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Journal of Clinical Immunology

, Volume 39, Issue 2, pp 188–194 | Cite as

Novel Heterogeneous Mutation of TNFAIP3 in a Chinese Patient with Behçet-Like Phenotype and Persistent EBV Viremia

  • Xiaolong Dong
  • Luyao Liu
  • Ying Wang
  • Xiaotao Yang
  • Wenjie Wang
  • Li Lin
  • Bijun Sun
  • Jia Hou
  • Wenjing Ying
  • Xiaoying Hui
  • Qinhua Zhou
  • Danru Liu
  • Haili Yao
  • Jinqiao SunEmail author
  • Xiaochuan WangEmail author
Original Article

Abstract

Purpose

Tumor necrosis factor alpha-induced protein 3 (TNFAIP3, A20) is a negative regulator of the nuclear factor-κB (NF-κB) pathway. It has recently been recognized that TNFAIP3 deficiency leads to early onset of autoinflammatory and autoimmune syndrome resembling Behçet’s disease. Here, we report a novel mutation in TNFAIP3 in a Chinese patient, who had Behçet-like phenotype and persistent Epstein-Barr virus (EBV) viremia.

Methods

The clinical data were collected. Immunological function was detected. Gene mutation was detected by whole-exome sequencing (WES) and confirmed by Sanger sequencing. mRNA and protein levels were detected in the patient under lipopolysaccharide (LPS) stimulation by real-time PCR and Western blot.

Results

The patient is a 13-year-old boy, presenting with intermittent fever for 5 months, who also experienced diffuse lymphadenopathy, arthritis, and recurrent multiple gastrointestinal ulcers. EBV DNA was detected in the serum and peripheral blood mononuclear cells of the patient. The immunological phenotype showed increased proportion of double-negative T cells (CD3+CD4−CD8−). A novel missense mutation (c.1428G > A) locating at the zinc fingers 2 (ZF2) domain of TNFAIP3 inherited from his mother was confirmed. Compared with age-matched healthy controls, decrease expression of A20 was observed in the patient. The NF-κB pathway was found to be overactivated, and the synthesis of TNF-α was upregulated in the patient-derived cells. However, cells from the mother showed a milder response to LPS than cells from the patient.

Conclusions

The present research indicated that the TNFAIP3 mutation of c.1428G > A (p.M476I) leads to the reduced suppression of NF-κB activation and accounted for the autoinflammatory phenotype and persistent EBV viremia in the patient.

Keywords

TNFAIP3 NF-κB autoinflammatory EBV viremia 

Notes

Acknowledgments

This study was supported by the National Natural Science Foundation of China (81471482), the Science and Technology Commission of Shanghai Municipality (14411965400), the Shanghai Hospital Development Center (SHDC12016228), and Children’s Hospital of Fudan University Funding (EK1125180110, EK112520180202). Many thanks to the patient and his parents.

Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Kastner DL, Aksentijevich I, Goldbachmansky R. Autoinflammatory disease reloaded: a clinical perspective. Cell. 2010;140(6):784–90.Google Scholar
  2. 2.
    Jesus AAD, Goldbach-Mansky R. Monogenic autoinflammatory diseases: concept and clinical manifestations. Clin Immunol. 2013;147(3):155–74.Google Scholar
  3. 3.
    Russo RAG, Brogan PA. Monogenic autoinflammatory diseases. Rheumatology. 2014;53(11):1927–39.Google Scholar
  4. 4.
    Baltimore D. NF-κB is 25. Nat Immunol. 2011;12(8):683–5.Google Scholar
  5. 5.
    Rui L, Schmitz R, Ceribelli M, Staudt LM. Malignant pirates of the immune system. Nat Immunol. 2011;12(10):933–40.Google Scholar
  6. 6.
    Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, et al. De-ubiquitination and ubiquitin ligase domains of A20 downregulate NF-B signalling. Nature. 2004;430(7000):694–9.Google Scholar
  7. 7.
    David LBDL, Emre ETEE, Eric GLEG, R-C RCA, Matthew TWMT, Colleen TC, et al. The ubiquitin-modifying enzyme A20 is required for termination of Toll-like receptor responses. Nat Immunol. 5:1052–60 Nature Immunology. 2005;6(1):114.Google Scholar
  8. 8.
    Hitotsumatsu O, Ahmad RC, Tavares R, Wang M, Philpott D, Turer EE, et al. The ubiquitin-editing enzyme A20 restricts nucleotide-binding oligomerization domain containing 2-triggered signals. Immunity. 2008;28(3):381–90.Google Scholar
  9. 9.
    Jäättelä M, Mouritzen H, Elling F, Bastholm L. A20 zinc finger protein inhibits TNF and IL-1 signaling. J Immunol. 1996;156(3):1166–73.Google Scholar
  10. 10.
    Lee EG, Boone DL, Chai S, Libby SL, Chien M, Lodolce JP, et al. Failure to regulate TNF-induced NF-κB and cell death responses in A20-deficient mice. Science. 2000;289(5488):2350–4.Google Scholar
  11. 11.
    Musone SL, Taylor KE, Nititham J, Chu C, Poon A, Liao W, et al. Sequencing of TNFAIP3 and association of variants with multiple autoimmune diseases. Genes Immun. 2011;12(3):176–82.Google Scholar
  12. 12.
    Lee YH, Bae SC, Choi SJ, Ji JD, Song GG. Associations between TNFAIP3 gene polymorphisms and rheumatoid arthritis: a meta-analysis. Inflamm Res. 2012;61(6):635–41.Google Scholar
  13. 13.
    Zhu L, Wang L, Wang X, Zhou L, Liao Z, Xu L, et al. Characteristics of A20 gene polymorphisms and clinical significance in patients with rheumatoid arthritis. J Transl Med. 2015;13(1):215.Google Scholar
  14. 14.
    Musone SL, Taylor KE, Lu TT, Nititham J, Ferreira RC, Ortmann W, et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat Genet. 2008;40(9):1062–4.Google Scholar
  15. 15.
    Elsby LM, Orozco G, Denton J, Worthington J, Ray DW, Donn RP. Functional evaluation of TNFAIP3 (A20) in rheumatoid arthritis. Clin Exp Rheumatol. 2010;28(5):708–14.Google Scholar
  16. 16.
    Fung EY, Smyth DJ, Howson JM, Cooper JD, Walker NM, Stevens H, et al. Analysis of 17 autoimmune disease-associated variants in type 1 diabetes identifies 6q23/TNFAIP3 as a susceptibility locus. Genes Immun. 2009;10(2):188–91.Google Scholar
  17. 17.
    Eyre S, Hinks A, Bowes J, Flynn E, Martin P, Wilson AG, et al. Overlapping genetic susceptibility variants between three autoimmune disorders: rheumatoid arthritis, type 1 diabetes and coeliac disease. Arthritis Res Ther, 12,5(2010-09-20). 2010;12(5):R175-R.Google Scholar
  18. 18.
    Burton PR, Clayton DG, Cardon LR, Craddock N, Deloukas P, Duncanson A, et al. Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls. Nature. 2007;447(7145):661–78.Google Scholar
  19. 19.
    Zhou Q, Wang H, Schwartz DM, Stoffels M, Park YH, Zhang Y, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48(1):67–73.Google Scholar
  20. 20.
    Duncan CJA, Dinnigan E, Theobald R, Grainger A, Skelton AJ, Hussain R, et al. Early-onset autoimmune disease due to a heterozygous loss-of-function mutation in TNFAIP3 (A20). Ann Rheum Dis. 2017.  https://doi.org/10.1136/annrheumdis-2016-210944.
  21. 21.
    Ohnishi H, Kawamoto N, Seishima M, Ohara O, Fukao T. A Japanese family case with juvenile onset Behçet’s disease caused by TNFAIP3 mutation. Allergol Int. 2017;66(1):146–8.Google Scholar
  22. 22.
    Tomonari S, Naoe K, Norimoto K, Keiko K, Yusuke T, Naoko N, et al. Novel heterozygous C243Y A20/TNFAIP3 gene mutation is responsible for chronic inflammation in autosomal-dominant Behçet’s disease. RMD Open. 2016;2(1):e000223.Google Scholar
  23. 23.
    Takagi M, Ogata S, Ueno H, Yoshida K, Yeh T, Hoshino A, et al. Haploinsufficiency of TNFAIP3 (A20) by germline mutation is involved in autoimmune lymphoproliferative syndrome. J Allergy Clin Immunol. 2017;139(6):1914–22.Google Scholar
  24. 24.
    Sun J, Ying W, Liu D, Hui X, Yu Y, Wang J, et al. Clinical and genetic features of 5 Chinese patients with X-linked lymphoproliferative syndrome. Scand J Immunol. 2013;78(5):463–7.Google Scholar
  25. 25.
    Livak KJ, Schmittgen TD. Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 2001;25(4):402–8.Google Scholar
  26. 26.
    Hayden MS, Ghosh S. Signaling to NF-kappaB. Genes Dev. 2004;18(18):2195–224.Google Scholar
  27. 27.
    Hymowitz SG, Wertz IE. A20: from ubiquitin editing to tumour suppression. Nat Rev Cancer. 2010;10(5):332–41.Google Scholar
  28. 28.
    Catrysse L, Vereecke L, Beyaert R, Van LG. A20 in inflammation and autoimmunity. Trends Immunol. 2014;35(1):22–31.Google Scholar
  29. 29.
    Song HY, Rothe M, Goeddel DV. The tumor necrosis factor-inducible zinc finger protein A20 interacts with TRAF1/TRAF2 and inhibits NF-kappaB activation. Proc Natl Acad Sci U S A. 1996;93(13):6721–5.Google Scholar
  30. 30.
    Ma A, Malynn BA. A20: linking a complex regulator of ubiquitylation to immunity and human disease. Nat Rev Immunol. 2012;12(11):774–85.Google Scholar
  31. 31.
    Kadowaki T, Ohnishi H, Kawamoto N, Hori T, Nishimura K, Kobayashi C, et al. Haploinsufficiency of A20 causes autoinflammatory and autoimmune disorders. J Allergy Clin Immunol. 2018;141(4):1485–8.Google Scholar
  32. 32.
    Nomoto J, Hiramoto N, Kato M, Sanada M, Maeshima AM, Taniguchi H, et al. Deletion of the TNFAIP3/A20 gene detected by FICTION analysis in classical Hodgkin lymphoma. BMC Cancer, 12,1(2012-10-05). 2012;12(1):457.Google Scholar
  33. 33.
    Kato M, Sanada M, Kato I, Sato Y, Takita J, Takeuchi K, et al. Frequent inactivation of A20 in B-cell lymphomas. Nature. 2009;459(7247):712–6.Google Scholar
  34. 34.
    Ando M, Sato Y, Takata K, Nomoto J, Nakamura S, Ohshima K, et al. A20 (TNFAIP3) deletion in Epstein-Barr virus-associated lymphoproliferative disorders/lymphomas. PLoS One. 2013;8(2):e56741.Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Clinical ImmunologyChildren’s Hospital of Fudan UniversityShanghaiChina
  2. 2.Kunming Children’s Hospital Affiliated to Kunming Medical UniversityKunmingChina

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