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Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome

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Abstract

Several studies have suggested that T cell-producing permeability factors might lead to proteinuria in minimal change nephrotic syndrome (MCNS). However, it is still unclear whether T-cell abnormalities cause MCNS. Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a rare disorder of the immune regulation system, which leads to severe autoimmune phenomena including autoimmune enteropathy, atopic dermatitis with high levels of serum immunoglobulin E (IgE), type 1 diabetes mellitus (T1DM), and severe infection such as sepsis, which frequently result in death within the first 2 years of life. This disease is caused by mutations in the FOXP3 gene that result in the defective development of regulatory T (Treg) cells. This report describes a 5-year-old boy with IPEX syndrome with a 3 bp deletion in the FOXP3 gene (c.748–750delAAG, p.250K.del) and a paucity of CD4+ CD25+ FOXP3+ T cells. The boy’s condition was complicated by MCNS in addition to many IPEX-related manifestations, such as atopic dermatitis, T1DM, enteropathy, sepsis and hemolytic anemia. This is the first report of IPEX syndrome complicated by MCNS, and our findings imply that Treg cell dysfunction may be crucial for the development of MCNS.

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References

  1. Shalhoub RJ (1974) Pathogenesis of lipoid nephrosis: a disorder of T-cell function. Lancet 2:556–560

    Article  CAS  PubMed  Google Scholar 

  2. Ochs HD, Ziegler SF, Torgerson TR (2005) FOXP3 acts as a rheostat of the immune response. Immunol Rev 203:156–164

    Article  CAS  PubMed  Google Scholar 

  3. van der Vliet HJ, Nieuwenhuis EE (2007) IPEX as a result of mutations in FOXP3. Clin Dev Immunol 2007:89017

    PubMed  PubMed Central  Google Scholar 

  4. Owen CJ, Jennings CE, Imrie H, Lachaux A, Bridges NA, Cheetham TD, Pearce SH (2003) Mutational analysis of the FOXP3 gene and evidence for genetic heterogeneity in the immunodysregulation, polyendocrinopathy, enteropathy syndrome. J Clin Endocrinol Metab 88:6034–6039

    Article  CAS  PubMed  Google Scholar 

  5. Roncador G, Brown PJ, Maestre L, Hue S, Martínez-Torrecuadrada JL, Ling KL, Pratap S, Toms C, Fox BC, Cerundolo V, Powrie F, Banham AH (2005) Analysis of FOXP3 protein expression in human CD4 + CD25 + regulatory T cells at the single-cell level. Eur J Immunol 35:1681–1691

    Article  CAS  PubMed  Google Scholar 

  6. Ziegler SF (2006) FOXP3: of mice and men. Annu Rev Immunol 24:209–226

    Article  CAS  PubMed  Google Scholar 

  7. Wildin RS, Smyk-Pearson S, Filipovich AH (2002) Clinical and molecular features of the immunodysregulation, polyendocrinopathy, enteropathy, X linked (IPEX) syndrome. J Med Genet 39:537–545

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Fuchizawa T, Adachi Y, Ito Y, Higashiyama H, Kanegane H, Futatani T, Kobayashi I, Kamachi Y, Sakamoto T, Tsuge I, Tanaka H, Banham AH, Ochs HD, Miyawaki T (2007) Developmental changes of FOXP3-expressing CD4+ CD25+ regulatory T cells and their impairment in patients with FOXP3 gene mutations. Clin Immunol 125:237–246

    Article  CAS  PubMed  Google Scholar 

  9. Li B, Samanta A, Song X, Furuuchi K, Iacono KT, Kennedy S, Katsumata M, Saouaf SJ, Greene MI (2006) FOXP3 ensembles in T-cell regulation. Immunol Rev 212:99–113

