Skip to main content
SpringerLink
Log in

CTLA-4 exon 1 +49A/G polymorphism is associated with renal involvement in pediatric Henoch–Schönlein purpura

  • Original Article
  • Published:
Pediatric Nephrology Aims and scope Submit manuscript

Abstract

Background

Henoch–Schönlein purpura (HSP) is a multisystemic vasculitis of unknown etiology. Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) and CD28 have been reported to be important candidate genes for conferring susceptibility to autoimmunity. In this study, we investigated the correlation of CTLA-4 and CD28 gene polymorphisms with HSP in children with and without renal involvement.

Methods

The CTLA-4 exon 1 +49A/G, promoter -318C/T and CD28 IVS3 +17T/C single nucleotide polymorphisms (SNPs) were genotyped in 110 children with HSP and 90 ethnically matched healthy controls through restriction fragment-length polymorphism (RFLP).

Results

The CTLA-4 (+49) GG genotype and G allele (GG + AG genotype) were more common in HSP patients with renal involvement (n = 52) than in HSP patients without renal involvement (n = 58) (P = 0.019 and 0.001, respectively). There were no significant differences in the prevalence of CTLA-4 (+49 A/G), (-318C/T) and CD28 IVS3 (+17 /T/C) polymorphisms between HSP patients and controls.

Conclusions

Our findings suggest that the CTLA-4 +49 GG genotype and G allele may contribute to increased risk for the development of renal damage in HSP patients.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Aalberse J, Dolman K, Ramnath G, Pereira RR, Davin JC (2007) Henoch Schonlein purpura in children: an epidemiological study among Dutch paediatricians on incidence and diagnostic criteria. Ann Rheum Dis 66:1648–1650

    Article  PubMed  Google Scholar 

  2. Lau KK, Suzuki H, Novak J, Wyatt RJ (2010) Pathogenesis of Henoch-Schönlein purpura nephritis. Pediatr Nephrol 25:19–26

    Article  PubMed  Google Scholar 

  3. Yang YH, Huang MT, Lin SC, Lin YT, Tsai MJ, Chiang BL (2000) Increased transforming growth factor-beta (TGF-beta)-secreting T cells and IgA anti-cardiolipin antibody levels during acute stage of childhood Henoch-Schönlein purpura. Clin Exp Immunol 122:285–290

    Article  PubMed  CAS  Google Scholar 

  4. Schmitt R, Carlsson F, Mörgelin M, Tati R, Lindahl G, Karpman D (2010) Tissue deposits of IgA-binding streptococcal M proteins in IgA nephropathy and Henoch-Schonlein purpura. Am J Pathol 176:608–618

    Article  PubMed  CAS  Google Scholar 

  5. Lafage-Pochitaloff M, Costello R, Couez D, Simonetti J, Mannoni P, Mawas C, Olive D (1990) Human CD28 and CTLA-4 Ig superfamily genes are located on chromosome 2 at bands q33-q34. Immunogenetics 31:198–201

    Article  PubMed  CAS  Google Scholar 

  6. Harper K, Balzano C, Rouvier E, Mattéi MG, Luciani MF, Golstein P (1991) CTLA-4 and CD28 activated lymphocyte molecules are closely related in both mouse and human as to sequence, message expression, gene structure, and chromosomal location. J Immunol 147:1037–1044

    PubMed  CAS  Google Scholar 

  7. Tivol EA, Borriello F, Schweitzer AN, Lynch WP, Bluestone JA, Sharpe AH (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547

    Article  PubMed  CAS  Google Scholar 

  8. Waterhouse P, Penninger JM, Timms E, Wakeham A, Shahinian A, Lee KP, Thompson CB, Griesser H, Mak TW (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988

    Article  PubMed  CAS  Google Scholar 

  9. Herold KC, Vezys V, Koons A, Lenschow D, Thompson C, Bluestone JA (1997) CD28/B7 costimulation regulates autoimmune diabetes induced with multiple low doses of streptozotocin. J Immunol 158:984–991

