The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment

Maria Chiriaco, Immacolata Brigida, Paola Ariganello, Silvia Di Cesare, Gigliola Di Matteo, Francesco Taus, Davide Cittaro, Dejan Lazarevic, Alessia Scarselli, Veronica Santilli, Enrico Attardi, Elia Stupka, Stefania Giannelli, Maurizio Fraziano, Andrea Finocchi, Paolo Rossi, Alessandro Aiuti, Paolo Palma, Caterina Cancrini

Research output: Contribution to journalArticle

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 19 year 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.

Original languageEnglish
Pages (from-to)20-28
Number of pages9
JournalClinical Immunology
Volume178
DOIs
Publication statusPublished - May 1 2017

Fingerprint

Phosphatidylinositol 3-Kinases
Bacillus
Macrophages
Exome
Lymphopenia
Mycobacterium bovis
Antibody Formation
Monocytes
B-Lymphocytes
Mutation
Infection
Genes
In Vitro Techniques
Therapeutics

Keywords

  • APDS
  • Mycobacterium bovis
  • Myeloid cells
  • PI3KCD

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

@article{e43aeca3a97c46a2841bd3f11c398354,
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 19 year 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 Gu{\`e}rin (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.",
keywords = "APDS, Mycobacterium bovis, Myeloid cells, PI3KCD",
author = "Maria Chiriaco and Immacolata Brigida and Paola Ariganello and {Di Cesare}, Silvia and {Di Matteo}, Gigliola and Francesco Taus and Davide Cittaro and Dejan Lazarevic and Alessia Scarselli and Veronica Santilli and Enrico Attardi and Elia Stupka and Stefania Giannelli and Maurizio Fraziano and Andrea Finocchi and Paolo Rossi and Alessandro Aiuti and Paolo Palma and Caterina Cancrini",
year = "2017",
month = "5",
day = "1",
doi = "10.1016/j.clim.2015.12.008",
language = "English",
volume = "178",
pages = "20--28",
journal = "Clinical Immunology",
issn = "1521-6616",
publisher = "Academic Press Inc.",

}

TY - JOUR

T1 - The case of an APDS patient

T2 - Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment

AU - Chiriaco, Maria

AU - Brigida, Immacolata

AU - Ariganello, Paola

AU - Di Cesare, Silvia

AU - Di Matteo, Gigliola

AU - Taus, Francesco

AU - Cittaro, Davide

AU - Lazarevic, Dejan

AU - Scarselli, Alessia

AU - Santilli, Veronica

AU - Attardi, Enrico

AU - Stupka, Elia

AU - Giannelli, Stefania

AU - Fraziano, Maurizio

AU - Finocchi, Andrea

AU - Rossi, Paolo

AU - Aiuti, Alessandro

AU - Palma, Paolo

AU - Cancrini, Caterina

PY - 2017/5/1

Y1 - 2017/5/1

N2 - 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 19 year 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.

AB - 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 19 year 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.

KW - APDS

KW - Mycobacterium bovis

KW - Myeloid cells

KW - PI3KCD

UR - http://www.scopus.com/inward/record.url?scp=85016167040&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85016167040&partnerID=8YFLogxK

U2 - 10.1016/j.clim.2015.12.008

DO - 10.1016/j.clim.2015.12.008

M3 - Article

C2 - 26732860

AN - SCOPUS:85016167040

VL - 178

SP - 20

EP - 28

JO - Clinical Immunology

JF - Clinical Immunology

SN - 1521-6616

ER -