Journal of Clinical Immunology

, Volume 39, Issue 2, pp 148–158 | Cite as

Immune Dysregulation and Disease Pathogenesis due to Activating Mutations in PIK3CD—the Goldilocks’ Effect

  • Stuart G. TangyeEmail author
  • Julia Bier
  • Anthony Lau
  • Tina Nguyen
  • Gulbu Uzel
  • Elissa K. Deenick
CME Review


“This porridge is too hot!” she exclaimed. So, she tasted the porridge from the second bowl. “This porridge is too cold,” she said. So, she tasted the last bowl of porridge. “Ahhh, this porridge is just right,” she said happily and she ate it all up. While this describes the adventures of Goldilocks in the classic fairytale “The Story of Goldilocks and the Three Bears,” it is an ideal analogy for the need for balanced signaling mediated by phosphatidylinositol-3-kinase (PI3K), a key signaling hub in immune cells. Either too little or too much PI3K activity is deleterious, even pathogenic—it needs to be “just right”! This has been elegantly demonstrated by the identification of inborn errors of immunity in key components of the PI3K pathway, and the impact of these mutations on immune regulation. Detailed analyses of patients with germline activating mutations in PIK3CD, as well as the parallel generation of novel murine models of this disease, have shed substantial light on the role of PI3K in lymphocyte development and differentiation, and mechanisms of disease pathogenesis resulting not only from PIK3CD mutations but genetic lesions in other components of the PI3K pathway. Furthermore, by being able to pharmacologically target PI3K, these monogenic conditions have provided opportunities for the implementation of precision medicine as a therapy, as well as to gain further insight into the consequences of modulating the PI3K pathway in clinical settings.


PI3 kinase activated PI3Kinase delta syndrome combined immunodeficiency 


Funding Information

Research performed in the Tangye and Deenick labs is supported by the National Health and Medical Research Council of Australia, Cancer Council NSW and NIAID, NIH. SGT was a Principal Research Fellow of the NHMRC; JB is supported by the Postgraduate Research Scholarship awarded by Fundação Estudar (Brazil); AL is supported by a Tuition Fee Scholarship from UNSW Sydney; TN is supported by a Research Training Program Scholarship awarded by the Australian Government; GU is supported by the Division of Intramural Research, National Institute of Allergy and Infectious Diseases, NIH; EKD is a Scientia Research Fellow of UNSW Sydney.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no competing financial interests.


  1. 1.
    Okkenhaug K. Signaling by the phosphoinositide 3-kinase family in immune cells. Annu Rev Immunol. 2013;31:675–704. Scholar
  2. 2.
    Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317–30. Scholar
  3. 3.
    Fruman DA, Chiu H, Hopkins BD, Bagrodia S, Cantley LC, Abraham RT. The PI3K pathway in human disease. Cell. 2017;170(4):605–35. Scholar
  4. 4.
    Jellusova J, Miletic AV, Cato MH, Lin WW, Hu Y, Bishop GA, et al. Context-specific BAFF-R signaling by the NF-kappaB and PI3K pathways. Cell Rep. 2013;5(4):1022–35. Scholar
  5. 5.
    Limon JJ, Fruman DA. Akt and mTOR in B cell activation and differentiation. Front Immunol. 2012;3:228. Scholar
  6. 6.
    Yong PF, Salzer U, Grimbacher B. The role of costimulation in antibody deficiencies: ICOS and common variable immunodeficiency. Immunol Rev. 2009;229(1):101–13. Scholar
  7. 7.
    Gigoux M, Shang J, Pak Y, Xu M, Choe J, Mak TW, et al. Inducible costimulator promotes helper T-cell differentiation through phosphoinositide 3-kinase. Proc Natl Acad Sci U S A. 2009;106(48):20371–6. Scholar
  8. 8.
    Ostiguy V, Allard EL, Marquis M, Leignadier J, Labrecque N. IL-21 promotes T lymphocyte survival by activating the phosphatidylinositol-3 kinase signaling cascade. J Leukoc Biol. 2007;82(3):645–56. Scholar
  9. 9.
    Fruman DA, Snapper SB, Yballe CM, Davidson L, Yu JY, Alt FW, et al. Impaired B cell development and proliferation in absence of phosphoinositide 3-kinase p85alpha. Science. 1999;283(5400):393–7.Google Scholar
  10. 10.
