Activated PI3K-Delta Syndrome: Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management
Abstract
Activated PI3 kinase delta syndrome (APDS) is a newly recognized primary immunodeficiency that was firstly discovered in 2013. APDS can result from gain-of-function mutations in PI3Kδ catalytic p110δ (PIK3CD known as APDS1) and regulatory p85α (PIK3R1 known as APDS2). Patients with APDS syndrome mostly present some major manifestations such as lymphadenopathy and autoimmune diseases like cytopenia and Immune thrombocytopenic purpura (ITP). Distinguishing APDS from the other antibody deficiencies such as the common variable immunodeficiency (CVID) and hyper IgM disorders is very important to use appropriate and targeted treatment strategies. In this review article, we attempted to discuss the pathogenesis, cell abnormality, clinical manifestations, diagnosis, and treatment of APDS disorder.
1. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies Nat Rev Immunol. 2016;16(11):702-14.
2. Zhang Q, Ma H, Ma J, Wang D, Zhao Y, Wang T, et al. Clinical and genetic analysis of immunodeficiency‐related diseases associated with PIK3CD mutations. Pediatr Investig. 2018;2(4):257-62.
3. Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369.
4. Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, et al. Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review. Clin Rev Allergy Immunol. 2019;10.1007/s12016-019-08738-9. doi:10.1007/s12016-019-08738-9 5. Singh A, Joshi V, Jindal AK, Mathew B, Rawat A. An updated review on activated PI3 kinase delta syndrome (APDS). Genes Dis. 2020;7(1):67-74.
6. Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676-87.
7. 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.
8. Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc Natl Acad Sci U S A 2017;114(8):1982-7.
9. 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.
10. 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 δ syndrome 2: A cohort study. J Allergy Clin Immunol. 2016;138(1):210-8.e9.
11. Condliffe AM, Chandra A. Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome. Front Immunol. 2018;9:338.
12. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4.
13. 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.
14. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science (New York, NY). 2013;342(6160):866-71.
15. Ewertowska M, Grześk E, Urbańczyk A, Dąbrowska A, Bąbol-Pokora K, Łęcka M, et al. Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys. Allergy Asthma Clin Immunol. 2020;16:22.
16. Lougaris V, Baronio M, Moratto D, Tampella G, Gazzurelli L, Facchetti M, et al. A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1). Clin Immunol. 2019;200:31-4.
17. 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 p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97.
18. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317-30.
19. Preite S, Gomez-Rodriguez J, Cannons JL, Schwartzberg PL. T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity. Immunol Rev. 2019;291(1):154-73.
20. Stokes CA, Condliffe AM. Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease. Biochem Soc Trans. 2018;46(2):361-9.
21. Magis-Escurra C, Reijers MH. Bronchiectasis. BMJ clinical evidence. BMJ Clin Evid. 2015;2015.
22. 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 δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543.
23. Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2019:1-11.
24. Martínez-Saavedra MT, García-Gomez S, Domínguez Acosta A, Mendoza Quintana JJ, Páez JP, García-Reino EJ, et al. Gain-of-function mutation in PIK3R1 in a patient with anarrow clinical phenotype of respiratory infections. Clin Immunol. 2016;173:117-120.
25. Asano T, Okada S, Tsumura M, Yeh TW, Mitsui-Sekinaka K, Tsujita Y, et al. Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome. Front Immunol. 2018;9:568.
26. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702-14.
27. Swan DJ, Aschenbrenner D, Lamb CA, Chakraborty K, Clark J, Pandey S, et al. Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ. Haematologica. 2019;104(10):e483-e6.
28. Preite S, Cannons JL, Radtke AJ, Vujkovic-Cvijin I, Gomez-Rodriguez J, Volpi S. Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity Nat Immunol. 2018;19(9):986-1000.
29. Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hülsdünker J, Eskandarian Z, et al. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183(2):221-9.
30. Cohen JI. Herpesviruses in the Activated Phosphatidylinositol-3-Kinase-δ Syndrome. Front Immunol. 2018;9:237.
31. Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood. 2014;124(15):2337-44.
32. Lucas M, Hugh-Jones K, Welby A, Misbah S, Spaeth P, Chapel H. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol. 2010;30 Suppl 1:S84-9.
33. Edgar JDM, Richter AG, Huissoon AP, Kumararatne DS, Baxendale HE, Bethune CA, et al. Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland. J Clin Immunol. 2018;38(2):204-13.
