Primary immunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency

• Published in: Journal of allergy and clinical immunology Vol. 142; no. 5; pp. 1650 - 1653.e2
• Main Authors: Sogkas, Georgios, Fedchenko, Mykola, Dhingra, Akshay, Jablonka, Alexandra, Schmidt, Reinhold E., Atschekzei, Faranaz
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.11.2018; Elsevier Limited
• Subjects: Adaptive immunity; Age; Antibiotics; Bioinformatics; Blood & organ donations; Cytotoxicity; Diarrhea; Granulocytes; Human subjects; Immune system; Immunodeficiency; Immunoglobulins; Inflammatory bowel disease; Kinases; Lymphocytes; Mutation; Patients; Phosphorylation; Pneumonia; Primary immunodeficiencies; Sepsis; Streptococcus infections
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2018.06.039

The consequences of PI3Kδ deficiency have been extensively characterized in mice, providing much of our knowledge on the biological role of PI3Kδ, such as its involvement in early development of B cells and regulation of adaptive immune responses.2 Heterozygous gain-of-function mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit δ gene (PIK3CD; the gene encoding p110δ) cause a primary immunodeficiency disorder characterized by both immunodeficiency and immune dysregulation (activated PI3Kδ syndrome). At the age of 8 years, he had recurrent diarrhea caused by inflammatory colitis, which was diagnosed as Crohn disease and successfully treated with mesalazine for approximately 2 years. Since the age of 12 years, he had recurrent respiratory tract infections, including 2 cases of severe pneumonia that required hospitalization and administration of intravenous antibiotics. Sorted cells were cultured in RPMI 1640 medium/10% FCS for 30 minutes in the presence of IC87114 (Merck, Whitehouse Station, NJ) or an equal amount of dimethyl sulfoxide and were subsequently stimulated with anti-CD3 antibody for 10 minutes, as described previously.E2 Cells were then permeabilized and prepared for staining with the Transcription Factor Phospho Buffer Set (BD Biosciences), according to the manufacturer's protocol; stained with an Alexa Fluor 647–conjugated mAb against phospho-AKT (Ser473; Cell Signaling, Danvers, Mass); and analyzed with a FACSCalibur flow cytometer (Becton Dickinson). Deceased patient Living patient Year of birth 1994 1995 Sex Male Male Infections Recurrent sinopulmonary infections since infancy, including 1 case of pneumonia accompanied by Streptococcus pneumoniae sepsis, chronic diarrhea (diagnosed as postenteritis syndrome) Osteomyelitis at age of 8 months, recurrent sinopulmonary infections since the 12th year of life, including 2 cases of severe pneumonia Other clinical manifestations Chronic diarrhea (diagnosed as postenteritis syndrome) Diagnosis of Crohn disease at age 12 years, diagnosis of psoriasis at age 18 years Serum immunoglobulin concentration IgG (g/L) 2.83 (5-13)∗ 2.7 (7-16) IgA (g/L) 0.16 (0.4-1.8) 0.3 (0.7-4) IgM (g/L) <0.15 (0.4-1.8) 0.53 (0.4-2.3) Complement Total complement activity CH50 (%) >165 (90-150) >165 (90-150) C3c (g/L) 1.55 (0.9-1.8) 1.22 (0.9-1.8) C4 (g/L) 0.38 (0.1-0.4) 0.26 (0.1-0.4) Lymphocyte subset analysis Lymphocyte count (cells/μL) 4,560 (1,700-6,900) 2,204 (1,000-2,800) CD3+ (relative %) 72% (43% to 76%) 80% (55% to 83%) CD3+CD4+ (relative %) 37% (23% to 48%) 37.3% (28% to 57%) CD3+CD8+ (relative %) 30% (14% to 33%) 40.1% (10% to 39%) CD3−CD16+CD56+ (relative %) 10.2% (4% to 23%) 8.4% (7% to 31%) CD19+ (relative %) 0.6% (14% to 44%) 1.3% (6% to 19%) Lymphocyte proliferation assay PHA (cells/μL) 45,567 (34,797) 34,298 (32,100) Concanavalin A (cells/μL) 22,032 (21,560) 8,208 (6,234) Pokeweed mitogen (cells/μL) NM 9,644 (11,001) IL-2 (cells/μL) 5,743 (4,734) 3,340 (4,011) Anti-CD3 antibody (cells/μL) 21,440 (20,674) 22,012 (25,325) Granulocyte phenotyping CD16 (%) NM 93 (96) CD32 (%) NM 100 (100) CD64 (%) NM 13 (1) CD18 (%) NM 100 (100) CD11b (%) NM 100 (100) CD15 (%) NM 94 (99) Granulocyte function tests Phagocytosis of Escherichia coli (%) 96 (100) 98 (99) Oxidative burst induction N-formyl-methionyl-leucyl-phenylalanine (%) NM 35 (8) E coli (%) 94 (96) 98 (100) Phorbol 12-myristate 13-acetate (%) 100 (99) 100 (100) NK cell activity Natural cytotoxicity (1:30) 5 (27) 4 (30) ADCC (1:30) 9 (42) 11 (58) Table I Characteristics of patients with PI3Kδ deficiency Lymphocytes 2204 cells/μL (38% of leukocytes) CD19+ B cells 1.3% CD27−IgM+IgD+ naive B cells 1% CD27+IgM+IgD+ memory B cells 0.1% CD27+IgM−IgD− switched memory B cells 0% CD38++IgM++ transitional B cells 0.1% CD38+++IgM−/+ plasma cells 0.1% CD21lowCD38low B cells 0% CD16+CD56+CD3− NK cells 8.4% CD3+ T cells 80% CD3+CD4+ helper cells 37.3 % CD3+CD8+ cytotoxic T cells 40.1% CD3+TCR2+ α/β T cells 65.8% CD4/CD8 double-negative TCR2+ cells 0.6% CD4+CD45RO+ CD4 memory cells 14.7% Circulating CXCR5+CD4+ T cells 1.8% CD4+CD25+CD127low regulatory T cells 3.1% CD4+CD45RA+ naive CD4 T cells 20% CD4+CD45RA+CD31+ recent thymic emigrant T cells 14.7% CD8+CD27−CD28− late CD8 effector cells 15.2% CD8+CD27+CD28− effector cells 3% Table E1 Peripheral B- and T-lymphocyte subsets in a patient aged 16 years with PI3Kδ deficiency