Cytokine storm syndromes， such as familial hemophagocytic lymphohistiocytosis (FHL)， are lethal disorders caused by uncontrolled， systemic immune activation. In the murine model of FHL， in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV)， disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However， this paradigm is insufficient to explain several fundamental aspects of FHL， namely， the inability of many pathogenic antigens to induce hyperinflammation， and the previously identified role of MyD88 in the disease. We now show ... More
Cytokine storm syndromes， such as familial hemophagocytic lymphohistiocytosis (FHL)， are lethal disorders caused by uncontrolled， systemic immune activation. In the murine model of FHL， in which perforin-deficient (Prf1(-/-)) mice are infected with lymphocytic choriomeningitis virus (LCMV)， disease is driven by overabundant interferon (IFN)γ-producing LCMV-specific CD8(+) T cells thought to arise from excessive antigen stimulation through the T-cell receptor. However， this paradigm is insufficient to explain several fundamental aspects of FHL， namely， the inability of many pathogenic antigens to induce hyperinflammation， and the previously identified role of MyD88 in the disease. We now show a novel role for the MyD88-dependent interleukin-33 (IL-33) receptor， ST2， in FHL. Expression of IL-33 and ST2 is upregulated in LCMV-infected Prf1(-/-) mice. Blockade of ST2 markedly improves survival of LCMV-infected Prf1(-/-) mice and reduces the severity of multiple disease parameters， including serum levels of IFNγ. This decrease in IFNγ corresponds to a reduction in both the frequency of IFNγ(+) LCMV-specific CD8(+) and CD4(+) T cells and the magnitude of IFNγ expression in these cells. These findings demonstrate that disruption of ST2 signaling in the murine model of FHL reduces T cell-mediated production of IFNγ and suggest a revised paradigm in which danger signals such as IL-33 are crucial amplifiers of immune dysregulation in FHL. Furthermore， this study provides evidence to support blockade of ST2 as a novel therapeutic strategy for FHL.