34. Berger M, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol. 2013;33(5):984-90.
35. 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 δ syndrome. J Allergy Clin Immunol. 2014;134(1):233-6.
36. Kannan JA, Dávila-Saldaña BJ, Zhang K, Filipovich AH, Kucuk ZY. Activated phosphoinositide 3-kinase δ syndrome in a patient with a former diagnosis of common variable immune deficiency, bronchiectasis, and lymphoproliferative disease. Ann Allergy Asthma Immunol . 2015;115(5):452-4.
37. 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.
38. 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 δ syndrome type 1. J Allergy Clin Immunol. 2019;143(1):266-75.
39. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308-16.
40. Jung S, Gámez-Díaz L, Proietti M, Grimbacher B. “Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology. Front Immunol. 2018;9:966.
2. Zhang Q, Ma H, Ma J, Wang D, Zhao Y, Wang T, et al. Clinical and genetic analysis of immunodeficiency‐related diseases associated with PIK3CD mutations. Pediatr Investig. 2018;2(4):257-62.
3. Michalovich D, Nejentsev S. Activated PI3 kinase delta syndrome: from genetics to therapy. Front Immunol. 2018;9:369.
4. Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, et al. Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review. Clin Rev Allergy Immunol. 2019;10.1007/s12016-019-08738-9. doi:10.1007/s12016-019-08738-9 5. Singh A, Joshi V, Jindal AK, Mathew B, Rawat A. An updated review on activated PI3 kinase delta syndrome (APDS). Genes Dis. 2020;7(1):67-74.
6. Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation. J Allergy Clin Immunol. 2019;143(5):1676-87.
7. 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.
8. Dornan GL, Siempelkamp BD, Jenkins ML, Vadas O, Lucas CL, Burke JE. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1. Proc Natl Acad Sci U S A 2017;114(8):1982-7.
9. 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.
10. 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 δ syndrome 2: A cohort study. J Allergy Clin Immunol. 2016;138(1):210-8.e9.
11. Condliffe AM, Chandra A. Respiratory Manifestations of the Activated Phosphoinositide 3-Kinase Delta Syndrome. Front Immunol. 2018;9:338.
12. Coulter TI, Chandra A, Bacon CM, Babar J, Curtis J, Screaton N, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase δ syndrome: A large patient cohort study. J Allergy Clin Immunol. 2017;139(2):597-606.e4.
13. 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.
14. Angulo I, Vadas O, Garçon F, Banham-Hall E, Plagnol V, Leahy TR, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science (New York, NY). 2013;342(6160):866-71.
15. Ewertowska M, Grześk E, Urbańczyk A, Dąbrowska A, Bąbol-Pokora K, Łęcka M, et al. Activated phosphoinositide 3-kinase delta syndrome 1 and 2 (APDS 1 and APDS 2): similarities and differences based on clinical presentation in two boys. Allergy Asthma Clin Immunol. 2020;16:22.
16. Lougaris V, Baronio M, Moratto D, Tampella G, Gazzurelli L, Facchetti M, et al. A novel monoallelic gain of function mutation in p110δ causing atypical activated phosphoinositide 3-kinase δ syndrome (APDS-1). Clin Immunol. 2019;200:31-4.
17. 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 p110δ result in T cell senescence and human immunodeficiency. Nat Immunol. 2014;15(1):88-97.
18. Okkenhaug K, Vanhaesebroeck B. PI3K in lymphocyte development, differentiation and activation. Nat Rev Immunol. 2003;3(4):317-30.
19. Preite S, Gomez-Rodriguez J, Cannons JL, Schwartzberg PL. T and B-cell signaling in activated PI3K delta syndrome: From immunodeficiency to autoimmunity. Immunol Rev. 2019;291(1):154-73.
20. Stokes CA, Condliffe AM. Phosphoinositide 3-kinase δ (PI3Kδ) in respiratory disease. Biochem Soc Trans. 2018;46(2):361-9.
21. Magis-Escurra C, Reijers MH. Bronchiectasis. BMJ clinical evidence. BMJ Clin Evid. 2015;2015.
22. 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 δ Syndrome: The European Society for Immunodeficiencies-Activated Phosphoinositide 3-Kinase δ Syndrome Registry. Front Immunol. 2018;9:543.
23. Jamee M, Moniri S, Zaki-Dizaji M, Olbrich P, Yazdani R, Jadidi-Niaragh F, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS): a systematic review. Clin Rev Allergy Immunol. 2019:1-11.
