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1.
Human TLR-7-, -8-, and -9-mediated induction of IFN-alpha/beta and -lambda Is IRAK-4 dependent and redundant for protective immunity to viruses 总被引:12,自引:0,他引:12
Yang K Puel A Zhang S Eidenschenk C Ku CL Casrouge A Picard C von Bernuth H Senechal B Plancoulaine S Al-Hajjar S Al-Ghonaium A Maródi L Davidson D Speert D Roifman C Garty BZ Ozinsky A Barrat FJ Coffman RL Miller RL Li X Lebon P Rodriguez-Gallego C Chapel H Geissmann F Jouanguy E Casanova JL 《Immunity》2005,23(5):465-478
Five TLRs are thought to play an important role in antiviral immunity, sensing viral products and inducing IFN-alpha/beta and -lambda. Surprisingly, patients with a defect of IRAK-4, a critical kinase downstream from TLRs, are resistant to common viruses. We show here that IFN-alpha/beta and -lambda induction via TLR-7, TLR-8, and TLR-9 was abolished in IRAK-4-deficient blood cells. In contrast, IFN-alpha/beta and -lambda were induced normally by TLR-3 and TLR-4 agonists. Moreover, IFN-beta and -lambda were normally induced by TLR-3 agonists and viruses in IRAK-4-deficient fibroblasts. We further show that IFN-alpha/beta and -lambda production in response to 9 of 11 viruses tested was normal or weakly affected in IRAK-4-deficient blood cells. Thus, IRAK-4-deficient patients may control viral infections by TLR-3- and TLR-4-dependent and/or TLR-independent production of IFNs. The TLR-7-, TLR-8-, and TLR-9-dependent induction of IFN-alpha/beta and -lambda is strictly IRAK-4 dependent and paradoxically redundant for protective immunity to most viruses in humans. 相似文献
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Enrique Soto-Perez-De-Celis Kah Poh Loh Capucine Baldini Nicolò Matteo Luca Battisti Yanin Chavarri-Guerra Nienke A. De Glas 《Expert opinion on investigational drugs》2013,22(10):787-801
ABSTRACTIntroduction: One-third of breast cancer (BC) cases worldwide occur in women aged 65 years and older, with 10 to 15% overexpressing the human epidermal growth factor receptor 2 (HER2). Although several HER2-targeted therapies have been developed, the lack of data regarding their use in older patients hampers evidence-based decision-making for this population.Areas Covered: We review current evidence on the efficacy and safety of HER2-targeted therapies in older adults with BC, focusing on approved therapies such as trastuzumab, lapatinib, pertuzumab, ado-trastuzumab-emtansine, and neratinib. Additionally, we discuss drugs under development to target the HER2-receptor, and to overcome resistance to existing therapies. Finally, we highlight the cardiotoxicity of HER2-targeted drugs among older adults.Expert Opinion: Older adults are underrepresented in trials of HER2-targeted therapies in BC. We propose strategies to increase recruitment of older adults in clinical trials in order to increase the evidence base to treat this growing population. 相似文献
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Joshua C. Black Elnaz Atabakhsh Jaegil Kim Kelly M. Biette Capucine Van Rechem Brendon Ladd Paul d. Burrowes Carlos Donado Hamid Mattoo Benjamin P. Kleinstiver Bing Song Grasiella Andriani J. Keith Joung Othon Iliopoulos Cristina Montagna Shiv Pillai Gad Getz Johnathan R. Whetstine 《Genes & development》2015,29(10):1018-1031
Copy number heterogeneity is a prominent feature within tumors. The molecular basis for this heterogeneity remains poorly characterized. Here, we demonstrate that hypoxia induces transient site-specific copy gains (TSSGs) in primary, nontransformed, and transformed human cells. Hypoxia-driven copy gains are not dependent on HIF1α or HIF2α; however, they are dependent on the KDM4A histone demethylase and are blocked by inhibition of KDM4A with a small molecule or the natural metabolite succinate. Furthermore, this response is conserved at a syntenic region in zebrafish cells. Regions with site-specific copy gain are also enriched for amplifications in hypoxic primary tumors. These tumors exhibited amplification and overexpression of the drug resistance gene CKS1B, which we recapitulated in hypoxic breast cancer cells. Our results demonstrate that hypoxia provides a biological stimulus to create transient site-specific copy alterations that could result in heterogeneity within tumors and cell populations. These findings have major implications in our understanding of copy number heterogeneity and the emergence of drug resistance genes in cancer. 相似文献
