± 2.6% of CD4+ T cells, all expressing Treg-specific markers (FOXP3, Helios, GARP, LAP, and CD152). Spe-Tregs were highly suppressive in vitro and also in vivo using a xeno-GVHD model established in immunodeficient mice. The specificity of their suppressive activity was demonstrated on their ability to significantly suppress the proliferation of autologous effector T cells stimulated by the same mDCs compared to third-party mDCs. Our data provide evidence that functional alloantigen Tregs can be generated under clinical-grade compliant conditions. Taking into account that 130 × 106 CD25+ cells can be obtained at large scale from standard leukapheresis, our cell process may give rise to a theoretical final number of 1 × 109 spe-Tregs. Thus, using our strategy, we can propose to prepare spe-Tregs for clinical trials designed to control HLA-mismatched GVHD or organ transplantation rejection. © 2015 Cognizant Comm. Corp.


Grimaldi-Bensouda L.,Paris West University Nanterre La Défense | Grimaldi-Bensouda L.,French National Conservatory of Arts and Crafts | Michel M.,University Paris Est Creteil | Aubrun E.,Paris West University Nanterre La Défense | And 23 more authors.
Blood | Year: 2012

The cause of immune thrombocytopenia (ITP) remains unknown. Studies have suggested immunizations as possible triggering factors of ITP through molecular mimicry. This case-control study explored potential associations between adult ITP and various routinely administered vaccines. A network of internal medicine and hematology centers across France recruited 198 incident (ie, newly diagnosed) cases of ITP between April 2008 and June 2011. These cases were compared with 878 age- and sex-matched controls without ITP recruited in general practice. Information on vaccination was obtained from patients' standardized telephone interviews. Sixty-six of 198 cases (33.3%) and 303 of 878 controls (34.5%) received at least 1 vaccine within the 12 months before the index date. We found no evidence of an increase in ITP after vaccination in the previous 6 or 12 months (adjusted odds ratio [OR] for the previous 12 months = 1.0; 95% confidence interval, 0.7-1.4). When the 2-month time window was used, higher ORs were observed for all vaccines (OR = 1.3). This increase was mainly attributable to the vaccination against diphtheria-tetanus-pertussis- poliomyelitis (OR = 1.5) and was not statistically significant. The results of the present study show that in an adult population, the exposure to common vaccines is on average not associated with an observable risk of developing ITP. © 2012 by The American Society of Hematology.


PubMed | University Hospital La Pitie Salpetriere
Type: Journal Article | Journal: Cell transplantation | Year: 2016

Natural regulatory T cells (Tregs) may have a great therapeutic potential to induce tolerance in allogeneic cells and organ transplantations. In mice, we showed that alloantigen-specific Tregs (spe-Tregs) were more efficient than polyclonal Tregs (poly-Tregs) in controlling graft-versus-host disease (GVHD). Here we describe a clinical-grade compliant method for generating human spe-Tregs. Tregs were enriched from leukapheresis products with anti-CD25 immunomagnetic beads, primed twice by allogeneic mature monocyte-derived dendritic cells (mDCs), and cultured during 3 weeks in medium containing interleukin 2 (IL-2), IL-15, and rapamycin. After 3 weeks of culture, final cell products were expanded 8.3-fold from the initial CD25(+) purifications. Immunophenotypic analyses of final cells indicate that they were composed of 88 2.6% of CD4(+) T cells, all expressing Treg-specific markers (FOXP3, Helios, GARP, LAP, and CD152). Spe-Tregs were highly suppressive in vitro and also in vivo using a xeno-GVHD model established in immunodeficient mice. The specificity of their suppressive activity was demonstrated on their ability to significantly suppress the proliferation of autologous effector T cells stimulated by the same mDCs compared to third-party mDCs. Our data provide evidence that functional alloantigen Tregs can be generated under clinical-grade compliant conditions. Taking into account that 130 10(6) CD25(+) cells can be obtained at large scale from standard leukapheresis, our cell process may give rise to a theoretical final number of 1 10(9) spe-Tregs. Thus, using our strategy, we can propose to prepare spe-Tregs for clinical trials designed to control HLA-mismatched GVHD or organ transplantation rejection.


Philippart F.,University of Paris Descartes | Vesin A.,Outcomerea | Levy-Soussan M.,University Hospital la Pitie Salpetriere | Timsit J.F.,Outcomerea | And 5 more authors.
Intensive Care Medicine | Year: 2013

Purpose: To assess preferences among individuals aged ≥80 years for a future hypothetical critical illness requiring life-sustaining treatments. Methods: Observational cohort study of consecutive community-dwelling elderly individuals previously hospitalised in medical or surgical wards and of volunteers residing in nursing homes or assisted-living facilities. The participants were interviewed at their place of residence after viewing films of scenarios involving the use of non-invasive mechanical ventilation (NIV), invasive mechanical ventilation (IMV), and renal replacement therapy after a period of invasive mechanical ventilation (RRT after IMV). Demographic, clinical, and quality-of-life data were collected. Participants chose among four responses regarding life-sustaining treatments: consent, refusal, no opinion, and letting the physicians decide. Results: The sample size was 115 and the response rate 87 %. Mean participant age was 84.8 ± 3.5 years, 68 % were female, and 81 % and 71 % were independent for instrumental activities and activities of daily living, respectively. Refusal rates among the elderly were 27 % for NIV, 43 % for IMV, and 63 % for RRT (after IMV). Demographic characteristics associated with refusal were married status for NIV [relative risk (RR), 2.9; 95 % confidence interval (95 %CI), 1.5-5.8; p = 0.002] and female gender for IMV (RR, 2.4; 95 %CI, 1.2-4.5; p = 0.01) and RRT (after IMV) (RR, 2.7; 95 %CI, 1.4-5.2; p = 0.004). Quality of life was associated with choices regarding all three life-sustaining treatments. Conclusions: Independent elderly individuals were rather reluctant to accept life-sustaining treatments, especially IMV and RRT (after IMV). Their quality of life was among the determinants of their choices. © 2013 Springer-Verlag Berlin Heidelberg and ESICM.

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