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Human Disorders of PI3K Biology

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Front. Immunol. | doi: 10.3389/fimmu.2018.00369

Activated PI3 kinase Delta syndrome: from genetics to therapy

  • 1GlaxoSmithKline (United Kingdom), United Kingdom
  • 2University of Cambridge, United Kingdom

Activated PI3 kinase Delta syndrome (APDS) is a primary immunodeficiency caused by dominant mutations that increase activity of phosphoinositide-3-kinase delta (PI3Kd). APDS can be caused by mutations in the PIK3CD gene that encodes PI3Kd catalytic subunit p110d (APDS1) or mutations in the PIK3R1 gene that encodes regulatory subunit p85a (APDS2). APDS research advanced rapidly after the initial discovery in 2013. More than 200 APDS patients have been identified around the world. Multiple novel APDS mutations were reported and molecular mechanisms leading to PI3Kd activation have been elucidated. The finding of APDS significantly increased our understanding of the role of PI3Kd in the human immune system. Perhaps most importantly, discovery of the molecular basis of this primary immunodeficiency suggested that APDS patients, who previously received only non-specific therapy, could be treated by a novel class of drugs that inhibits PI3Kd activity. This led to the ongoing clinical trials of selective PI3Kd inhibitors in APDS patients. Overall, the APDS story provides an excellent example of translational research, beginning with patients who had an unknown disease cause and leading to a novel specific knowledge-based treatment.

Keywords: APDs, PID, PI3K-delta, Mutation, inhibitor

Received: 14 Dec 2017; Accepted: 09 Feb 2018.

Edited by:

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

Reviewed by:

Yuval Itan, Icahn School of Medicine at Mount Sinai, United States
James E. Thaventhiran, MRC Toxicology Unit (MRC), United Kingdom  

Copyright: © 2018 Michalovich and Nejentsev. 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: Dr. Sergey Nejentsev, University of Cambridge, Cambridge, United Kingdom,