Skip to main content

Advertisement

SpringerLink
Log in

Association of IRF5 Polymorphisms with Susceptibility to Hemophagocytic Lymphohistiocytosis in Children

  • Published:
Journal of Clinical Immunology Aims and scope Submit manuscript

Abstract

Introduction

Hemophagocytic lymphohistiocytosis (HLH) is a hyperinflammatory syndrome and has a varied genetic background. The polymorphism of interferon regulatory factor 5 gene (IRF5) was reported to be associated with susceptibility to macrophage activation syndrome. IRF5 acts as a master transcription factor in the activation of pro-inflammatory cytokines. We assessed associations of IRF5 gene polymorphisms with susceptibility to secondary HLH.

Methods

Three IRF5 single nucleotide polymorphisms (rs729302, rs2004640, and rs2280714) were genotyped using TaqMan assays in 82 secondary HLH patients and 188 control subjects.

Results

There was a significant association of the GT/TT genotype at rs2004640 with secondary HLH susceptibility (p < 0.01). The IRF5 haplotype (rs729302 A, rs2004640 T, and rs2280714 T) was associated with secondary HLH susceptibility (p < 0.01).

Conclusions

These findings indicate that IRF5 is a genetic factor influencing the susceptibility to secondary HLH and that the IRF5-associated immune response contributes to the pathogenesis of HLH.

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. Gupta S, Weitzman S. Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol. 2010;6(1):137–54.

    Article  PubMed  Google Scholar 

  2. Janka GE. Hemophagocytic syndromes. Blood Rev. 2007;21(5):245–53.

    Article  PubMed  CAS  Google Scholar 

  3. Henter JI, Elinder G, Soder O, Ost A. Incidence in Sweden and clinical features of familial hemophagocytic lymphohistiocytosis. Acta Paediatr Scand. 1991;80(4):428–35.

    Article  PubMed  CAS  Google Scholar 

  4. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, et al. HLH-2004: Diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer. 2007;48(2):124–31.

    Article  PubMed  Google Scholar 

  5. Jordan MB, Hildeman D, Kappler J, Marrack P. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood. 2004;104(3):735–43.

    Article  PubMed  CAS  Google Scholar 

  6. Marcenaro S, Gallo F, Martini S, Santoro A, Griffiths GM, Arico M, et al. Analysis of natural killer-cell function in familial hemophagocytic lymphohistiocytosis (FHL): defective CD107a surface expression heralds Munc13-4 defect and discriminates between genetic subtypes of the disease. Blood. 2006;108(7):2316–23.

    Article  PubMed  CAS  Google Scholar 

  7. Schneider EM, Lorenz I, Muller-Rosenberger M, Steinbach G, Kron M, Janka-Schaub GE. Hemophagocytic lymphohistiocytosis is associated with deficiencies of cellular cytolysis but normal expression of transcripts relevant to killer-cell-induced apoptosis. Blood. 2002;100(8):2891–8.

    Article  PubMed  CAS  Google Scholar 

  8. Akashi K, Hayashi S, Gondo H, Mizuno S, Harada M, Tamura K, et al. Involvement of interferon-gamma and macrophage colony-stimulating factor in pathogenesis of haemophagocytic lymphohistiocytosis in adults. Br J Haematol. 1994;87(2):243–50.

    Article  PubMed  CAS  Google Scholar 

  9. Imashuku S, Hibi S, Sako M, Ishii T, Kohdera U, Kitazawa K, et al. Heterogeneity of immune markers in hemophagocytic lymphohistiocytosis: comparative study of 9 familial and 14 familial inheritance-unproved cases. J Pediatr Hematol Oncol. 1998;20(3):207–14.

    Article  PubMed  CAS  Google Scholar 

  10. Ohga S, Matsuzaki A, Nishizaki M, Nagashima T, Kai T, Suda M, et al. Inflammatory cytokines in virus-associated hemophagocytic syndrome. Interferon-gamma as a sensitive indicator of disease activity. Am J Pediatr Hematol Oncol. 1993;15(3):291–8.

    PubMed  CAS  Google Scholar 

  11. Janka GE. Familial and acquired hemophagocytic lymphohistiocytosis. Eur J Pediatr. 2007;166(2):95–109.

    Article  PubMed  Google Scholar 

  12. Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, et al. Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell. 2003;115(4):461–73.

    Article  PubMed  CAS  Google Scholar 

  13. Ishii E, Ohga S, Imashuku S, Yasukawa M, Tsuda H, Miura I, et al. Nationwide survey of hemophagocytic lymphohistiocytosis in Japan. Int J Hematol. 2007;86(1):58–65.

