Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome.
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Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome. / Jessen, Birthe; Maul-Pavicic, Andrea; Ufheil, Heike; Vraetz, Thomas; Enders, Anselm; Lehmberg, Kai; Längler, Alfred; Gross-Wieltsch, Ute; Bay, Ali; Kaya, Zuhre; Bryceson, Yenan T; Koscielniak, Ewa; Badawy, Sherif; Davies, Graham; Hufnagel, Markus; Schmitt-Graeff, Annette; Aichele, Peter; Zur Stadt, Udo; Schwarz, Klaus; Ehl, Stephan.
In: BLOOD, Vol. 118, No. 17, 17, 2011, p. 4620-4629.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Subtle differences in CTL cytotoxicity determine susceptibility to hemophagocytic lymphohistiocytosis in mice and humans with Chediak-Higashi syndrome.
AU - Jessen, Birthe
AU - Maul-Pavicic, Andrea
AU - Ufheil, Heike
AU - Vraetz, Thomas
AU - Enders, Anselm
AU - Lehmberg, Kai
AU - Längler, Alfred
AU - Gross-Wieltsch, Ute
AU - Bay, Ali
AU - Kaya, Zuhre
AU - Bryceson, Yenan T
AU - Koscielniak, Ewa
AU - Badawy, Sherif
AU - Davies, Graham
AU - Hufnagel, Markus
AU - Schmitt-Graeff, Annette
AU - Aichele, Peter
AU - Zur Stadt, Udo
AU - Schwarz, Klaus
AU - Ehl, Stephan
PY - 2011
Y1 - 2011
N2 - 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.
AB - 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.
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred C57BL
KW - Genetic Predisposition to Disease
KW - Base Sequence
KW - Mice, Transgenic
KW - Individuality
KW - Chediak-Higashi Syndrome/etiology/genetics/immunology
KW - Disease Susceptibility/immunology
KW - Lymphocyte Activation/genetics/immunology
KW - Lymphohistiocytosis, Hemophagocytic/etiology/genetics/immunology
KW - Perforin/genetics
KW - T-Lymphocytes, Cytotoxic/immunology/physiology
KW - Vesicular Transport Proteins/genetics
KW - Animals
KW - Humans
KW - Cells, Cultured
KW - Disease Models, Animal
KW - Mice
KW - Mice, Inbred C57BL
KW - Genetic Predisposition to Disease
KW - Base Sequence
KW - Mice, Transgenic
KW - Individuality
KW - Chediak-Higashi Syndrome/etiology/genetics/immunology
KW - Disease Susceptibility/immunology
KW - Lymphocyte Activation/genetics/immunology
KW - Lymphohistiocytosis, Hemophagocytic/etiology/genetics/immunology
KW - Perforin/genetics
KW - T-Lymphocytes, Cytotoxic/immunology/physiology
KW - Vesicular Transport Proteins/genetics
M3 - SCORING: Journal article
VL - 118
SP - 4620
EP - 4629
JO - BLOOD
JF - BLOOD
SN - 0006-4971
IS - 17
M1 - 17
ER -
