磷脂酰肌醇3激酶δ过度活化综合征治疗进展

doi:10.16138/j.1673-6087.2024.02.10

摘要/Abstract

摘要：

磷脂酰肌醇3激酶δ（phosphoinositide 3-kinase δ，PI3Kδ）过度活化综合征（activated phosphoinositide 3-kinase δ syndrome，APDS）于2013年首次报道。APDS是一种PIK3CD基因或PIK3R1基因突变导致的常染色体显性遗传的原发性免疫缺陷病（primary immunodeficiency disease，PID），临床表现为反复呼吸道感染、非肿瘤性淋巴组织增生、自身免疫性疾病及淋巴瘤等。本文详细介绍了APDS治疗方案，除常规针对免疫缺陷治疗外，如抗菌药物预防、免疫球蛋白替代治疗及造血干细胞移植等，还讨论了针对性更强的哺乳动物雷帕霉素靶蛋白（mammalian target of rapamycin，mTOR）抑制剂和PI3Kδ抑制剂。

关键词: PI3Kδ过度活化综合征, 造血干细胞移植, mTOR抑制剂, PI3Kδ抑制剂

Abstract:

Phosphoinositide 3-kinase δ (PI3Kδ) activated phosphoinositide 3-kinase δ syndrome (APDS) was first reported in 2013. APDS is an autosomal dominant primary immunodeficiency disease (PID) caused by mutations in the PIK3CD gene or PIK3R1 gene. The clinical manifestations of APDS are recurrent respiratory tract infection, non-neoplastic lymphoid hyperplasia, autoimmune diseases and lymphoma. In this paper, the treatment of APDS is introduced in detail. In addition to conventional treatment for immunodeficiency, treatment such as antimicrobial prophylaxis, immunoglobulin replacement therapy and hematopoietic stem cell transplantation were reviewed, and more specific mammalian target of rapamycin (mTOR) inhibitors and PI3Kδ inhibitors were also discussed.

Key words: PI3Kδ overactivation syndrome, Hematopoietic stem cell transplantation, mTOR inhibitor, PI3Kδ inhibitor

中图分类号:

吴涛, 刘文慧. 磷脂酰肌醇3激酶δ过度活化综合征治疗进展[J]. 内科理论与实践, 2024, 19(02): 140-143.

WU Tao, LIU Wenhui. Progress in treatment of activated phosphoinositide 3-kinase δ syndrome[J]. Journal of Internal Medicine Concepts & Practice, 2024, 19(02): 140-143.

