Activated PI3-Kinase Delta Syndrome (APDS)/p110d-Activating Mutations Causing Senescent T Cells, Lymphadenopathy, and Immunodeficiency (PASLI)
An immunodeficiency defined by PIK3CD gain-of-function mutations encoding for the p110δ catalytic subunit of the phosphatidylinositol3-kinase delta (PI3K δ) (activated PI3K delta syndrome (APDS) 1) (Angulo et al. 2013) or by autosomal dominant mutations in PIK3R1 encoding the regulatory subunit p85α (APDS2) (Deau et al. 2014).
So far (2018), over 100 patients with mutations in PIK3CD and over 50 patients with mutations in PIK3R1 have been identified (Lougaris et al. 2015; Coulter et al. 2016; Elkaim et al. 2016; Crank et al. 2014; Kracker et al. 2014; Wentink et al. 2017; Petrovski et al. 2016; Tsujita et al. 2016; Takeda et al. 2017; Dulau Florea et al. 2017; Heurtier et al. 2017).
Most APDS patients present with recurrent bacterial respiratory tract infections and lymphoproliferation. Pneumonia (85%), bronchiectasis (60%), and lymphadenopathies/splenomegaly (75%) were frequently observed in APDS1 patients, often with childhood onset (Coulter et al. 2016). Other complications reported include herpes virus (especially EBV and CMV) infections and reactivations (49%), autoimmune-induced cytopenia (17%), and occurrence of B lymphomas (diffuse large B cell, marginal zone, non-Hodgkin lymphomas) that affected 13% of APDS patients (Coulter et al. 2016; Kracker et al. 2014). Neurodevelopmental delay was reported for APDS patients (19%) indicating a function of p110δ in cells from the central nervous system (Coulter et al. 2016).
APDS2 is a combined immunodeficiency with a variable clinical phenotype and complications such as severe bacterial and viral infections, lymphoproliferation, and lymphoma similar to APDS1 (Elkaim et al. 2016). Growth retardation (45%) and mild neurodevelopmental delay (31%) were frequently noticed for APDS2 patients (Elkaim et al. 2016). These clinical complications together with microcephaly, joint extensibility, and increased glucose levels in the blood, although rarely reported for APDS2 patients, suggest disturbed PI3K signaling also in non-lymphoid lineage cells (Elkaim et al. 2016; Petrovski et al. 2016).
Several different GoF mutations of p110δ responsible for APDS1 (E81K (Takeda et al. 2017; Heurtier et al. 2017), G124D (Takeda et al. 2017; Heurtier et al. 2017), N334 K (Lucas et al. 2014a), R405C (Rae et al. 2017), C416R (Crank et al. 2014), E525K (Lucas et al. 2014a), E525A (Tsujita et al. 2016), R929C (Wentink et al. 2017), E1021K (Angulo et al. 2013), and E1025G (Dulau Florea et al. 2017)) have been reported so far; the most frequent of them being E1021K located in the kinase domain. The GoF PIK3CD mutations are next to the kinase domain located in the adapter-binding domain and the linker between the adapter-binding domain, the protein kinase C homology-2 (C2) domain, and the helical domain of p100δ. The GoF PIK3CD mutations in those domains are located in parts involved in the interaction with the regulatory PI3K subunit (Takeda et al. 2017; Heurtier et al. 2017).
Heterozygous mutations in PIK3R1 affecting the splice donor or splice acceptor site of exon 11 (coding exon 10) result in alternative splicing and deletion of exon 11 which encodes a part of the PI3Kδ−interacting domain of p85α are responsible for APDS2 (Deau et al. 2014; Elkaim et al. 2016). A missense mutation N546 K in p85α located in the inter-SH2 domain of p85α (Wentink et al. 2017) also increases PI3Kδ activity.
Of note, SHORT syndrome, which is a rare autosomal dominant multisystem disease due to loss-of-PI3K activity, is also caused by heterozygous mutations in the PIK3R1 gene. Mutations causing SHORT syndrome (e.g., p.R649W, p.N636Tfs*, and p.Y657*) are affecting especially the C-terminal part of p85α (Chudasama et al. 2013; Dyment et al. 2013; Thauvin-Robinet et al. 2013).
Class IA PI3Ks are composed of a p110 catalytic subunit (p110α, p110β, or p110δ) and a regulatory subunit (p85α, p55α, p50α, p85β, or p55γ) that regulates the stability, cellular localization, and function of p110. Class IA PI3Ks convert phosphatidylinositol 4,5-bisphosphate into phosphatidylinositol 3,4,5-trisphosphate, an important phospholipid secondary messenger (Okkenhaug 2013). Expression of the p110δ catalytic subunit is restricted mainly to leukocytes, whereas p110α and p110β are ubiquitously expressed. The widely expressed p85α regulatory subunit is the predominant regulatory subunit in lymphocytes.
PI3Kδ is expressed in both T and B lymphocytes, and patients suffer from a very variable immunodeficiency, which can present as a partial humoral or combined defect; patients can evolve into a profound combined immunodeficiency. A large proportion of patients was previously diagnosed as CSR-Ds because of increased IgM and reduced IgG (essentially IgG2 and IgG4) and IgA levels in serum, impaired antibody responses (especially to polysaccharide antigens), and a strongly decreased number of switched B cells contrasting to a strikingly increased number of transitional B cells. Somatic hyper-mutation frequency was found normal in the decreased CD27+ B cell subset (Angulo et al. 2013). Besides the B cell defect, patients suffer from T lymphopenia, decreased numbers of naïve CD4+ and CD8+ T cells, increased number of CD8 senescent CD57+ T cells, defective proliferation to antigens, and increased activation-induced cell death indicating an intrinsic T cell defect (Angulo et al. 2013; Deau et al. 2014; Lucas et al. 2014a).
Diagnosis is made by genetic analysis of PIK3CD and PIK3R1, respectively. Suspicion should be raised in patients with respiratory tract infections, lymphoproliferative disease, dysgammaglobulinemia especially with elevated serum IgM, and expansion of transitional B cells. Functional analysis includes the evaluation of ribosomal protein S6 phosphorylation (Ser235/236) in B lymphocytes and AKT phosphorylation (Ser473) in IL2 propagated T cell blasts of patients (Lucas et al. 2014a; Heurtier et al. 2017).
Treatment of APDS1 and APDS2 patients is very much dependent on the clinical presentation: successful hematopoietic stem cell transplantation was reported (Nademi et al. 2016; Kuhlen et al. 2016) and should be considered for severe forms. Ig replacement therapy is indicated for the patients with a predominant humoral defect. Inhibition of the mTOR pathway by rapamycin has shown its efficacy especially for patients presenting with lymphoproliferation (Lucas et al. 2014a; Coulter et al. 2016). Interesting perspectives for the future may be represented by specific inhibitors of PI3Kδ, currently on trial (Rao et al. 2017).