    Article  CAS  PubMed  Google Scholar 

  10. Bacchetta R, Passerini L, Gambineri E, Dai M, Allan SE, Perroni L, Dagna-Bricarelli F, Sartirana C, Matthes-Martin S, Lawitschka A, Azzari C, Ziegler SF, Levings MK, Roncarolo MG (2006) Defective regulatory and effector T cell functions in patients with FOXP3 mutations. J Clin Invest 116:1713–1722

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Moudgil A, Perriello P, Loechelt B, Przygodzki R, Fitzerald W, Kamani N (2007) Immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome: an unusual cause of proteinuria in infancy. Pediatr Nephrol 22:1799–1802

    Article  PubMed  Google Scholar 

  12. Ellis D, Fisher SE, Smith WI Jr, Jaffe R (1982) Familial occurrence of renal and intestinal disease associated with tissue autoantibodies. Am J Dis Child 136:323–326

    CAS  PubMed  Google Scholar 

  13. Kobayashi I, Shiari R, Yamada M, Kawamura N, Okano M, Yara A, Iguchi A, Ishikawa N, Ariga T, Sakiyama Y, Ochs HD, Kobayashi K (2001) Novel mutations of FOXP3 in two Japanese patients with immune dysregulation, polyendocrinopathy, enteropathy, X linked syndrome (IPEX). J Med Genet 38:874–876

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sakaguchi S, Ono M, Setoguchi R, Yagi H, Hori S, Fehervari Z, Shimizu J, Takahashi T, Nomura T (2006) Foxp3 + CD25 + CD4 + natural regulatory T cells in dominant self-tolerance and auto-immune disease. Immunol Rev 212:8–27

    Article  CAS  PubMed  Google Scholar 

  15. Ono M, Shimizu J, Miyachi Y, Sakaguchi S (2006) Control of autoimmune myocarditis and multiorgan inflammation by glucocorticoid-induced TNF receptor family-related protein(high), Foxp3-expressing CD25+ and CD25- regulatory T cells. J Immunol 176:4748–4756

    Article  CAS  PubMed  Google Scholar 

  16. Sakaguchi S, Yamaguchi T, Nomura T, Ono M (2008) Regulatory T cells and immune tolerance. Cell 133:775–787

    Article  CAS  PubMed  Google Scholar 

  17. Hardwicke J, Soothill JF, Squire JR, Holti G (1959) Nephrotic syndrome and pollen hypersensitivity. Lancet I:500–502

    Article  Google Scholar 

  18. Wittig HJ, Goldman AS (1970) Nephrotic syndrome associated with inhaled allergens. Lancet I:542–543

    Article  Google Scholar 

  19. Reeves WG, Cameron JS, Johansson SG, Ogg CS, Peters DK, Weller RO (1975) Seasonal nephrotic syndrome. Description and immunological findings. Clin Allergy 5:121–137

    Article  CAS  PubMed  Google Scholar 

  20. Yap HK, Yip WCL, Lee BW, Ho TF, Teo J, Aw SE, Tay JSH (1983) The incidence of atopy in steroid-responsive nephrotic syndrome: clinical and immunological parameters. Ann Allergy 51:590–594

    CAS  PubMed  Google Scholar 

  21. Yokoyama H, Kida H, Tani Y, Abe T, Tomosugi N, Koshino Y, Hattori N (1985) Immunodynamics of minimal change nephrotic syndrome in adults T and B lymphocyte subsets and serum immunoglobulin levels. Clin Exp Immunol 61:601–607

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Goldman M, Hébert D, Geary DF (2002) Management of steroid-sensitive nephrotic syndrome in children with type 1 diabetes. Pediatr Nephrol 17:351–354

    Article  PubMed  Google Scholar 

  23. Kemper MJ, Meyer-Jark T, Lilova M, Müller-Wiefel DE (2003) Combined T- and B-cell activation in childhood steroid-sensitive nephrotic syndrome. Clin Nephrol 60:242–247

    Article  CAS  PubMed  Google Scholar 

  24. Shen Z, Chen L, Hao F, Wang G, Fan P, Liu Y(2008) Intron-1 rs3761548 is related to the defective transcription of Foxp3 in psoriasis through abrogating E47/c-Myb binding. J Cell Mol Med doi:https://doi.org/10.1111/j.1582-4934.2008.00370.x

