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• W2897987907 abstract "Human class IA phosphoinositide 3-kinases (PI3Ks) are lipid kinases that catalyze the phosphorylation of inactive phosphatitdylinositol-4,5-biphosphonate (PIP2) to biologically active phosphatitdylinositol-3,4,5-trisphonate (PIP3), leading to signaling that regulates cell growth, survival, and metabolism.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1177) Google Scholar Three catalytic subunits (p110α, p110β, and p110δ) heterodimerize with 1 of 5 regulatory subunits.1Fruman D.A. Chiu H. Hopkins B.D. Bagrodia S. Cantley L.C. Abraham R.T. The PI3K pathway in human disease.Cell. 2017; 170: 605-635Abstract Full Text Full Text PDF PubMed Scopus (1177) Google Scholar The importance of the p110δ in host immunity has been demonstrated by gain-of-function p110δ mutants, resulting in Activated Protein Kinase Delta Syndrome, and much more recently, human deficiency of p110δ.2Lucas C.L. Chandra A. Nejentsev S. Condliffe A.M. Okkenhaug K. PI3Kδ and primary immunodeficiencies.Nat Rev Immunol. 2016; 16: 702-714Crossref PubMed Scopus (195) Google Scholar, 3Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Sogkas G. Fedchenko M. Dhingra A. Jablonka A. Schmidt R.E. Atschekzei F. Primary immunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency.J Allergy Clin Immunol. 2018; 142: 1650-1653.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Here, we report an immunodeficiency due to a kinase-dead PI3Kδ mutant, illustrating the importance of p110δ catalytic activity in adaptive immunity. The patient was the son of consanguineous Pakistani parents, whose other son died at age 6 months because of sepsis. The patient received the attenuated BCG, polio, and measles vaccines without sequelae and was healthy until age 6 years, when he presented with chronic diarrhea and polyarticular arthritis affecting his knees and ankles. He was empirically treated with steroids for 2 months, leading to complete resolution of his symptoms. Over the subsequent 5 years, he had episodes of colitis treated with prednisone, sulfasalazine, and methotrexate for presumed inflammatory bowel disease. Because of worsening colitis, he underwent an upper endoscopy and colonoscopy that revealed candida esophagitis as well as increased intraepithelial lymphocytes and moderate villous blunting in the duodenum. His laboratory evaluation was notable for leukocytosis, neutrophilia, mild monocytosis, and thrombocytosis (Table I). He had normal numbers of T, B, and natural killer cells and normal percentages of T- and B-cell subsets. His serum levels of IgG and IgA were decreased. Ca2+ flux in response to anti-CD3 crosslinking on T cells was decreased (Fig 1, A), although proliferation to anti-CD3+CD28 stimulation was robust (Table I). Whole-exome sequencing of the patient revealed a novel homozygous frameshift mutation in PIK3CD (c.2558_2559delAT; p.Asp853Glyfs*20), disrupting exons 20 to 24 encoding 171 amino acids of the ATP binding site within the catalytic domain (Fig 1, B and C). This mutation is not in the 1000 Genomes, ExAC, or the National Heart, Lung, and Blood Institute Exome Sequencing Project databases. The patient was treated with immunoglobulin replacement therapy, antifungal prophylaxis, and prophylactic antibiotics, but died at the age of 14 years because of a severe pneumonia and sepsis shortly after the mutation was identified.Table IImmunological profile of the patient at age 11 yearsHemogram (103 cells/μL) White blood cells15.6 (4-10) Neutrophils10.5 (2.0-7.5) Lymphocytes3.2 (1.0-4.0) Monocytes1.2 (0.2-1.0) Platelets537 (150-400)Lymphocyte subsets (103Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar cells/μL) CD3+, 103 cells/μL1.7 (1.4-3.3)CD3+CD4+, 103 cells/μL0.6 (0.53-1.3)CD45RA+CCR7+ naive, % CD4+62.7 (57.1-84.8)CD45RA–CCR7+ central memory, % CD4+29.0 (11.2-30.0)CD45RA–CCR7– effector memory, % CD4+7.4 (3.3-15.2)CD45RA+CCR7– TEMRA, % CD4+0.7 (0.4-2.6)Recent thymic emigrants CD45RA+CD31+, % CD4+33.0 (41.2-81.5) CD3+CD8+, 103 cells/μL0.8 (0.33-0.92)CD45RA+CCR7+ naive, % CD8+58.2 (28.4-80.0)CD45RA–CCR7+ central memory, % CD8+6.0 (1.0-4.5)CD45RA–CCR7– effector memory, % CD8+22.5 (6.2-29.3)CD45RA+CCR7– TEMRA, % CD8+13.3 (9.1-40.1) CD19+, 103 cells/μL0.4 (0.11-0.57)CD27 – IgD+ naive, % CD19+80.5 (51.3-82.5)CD27+IgD+ unswitched memory, % CD19+4.4 (4.5-18.2)CD27+IgD– switched memory, % CD19+8.4 (8.5-25.6) CD3– CD56+, 103 cells/μL0.08 (0.07-0.48)Immunoglobulins (mg/dL) IgG201 (650-1600) IgM58 (50-300) IgA22 (40-350)Proliferation (% of control) Anti-CD3+CD28120%Boldface values are outside the normal ranges listed in parentheses. Open table in a new tab Boldface values are outside the normal ranges listed in parentheses. Because of the patient's death, analysis of p110δD853Gfs protein expression was not possible. Therefore, HEK293T cells were transiently transfected with constructs encoding N-terminal FLAG-tagged wild-type (WT) or mutant p110δ. Immunoblotting revealed expression of mutant PI3KδD853Gfs at a level comparable to that of WT p110δ (Fig 1, D). To assess kinase activity, WT and mutant p110δ were cotransfected in Expi293FTM cells with the polyhistidine-tagged p85α regulatory subunit. Nickel-nitrilotriacetic acid agarose was used to purify PI3K complexes composed of His-p85α and WT or mutant p110δ. The PI3KδD853Gfs mutant copurified with His-tagged p85α (Fig 1, E), but lacked kinase activity, as demonstrated by failure of recombinant PI3KδD853Gfs to convert PIP2 to PIP3 (Fig 1, F). During the preparation of this manuscript, 2 kindreds with loss-of-function (LOF) variants in PIK3CD were published, all of whom had hypogammaglobulinemia and recurrent sinopulmonary infections (see Table E1 in this article's Online Repository at www.jacionline.org).3Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Sogkas G. Fedchenko M. Dhingra A. Jablonka A. Schmidt R.E. Atschekzei F. Primary immunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency.J Allergy Clin Immunol. 2018; 142: 1650-1653.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar Protein expression of PI3Kδ was absent in 1 kindred, which also harbored a pathogenic mutation in the gene encoding the small kinetochore-associated protein, and was not investigated in the other kindred.3Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar, 4Sogkas G. Fedchenko M. Dhingra A. Jablonka A. Schmidt R.E. Atschekzei F. Primary immunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency.J Allergy Clin Immunol. 2018; 142: 1650-1653.e2Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar This study is therefore the first report of a patient with a combined immunodeficiency due to a kinase-dead p110δ mutant. Pik3cd−/− mice lacking PIK3CD as well as the kinase-dead p110δD910A mutant have indicated the importance of PI3Kδ in B-cell development and function.5Okkenhaug K. Bilancio A. Farjot G. Priddle H. Sancho S. Peskett E. et al.Impaired B and T cell antigen receptor signaling in p110δ PI 3-kinase mutant mice.Science. 2002; 297: 1031-1034PubMed Google Scholar, 6Clayton E. Bardi G. Bell S.E. Chantry D. Downes C.P. Gray A. et al.A crucial role for the p110δ subunit of phosphatidylinositol 3-kinase in B cell development and activation.J Exp Med. 2002; 196: 753-763Crossref PubMed Scopus (383) Google Scholar Specifically, the Pik3cd−/− and p110δD910A mice have absent marginal zone B cells and B-1 peritoneal B cells, hypogammaglobulinemia, impaired proliferation to IgM or CD40 ligation, and defective responses to T-independent and T-dependent antigen stimulation. Although p110δ is essential for B-cell function, it does not appear to be essential for the maintenance of total B-cell numbers. Normal B-cell numbers have been found in the Pik3cd−/− mice, the previously reported kindred lacking p110δ expression,3Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar and our patient with the kinase-dead p110δD853Gfs mutant. This may reflect the redundancy between p110δ and p110α in the antigen-independent, tonic B-cell receptor signaling important for the development and survival of follicular B cells.7Ramadani F. Bolland D.J. Garcon F. Emery J.L. Vanhaesebroeck B. Corcoran A.E. et al.The PI3K isoforms p110α and p110δ are essential for pre–B cell receptor signaling and B cell development.Sci Signal. 