    PubMed  CAS  Google Scholar 

  10. Ahmed S, Ihara K, Kanemitsu S, Nakashima H, Otsuka T, Tsuzaka K, Takeuchi T, Hara T (2001) Association of CTLA-4 but not CD28 gene polymorphisms with systemic lupus erythematosus in the Japanese population. Rheumatology 40:662–667

    Article  PubMed  CAS  Google Scholar 

  11. Chen L (2004) Co-inhibitory molecules of the B7-CD28 family in the control of T-cell immunity. Nat Rev Immunol 4:336–347

    Article  PubMed  CAS  Google Scholar 

  12. Kouki T, Sawai Y, Gardine CA, Fisfalen ME, Alegre ML, DeGroot LJ (2000) CTLA-4 gene polymorphism at position 49 in exon 1 reduces the inhibitory function of CTLA-4 and contributes to the pathogenesis of Graves’ disease. J Immunol 165:6606–6611

    PubMed  CAS  Google Scholar 

  13. Lei C, Dongqing Z, Yeqing S, Oaks MK, Lishan C, Jianzhong J, Jie Q, Fang D, Ningli L, Xinghai H, Daming R (2005) Association of the CTLA-4 gene with rheumatoid arthritis in Chinese Han population. Eur J Hum Genet 13:823–828

    Article  PubMed  Google Scholar 

  14. Gunesacar R, Erken E, Bozkurt B, Ozer HT, Dinkci S, Erken EG, Ozbalkan Z (2007) Analysis of CD28 and CTLA-4 gene polymorphisms in Turkish patients with Behcet’s disease. Int J Immunogenet 34:45–49

    Article  PubMed  CAS  Google Scholar 

  15. Mills JA, Michel BA, Bloch DA, Calabrese LH, Hunder GG, Arend WP, Edworthy SM, Fauci AS, Leavitt RY, Lie JT (1990) The American College of Rheumatology 1990 criteria for the classification of Henoch-Schönlein purpura. Arthritis Rheum 33:1114–1121

    Article  PubMed  CAS  Google Scholar 

  16. Rigante D (2006) Clinical overview of vasculitic syndromes in the pediatric age. Eur Rev Med Pharmacol Sci 10:337–345

    PubMed  CAS  Google Scholar 

  17. Tizard EJ, Hamilton-Ayres MJ (2008) Henoch Schonlein purpura. Arch Dis Child Educ Pract Ed 93:1–8

    Article  PubMed  CAS  Google Scholar 

  18. Ronkainen J, Nuutinen M, Koskimies O (2002) The adult kidney 24 years after childhood Henoch-Schonlein purpura: a retrospective cohort study. Lancet 360:666–670

    Article  PubMed  Google Scholar 

  19. Chikuma S, Abbas AK, Bluestone JA (2005) B7-independent inhibition of T cells by CTLA-4. J Immunol 175:177–181

    PubMed  CAS  Google Scholar 

  20. Chikuma S, Bluestone JA (2003) CTLA-4 and tolerance: the biochemical point of view. Immunol Res 28:241–253

    Article  PubMed  CAS  Google Scholar 

  21. Nistico L, Buzzetti R, Prichard LE, Van der Auwera B, Giovannini C, Bosi E, Larrad MT, Rios MS, Chow CC, Cockram CS, Jacobs K, Mijovic C, Bain SC, Barnett AH, Vandewalle CL, Schuit F, Gorus FK, Tosi R, Pozzilli P, Todd JA (1996) The CTLA-4 gene region of chromosome 2q33 is linked to, and associated with, type 1 diabetes. Belgian Diabetes Registry. Hum Mol Genet 5:1075–1080

    Article  PubMed  CAS  Google Scholar 

  22. Maurer M, Loserth S, Kolb-Maurer A, Ponath A, Wiese S, Kruse N, Rieckmann P (2002) A polymorphism in the human cytotoxic T-lymphocyte antigen 4 (CTLA4) gene (exon 1 +49) alters T-cell activation. Immunogenetics 54:1–8