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Despina Moshous Emmanuel Martin Wassila Carpentier Annick Lim Isabelle Callebaut Danielle Canioni Fabian Hauck Jacek Majewski Jeremy Schwartzentruber Patrick Nitschke Nicolas Sirvent Pierre Frange Capucine Picard Stéphane Blanche Patrick Revy Alain Fischer Sylvain Latour Nada Jabado Jean-Pierre de Villartay 《The Journal of allergy and clinical immunology》2013
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Mathieu Fusaro Jérémie Rosain Virginie Grandin Nathalie Lambert Sylvain Hanein Cécile Fourrage Nicholas Renaud Marine Gil Samuel Chevalier Wadih Abou Chahla Brigitte Bader-Meunier Vincent Barlogis Stéphane Blanche David Boutboul Martin Castelle Thibault Comont Jean-Sébastien Diana Claire Fieschi Capucine Picard 《The Journal of allergy and clinical immunology》2021,147(2):734-737
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Benjamin Fournier Maud Tusseau Marine Villard Christophe Malcus Emilie Chopin Emmanuel Martin Debora Jorge Cordeiro Nicole Fabien Mathieu Fusaro Alexandra Gauthier Nathalie Garnier David Goncalves Sonia Lounis Christelle Lenoir Anne-Laure Mathieu Marion Moreews Magali Perret Capucine Picard Sylvain Latour 《The Journal of allergy and clinical immunology》2021,147(2):740-743.e9
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Seguier Julie Briantais Antoine Ebbo Mikael Meunier Benoit Aurran Thérèse Coze Stéphanie Kaphan Elsa De Sainte Marie Benjamin Sbihi Zineb Latour Sylvain Cerf-Bensussan Nadine Picard Capucine Vély Frédéric Barlogis Vincent Schleinitz Nicolas 《Journal of clinical immunology》2021,41(8):1975-1978
Journal of Clinical Immunology - 相似文献
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Yun Ling Sophie Cypowyj Caner Aytekin Miguel Galicchio Yildiz Camcioglu Serdar Nepesov Aydan Ikinciogullari Figen Dogu Aziz Belkadi Romain Levy Mélanie Migaud Bertrand Boisson Alexandre Bolze Yuval Itan Nicolas Goudin Julien Cottineau Capucine Picard Laurent Abel Jacinta Bustamante Jean-Laurent Casanova Anne Puel 《The Journal of experimental medicine》2015,212(5):619-631
Chronic mucocutaneous candidiasis (CMC) is characterized by recurrent or persistent infections of the skin, nail, oral, and genital mucosae with Candida species, mainly C. albicans. Autosomal-recessive (AR) IL-17RA and ACT1 deficiencies and autosomal-dominant IL-17F deficiency, each reported in a single kindred, underlie CMC in otherwise healthy patients. We report three patients from unrelated kindreds, aged 8, 12, and 37 yr with isolated CMC, who display AR IL-17RC deficiency. The patients are homozygous for different nonsense alleles that prevent the expression of IL-17RC on the cell surface. The defect is complete, abolishing cellular responses to IL-17A and IL-17F homo- and heterodimers. However, in contrast to what is observed for the IL-17RA– and ACT1-deficient patients tested, the response to IL-17E (IL-25) is maintained in these IL-17RC–deficient patients. These experiments of nature indicate that human IL-17RC is essential for mucocutaneous immunity to C. albicans but is otherwise largely redundant.In humans, chronic mucocutaneous candidiasis (CMC) is characterized by infections of the skin, nail, digestive, and genital mucosae with Candida species, mainly C. albicans, a commensal of the gastrointestinal tract in healthy individuals (Puel et al., 2012). CMC is frequent in acquired or inherited disorders involving profound T cell defects (Puel et al., 2010b; Vinh, 2011; Lionakis, 2012). Human IL-17 immunity has recently been shown to be essential for mucocutaneous protection