Advertisement

Pediatric Nephrology

, Volume 33, Issue 2, pp 287–293 | Cite as

FOXP3+ T cells are present in kidney biopsy samples in children with tubulointerstitial nephritis and uveitis syndrome

  • Sari H. Rytkönen
  • Petri Kulmala
  • Helena Autio-Harmainen
  • Pekka Arikoski
  • Kira Endén
  • Janne Kataja
  • Tuomo Karttunen
  • Matti Nuutinen
  • Timo Jahnukainen
Original Article

Abstract

Background

Tubulointerstitial nephritis (TIN) is an inflammatory disease of unknown pathogenesis. To evaluate a possible role of regulatory T cells (Tregs) in the pathophysiology of TIN with (TINU) and without uveitis, we investigated the presence and quantity of FOXP3+ T regulatory lymphocytes in diagnostic kidney biopsies from pediatric patients.

Methods

A total of 33 patients (14 TIN and 19 TINU) were enrolled. The quantity of CD4+, FOXP3+ and double-positive T cells in formalin-fixed kidney biopsies was determined using double label immunohistochemistry with anti-human CD4 and FOXP3 antibodies.

Results

FOXP3 staining was successful in all 33 patients. In patients with chronic uveitis, the density of FOXP3+ cells was significantly lower (p = 0.046) than in TIN patients without uveitis or with uveitis lasting <3 months. CD4+ staining was successful in 23 patients. The density of all lymphocytes (CD4+, CD4+FOXP3+ and FOXP3+ cells) was significantly lower (p = 0.023) in patients with chronic uveitis than in other patients.

Conclusions

FOXP3+ T cells are present in kidney biopsy samples from TIN and TINU patients. In patients with chronic uveitis, the density of FOXP3+ T cells is significantly lower than in other patients, suggesting a different pathomechanism for these clinical conditions.

Keywords

Tubulointerstitial nephritis Regulatory T cell Child Biopsy Uveitis FOXP3 

Notes

Acknowledgements

We would like to thank Mrs Heli Ylisuutari for her excellent contribution to the preparation and execution of the immunohistochemical stainings.

Funding

This study has been supported by the Foundation for Pediatric Research, Finnish Medical Foundation, the Sigrid Juselius Foundation, and the Alma and K.A. Snellman Foundation, Oulu, Finland.

Compliance with ethical standards

Conflicts of interest

The authors declare that they have no conflicts of interest.

Statement of human rights

The study adhered to the tenets of the Declaration of Helsinki and the study protocol was approved by the ethics committee. All participants and/or their parents gave their informed consent to the study.