    Suzuki H, Terauchi Y, Fujiwara M, Aizawa S, Yazaki Y, Kadowaki T, et al. Xid-like immunodeficiency in mice with disruption of the p85alpha subunit of phosphoinositide 3-kinase. Science. 1999;283(5400):390–2.Google Scholar
  11. 11.
    Clayton E, Bardi G, Bell SE, Chantry D, Downes CP, Gray A, et al. A crucial role for the p110delta subunit of phosphatidylinositol 3-kinase in B cell development and activation. J Exp Med. 2002;196(6):753–63.Google Scholar
  12. 12.
    Okkenhaug K, Bilancio A, Farjot G, Priddle H, Sancho S, Peskett E, et al. Impaired B and T cell antigen receptor signaling in p110delta PI 3-kinase mutant mice. Science. 2002;297(5583):1031–4. Scholar
  13. 13.
    Jou ST, Carpino N, Takahashi Y, Piekorz R, Chao JR, Carpino N, et al. Essential, nonredundant role for the phosphoinositide 3-kinase p110delta in signaling by the B-cell receptor complex. Mol Cell Biol. 2002;22(24):8580–91.Google Scholar
  14. 14.
    Srinivasan L, Sasaki Y, Calado DP, Zhang B, Paik JH, DePinho RA, et al. PI3 kinase signals BCR-dependent mature B cell survival. Cell. 2009;139(3):573–86. Scholar
  15. 15.
    Anzelon AN, Wu H, Rickert RC. Pten inactivation alters peripheral B lymphocyte fate and reconstitutes CD19 function. Nat Immunol. 2003;4(3):287–94. Scholar
  16. 16.
    Suzuki A, Kaisho T, Ohishi M, Tsukio-Yamaguchi M, Tsubata T, Koni PA, et al. Critical roles of Pten in B cell homeostasis and immunoglobulin class switch recombination. J Exp Med. 2003;197(5):657–67.Google Scholar
  17. 17.
    Sander S, Chu VT, Yasuda T, Franklin A, Graf R, Calado DP, et al. PI3 kinase and FOXO1 transcription factor activity differentially control B cells in the germinal center light and dark zones. Immunity. 2015;43(6):1075–86. Scholar
  18. 18.
    Dominguez-Sola D, Kung J, Holmes AB, Wells VA, Mo T, Basso K, et al. The FOXO1 transcription factor instructs the germinal center dark zone program. Immunity. 2015;43(6):1064–74. Scholar
  19. 19.
    Omori SA, Cato MH, Anzelon-Mills A, Puri KD, Shapiro-Shelef M, Calame K, et al. Regulation of class-switch recombination and plasma cell differentiation by phosphatidylinositol 3-kinase signaling. Immunity. 2006;25(4):545–57. Scholar
  20. 20.
    Dengler HS, Baracho GV, Omori SA, Bruckner S, Arden KC, Castrillon DH, et al. Distinct functions for the transcription factor Foxo1 at various stages of B cell differentiation. Nat Immunol. 2008;9(12):1388–98. Scholar
  21. 21.
    Suzuki A, Yamaguchi MT, Ohteki T, Sasaki T, Kaisho T, Kimura Y, et al. T cell-specific loss of Pten leads to defects in central and peripheral tolerance. Immunity. 2001;14(5):523–34.Google Scholar
  22. 22.
    Okkenhaug K, Patton DT, Bilancio A, Garcon F, Rowan WC, Vanhaesebroeck B. The p110delta isoform of phosphoinositide 3-kinase controls clonal expansion and differentiation of Th cells. J Immunol. 2006;177(8):5122–8.Google Scholar
  23. 23.
    Soond DR, Bjorgo E, Moltu K, Dale VQ, Patton DT, Torgersen KM, et al. PI3K p110delta regulates T-cell cytokine production during primary and secondary immune responses in mice and humans. Blood. 2010;115(11):2203–13. Scholar
  24. 24.
    Rolf J, Bell SE, Kovesdi D, Janas ML, Soond DR, Webb LM, et al. Phosphoinositide 3-kinase activity in T cells regulates the magnitude of the germinal center reaction. J Immunol. 2010;185(7):4042–52. Scholar
  25. 25.
