Skip to main content
SpringerLink
Log in

Impairment of Immune Function in Children with Familial Hemophagocytic Lymphohistiocytosis

  • Chapter
  • First Online:
Prospect in Pediatric Diseases Medicine

Part of the book series: Advances in Experimental Medicine and Biology ((NR,volume 912))

Abstract

Hemophagocytic lymphohistiocytosis (HLH) is a severe systemic syndrome associated with hyperactivation of macrophages and impaired regulation of the immune system. Two forms of HLH are currently recognized: genetically determined or familial (FHLH), and secondarily developed in the course of primary diseases, like autoimmune disorders, rheumatoid disorders, cancers, or infections. In the Polish population, FHLH is rather rare. The aim of the present study was to assess the immune function in a group of children with clinical symptoms suggesting FHLH. Forty five children with suspected HLH of the median age of 4 years and 15 healthy children, taken as a control group, were enrolled into the study. All presented results were obtained with the use of flow cytometry. In the HLH group, there were only three cases identified with the UNC13D gene mutation responsible for the FHLH3 phenotype. Another four children, without known mutation, were classified as FHLH because of frequent recurrence of the disease. In all cases of FHLH, cell cytotoxicity was impaired compared with healthy children (p = 0.003). Perforin expression in FHLH was normal or higher than that observed in controls (p = 0.09). In case of patients with mutation in the Munc13 protein, degranulation was lower than that in healthy children (<5 %). The findings of this study demonstrate that children with known mutations responsible for the FHLH development are immunocompromised. However, it requires further elucidation whether the presence of currently unknown mutations could lead to a similar phenotype.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abdelkefi A, Ben Jamil W, Torjman L, Ladeb S, Ksouri H, Lakhal A, Ben Hassen A, Ben Abdeladhim A, Ben Othman T (2009) Hemophagocytic syndrome after hematopoietic stem cell transplantation: a prospective observational study. Int J Hematol 89:368–373

    Article  PubMed  Google Scholar 

  • Arneson LN, Brickshawana A, Segovis CM, Schoon RA, Dick CJ, Leibson PJ (2007) Cutting edge: syntaxin 11 regulates lymphocyte-mediated secretion and cytotoxicity. J Immunol 179:3397–3401

    Article  CAS  PubMed  Google Scholar 

  • Bryceson YT, Rudd E, Zheng C, Edner J, Ma D, Wood SM, Bechensteen AG, Boelens JJ, Celkan T, Farah RA, Hultenby K, Winiarski J, Roche PA, Nordenskjold M, Henter JI, Long EO, Ljunggren HG (2007) Defective cytotoxic lymphocyte degranulation in syntaxin-11 deficient familial hemophagocytic lymphohistiocytosis 4 (FHL4) patients. Blood 110:1906–1915

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bryceson YT, Fauriat C, Nunes JM, Wood SM, Bjorkstrom NK, Long EO, Ljunggren HG (2010) Functional analysis of human NK cells by flow cytometry. Methods Mol Biol 612:335–352

    Article  CAS  PubMed  Google Scholar 

  • Bryceson YT, Pende D, Maul-Pavicic A, Gilmour KC, Ufheil H, Vraetz T, Chiang SC, Marcenaro S, Meazza R, Bondzio I, Walshe D, Janka G, Lehmberg K, Beutel K, zur Stadt U, Binder N, Arico M, Moretta L, Henter JI, Ehl S (2012) A prospective evaluation of degranulation assays in the rapid diagnosis of familial hemophagocytic syndromes. Blood 119:2754–2763

    Article  CAS  PubMed  Google Scholar 

  • Canna SW, Behrens EM (2012) Not all hemophagocytes are created equally: appreciating the heterogeneity of the hemophagocytic syndromes. Curr Opin Rheumatol 24:113–118

    Article  PubMed  PubMed Central  Google Scholar 

  • Clementi R, Emmi L, Maccario R, Liotta F, Moretta L, Danesino CM, Arico M (2002) Adult onset and atypical presentation of hemophagocytic lymphohistiocytosis in siblings carrying PRF1 mutations. Blood 100:2266–2267

    Article  CAS  PubMed  Google Scholar 

  • Feldmann J, Callebaut I, Raposo G, Certain S, Bacq D, Dumont C, Lambert N, Ouachee-Chardin M, Chedeville G, Tamary H, Minard-Colin V, Vilmer E, Blanche S, Le Deist F, Fischer A, de Saint BG (2003) Munc13-4 is essential for cytolytic granules fusion and is mutated in a form of familial hemophagocytic lymphohistiocytosis (FHL3). Cell 115:461–473

    Article  CAS  PubMed  Google Scholar 

  • Gupta S, Weitzman S (2010) Primary and secondary hemophagocytic lymphohistiocytosis: clinical features, pathogenesis and therapy. Expert Rev Clin Immunol 6:137–154

