title: The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment.
abstract: Activated PI3-kinase delta syndrome (APDS) was recently reported as a novel primary immunodeficiency caused by heterozygous gain-of-function mutations in PIK3CD gene. Here we describe immunological studies in a 19year old APDS patient for whom genetic diagnosis was discovered by Whole Exome Sequencing (WES) analysis. In addition to the progressive lymphopenia and defective antibody production we showed that the ability of the patient's B cells to differentiate in vitro is severely reduced. An in depth analysis of the myeloid compartment showed an increased expression of CD83 activation marker on monocytes and mono-derived DC cells. Moreover, monocytes-derived macrophages (MDMs) failed to solve the Mycobacterium bovis bacillus Calmette Guèrin (BCG) infection in vitro. Selective p110δ inhibitor IC87114 restored the MDM capacity to kill BCG in vitro. Our data show that the constitutive activation of Akt-mTOR pathway induces important alterations also in the myeloid compartment providing new insights in order to improve the therapeutic approach in these patients.
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Chiriaco
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (TIGET), Italy.
authors.forename: Immacolata
authors.initials: I
authors.lastname: Brigida
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ariganello
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Silvia
authors.initials: S
authors.lastname: Di Cesare
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Di Matteo
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Taus
authors.affiliation: Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Davide
authors.initials: D
authors.lastname: Cittaro
authors.affiliation: Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Dejan
authors.initials: D
authors.lastname: Lazarevic
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Scarselli
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Veronica
authors.initials: V
authors.lastname: Santilli
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Enrico
authors.initials: E
authors.lastname: Attardi
authors.affiliation: Center for Translational Genomics and BioInformatics, San Raffaele Scientific Institute, Milan, Italy.
authors.forename: Elia
authors.initials: E
authors.lastname: Stupka
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (TIGET), Italy.
authors.forename: Stefania
authors.initials: S
authors.lastname: Giannelli
authors.affiliation: Department of Biology, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Maurizio
authors.initials: M
authors.lastname: Fraziano
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Finocchi
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Rossi
authors.affiliation: San Raffaele Telethon Institute for Gene Therapy (TIGET), Italy; Pediatric Immunohematology, San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Aiuti
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy; Department of Systems Medicine, University of Rome "Tor Vergata", Rome, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Palma
authors.affiliation: University Department of Pediatrics, Unit of Immune and Infectious Diseases, Childrens' Hospital Bambino Gesù, Rome, Italy. Electronic address: cancrini@med.uniroma2.it.
authors.forename: Caterina
authors.initials: C
authors.lastname: Cancrini
mesh_terms: D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D001402:B-Lymphocytes / Q000276:immunology*; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology*; D058534:Class I Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology*; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology*; D066298:In Vitro Techniques; D007249:Inflammation; D008231:Lymphopenia / Q000235:genetics / Q000276:immunology; D008264:Macrophages / Q000187:drug effects / Q000276:immunology*; D008297:Male; D009163:Mycobacterium bovis / Q000276:immunology; D000081207:Primary Immunodeficiency Diseases; D051057:Proto-Oncogene Proteins c-akt / Q000276:immunology; D011799:Quinazolines / Q000494:pharmacology; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000276:immunology; D055815:Young Adult
chemical_list: C477872:IC 87114; D011799:Quinazolines; C546842:MTOR protein, human; D058534:Class I Phosphatidylinositol 3-Kinases; C486018:PIK3CD protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D000225:Adenine
keywords: APDS; Mycobacterium bovis; Myeloid cells; PI3KCD