    Awasthi A, Samarakoon A, Dai X, Wen R, Wang D, Malarkannan S. Deletion of PI3K-p85alpha gene impairs lineage commitment, terminal maturation, cytokine generation and cytotoxicity of NK cells. Genes Immun. 2008;9(6):522–35. Scholar
  26. 26.
    Guo H, Samarakoon A, Vanhaesebroeck B, Malarkannan S. The p110 delta of PI3K plays a critical role in NK cell terminal maturation and cytokine/chemokine generation. J Exp Med. 2008;205(10):2419–35. Scholar
  27. 27.
    Conley ME, Dobbs AK, Quintana AM, Bosompem A, Wang YD, Coustan-Smith E, et al. Agammaglobulinemia and absent B lineage cells in a patient lacking the p85alpha subunit of PI3K. J Exp Med. 2012;209(3):463–70. Scholar
  28. 28.
    Crank MC, Grossman JK, Moir S, Pittaluga S, Buckner CM, Kardava L, et al. Mutations in PIK3CD can cause hyper IgM syndrome (HIGM) associated with increased cancer susceptibility. J Clin Immunol. 2014;34(3):272–6. Scholar
  29. 29.
    Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hulsdunker J, Eskandarian Z, et al. Activating PI3Kdelta mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183(2):221–9. Scholar
  30. 30.
    Hartman HN, Niemela J, Hintermeyer MK, Garofalo M, Stoddard J, Verbsky JW, et al. Gain of function mutations of PIK3CD as a cause of primary Sclerosing cholangitis. J Clin Immunol. 2014;35:11–4. Scholar
  31. 31.
    Bier J, Rao G, Payne K, Brigden H, French E, Pelham SJ, et al. Activating mutations in PIK3CD disrupt the differentiation and function of human and murine CD4(+) T cells. J Allergy Clin Immunol. 2019.
  32. 32.
    Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597–606 e4. Scholar
  33. 33.
    Edwards ESJ, Bier J, Cole TS, Wong M, Hsu P, Berglund LJ, et al. Activating PIK3CD mutations impair human cytotoxic lymphocyte differentiation and function and EBV immunity. J Allergy Clin Immunol. 2019;143(1):276–91 e6. Scholar
  34. 34.
    Kracker S, Curtis J, Ibrahim MA, Sediva A, Salisbury J, Campr V, et al. Occurrence of B-cell lymphomas in patients with activated phosphoinositide 3-kinase delta syndrome. J Allergy Clin Immunol. 2014;134(1):233–6. Scholar
  35. 35.
    Goto F, Uchiyama T, Nakazawa Y, Imai K, Kawai T, Onodera M. Persistent impairment of T-cell regeneration in a patient with activated PI3K delta syndrome. J Clin Immunol. 2017;37(4):347–50. Scholar
  36. 36.
    Wentink M, Dalm V, Lankester AC, van Schouwenburg PA, Scholvinck L, Kalina T, et al. Genetic defects in PI3Kdelta affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections. Clin Immunol. 2017;176:77–86. Scholar
  37. 37.
    Wentink MWJ, Mueller YM, Dalm V, Driessen GJ, van Hagen PM, van Montfrans JM, et al. Exhaustion of the CD8(+) T cell compartment in patients with mutations in phosphoinositide 3-Kinase Delta. Front Immunol. 2018;9:446. Scholar
  38. 38.
    Maccari ME, Abolhassani H, Aghamohammadi A, Aiuti A, Aleinikova O, Bangs C, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase delta syndrome: the European Society for Immunodeficiencies-Activated Phosphoinositide 3-kinase delta syndrome registry. Front Immunol. 2018;9:543. Scholar
  39. 39.
    Tsujita Y, Mitsui-Sekinaka K, Imai K, Yeh TW, Mitsuiki N, Asano T, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase delta syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016;138(6):1672–80 e10. Scholar
  40. 40.
    Michalovich D, Nejentsev S. Activated PI3 Kinase Delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369. Scholar
  41. 41.
    Dulau Florea AE, Braylan RC, Schafernak KT, Williams KW, Daub J, Goyal RK, et al. Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD. J Allergy Clin Immunol. 2017;139(3):1032–5 e6. Scholar
  42. 42.
    Nademi Z, Slatter MA, Dvorak CC, Neven B, Fischer A, Suarez F, et al. Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome. J Allergy Clin Immunol. 2017;139(3):1046–9. Scholar
  43. 43.
