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Primary immunodeficiency (PID) is an umbrella term that includes a large heterogeneous group of disorders that are characterised by defects in the development and/or function of the immune system.1 At the broadest level, PIDs are classified as disorders of adaptive immunity or innate immunity.1 Adaptive immunity disorders are those that affect T-cells, B-cells, or both – termed ‘combined immunodeficiency’ or CID.1 Innate immunity disorders are those that affect phagocytes and complement components.1 Although the clinical manifestations of PIDs vary widely, many involve an increased susceptibility to infection, with patients commonly presenting with recurrent sinus or ear infections or pneumonias, with other characteristics that may include failure to thrive; poor response to long-term antibiotics; persistent thrush or skin abscesses; multiple autoimmune diseases, and a family history of PID.1
Activated PI3Kδ syndrome (APDS, formerly known as PASLI) was recognised in 2013 as rare type of combined immunodeficiency disorder (CID). APDS is a progressive primary immunodeficiency and regulatory disorder that can lead to end-organ damage and early mortality.2-7 There is no approved treatment for APDS and current management is symptom based.5-8
APDS is a primary immunodeficiency (PI) that causes both immune deficiency (resulting in frequent infections) and immune dysregulation (resulting in autoimmune complications).2,3
The phosphatidylinositol 3-kinases (PI3K) are a family of lipid kinases present in all cell types that are activated by a variety of cell-surface receptors to regulate a wide range of downstream targets that affect cellular metabolism, growth, survival, differentiation, adhesion and migration.1 There are two genes implicated in APDS, PIK3CD and PIK3R1, whose products are expressed only in lymphocytes.2,3 Specific mutations in either PIK3CD or PIK3R1 lead to gain of function (GoF) in the P110δ catalytic subunit, and loss of function (LoF) in the p85α regulatory subunit, respectively, the result of which is hyperactive PI3Kδ signalling and the clinical symptoms of APDS.4,5
Mutations in the P110δ catalytic subunit give way to APDS1; mutations in the p85α regulatory subunit lead to APDS2; both are the result of a hyperactive PI3Kδ signalling pathway.1,5-7
The PI3Kδ signalling network plays a fundamental role in signal transduction in mammalian immune cells and is required for the maintenance of both proper adaptive immunity and self-tolerance (avoidance of auto-immune reactions).1-5 Downstream targets of PI3K include AKT, mTOR, and FOXO1, which play key roles in determining the fate of T-cells and B-cells.1
Balanced signaling in the PI3Kδ pathway is essential for growth, cognition and healthy immune function; fine-tuning of PI3Kδ activity results in normal development of B and T cells, as well as normal growth and cognitive development.6-10 The healthy individual needs to be able to adjust the balance to allow for reduced PI3K signalling for greater activation of the FOXO pathway and increased immune cell proliferation, and increased PI3K signalling for greater activation of the mTOR pathway and increased differentiation. Hyperactive PI3Kδ prevents this fine-tuning and reduces the ability of immune cells to promote FOXO activity and inhibit mTOR activity, resulting in altered development of B and T cells, and which affects growth and cognitive development.6,7,10-13
APDS symptoms are caused by hyperactive PI3Kδ signalling due to specific mutations in either PIK3CD or PIK3R1
The initial presentation of APDS varies and it can often be incompletely diagnosed as a CVID or CID. The initial hallmark of APDS is recurrent sinopulmonary infections, often in combination with lymphadenopathy; however, genetic testing is required for a definitive diagnosis of APDS.
APDS can have a significant burden on patients’ quality of life due to complications associated with the frequent sinopulmonary infections and fatigue,4,6 7-10 and the consequent interventions required. Patients see multiple doctors throughout both the diagnosis and management stages, so the multiple appointments and referrals, hospitalisations, surgical interventions and polypharmacy can be a significant burden in their daily life.1-7
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