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Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome
Faculty
Not Specified
Year:
2011
Type of Publication:
Article
Pages:
4620-4629
Authors:
Badawy, Sherif, Jessen, Birthe, Maul-Pavicic, Andrea, Ufheil, Heike, Vraetz, Thomas, Enders, Anselm, Lehmberg, Kai, Laengler, Alfred, Gross-Wieltsch, Ute, Bay, Ali, Kaya, Zuhre, Bryceson, Yenan T, Koscielniak, Ewa, Davies, Graham, Hufnagel, Markus, Schmitt-Graeff, Annette, Aichele, Peter, zur Stadt, Udo, Schwarz, Klaus, Ehl, Stephan
DOI:
10.1182/blood-2011-05-356113
Journal:
BLOOD AMER SOC HEMATOLOGY
Volume:
118
Research Area:
Hematology
ISSN
ISI:000296368700023
Keywords :
Subtle differences , , cytotoxicity determine susceptibility , hemophagocytic
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 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. (Blood. 2011; 118(17): 4620-4629)
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