Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome

Birthe Jessen, Andrea Maul-Pavicic, Heike Ufheil, Thomas Vraetz, Anselm Enders, Kai Lehmberg, Alfred Längler, Ute Gross-Wieltsch, Ali Bay, Zuhre Kaya, Yenan T. Bryceson, Ewa Koscielniak, Sherif Badawy, Graham Davies, Markus Hufnagel, Annette Schmitt-Graeff, Peter Aichele, Udozur Stadt, Klaus Schwarz, Stephan Ehl*

*Corresponding author for this work

Research output: Contribution to journalArticle

51 Scopus citations

Abstract

Perforin-mediated cytotoxicity is important for controlling viral infections, but also for limiting immune reactions. Failure of this cytotoxic pathway leads to hemophagocytic lymphohistiocytosis (HLH), a life-threatening disorder of uncontrolled T-cell and macrophage activation. We studied susceptibility to HLH in 2 mouse strains (souris and beige J) and a cohort of patients with partial defects in perforin secretion resulting from different mutations in the LYST gene. Although both strains lacked NK-cell cytotoxicity, only souris mice developed all clinical and histopathologic signs of HLH after infection with lymphocytic choriomeningitis virus. The 2 strains showed subtle differences in CTL cytotoxicity in vitro that had a large impact on virus control in vivo. Whereas beige J CTLs eliminated lymphocytic choriomeningitis virus infection, souris CTLs failed to control the virus, which was associated with the development of HLH. In LYST-mutant patients with Chediak-Higashi syndrome, CTL cytotoxicity was reduced in patients with early-onset HLH, whereas it was retained in patients who later or never developed HLH. Thus, the risk of HLH development is set by a threshold that is determined by subtle differences in CTL cytotoxicity. Differences in the cytotoxic capacity of CTLs may be predictive for the risk of Chediak-Higashi syndrome patients to develop HLH.

Original languageEnglish (US)
Pages (from-to)4620-4629
Number of pages10
JournalBlood
Volume118
Issue number17
DOIs
StatePublished - Oct 27 2011

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ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Jessen, B., Maul-Pavicic, A., Ufheil, H., Vraetz, T., Enders, A., Lehmberg, K., Längler, A., Gross-Wieltsch, U., Bay, A., Kaya, Z., Bryceson, Y. T., Koscielniak, E., Badawy, S., Davies, G., Hufnagel, M., Schmitt-Graeff, A., Aichele, P., Stadt, U., Schwarz, K., & Ehl, S. (2011). Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. Blood, 118(17), 4620-4629. https://doi.org/10.1182/blood-2011-05-356113