Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan.

Activated phosphatidyl inositol 3-kinase-delta syndrome (APDS) due to gain-of-function variant in the class IA PI3K catalytic subunit p110δ (responsible gene: PIK3CD) was described in 2013. The disease is characterized by recurrent airway infections and bronchiectasis. It is associated with hyper-IgM syndrome due to the defect of immunoglobulin class switch recombination and decreased CD27-positive memory B cells.

A complementary approach for genetic diagnosis of inborn errors of immunity using proteogenomic analysis.

Advances in next-generation sequencing technology have identified many genes responsible for inborn errors of immunity (IEI). However, there is still room for improvement in the efficiency of genetic diagnosis. Recently, RNA sequencing and proteomics using peripheral blood mononuclear cells (PBMCs) have gained attention, but only some studies have integrated these analyses in IEI.

Clinical Courses of IKAROS and CTLA4 Deficiencies: A Systematic Literature Review and Retrospective Longitudinal Study.

IKAROS and CTLA4 deficiencies are inborn errors of immunity and show similar clinical phenotypes, including hypogammaglobulinemia and autoimmune diseases (ADs). However, the differences in clinical features and pathogenesis of these are not fully understood. Therefore, we performed systematic literature reviews for IKAROS and CTLA4 deficiencies.

The Primary Immunodeficiency Database in Japan.

The Primary Immunodeficiency Database in Japan (PIDJ) is a registry of primary immunodeficiency diseases (PIDs) that was established in 2007. The database is a joint research project with research groups associated with the Ministry of Health, Labor and Welfare; the RIKEN Research Center for Allergy and Immunology (RCAI); and the Kazusa DNA Research Institute (KDRI). The PIDJ contains patient details, including the age, sex, clinical and laboratory findings, types of infections, genetic analysis results, and treatments administered.

Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase δ syndrome type 1.

Background: Activated phosphatidylinositol-3-OH kinase δ syndrome type 1 (APDS1) is a recently described primary immunodeficiency syndrome characterized by recurrent respiratory tract infections, lymphoid hyperplasia, and Herpesviridae infections caused by germline gain-of-function mutations of PIK3CD. Hematopoietic stem cell transplantation (HSCT) can be considered to ameliorate progressive immunodeficiency and associated malignancy, but appropriate indications, methods, and outcomes of HSCT for APDS1 remain undefined.

Objective: Our objective was to analyze the clinical manifestations, laboratory findings, prognosis, and treatment of APDS1 and explore appropriate indications and methods of HSCT.

Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome.

Activated PI3Kδ syndrome (APDS) is a primary immunodeficiency characterized by recurrent respiratory tract infections, lymphoproliferation, and defective IgG production. Heterozygous mutations in , or , 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.

Droplet Digital PCR-Based Chimerism Analysis for Primary Immunodeficiency Diseases.

Objective: In the current study, we aimed to accurately evaluate donor/recipient or male/female chimerism in samples from patients who underwent hematopoietic stem cell transplantation (HSCT).

Methods: We designed the droplet digital polymerase chain reaction (ddPCR) for SRY and RPP30 to detect the male/female chimerism. We also developed mutation-specific ddPCR for four primary immunodeficiency diseases.

Common Variable Immunodeficiency Caused by FANC Mutations.

Common variable immunodeficiency (CVID) is the most common adult-onset primary antibody deficiency disease due to various causative genes. Several genes, which are known to be the cause of different diseases, have recently been reported as the cause of CVID in patients by performing whole exome sequencing (WES) analysis. Here, we found FANC gene mutations as a cause of adult-onset CVID in two patients.

Abnormal hematopoiesis and autoimmunity in human subjects with germline IKZF1 mutations.

Background: Ikaros, which is encoded by IKZF1, is a transcriptional factor that play a critical role in hematopoiesis. Somatic IKZF1 alterations are known to be involved in the pathogenesis of leukemia in human subjects. Recently, immunodeficiency caused by germline IKZF1 mutation has been described.

Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency.

Background: Activated phosphatidylinositol 3-kinase δ syndrome (APDS) is a recently discovered primary immunodeficiency disease (PID). Excess phosphatidylinositol 3-kinase (PI3K) activity linked to mutations in 2 PI3K genes, PIK3CD and PIK3R1, causes APDS through hyperphosphorylation of AKT, mammalian target of rapamycin (mTOR), and S6.

Objective: This study aimed to identify novel genes responsible for APDS.

Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase δ syndrome 2: A cohort study.

Background: Activated phosphoinositide 3-kinase δ syndrome (APDS) 2 (p110δ-activating mutations causing senescent T cells, lymphadenopathy, and immunodeficiency [PASLI]-R1), a recently described primary immunodeficiency, results from autosomal dominant mutations in PIK3R1, the gene encoding the regulatory subunit (p85α, p55α, and p50α) of class IA phosphoinositide 3-kinases.

Objectives: We sought to review the clinical, immunologic, and histopathologic phenotypes of APDS2 in a genetically defined international patient cohort.

Methods: The medical and biological records of 36 patients with genetically diagnosed APDS2 were collected and reviewed.

Clinical features and hematopoietic stem cell transplantations for CD40 ligand deficiency in Japan.

Background: The long-term outcome of X-linked hyper-IgM syndrome (XHIM) caused by mutations in CD40LG is poor, and the only curative treatment is hematopoietic stem cell transplantation (HSCT).

Objective: We sought to determine the clinical features and factors affecting outcomes in patients with XHIM.

Methods: We enrolled and retrospectively analyzed data from 56 Japanese patients with XHIM, including 29 patients who received HSCT.

Analysis of somatic hypermutations in the IgM switch region in human B cells.

Background: The molecular mechanism of class-switch recombination (CSR) in human subjects has not been fully elucidated. The CSR-induced mutations occurring in the switch region of the IgM gene (Smu-SHMs) in in vitro CSR-activated and in vivo switched B cells have been analyzed in mice but not in human subjects.

Objective: We sought to better characterize the molecular mechanism of CSR in human subjects.