24. Martínez-Saavedra MT, García-Gomez S, Domínguez Acosta A, Mendoza Quintana JJ, Páez JP, García-Reino EJ, et al. Gain-of-function mutation in PIK3R1 in a patient with anarrow clinical phenotype of respiratory infections. Clin Immunol. 2016;173:117-120.
25. Asano T, Okada S, Tsumura M, Yeh TW, Mitsui-Sekinaka K, Tsujita Y, et al. Enhanced AKT Phosphorylation of Circulating B Cells in Patients With Activated PI3Kδ Syndrome. Front Immunol. 2018;9:568.
26. Lucas CL, Chandra A, Nejentsev S, Condliffe AM, Okkenhaug K. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702-14.
27. Swan DJ, Aschenbrenner D, Lamb CA, Chakraborty K, Clark J, Pandey S, et al. Immunodeficiency, autoimmune thrombocytopenia and enterocolitis caused by autosomal recessive deficiency of PIK3CD-encoded phosphoinositide 3-kinase δ. Haematologica. 2019;104(10):e483-e6.
28. Preite S, Cannons JL, Radtke AJ, Vujkovic-Cvijin I, Gomez-Rodriguez J, Volpi S. Hyperactivated PI3Kδ promotes self and commensal reactivity at the expense of optimal humoral immunity Nat Immunol. 2018;19(9):986-1000.
29. Elgizouli M, Lowe DM, Speckmann C, Schubert D, Hülsdünker J, Eskandarian Z, et al. Activating PI3Kδ mutations in a cohort of 669 patients with primary immunodeficiency. Clin Exp Immunol. 2016;183(2):221-9.
30. Cohen JI. Herpesviruses in the Activated Phosphatidylinositol-3-Kinase-δ Syndrome. Front Immunol. 2018;9:237.
31. Seidel MG. Autoimmune and other cytopenias in primary immunodeficiencies: pathomechanisms, novel differential diagnoses, and treatment. Blood. 2014;124(15):2337-44.
32. Lucas M, Hugh-Jones K, Welby A, Misbah S, Spaeth P, Chapel H. Immunomodulatory therapy to achieve maximum efficacy: doses, monitoring, compliance, and self-infusion at home. J Clin Immunol. 2010;30 Suppl 1:S84-9.
33. Edgar JDM, Richter AG, Huissoon AP, Kumararatne DS, Baxendale HE, Bethune CA, et al. Prescribing Immunoglobulin Replacement Therapy for Patients with Non-classical and Secondary Antibody Deficiency: an Analysis of the Practice of Clinical Immunologists in the UK and Republic of Ireland. J Clin Immunol. 2018;38(2):204-13.
34. Berger M, Jolles S, Orange JS, Sleasman JW. Bioavailability of IgG administered by the subcutaneous route. J Clin Immunol. 2013;33(5):984-90.
35. 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 δ syndrome. J Allergy Clin Immunol. 2014;134(1):233-6.
36. Kannan JA, Dávila-Saldaña BJ, Zhang K, Filipovich AH, Kucuk ZY. Activated phosphoinositide 3-kinase δ syndrome in a patient with a former diagnosis of common variable immune deficiency, bronchiectasis, and lymphoproliferative disease. Ann Allergy Asthma Immunol . 2015;115(5):452-4.
37. 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.
38. 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 δ syndrome type 1. J Allergy Clin Immunol. 2019;143(1):266-75.
39. Quinti I, Soresina A, Spadaro G, Martino S, Donnanno S, Agostini C, et al. Long-term follow-up and outcome of a large cohort of patients with common variable immunodeficiency. J Clin Immunol. 2007;27(3):308-16.
40. Jung S, Gámez-Díaz L, Proietti M, Grimbacher B. “Immune TOR-opathies,” a Novel Disease Entity in Clinical Immunology. Front Immunol. 2018;9:966.
| Files | ||
| Issue | Vol 3, No 3 (2020) | |
| Section | Review Article | |
| DOI | https://doi.org/10.22034/igj.2020.247410.1049 | |
| Keywords | ||
| Activated PI3 kinase delta syndrome (APDS) phosphatidylinositol-4 5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) phosphoinositide-3-kinase regulatory subunit 1 (PIK3R1) | ||
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How to Cite
1.
Aghamohamadi N, Zarezadeh Mehrabadi A. Activated PI3K-Delta Syndrome: Pathogenesis, Clinical Manifestations, Diagnosis, Classification, and Management. Immunol Genet J. 2020;3(3):8-15.
