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Report of a Chinese Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome

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Abstract

Purpose

We aimed to report the clinical manifestations and immunological features of activated phosphatidylinositol 3-kinase δ syndrome 1 (APDS1) in a Chinese cohort. Moreover, we investigated the efficacy and safety of rapamycin therapy for Chinese patients with APDS1.

Methods

Fifteen Chinese patients with APDS1 from 14 unrelated families were enrolled in this study. These patients were diagnosed based on clinical features, immunological phenotype, and whole-exome sequencing. Four patients were treated with rapamycin, and the clinical efficacy and safety of rapamycin were observed. The changes of phosphorylation of Akt and mammalian target of rapamycin (mTOR) signaling pathway after rapamycin treatment were detected by flow cytometry and real-time PCR.

Results

The common clinical manifestations of the patients included lymphadenopathy (93%), recurrent sinopulmonary infections (93%), hepatosplenomegaly (93%), and diarrhea (78%). Epstein-Barr virus (EBV) (80%) and fungus (Aspergillus) (47%) were the most common pathogens. Immunological phenotype included elevated Immunoglobulin (Ig) M levels (100%), decreased naive T cells, increased senescent T cells, and expanded transitional B cells. Whole-exome sequencing indicated that 13 patients had heterogeneous PIK3CD E1021K mutations, 1 patient had heterogeneous E1025G mutation and 1 patient had heterogeneous Y524N mutation. Gain-of-function (GOF) PIK3CD mutations increased the phosphorylation of the Akt-mTOR signaling pathway. Four patients underwent rapamycin therapy, experiencing substantial improvement in clinical symptoms and immunological phenotype. Rapamycin inhibited the activated Akt-mTOR signaling pathway.

Conclusions

We described 15 Chinese patients with APDS1. Treatment with the mTOR inhibitor rapamycin improved patient outcomes.

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Acknowledgments

Many thanks to the patients and their parents.

Funding

This study was supported by the National Natural Science Foundation of China (81471482), Science and Technology Commission of Shanghai Municipality (14411965400), and Shanghai Hospital Development Center (SHDC12016228).

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Author notes

  1. Ying Wang, Wenjie Wang and Luyao Liu contributed equally to this work.

Authors and Affiliations

  1. Department of Clinical Immunology, Children’s Hospital of Fudan University, 399 Wanyuan Road, Shanghai, 201102, China

    Ying Wang, Wenjie Wang, Luyao Liu, Jia Hou, Wenjing Ying, Xiaoying Hui, Qinhua Zhou, Danru Liu, Haili Yao, Jinqiao Sun & Xiaochuan Wang

Authors
  1. Ying Wang
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  2. Wenjie Wang
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  3. Luyao Liu
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  4. Jia Hou
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  6. Xiaoying Hui
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  7. Qinhua Zhou
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  11. Xiaochuan Wang
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Corresponding authors

Correspondence to Jinqiao Sun or Xiaochuan Wang.

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Conflict of Interest

The authors declare that they have no conflict of interest.

Electronic supplementary material

Supplemental Fig. 1

Changes of the expression of CD57 on T cells. a and b: The expression of CD57 on the CD4+ T cells/CD8+ T cells in four patients with rapamycin treatment at 0 month, 3 months, 6 months and 12 months. P2 stopped rapamycin therapy after 6 months, and p10 received rapamycin therapy for only 3 months. (PNG 227 kb)

High resolution image (TIF 3867 kb)

Supplemental Fig. 2

CD57 expression on T cells in APDS1 patients. a and b: CD57 expression on CD4+ T cells/CD8+ T cells in a healthy control and patient 5. Proportion of CD57 + CD4+ T cells/CD57 + CD8+ T cells was compared at 3 months, 6 months and 12 months of rapamycin treatment. (PNG 295 kb)

High resolution image (TIF 326 kb)

Supplemental Fig. 3

Flow cytometry analysis showing levels of phospho-AKT (pAKT) protein (Ser473 and Thr308) and pS6 (Ser235/236 and Ser240/244) in CD3+ T cells in patient 10 and a healthy control. Levels of pAKT and pS6 were analyzed without and with rapamycin at 3 months. (PNG 412 kb)

High resolution image (TIF 2157 kb)

Supplementary Table 1

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Supplementary Table 4

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Supplementary Table 5

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Wang, Y., Wang, W., Liu, L. et al. Report of a Chinese Cohort with Activated Phosphoinositide 3-Kinase δ Syndrome. J Clin Immunol 38, 854–863 (2018). https://doi.org/10.1007/s10875-018-0568-x

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  • DOI: https://doi.org/10.1007/s10875-018-0568-x

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