    Article  PubMed  Google Scholar 

  23. Ligers A, Teleshova N, Masterman T, Huang WX, Hillert J (2001) CTLA-4 gene expression is influenced by promoter and exon 1 polymorphisms. Genes Immun 2:145–152

    Article  PubMed  CAS  Google Scholar 

  24. Stohl W, Jacob N, Quinn WJ 3rd, Cancro MP, Gao H, Putterman C, Gao X, Pricop L, Koss MN (2008) Global T cell dysregulation in non-autoimmune-prone mice promotes rapid development of BAFF-independent, systemic lupus erythematosus-like autoimmunity. J Immunol 181:833–841

    PubMed  CAS  Google Scholar 

  25. Wang XB, Zhao X, Giscombe R, Lefvert AK (2002) A CTLA-4 gene polymorphism at position -318 in the promoter region affects the expression of protein. Genes Immun 3:233–234

    Article  PubMed  Google Scholar 

  26. Braun J, Donner H, Siegmund T, Walfish PG, Usadel KH, Badenhoop K (1998) CTLA-4 promoter variants in patients with Graves’ disease and Hashimoto’s thyroiditis. Tissue Antigens 51:563–566

    Article  PubMed  CAS  Google Scholar 

  27. Balbi G, Ferrera F, Rizzi M, Piccioli P, Morabito A, Cardamone L, Ghio M, Palmisano GL, Carrara P, Pedemonte S, Sessarego M, De Angioletti M, Notaro R, Indiveri F, Pistillo MP (2007) Association of -318 C/T and +49 A/G cytotoxic T lymphocyte antigen-4 (CTLA-4) gene polymorphisms with a clinical subset of Italian patients with systemic sclerosis. Clin Exp Immunol 149:40–47

    Article  PubMed  CAS  Google Scholar 

  28. Heward JM, Allahabadia A, Carr-Smith J, Daykin J, Cockram CS, Gordon C, Barnett AH, Franklyn JA, Gough SC (1998) No evidence for allelic association of a human CTLA-4 promoter polymorphism with autoimmune thyroid disease in either population-based case-control or family-based studies. Clin Endocrinol (Oxf) 49:331–334

    Article  CAS  Google Scholar 

  29. Bagos PG, Karnaouri AC, Nikolopoulos GK, Hamodrakas SJ (2007) No evidence for association of CTLA-4 gene polymorphisms with the risk of developing multiple sclerosis: a meta-analysis. Mult Scler 13:156–168

    Article  PubMed  CAS  Google Scholar 

  30. Albert LJ, Inman RD (1999) Molecular mimicry and autoimmunity. N Engl J Med 341:2068–2074

    Article  PubMed  CAS  Google Scholar 

  31. Fujinami RS, von Herrath MG, Christen U, Whitton JL (2006) Molecular mimicry, bystander activation, or viral persistence: infections and autoimmune disease. Clin Microbiol Rev 19:80–94

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgements

The authors gratefully acknowledge Mrs. Yan-Ping Shi for her assistance with the case collection, as well as the enrolled children and their parents for their consent. This research project was supported by the Sichuan Provincial Health Office of Scientific Research (2010-100144).

Author information

Authors and Affiliations

  1. Department of Pediatrics, Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, 637000, People’s Republic of China

    Jian-Jun Wang, Huang Yue & Wu Chun

  2. Department of Traditional Chinese Medicine, Xi’an Children’s Hospital, Xi’an University of Medicine, Xi’an, Shanxi, 710033, People’s Republic of China

    Yan-Ping Shi

  3. Department of Pediatrics, Chinese PLA General Hospital, Beijing, 100853, People’s Republic of China

    Li-Ping Zou

Authors
  1. Jian-Jun Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yan-Ping Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Huang Yue
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Wu Chun
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Li-Ping Zou
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Li-Ping Zou.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wang, JJ., Shi, YP., Yue, H. et al. CTLA-4 exon 1 +49A/G polymorphism is associated with renal involvement in pediatric Henoch–Schönlein purpura. Pediatr Nephrol 27, 2059–2064 (2012). https://doi.org/10.1007/s00467-012-2216-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00467-012-2216-7

Keywords

Search

Navigation