  25. Park O, Grishina I, Leung PS, Gershwin ME, Prindiville T (2005) Analysis of the Foxp3/scurfin gene in Crohn’s disease. Ann N Y Acad Sci 1051:218–228

    Article  CAS  PubMed  Google Scholar 

  26. Bassuny WM, Ihara K, Sasaki Y, Kuromaru R, Kohno H, Matsuura N, Hara T (2003) A functional polymorphism in the promoter/enhancer region of the FOXP3/scurfin gene associated with type 1 diabetes. Immunogenetics 55:149–156

    Article  CAS  PubMed  Google Scholar 

  27. Rubio-Cabezas O, Minton JA, Caswell R, Shield JP, Deiss D, Sumnik Z, Cayssials A, Herr M, Loew A, Lewis V, Ellard S, Hattersley AT (2009) Clinical heterogeneity in patients with FOXP3 mutations presenting with permanent neonatal diabetes. Diabetes Care 32:111–116

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Faul C, Donnelly M, Merscher-Gomez S, Chang YH, Franz S, Delfgaauw J, Chang JM, Choi HY, Campbell KN, Kim K, Reiser J, Mundel P (2008) The actin cytoskeleton of kidney podocytes is a direct target of the antiproteinuric effect of cyclosporine A. Nat Med 14:931–938

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Takemoto M, He L, Norlin J, Patrakka J, Xiao Z, Petrova T, Bondjers C, Asp J, Wallgard E, Sun Y, Samuelsson T, Mostad P, Lundin S, Miura N, Sado Y, Alitalo K, Quaggin SE, Tryggvason K, Betsholtz C (2006) Large-scale identification of genes implicated in kidney glomerulus development and function. EMBO J 25:1160–1174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. He L, Sun Y, Takemoto M, Norlin J, Tryggvason K, Samuelsson T, Betsholtz C (2008) The glomerular transcriptome and a predicted protein–protein interaction network. J Am Soc Nephrol 19:260–268

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Takemoto M, Asker N, Gerhardt H, Lundkvist A, Johansson BR, Saito Y, Betsholtz C (2002) A new method for large scale isolation of kidney glomeruli from mice. Am J Pathol 161:799–805

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgments

This study was supported by a Grant in Aid for Scientific Research (C-18590920) (to K.I.) from the Japan Society for the Promotion of Science. The authors thank Ms. Yoshimi Nozu for her help with the genetic analysis.

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Authors and Affiliations

  1. Department of Pediatrics, Kobe University Graduate School of Medicine, Kobe, Japan

    Yuya Hashimura, Kandai Nozu, Akira Hayakawa & Masafumi Matsuo

  2. Department of Pediatrics, Graduate School of Medicine, University of Toyama, Toyama, Japan

    Hirokazu Kanegane & Toshio Miyawaki

  3. Department of Pediatrics, Wakayama Medical University, Wakayama, Japan

    Norishige Yoshikawa & Koichi Nakanishi

  4. Clinical Cell Biology and Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan

    Minoru Takemoto

  5. Division of Child Health and Development, Department of Pediatrics, Kobe University Graduate School of Medicine, 5-1 Kusunoki-cho 7 chome, Chuo-ku, Kobe, 650-0017, Japan

    Kazumoto Iijima

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  1. Yuya Hashimura
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  2. Kandai Nozu
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  3. Hirokazu Kanegane
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  8. Minoru Takemoto
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Correspondence to Kazumoto Iijima.

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Hashimura, Y., Nozu, K., Kanegane, H. et al. Minimal change nephrotic syndrome associated with immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome. Pediatr Nephrol 24, 1181–1186 (2009). https://doi.org/10.1007/s00467-009-1119-8

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  • DOI: https://doi.org/10.1007/s00467-009-1119-8

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