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

Author:

Jessen Birthe1,Maul-Pavicic Andrea1,Ufheil Heike1,Vraetz Thomas1,Enders Anselm2,Lehmberg Kai3,Längler Alfred4,Gross-Wieltsch Ute5,Bay Ali6,Kaya Zuhre7,Bryceson Yenan T.8,Koscielniak Ewa5,Badawy Sherif9,Davies Graham10,Hufnagel Markus1112,Schmitt-Graeff Annette13,Aichele Peter14,zur Stadt Udo15,Schwarz Klaus116,Ehl Stephan1

Affiliation:

1. Center of Chronic Immunodeficiency, University Medical Center Freiburg and University of Freiburg, Freiburg, Germany;

2. Ramaciotti Immunization Genomics Laboratory, John Curtin School of Medical Research, Australian National University, Acton, Australia;

3. Department of Haematology and Oncology, Children's Hospital, University of Hamburg, Hamburg, Germany;

4. Gemeinschaftskrankenhaus Herdecke, Department of Paediatric and Adolescent Medicine, Herdecke and University of Witten/Herdecke, Witten, Germany;

5. Pediatric Hematology, Oncology and Immunology, Klinikum Stuttgart/Olgahospital, Stuttgart, Germany;

6. Department of Pediatrics, Division of Pediatric Hematology, Gaziantep University, Gaziantep, Turkey;

7. Pediatric Hematology Unit of the Department of Pediatrics, Medical School of Gazi University, Ankara, Turkey;

8. Center for Infectious Medicine, Department of Medicine, Karolinska Institutet, Karolinska University Hospital Huddinge, Stockholm, Sweden;

9. Department of Pediatrics, Zagazig University, Zagazig, Egypt;

10. Immunology Department, Great Ormond Street Hospital for Children, London, United Kingdom;

11. Department of Paediatrics, University Hospital Kiel, Kiel, Germany;

12. Center for Pediatrics and Adolescent Medicine, University Medical Center Freiburg, Freiburg, Germany;

13. Institute of Pathology, Department of General Pathology, University of Freiburg, Freiburg, Germany;

14. Institute for Medical Microbiology and Hygiene, Department of Immunology, University of Freiburg, Freiburg, Germany;

15. Centre for Diagnostics, University Medical Center, Hamburg-Eppendorf and Research Institute, Children's Cancer Center, Hamburg, Germany; and

16. Institute for Transfusion Medicine, University Hospital Ulm and Institute for Clinical Transfusion Medicine and Immunogenetics, Ulm, Germany

Abstract

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 beigeJ) 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 beigeJ 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.

Publisher

American Society of Hematology

Subject

Cell Biology,Hematology,Immunology,Biochemistry

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