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Human Disorders of PI3K Biology

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Front. Immunol. | doi: 10.3389/fimmu.2018.00338

RESPIRATORY MANIFESTATIONS OF THE ACTIVATED PHOSPHOINOSITIDE 3-KINASE DELTA SYNDROME

 Alison M. Condliffe1* and Anita Chandra2, 3
  • 1University of Sheffield, United Kingdom
  • 2Medicine, University of Cambridge, United Kingdom
  • 3Lymphocyte Signalling and Development, Babraham Institute (BBSRC), United Kingdom

The Activated Phosphoinositide 3-kinase δ Syndrome (APDS), also known as p110δ-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI), is a combined immunodeficiency syndrome caused by gain-of-function mutations in the phosphoinositide 3-kinase (PI3K) genes PIK3CD (encoding p110δ: APDS1 or PASLI-CD) and PIK3R1 (encoding p85α: APDS2 or PASLI-R1). Whilst the disease is clinically heterogeneous, respiratory symptoms and complications are near universal and often severe. Infections of the ears, sinuses and upper and lower respiratory tracts are the earliest and most frequent manifestation of APDS, secondary to both respiratory viruses and to bacterial pathogens typical of defective B cell function. End organ damage in the form of small airways disease and bronchiectasis frequently complicates APDS, but despite documented T cell defects, opportunistic infections have rarely been observed. Antimicrobial (principally antibiotic) prophylaxis and/or immunoglobulin replacement have been widely used to reduce the frequency and severity of respiratory infection in APDS, but outcome data to confirm the efficacy of these interventions is limited. Despite these measures, APDS patients are often afflicted by benign lymphoproliferative disease, which may present in the respiratory system as tonsillar/adenoidal enlargement, mediastinal lymphadenopathy or mucosal nodular lymphoid hyperplasia, potentially causing airways obstruction and compounding the infection phenotype. Treatment with rapamycin and PI3Kδ inhibitors has been reported to be of benefit in benign lymphoproliferation, but hematopoietic stem cell transplantation (ideally undertaken before permanent airway damage is established) remains the only curative treatment for APDS.

Keywords: Activated PI3K Delta Syndrome, respiratory infection, Pneumonia, Bronchiectasis, Antibody deficiency, LYMPHOPROLIFERATION

Received: 28 Nov 2017; Accepted: 06 Feb 2018.

Edited by:

Stuart G. Tangye, Garvan Institute of Medical Research, Australia

Reviewed by:

Marina CAVAZZANA, Necker-Enfants Malades Hospital, France
Kenneth N. Olivier, National Heart Lung and Blood Institute (NIH), United States  

Copyright: © 2018 Condliffe and Chandra. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Alison M. Condliffe, University of Sheffield, Department of Infection, Immunity and Cardiovascular Diseases, Sheffield, S10 2RX, United Kingdom, a.m.condliffe@sheffield.ac.uk