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Haploinsufficiency of A20 Due to Novel Mutations in TNFAIP3

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Abstract

Haploinsufficiency of A20 (HA20) is a newly described immune dysregulation disease due to the loss-of-function mutation in TNFAIP3. In the present study, we report six patients from four unrelated Chinese families with distinct pathogenic mutations in TNFAIP3, including three novel variants. All of the patients presented with early-onset autoimmune/auto-inflammatory diseases, including Crohn’s disease, Behcet’s disease, systemic lupus erythematosus, and unclassified auto-inflammatory syndrome. Immunological phenotype tests showed elevated levels of serum pro-inflammatory cytokines, reduced naïve B cells and TFH cells, an inverted CD4:CD8 ratio, and increased susceptibility to restimulation-induced cell death (RICD) and FASL-induced apoptosis in derived T cells. Insufficient expression of A20 was found in these patients. A20 truncated protein was detected in mutant-transfected 293T cells. Upon TNF-α stimulation, the NF-κB pathway was over-activated in both derived T cells of these patients and mutant-transfected Hela cells. In conclusion, clinical manifestations are diverse in patients with HA20, even in those with the same TNFAIP3 mutation. A20 inhibits the NF-κB pathway and plays a crucial role in the regulation of cell death. Haploinsufficiency of A20 leads to defects in both innate and adaptive immunity.

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Acknowledgments

We thank all the patients, their families, and healthy controls for the participation. We thank Lixin Zheng (Molecular Development of the Immune System Section, Laboratory of Immune System Biology, and Clinical Genomics Program, Division of Intramural Research, National Institute of Allergy and Infectious Diseases) for pEGFP-C1 (Addgene plasmid) as a gift. We especially thank Sicai Zhang for the correction of grammatical errors.

Funding

This work was supported by the Sanming Project of Medicine in Shenzhen (SZSM201812002) and Science and Technology Planning Project of Shenzhen Municipality (JCY20170303155201082).

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Author notes

  1. Tingyan He and Yanyan Huang contributed equally to this work.

Authors and Affiliations

  1. Department of Rheumatology and Immunology, Shenzhen Children’s hospital, 7019 Yitian Road, Shenzhen, 518026, China

    Tingyan He, Yanyan Huang, Ying Luo, Yu Xia, LinLin Wang, Jiayun Ling & Jun Yang

  2. Department of Pathology, Shenzhen Children’s hospital, 7019 Yitian Road, Shenzhen, 518026, China

    Huan Zhang

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  1. Tingyan He
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Contributions

Tingyan He and Yanyan Huang contributed equally to this work. Tingyan He and Yanyan Huang performed the main experiments, analyzed the data, and drafted the manuscript. Huan Zhang and Jiayun Ling collected clinical data from the patient. Ying Luo, Yu Xia, and LinLin Wang helped with experiments. Jun Yang reviewed the manuscript. All authors read and approved the final manuscript.

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Correspondence to Jun Yang.

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All participated family members were enrolled upon approval of the ethics committee of Shenzhen Children’s hospital and provided written consent.

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The authors declare that they have no conflict of interest.

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He, T., Huang, Y., Luo, Y. et al. Haploinsufficiency of A20 Due to Novel Mutations in TNFAIP3. J Clin Immunol 40, 741–751 (2020). https://doi.org/10.1007/s10875-020-00792-9

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  • DOI: https://doi.org/10.1007/s10875-020-00792-9

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