Abstract
Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in PIK3CD, PIK3R1, or PTEN, which are related to the hyperactive phosphoinositide 3-kinase (PI3K) signaling, were recently presented to cause APDS1 or APDS2 (APDSs), or APDS-like (APDS-L) disorder. In this study, we examined the AKT phosphorylation of peripheral blood lymphocytes and monocytes in patients with APDSs and APDS-L by using flow cytometry. CD19+ B cells of peripheral blood in APDS2 patients showed the enhanced phosphorylation of AKT at Ser473 (pAKT) without any specific stimulation. The enhanced pAKT in CD19+ B cells was normalized by the addition of a p110δ inhibitor. In contrast, CD3+ T cells and CD14+ monocytes did not show the enhanced pAKT in the absence of stimulation. These findings were similarly observed in patients with APDS1 and APDS-L. Among CD19+ B cells, enhanced pAKT was prominently detected in CD10+ immature B cells compared with CD10− mature B cells. Enhanced pAKT was not observed in B cells of healthy controls, patients with common variable immunodeficiency, and hyper IgM syndrome due to CD40L deficiency. These results suggest that the enhanced pAKT in circulating B cells may be useful for the discrimination of APDS1, APDS2, and APDS-L from other antibody deficiencies.
Highlights
Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency (PID) characterized by recurrent respiratory tract infections, chronic Epstein Barr virus and cytomegalovirus infections, lymphoproliferation, increased lymphoma susceptibility, and poor antibody production [1,2,3,4]
The recent identification of activated PI3Kδ syndrome 1 (APDS1) and activated PI3Kδ syndrome 2 (APDS2) (APDSs) and activated PI3Kδ syndrome (APDS)-L revealed that the hyperactive phosphoinositide 3-kinase (PI3K)/AKT signaling affects the immune system in humans, leading to the development of PID
The identified mutations in PIK3R1 were de novo in Family B, C, and D, since we found no was synthesized to assess the significance of the nucleotide substitution, 1425 + 2 T > A, on splicing. (C,D) The RT-polymerase chain reaction (PCR) fragment was cloned into a pGEM-T easy vector
Summary
Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency (PID) characterized by recurrent respiratory tract infections, chronic Epstein Barr virus and cytomegalovirus infections, lymphoproliferation, increased lymphoma susceptibility, and poor antibody production [1,2,3,4]. Heterozygous gain-of-function mutations in PIK3CD, which encodes the catalytic subunit p110δ of phosphoinositide 3-kinase (PI3K), have been identified in patients with APDS1 [1, 3]. Phosphoinositide 3-kinases convert phosphatidylinositol 3,4-triphosphate (PIP2) to phosphatidylinositol 3,4,5-triphosphate (PIP3) and are involved in cellular functions including proliferation, differentiation, survival, and trafficking [7, 8]. Both p110δ and p85α belong to class IA PI3Ks and have an essential role in the differentiation, development, and functions of several distinct stages of B- and T-lymphocytes [7, 8]. The recent identification of APDS1 and APDS2 (APDSs) and APDS-L revealed that the hyperactive PI3K/AKT signaling affects the immune system in humans, leading to the development of PID
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