References

  1. 1.
    Takemura T, Okada M, Hino S, Fukushima K, Yamamoto S, Miyazato H, Maruyama K, Yoshioka K (1999) Course and outcome of tubulointerstitial nephritis and uveitis syndrome. Am J Kidney Dis 34:1016–1021CrossRefPubMedGoogle Scholar
  2. 2.
    Saarela V, Nuutinen M, Ala-Houhala M, Arikoski P, Rönnholm K, Jahnukainen T (2013) Tubulointerstitial nephritis and uveitis syndrome in children: a prospective multicenter study. Ophthalmology 120:1476–1481CrossRefPubMedGoogle Scholar
  3. 3.
    Ellis D, Fried WA, Yunis EJ, Blau EB (1981) Acute interstitial nephritis in children: a report of 13 cases and review of the literature. Pediatrics 67:862–870PubMedGoogle Scholar
  4. 4.
    Fiorentino M, Bolignano D, Tesar V, Pisano A, Van Biesen W, D'Arrigo G, Tripepi G, Gesualdo L, ERA-EDTA Immunonephrology Working Group (2016) Renal biopsy in 2015—from epidemiology to evidence-based indications. Am J Nephrol 43:1–19CrossRefPubMedGoogle Scholar
  5. 5.
    Praga M, Sevillano A, Auñón P, González E (2015) Changes in the aetiology, clinical presentation and management of acute interstitial nephritis, an increasingly common cause of acute kidney injury. Nephrol Dial Transplant 30:1472–1479CrossRefPubMedGoogle Scholar
  6. 6.
    Sanchez-Burson J, Garcia-Porrua C, Montero-Granados R, Gonzalez-Escribano F, Gonzalez-Gay MA (2002) Tubulointerstitial nephritis and uveitis syndrome in southern Spain. Semin Arthritis Rheum 32:125–129CrossRefPubMedGoogle Scholar
  7. 7.
    Reddy AK, Hwang YS, Mandelcorn ED, Davis JL (2014) HLA-DR, DQ class II DNA typing in pediatric panuveitis and tubulointerstitial nephritis and uveitis. Am J Ophthalmol 157:678–686CrossRefPubMedGoogle Scholar
  8. 8.
    Levinson RD, Park MS, Rikkers SM, Reed EF, Smith JR, Martin TM, Rosenbaum JT, Foster CS, Sherman MD, Holland GN (2003) Strong associations between specific HLA-DQ and HLA-DR alleles and the tubulointerstitial nephritis and uveitis syndrome. Invest Ophthalmol Vis Sci 44:653–657CrossRefPubMedGoogle Scholar
  9. 9.
    Peräsaari J, Saarela V, Nikkilä J, Ala-Houhala M, Arikoski P, Kataja J, Rönnholm K, Merenmies J, Nuutinen M, Jahnukainen T (2013) HLA associations with tubulointerstitial nephritis with or without uveitis in Finnish pediatric population: a nation-wide study. Tissue Antigens 81:435–441CrossRefPubMedGoogle Scholar
  10. 10.
    Dummer CD, Carpio VN, Gonçalves LF, Manfro RC, Veronese FV (2012) FOXP3+ regulatory T cells: from suppression of rejection to induction of renal allograft tolerance. Transpl Immunol 26:1–10CrossRefPubMedGoogle Scholar
  11. 11.
    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 212:99–113CrossRefPubMedGoogle Scholar
  12. 12.
    Bestard O, Cruzado JM, Rama I, Torras J, Gomà M, Serón D, Moreso F, Gil-Vernet S, Grinyó JM (2008) Presence of FoxP3+ regulatory T cells predicts outcome of subclinical rejection of renal allografts. J Am Soc Nephrol 19:2020–2026CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Bestard O, Cuñetti L, Cruzado JM, Lucia M, Valdez R, Olek S, Melilli E, Torras J, Mast R, Gomà M, Franquesa M, Grinyó JM (2011) Intragraft regulatory T cells in protocol biopsies retain foxp3 demethylation and are protective biomarkers for kidney graft outcome. Am J Transplant 11:2162–2172CrossRefPubMedGoogle Scholar
  14. 14.
