PI3K pathway defects leading to immunodeficiency and immune dysregulation

The phosphatidylinositol 3-kinase (PI3K) signaling pathway is involved in a broad range of cellular processes, including growth, metabolism, differentiation, proliferation, motility, and survival. The PI3K delta enzyme complex is primarily present in the immune system and comprises a catalytic (p110 delta) and regulatory (p85 alpha) subunit. Dynamic regulation of PI3K delta activity is required to ensure normal function and differentiation of immune cells. In the last decade, discovery of germline mutations in genes involved in the PI3K delta pathway (PIK3CD, PIK3R1, or phosphatase and tensin homolog [PTEN]) proved that both overactivation and underactivation (gain of function and loss of function, respectively) of PI3K delta lead to impaired and dysregulated immunity. Although a small group of patients reported to underactivate PI3K delta show predominantly humoral defects and autoimmune features, more than 200 patients have been described with overactivation of PI3K delta, presenting with a much more complex phenotype of combined immunodeficiency and immune dysregulation. The clinical and immunologic characterization, as well as current pathophysiologic understanding and specific therapies for PI3K pathway defects leading to immunodeficiency and immune dysregulation, are reviewed here.