title: Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome.
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.
authors: University of Freiburg, Freiburg, Germany.
authors: Birthe
authors: B
authors: Jessen
authors: Andrea
authors: A
authors: Maul-Pavicic
authors: Heike
authors: H
authors: Ufheil
authors: Thomas
authors: T
authors: Vraetz
authors: Anselm
authors: A
authors: Enders
authors: Kai
authors: K
authors: Lehmberg
authors: Alfred
authors: A
authors: Längler
authors: Ute
authors: U
authors: Gross-Wieltsch
authors: Ali
authors: A
authors: Bay
authors: Zuhre
authors: Z
authors: Kaya
authors: Yenan T
authors: YT
authors: Bryceson
authors: Ewa
authors: E
authors: Koscielniak
authors: Sherif
authors: S
authors: Badawy
authors: Graham
authors: G
authors: Davies
authors: Markus
authors: M
authors: Hufnagel
authors: Annette
authors: A
authors: Schmitt-Graeff
authors: Peter
authors: P
authors: Aichele
authors: Udo
authors: U
authors: Zur Stadt
authors: Klaus
authors: K
authors: Schwarz
authors: Stephan
authors: S
authors: Ehl
mesh_terms: D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D002609:Chediak-Higashi Syndrome / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D004195:Disease Models, Animal; D004198:Disease Susceptibility / Q000276:immunology; D020022:Genetic Predisposition to Disease; D006801:Humans; D007206:Individuality; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D051359:Lymphohistiocytosis, Hemophagocytic / Q000209:etiology* / Q000235:genetics / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D054353:Perforin / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000502:physiology; D033921:Vesicular Transport Proteins / Q000235:genetics
chemical_list: C102161:LYST protein, human; D033921:Vesicular Transport Proteins; D054353:Perforin