In this issue of Blood, Rao et al describe efficacy of the oral phosphoinositide 3-kinase delta (PI3Kδ) inhibitor leniolisib in patients with activated phosphoinositide 3-kinase delta syndrome (APDS).
PI3Kδ is heterodimeric enzyme with critical subunits, p110δ and p85α. APDS is a primary immunodeficiency caused by a pathogenic variant in the PIK3CD gene, encoding the catalytic p110δ subunit (APSD1), or the PIK3R1 gene, encoding the regulatory p85α subunit (APSD2). Variants affecting p110δ lead to downstream hyperactivation of the AKT/mTOR/pS6K signaling pathway, whereas variants affecting p85α cause loss of p85α-mediated inhibition of p110δ activity, and therefore, constitutive activity of PI3Kδ. Hyperactivation of the mTOR pathway—critical for cell growth, proliferation, differentiation, and survival—has many immunologic sequalae, including skewed differentiation of CD8+ T cells to short-lived effector cells, and impaired memory B- and T-cell development. Immune dysregulation is associated with hypogammaglobulinemia (often with conserved or increased immunoglobulin M levels), lymphopenia, and CD4+ T-cell reduction.