2010; 3: ra60Crossref PubMed Scopus (164) Google Scholar In contrast, MZ and B1 cell development depends on antigen-driven BCR signaling that requires intact p110δ. The p110δD910A mice as well as 3 of the 4 previously reported patients with LOF variants in PIK3CD have susceptibility to colitis, which is also a potential adverse effect associated with p110δ inhibitors used to treat solid and hematopoietic malignancies. This has been attributed to reduced secretion of IL-10 and increased secretion of IL-12/23 from colonic macrophages in response to enteric microbiota.8Steinbach E.C. Kobayashi T. Russo S.M. Sheikh S.Z. Gipson G.R. Kennedy S.T. et al.Innate PI3K p110δ regulates Th1/Th17 development and microbiota-dependent colitis.J Immunol. 2014; 192: 3958-3968Crossref PubMed Scopus (40) Google Scholar However, colitis is not a universal feature shared by all patients with LOF PIK3CD variants or p110δ inhibition, and has not been reported in Pik3cd−/− mice. Therefore, the susceptibility to colitis may reflect differences in microbiota, genetic background, or environmental factors. Our patient experienced no adverse sequelae from live vaccines and had normal T-cell proliferation to anti-CD3+CD28 stimulation. However, the p110δD853Gfs mutant impaired Ca2+ flux in T cells after anti-CD3 crosslinking (Fig 1, B). Previous reports of human PI3K deficiency have not assessed Ca2+ flux in patient lymphocytes; reduced Ca2+ flux has been shown in T cells from p110δD910A mice. Because the magnitude and frequency of Ca2+ flux oscillations in T cells correlates with the strength of downstream TCR signaling,9Dura B. Dougan S.K. Barisa M. Hoehl M.M. Lo C.T. Ploegh H.L. et al.Profiling lymphocyte interactions at the single-cell level by microfluidic cell pairing.Nat Commun. 2015; 6 (Available at:): 5940http://www.nature.com/articles/ncomms6940Crossref PubMed Scopus (123) Google Scholar our patient's reduced Ca2+ flux reflects a component of impaired cellular immunity in this disease. Of note, opportunistic infections with Pneumocystic jiroveci and Klebsiella aerogenes were reported in 1 patient with the p110δQ73X1 variant who also had a homozygous mutation in SKAP. Two of the 5 reported patients (40%) with LOF PIK3CD variants are deceased because of sepsis, indicating the severity of this immunodeficiency. Precise regulation of p110δ activity is required for the maintenance of host immunity. Our patient demonstrates the essential contribution of the p110δ catalytic domain. Additional patients and studies are needed to determine the outcomes of hematopoietic stem cell transplantation for the treatment of this immunodeficiency. Table E1Comparison of patients with loss-of-function mutations in PIK3CDCharacteristicPublicationCurrentSharfe et alE1Sharfe N. Karanxha A. Dadi H. Merico D. Chitayat D. Herbrick J.-A. et al.Dual loss of p110δ PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features.J Allergy Clin Immunol. 2018; 142: 618-629Abstract Full Text Full Text PDF PubMed Scopus (21) Google ScholarSogkas et alE2Sogkas G. Fedchenko M. Dhingra A. Jablonka A. Schmidt R.E. Atschekzei F. Primary fimmunodeficiency disorder caused by phosphoinositide 3–kinase δ deficiency.J Allergy Clin Immunol. 2018; 142: 1650-1653.e2Abstract Full Text Full Text PDF PubMed Scopus (36) Google ScholarNumber of patients12 siblings2 siblingsGenetic findings PIK3CD mutationD853Gfs*20Q721XV552Sfs*26 Truncated domainC-lobeN-lobeHelical p110δ protein expressionPresentAbsentNot reported Additional pathogenic mutationNoneL210fs in KNSTRN encoding SKAPNoneImmunophenotyping B-cell number (cells/μL)NormalBorderline low – normalReduced Hypogammaglobulinemia+++ T-cell numberNormalNormalNormal T-cell proliferationNormalReducedNormalClinical features Age at time of study (y)1114 and 2013 and 16 Current statusDeceased from sepsisAlive1 deceased from catheter-associated sepsis1 alive InfectionsPulmonary infectionsCandida esophagitisSinopulmonary infectionsOral candidiasisUrinary tract infectionsSinopulmonary infectionsSepsisOsteomyelitis Opportunistic infectionsNonePneumocystis jiroveciKlebsiella aerogenesNone Colitis+++ Other featuresArthritisFacial dysmorphismSkeletal abnormalitiesDevelopmental delayOptic nerve atrophyArthritisPsoriasisNone Open table in a new tab" @default.
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• W2897987907 title "Human primary immunodeficiency caused by expression of a kinase-dead p110δ mutant" @default.
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