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. (Blood. 2011; 118(17):4620-4629)

Hemophagocytic lymphohistiocytosis in syntaxin-11–deficient mice: T-cell exhaustion limits fatal disease

“…25 Mice with deficiencies in genes of the cytolytic machinery do not develop HLH spontaneously. [26][27][28][29] However, after LCMV infection, these mice exhibit clinical symptoms and laboratory abnormalities characteristic for HLH patients, with the exception that fever diagnosed in patients is mirrored by a drop in ear temperature in mice. We evaluated HLH in Stx11 Ϫ/Ϫ mice after infection with LCMV compared with heterozygous (Stx11 ϩ/Ϫ ) littermates, perforindeficient (PKO) and C57BL/6 (B6) mice.…”

The risk of hemophagocytic lymphohistiocytosis in Hermansky-Pudlak syndrome type 2

“…The interferon (IFN)-g enzyme-linked immunosorbent assay was performed as described previously. 17 Blood cell counts were determined with the Sysmex KX-21 hematology analyzer.…”

“…Although mice deficient in perforin, Rab27a, Lyst, Unc13d, or Syntaxin-11 do not develop HLH spontaneously, they develop all clinical features of the disease after infection with lymphocytic choriomeningitis virus (LCMV). [15][16][17][18][19][20] This approach allowed us to compare the susceptibility to HLH of pearl mice with that of other cytotoxicity mutants after a defined viral trigger and to assess the impact of an additional heterozygous Rab27a mutation on the phenotype. Second, we performed a survey of all 12 published and 10 previously unreported HPS2 patients to document the clinical evolution of their disease and-if availablethe extent of their cytotoxicity defect.…”

Distinct severity of HLH in both human and murine mutants with complete loss of cytotoxic effector PRF1, RAB27A, and STX11

“…Four murine HLH models are available: perforin-deficient (Prf1 Ϫ/Ϫ ), 15 ashen (Rab27a Ϫ/Ϫ ), 16 jinx (Unc13d Ϫ/Ϫ ), 17 and souris (Lyst Ϫ/Ϫ ). 18 On lymphocytic choriomeningitis virus (LCMV) infection, all 4 models develop most of the HLH features observed in patients. By studying these murine models, we and others have highlighted the pivotal role played by CD8 ϩ T cells and IFN-␥ in the development of HLH, the latter being a putative therapeutic target.…”