    Nie J, Li YY, Zheng SG, Tsun A, Li B (2015) FOXP3(+) Treg cells and gender bias in autoimmune diseases. Front Immunol 6:493CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Paust HJ, Ostmann A, Erhardt A, Turner JE, Velden J, Mittrücker HW, Sparwasser T, Panzer U, Tiegs G (2011) Regulatory T cells control the Th1 immune response in murine crescentic glomerulonephritis. Kidney Int 80:154–164CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Wolf D, Hochegger K, Wolf AM, Rumpold HF, Gastl G, Tilg H, Mayer G, Gunsilius E, Rosenkranz AR (2005) CD4+CD25+ regulatory T cells inhibit experimental anti-glomerular basement membrane glomerulonephritis in mice. J Am Soc Nephrol 16:1360–1370CrossRefPubMedGoogle Scholar
  17. 17.
    Sheikine Y, Woda CB, Lee PY, Chatila TA, Keles S, Charbonnier LM, Schmidt B, Rosen S, Rodig NM (2015) Renal involvement in the immunodysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) disorder. Pediatr Nephrol 30:1197–1202CrossRefPubMedGoogle Scholar
  18. 18.
    Mizushima I, Yamada K, Fujii H, Inoue D, Umehara H, Yamagishi M, Yamaguchi Y, Nagata M, Matsumura M, Kawano M (2012) Clinical and histological changes associated with corticosteroid therapy in IgG4-related tubulointerstitial nephritis. Mod Rheumatol 22:859–870CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Afeltra A, Gigante A, Margiotta DP, Taffon C, Cianci R, Barbano B, Liberatori M, Amoroso A, Rossi Fanelli F (2015) The involvement of T regulatory lymphocytes in a cohort of lupus nephritis patients: a pilot study. Intern Emerg Med 10:677–683CrossRefPubMedGoogle Scholar
  20. 20.
    Jahnukainen T, Saarela V, Arikoski P, Ylinen E, Rönnholm K, Ala-Houhala M, Nuutinen M (2013) Prednisone in the treatment of tubulointerstitial nephritis in children. Pediatr Nephrol 28:1253–1260CrossRefPubMedGoogle Scholar
  21. 21.
    Jahnukainen T, Ala-Houhala M, Karikoski R, Kataja J, Saarela V, Nuutinen M (2011) Clinical outcome and occurrence of uveitis in children with idiopathic tubulointerstitial nephritis. Pediatr Nephrol 26:291–299CrossRefPubMedGoogle Scholar
  22. 22.
    Joyce E, Glasner P, Ranganathan S, Swiatecka-Urban A (2017) Tubulointerstitial nephritis: diagnosis, treatment, and monitoring. Pediatr Nephrol 32:577–587CrossRefPubMedGoogle Scholar
  23. 23.
    Praga M, González E (2010) Acute interstitial nephritis. Kidney Int 77:956–961CrossRefPubMedGoogle Scholar
  24. 24.
    Cheng M, Gu X, Herrera GA (2016) Dendritic cells in renal biopsies of patients with acute tubulointerstitial nephritis. Hum Pathol 54:113–120CrossRefPubMedGoogle Scholar
  25. 25.
    Donadio ME, Loiacono E, Peruzzi L, Amore A, Camilla R, Chiale F, Vergano L, Boido A, Conrieri M, Bianciotto M, Bosetti FM, Coppo R (2014) Toll-like receptors, immunoproteasome and regulatory T cells in children with Henoch-Schönlein purpura and primary IgA nephropathy. Pediatr Nephrol 29:1545–1551CrossRefPubMedGoogle Scholar
  26. 26.
    Shao X, Jiang C, Li Y, Jiang X, Xu H, Ying P, Qiu J, Lin J, Zheng S, Chang L, Huang Y (2014) Function of CD4(+) CD25(+) regulatory T cells in Henoch-Schonlein purpura nephritis in children. Zhonghua Er Ke Za Zhi 52:516–520PubMedGoogle Scholar
  27. 27.
    Taflin C, Nochy D, Hill G, Frouget T, Rioux N, Vérine J, Bruneval P, Glotz D (2010) Regulatory T cells in kidney allograft infiltrates correlate with initial inflammation and graft function. Transplantation 89:194–199CrossRefPubMedGoogle Scholar
  28. 28.
    Oda JM, Hirata BK, Guembarovski RL, Watanabe MA (2013) Genetic polymorphism in FOXP3 gene: imbalance in regulatory T-cell role and development of human diseases. J Genet 92:163–171CrossRefPubMedGoogle Scholar
  29. 29.
    Ghali JR, Wang YM, Holdsworth SR, Kitching AR (2016) Regulatory T cells in immune-mediated renal disease. Nephrology (Carlton) 21:86–96CrossRefGoogle Scholar
