Date Published: January 13, 2010
Publisher: Public Library of Science
Author(s): Claudia A. Nold-Petry, Thomas Lehrnbecher, Andrea Jarisch, Dirk Schwabe, Josef M. Pfeilschifter, Heiko Muhl, Marcel F. Nold, Cheryl A. Stoddart. http://doi.org/10.1371/journal.pone.0008663
Abstract: Familial hemophagocytosis (FHL) is a rare disease associated with defects in proteins involved in CD8+ T-cell cytotoxicity. Hyperactivation of immune cells results in a perilous, Th1-driven cytokine storm. We set out to explore the regulation of cytokines in an FHL patient who was clinically stable on low-dose immunosuppressive therapy after bone marrow transplantation over a six-month period. During this period, chimerism analyses showed that the fraction of host cells was between 1 and 10%. Both parents of the patient as well as healthy volunteers were studied for comparison.
Partial Text: Hemophagocytic lymphohistiocytosis (HLH), also called hemophagocytic or macrophage activation syndrome, is the name of a group of rare diseases characterized by a dysregulation of the immune system. HLH can be inherited, but occurs more commonly secondary to causes such as viral (including H5N1) or bacterial infections or cancer. The group of inherited HLH comprises familial HLH (FHL) and the Chédiak-Higashi and Griscelli syndromes, which are associated with various gene defects, but are nearly identical in clinical presentation. Clinical features, which are shared by the inherited and the acquired forms, include nonremitting high fever, hepatosplenomegaly, cytopenia of at least two lineages, and/or elevations in pro-inflammatory cytokines and soluble CD25. In severe cases, multi-organ failure may ensue. Phagocytosis of hematopoetic cells in the bone marrow, spleen, or lymph nodes caused by dysregulation of T-cells, NK cells, and macrophages is characteristic of HLH. FHL usually is manifest in infancy with fulminant failure of several organs and, without chemo- and immunotherapy followed by bone marrow transplantation (BMT), is almost always fatal.
Previous studies have revealed a pivotal role for Th1 cytokines in patients with FHL. For instance, antibodies to IFNγ, but not to other cytokines, improved the course of the disease including survival in an animal model of FHL . In patients, IL-18 – and IFNγ  correlate with disease severity. Although both IL-18BP and IP-10 were elevated in WB cultures from our patient under steady-state conditions, the near absent induction of the Th1 antagonist IL-18BP by IFNγ was striking. In contrast, LPS-induced increases in the pro-inflammatory chemokines IP-10 (14-fold) and IL-8 (20-fold) were comparable to or even greater than in control subjects. This suggests the conclusion that, despite BMT and immunosuppression, regulation of IL-18BP is severely impaired in the FHL patient. The induction of IL-18BP by interferons, demonstrated by Paulukat et al in vitro , by Kaser et al in vivo , as well as the characterization of the IFNγ-responsive promoter ,  each constitute a negative-feedback loop to reduce IFN activity and the subsequent Th1 responses . Hence, our data appear to reveal a fundamental pathophysiological mechanism of HLH, that is, escape of IL-18BP from IFNγ stimulation. Consistent with this concept is the observation that in secondary HLH, low levels of IL-18BP result in high free IL-18 . Of note, IL-18BP also reduces inflammation caused by IL-18 directly, i.e. independent of IFNγ. This fact should be taken into account when the results of two other studies are contemplated, in which a dysregulation of the IL-18/IL-18BP equilibrium in systemic lupus erythematosus (SLE)  and Wegener’s granulomatosis (WG)  was reported. In fact, analysis of the responsiveness of IL-18BP production to IFN stimulation may be a worthwhile topic of research in SLE and WG.