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Novel CD81 Mutations in a Chinese Patient Led to IgA Nephropathy and Impaired BCR Signaling

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Abstract

Purpose

CD81 deficiency is an extremely rare primary immunodeficiency disease characterized by severe and recurrent infections, IgA-related nephropathy, and profound hypogammaglobulinemia. Only one patient has been reported so far, and the pathogenesis remains unclear. Here, we identified a new case of CD81 deficiency and described its pathogenesis.

Methods

We analyzed the clinical, genetic, and immunological features of the patient with CD81 deficiency, and explored the pathogenesis of her antibody deficiencies.

Results

The major manifestation of this patient was unexpectedly not recurrent infections but IgA nephropathy with aberrant serum galactose-deficient IgA1. Whole-exome sequencing revealed novel biallelic mutations in CD81 gene that abolished the surface expression of CD81. B cells from the patient lack membrane CD19 and showed reduced switched memory B cells and transitional B cells. Decreased expression of key molecules pY and pBTK in BCR signaling were demonstrated by confocal microscopy. RNA sequencing revealed that genes associated with BCR signaling and immunoglobulins were downregulated in CD81-deficient B cells. In addition, the patient showed increased frequency of T follicular helper cells that biased to Th1-like subsets.

Conclusion

We reported the second patient with CD81 deficiency in the world and illustrated aberrant BCR signaling in the patient, therefore helping to unravel the mechanism of antibody deficiency in CD81-deficient patients.

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Data Availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Acknowledgements

We are grateful for the support, cooperation, and trust of the patients, donors, and their families.

Funding

This work was supported by National Natural Science Foundation of China (grant number 82070135), Graduate Mentor Team of Chongqing Municipal Education Commission (grant number 2019–09-66), General Project of Chongqing Natural Science Foundation (grant number cstc2020jcyj-msxmX0607), and Future Medical Youth Innovation Team Development Support Program of CMU.

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Authors and Affiliations

  1. Department of Pediatric Research Institute, Ministry of Education Key Laboratory of Child Development and Disorders, National Clinical Research Center for Child Health and Disorders, China International Science and Technology Cooperation base of Child development and Critical Disorders, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Lu Yang, Hongqiang Du, Ran Chen, Yanan Li, Lina Zhou, Yuan Ding, Xuemei Tang, Yunfei An & Xiaodong Zhao

  2. Chongqing Key Laboratory of Child Infection and Immunity, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Lu Yang, Hongqiang Du, Ran Chen, Yanan Li, Lina Zhou, Yuan Ding, Xuemei Tang, Yunfei An & Xiaodong Zhao

  3. Division of Rheumatology and Immunology, Children’s Hospital of Chongqing Medical University, Chongqing, China

    Lu Yang, Hongqiang Du, Yanan Li, Lina Zhou, Yuan Ding, Xuemei Tang, Yunfei An & Xiaodong Zhao

  4. Department of Nephrology and Rheumatology, Children’s Hospital Affiliated to Zhengzhou University, Henan Children’s Hospital, Zhengzhou Children’s Hospital, Zhengzhou, China

    Ping Liu, Xiangli Wang & Cuihua Liu

  5. Department of Biology, Southern University of Science and Technology, Shenzhen, China

    Bo Zhou

  6. Institute of Immunology, PLA, Third Military Medical University, Chongqing, China

    Yongwen Chen

  7. The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China

    Xiaodong Zhao

Authors
  1. Lu Yang
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  2. Ping Liu
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  3. Hongqiang Du
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  4. Ran Chen
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  8. Xiangli Wang
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  10. Yuan Ding
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  11. Xuemei Tang
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  13. Yunfei An
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  14. Xiaodong Zhao
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Contributions

Lu Yang and Ping Liu contributed equally to this study. Lu Yang performed experiments, analyzed data, and drafted the manuscript. Ping Liu collected clinical data, managed, and followed the patient. Xiaodong Zhao and Yunfei An designed this study and revised the manuscript. Ran Chen performed the B cell ELISPOTs. Hongqiang Du, Yanan Li, Lina Zhou, Yuan Ding, Xuemei Tang, and Yongwen Chen provided experimental expertise and scientific sights in designing the project. Xiangli Wang and Cuihua Liu helped manage and follow the patient. Bo Zhou helped analyze data of RNA sequencing. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Yunfei An or Xiaodong Zhao.

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Ethics Approval

The study was performed following Declaration of Helsinki and approved by the Institutional Review Board of Children’s Hospital of Chongqing Medical University (2021–138).

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Written informed consents for involvement in this study were provided by parents.

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Written informed consent for publication of the study was obtained from the patient’s parents.

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The authors declare no competing interests.

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Yang, L., Liu, P., Du, H. et al. Novel CD81 Mutations in a Chinese Patient Led to IgA Nephropathy and Impaired BCR Signaling. J Clin Immunol 42, 1672–1684 (2022). https://doi.org/10.1007/s10875-022-01333-2

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  • DOI: https://doi.org/10.1007/s10875-022-01333-2

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