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.

Chiriaco, M., Brigida, I., Ariganello, P., Di Cesare, S., Di Matteo, G., Taus, F., et al. (2017). The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. CLINICAL IMMUNOLOGY, 178, 20-28 [10.1016/j.clim.2015.12.008].

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

Chiriaco M.;Brigida I.;Di Cesare S.;Di Matteo G.;Taus F.;Fraziano M.;Finocchi A.;Rossi P.;Aiuti A.;Palma P.;Cancrini C.
2017-05-01

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.
mag-2017
Pubblicato
Rilevanza internazionale
Articolo
Esperti anonimi
Settore MED/38 - PEDIATRIA GENERALE E SPECIALISTICA
Settore BIO/19 - MICROBIOLOGIA GENERALE
English
APDS; Mycobacterium bovis; Myeloid cells; PI3KCD; Adenine; B-Lymphocytes; Cell Differentiation; Class I Phosphatidylinositol 3-Kinases; Dendritic Cells; Humans; Immunologic Deficiency Syndromes; In Vitro Techniques; Inflammation; Lymphopenia; Macrophages; Male; Mycobacterium bovis; Proto-Oncogene Proteins c-akt; Quinazolines; Signal Transduction; TOR Serine-Threonine Kinases; Young Adult
Chiriaco, M., Brigida, I., Ariganello, P., Di Cesare, S., Di Matteo, G., Taus, F., et al. (2017). The case of an APDS patient: Defects in maturation and function and decreased in vitro anti-mycobacterial activity in the myeloid compartment. CLINICAL IMMUNOLOGY, 178, 20-28 [10.1016/j.clim.2015.12.008].
Chiriaco, M; Brigida, I; Ariganello, P; Di Cesare, S; Di Matteo, G; Taus, F; Cittaro, D; Lazarevic, D; Scarselli, A; Santilli, V; Attardi, E; Stupka, ...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/2108/219338
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