Primary Immunodeficiency with the PI3K Delta Activation: Clinical Features and Prospective Therapy

Cover Page


Cite item

Full Text

Open Access Open Access
Restricted Access Access granted
Restricted Access Subscription or Fee Access

Abstract

Primary immunodeficiency (PID) constitute a polymorphic group of genetic life-threatening disorders. APDS (activated phosphoinositide 3-kinase δ) represents a rare PID caused by monoallelic gain of function defects in the PIK3CD gene, or monoallelic loss of function defects in the PIK3R1 and PTEN genes. Disease symptoms usually manifest early in life and include recurrent bacterial infections, non-malignant and malignant lymphoproliferation, persistent herpes virus infections and a whole spectrum of autoimmune manifestations. Immunological features include T and B lymphocytes defects. APDS treatment including immunoglobulin substitution and immunosuppression does not always lead to complete remission of the disease. Hematopoietic stem cell transplantation is a curative option leading to disease resolution in 75–80% of the patients. In 2023 FDA approved leniolisib — selective PI3Kδ inhibitor — for APDS treatment. In the clinical trial the preparation demonstrated safety and efficacy for the patients with APDS ages 12 and above. Approval of the drug created specifically to treat this rare variant of PID opens a new era of the targeted treatment for the patients with this orphan disease.

Full Text

Restricted Access

About the authors

Ekaterina Yu. Selina

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Author for correspondence.
Email: selina-katya1998@yandex.ru
ORCID iD: 0009-0003-6545-1435