    Okano T, Imai K, Tsujita Y, Mitsuiki N, Yoshida K, Kamae C, et al. Hematopoietic stem cell transplantation for progressive combined immunodeficiency and lymphoproliferation in patients with activated phosphatidylinositol-3-OH kinase delta syndrome type 1. J Allergy Clin Immunol. 2019;143(1):266–75. Scholar
  44. 44.
    Deau MC, Heurtier L, Frange P, Suarez F, Bole-Feysot C, Nitschke P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923–8. Scholar
  45. 45.
    Lucas CL, Zhang Y, Venida A, Wang Y, Hughes J, McElwee J, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537–47. Scholar
  46. 46.
    Elkaim E, Neven B, Bruneau J, Mitsui-Sekinaka K, Stanislas A, Heurtier L, et al. Clinical and immunologic phenotype associated with activated phosphoinositide 3-kinase delta syndrome 2: a cohort study. J Allergy Clin Immunol. 2016;138(1):210–8 e9. Scholar
  47. 47.
    Bravo Garcia-Morato M, Garcia-Minaur S, Molina Garicano J, Santos Simarro F, Del Pino Molina L, Lopez-Granados E, et al. Mutations in PIK3R1 can lead to APDS2, SHORT syndrome or a combination of the two. Clin Immunol. 2017;179:77–80. Scholar
  48. 48.
    Kuhlen M, Honscheid A, Loizou L, Nabhani S, Fischer U, Stepensky P, et al. De novo PIK3R1 gain-of-function with recurrent sinopulmonary infections, long-lasting chronic CMV-lymphadenitis and microcephaly. Clin Immunol. 2016;162:27–30. Scholar
  49. 49.
    Petrovski S, Parrott RE, Roberts JL, Huang H, Yang J, Gorentla B, et al. Dominant splice site mutations in PIK3R1 cause hyper IgM syndrome, lymphadenopathy and short stature. J Clin Immunol. 2016;36(5):462–71. Scholar
  50. 50.
    Lougaris V, Faletra F, Lanzi G, Vozzi D, Marcuzzi A, Valencic E, et al. Altered germinal center reaction and abnormal B cell peripheral maturation in PI3KR1-mutated patients presenting with HIGM-like phenotype. Clin Immunol. 2015;159(1):33–6. Scholar
  51. 51.
    Olbrich P, Lorenz M, Cura Daball P, Lucena JM, Rensing-Ehl A, Sanchez B, et al. Activated PI3Kdelta syndrome type 2: two patients, a novel mutation, and review of the literature. Pediatr Allergy Immunol. 2016;27(6):640–4. Scholar
  52. 52.
    Martinez-Saavedra MT, Garcia-Gomez S, Dominguez Acosta A, Mendoza Quintana JJ, Paez JP, Garcia-Reino EJ, et al. Gain-of-function mutation in PIK3R1 in a patient with a narrow clinical phenotype of respiratory infections. Clin Immunol. 2016;173:117–20. Scholar
  53. 53.
    Browning MJ, Chandra A, Carbonaro V, Okkenhaug K, Barwell J. Cowden’s syndrome with immunodeficiency. J Med Genet. 2015;52(12):856–9. Scholar
  54. 54.
    Driessen GJ, H IJ, Wentink M, Yntema HG, van Hagen PM, van Strien A, et al. Increased PI3K/Akt activity and deregulated humoral immune response in human PTEN deficiency. J Allergy Clin Immunol. 2016;138(6):1744–7 e5. Scholar
  55. 55.
    Tang P, Upton JEM, Barton-Forbes MA, Salvadori MI, Clynick MP, Price AK, et al. Autosomal recessive Agammaglobulinemia due to a homozygous mutation in PIK3R1. J Clin Immunol. 2017;38:88–95. Scholar
  56. 56.
    Angulo I, Vadas O, Garcon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase delta gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–71. Scholar
  57. 57.
    Lucas CL, Kuehn HS, Zhao F, Niemela JE, Deenick EK, Palendira U, et al. Dominant-activating germline mutations in the gene encoding the PI(3)K catalytic subunit p110delta result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88–97. Scholar
  58. 58.
    Takeda AJ, Zhang Y, Dornan GL, Siempelkamp BD, Jenkins ML, Matthews HF, et al. Novel PIK3CD mutations affecting N-terminal residues of p110delta cause activated PI3Kdelta syndrome (APDS) in humans. J Allergy Clin Immunol. 2017;140(4):1152–6 e10. Scholar
  59. 59.
    Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kdelta regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc Natl Acad Sci U S A. 2017;114(8):1982–7. Scholar
  60. 60.
    Jou ST, Chien YH, Yang YH, Wang TC, Shyur SD, Chou CC, et al. Identification of variations in the human phosphoinositide 3-kinase p110delta gene in children with primary B-cell immunodeficiency of unknown aetiology. Int J Immunogenet. 2006;33(5):361–9. Scholar
  61. 61.
    Rae W, Ramakrishnan KA, Gao Y, Ashton-Key M, Pengelly RJ, Patel SV, et al. Precision treatment with sirolimus in a case of activated phosphoinositide 3-kinase delta syndrome. Clin Immunol. 2016;171:38–40. Scholar
  62. 62.
    Rao VK, Webster S, Dalm V, Sediva A, van Hagen PM, Holland S, et al. Effective 'Activated PI3Kdelta Syndrome'-targeted therapy with the PI3Kdelta inhibitor leniolisib. Blood. 2017;130:2307–16. Google Scholar
  63. 63.
    Avery DT, Kane A, Nguyen T, Lau A, Nguyen A, Lenthall H, et al. Germline-activating mutations in PIK3CD compromise B cell development and function. J Exp Med. 2018;215(8):2073–95. Scholar
  64. 64.
    Preite S, Cannons JL, Radtke AJ, Vujkovic-Cvijin I, Gomez-Rodriguez J, Volpi S, et al. Hyperactivated PI3Kdelta promotes self and commensal reactivity at the expense of optimal humoral immunity. Nat Immunol. 2018;19(9):986–1000. Scholar
  65. 65.
    Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136(4):993–1006 e1. Scholar
  66. 66.
    Morita R, Schmitt N, Bentebibel SE, Ranganathan R, Bourdery L, Zurawski G, et al. Human blood CXCR5(+)CD4(+) T cells are counterparts of T follicular cells and contain specific subsets that differentially support antibody secretion. Immunity. 2011;34(1):108–21. Scholar
  67. 67.
    Unger S, Seidl M, van Schouwenburg P, Rakhmanov M, Bulashevska A, Frede N, et al. The TH1 phenotype of follicular helper T cells indicates an IFN-gamma-associated immune dysregulation in patients with CD21low common variable immunodeficiency. J Allergy Clin Immunol. 2018;141(2):730–40. Scholar
  68. 68.
    Zhang TT, Okkenhaug K, Nashed BF, Puri KD, Knight ZA, Shokat KM, et al. Genetic or pharmaceutical blockade of p110delta phosphoinositide 3-kinase enhances IgE production. J Allergy Clin Immunol. 2008;122(4):811–9 e2. Scholar
  69. 69.
    Cannons JL, Preite S, Kapnick SM, Uzel G, Schwartzberg PL. Genetic defects in phosphoinositide 3-kinase delta influence CD8(+) T cell survival, differentiation, and function. Front Immunol. 2018;9:1758. Scholar
  70. 70.
    Kaech SM, Cui W. Transcriptional control of effector and memory CD8+ T cell differentiation. Nat Rev Immunol. 2012;12(11):749–61. Scholar
  71. 71.
    Ruiz-Garcia R, Vargas-Hernandez A, Chinn IK, Angelo LS, Cao TN, Coban-Akdemir Z, et al. Mutations in PI3K110delta cause impaired natural killer cell function partially rescued by rapamycin treatment. J Allergy Clin Immunol. 2018;142:605–617.e7. Scholar
  72. 72.
    Browne CD, Del Nagro CJ, Cato MH, Dengler HS, Rickert RC. Suppression of phosphatidylinositol 3,4,5-trisphosphate production is a key determinant of B cell anergy. Immunity. 2009;31(5):749–60. Scholar
  73. 73.
    Chen Z, Getahun A, Chen X, Dollin Y, Cambier JC, Wang JH. Imbalanced PTEN and PI3K signaling impairs class switch recombination. J Immunol. 2015;195(11):5461–71. Scholar
  74. 74.
    Miletic AV, Anzelon-Mills AN, Mills DM, Omori SA, Pedersen IM, Shin DM, et al. Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. J Exp Med. 2010;207(11):2407–20. Scholar
  75. 75.
