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Publication Details
AFRICAN RESEARCH NEXUS
SHINING A SPOTLIGHT ON AFRICAN RESEARCH
biochemistry, genetics and molecular biology
Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome
Blood, Volume 118, No. 17, Year 2011
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Description
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. © 2011 by The American Society of Hematology.
Authors & Co-Authors
Jessen, Birthe
Unknown Affiliation
Maul-Pavicic, Andrea
Unknown Affiliation
Ufheil, Heike
Unknown Affiliation
Vraetz, Thomas
Unknown Affiliation
Enders, Anselm
Unknown Affiliation
Lehmberg, Kai
Unknown Affiliation
Laengler, Alfred
Unknown Affiliation
Gross-Wieltsch, Ute
Unknown Affiliation
Bay, Ali
Unknown Affiliation
Kaya, Zühre
Unknown Affiliation
Bryceson, Yenan Troi
Unknown Affiliation
Kościelniak, Ewa
Unknown Affiliation
Badawy, Sherif M.
Unknown Affiliation
Davies, Graham E.
Unknown Affiliation
Hufnagel, Markus
Unknown Affiliation
Schmitt-Graeff, Annette
Unknown Affiliation
Aichele, Peter
Unknown Affiliation
Zur Stadt, Udo
Unknown Affiliation
Schwarz, Klaus
Unknown Affiliation
Ehl, Stephan R.
Unknown Affiliation
Statistics
Citations: 81
Authors: 20
Affiliations: 15
Identifiers
Doi:
10.1182/blood-2011-05-356113
ISSN:
00064971
Research Areas
Genetics And Genomics
Study Design
Cohort Study