MD

Russian Federation, Moscow

Anna Yu. Shcherbina

Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology and Immunology

Email: shcher26@hotmail.com
ORCID iD: 0000-0002-3113-4939
SPIN-code: 6759-0031

MD, PhD, Professor of the RAS

Russian Federation, Moscow

References

  1. Tangye SG, Al-Herz W, Bousfiha A, et al. Human Inborn Errors of Immunity: 2022 Update on the Classification from the International Union of Immunological Societies Expert Committee. J Clin Immunol. 2022;42(7):1473–1507. doi: https://doi.org/10.1007/s10875-022-01289-3
  2. Jamee M., Moniri S., Zaki-Dizaji M, et al. Clinical, Immunological, and Genetic Features in Patients with Activated PI3Kδ Syndrome (APDS): a Systematic Review. Clinic Rev Allergy Immunol. 2020;59(3):323–333. doi: https://doi.org/10.1007/s12016-019-08738-9
  3. Coulter TI, Cant AJ. The Treatment of Activated PI3Kδ Syndrome. Front Immunol. 20187;9:2043. doi: https://doi.org/10.3389/fimmu.2018.02043
  4. Angulo I, Vadas O, Garçon F, et al. Phosphoinositide 3-kinase δ gene mutation predisposes to respiratory infection and airway damage. Science. 2013;342(6160):866–871. doi: https://doi.org/10.1126/science.1243292
  5. Deau MC, Heurtier L, Frange P, et al. A human immunodeficiency caused by mutations in the PIK3R1 gene. J Clin Invest. 2014;124(9):3923–3928. doi: https://doi.org/10.1172/JCI75746
  6. Tsujita Y, Mitsui-Sekinaka K, Imai K, et al. Phosphatase and tensin homolog (PTEN) mutation can cause activated phosphatidylinositol 3-kinase δ syndrome-like immunodeficiency. J Allergy Clin Immunol. 2016;138(6):1672–1680.e10. doi: https://doi.org/10.1016/j.jaci.2016.03.055
  7. Lucas CL, Chandra A, Nejentsev S, et al. PI3Kδ and primary immunodeficiencies. Nat Rev Immunol. 2016;16(11):702–714. doi: https://doi.org/10.1038/nri.2016.93
  8. Michalovich D, Nejentsev S. Activated PI3 Kinase Delta Syndrome: From Genetics to Therapy. Front Immunol. 2018;27(9):369. doi: https://doi.org/10.3389/fimmu.2018.00369
  9. Lucas CL, Kuehn HS, Zhao F, 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. doi: https://doi.org/10.1038/ni.2771
  10. Lucas CL, Zhang Y, Venida A, et al. Heterozygous splice mutation in PIK3R1 causes human immunodeficiency with lymphoproliferation due to dominant activation of PI3K. J Exp Med. 2014;211(13):2537–2547. doi: https://doi.org/10.1084/jem.20141759
  11. Redenbaugh V, Coulter T. Disorders Related to PI3Kδ Hyperactivation: Characterizing the Clinical and Immunological Features of Activated PI3-Kinase Delta Syndromes. Front Pediatr. 2021;9:702872. doi: https://doi.org/10.3389/fped.2021.702872
  12. Аналитический отчет на основании данных регистра пациентов с первичными иммунодефицитными состояниями. Данные от 29.12.2021. Доступно по: https://naepid.ru/registr-pid/registr-pid/
  13. Кондратенко И.В., Бологов А.А. Первичные иммунодефициты: учеб. пособие для врачей-педиатров, иммунологов, медицинских генетиков и молекулярных биологов. — М.: ИндексМед Медиа, 2020. — 791 с. [Kondratenko IV, Bologov AA. Pervichnye immunodeficity: ucheb. posobie dlya vrachej-pediatrov, immunologov, medicinskih genetikov i molekulyarnyh biologov. Moscow: IndeksMed Media; 2020. 791 s. (In Russ.)]
  14. Dornan GL, Burke JE. Molecular Mechanisms of Human Disease Mediated by Oncogenic and Primary Immunodeficiency Mutations in Class IA Phosphoinositide 3-Kinases. Front Immunol. 2018;9:575. doi: https://doi.org/10.3389/fimmu.2018.00575
  15. Heurtier L, Deau MC, Kracker S. Hyper-activated PI3K-δ in immunodeficiency. Oncotarget. 2015;6(21):18242–18243. doi: https://doi.org/10.18632/oncotarget.4884
  16. Tzenaki N, Papakonstanti EA. p110δ PI3 kinase pathway: emerging roles in cancer. Front Oncol. 2013;3:40. doi: https://doi.org/10.3389/fonc.2013.00040
  17. Thouenon R, Moreno-Corona N, Poggi L, et al. Activated PI3Kinase Delta Syndrome-A Multifaceted Disease. Front Pediatr. 2021;9:652405. doi: https://doi.org/10.3389/fped.2021.652405
  18. Lucas CL, Kuehn HS, Zhao F, 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. doi: https://doi.org/10.1038/ni.2771
  19. Carpier JM, Lucas CL. Epstein–Barr Virus Susceptibility in Activated PI3Kδ Syndrome (APDS) Immunodeficiency. Front Immunol. 2018;8:2005. doi: https://doi.org/10.3389/fimmu.2017.02005
  20. Maccari ME, Abolhassani H, Aghamohammadi A, 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. doi: https://doi.org/10.3389/fimmu.2018.00543
  21. Mace EM. Phosphoinositide-3-Kinase Signaling in Human Natural Killer Cells: New Insights from Primary Immunodeficiency. Front Immunol. 2018;9:445. doi: https://doi.org/10.3389/fimmu.2018.00445
  22. Coulter TI, Chandra A, Bacon CM, et al. Clinical spectrum and features of activated phosphoinositide 3-kinase delta syndrome: a large patient cohort study. J Allergy Clin Immunol. 2016;139(2):597–606.e4. doi: https://doi.org/10.1016/j.jaci.2016.06.021
  23. Duggan S, Al-Salama ZT. Leniolisib: First Approval. Drugs. 2023;83(10):943–948. doi: https://doi.org/10.1007/s40265-023-01895-4
  24. Okano T, Imai K, Tsujita Y, 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):266–275. doi: https://doi.org/10.1016/j.jaci.2018.04.032
  25. Nademi Z, Slatter MA, Dvorak CC, et al. Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome. J Allergy Clin Immunol. 2017;139(3):1046–1049. doi: https://doi.org/10.1016/j.jaci.2016.09.040
  26. Rao VK, Webster S, Dalm VASH, et al. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib. Blood. 2017;130(21):2307–2316. doi: https://doi.org/10.1182/blood-2017-08-801191
  27. Pharming Technologies B.V. JOENJA® (leniolisib) tablets, for oral use. 2023. Available from: 29 Mar 2023. https://www.accessdata.fda.gov/drugsatfda_docs/label/2023/217759s000lbl.pdf (аccessed: 29.03.2023).
  28. Rao VK, Webster S, Šedivá A, et al. A randomized, placebo-controlled phase 3 trial of the PI3Kδ inhibitor leniolisib for activated PI3Kδ syndrome. Blood. 2023;141(9):971–983. doi: https://doi.org/10.1182/blood.2022018546

Supplementary files

Supplementary Files
Action
1. JATS XML
Download
2. Fig.1. Schematic representation of mutations in the genes encoding the catalytic p110δ and regulatory p85α subunits of PI3-kinase, leading to the development of APDS (the most common variants are highlighted in red) [2]

Download (145KB)
Indexing metadata
3. Fig.2. Distribution of primary diagnoses in patients with APDS [2], %. Note. CVID - common variable immune deficiency; ALPS - autoimmune lymphoproliferative syndrome; X-AG - X-linked agammaglobulinemia; CIN - combined immune deficiency.

Download (112KB)
Indexing metadata

Copyright (c) 2023 "Paediatrician" Publishers LLC



This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies