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The mTORC1 pathway participate in hyper-function of B cells in immune thrombocytopenia

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Abstract

B cell hyper-function plays an important role in the pathogenesis of immune thrombocytopenia (ITP), but the molecular mechanisms underlying such changes remain unclear. We sought to identify regulators of B cell dysfunction in ITP patients through transcriptome sequencing and the use of inhibitors. B cells were isolated from PBMC of 25 ITP patients for B cell function test and transcriptome sequencing. For the potential regulatory factors identified by transcriptome sequencing, the corresponding protein inhibitors were used to explore the regulatory effect of the regulatory factors on B cell dysfunction in vitro. In this study, increased antibody production, enhanced terminal differentiation and highly expressed costimulatory molecules CD80 and CD86 were found in B cells of patients with ITP. In addition, RNA sequencing revealed highly activated mTOR pathway in these pathogenic B cells, indicating that the mTOR pathway may be involved in B cell hyper-function. Furthermore, mTOR inhibitors rapamycin or Torin1 effectively blocked the activation of mTORC1 in B cells, resulting in reduce antibody secretion, impaired differentiation of B cells into plasmablasts and downregulation of costimulatory molecules. Interestingly, as an unspecific inhibitor of mTORC2 besides mTORC1, Torin1 did not show a stronger capacity to modulate B cell function than rapamycin, suggesting that the regulation of B cells by Torin1 may depend on blockade of mTORC1 rather than mTORC2 pathway. These results indicated that the activation of mTORC1 pathway is involved in B cell dysfunction in patients with ITP, and inhibition of mTORC1 pathway might be a potential therapeutic approach for ITP.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the Natural Science Foundation of Shandong Province (ZR2021MH188), the National Natural Science Foundation of China (No. 81300383, No. 81900121, No. 81973994, No. 82070122), the Taishan Scholars Program (No. tsqn202103167), the Clinical Research Project of Shandong University (2020SDUCRCC015), the Young Taishan Scholar Foundation of Shandong Province (No. tsqn201909175), the Natural Science Foundation for Distinguished Young Scholar of Shandong Province (ZR2021JQ28) and the Clinical Research Center of Shandong University (No. 2020SDUCRCC009).

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Author notes

  1. YJX, LL and YH contributed equally to this work.

Authors and Affiliations

  1. Department of Hematology, Qilu Hospital of Shandong University, Jinan, China

    Yujiao Xiang, Lu Liu, Yu Hou, Shuqian Xu, Hai Zhou, Linlin Shao, Guosheng Li, Tianshu Yu, Qiang Liu, Meijuan Xue, Junhui Yang, Jun Peng, Ming Hou & Yan Shi

  2. Shandong Provincial Key Laboratory of Immunohematology, Qilu Hospital of Shandong University, Jinan, China

    Yu Hou, Jun Peng & Ming Hou

  3. Department of Hematology, Taian Central Hospital, Taian, China

    Shenghong Du

  4. Shandong Provincial Clinical Research Center in Hematological Diseases, Jinan, China

    Ming Hou

  5. Leading Research Group of Scientific Innovation, Department of Science and Technology of Shandong Province, Qilu Hospital of Shandong University, Jinan, China

    Ming Hou

  6. Department of Hematology, Qilu Hospital (Qingdao) of Shandong University, Qingdao, China

    Lu Liu & Yu Hou

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  1. Yujiao Xiang
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Contributions

All authors contributed to the study conception and design. YX and YS designed the research and revised the manuscript. YX and LL performed the experiments, analyzed the data and wrote the article. YH, SD, SX, HZ, LS, GL, TY, QL, MX, JY, PJ and MH contributed to the experimental work and the collection of patients’ features. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Yan Shi.

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The study was in compliance with the Declaration of Helsinki and approved by the Ethics Committee of Qilu Hospital, Shandong University. Informed consent was obtained from all patients for being included in the study.

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The authors declare no competing interests.

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Xiang, Y., Liu, L., Hou, Y. et al. The mTORC1 pathway participate in hyper-function of B cells in immune thrombocytopenia. Ann Hematol 102, 2317–2327 (2023). https://doi.org/10.1007/s00277-023-05348-6

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