Abstract
Autosomal dominant gain-of-function mutations in the PIK3CD gene encoding the catalytic subunit p110δ of phosphoinositide 3-kinase-δ (PI3K-δ) or autosomal dominant loss-of-function mutations in the PIK3R1 gene encoding the p85α, p55α and p50α regulatory subunits cause Activated PI3-kinase-δ syndrome (APDS; referred as type 1 APDS and type 2 APDS, respectively). Consequences of these mutations are PI3K-δ hyperactivity. Clinical presentation described for both types of APDS patients is very variable, ranging from mild or asymptomatic features to profound combined immunodeficiency. Massive lymphoproliferation, bronchiectasis, increased susceptibility to bacterial and viral infections and, at a lesser extent, auto-immune manifestations and occurrence of cancer, especially B cell lymphoma, have been described for both types of APDS patients. Here, we review clinical presentation and treatment options as well as fundamental immunological and biological features associated to PI3K-δ increased signaling.
Highlights
Class IA PI3Kinase (PI3K) molecules are composed of a p110 catalytic subunit and a regulatory subunit
Clinical presentation and immunological abnormalities of both types of associated primary combined immunodeficiency syndrome (APDS) are very similar a large heterogeneity on a patient-to-patient comparison has been noticed indicating that environmental factor(s), including infections with different pathogens, as well as other genetic “modifying” factor(s) likely contribute to the disease presentation
Clinical complications such as recurrent respiratory infections, adenopathy and intestinal problems are together with frequently reported immunological abnormalities first and major diagnostic indications to consider further investigation of the PI3Kδ signaling activation
Summary
Class IA PI3Kinase (PI3K) molecules are composed of a p110 catalytic subunit and a regulatory subunit. For both types of APDS patients, peripheral blood (PB) immunophenotyping of B lymphocyte subsets indicated an increased frequency of transitional B cells (CD19+Ig(M)D+CD38+CD24+CD27– or CD20+CD10+CD27-), a reduced frequency of naïve B
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