    Article  PubMed  Google Scholar 

  14. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, et al. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science. 1999;286(5446):1957–9.

    Article  PubMed  CAS  Google Scholar 

  15. zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, et al. Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet. 2005;14(6):827–34.

    Article  PubMed  CAS  Google Scholar 

  16. zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, et al. Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet. 2009;85(4):482–92.

    Article  PubMed  Google Scholar 

  17. Fisman DN. Hemophagocytic syndromes and infection. Emerg Infect Dis. 2000;6(6):601–8.

    Article  PubMed  CAS  Google Scholar 

  18. Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C. Infections associated with haemophagocytic syndrome. Lancet Infect Dis. 2007;7(12):814–22.

    Article  PubMed  Google Scholar 

  19. Grom AA, Mellins ED. Macrophage activation syndrome: advances towards understanding pathogenesis. Curr Opin Rheumatol. 2010;22(5):561–6.

    Article  PubMed  Google Scholar 

  20. Kelly A, Ramanan AV. Recognition and management of macrophage activation syndrome in juvenile arthritis. Curr Opin Rheumatol. 2007;19(5):477–81.

    Article  PubMed  CAS  Google Scholar 

  21. Yanagimachi M, Naruto T, Miyamae T, Hara T, Kikuchi M, Hara R, et al. Association of IRF5 polymorphisms with susceptibility to macrophage activation syndrome in patients with juvenile idiopathic arthritis. J Rheumatol. 2011;38:769–74.

    Article  PubMed  CAS  Google Scholar 

  22. Takaoka A, Yanai H, Kondo S, Duncan G, Negishi H, Mizutani T, et al. Integral role of IRF-5 in the gene induction programme activated by Toll-like receptors. Nature. 2005;434(7030):243–9.

    Article  PubMed  CAS  Google Scholar 

  23. Taniguchi T, Ogasawara K, Takaoka A, Tanaka N. IRF family of transcription factors as regulators of host defense. Annu Rev Immunol. 2001;19:623–55.

    Article  PubMed  CAS  Google Scholar 

  24. Henter JI, Arico M, Egeler RM, Elinder G, Favara BE, Filipovich AH, et al. HLH-94: a treatment protocol for hemophagocytic lymphohistiocytosis. HLH Study Group of the Histiocyte Society. Med Pediatr Oncol. 1997;28(5):342–7.

    Article  PubMed  CAS  Google Scholar 

  25. Arico M, Janka G, Fischer A, Henter JI, Blanche S, Elinder G, et al. Hemophagocytic lymphohistiocytosis. Report of 122 children from the International Registry. FHL Study Group of the Histiocyte Society. Leukemia. 1996;10(2):197–203.

    PubMed  CAS  Google Scholar 

  26. Petty RE, Southwood TR, Manners P, Baum J, Glass DN, Goldenberg J, et al. International League of Associations for Rheumatology classification of juvenile idiopathic arthritis: second revision, Edmonton, 2001. J Rheumatol. 2004;31(2):390–2.

    PubMed  Google Scholar 

  27. Ravelli A, Magni-Manzoni S, Pistorio A, Besana C, Foti T, Ruperto N, et al. Preliminary diagnostic guidelines for macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. J Pediatr. 2005;146(5):598–604.

    Article  PubMed  Google Scholar 

  28. Matsuda K, Nakazawa Y, Yanagisawa R, Honda T, Ishii E, Koike K. Detection of T-cell receptor gene rearrangement in children with Epstein–Barr virus-associated hemophagocytic lymphohistiocytosis using the BIOMED-2 multiplex polymerase chain reaction combined with GeneScan analysis. Clin Chim Acta. 2011;412:1554–8.

    Article  PubMed  CAS  Google Scholar 

  29. Gonzalez JR, Armengol L, Sole X, Guino E, Mercader JM, Estivill X, et al. SNPassoc: an R package to perform whole genome association studies. Bioinformatics. 2007;23(5):644–5.

    Article  PubMed  Google Scholar 

  30. Lake SL, Lyon H, Tantisira K, Silverman EK, Weiss ST, Laird NM, et al. Estimation and tests of haplotype–environment interaction when linkage phase is ambiguous. Hum Hered. 2003;55(1):56–65.