    Stark AK, Chandra A, Chakraborty K, Alam R, Carbonaro V, Clark J, et al. PI3Kdelta hyper-activation promotes development of B cells that exacerbate Streptococcus pneumoniae infection in an antibody-independent manner. Nat Commun. 2018;9(1):3174. Scholar
  76. 76.
    Wray-Dutra MN, Al Qureshah F, Metzler G, Oukka M, James RG, Rawlings DJ. Activated PIK3CD drives innate B cell expansion yet limits B cell-intrinsic immune responses. J Exp Med. 2018;215(10):2485–96. Scholar
  77. 77.
    Preite S, Huang B, Cannons JL, McGavern DB, Schwartzberg PL. PI3K orchestrates T follicular helper cell differentiation in a context dependent manner: implications for autoimmunity. Front Immunol. 2018;9:3079. Scholar
  78. 78.
    Chudasama KK, Winnay J, Johansson S, Claudi T, Konig R, Haldorsen I, et al. SHORT syndrome with partial lipodystrophy due to impaired phosphatidylinositol 3 kinase signaling. Am J Hum Genet. 2013;93(1):150–7. Scholar
  79. 79.
    Dyment DA, Smith AC, Alcantara D, Schwartzentruber JA, Basel-Vanagaite L, Curry CJ, et al. Mutations in PIK3R1 cause SHORT syndrome. Am J Hum Genet. 2013;93(1):158–66. Scholar
  80. 80.
    Thauvin-Robinet C, Auclair M, Duplomb L, Caron-Debarle M, Avila M, St-Onge J, et al. PIK3R1 mutations cause syndromic insulin resistance with lipoatrophy. Am J Hum Genet. 2013;93(1):141–9. Scholar
  81. 81.
    Marsh DJ, Coulon V, Lunetta KL, Rocca-Serra P, Dahia PL, Zheng Z, et al. Mutation spectrum and genotype-phenotype analyses in Cowden disease and Bannayan-Zonana syndrome, two hamartoma syndromes with germline PTEN mutation. Hum Mol Genet. 1998;7(3):507–15.Google Scholar
  82. 82.
    Chen HH, Handel N, Ngeow J, Muller J, Huhn M, Yang HT, et al. Immune dysregulation in patients with PTEN hamartoma tumor syndrome: analysis of FOXP3 regulatory T cells. J Allergy Clin Immunol. 2017;139(2):607–20 e15. Scholar
  83. 83.
    Zhang K, Husami A, Marsh R, Jordan MB. Identification of a phosphoinositide 3-kinase (PI-3K) p110 delta (PIK3CD) deficent individual. J Clin Immunol. 2013;33:673–4.Google Scholar
  84. 84.
    Sogkas G, Fedchenko M, Dhingra A, Jablonka A, Schmidt RE, Atschekzei F. Primary immunodeficiency disorder caused by phosphoinositide 3-kinase delta deficiency. J Allergy Clin Immunol. 2018;142(5):1650–3 e2. Scholar
  85. 85.
    Cohen SB, Bainter W, Johnson JL, Lin TY, Wong JCY, Wallace JG, et al. Human primary immunodeficiency caused by expression of a kinase-dead p110delta mutant. J Allergy Clin Immunol. 2018;143:797–799.e2. Scholar
  86. 86.
    Sharfe N, Karanxha A, Dadi H, Merico D, Chitayat D, Herbrick JA, et al. Dual loss of p110delta PI3-kinase and SKAP (KNSTRN) expression leads to combined immunodeficiency and multisystem syndromic features. J Allergy Clin Immunol. 2018;142(2):618–29. Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Stuart G. Tangye
    • 1
    • 2
    Email author
  • Julia Bier
    • 1
    • 2
  • Anthony Lau
    • 1
    • 2
  • Tina Nguyen
    • 1
    • 2
  • Gulbu Uzel
    • 3
  • Elissa K. Deenick
    • 1
    • 2
  1. 1.Immunology, Garvan Institute of Medical ResearchDarlinghurstAustralia
  2. 2.St Vincent’s Clinical SchoolUniversity of New South WalesDarlinghurstAustralia
  3. 3.Laboratory of Clinical Immunology and MicrobiologyNational Institutes of Allergy and Infectious Diseases, National Institutes of HealthBethesdaUSA

Personalised recommendations