  30. 30.
    Free ME, Bunch DO, McGregor JA, Jones BE, Berg EA, Hogan SL, Hu Y, Preston GA, Jennette JC, Falk RJ, Su MA (2013) Patients with antineutrophil cytoplasmic antibody-associated vasculitis have defective Treg cell function exacerbated by the presence of a suppression-resistant effector cell population. Arthritis Rheum 65:1922–1933CrossRefPubMedGoogle Scholar
  31. 31.
    Rimbert M, Hamidou M, Braudeau C, Puéchal X, Teixeira L, Caillon H, Néel A, Audrain M, Guillevin L, Josien R (2011) Decreased numbers of blood dendritic cells and defective function of regulatory T cells in antineutrophil cytoplasmic antibody-associated vasculitis. PLoS One 6:e18734CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Morgan MD, Day CJ, Piper KP, Khan N, Harper L, Moss PA, Savage CO (2010) Patients with Wegener's granulomatosis demonstrate a relative deficiency and functional impairment of T-regulatory cells. Immunology 130:64–73CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Abdulahad WH, Stegeman CA, van der Geld YM, Doornbos-van der Meer B, Limburg PC, Kallenberg CG (2007) Functional defect of circulating regulatory CD4+ T cells in patients with Wegener's granulomatosis in remission. Arthritis Rheum 56:2080–2091CrossRefPubMedGoogle Scholar
  34. 34.
    Klapa S, Mueller A, Csernok E, Fagin U, Klenerman P, Holl-Ulrich K, Gross WL, Lamprecht P (2010) Lower numbers of FoxP3 and CCR4 co-expressing cells in an elevated subpopulation of CD4+CD25high regulatory T cells from Wegener's granulomatosis. Clin Exp Rheumatol 28 (1 Suppl 57]:72–80PubMedGoogle Scholar
  35. 35.
    Xing Q, Wang B, Su H, Cui J, Li J (2012) Elevated Th17 cells are accompanied by FoxP3+ Treg cells decrease in patients with lupus nephritis. Rheumatol Int 32:949–958CrossRefPubMedGoogle Scholar
  36. 36.
    Li H, Li Q, Ji C, Gu J (2016) Ankylosing spondylitis patients with HLA-B*2704 have more uveitis than patients with HLA-B*2705 in a north Chinese population. Ocul Immunol Inflamm 18:1–5Google Scholar
  37. 37.
    Angeles-Han ST, McCracken C, Yeh S, Jang SR, Jenkins K, Cope S, Bohnsack J, Hersh A, Thompson SD, Prahalad S (2015) HLA associations in a cohort of children with juvenile idiopathic arthritis with and without uveitis. Invest Ophthalmol Vis Sci 56:6043–6048CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Skarsvåg S, Hansen KE, Holst A, Moen T (1992) Distribution of HLA class II alleles among Scandinavian patients with systemic lupus erythematosus (SLE): an increased risk of SLE among non[DRB1*03,DQA1*0501,DQB1*0201] class II homozygotes? Tissue Antigens 40:128–133CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2017

Authors and Affiliations

  1. 1.PEDEGO Research Unit and Medical Research Center (MRC) OuluUniversity of Oulu and Oulu University HospitalOuluFinland
  2. 2.Biomedicine Research Unit, Clinical Microbiology and ImmunologyUniversity of OuluOuluFinland
  3. 3.Cancer and Translational Medicine Research UnitUniversity of Oulu, and Department of Pathology, Oulu University HospitalOuluFinland
  4. 4.Department of PediatricsUniversity of Eastern-Finland and Kuopio University HospitalKuopioFinland
  5. 5.Department of PediatricsTampere University HospitalTampereFinland
  6. 6.Department of Pediatric Nephrology and Transplantation, Children’s HospitalHelsinki University Hospital and Helsinki UniversityHelsinkiFinland
  7. 7.Pediatric and Adolescent MedicineTurku University HospitalTurkuFinland

Personalised recommendations