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Le Touquet – Paris-Plage, France

Mazerolles F.,French Institute of Health and Medical Research | Mazerolles F.,Paris-Sorbonne University | Picard C.,Paris-Sorbonne University | Picard C.,Laboratory of Human Genetics of Infectious Diseases | And 10 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: The generation of high-affinity antibodies requires the presence of a population of CD4+ T cells (follicular TH [TFH] cells) in the lymph node follicles. These cells differ from TH1, TH2, and TH17 effector cells in that they strongly express activation markers and the chemokine receptor CXCR5 and secrete large amounts of IL-21 and CXCL13. Small numbers of nonactivated CD4 +CD45RO+CXCR5+ T cells are also found in the blood. Objective: We sought to obtain in vitro a population close to the T FH cells and to study the presence of this cell population among patients with autosomal dominant hyper-IgE syndrome carrying heterozygous signal transducer and activator of transcription 3 (STAT3) mutations that impair the IL-21 signaling required for B-cell differentiation. Methods: CD4 +CD45RO+CXCR5+ T cells were isolated from blood and activated by CD3/T-cell receptor. Results: We found that CD4 +CD45RO+CXCR5+ activated T cells corresponding to circulating bona fide memory TFH cells and that STAT3-deficient patients have abnormally low numbers of "TFH-like" blood T cells. However, STAT3-deficient TFH cells have much the same phenotypic and functional characteristics as TFH cells from healthy control subjects. The ability of STAT3-deficient TFH cells to produce IL-21 on CD28/T-cell receptor activation and to proliferate did not differ from that observed for control TFH cells in vitro. Although the STAT3-deficient TFH cells were also able to help control B cells to produce IgG and IgA, induction of IgG production by naive B cells was impaired. Conclusion: Heterozygous mutations in STAT3 lead to reduced numbers of circulating TFH-like cells, a finding that might account (at least in part) for the observed defect in antibody production. © 2013 American Academy of Allergy, Asthma & Immunology. Source

Perez De Diego R.,University Institute of La Paz | Mulvey C.,University College London | Mulvey C.,University of Cambridge | Casanova J.-L.,Laboratory of Human Genetics of Infectious Diseases | And 5 more authors.
Expert Review of Proteomics | Year: 2014

The genetic theory of infectious diseases has proposed that susceptibility to life-threatening infectious diseases in childhood, occurring in the course of primary infection, results mostly from individually rare but collectively diverse single-gene variants. Recent evidence of an ever-expanding spectrum of genes involved in susceptibility to infectious disease indicates that the paradigm has important implications for diagnosis and treatment. One such pathology is childhood herpes simplex encephalitis, which shows a pattern of rare but diverse disease-disposing genetic variants. The present report shows how proteomics can help to understand susceptibility to childhood herpes simplex encephalitis and other viral infections, suggests that proteomics may have a particularly important role to play, emphasizes that variation over the population is a critical issue for proteomics and notes some new challenges for proteomics and related bioinformatics tools in the context of rare but diverse genetic defects. © 2014 Informa UK, Ltd. Source

Olbrich P.,Institute Biomedicina Of Seville | Martinez-Saavedra M.T.,University of Las Palmas de Gran Canaria | Perez-Hurtado J.M.,Pediatric Hematology Unit | Sanchez C.,Institute Biomedicina Of Seville | And 16 more authors.
Pediatric Blood and Cancer | Year: 2015

Autosomal recessive (AR) complete Interferon-γ Receptor1 (IFN-γR1) deficiency is a rare variant of Mendelian susceptibility to mycobacterial disease (MSMD). Although hematopoietic stem cell transplantation (HSCT) remains the only curative treatment, outcomes are heterogeneous; delayed engraftment and/or graft rejection being commonly observed. This case report and literature review expands the knowledge about this rare but potentially fatal pathology, providing details regarding diagnosis, antimicrobial treatment, transplant performance, and outcome that may help to guide physicians caring for patients with AR complete IFN-γR1 or IFN-γR2 deficiency. © 2015 Wiley Periodicals, Inc. Source

Perez De Diego R.,Laboratory of Human Genetics of Infectious Diseases | Perez De Diego R.,University of Paris Descartes | Perez De Diego R.,Rockefeller University | Perez De Diego R.,University Institute of La Paz | And 21 more authors.
Journal of Allergy and Clinical Immunology | Year: 2013

Background: Inborn errors in Toll-like receptor 3 (TLR3)-IFN type I and III pathways have been implicated in susceptibility to herpes simplex virus encephalitis (HSE) in children, but most patients studied do not carry mutations in any of the genes presently associated with HSE susceptibility. Moreover, many patients do not display any TLR3-IFN-related fibroblastic phenotype. Objective: To study other signaling pathways downstream of TLR3 and/or other independent pathways that may contribute to HSE susceptibility. Methods: We used the stable isotope labeling of amino acids in cell culture proteomics methodology to measure changes in the human immortalized fibroblast proteome after TLR3 activation. Results: Cells from healthy controls were compared with cells from a patient with a known genetic etiology of HSE (UNC-93B -/-) and also to cells from an HSE patient with an unknown gene defect. Consistent with known variation in susceptibility of individuals to viral infections, substantial variation in the response level of different healthy controls was observed, but common functional networks could be identified, including upregulation of superoxide dismutase 2. The 2 patients with HSE studied show clear differences in functional response networks when compared with healthy controls and also when compared with each other. Conclusions: The present study delineates a number of novel proteins, TLR3-related pathways, and cellular phenotypes that may help elucidate the genetic basis of childhood HSE. Furthermore, our results reveal superoxide dismutase 2 as a potential therapeutic target for amelioration of the neurologic sequelae caused by HSE. © 2013 American Academy of Allergy, Asthma & Immunology. Source

Jeremiah N.,French Institute of Health and Medical Research | Jeremiah N.,University of Paris Pantheon Sorbonne | Neven B.,French Institute of Health and Medical Research | Neven B.,University of Paris Pantheon Sorbonne | And 34 more authors.
Journal of Clinical Investigation | Year: 2014

Innate immunity to viral infection involves induction of the type I IFN response; however, dysfunctional regulation of this pathway leads to inappropriate inflammation. Here, we evaluated a nonconsanguineous family of mixed European descent, with 4 members affected by systemic inflammatory and autoimmune conditions, including lupus, with variable clinical expression. We identified a germline dominant gain-of-function mutation in TMEM173, which encodes stimulator of type I IFN gene (STING), in the affected individuals. STING is a key signaling molecule in cytosolic DNA-sensing pathways, and STING activation normally requires dimerization, which is induced by 2′3′ cyclic GMP-AMP (cGAMP) produced by the cGAMP synthase in response to cytosolic DNA. Structural modeling supported constitutive activation of the mutant STING protein based on stabilized dimerization. In agreement with the model predictions, we found that the STING mutant spontaneously localizes in the Golgi of patient fibroblasts and is constitutively active in the absence of exogenous 2′3′-cGAMP in vitro. Accordingly, we observed elevated serum IFN activity and a type I IFN signature in peripheral blood from affected family members. These findings highlight the key role of STING in activating both the innate and adaptive immune responses and implicate aberrant STING activation in features of human lupus. © 2014, American Society for Clinical Investigation. All rights reserved. Source

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