In a study by Priete and research groups from the USA and Italy,1 a mouse model with a mutation in the P13K gene that causes the activation of the P13K pathway was used to demonstrate the cellular and molecular mechanisms underlying the main biological and clinical features of the rare human immunodeficiency disease known as APDS or activated P13kδ syndrome. In humans, the overactivation of the P13Kδ pathway causes recurrent respiratory infections with secondary bronchiectasis, lymphopenia, lymphoproliferation, and poor vaccination responses.2 The P13Kδ mouse model has a gain-of-function (GOF) mutation in the P13Kδ gene and shows lymphopenia, lymphoproliferation, and poor responses to vaccination, similar to the findings in human disease. These findings suggested that the P13Kδ-GOF mouse could be a useful tool to dissect the cellular and molecular mechanisms and pathways that contribute to the similar human disease. The authors then probed the immune response/s in the P13Kδ GOF mouse model using a variety of challenges and methods to identify where and how the P13Kδ-GOF-activated gene disturbs the cellular and molecular pathways of competent antibody formation and used comparisons with wild-type (WT) mice and normal human donors to help define the APDS phenotype and the P13Kδ-GOF mutant mouse model (MM).
The cell membrane receptor is triggered by growth factors that cause the dimerization and phosphorylation of the P13K gene, which in the case of APDS and the GOF P13Kδ mouse, comprises a combination of the mutant catalytic subunit p110δ and the regulator unit p85α. The catalytic subunit and the regulator come together inside the cell membrane with the support of 3 recycled phosphoinositol phosphate groups (called PIP3, 4, 5) to form activated P13Kδ, which phosphorylates protein kinase B (called AKT), and phosphorylated AKT in turn phosphorylates and activates FOXO in the cell nucleus, causing the transcription of multiple factors associated with cell growth, cancer, and diabetes. The P13K pathway is normally highly regulated by many control mechanisms, including the phosphatase and tensin homolog pathway, which blocks P13K activation through reverse PIP recycling: molecular processes that cause ATK dephosphorylation; mTOR (also known as mammalian target of rapamycin) which dephosphorylates FOXO, causing it to leave the nucleus and be degraded through proteosomal/lysosomal mechanisms, thus preventing ongoing transcription and cell growth.4 In this research, the authors used these checkpoint inhibitors to explore how the molecular processes underlying the function of the P13Kδ-GOF gene caused the disruption of the immune process, leading to the phenotype of APDS disease (Fig. 1a).
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