*6.1. Activated Phosphoinositide 3-Kinase d Syndrome*

APDS is a combined immunodeficiency disorder associated with an increased risk of sinusitis, respiratory infections, severe herpesvirus infections, and a high rate of autoimmunity and lymphoproliferation. Indeed, autoimmune and lymphoproliferative manifestations (diffuse lymphadenopathy, hepatomegaly, splenomegaly) are the presenting sign in more than half of the patients diagnosed with APDS [99,100]. Autoimmunity occurs in about two-thirds of the patients with APDS, and the clinical expression of autoimmunity consists mostly of the finding of autoimmune cytopenia, arthritis, and enteropathy [101]. The disease is caused by mutations affecting the phosphoinositide 3-kinase (PI3K) molecular complex, which is involved in numerous signaling pathways activated after the binding of TCR and BCR with their ligands and influences cellular metabolism, proliferation, and differentiation of B and T lymphocytes [102] (Figure 1). Patients with GOF mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase Catalytic Subunit δ (PIK3CD) gene are classified as affected by APDS1, while loss of function mutation in the Phosphoinositide-3- Kinase Regulatory Subunit 1 (PIK3R1) is diagnostic for APDS2 [101]. These two molecular defects are responsible for the uncontrolled activation of the PI3K-dependent molecular pathways, including the intracellular events linked to the activation of mTOR. In APDS, a shift in cellular metabolic and proliferative activity is observed, and patients usually display a peculiar immunological phenotype, featured by high levels of senescent T lymphocytes, effector memory T cells, progressive B lymphocytopenia, and reduced absolute numbers of naïve T cells [101]. The serum levels of immunoglobulin are extremely variable, since patients can present with a CVID-like phenotype, an HIGM picture, or in some cases, hypergammaglobulinemia [99].

A correct diagnosis of APDS is mandatory since it significantly influences the therapeutic approach and the follow-up. Concerning follow-up, the surveillance against the development of lymphoid neoplasms is a central feature, since patients with APDS have an increased risk of developing lymphomas and, particularly, non-Hodgkin's lymphomas [62,101]. Treatment of APDS comprehends the immunoglobulin replacement therapy, when necessary, and the measures to control autoimmunity and lymphoproliferation. To this point, sirolimus, an mTOR inhibitor, is commonly used as a first-line strategy, while selective PI3K inhibitors (leniolisib, nemiralisib) are given in refractory cases [101]. Finally, patients with APDS could benefit from HSCT, although there is no uniform consensus on the timing of the transplantation and the conditioning regimen [103].