    Article  PubMed  Google Scholar 

  • Henter JI, Arico M, Elinder G, Imashuku S, Janka G (1998) Familial hemophagocytic lymphohistiocytosis. Primary hemophagocytic lymphohistiocytosis. Hematol Oncol Clin North Am 12:417–433

    Article  CAS  PubMed  Google Scholar 

  • Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH, Imashuku S, Ladisch S, McClain K, Webb D, Winiarski J, Janka G (2007) HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr Blood Cancer 48:124–131

    Article  PubMed  Google Scholar 

  • Horne A, Ramme KG, Rudd E, Zheng C, Wali Y, al-Lamki Z, Gurgey A, Yalman N, Nordenskjold M, Henter JI (2008) Characterization of PRF1, STX11 and UNC13D genotype-phenotype correlations in familial hemophagocytic lymphohistiocytosis. Br J Haematol 143:75–83

    Article  PubMed  Google Scholar 

  • Ishii E, Ueda I, Shirakawa R, Yamamoto K, Horiuchi H, Ohga S, Furuno K, Morimoto A, Imayoshi M, Ogata Y, Zaitsu M, Sako M, Koike K, Sakata A, Takada H, Hara T, Imashuku S, Sasazuki T, Yasukawa M (2005) Genetic subtypes of familial hemophagocytic lymphohistiocytosis: correlations with clinical features and cytotoxic T lymphocyte/natural killer cell functions. Blood 105:3442–3448

    Article  CAS  PubMed  Google Scholar 

  • Janka G (2009) Hemophagocytic lymphohistiocytosis: when the immune system runs amok. Klin Padiatr 221(5):278–285

    Article  CAS  PubMed  Google Scholar 

  • Jordan MB, Hildeman D, Kappler J, Marrack P (2004) An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104:735–743

    Article  CAS  PubMed  Google Scholar 

  • Komp DM, McNamara J, Buckley P (1989) Elevated soluble interleukin-2 receptor in childhood hemophagocytic histiocytic syndromes. Blood 73:2128–2132

    CAS  PubMed  Google Scholar 

  • Machaczka M, Vaktnas J, Klimkowska M, Hagglund H (2011a) Malignancy-associated hemophagocytic lymphohistiocytosis in adults: a retrospective population-based analysis from a single center. Leuk Lymphoma 52:613–619

    Article  PubMed  Google Scholar 

  • Machaczka M, Klimkowska M, Regenthal S, Hagglund H (2011b) Gaucher disease with foamy transformed macrophages and erythrophagocytic activity. J Inherit Metab Dis 34:233–235

    Article  PubMed  Google Scholar 

  • Malloy CA, Polinski C, Alkan S, Manera R, Challapalli M (2004) Hemophagocytic lymphohistiocytosis presenting with nonimmune hydrops fetalis. J Perinatol 24:458–460

    Article  PubMed  Google Scholar 

  • Marsh RA, Satake N, Biroschak J, Jacobs T, Johnson J, Jordan MB, Bleesing JJ, Filipovich AH, Zhang K (2010) STX11 mutations and clinical phenotypes of familial hemophagocytic lymphohistiocytosis in North America. Pediatr Blood Cancer 55:134–140

    PubMed  Google Scholar 

  • Meeths M, Chiang SC, Wood SM, Entesarian M, Schlums H, Bang B, Nordenskjold E, Bjorklund C, Jakovljevic G, Jazbec J, Hasle H, Holmqvist BM, Rajic L, Pfeifer S, Rosthoj S, Sabel M, Salmi TT, Stokland T, Winiarski J, Ljunggren HG, Fadeel B, Nordenskjold M, Henter IJ, Bryceson YT (2011) Familial hemophagocytic lymphohistiocytosis type 3 (FHL3) caused by deep intronic mutation and inversion in UNC13D. Blood 118:5783–5793

    Article  CAS  PubMed  Google Scholar 

  • Molleran L, Lee S, Villanueva J, Sumegi J, Zhang K, Kogawa K, Davis J, Filipovich AH (2004) Characterisation of diverse PRF1 mutations leading to decreased natural killer cell activity in North American families with haemophagocytic lymphohistiocytosis. J Med Genet 41:137–144

    Article  PubMed Central  Google Scholar 

  • Mougiakakos D, Machaczka M, Jitschin R, Klimkowska M, Entesarian M, Bryceson YT, Henter JI, Sander B, Le Blanc K (2012) Treatment of familial hemophagocytic lymphohistiocytosis with third-party mesenchymal stromal cells. Stem Cells Dev 21:3147–3151

    Article  CAS  PubMed  Google Scholar 

  • Ohadi M, Lalloz MR, Sham P, Zhao J, Dearlove AM, Shiach C, Kinsey S, Rhodes M, Layton DM (1999) Localization of a gene for familial hemophagocytic lymphohistiocytosis at chromosome 9q21.3-22 by homozygosity mapping. Am J Hum Genet 64:165–171