against C. albicans (Puel et al., 2010b, 2012; Cypowyj et al., 2012; Engelhardt and Grimbacher, 2012; Huppler et al., 2012; Ling and Puel, 2014). Indeed, patients with primary immunodeficiencies and syndromic CMC have been shown to display impaired IL-17 immunity (Puel et al., 2010b). Most patients with autosomal-dominant (AD) hyper-IgE syndrome (AD-HIES) and STAT3 deficiency (de Beaucoudrey et al., 2008; Ma et al., 2008; Milner et al., 2008; Renner et al., 2008; Chandesris et al., 2012) and some patients with invasive fungal infection and autosomal-recessive (AR) CARD9 deficiency (Glocker et al., 2009; Lanternier et al., 2013) or Mendelian susceptibility to mycobacterial diseases (MSMD) and AR IL-12p40 or IL-12Rβ1 deficiency (de Beaucoudrey et al., 2008, 2010; Prando et al., 2013; Ouederni et al., 2014) have low proportions of IL-17A–producing T cells and CMC (Cypowyj et al., 2012; Puel et al., 2012). Patients with AR autoimmune polyendocrine syndrome type 1 (APS-1) and AIRE deficiency display CMC and high levels of neutralizing autoantibodies against IL-17A, IL-17F, and/or IL-22 (Browne and Holland, 2010; Husebye and Anderson, 2010; Kisand et al., 2010, 2011; Puel et al., 2010a).These findings paved the way for the discovery of the first genetic etiologies of CMC disease (CMCD), an inherited condition affecting individuals with none of the aforementioned primary immunodeficiencies (Puel et al., 2011; Casanova and Abel, 2013; Casanova et al., 2013, 2014). AR IL-17RA deficiency, AR ACT1 deficiency, and AD IL-17F deficiency were described, each in a single kindred (Puel et al., 2011; Boisson et al., 2013). A fourth genetic etiology of CMCD, which currently appears to be the most frequent, has also been reported: heterozygous gain-of-function (GOF) mutations of STAT1 impairing the development of IL-17–producing T cells (Liu et al., 2011; Smeekens et al., 2011; van de Veerdonk et al., 2011; Hori et al., 2012; Takezaki et al., 2012; Tóth et al., 2012; Al Rushood et al., 2013; Aldave et al., 2013; Romberg et al., 2013; Sampaio et al., 2013; Soltész et al., 2013; Uzel et al., 2013; Wildbaum et al., 2013; Frans et al., 2014; Kilic et al., 2014; Lee et al., 2014; Mekki et al., 2014; Mizoguchi et al., 2014; Sharfe et al., 2014; Yamazaki et al., 2014). We studied three unrelated patients with CMCD without mutations of IL17F, IL17RA, ACT1, or STAT1. We used a genome-wide approach based on whole-exome sequencing (WES). We found AR complete IL-17RC deficiency in all three patients. 相似文献
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John Routes Mario Abinun Waleed Al-Herz Jacinta Bustamante Antonio Condino-Neto Maria Teresa De La Morena Amos Etzioni Eleonora Gambineri Elie Haddad Lisa Kobrynski Francoise Le Deist Shigeaki Nonoyama Joao Bosco Oliveira Elena Perez Capucine Picard Nima Rezaei John Sleasman Kathleen E. Sullivan Troy Torgerson 《Journal of clinical immunology》2014,34(4):398-424
Primary immunodeficiencies are intrinsic defects in the immune system that result in a predisposition to infection and are frequently accompanied by a propensity to autoimmunity and/or immunedysregulation. Primary immunodeficiencies can be divided into innate immunodeficiencies, phagocytic deficiencies, complement deficiencies, disorders of T cells and B cells (combined immunodeficiencies), antibody deficiencies and immunodeficiencies associated with syndromes. Diseases of immune dysregulation and autoinflammatory disorder are many times also included although the immunodeficiency in these disorders are often secondary to the autoimmunity or immune dysregulation and/or secondary immunosuppression used to control these disorders. Congenital primary immunodeficiencies typically manifest early in life although delayed onset are increasingly recognized. The early diagnosis of congenital immunodeficiencies is essential for optimal management and improved outcomes. In this International Consensus (ICON) document, we provide the salient features of the most common congenital immunodeficiencies. 相似文献