    Article  PubMed  CAS  Google Scholar 

  31. Shimane K, Kochi Y, Yamada R, Okada Y, Suzuki A, Miyatake A, et al. A single nucleotide polymorphism in the IRF5 promoter region is associated with susceptibility to rheumatoid arthritis in the Japanese population. Ann Rheum Dis. 2009;68(3):377–83.

    Article  PubMed  CAS  Google Scholar 

  32. Graham RR, Kozyrev SV, Baechler EC, Reddy MV, Plenge RM, Bauer JW, et al. A common haplotype of interferon regulatory factor 5 (IRF5) regulates splicing and expression and is associated with increased risk of systemic lupus erythematosus. Nat Genet. 2006;38(5):550–5.

    Article  PubMed  CAS  Google Scholar 

  33. Henter JI, Ehrnst A, Andersson J, Elinder G. Familial hemophagocytic lymphohistiocytosis and viral infections. Acta Paediatr. 1993;82(4):369–72.

    Article  PubMed  CAS  Google Scholar 

  34. Barnes BJ, Kellum MJ, Field AE, Pitha PM. Multiple regulatory domains of IRF-5 control activation, cellular localization, and induction of chemokines that mediate recruitment of T lymphocytes. Mol Cell Biol. 2002;22(16):5721–40.

    Article  PubMed  CAS  Google Scholar 

  35. Hao S, Li P, Zhao J, Hu Y, Hou Y. 17beta-estradiol suppresses cytotoxicity and proliferative capacity of murine splenic NK1.1+ cells. Cell Mol Immunol. 2008;5(5):357–64.

    Article  PubMed  CAS  Google Scholar 

  36. Krausgruber T, Blazek K, Smallie T, Alzabin S, Lockstone H, Sahgal N, et al. IRF5 promotes inflammatory macrophage polarization and T(H)1–T(H)17 responses. Nat Immunol. 2011;12(3):231–8.

    Article  PubMed  CAS  Google Scholar 

  37. Krausgruber T, Saliba D, Ryzhakov G, Lanfrancotti A, Blazek K, Udalova IA. IRF5 is required for late-phase TNF secretion by human dendritic cells. Blood. 2010;115(22):4421–30.

    Article  PubMed  CAS  Google Scholar 

  38. Sumazaki R, Kanegane H, Osaki M, Fukushima T, Tsuchida M, Matsukura H, et al. SH2D1A mutations in Japanese males with severe Epstein–Barr virus-associated illnesses. Blood. 2001;98(4):1268–70.

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by a grant from Yokohama Foundation for Advancement of Medical Science. We thank the physicians who participated in the HLH-94 and HLH-2004 studies in Japan and all members of the HLH Study Committee of the Japan Leukemia/Lymphoma Study Group. We also thank M Maesato for her secretarial assistance.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Masakatsu Yanagimachi, Hiroaki Goto, Takako Miyamae, Keisuke Kadota, Tomoyuki Imagawa, Masaaki Mori & Shumpei Yokota

  2. CNV Laboratory, DNA Chip Research Institute, Yokohama, Japan

    Hidenori Sato

  3. Department of Pediatrics, Shinshu University School of Medicine, Matsumoto, Japan

    Ryu Yanagisawa

  4. Department of Biostatistics and Epidemiology, Yokohama City University Graduate School of Medicine, Yokohama, Japan

    Tetsuji Kaneko & Satoshi Morita

  5. Department of Pediatrics, Ehime University Graduate School of Medicine, Ehime, Japan

    Eiichi Ishii

  6. The HLH Study Committee, Japanese Pediatric Leukemia/Lymphoma Study Group, Nagoya, Japan

    Eiichi Ishii

Authors
  1. Masakatsu Yanagimachi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Hiroaki Goto
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Takako Miyamae
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Keisuke Kadota
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Tomoyuki Imagawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Masaaki Mori
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Hidenori Sato
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Ryu Yanagisawa
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Tetsuji Kaneko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Satoshi Morita
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Eiichi Ishii
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Shumpei Yokota
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Hiroaki Goto.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Table 1

Association of polymorphisms in the IRF5 gene with susceptibility to non-MAS HLH (DOC 26 kb)

Supplementary Table 2

Comparison of IRF5 haplotypes in patients with subtypes of secondary HLH (DOC 26 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yanagimachi, M., Goto, H., Miyamae, T. et al. Association of IRF5 Polymorphisms with Susceptibility to Hemophagocytic Lymphohistiocytosis in Children. J Clin Immunol 31, 946–951 (2011). https://doi.org/10.1007/s10875-011-9583-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10875-011-9583-x

Keywords

Search

Navigation