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Przybylski M, Dzieciatkowski T, Zdunczyk D, Jedrzejczak WW, Luczak M (2010) Microbiological findings and treatment of EBV-associated hemophagocytic lymphohistiocytosis: a case report. Arch Immunol Ther Exp (Warsz) 58:247–252

    Article  Google Scholar 

  • Rouphael NG, Talati NJ, Vaughan C, Cunningham K, Moreira R, Gould C (2007) Infections associated with haemophagocytic syndrome. Lancet Infect Dis 7:814–822

    Article  PubMed  Google Scholar 

  • Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S, Mathew PA, Henter JI, Bennett M, Fischer A, de Saint BG, Kumar V (1999) Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–1959

    Article  CAS  PubMed  Google Scholar 

  • Voskoboinik I, Thia MV, De Bono A, Browne K, Cretney E, Jackson JT, Darcy PK, Jane SM, Smyth MJ, Trapani MJ (2004) The functional basis for hemophagocytic lymphohistiocytosis in a patient with co-inherited missense mutations in the perforin (PFN1) gene. J Exp Med 200:811–816

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Weitzman S (2011) Approach to hemophagocytic syndromes. Hematol Am Soc Hematol Educ Prog 2011:178–183

    Google Scholar 

  • Zhang K, Filipovich AH, Johnson J, Marsh RA, Villanueva J (1993) Hemophagocytic Lymphohistiocytosis, Familial. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, Bean LJH, Bird TD, Fong CT, Mefford HC, Smith RJH, Stephens K (eds) Gene reviews. University of Washington, Seattle; 1993–2015. 2006 Mar 22 (updated 2013 Jan 17)

    Google Scholar 

  • zur Stadt U, Schmidt S, Kasper B, Beutel K, Diler AS, Henter JI, Kabisch H, Schneppenheim R, Nurnberg P, Janka G, Hennies HC (2005) Linkage of familial hemophagocytic lymphohistiocytosis (FHL) type-4 to chromosome 6q24 and identification of mutations in syntaxin 11. Hum Mol Genet 14:827–834

    Article  CAS  PubMed  Google Scholar 

  • zur Stadt U, Rohr J, Seifert W, Koch F, Grieve S, Pagel J, Strauss J, Kasper B, Nurnberg G, Becker C, Maul-Pavicic A, Beutel K, Janka G, Griffiths G, Ehl S, Hennies HC (2009) Familial hemophagocytic lymphohistiocytosis type 5 (FHL-5) is caused by mutations in Munc18-2 and impaired binding to syntaxin 11. Am J Hum Genet 85:482–492

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

Supported by grant 0989/B/P01/2011/40 from the Polish National Science Center (NCN).

Conflicts of Interest

The authors declare no conflicts of interest in relation to this article.

Author information

Authors and Affiliations

  1. Department of Laboratory Diagnostics and Clinical Immunology of Developmental Age, Warsaw Medical University, Warsaw, Poland

    K. Popko, E. Górska & U. Demkow

  2. Department of Pediatrics, Oncology, Hematology and Diabetology, Medical University of Lodz, Lodz, Poland

    J. Jasińska

  3. Department of Pediatrics, Oncology and Hematology, Jagiellonian University Medical College, Cracow, Poland

    W. Balwierz

  4. Department of Pediatrics, Hematology, Oncology and Endocrinology, Gdansk Medical University, Gdansk, Poland

    L. Maciejka-Kembłowska

  5. Department of Pediatric Hematology and Oncology, Regional Children’s Hospital, Olsztyn, Poland

    W. Badowska

  6. Department of Pediatric Oncology and Hematology, Poznan Medical University, Poznan, Poland

    J. Wachowiak

  7. Department of Pediatrics, Hematology, Oncology and Transplantology, Children’s Hospital, Lublin, Poland

    K. Drabko

  8. Department of Pediatrics, Hematology and Oncology, Warsaw Medical University, 63A Żwirki i Wigury St., 02-091, Warsaw, Poland

    I. Malinowska

Authors
  1. K. Popko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. J. Jasińska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. E. Górska
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. U. Demkow
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. W. Balwierz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. Maciejka-Kembłowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. W. Badowska
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. J. Wachowiak
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. K. Drabko
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. I. Malinowska
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to I. Malinowska .

Editor information

Editors and Affiliations

  1. Institute of Nursing, PublicHigher Medical Professional School Institute of Nursing, Opole, Poland

    Mieczyslaw Pokorski

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Popko, K. et al. (2016). Impairment of Immune Function in Children with Familial Hemophagocytic Lymphohistiocytosis. In: Pokorski, M. (eds) Prospect in Pediatric Diseases Medicine. Advances in Experimental Medicine and Biology(), vol 912. Springer, Cham. https://doi.org/10.1007/5584_2016_210

Download citation

Publish with us

Policies and ethics

Search

Navigation