参考文献 24

[1]	Jamee M, Moniri S, Zaki-Dizaji M, et al. Clinical, immunological, and genetic features in patients with activated PI3Kδ syndrome (APDS)[J]. Clin Rev Allergy Immunol, 2020, 59(3):323-333.
[2]	Fruman DA, Chiu H, Hopkins BD, et al. The PI3K pathway in human disease[J]. Cell, 2017, 170(4):605-635. doi: S0092-8674(17)30865-6 pmid: 28802037
[3]	Bilanges B, Posor Y, Vanhaesebroeck B. PI3K isoforms in cell signalling and vesicle trafficking[J]. Nat Rev Mol Cell Biol, 2019, 20(9):515-534.
[4]	Thouenon R, Moreno-Corona N, Poggi L, et al. Activated PI3 kinase delta syndrome[J]. Front Pediatr, 2021,9:652405.
[5]	Dornan GL, Siempelkamp BD, Jenkins ML, et al. Conformational disruption of PI3Kδ regulation by immunodeficiency mutations in PIK3CD and PIK3R1[J]. Proc Natl Acad Sci U S A, 2017, 114(8):1982-1987.
[6]	Nunes-Santos CJ, Uzel G, Rosenzweig SD. PI3K pathway defects leading to immunodeficiency and immune dysregulation[J]. J Allergy Clin Immunol, 2019, 143(5):1676-1687. doi: S0091-6749(19)30421-X pmid: 31060715
[7]	Brodsky NN, Lucas CL. Infections in activated PI3K delta syndrome (APDS)[J]. Curr Opin Immunol, 2021,72:146-157.
[8]	Coulter TI, Cant AJ. The treatment of activated PI3Kδ syndrome[J]. Front Immunol, 2018,9:2043.
[9]	Chiriaco M, Brigida I, Ariganello P, et al. The case of an APDS patient[J]. Clin Immunol, 2017,178:20-28.
[10]	Edgar JDM, Richter AG, Huissoon AP, et al. Prescribing immunoglobulin replacement therapy for patients with non-classical and secondary antibody deficiency[J]. J Clin Immunol, 2018, 38(2):204-213.
[11]	Singh A, Joshi V, Jindal AK, et al. An updated review on activated PI3 kinase delta syndrome (APDS)[J]. Genes Dis, 2019, 7(1):67-74.
[12]	Lougaris V, Cancrini C, Rivalta B, et al. Activated phosphoinositide 3-dinase delta syndrome (APDS)[J]. Pediatr Allergy Immunol, 2022, 33 Suppl 27: 69-72.
[13]	Moriya K, Mitsui-Sekinaka K, Sekinaka Y, et al. Clinical practice guideline for activated phosphatidyl inositol 3-kinase-delta syndrome in Japan[J]. Immunol Med, 2023, 46(4):153-157.
[14]	Durandy A, Kracker S. Increased activation of PI3 kinase-δ predisposes to B-cell lymphoma[J]. Blood, 2020, 135(9):638-643. doi: 10.1182/blood.2019002072 pmid: 31942637
[15]	Yang X, Xi R, Bai J, et al. Successful haploidentical hematopoietic stem cell transplantation for activated phosphoinositide 3-kinase δ syndrome[J]. Medicine (Baltimore), 2023, 102(5):e32816.
[16]	Dimitrova D, Nademi Z, Maccari ME, et al. International retrospective study of allogeneic hematopoietic cell transplantation for activated PI3K-delta syndrome[J]. J Allergy Clin Immunol, 2022, 149(1):410-421.
[17]	Nademi Z, Slatter MA, Dvorak CC, et al. Hematopoietic stem cell transplant in patients with activated PI3K delta syndrome[J]. J Allergy Clin Immunol, 2017, 139(3):1046-1049. doi: S0091-6749(16)31288-X pmid: 27847301
[18]	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 delta syndrome type 1[J]. J Allergy Clin Immunol, 2019, 143(1):266-275.
[19]	Jung S, Gámez-Díaz L, Proietti M, et al. “Immune TOR-opathies,” a novel disease entity in clinical immunology[J]. Front Immunol, 2018,9:966.
[20]	Vanselow S, Wahn V, Schuetz C. Activated PI3Kδ syndrome - reviewing challenges in diagnosis and treatment[J]. Front Immunol, 2023,14:1208567.
[21]	Maccari ME, Abolhassani H, Aghamohammadi A, et al. Disease evolution and response to rapamycin in activated phosphoinositide 3-kinase δ syndrome front immunol[J]. Front Immunol, 2018,9:543.
[22]	Rao VK, Webster S, Dalm VASH, et al. Effective “activated PI3Kδ syndrome”-targeted therapy with the PI3Kδ inhibitor leniolisib[J]. Blood, 2017, 130(21):2307-2316.
[23]	Cahn A, Hamblin JN, Begg M, et al. Safety, pharmacokinetics and dose-response characteristics of GSK2269557, an inhaled PI3Kδ inhibitor under development for the treatment of COPD[J]. Pulm Pharmacol Ther, 2017,46:69-77.
[24]	Begg M, Amour A, Jarvis E, et al. An open label trial of nemiralisib, an inhaled PI3 kinase delta inhibitor for the treatment of activated PI3 kinase delta syndrome[J]. Pulm Pharmacol Ther, 2023,79:102201.